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Increasing interest has been given to the risks and benefits of terminating large clinical trials before reaching pre-specified targets, as such decision can greatly impact the implementation of findings. Department of Veterans Affairs Cooperative Studies Program (VA CSP) is a research infrastructure dedicated to conducting high-quality clinical research. A scoping review was performed to characterize barriers preventing the attainment of pre-specified recruitment, statistical power, or sample size targets in VA CSP trials. A trial was eligible for inclusion if the trial was sponsored by the VA CSP, primary findings were published within the last 10 years, and a decision was made to terminate enrollment or follow-up prior to meeting a priori recruitment or endpoint targets. Following screening, a total of 29 clinical trials were identified. In 11 trials (37.9%), a decision was made to terminate the trial early. The most common reason for early termination was related to under-recruitment (N=5). Other reasons included early detection of safety signals (N=2), futility (N=1), and benefit (N=1). Under-recruitment can lead to underpowered study results, which may result in a failure to detect a true effect and hinder implementation of trial findings. This review highlights recruitment as a critical facet of trial conduct which may hinder the production of high-quality data, and thus warrant additional attention. Solutions to enhance recruitment now implemented by the VA CSP, including dedicated enrollment infrastructure and screening facilitated by informatics approaches, show promise in reducing this cause for early termination.

Objective To evaluate the severity of neonatal opioid withdrawal syndrome (NOWS) in infants prenatally exposed to medications for opioid use disorder (MOUD) and serotonin reuptake inhibitors (SRI). Methods A prospective cohort included 148 maternal-infant pairs categorized into MOUD (n = 127) and MOUD + SRI (n = 27) groups. NOWS severity was operationalized as the infant's need for pharmacologic treatment with opioids, duration of hospitalization, and duration of treatment. The association between prenatal SRI exposure and the need for pharmacologic treatment (logistic regression), time-to-discharge, and time-to-treatment discontinuation (Cox proportional hazards modeling) was examined after adjusting for the type of maternal MOUD, use of hydroxyzine, other opioids, benzodiazepines/sedatives, alcohol, tobacco, marijuana, gestational age, and breastfeeding. Results Infants in the MOUD + SRI group were more likely to receive pharmacologic treatment for NOWS (OR = 3.58; 95% CI: 1.31; 9.76) and had a longer hospitalization (median: 11 vs. 6 days; HR = 0.54; 95% CI: 0.33; 0.89) compared to the MOUD group. With respect to time-to-treatment discontinuation, no association was observed in infants who received treatment (HR = 0.59; 95% CI: 0.26, 1.32); however, significant differences were observed in the entire sample (HR = 0.55; 95% CI: 0.34, 0.89). Conclusions Use of SRIs among pregnant women on MOUD might be associated with more severe NOWS. Impact A potential drug-drug interaction between maternal SRIs and opioid medications that inhibit the reuptake of serotonin has been hypothesized but not carefully evaluated in clinical studies. Results of this prospective cohort indicate that the use of SRIs among pregnant women on MOUD is associated with more severe neonatal opioid withdrawal syndrome. This is the first prospective study which carefully examined effect modification between the type of maternal MOUD and SRI use on neonatal outcomes. This report lays the foundation for treatment optimization in pregnant women with co-occurring mental health and substance use disorders.

Prenatal alcohol exposure (PAE) can result in long-lasting changes to physical, behavioral, and cognitive functioning in children. PAE might result in decreased white matter integrity, corticothalamic tract integrity, and alpha cortical oscillations. Previous investigations of alpha oscillations in PAE/fetal alcohol spectrum disorder (FASD) have focused on average spectral power at specific ages; therefore, little is known about alpha peak frequency (APF) or its developmental trajectory making this research novel. Using resting-state MEG data, APF was determined from parietal/occipital regions in participants with PAE/FASD or typically developing controls (TDC). In total, MEG data from 157 infants, children, and adolescents ranging in age from 6 months to 17 years were used, including 17 individuals with PAE, 61 individuals with an FASD and 84 TDC. In line with our hypothesis, we found that individuals with PAE/FASD had significantly reduced APF relative to TDC. Both age and group were significantly related to APF with differences between TDC and PAE/FASD persisting throughout development. We did not find evidence that sex or socioeconomic status had additional impact on APF. Reduced APF in individuals with an FASD/PAE may represent a long-term deficit and demonstrates the detrimental impact prenatal alcohol exposure can have on neurophysiological processes.

Prenatal opioid exposure (POE) is commonly associated with neonatal opioid withdrawal syndrome (NOWS), which is characterized by a broad variability in symptoms and severity. Currently there are no diagnostic tools to reliably predict which infants will develop severe NOWS, while risk stratification would allow for proactive decisions about appropriate clinical monitoring and interventions. The aim of this prospective cohort study was to assess if extracellular microRNAs (miRNAs) in umbilical cord plasma of infants with POE could predict NOWS severity. Participants (n = 58) consisted of pregnant women receiving medications for opioid use disorder and their infants. NOWS severity was operationalized as the need for pharmacologic treatment and prolonged hospitalization (≥ 14 days). Cord blood miRNAs were assessed using semi-quantitative qRT-PCR arrays. Receiver operating characteristic curves and area under the curve (AUC) were estimated. The expression of three miRNAs (miR-128-3p, miR-30c-5p, miR-421) predicted need for pharmacologic treatment (AUC: 0.85) and prolonged hospitalization (AUC: 0.90). Predictive validity improved after two miRNAs (let-7d-5p, miR-584-5p) were added to the need for pharmacologic treatment model (AUC: 0.94) and another two miRNAs (let-7b-5p, miR-10-5p) to the prolonged hospitalization model (AUC: 0.99). Infant cord blood extracellular miRNAs can proactively identify opioid-exposed neonates at high-risk for developing severe NOWS.

With significant increases in opioid use/misuse and persistent high prevalence of prenatal alcohol exposure (PAE), identifying infants at risk for long-term developmental sequelae due to these exposures remains an urgent need. This study reports on developmental outcomes in young children from a prospective cohort, ENRICH-1, which recruited pregnant women and followed up maternal-infant pairs.Subjects were assigned to four study groups based on prenatal use of medications for opioid use disorder (MOUD), PAE, MOUD+PAE, and unexposed controls (UC). Mixed effects modeling was used to evaluate changes in the Bayley Scales of Infant Development-III (BSID-III) Cognitive, Language, and Motor scores between 6 and 20 months.There was a significant three-way interaction (MOUD-by-PAE-by-Time) with respect to the BSID-III Cognitive (p = 0.045) and Motor (p = 0.033) scales. Significant changes between the two evaluations were observed for MOUD group in Cognitive and Language scores; for PAE group in Cognitive, Language, and Motor scores, and for MOUD+PAE group in Language scores after adjusting for child sex and family socio-economic status. The developmental scores for the UC remained stable.Observed decline in neurodevelopmental scores during the first 2 years of life emphasizes the importance of a longitudinal approach when evaluating children with prenatal polysubstance exposure.BSID-III scores were stable during the first 2 years of life for unexposed children. BSID-III scores declined for children with prenatal exposures to alcohol and/or opioids. Standard developmental tests may not be sensitive enough during the first year of life. Findings emphasize the need for repeated evaluations of children who are at high risk.

Background: Women with opioid use disorder (OUD) are encouraged to breastfeed, but have lower breastfeeding rates than the general population. Objective: We examined self-reported barriers and moti...

This review addresses underlying physiological, cellular, and molecular factors that alter the developing fetal brain stress circuits and responses of the hypothalamic-pituitary-adrenal (HPA) axis caused by maternal stress and prenatal alcohol exposure (PAE). An emphasis is placed on the contribution of the placenta following maternal stress separately, and as a co-occurrence with PAE. Altered fetal HPA axis ultimately results in dysregulation of the brain stress-response system long after birth and possibly lifelong. Additional consideration of the role of placentally-derived endocrine and sex hormones, as well as a brief discussion of epigenetic mechanisms of altered placental expression of genes encoding the glucocorticoid receptor and the enzymes 11β-HSD that rapidly convert glucocorticoids into its active or inactive forms are reviewed. Data highlighting the strong, reciprocal interactions between the neuroimmune and neuroendocrine systems during fetal development that are impacted by maternal stress and PAE are considered, emphasizing the role of the placenta as a key contributor to the dysregulation of these systems. In view of the maternal-placental-fetal interface, important physiological, cellular, and molecular factors underlying later life dysregulated stress responses are additionally considered. Literature from animal models of PAE and maternal stress is reviewed that support clinical observations of the effect of maternal stress and alcohol exposure during fetal development on later-life adult stress responses and associated mood dysregulation. An appreciation of dysregulated stress responses in individuals with fetal alcohol spectrum disorders (FASD) are addressed given the greater prevalence of adult dysregulated stress responses and a greater co-occurrence of mood disorders in individuals diagnosed with FASD.

To evaluate the severity of neonatal opioid withdrawal syndrome (NOWS) in infants prenatally exposed to medications for opioid use disorder (MOUD) and serotonin reuptake inhibitors (SRI).A prospective cohort included 148 maternal-infant pairs categorized into MOUD (n = 127) and MOUD + SRI (n = 27) groups. NOWS severity was operationalized as the infant's need for pharmacologic treatment with opioids, duration of hospitalization, and duration of treatment. The association between prenatal SRI exposure and the need for pharmacologic treatment (logistic regression), time-to-discharge, and time-to-treatment discontinuation (Cox proportional hazards modeling) was examined after adjusting for the type of maternal MOUD, use of hydroxyzine, other opioids, benzodiazepines/sedatives, alcohol, tobacco, marijuana, gestational age, and breastfeeding.Infants in the MOUD + SRI group were more likely to receive pharmacologic treatment for NOWS (OR = 3.58; 95% CI: 1.31; 9.76) and had a longer hospitalization (median: 11 vs. 6 days; HR = 0.54; 95% CI: 0.33; 0.89) compared to the MOUD group. With respect to time-to-treatment discontinuation, no association was observed in infants who received treatment (HR = 0.59; 95% CI: 0.26, 1.32); however, significant differences were observed in the entire sample (HR = 0.55; 95% CI: 0.34, 0.89).Use of SRIs among pregnant women on MOUD might be associated with more severe NOWS.A potential drug-drug interaction between maternal SRIs and opioid medications that inhibit the reuptake of serotonin has been hypothesized but not carefully evaluated in clinical studies. Results of this prospective cohort indicate that the use of SRIs among pregnant women on MOUD is associated with more severe neonatal opioid withdrawal syndrome. This is the first prospective study which carefully examined effect modification between the type of maternal MOUD and SRI use on neonatal outcomes. This report lays the foundation for treatment optimization in pregnant women with co-occurring mental health and substance use disorders.

It has been known for over 4 decades that prenatal alcohol exposure (PAE) can adversely affect neurodevelopment and behavior (NDB). Yet, early detection of altered NDB due to PAE continues to present a major clinical challenge. Identification of altered NDB in the first 2years of life, before higher-order cognitive processes develop, invites early interventions for affected children to improve long-term outcomes. Studies published in English from January of 1980 to July of 2018 were identified in PubMed/MEDLINE. The review focused on prospective birth cohort studies which used standardized NDB assessments in children up to 2years of age, wherein PAE was the main exposure and NDB was the main outcome. NDB was categorized into the domains of neurocognitive, adaptive, and self-regulation based on the 2016 Updated Clinical Guidelines for Diagnosing fetal alcohol spectrum disorder. An initial search resulted in 1,867 articles for which we reviewed abstracts; 114 were selected for full-text review; and 3 additional abstracts were identified through review of references in eligible publications. Thirty-one publications met criteria and were included: of these, 24 reported neurocognitive outcomes, 24 reported adaptive behavior outcomes, and 12 reported outcomes in the domain of self-regulation. Although self-regulation was assessed in the fewest number of studies, 8/12 (75%) reported PAE-associated deficits. In contrast, results were mixed for the other 2 domains: 13/24 (54%) of the selected studies that included neurocognitive outcomes showed poorer performance following PAE, and 8/24 (33%) studies that assessed adaptive functioning found significant differences between PAE and comparison infants. There is considerable evidence to support the value of early-life assessments of infant NDB when PAE is known or suspected. More studies focusing on infant self-regulation, in particular, are needed to determine the utility of early evaluation of this critical developmental domain in infants with PAE.

Background The need for earlier recognition of children at risk for neurobehavioral problems associated with prenatal ethanol exposure (PAE) has prompted investigations of biomarkers prognostic for altered fetal development. Here, we examined whether PAE alters the expression of angiogenesis-related proteins and cytokines in human placenta in subjects from an Ethanol, Neurodevelopment, Infant and Child Health prospective cohort. Methods PAE was ascertained by screening questionnaires, Time-line Follow-back interviews and a panel of ethanol biomarkers at two study visits. After delivery, placental tissue samples were collected for protein analysis. Results No significant differences in the prevalence of substance use, demographic or medical characteristics were observed between the No PAE and PAE groups. PAE was associated with significant reductions in placental expression of VEGFR2 and annexin-A4, while the levels of VEGFR1 and CCM-3 trended downward. A trend toward higher expression of the cytokines TNF-α and IL-13 was also observed in the PAE group. Receiver operating characteristic analyses of the data demonstrated a moderate-to-high degree of diagnostic accuracy for individual placental proteins. Combinations of proteins substantially increased their ability to differentiate between PAE and No PAE subjects. Conclusions These results establish the feasibility of harvesting placental tissue for protein analyses of PAE in a prospective manner. In addition, given the importance of vascular remodeling in both placenta and developing brain, the role of angiogenic and cytokine proteins in this process warrants further investigation for their utility for predicting alterations in brain development, as well as their mechanistic role in PAE-induced pathology.

Background The number of children with prenatal polysubstance exposure is increasing. Supportive mother-child interaction is a protective factor, which can ameliorate adverse effects of prenatal polysubstance exposure on developmental outcomes. Aim To examine the role of maternal verbal scaffolding on cognitive and language development in children with prenatal polysubstance exposure. Study design Pregnant women were recruited, and we prospectively followed mother-child dyads to 20 months of age. This analysis included 66 dyads (33 healthy controls and 33 with prenatal polysubstance exposure). Multivariable linear regression modelling was used to examine the cross-sectional association between maternal scaffolding and Bayley Scales of Infant and Toddler Development (BSID-III) score, as well as an interaction between the study group and scaffolding score. Outcome measures The BSID-III cognitive and language score was used. Videotaped mother-child play was coded to obtain a maternal verbal scaffolding score. Effect sizes were measured using average differences in scores between groups. Results There was no evidence of an association between study group and maternal scaffolding scores. Children in the polysubstance exposure group had lower cognitive and language scores compared to controls, but this association was not statistically significant after controlling for maternal education. Maternal scaffolding was predictive of language scores, with scores increasing by 1.24 points on average (95% CI: 0.42, 2.06) for every 1-point increase in scaffolding score after adjustment for covariates. There was no evidence of a study group-by-scaffolding interaction with respect to the language or cognitive scores. Conclusions Maternal scaffolding during play was associated with language development in children with and without prenatal polysubstance exposure.

There are significant barriers in engaging pregnant and postpartum women that are considered high-risk (e.g., those experiencing substance use and/or substance use disorders (SUD)) into longitudinal research studies. To improve recruitment and retention of this population in studies spanning from the prenatal period to middle childhood, it is imperative to determine ways to improve key research engagement factors. The current manuscript uses a qualitative approach to determine important factors related to recruiting, enrolling, and retaining high-risk pregnant and postpartum women. The current sample included 41 high-risk women who participated in focus groups or individual interviews. All interviews were analyzed to identify broad themes related to engaging high-risk pregnant and parenting women in a 10-year longitudinal research project. Themes were organized into key engagement factors related to the following: (1) recruitment strategies, (2) enrollment, and (3) retention of high-risk pregnant and parenting women in longitudinal research studies. Results indicated recruitment strategies related to ideal recruitment locations, material, and who should share research study information with high-risk participants. Related to enrollment, key areas disclosed focused on enrollment decision-making, factors that create interest in joining a research project, and barriers to joining a longitudinal research study. With regard to retention, themes focused on supports needed to stay in research, barriers to staying in research, and best ways to stay in contact with high-risk participants. Overall, the current qualitative data provide preliminary data that enhance the understanding of a continuum of factors that impact engagement of high-risk pregnant and postpartum women in longitudinal research with current results indicating the need to prioritize recruitment, enrollment, and retention strategies in order to effectively engage vulnerable populations in research.

BACKGROUND Accurate characterization of prenatal alcohol exposure (PAE) is challenging due to inconsistent use of screening questionnaires in routine prenatal care and substantial underreporting due to stigma associated with alcohol use in pregnancy. The aim of this study was to identify self-report tools that are efficient in accurately characterizing PAE. METHODS Participants meeting eligibility criteria for mild-to-moderate PAE were recruited into the University of New Mexico Ethanol, Neurodevelopment, Infant and Child Health cohort (N = 121) and followed prospectively. Timeline follow-back (TLFB) interviews were administered at baseline to capture alcohol use in the periconceptional period and 30 days before enrollment; reported quantity was converted to oz absolute alcohol (AA), multiplied by frequency of use and averaged across 2 TLBF calendars. The interview also included questions about timing and number of drinks at the most recent drinking episode, maximum number of drinks in a 24-hour period since the last menstrual period, and number of drinks on "special occasions" (irrespective of whether these occurred within the TLFB reported period). Continuous measures of alcohol use were analyzed to yield the number of binge episodes by participants who consumed ≥4 drinks/occasion. The proportion of women with ≥1 binge episode was also tabulated for each type of assessment. RESULTS Average alcohol consumption was 0.6 ± 1.3 oz of AA/day (≈ 8.4 drinks/wk). Only 3.3% of participants reported ≥1 binge episode on the TLFB, 19.8% had ≥1 binge episode when asked about "special occasions," and 52.1% when asked about the number of drinks the last time they drank alcohol. An even higher prevalence (89.3%) of bingeing was obtained based on the maximum number of drinks consumed in a 24-hour period. CONCLUSIONS Self-reported quantity of alcohol use varies greatly based on type of questions asked. Brief targeted questions about maximum number of drinks in 24 hours and total number of drinks during the most recent drinking episode provide much higher estimates of alcohol use and thus might be less affected by self-reporting bias.

Background Prenatal alcohol exposure (PAE) can result in detrimental developmental complications. The objective of this study was to estimate the most recent PAE prevalence data for the state of West Virginia (WV) and associated factors. Method In all, 1830 newborn residual dried blood spots (DBS) in the WV Newborn Screening Repository were analyzed for phosphatidylethanol (PETH). Data were matched with Project WATCH data (94% match, N = 1729). Results The prevalence of late pregnancy PAE was 8.10% (95%CI: 6.81, 9.38) for all births, 7.61% (95%CI: 6.26, 8.97) for WV residents only, and ranged from 2.27 to 17.11% by region. The significant factors associated with PAE included smoking (OR: 2.03, 95% CI: 1.40, 2.94), preterm births (OR: 1.88; 95% CI: 1.23, 2.89), birth weight of ≤2000 g vs. >3000 g (OR: 2.62, 95%CI: 1.19, 5.79), no exclusive breastfeeding intention (OR: 1.45, 95% CI: 1.02, 2.04), and not exclusively breastfeeding before discharge (OR: 1.61; 95% CI: 1.09, 2.38). Conclusion The prevalence of PAE is higher than previously shown for the state. Accurate and timely estimates are vital to inform public health workers, policymakers, researchers, and clinicians to develop and promote effective prevention strategies to lower PAE prevalence and provide targeted interventions and treatment services for infants affected by PAE.

Background: Although misuse of prescription opioids has reached epidemic proportions, pharmacy-based preventive services to combat this epidemic are limited. The aims of this study were to identify barriers and facilitators to the dispensing of intranasal naloxone (INN) by pharmacists in New Mexico. Methods: For this mixed-methods study, a qualitative component (focus group) informed the development of a quantitative component (electronic survey) distributed to all pharmacists registered with the New Mexico Board of Pharmacy and practicing in the state. A 46-item survey included questions about pharmacists’ concerns regarding dispensing INN, barriers and facilitators to dispensing INN, efforts needed to increase availability and utilization of pharmacist-dispensed INN, and characteristics of respondents and their pharmacies. Results: Pharmacists from all geographical regions and all types of pharmacy settings were represented in the sample (final N = 390, participation rate 23.5%, including a subset of 182 community pharmacists). The main barriers identified were (1) out-of-pocket costs for patients; (2) time constraints for pharmacists; and (3) inadequate reimbursement for pharmacists. The main facilitators were (1) increased awareness among opioid-using patients and family members about the need for INN; (2) additional education to the general public; and (3) additional training for pharmacists on how to initiate discussions about INN with high-risk patients. Some community pharmacists were concerned that INN dispensing would promote opioid abuse (16.5%) and attract undesirable clientele (14.3%). In a multivariable logistic regression analysis of a community pharmacy subset, a higher number of concerns about INN (odds ratio [OR] = 0.87; 95% confidence interval [CI]: 0.82–0.93) and a pharmacy setting in a chain grocery or a “big box” store (OR = 0.38; 95% CI: 0.16–0.92) were associated with decreased odds of dispensing INN. Conclusions: Effective intervention strategies for increasing dispensing of intranasal naloxone by pharmacists should focus on pharmacists’ concerns, include education to multiple audiences, and address provider-level, system-level, and society-level barriers.

Background Prenatal care programs for women with opioid use disorder (OUD) often focus treatment/counseling plans around illicit substances, while concurrent use of alcohol might present an equal or greater risk to the fetus. Methods This study evaluated self-reported prevalence of alcohol use in patients participating in a comprehensive prenatal care program for women with substance use disorder (SUD; n = 295), of which 95% are treated for OUD, and pregnant women being served through general obstetrical clinics at the University of New Mexico (n = 365). During the screening phase of a prospective study, patients were asked to report alcohol use in the periconceptional period, and between the last menstrual period and pregnancy recognition. Results The screening interview was conducted at 22.3 (median = 22; Q1 = 16; Q3 = 29) gestational weeks. Among patients screened at the SUD clinic, 28.8% and 24.1% reported at least one binge drinking episode in the periconceptional period and in early pregnancy, respectively. The prevalence of binge drinking was similar in the general obstetrics population (24.7% and 24.4%, respectively). Among those who reported drinking in early pregnancy, median number of binge drinking episodes was higher among patients screened at the SUD clinic (median = 3; Q1 = 1; Q3 = 10) compared to the general obstetrics group (median = 1; Q1 = 1; Q3 = 3; p Conclusions This study demonstrates a high prevalence of prenatal alcohol use in early pregnancy in both groups, while patients with SUD/OUD consume more alcohol. These findings underscore the need for targeted screening and intervention for alcohol use in all pregnant women, especially those with SUD/OUD.

Earlier identification of children with prenatal alcohol exposure (PAE) remains a challenge. The objective of this study was to identify neurobehavioral (NB) outcomes associated with PAE in infants. This manuscript evaluates NB outcomes at 6.33±1.12 months of age in 93 infants (39 PAE and 54 No-PAE) recruited prospectively into the ENRICH cohort. PAE was assessed by prospective repeated TLFB interviews and a panel of ethanol biomarkers. NB outcomes were evaluated by the Bayley Scales of Infant Development (BSID-III), Parenting Stress Index (PSI), Infant Behavior Questionnaire (IBQ-R), and Infant Sensory Profile (ISP). Mean maternal age at enrollment was 28.18±5.75, and 64.52% were Hispanic/Latina. Across three TLFB calendars, absolute alcohol per day in the PAE group was 0.44±0.72, corresponding to low-moderate alcohol consumption. While no association was observed between PAE and BSID-III (P’s>0.05), PAE was associated with higher scores on the PSI difficult child scale ( =13.9; P=0.015), total stress ( =13.9; P=0.010), and IBQ negative affect ( =8.60; P=0.008) measures after adjustment for covariates. Caregiver-reported assessments may provide a currently unrecognized opportunity to identify behavioral deficits, point to early interventions, and should be included in clinical assessments of infants at-risk for fetal alcohol spectrum disorder.

Background Influenza virus is responsible for substantial morbidity and mortality. Specific populations are at higher risk for exacerbations from influenza virus, such as patients with chronic obstructive pulmonary disease (COPD). Influenza vaccination coverage among COPD patients is low. Pharmacists can improve influenza vaccination among COPD patients by recognizing factors that influence vaccination and addressing these factors. Objectives To (1) determine the recent influenza vaccination coverage among patients with COPD, (2) identify factors that were associated with immunization, and (3) interpret the results based upon Andersen's healthcare utilization model. Methods The 2012 Behavioral Risk Factor Surveillance System (BRFSS) was accessed for the study. Among respondents age ≥ 25 years with COPD, presence of influenza vaccination was captured along with demographic, provider, insurance, and clinical variables. Weighted multiple logistic regression was used to identify significant factors associated with receiving influenza vaccination. The findings were interpreted according to predisposing, enabling, and need factors relevant to Anderson's model. Results Influenza vaccination rate was 53% among COPD patients. Older age was a significant predisposing factor that increased vaccination (adjusted odds ratio [AOR] = 2.4; 95% CI:2.02–2.88). Predisposing factors that decreased vaccination were being Black or Hispanic (AOR = 0.72, 95% CI:0.59–0.86, and AOR = 0.78, 95% CI:0.61–0.98 respectively), and being a non smoker (former and never smokers had higher vaccination rates [AOR = 1.53, 95% CI = 1.3–1.72, and AOR = 1.36, 95% CI = 1.19–1.55 respectively]). Significant enabling factors included having health insurance (AOR = 1.68, 95% CI = 1.37–2.06), a primary physician (AOR = 1.63, 95% CI = 1.30–2.02), and the ability to see a physician regardless of cost (AOR = 1.33, 95% CI = 1.17–1.52). Significant need factors included the presence of comorbidities such as asthma (AOR = 1.18, 95% CI = 1.1–1.3), or diabetes (AOR = 1.36, 95% CI = 1.20–1.53), activity limitation (AOR = 1.16, 95% CI = 1.04–1.29), and having the last medical checkup within less than one year (AOR = 1.49, 95% CI = 1.31–1.70). Conclusion Influenza vaccination coverage among COPD patients is far below the Healthy People 2020 national goal. Several predisposing, enabling, and need factors influenced vaccination rate among COPD patients. Pharmacists can improve vaccination rate among COPD patients by recognizing these influencing factors and by acting as advocates, counselors, and administrators of influenza vaccine. Ultimately, with the collaborative efforts of other healthcare providers and public health initiatives, pharmacists can help achieve Healthy People 2020 objectives related to influenza vaccination.

Early identification of children who experience developmental delays due to prenatal alcohol exposure (PAE) remains a challenge for individuals who do not exhibit facial dysmorphia. It is well-established that children with PAE may still exhibit the cognitive and behavioral difficulties, and individuals without facial dysmorphia make up the majority of individuals affected by PAE. This study employed a prospective cohort design to capture alcohol consumption patterns during pregnancy and then followed the infants to 6 months of age. Infants were assessed using magnetoencephalography to capture neurophysiological indicators of brain development and the Bayley Scales of Infant Development-III to measure behavioral development. To account for socioeconomic and family environmental factors, we employed a two-by-two design with pregnant women who were or were not using opioid maintenance therapy (OMT) and did or did not consume alcohol during pregnancy. Based on prior studies, we hypothesized that infants with PAE would exhibit broad increased spectral amplitude relative to non-PAE infants. We also hypothesized that the developmental shift from low to high frequency spectral amplitude would be delayed in infants with PAE relative to controls. Our results demonstrated broadband increased spectral amplitude, interpreted as hypersynchrony, in PAE infants with no significant interaction with OMT. Unlike prior EEG studies in neonates, our results indicate that this hypersynchrony was highly lateralized to left hemisphere and primarily focused in temporal/lateral frontal regions. Furthermore, there was a significant positive correlation between estimated number of drinks consumed during pregnancy and spectral amplitude revealing a dose-response effect of increased hypersynchrony corresponding to greater alcohol consumption. Contrary to our second hypothesis, we did not see a significant group difference in the contribution of low frequency to high frequency amplitude at 6 months of age. These results provide new evidence that hypersynchrony, previously observed in neonates prenatally exposed to high levels of alcohol, persists until 6 months of age and this measure is detectable with low to moderate exposure of alcohol with a dose-response effect. These results indicate that hypersynchrony may provide a sensitive early marker of prenatal alcohol exposure in infants up to 6 months of age., Highlights • 6 month old infants with prenatal alcohol exposure exhibit broadband hypersynchrony. • Hypersynchrony was positively correlated with number of drinks consumed prenatally. • Distribution of low frequency to high frequency amplitude did not differ by group. • Hypersynchrony may provide an early marker of prenatal alcohol exposure in infants.

Objective Understanding the impact of substance use during pregnancy on fetal development and child health is essential for designing effective approaches for reducing prenatal substance exposures and improving child outcomes. Research on the developmental impacts of prenatal substance exposure has been limited by legal, ethical, and practical challenges. This study examined approaches to engage substance-using (with an emphasis on opioids) pregnant persons in longitudinal research, from multi-stakeholder perspectives. Methods The present study solicited the expertise of 1) an advisory group of community stakeholders, including people with lived experienced of opioid/substance use; and 2) an online survey with content experts. Qualitative analysis examined facilitators and barriers to recruiting and retaining substance-using pregnant persons through a socioecological lens at the individual, interpersonal, organizational, community, and policy levels. Results Stakeholders (N = 19) prioritized stigma, loss of confidentiality, legal consequences, and instability (e.g., homelessness and poverty) as important barriers that prevent substance-using persons from enrolling in research studies. Of 70 survey respondents, most self-identified as researchers (n = 37), followed by clinicians (n = 19), and ‘others’ (n = 14). Survey respondents focused on retention strategies that build trusting relationships with participants, including incentives (e.g., transportation and childcare support), participant-friendly study design, and team-related factors, (e.g., attitudes and practices). Conclusion The stakeholder input and survey data offer key insights strengthening our understanding of facilitators and barriers to research participation, and ways to overcome barriers among substance-using pregnant persons. A socioecological framework can be used to identify and address these factors to increase recruitment and long-term retention of high-risk populations.

The opioid epidemic in the United States has led to a significant increase in the incidence of neonatal opioid withdrawal syndrome (NOWS); however, the understanding of long-term consequences of NOWS is limited. The objective of this study was to evaluate post-discharge healthcare utilization in infants with NOWS and examine the association between NOWS severity and healthcare utilization. A retrospective cohort design was used to ascertain healthcare utilization in the first year after birth-related discharge using the CERNER Health Facts® database. ICD-9/ICD-10 diagnostic codes were used to identify live births and to classify infants into two study groups: NOWS and uncomplicated births (a 25% random sample). Evaluated outcomes included rehospitalization, emergency department (ED) visits within 30-days and one-year after discharge, and a composite one-year utilization event (either hospitalization or emergency department visit during that year). NOWS severity was operationalized as pharmacologic treatment, length of hospitalization, and medical conditions often associated with NOWS. In 3,526 infants with NOWS (restricted to gestational age ≥ 33 weeks), NOWS severity was associated with an increase in composite one-year utilization (OR: 1.1; 95% CI: 1.04–1.2) after adjusting for prematurity, sepsis, jaundice, use of antibiotics, infant sex, insurance status, race, hospital bed size, year of birth, and census division. In a subset of full-term infants (3008 with NOWS and 88,452 uncomplicated births), having a NOWS diagnosis was associated with higher odds of a 30-day (OR: 1.6; 95% CI: 1.03–2.4) and one-year rehospitalization (OR: 1.6; 95% CI: 1.1–2.4) after adjusting for infant sex, race, type of medical insurance, hospital location, census division, year of primary encounter, hospital bed size, and medical conditions. This study found higher healthcare utilization during the first year of life in infants diagnosed with NOWS, especially those with severe NOWS. Findings suggest a need for closer post-discharge follow-up and management of infants with NOWS.

The rates of opioid use disorder during pregnancy have more than quadrupled in the last decade, resulting in numerous infants suffering exposure to opioids during the perinatal period, a critical period of central nervous system (CNS) development. Despite increasing use, the characterization and definition of the molecular and cellular mechanisms of the long-term neurodevelopmental impacts of opioid exposure commencing in utero remains incomplete. Thus, in consideration of the looming public health crisis stemming from the multitude of infants with prenatal opioid exposure entering school age, we undertook an investigation of the effects of perinatal methadone exposure in a novel preclinical model. Specifically, we examined the effects of opioids on the developing brain to elucidate mechanisms of putative neural cell injury, to identify diagnostic biomarkers and to guide clinical studies of outcome and follow-up. We hypothesized that methadone would induce a pronounced inflammatory profile in both dams and their pups, and be associated with immune system dysfunction, sustained CNS injury, and altered cognition and executive function into adulthood. This investigation was conducted using a combination of cellular, molecular, biochemical, and clinically translatable biomarker, imaging and cognitive assessment platforms. Data reveal that perinatal methadone exposure increases inflammatory cytokines in the neonatal peripheral circulation, and reprograms and primes the immune system through sustained peripheral immune hyperreactivity. In the brain, perinatal methadone exposure not only increases chemokines and cytokines throughout a crucial developmental period, but also alters microglia morphology consistent with activation, and upregulates TLR4 and MyD88 mRNA. This increase in neuroinflammation coincides with reduced myelin basic protein and altered neurofilament expression, as well as reduced structural coherence and significantly decreased fractional anisotropy on diffusion tensor imaging. In addition to this microstructural brain injury, adult rats exposed to methadone in the perinatal period have significant impairment in associative learning and executive control as assessed using touchscreen technology. Collectively, these data reveal a distinct systemic and neuroinflammatory signature associated with prenatal methadone exposure, suggestive of an altered CNS microenvironment, dysregulated developmental homeostasis, complex concurrent neural injury, and imaging and cognitive findings consistent with clinical literature. Further investigation is required to define appropriate therapies targeted at the neural injury and improve the long-term outcomes for this exceedingly vulnerable patient population.

BACKGROUND: While Fetal Alcohol Spectrum Disorders (FASD) represent a significant public health problem, Native Americans are underrepresented in population and targeted screening programs. Prior reports suggest that Native American tribal communities may have higher prevalence of alcohol use during pregnancy; however, systematic examination using ethanol biomarkers is lacking. METHODS: This study utilized data collected through the Navajo Birth Cohort Study (NBCS) – a birth cohort study of a Southwestern tribal community. Prevalence of prenatal alcohol exposure (PAE) was assessed by a battery of meconium biomarkers among 333 NBCS participants. Meconium samples were analyzed for nine individual fatty acid ethyl ester (FAEE) species, ethyl glucuronide (EtG), and ethyl sulfate (EtS) by LC-MS/MS. RESULTS: Participants were recruited from 5 hospitals at the Navajo Nation located in Arizona (Chinle, Tséhootsooí, Tuba City) and New Mexico (Gallup, Shiprock). All participants identified as Native American; most reported personal income of

Longitudinal cohort studies present unique methodological challenges, especially when they focus on vulnerable populations, such as pregnant women. The purpose of this review is to synthesize the existing knowledge on recruitment and retention (RR) of pregnant women in birth cohort studies and to make recommendations for researchers to improve research engagement of this population. A scoping review and content analysis were conducted to identify facilitators and barriers to the RR of pregnant women in cohort studies. The search retrieved 574 articles, with 38 meeting eligibility criteria and focused on RR among English-speaking, adult women, who are pregnant or in early postpartum period, enrolled in birth cohort studies. Selected studies were birth cohort (including longitudinal) (n = 20), feasibility (n = 14), and other (n = 4) non-interventional study designs. The majority were from low-risk populations. Abstracted data were coded according to emergent theme clusters. The majority of abstracted data (79%) focused on recruitment practices, with only 21% addressing retention strategies. Overall, facilitators were reported more often (75%) than barriers (25%). Building trusting relationships and employing diverse recruitment methods emerged as major recruitment facilitators; major barriers included heterogeneous participant reasons for refusal and cultural factors. Key retention facilitators included flexibility with scheduling, frequent communication, and culturally sensitive practices, whereas participant factors such as loss of interest, pregnancy loss, relocation, multiple caregiver shifts, and substance use/psychiatric problems were cited as major barriers. Better understanding of facilitators and barriers of RR can help enhance the internal and external validity of future birth/pre-birth cohorts. Strategies presented in this review can help inform investigators and funding agencies of best practices for RR of pregnant women in longitudinal studies.

BACKGROUND: Infants with prenatal substance exposure are at increased risk for developmental problems, with self-regulatory challenges being some of the most pronounced. The current study aimed to investigate the extent to which prenatal substance exposure (alcohol, opioids) impacts infant self-regulation during a relational stressor and the association between self-regulation and infant affect. METHODS: Participants were 100 mother-child dyads recruited prenatally (Mean = 23.8 gestational weeks) and completed the Still Face Paradigm (SFP) when infants were 5 to 8 months of age (Mean = 6.9 months) as part of an ENRICH prospective birth cohort study. Based on prospective repeated assessment of maternal substance use in pregnancy, infants were grouped into: 1) Unexposed controls; 2) Alcohol-exposed; 3) Opioid-exposed due to maternal use of medications for opioid use disorder (MOUD) with or without other opioids; 4) MOUD and alcohol. Infant stress reactivity (negative affect) and self-regulation were assessed during the validated 5-episode SFP. Mixed effects linear models were used to analyze differences in the percent of self-regulation and percent of negative affect among the study groups across SFP episodes, as well as the group-by-self-regulation interaction with respect to infant negative affect. RESULTS: The MOUD+Alcohol group demonstrated significantly lower self-regulation at baseline compared to controls (p < 0.05). There was a significant group-by-self-regulation interaction (p = 0.028). Higher self-regulation was associated with lower negative affect across SFP episodes in the MOUD+Alcohol group (p = 0.025) but not other groups. CONCLUSION: Self-regulation skills are particularly important for emotional modulation in infants with prenatal polysubstance exposure, highlighting the development of these skills as a promising intervention target.

To assess the feasibility of a standardized approach to biometric measurement of the fetal frontal lobe and to construct frontal lobe growth trajectories throughout gestation.A sonographic 3-dimensional (3D) volume set was obtained and measured in 101 patients between 16.1 and 33.7 gestational weeks. Measurements were obtained by 2 independent raters. To model the relationship between gestational age and each frontal lobe measurement, flexible linear regression models were fit using penalized regression splines.The sample contained an ethnically diverse population (7.9% Native Americans, 45.5% Hispanics/Latinas). There was high interrater reliability (correlation coefficients 0.95, 1.0, and 0.87 for frontal lobe length, width, and height; p values0.001). Graphs of the growth trajectories and corresponding percentiles were estimated as a function of gestational age. The estimated rates of frontal lobe growth were 0.096 cm/week, 0.247 cm/week, and 0.111 cm/week for length, width, and height, respectively.To our knowledge, this is the first study to examine fetal frontal lobe growth trajectories through 3D prenatal ultrasound examination. Such normative data will allow for future prenatal evaluation of a particular disease state by 3D ultrasound imaging.

Background While use of prescription opioids and medication assisted therapy (MAT) for opioid use disorder in pregnancy, as well as the incidence of neonatal opioid withdrawal syndrome (NOWS) continue to rise, little is known about outcomes for children with NOWS beyond the newborn period. Methods We examined 1) prenatal MAT exposure vs. unexposed healthy controls [HC]; and 2) treatment for NOWS and NOWS severity on infant neurodevelopmental and behavioral outcomes at 5–8 months of age in 78 maternal-infant pairs from the ENRICH prospective cohort study. Data were obtained from 3 study visits: prenatal, delivery, and neurodevelopmental evaluation at 5–8 months of age. Neurodevelopmental outcomes included the Bayley Scales of Infant Development [BSID-III], caregiver questionnaires (Parenting Stress Index [PSI-SF], Infant Behavior Questionnaire [IBQ-R], Sensory Profile), and the experimental Still-Face Paradigm (SFP). Results No differences in the BSID-III, PSI-SF, or IBQ-R scores were observed between MAT and HC groups; however, MAT-exposed and HC infants differed with respect to SFP self-regulation (β = −18.9; p = 0.01) and Sensory Profile sensation seeking (OR = 4.87; 95% CI: 1.55; 15.30) after adjusting for covariates. No significant differences between Treated-for-NOWS vs. not-Treated-for-NOWS were observed. Shorter timing to NOWS treatment initiation was associated with higher Total Stress (β = −9.08; p = 0.035), while longer hospitalization was associated with higher Parent-child dysfunctional interaction (p = 0.018) on PSI-SF. Conclusions Our results provide additional evidence of little-to-no effect of MAT and pharmacological treatment of NOWS on infant neurodevelopmental and behavioral outcomes at 5–8 months of age. However, prolonged hospitalization might increase family psychosocial stress and requires further examination.

Background: Pharmacy residents’ knowledge of biostatistics is a self-identified deficit. Objective: To describe statistical training practices across postgraduate year 1 (PGY1) pharmacy residency programs and correlate training practices with residency program directors’ (RPDs) confidence in their residents’ statistical abilities. Methods: A 13-item survey was sent to PGY1 RPDs and included questions regarding respondents’ institution, program characteristics, type and amount of statistical training offered and desired, as well as performance of statistics, resident project publication rates, and RPDs’ confidence in residents’ statistical abilities. Results: Of the 1054 RPDs invited to participate in the survey, 202 (19.7%) surveys were completed. Nearly 25% of PGY1 pharmacy residency programs in this sample offered no statistical training to their residents. The most common types of training were study design considerations/selecting statistical tests (64.9%), descriptive statistics (59.9%), and database development/data manipulation (46.6%). The majority (60.9%) of RPDs had low confidence in their residents’ abilities to perform their own statistical analysis. After adjusting for significant covariates, residents receiving complex statistical training (odds ratio [OR]: 6.76; 95% confidence interval [CI]: 2.7-24.9) and a publication rate >50% (OR: 5.63; 95% CI: 1.61-19.69) were associated with higher RPD confidence in residents’ abilities to perform statistical analyses. Conclusion: The sample of programs in this survey indicates that statistical training for many residents may be limited, and many RPDs are not confident in their residents’ abilities to perform statistical analysis of research projects. Statistical training and opportunities to enhance research skills may be an area for future growth in pharmacy residency training programs.

Background The analysis of phosphatidylethanol, a promising direct ethanol metabolite, in dry blood spots (PEth-DBS) is advantageous due to ease of storage, transportation and minimal invasiveness of capillary blood collection. One potential application of PEth-DBS is to confirm prenatal alcohol exposure in newborns suspected of FASD; however, stability of PEth-DBS is largely unknown. Methods Phlebotomized samples from 31 adults with a history of alcoholism, admitted to the University of New Mexico Emergency Department, were analyzed for blood alcohol content and pipetted onto DBS cards (13 spots per patient). The first spot was analyzed within 2 weeks of collection for a baseline PEth; the remaining 12 spots were allocated into three temperature conditions (room temperature, 4°C, −80°C) for the repeated measures analysis. In addition, 5 newborn DBS samples with a baseline PEth>LOD were obtained from a prospective cohort at UNM and re-analyzed at 4 months after storage at −80°C. A mixed linear model was fitted to examine the effects of temperature, time and temperature–time interaction on PEth degradation over the first 9 months. Results The baseline PEth levels were 592.8 ± 86.7 ng/ml and 18.3 ± 4.8 ng/ml in adult and newborn samples, respectively. All DBS samples remained positive in successive samples in all temperature conditions. Results of mixed linear model demonstrated a significant effect of temperature ( P < 0.001) on PEth degradation over 9 months. Conclusions PEth-DBS appears to be relatively stable, especially when stored at lower temperatures. These initial results are encouraging and highlight the PEth-DBS potential in retrospective assessment of alcohol exposure.

While direct ethanol metabolites, including ethylglucuronide (EtG), play an important role for the confirmation of prenatal alcohol exposure (PAE), their utility is often limited by their short half-lives in blood and urine. Maternal hair might allow for a retrospective measure of PAE for up to several months. This study examined the validity of hair EtG (hEtG) relative to self-reporting and five other biomarkers (gamma glutamyltranspeptidase [GGT], carbohydrate-deficient transferrin [%dCDT], urine ethyl glucuronide [uEtG], urine ethyl sulfate [uEtS], and phosphatidylethanol [PEth]) in 85 pregnant women. Patients were recruited from a University of New Mexico prenatal clinic, which provides care to women with substance abuse and addiction disorders, and followed until early postpartum. The composite index, which was based on self-reported measures of alcohol use and allowed us to classify subjects into PAE (n = 42) and control (n = 43) groups, was the criterion measure used to estimate the sensitivity and specificity of hEtG and other biomarkers. Proximal segments of hair were collected at enrollment (average 22.0 gestational weeks) and analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS). At the same visit, maternal blood and urine specimens were collected for analysis of GGT, %dCDT, PEth, uEtG, and uEtS. The study population included mostly opioiddependent (80%) patients, a large proportion of ethnic minorities (75.3% Hispanic/Latina, 8.2% American Indian, 4.7% African-American), and patients with low education (48.2% < high school). The mean maternal age at enrollment was 26.7 ± 4.8 years. Hair EtG demonstrated 19% sensitivity and 86% specificity. The sensitivities of other biomarkers were comparable (5–20%) to hEtG in this cohort, but specificities were higher (98–100%). Hair EtG sensitivity improved when combined with other biomarkers, especially with GGT (32.5%) and PEth (27.5%). In addition, validity of hEtG improved in patients with less frequent shampooing and those who did not use hair dyes/chemical treatments. Mothers of two children with Fetal Alcohol Syndrome had hEtG levels of 158 and 58 pg/mg. These data suggest that hEtG alone, as measured in maternal hair, is not a sufficiently sensitive or specific biomarker to be used separately for the identification of PAE, but might be useful in a battery along with other maternal biomarkers.

This study assesses validity of self-report for the use of major classes of illicit drugs and opioid-maintenance therapy among pregnant women at a substance abuse treatment program. Analyses used data collected from 83 pregnant women in a prospective cohort study at the University of New Mexico. Study participants with a history of substance abuse were screened and, if eligible, enrolled during an early prenatal care visit. A follow-up interview was conducted shortly after delivery. Self-reported information about drug use later in pregnancy was compared with urine drug screen (UDS) results collected during the third trimester. Simple kappa (k) and prevalence-and-bias-adjusted kappa (PABAK) coefficients were calculated as the measures of agreement. Sensitivity and specificity of self-report for each drug class were estimated using UDS as the ‘gold standard’. The sample included a large proportion of ethnic minority (80 % Hispanic/Latina and 7 % American Indian) and socially disadvantaged (50 % less than high school education and 94 % Medicaid-insured) pregnant women. On average, patients had 4.8 ± 3.0 urine drug screens during the third trimester. Sensitivity of self-report was low (

This study examined the effects of prenatal alcohol exposure (PAE) on the incidence and severity of neonatal abstinence syndrome (NAS).For this pilot study, 70 pregnant women on opioid maintenance therapy (OMT) were recruited from a perinatal substance abuse clinic. Subjects were categorized into three study groups based on the timing of alcohol use during pregnancy as assessed by repeated self-reported measures and a comprehensive panel of ethanol biomarkers. NAS outcomes included: duration of hospital stay, the need for pharmacological treatment of NAS, newborn age at the initiation of NAS treatment, duration of treatment and cumulative methadone dose administered.The study included a large proportion of ethnic minorities (81.4% Hispanic, 5.7% American Indian), women with less than a high school education (52.2%) and unplanned pregnancy (82.9%). In multivariate analysis, PAE was not associated with NAS outcomes; however, one newborn diagnosed with fetal alcohol syndrome (FAS) demonstrated much more severe NAS compared to other PAE infants. Interestingly, 3rd trimester PAE was associated with a higher prevalence of microcephaly (62.5%) compared to the PAE abstaining group (36.8%; p = 0.08).In this study, PAE was not associated with NAS severity; however, further examination in a larger study is needed.

To evaluate the effects of prenatal polydrug and exclusive opioid use on fetal growth outcomes.This analysis relied on the data obtained from two prospective cohorts at the University of New Mexico. For both cohorts, pregnant women were recruited during one of their prenatal care visits and followed up to delivery. The merged sample included 59 polydrug users, 22 exclusive opioid users, and 278 abstinent controls. Continuous growth measures (birth weight, height, occipital frontal circumference [OFC], and corresponding sex-specific percentiles) were compared by ANOVA and ANCOVA in bivariate and multivariable analyses, respectively. Categorical outcomes (prevalence of small-for-gestational age [SGA] for weight, length, and OFC) were compared among groups by Chi-square and multivariable logistic regression analyses..The sample included a large proportion of ethnic minorities (78.8% Hispanic) and patients with low educational attainment (68% ≤ high school). The risk of microcephaly (OFC10Given that microcephaly is often associated with serious neurocognitive and behavioral deficits later in life, our finding of 49.2% incidence of microcephaly among polydrug users is alarming and requires further investigation.

Background Accurate confirmation of prenatal alcohol exposure (PAE) is required as a diagnostic criterion for the majority of children adversely affected by PAE who do not manifest the physical features associated with fetal alcohol syndrome. A number of ethanol biomarkers have been used to assess PAE, often with suboptimal results. The purpose of this study was to evaluate the feasibility and cost of PAE screening in newborns by measuring phosphatidylethanol (PEth) in dried blood spot (DBS) cards. Methods The feasibility of collecting an additional DBS card during routine newborn screening and the background prevalence of PAE were evaluated in a de-identified sample of newborn children delivered at the University of New Mexico Hospital. Electronic orders to collect DBS cards from newborns who continue to bleed after the routine newborn screen, glucose, or hematocrit testing were initiated for all infants delivered during a 4-week time frame. Specimens were sent to a contract laboratory for PEth analysis by liquid chromatography–tandem mass spectrometry. A cost analysis was conducted to compare the cost of PAE screening by PEth in DBS versus PEth in conventional blood specimens and by meconium fatty acid ethyl esters. Results From 230 collected cards, 201 (87.4%) had at least 1 full blood spot (amount sufficient for PEth analysis), and 6.5% had PEth >20 ng/ml indicative of potential PAE in late pregnancy. PAE screening by PEth in DBS is logistically simpler and less expensive compared with 2 other screening approaches. Conclusions These results indicate that screening for PAE in DBS cards is a feasible procedure and that a majority of infants have enough blood after the routine heel prick to fill an additional card. Moreover, screening by PEth analysis from DBS cards is cost-efficient. The acceptability of such screening by parents and corresponding ethical issues remain to be investigated.

Fetal Alcohol Spectrum Disorders (FASD) might be 10-15 times more prevalent among foster/adopted children compared to the general population; however, many of these children remain undiagnosed or misdiagnosed. The lack of confirmed prenatal alcohol exposure (PAE) may be a key barrier to diagnosis. Our sample included 681 patients evaluated for FASD, according to the University of Washington 4-Digit Diagnostic Code, at a pediatric specialty clinic. Guardianship status and other patient characteristics were evaluated by multinomial logistic regression as potential predictors of being classified into one of the following FASD groups: 1) full or partial Fetal Alcohol Syndrome (FAS/pFAS; n = 97); 2) Static Encephalopathy/Alcohol-Exposed (SE/AE) or Neurobehavioral Disorder/Alcohol-Exposed (ND/AE) (n = 135); and 3) some features of FASD (equivalent to pFAS, SE/AE or ND/AE phenotypes) but unknown PAE (n = 449). Median age at assessment was 7.0 years, non-Hispanic White constituted the predominant racial/ethnic group (49.5%), and the majority (81.8%) lacked involvement from a biological parent/relative. Many patients (66.0%) had some features of FASD but lacked reliable PAE information. Children classified into the 'some features/unknown PAE' group had higher median age of assessment (8 years) compared to other groups (6 years; p 0.001). No association was observed between race/ethnicity or child's sex and FASD outcomes (p 0.05). Adopted/foster children were 2.8 times as likely (95% CI: 1.6; 4.8) to be classified into the 'some features/unknown PAE' group compared to children living with a parent/relative after adjusting for covariates. This study's findings indicate that adopted/foster children are more likely to have unknown PAE and not receive a FASD diagnosis, potentially denying them access to specialized services, treatment, and rehabilitation.

Research skills to evaluate practice, review data, and assimilate scientific evidence to improve patient care or the medication-use system are requirements for completion of a postgraduate year 1 ASHP-accredited residency.[1][1] However, most pharmacy school graduates have limited experience with

The objectives of this study were to ascertain the prevalence and potential sources of lead exposure among pregnant women residing in a socially-disadvantaged immigrant community in Albuquerque, New Mexico. Pregnant women (n = 140) receiving prenatal care through a community clinic participated in a structured interview and screening to measure their blood lead levels (BLLs). Potential sources of lead exposure were ascertained by the CDC and New Mexico Department of Health questionnaires. Self-reported risk factors were examined as predictors of BLLs using multiple linear regression and partial least squares discriminant analysis. Most patients were Spanish-speaking (88.6%), Latina (95%), foreign-born (87.1%), lacked health insurance (86.4%), and had a high school education or lower (84.3%). While risk factors were prevalent in this population, only three women (2.1%) had BLLs ≥3 μg/dL. Results of multivariate analyses demonstrated that pica symptoms in pregnancy, history of elevated BLLs before pregnancy, use of non-commercial pottery, and living in older houses were important predictors of elevated BLLs. Although the prevalence of other risk factors relevant to immigrant communities (i.e., use of traditional/folk remedies and cosmetics, seasonings and food products from Mexico) was high, they were not predictive of elevated BLLs. Clinics providing prenatal care to immigrant Hispanic communities should carefully assess patients' pica symptoms, use of non-commercial pottery, and a history of elevated BLLs. Moreover, additional efforts need to focus on the development of screening questionnaires which better reflect exposures of concern in this population.

Despite evidence that consuming alcohol during pregnancy is harmful for the developing fetus, more than 10% of women in the United States report at least some alcohol use during pregnancy (Tan et al., 2015). The prevalence of fetal alcohol syndrome in the United States ranges from 0.5 to 2.0 per 1,000 live births in the general population to 1.4 to 9.8 per 1,000 live births in high‐risk groups (May and Gossage, 2001). Based on active case ascertainment methods, the prevalence of the entire continuum of fetal alcohol spectrum disorder (FASD) has been estimated to be as high as 24 to 48 per 1,000 live births, or 2 to 5% in the United States (May et al., 2014). However, the identification of children adversely affected by prenatal alcohol exposure (PAE) can be difficult because many of them do not exhibit any of the physical features associated with PAE and mainly manifest with neurocognitive deficits later in life. In the absence of the physical features and without accurate information on PAE, it is difficult to make a diagnosis of FASD. While ethanol (EtOH) biomarkers, as an objective measure, can help to overcome the limitations of self‐report on alcohol use during pregnancy, none of the existing biomarkers of alcohol consumption are 100% sensitive or specific (Bakhireva and Savage, 2011). Given these limitations, the identification of more sensitive and specific biomarkers that either alone or in combination with other clinical and self‐report measures can provide more accurate information on PAE would result in better identification of children with FASD and increase the opportunities for earlier diagnosis and interventions. MicroRNAs (miRNAs) are approximately 22‐nucleotide single‐stranded non‐protein‐coding RNA molecules that serve primarily to silence the expression of mRNA transcripts to which they hybridize by base pairing. miRNA biogenesis involves the processing of primary miRNA transcripts (pri‐miRNA) to hairpin precursor structures (pre‐miRNA), which are then exported to the cytoplasm where either strand may be loaded into the RNA‐induced silencing complex (RISC). The strand previously called the miRNA star (miRNA*) was generally thought to be rapidly degraded. However, miRNA* sequences have been found in RISC and shown to impact disease states such as cancer (Jazdzewski et al., 2009). The nomenclature is now changing to describe from which arm of the precursor the miRNA originates, 5′ (5p) or 3′ (3p). Mature miRNAs can bind thousands of transcripts in a cell, making them “master regulators” of gene expression (Bartel, 2004). Moreover, miRNAs have been shown to control many complex biological processes, from embryonic development to the promotion (or inhibition) of various pathological conditions, including cancers and neurodevelopmental disorders (Sayed and Abdellatif, 2011). Recent animal model and cell culture studies suggest that miRNAs play an important role in the mechanisms underlying the deleterious effects of PAE (Balaraman et al., 2013). EtOH suppresses miRs‐9, ‐21, ‐153, and ‐335 in cultured fetal mouse neural stem cells, coordinately regulating genes that make cells resistant to apoptosis, with increased proliferation and aberrant differentiation (Sathyan et al., 2007). miRs‐9(‐5p), 9*(‐3p), and ‐153 are repressed by EtOH exposure in the developing zebrafish brain (Tal et al., 2012). EtOH exposure in the developing mouse brain increases the expression of miRs‐10a and ‐10b, with a concomitant decrease in the target gene homeobox A1 (HOXA1; Wang et al., 2009), which is essential for normal embryonic development. Alterations in miRNA expression were also found in primary neuronal cultures from the cortex of mice at embryonic day 15 following chronic intermittent EtOH exposure and withdrawal (Guo et al., 2012). Finally, differences in miRNA expression were seen in the amygdala and striatum of rats at postnatal day 42 that were exposed to EtOH prenatally and subjected to social enrichment training postnatally (Ignacio et al., 2014). In addition to working inside the cell, miRNAs can be secreted and transferred between cells, indicating that they participate in cell‐to‐cell communication (Valadi et al., 2007). miRNAs are present not only in blood plasma and serum but also in a variety of cell‐free body fluids including urine and saliva, making them attractive as potential biomarkers. In the circulation, they are found in vesicles such as exosomes, microvesicles, and apoptotic bodies (Valadi et al., 2007; Zernecke et al., 2009) as well as in association with proteins (Vickers et al., 2011). Because of their association with vesicles and proteins, circulating miRNAs are resistant to degradation and can be accurately measured even when present at very low levels (Mitchell et al., 2008). Thus, circulating miRNAs have great promise as biomarkers of a variety of disease conditions from cancer to myocardial infarction (Etheridge et al., 2011). Although extracellular miRNAs have been investigated in animal models of PAE (Balaraman et al., 2014), the utility of these biomarkers in humans has not been reported thus far. The goal of the present study was to identify alterations in miRNA expression in maternal serum that could predict maternal alcohol consumption in pregnant women and further elucidate the mechanisms of fetal alcohol effects.

Maternal alcohol consumption during pregnancy and fetal alcohol spectrum disorders (FASDs) represent a significant public health problem. The influence of the male partner's alcohol consumption patterns and the quality of the partner's intimate relationship might be important factors to consider in the design of successful FASD prevention programs.As part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, 166 pregnant women in two regions in Ukraine participated in an in-person interview at an average gestational age of 18-19 weeks. Subjects were classified cross-sectionally as abstainers/light drinkers (n = 80), defined as low or no consumption of alcohol in the periconceptional period and none in the most recent 2 weeks of pregnancy; discontinuers (n = 43), defined as moderate to heavy alcohol use in the periconceptional period but none during the most recent 2 weeks of pregnancy; or continuing drinkers (n = 43), defined as continued moderate to heavy alcohol use within the most recent 2 weeks of pregnancy. Women also reported on their partner's drinking behavior and on the quality of their intimate relationship.Heavy paternal drinking was significantly associated with both continuing maternal drinking in the most recent 2 weeks (adjusted odds ratio [OR] = 34.1; 95% CI [5.9, 195.8]) and being a risky drinker only around conception (adjusted OR = 27.0; 95% CI [5.0, 147.7]). In addition, women who consumed alcohol during pregnancy had lower mean scores for satisfaction with partners' relationship and ability to discuss problems (p.05) compared with light drinkers/abstainers.This study suggests that development of partner-based interventions, as opposed to those solely focused on maternal drinking, might be warranted as a strategy to prevent FASD.

Study Objective. To examine the role of concurrent 3–hydroxy-3–methylglutaryl coenzyme A reductase inhibitor (statin) use and postmenopausal hormone therapy on osteoporosis-related fractures. Design. Case-control study. Data Source. Large integrated health plan in New Mexico. Patients. Case patients were 1001 women with incident fractures of the hip, wrist, forearm, or spine that occurred between January 1, 2000, and December 31, 2005, and controls were 2607 women without fractures during the same time frame; both groups were selected from the same population of women aged 50 years or older who utilized health plan services during the study time frame. Measurements and Main Results. Postmenopausal hormone therapy use was classified as “current” (12 mo before index date) or “never or past.” The risk of fractures was ascertained among continuous (≥80% medication possession ratio during 12 mo before the index date) and current (3 mo before index date) statin users relative to patients without hyperlipidemia who did not use lipid-lowering drugs. The interaction between statins and hormone therapy was examined in multivariable logistic regression. The association between statin use and fractures was examined separately among current and never or past hormone therapy users after controlling for other risk factors. Nineteen percent of the study participants were current hormone therapy users; 9.5% were current and 4.8% were continuous statin users. No association between continuous statin use and fractures was observed among never or past hormone therapy users (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.53–1.22). In contrast, a strong protective effect (OR 0.19, 95% CI 0.04–0.87) was observed among women who concurrently used statins and hormone therapy for 1 year, independent of age; corticosteroid, bisphosphonate, thiazide diuretic, calcitonin, methotrexate, or antiepileptic drug use; chronic kidney disease; and Charlson comorbidity index. Conclusion. Concurrent statin use and hormone therapy may have a synergistic protective effect on skeletal fractures beyond the additive effect of each individual therapy.

Amlodipine is a long-acting calcium channel blocker capable of producing hypotension and dysrhythmia in overdose. The toxic doses of amlodipine in children are unclear.The purposes of this study were to describe amlodipine poisoning in children and to determine whether a dose-response relationship could be detected in this population using standardized call data from United States (US) poison centers.1251 amlodipine-only ingestions in children6 years of age were reviewed. Cases with doses coded as "Exact" or "Estimated" and with dose, age, and medical outcome were analyzed (n = 678). Ingestions reported as a "taste or lick" (n = 53) were included as a dose of 1/10 of the dosage form involved. A clinically important response was defined as bradycardia, hypotension, dysrhythmia, conduction disturbance, or hyperglycemia. The risk of such responses was examined over four dosage intervals (2.5 mg, 2.5-5 mg, 5.1-10 mg, and10 mg).The median estimated dose ingested was 5 mg (range 0.25-200 mg). Clinically important responses developed in 27 patients (3.98%), and the prevalence of such response significantly increased from 0% for the lowest to 11.1% for the highest dose interval (p = 0.001). The smallest dose to produce a clinically important response was 2.5 mg (0.15 mg/kg). Children who ingested10 mg were 4.4 times more likely to develop clinically important responses than those ingestingor = 5 mg.Hypotension may occur in children with amlodipine doses as low as 2.5 mg. The National Poison Data System might provide useful insights regarding dose-response.

Objectives The aim of this pilot study was to explore possible ultrasound parameters for the early detection of alcohol-mediated fetal somatic and central nervous system (CNS) maldevelopment. Maternal alcohol ingestion during pregnancy may lead to fetal alcohol spectrum disorders (FASD), which encompass a broad range of structural abnormalities including growth impairment, specific craniofacial features and CNS abnormalities. Early detection of fetuses at risk of FASD would support earlier interventions. Methods We performed a longitudinal prospective pilot study from 2004 to 2006 at two sites in Ukraine. A sample of pregnant women who reported consuming moderate-to-heavy amounts of alcohol participated in a comprehensive maternal interview, and received ultrasound evaluation of fetal growth and specific fetal brain measurements during the second and third trimesters. These measurements were compared with those collected from a group of pregnant women who consumed little-to-no alcohol during pregnancy, and who were recruited and followed in the same manner. Results From 6745 screened women, 84 moderate-to-heavy alcohol users and 82 comparison women were identified and ultrasound examinations performed. After controlling for maternal smoking, alcohol-exposed fetuses had shorter mean femur length, caval–calvarial distance and frontothalamic measurements in the second trimester (P < 0.05), and alcohol-exposed fetuses also had shorter frontothalamic distance measurements in the third trimester relative to comparison fetuses (P < 0.05). In addition, after controlling for maternal smoking, both mean orbital diameter and biparietal diameter measurements were significantly smaller on average in the alcohol-exposed group in the third trimester relative to comparison fetuses (P < 0.05). Conclusions Significant differences in selected somatic and brain measurements were noted between alcohol-exposed and comparison fetuses, suggesting these markers may be further explored for clinical utility in prenatal identification of affected children. Further study correlating these findings with alcohol-related physical features of the newborn and subsequent comparisons of neuro-developmental outcomes will help define potential uses of prenatal ultrasound for intervention and prevention of FASD. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.

Objective: Whether osteoporosis and calcification of atherosclerotic plaque are two independent, age-related processes or linked by similar mechanisms of bone mineralization and plaque calcification is unknown. This study examines the sex-specific association between bone mineral density (BMD) and coronary artery calcification with a particular focus on hormone therapy (HT). Design: Participants were 180 men (aged 47-86 years) and 186 women (aged 58-81 years) without a history of heart disease who had hip and spine BMD assessed by dual-energy x-ray absorptiometry and coronary artery calcium score (CACS) measured by electron-beam computed tomography. Calcium scores were categorized into none/minimal (≤10), mild (11-100), moderate (101-399), and severe (≥400). Ordinal and binary logistic regressions examined the associations between site-specific BMD and CACS. Results: In men and women not using HT, there was no age-independent association between BMD at any site and CACS. In contrast, among current HT users an inverse association of BMD with coronary artery calcification was observed at the total hip (odds ratio [OR] = 0.56, 95% CI, 0.33-0.95), trochanter (OR = 0.55, 95% CI, 0.32-0.93), and intertrochanter area (OR = 0.60, 95% CI, 0.41-0.86) after adjustment for age and other risk factors. Other skeletal sites showed similar, but not statistically significant, associations (P < 0.1). Conclusion: Lack of association between BMD and CACS in men and women not using HT and the inverse association in women on HT suggest that the association between coronary and bone calcium might be mediated by estrogen.

A total of 230 feral African clawed frogs, Xenopus laevis, from 3 localities in southern California were examined for parasites. The following species were found: 3 species of Protozoa, Nyctotherus sp., Balantidium xenopodis, Protoopalina xenopodus; 2 species of Monogenea, Protopolystoma xenopodis, Gyrdicotylus gallieni; 1 species of Digenea, Clinostomum sp. (as metacercariae); 1 species of Cestoda, Cephalochlamys namaquensis; 2 species of Nematoda, Contracaecum sp. (as larvae), Eustrongylides sp. (as larvae); and 1 species of Acanthocephala, Acanthocephalus sp. (as cystacanth). Of these, the protozoans P. xenopodus and B. xenopodis, both monogeneans, and the cestode have an African origin. Contracaecum sp., Eustrongylides sp., and Acanthocephalus sp. have not been previously reported from X. laevis.

Background The determinants of change in bone mineral density (BMD) have been well characterized in women but not in men. This prospective study describes the patterns of BMD change at the hip and spine, incidence of osteoporosis, and modifiable predictors of bone loss in 507 ambulatory community-dwelling men aged 45 to 92 years. Methods Bone mineral density was assessed at the hip and lumbar spine by dual-energy x-ray absorptiometry (DEXA) between 1988 and 1992 and again 4 years later. BMD change was examined both as a continuous and a dichotomous (BMD loss vs no change/gain) variable. Incidence of osteoporosis was evaluated based on t -scores. Data were analyzed in 2002. Results Annual BMD loss averaged 0.47% at the total hip and 0.34% at the femoral neck with an annual average of 0.22% gain at the spine. The rate of BMD loss at the hip and incidence of osteoporosis increased significantly with age. The main predictors of BMD loss were age ≥75 years, baseline BMI 2 , 4-year weight loss of ≥5%, current smoking, and physical inactivity. Moderate alcohol consumption showed some bone-sparing effect. Diuretic and calcium supplement use were not associated with bone loss. Conclusions Relatively healthy community-dwelling men lose bone with age, and men aged ≥75 years are particularly vulnerable. Potentially modifiable characteristics such as low body mass, weight loss, smoking, and physical inactivity were important predictors of bone loss and should be considered for the prevention of osteoporosis in men.

Aims: Carbohydrate-deficient transferrin (%CDT) is a well-established and highly specific biomarker for sustained heavy consumption of alcohol. However, in pregnant women, the specificity of this biomarker might be affected by advanced gestational age, even after accounting for increased transferrin concentrations in pregnancy. The goal of this prospective study was to assess the variability in %CDT during pregnancy among alcohol-abstaining patients. Methods: Patients were recruited during one of the first prenatal care visits and followed-up to term. Abstinence was confirmed by maternal self-report and by alcohol biomarkers. Biomarkers assessed in the mother included serum gamma-glutamyltranspeptidase, urine ethyl glucuronide and ethyl sulfate, and whole blood phosphatidylethanol (PEth). In addition, PEth was measured in a dry blood spot card obtained from a newborn. For %CDT analysis, serum samples were collected at baseline and at term and analyzed by an internationally validated high-performance liquid chromatography and spectrophotometric detection method. Results: At recruitment (mean gestational age 22.6 ± 7.3 weeks), the mean %CDT concentration was 1.49 ± 0.30%, while at term, it increased to 1.67 ± 0.28% (P = 0.001). Using a conventional cutoff concentration %CDT >1.7%, 22.9 and 45.7% of the sample would be classified as ‘positive’ for this biomarker at recruitment and at term, respectively (P = 0.011 ). Conclusion: These results suggest that a conventional cutoff of 1.7% might be too low for pregnant women and would generate false-positive results. We propose that %CDT >2.0% be used as a cutoff concentration indicative of alcohol exposure in pregnant women. The sensitivity of %CDT at this cutoff for heavy drinking during pregnancy needs to be assessed further.