Associations Between Prenatal Vitamin D and Placental Gene Expression.

BACKGROUND: Vitamin D is a hormone regulating gene transcription. Prenatal vitamin D has been linked to immune and vascular function in the placenta, a key organ of pregnancy. Transcriptome-wide RNA-sequencing can provide a more complete representation of the placental effects of vitamin D. OBJECTIVE: We investigated the association between prenatal vitamin D levels and placental gene expression in a large, prospective pregnancy cohort. METHODS: Participants were recruited in Shelby County, Tennessee in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Vitamin D (plasma total 25-hydroxyvitatmin D, [25(OH)D]) was measured at mid-pregnancy (16-28 weeks) and delivery. RNA was sequenced from placental samples collected at birth. We identified differentially expressed genes (DEGs) using adjusted linear regression models. We also conducted weighted gene co-expression network analysis (WGCNA). RESULTS: The median 25(OH)D of participants was 21.8 ng/mL at mid-pregnancy (N=774, IQR: 15.4-26.5 ng/mL) and 23.6 ng/mL at delivery (N=753, IQR: 16.8-29.1 ng/mL). Placental expression of 17 DEGs was associated with 25(OH)D at mid-pregnancy, but only 1 DEG was associated with 25(OH)D at delivery. DEGs were related to energy metabolism, cytoskeletal function, and transcriptional regulation. We identified 2 WGCNA gene modules whose expression was associated with 25(OH)D at mid-pregnancy and 1 module associated with 25(OH)D at delivery. These modules were enriched for genes related to mitochondrial and cytoskeletal function and were regulated by transcription factors including ARNT2 and FOSL2. We also identified 12 modules associated with 25(OH)D in females and 1 module in males. CONCLUSIONS: 25(OH)D during mid-pregnancy, but not at delivery, is associated with placental gene expression at birth. Future research is needed to investigate a potential role of vitamin D in modulating placental mitochondrial metabolism, intracellular transport, and transcriptional regulation during pregnancy.

Prenatal exposure to polycyclic aromatic hydrocarbons and executive functions at school age: Results from a combined cohort study.

BACKGROUND: Executive functions develop rapidly in childhood, enabling problem-solving, focused attention, and planning. Exposures to environmental toxicants in pregnancy may impair healthy executive function development in children. There is increasing concern regarding polycyclic aromatic hydrocarbons (PAHs) given their ability to transfer across the placenta and the fetal blood-brain barrier, yet evidence from epidemiological studies is limited. METHODS: We examined associations between prenatal PAH exposure and executive functions in 814 children of non-smoking mothers from two U.S. cohorts in the ECHO-PATHWAYS Consortium. Seven mono-hydroxylated PAH metabolites were measured in mid-pregnancy urine and analyzed individually and as mixtures. Three executive function domains were measured at age 8-9: cognitive flexibility, working memory, and inhibitory control. A composite score quantifying overall performance was further calculated. We fitted linear regressions adjusted for socio-demographics, maternal health behaviors, and psychological measures, and examined modification by child sex and stressful life events in pregnancy. Bayesian kernel machine regression was performed to estimate the interactive and overall effects of the PAH mixture. RESULTS: The results from primary analysis of linear regressions were generally null, and no modification by child sex or maternal stress was indicated. Mixture analyses suggested several pairwise interactions between individual PAH metabolites in varied directions on working memory, particularly interactions between 2/3/9-FLUO and other PAH metabolites, but no overall or individual effects were evident. CONCLUSION: We conducted a novel exploration of PAH-executive functions association in a large, combined sample from two cohorts. Although findings were predominantly null, the study carries important implications for future research and contributes to evolving science regarding developmental origins of diseases.

Associations Between Prenatal Vitamin D and Placental Gene Expression.

Background: Vitamin D is a hormone regulating gene transcription. Prenatal vitamin D has been linked to immune and vascular function in the placenta, a key organ of pregnancy. To date, studies of vitamin D and placental gene expression have focused on a limited number of candidate genes. Transcriptome-wide RNA sequencing can provide a more complete representation of the placental effects of vitamin D. Objective: We investigated the association between prenatal vitamin D levels and placental gene expression in a large, prospective pregnancy cohort. Methods: Participants were recruited in Shelby County, Tennessee in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Vitamin D level (plasma total 25-hydroxyvitatmin D, [25(OH)D]) was measured at mid-pregnancy (16-28 weeks' gestation) and delivery. Placenta samples were collected at birth. RNA was isolated and sequenced. We identified differentially expressed genes (DEGs) using adjusted linear regression models. We also conducted weighted gene co-expression network analysis (WGCNA). Results: The median 25(OH)D of participants was 21.8 ng/mL at mid-pregnancy (N=774, IQR: 15.4-26.5 ng/mL) and 23.6 ng/mL at delivery (N=753, IQR: 16.8-29.1 ng/mL). Placental expression of 25 DEGs was associated with 25(OH)D at mid-pregnancy, but no DEG was associated with 25(OH)D at delivery. DEGs were related to energy metabolism, cytoskeletal function, and RNA transcription. Using WGCNA, we identified 2 gene modules whose expression was associated with 25(OH)D at mid-pregnancy and 1 module associated with 25(OH)D at delivery. These modules were enriched for genes related to mitochondrial and cytoskeletal function, and were regulated by transcription factors including ARNT2, BHLHE40, FOSL2, JUND, and NFKB1. Conclusions: Our results indicate that 25(OH)D during mid-pregnancy, but not at delivery, is associated with placental gene expression at birth. Future research is needed to investigate a potential role of vitamin D in programming placental mitochondrial metabolism, intracellular transport, and transcriptional regulation during pregnancy.

Sex-specific associations between placental corticotropin releasing hormone and problem behaviors in childhood.

Placental corticotropin-releasing hormone (pCRH) is a neuroactive peptide produced in high concentrations in mid-late pregnancy, during key periods of fetal brain development. Some evidence suggests that higher pCRH exposure during gestation is associated with adverse neurodevelopment, particularly in female offspring. In 858 mother-child dyads from the sociodemographically diverse CANDLE cohort (Memphis, TN), we examined: (1) the slope of pCRH rise in mid-late pregnancy and (2) estimated pCRH at delivery as a measure of cumulative prenatal exposure. When children were 4 years-old, mothers reported on problem behaviors using the Child Behavior Checklist (CBCL) and cognitive performance was assessed by trained psychologists using the Stanford-Binet Intelligence Scales. We fitted linear regression models examining pCRH in relation to behavioral and cognitive performance measures, adjusting for covariates. Using interaction models, we evaluated whether associations differed by fetal sex, breastfeeding, and postnatal neighborhood opportunity. In the full cohort, log-transformed pCRH measures were not associated with outcomes; however, we observed sex differences in some models (interaction p-values≤0.01). In male offspring, an interquartile (IQR) increase in pCRH slope (but not estimated pCRH at delivery), was positively associated with raw Total (ß=3.06, 95%CI: 0.40, 5.72), Internalizing (ß=0.89, 95%CI: 0.03, 1.76), and Externalizing (ß=1.25, 95%CI: 0.27, 2.22) Problem scores, whereas, in females, all associations were negative (Total Problems: ß=-1.99, 95%CI: -3.89, -0.09; Internalizing: ß=-0.82, 95%CI: -1.42, -0.23; Externalizing: ß=-0.56, 95%CI: -1.34, 0.22). No associations with cognitive performance were observed nor did we observe moderation by breastfeeding or postnatal neighborhood opportunity. Our results provide further evidence that prenatal pCRH exposure may impact subsequent child behavior in sex-specific ways, however in contrast to prior studies suggesting adverse impacts in females, steeper mid-gestation pCRH rise was associated with more problem behaviors in males, but fewer in females.

Latent Class Analysis of Prenatal Substance Exposure and Child Behavioral Outcomes.

OBJECTIVES: To predict behavioral disruptions in middle childhood, we identified latent classes of prenatal substance use. STUDY DESIGN: As part of the Environmental influences on Child Health Outcomes Program, we harmonized prenatal substance use data and child behavior outcomes from 2195 women and their 6- to 11-year-old children across 10 cohorts in the US and used latent class-adjusted regression models to predict parent-rated child behavior. RESULTS: Three latent classes fit the data: low use (90.5%; n = 1986), primarily using no substances; licit use (6.6%; n = 145), mainly using nicotine with a moderate likelihood of using alcohol and marijuana; and illicit use (2.9%; n = 64), predominantly using illicit substances along with a moderate likelihood of using licit substances. Children exposed to primarily licit substances in utero had greater levels of externalizing behavior than children exposed to low or no substances (P = .001, d = .64). Children exposed to illicit substances in utero showed small but significant elevations in internalizing behavior than children exposed to low or no substances (P < .001, d = .16). CONCLUSIONS: The differences in prenatal polysubstance use may increase risk for specific childhood problem behaviors; however, child outcomes appeared comparably adverse for both licit and illicit polysubstance exposure. We highlight the need for similar multicohort, large-scale studies to examine childhood outcomes based on prenatal substance use profiles.

Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder.

BACKGROUND: Buprenorphine-naloxone is a medication shown to improve outcomes for individuals seeking treatment for opioid use disorder (OUD); however, outcomes are limited by low medication adherence rates. This is especially true during the early stages of treatment. METHODS: The present study proposes to utilize a sequential multiple assignment randomized trial design to compare two psychological interventions targeting buprenorphine-naloxone adherence: (1) contingency management (CM) and (2) brief motivational interviewing plus substance-free activities session plus mindfulness (BSM). Participants will be N = 280 adults who present to a university-based addictions clinic seeking treatment for OUD. Participants will be randomized to condition to receive 4 sessions of their assigned intervention (CM or BSM). Participants who are adherent, defined as attending physician appointments and having buprenorphine present in urine toxicology, will enter maintenance intervention for an additional 6 months. Those who are not adherent will be re-randomized to receive either the other intervention or both interventions. Follow-up will occur at 8 months post-randomization. CONCLUSIONS: This novel design will examine the benefit of sequential treatment decisions following non-adherence. The primary outcome of this study is buprenorphine-naloxone medication adherence, as assessed by physician visit attendance and presence of buprenorphine in urine. Results will elicit the relative efficacy of CM and BSM compared to one another and whether keeping the initial treatment approach when adding the alternative approach for initially non-adherent individuals is beneficial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04080180.

A randomized controlled trial to reduce post-cessation weight gain.

BACKGROUND/OBJECTIVES: Weight gain is a barrier to smoking cessation. Previous interventions targeting weight gain while quitting smoking have largely been unsuccessful. The current study aimed to assess the efficacy of weight stability and weight loss interventions compared to a low-intensity, self-guided bibliotherapy weight management group. SUBJECTS/METHODS: A randomized controlled trial with 12-month follow-up from 2018 to 2022 was conducted with participants (N = 305) who reported smoking at least five cigarettes per day for the last year and interest in quitting initially recruited from the Memphis, TN, USA area. Recruitment was expanded nationally with the onset of the COVID-19 pandemic. Subsequently, 276 completed 12-month follow-up. INTERVENTIONS/METHODS: The Bibliotherapy group was provided a weight management book. Both the Stability and Loss groups met via telephone for eight weeks to learn strategies for maintaining/losing weight, respectively. All three groups then received the same six-week smoking cessation intervention, with six months of varenicline provided. RESULTS: Individuals in the Loss group lost more weight (-2.01 kg, SE = 1.58) than individuals in the Bibliotherapy group (+1.08 kg, SE = 1.49, p = 0.0004), while the Stability group (-0.30 kg, SE = 1.56) was not significantly different from the Bibliotherapy group (p = 0.17). Those in the Stability group did not gain a significant amount of weight. Participants in the Loss group did not gain back all weight lost after smoking cessation and ended the study approximately 2.01 kg lower than baseline. The Bibliotherapy group did not gain the amount of weight expected after cessation. There were no significant differences between groups related to self-reported smoking cessation at each time point except at eight-month follow-up (p = 0.005). CONCLUSIONS AND RELEVANCE: Results indicated the Stability and the Loss interventions were effective for preventing post-smoking cessation weight gain, with the Loss group having the benefit of sustained weight loss. These interventions may be helpful to implement to combat weight gain and potentially facilitate smoking cessation. TRIAL REGISTRATION: The trial is registered on clinicaltrials.gov (NCT03156660).

A Multi-Cohort Examination of the Independent Contributions of Maternal Childhood Adversity and Pregnancy Stressors to the Prediction of Children's Anxiety and Depression.

Women's social experiences can have long-term implications for their offspring's health, but little is known about the potential independent contributions of multiple periods of stress exposures over time. This study examined associations of maternal exposure to adversity in childhood and pregnancy with children's anxiety and depression symptoms in a large, sociodemographically diverse sample. Participants were 1389 mother-child dyads (child age M = 8.83 years; SD = 0.66; 42% Black, 42% White; 6% Hispanic) in the ECHO-PATHWAYS Consortium's three U.S. pregnancy cohorts. Women reported their exposure to childhood traumatic events (CTE) and pregnancy stressful life events (PSLE). Children self-reported on their symptoms of anxiety and depression at age 8-9 years. Regression analyses estimated associations between maternal stressors and children's internalizing problems, adjusting for confounders, and examined child sex as a modifier. Exploratory interaction analyses examined whether geospatially-linked postnatal neighborhood quality buffered effects. In adjusted models, PSLE counts positively predicted levels of children's anxiety and depression symptoms ([ßAnxiety=0.08, 95%CI [0.02, 0.13]; ßDepression=0.09, 95%CI [0.03, 0.14]); no significant associations were observed with CTE. Each additional PSLE increased odds of clinically significant anxiety symptoms by 9% (95%CI [0.02, 0.17]). Neither sex nor neighborhood quality moderated relations. Maternal stressors during pregnancy appear to have associations with middle childhood anxiety and depression across diverse sociodemographic contexts, whereas maternal history of childhood adversity may not. Effects appear comparable for boys and girls. Policies and programs addressing prevention of childhood internalizing symptoms may benefit from considering prenatal origins and the potential two-generation impact of pregnancy stress prevention and intervention.

Characteristics of Individuals in the United States Who Used Opioids During Pregnancy.

Background: Opioid use has disproportionally impacted pregnant people and their fetuses. Previous studies describing opioid use among pregnant people are limited by geographic location, type of medical coverage, and small sample size. We described characteristics of a large, diverse group of pregnant people who were enrolled in the Environmental Influences on Child Health Outcomes (ECHO) Program, and determined which characteristics were associated with opioid use during pregnancy. Materials and Methods: Cross-sectional data obtained from 21,905 pregnancies of individuals across the United States enrolled in the ECHO between 1990 and 2021 were analyzed. Medical records, laboratory testing, and self-report were used to determine opioid-exposed pregnancies. Multiple imputation methods using fully conditional specification with a discriminant function accounted for missing characteristics data. Results: Opioid use was present in 2.8% (n = 591) of pregnancies. The majority of people who used opioids in pregnancy were non-Hispanic White (67%) and had at least some college education (69%). Those who used opioids reported high rates of alcohol use (32%) and tobacco use (39%) during the pregnancy; although data were incomplete, only 5% reported heroin use and 86% of opioid use originated from a prescription. After adjustment, non-Hispanic White race, pregnancy during the years 2010-2012, higher parity, tobacco use, and use of illegal drugs during pregnancy were each significantly associated with opioid use during pregnancy. In addition, maternal depression was associated with increased odds of opioid use during pregnancy by more than two-fold (adjusted odds ratio 2.42, 95% confidence interval: 1.95-3.01). Conclusions: In this large study of pregnancies from across the United States, we found several factors that were associated with opioid use among pregnant people. Further studies examining screening for depression and polysubstance use may be useful for targeted interventions to prevent detrimental opioid use during pregnancy, while further elucidation of the reasons for use of prescription opioids during pregnancy should be further explored.

A critical review of cannabis in medicine and dentistry: A look back and the path forward.

INTRODUCTION: In the last two decades, our understanding of the therapeutic utility and medicinal properties of cannabis has greatly changed. This change has been accompanied by widespread cannabis use in various communities and different age groups, especially within the United States. With this increase, we should consider the potential effects of cannabis-hemp on general public health and how they could alter therapeutic outcomes. MATERIAL AND METHODS: The present investigation examined cannabis use for recreational and therapeutic use and a review of pertinent indexed literature was performed. The focused question evaluates "how cannabis or hemp products impact health parameters and do they provide potential therapeutic value in dentistry, and how do they interact with conventional medicines (drugs)." Indexed databases (PubMed/Medline, EMBASE) were searched without any time restrictions but language was restricted to English. RESULTS: The review highlights dental concerns of cannabis usage, the need to understand the endocannabinoid system (ECS), cannabinoid receptor system, its endogenous ligands, pharmacology, metabolism, current oral health, and medical dilemma to ascertain the detrimental or beneficial effects of using cannabis-hemp products. The pharmacological effects of pure cannabidiol (CBD) have been studied extensively while cannabis extracts can vary significantly and lack empirical studies. Several metabolic pathways are affected by cannabis use and could pose a potential drug interaction. The chronic use of cannabis is associated with health issues, but the therapeutic potential is multifold since there is a regulatory role of ECS in many pathologies. CONCLUSION: Current shortcomings in understanding the benefits of cannabis or hemp products are limited due to pharmacological and clinical effects not being predictable, while marketed products vary greatly in phytocompounds warrant further empirical investigation. Given the healthcare challenges to manage acute and chronic pain, this review highlights both cannabis and CBD-hemp extracts to help identify the therapeutic application for patient populations suffering from anxiety, inflammation, and dental pain.

Planning a Change Easily (PACE) for smokers who are not ready to quit: a telephone-based, randomized controlled trial.

AIMS: To compare brief advice (BA), motivational interviewing (MI), rate reduction (RR), and combined MI and RR (MI + RR) to promote smoking cessation in smokers not ready to quit. DESIGN: Randomized controlled trial with four parallel groups of smoking cessation intervention. Participants were randomly assigned 1:2:2:2 to receive one of the following interventions: BA (n = 128), MI (n = 258), RR (n = 257), and MI + RR (n = 260). SETTING: The United States. All participant contact occurred over the telephone to be consistent with the typical quit line format. PARTICIPANTS: A total of 903 adult smokers. Participants had a mean age of 49 (SD = 13.3) years and were 28.9% male and 63.3% Caucasian. INTERVENTIONS: The BA group received advice similar to typical smoking cessation quit lines. The MI group received advice using basic MI principles to elicit language that indicates behavioral change. The RR group received behavioral skills training and nicotine gum. The MI + RR group combined elements of MI and RR conditions. All interventions were six sessions. MEASUREMENTS: The primary outcome measure was self-reported point prevalence at 12 months. The secondary outcome was self-reported prolonged abstinence at 12 months. FINDINGS: Intention to treat (ITT) point prevalence at 12 months indicated that BA (10.9%) had significantly lower point prevalence rates than RR (27.2%, OR = 3.17, 1.69-5.94), and MI + RR (26.9%, OR = 3.16, 1.68-5.93). BA did not have a significantly lower point prevalence rate than MI (15.5%, OR = 1.56, 95% CI = 0.81-3.02). CONCLUSIONS: This randomized controlled trial provided evidence that rate reduction, which offers structured behavioral skills and nicotine gum, either alone or combined with motivational interviewing, is the most effective form of cessation intervention for smokers not ready to quit.

Using wearable technology to detect prescription opioid self-administration.

ABSTRACT: Appropriate monitoring of opioid use in patients with pain conditions is paramount, yet it remains a very challenging task. The current work examined the use of a wearable sensor to detect self-administration of opioids after dental surgery using machine learning. Participants were recruited from an oral and maxillofacial surgery clinic. Participants were 46 adult patients (26 female) receiving opioids after dental surgery. Participants wore Empatica E4 sensors during the period they self-administered opioids. The E4 collected physiological parameters including accelerometer x-, y-, and z-axes, heart rate, and electrodermal activity. Four machine learning models provided validation accuracies greater than 80%, but the bagged-tree model provided the highest combination of validation accuracy (83.7%) and area under the receiver operating characteristic curve (0.92). The trained model had a validation sensitivity of 82%, a specificity of 85%, a positive predictive value of 85%, and a negative predictive value of 83%. A subsequent test of the trained model on withheld data had a sensitivity of 81%, a specificity of 88%, a positive predictive value of 87%, and a negative predictive value of 82%. Results from training and testing model of machine learning indicated that opioid self-administration could be identified with reasonable accuracy, leading to considerable possibilities of the use of wearable technology to advance prevention and treatment.

Opioid Use Patterns After Primary Total Knee Replacement.

Orthopedic surgeries are associated with the prescription of more narcotics than any other surgical specialty, particularly for total knee replacement (TKR) surgery. The authors examined controlled substance prescriptions following TKR surgery in a sample of 560 TKR patients. Results indicated that of all the 5164 prescriptions documented on the controlled substance monitoring database, 64% were for opioid medications. More than half of the patients received controlled substances from both the surgery site provider and a nonsurgery site provider in the year following surgery. The authors recommend that providers consider the possibility of outside prescribing when prescribing opioid analgesic.

Maternal Plasma 25-Hydroxyvitamin D during Gestation Is Positively Associated with Neurocognitive Development in Offspring at Age 4-6 Years.

BACKGROUND: Vitamin D is critical to embryonic neuronal differentiation and other developmental processes that may affect future neurocognitive function. However, observational studies have found inconsistent associations between gestational vitamin D and neurocognitive outcomes. OBJECTIVES: We examined the association of gestational 25-hydroxyvitamin D [25(OH)D] with children's IQ at 4-6 y, and explored whether associations differed by race. METHODS: This study used data from the CANDLE (Conditions Affecting Neurocognitive Development and Learning in Early Childhood) cohort. Between 2006 and 2011, CANDLE recruited 1503 women in their second trimester of healthy singleton pregnancies. Inclusion criteria for this analysis were gestation of ≥34 wk and availability of 25(OH)D and IQ data. Associations between second-trimester 25(OH)D plasma concentration and Stanford-Binet IQ scores in offspring at 4-6 y were examined using multivariable linear regression; interaction terms were used to explore possible effect modification by race. RESULTS: Mean ± SD 25(OH)D concentration among 1019 eligible dyads was 21.6 ± 8.4 ng/mL, measured at a mean ± SD gestational age of 23.0 ± 3.0 wk. Vitamin D deficiency [25(OH)D < 20 ng/mL] was observed in 45.6%. Maternal 25(OH)D differed by race with a mean ± SD of 19.8 ± 7.2 ng/mL in Blacks sand 25.9 ± 9.3 ng/mL in Whites ( P  < 0.001). In adjusted models a 10-ng/mL increase in 25(OH)D was associated with a 1.17-point higher Full Scale IQ (95% CI: 0.27, 2.06 points), a 1.17-point higher Verbal IQ (95% CI: 0.19, 2.15 points), and a 1.03-point higher Nonverbal IQ (95% CI: 0.10, 1.95 points). We observed no evidence of effect modification by race. CONCLUSIONS: Second-trimester maternal 25(OH)D was positively associated with IQ at 4-6 y, suggesting that gestational vitamin D status may be an important predictor of neurocognitive development. These findings may help inform prenatal nutrition recommendations and may be especially relevant for Black and other dark-skinned women at high risk of vitamin D deficiency.

Conceptualizing the UPPS-P model of impulsive personality through network analysis: Key dimensions and general robustness across young adulthood.

OBJECTIVE: Within the UPPS-P model of impulsive personality, negative urgency, positive urgency, lack of premeditation, lack of perseverance, and sensation seeking dimensions have been linked to unique etiological mechanisms and outcomes. Yet, additional research is needed exploring direct relations among dimensions to determine how these relations may contribute to the nature of impulsive personality and its correlates. The current study used network analysis to clarify relations among UPPS-P dimensions and assess global robustness of these relations across young adulthood. METHOD: Participants included a longitudinal sample of 525 college students (48% male, 18-26 years) who completed the UPPS-P once per year for three consecutive years. RESULTS: Network structure was globally robust with particularly strong relations emerging between positive and negative urgency, as well as between lack of premeditation and lack of perseverance, across waves. Lack of premeditation consistently emerged as a central dimension. Additional analyses suggested lack of premeditation and sensation seeking as most robustly related with retrospectively reported frequency of alcohol use. CONCLUSIONS: Results suggested general robustness in the relations among impulsive personality dimensions, with relations involving lack of premeditation being particularly important for characterizing impulsive personality's nature. Sensation seeking and lack of premeditation may warrant particular focus when linking impulsive personality with frequency of alcohol use.

Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter.

BACKGROUND: A long-term opioid use has been associated with hypermethylation of the opioid receptor mu 1 (OPRM1) promoter. Very little is currently known about the early epigenetic response to therapeutic opioids. Here, we examine whether we can detect DNA methylation changes associated with a few days' use of prescribed opioids. Genome-wide DNA methylation was assayed in a cohort of 33 opioid-naïve participants who underwent standard dental surgery followed by opioid self-administration. Saliva samples were collected before surgery (visit 1), and at two postsurgery visits at 2.7 ± 1.5 days (visit 2), and 39 ± 10 days (visit 3) after the discontinuation of opioid analgesics. RESULTS: The perioperative methylome underwent significant changes over the three visits that were primarily due to postoperative inflammatory response and cell heterogeneity. To specifically examine the effect of opioids, we started with a candidate gene approach and evaluated 10 CpGs located in the OPRM1 promoter. There was a significant cross-sectional variability in opioid use, and for participants who self-administered the prescribed drugs, the total dosage ranged from 5-210 morphine milligram equivalent (MME). Participants were categorized by cumulative dosage into three groups: < 25 MME, 25-90 MME, and ≥ 90 MME. Using mixed-effects modeling, 4 CpGs had significant positive associations with opioid dose at two-tailed p value < 0.05, and overall, 9 of the 10 OPRM1 promoter CpGs showed the predicted higher methylation in the higher dose groups relative to the lowest dose group. After adjustment for age, cellular heterogeneity, and past tobacco use, the promoter mean methylation also had positive associations with cumulative MME (regression coefficient = 0.0002, one-tailed p value = 0.02) and duration of opioid use (regression coefficient = 0.003, one-tailed p value = 0.001), but this effect was significant only for visit 3. A preliminary epigenome-wide association study identified a significant CpG in the promoter of the RAS-related signaling gene, RASL10A, that may be predictive of opioid dosage. CONCLUSION: The present study provides evidence that the hypermethylation of the OPRM1 promoter is in response to opioid use and that epigenetic differences in OPRM1 and other sites are associated with a short-term use of therapeutic opioids.

Sexually Transmitted Infections and Contraceptive Use in Adolescents.

INTRODUCTION: Although a number of contraception methods exist, long-acting reversible contraceptives have been recommended for female adolescents owing to their low failure rates. However, concern exists that the increasing use of long-acting reversible contraceptive among female adolescents may have unintended consequences of decreasing condom use for the prevention of sexually transmitted infections. Despite this concern, few studies have directly explored the relationship between the use of long-acting reversible contraceptive versus other forms of contraception and diagnosis of sexually transmitted infections in female adolescents. This study compares the rates of sexually transmitted infection diagnosis following various forms of contraceptive use. METHODS: This study was an archival data analysis of single state Medicaid claims retrieved for female adolescents, aged 14-19 years, who received a contraceptive prescription and had 1 year of follow-up data available (n=62,550) between 2011 and 2015. Incidence of sexually transmitted infections was the outcome of interest. Data analysis was conducted in 2018. RESULTS: Compared with the contraceptive pill, hormonal implant (a form of long-acting reversible contraceptives) was associated with significantly lower risk of sexually transmitted infections (hazard ratio=0.81; 95% CI=0.70, 0.93; p=0.004), and hormonal injection was associated with higher risk of sexually transmitted infections (hazard ratio=1.08; 95% CI=1.00, 1.16; p=0.040). CONCLUSIONS: This analysis provides strong evidence that the risk for the acquisition of sexually transmitted infections is no higher for long-acting reversible contraceptives than for other forms of contraception. These results support the use of long-acting reversible contraceptive in female adolescents, as proposed and reaffirmed by the American College of Obstetricians and Gynecologists and American Academy of Pediatrics.

Addiction Medicine Training Fellowships in North America: A Recent Assessment of Progress and Needs.

OBJECTIVES: Although unhealthy substance use and addiction contribute to 1 in 4 deaths and are estimated to cost the US more than $740 billion annually, fewer than 12 hours of physician education over the 7 years of medical school and primary residency training specifically address alcohol and other drug-related issues. Addiction Medicine was formally recognized as a medical subspecialty in 2016 to address the need for physicians trained in prevention, treatment, and management of substance use. This study examines the characteristics of the Addiction Medicine fellowships in operation during this critical period in the subspecialty's development to identify needs and potential. METHODS: This study is a cross-sectional survey of Addiction Medicine Fellowship Directors from 46 fellowships accredited as of 2017 (43 in the United States and 3 in Canada). The response rate was 100%. RESULTS: Directors estimated significant growth in available fellowship slots between 2016 to 2017 and 2017 to 2018 (F = 49.584, P < .001). The majority of Directors reported that demand for their graduates was high (79.5%). Fellow training in screening, brief intervention, and referral to treatment spanned many substances and age groups, although fewer programs focused on nicotine and on adolescent populations. Notably, most directors reported that graduates completed waiver training to prescribe buprenorphine-naloxone (77.5%) and gained clinical experience in an opioid treatment setting (89.1%). Funding was the #1 need among 56.8% of Directors. CONCLUSIONS: Despite significant growth in Addiction Medicine fellowships over the past 6 years, meeting future workforce demands for Addiction Medicine specialists depends on access to funding to support fellowships.

Cumulative Risk of Substance Use in Community College Students.

BACKGROUND AND OBJECTIVES: Substance use in community college students has been explored in only a handful of studies. Differences in population characteristics and substance use between 2- and 4-year students suggest that different factors may promote and thwart this behavior. Cumulative risk is a parsimonious methodology that provides better model stability and more statistical power, yet it has only been recently used in substance use research. The aim of this study is to investigate multiple aspects of substance use risk in a population in need of substance use prevention and intervention services. METHODS: We conducted a cross-sectional study of community college students (N = 288; 75% female) examining the relative contributions of different domains of cumulative risk (eg, life stressors, academic stressors, and mental health diagnoses) to develop different profiles of risk across substance use classes (ie, alcohol, cigarette, marijuana, and hard drug use). RESULTS: Cumulative risk analyses indicated that alcohol and tobacco use were associated with the domains of life stressors and peer/family substance use, marijuana use with peer/family substance use and stressful childhood experiences, and hard drug use with peer/family substance use, lack of social support, low access to care, and stressful childhood experiences. DISCUSSION AND CONCLUSIONS: Different strategies for prevention and intervention may be necessary to effectively address different forms of substance use in this population. SCIENTIFIC SIGNIFICANCE: The risk domain profiles related to specific drugs may lead to targeted interventions to reduce substance use in community college students. (Am J Addict 2020;29:97-104).

A randomized pilot program to reduce opioid use following dental surgery and increase safe medication return.

Research indicates that increased cumulative exposure (duration of administration and strength of dose) is associated with long-term opioid use. Because dentists represent some of the highest opioid prescribing medical professionals in the US, dental practices offer a critical site for intervention. The current study used a randomized clinical trial design to examine the efficacy of an opioid misuse prevention program (OMPP), presented as a brief intervention immediately prior to dental extraction surgery. The OMPP provided educational counseling about risks and appropriate use of opioid medication, as well as 28 tablets of ibuprofen (200 mg) and 28 tablets of acetaminophen (500 mg) for weaning off opioid medication. This was compared with a Treatment as Usual (TAU) control condition. Participants were individuals presenting for surgery who were eligible for opioid medication (N = 76). Follow up assessment was conducted at 1 week following surgery, with 4 individuals refusing follow up or not prescribed opioid. Intent to treat analysis indicated a non-significant treatment group effect (N = 72, Beta = 0.16, p = .0835), such that the OMPP group self-reported less opioid use (in morphine milligram equivalents, MMEs) than the TAU group (37.94 vs. 47.79, effect size d = 0.42). Sensitivity analysis, excluding individuals with complications following surgery (n = 6) indicated a significant treatment group effect (N = 66, Beta = 0.24, p = .0259), such that the OMPP group self-reported significantly less MMEs than the TAU group (29.74 vs. 43.59, effect size d = 0.56). Results indicate that a 10-minute intervention and provision of non-narcotic pain medications may reduce the amount of self-administered opioid medication following dental surgery.