IL17RB genetic variants are associated with acamprosate treatment response in patients with alcohol use disorder: A proteomics-informed genomics study.

Acamprosate is a Food and Drug Administration (FDA) approved medication for the treatment of alcohol use disorder (AUD). However, only a subset of patients achieves optimal treatment outcomes. Currently, no biological measures are utilized to predict response to acamprosate treatment. We applied our established pharmaco-omics informed genomics strategy to identify potential biomarkers associated with acamprosate treatment response. Specifically, our previous open-label acamprosate clinical trial recruited 442 patients with AUD who were treated with acamprosate for three months. We first performed proteomics using baseline plasma samples to identify potential biomarkers associated with acamprosate treatment outcomes. Next, we applied our established "proteomics-informed genome-wide association study (GWAS)" research strategy, and identified 12 proteins, including interleukin-17 receptor B (IL17RB), associated with acamprosate treatment response.​ A GWAS for IL17RB concentrations identified several genome-wide significant signals. Specifically, the top hit single nucleotide polymorphism (SNP) rs6801605 with a minor allele frequency of 38% in the European American population mapped 4 kilobase (Kb) upstream of IL17RB, and intron 1 of the choline dehydrogenase (CHDH) gene on chromosome 3 (p: 4.8E-20). The variant genotype (AA) for the SNP rs6801605 was associated with lower IL17RB protein expression. In addition, we identified a series of genetic variants in IL17RB that were associated with acamprosate treatment outcomes. Furthermore, the variantgenotypes for all of those IL17RB SNPs were protective for alcohol relapse. Finally, we demonstrated that the basal level of mRNA expression of IL17RB was inversely correlated with those of nuclear factor-κB (NF-κB) subunits, and a significantly higher expression of NF-κB subunits was observed in AUD patients who relapsed to alcohol use. In summary, this study illustrates that IL17RB genetic variants might contribute to acamprosate treatment outcomes. This series of studies represents an important step toward generating functional hypotheses that could be tested to gain insight into mechanisms underlying acamprosate treatment response phenotypes. (The ClinicalTrials.gov Identifier: NCT00662571).

Prevalence of stress and related factors among healthcare students: a cross - sectional study in Can Tho City, Vietnam.

Background: Stress is a major public health issue that can impact both physical and mental well-being. It is prevalent in many areas of modern life, including education. Healthcare students are at a high risk of experiencing stress due to the unique demands of their fields of study. Study design and methods: An online survey was conducted on 2,515 undergraduate students pursuing degrees in medicine, preventive medicine, pharmacy, and nursing at Can Tho University of Medicine and Pharmacy in Can Tho City, Vietnam. Results: Using the Perceived Stress Scale-10 (PSS-10), it was found that 35.2% of students reported mild stress, 62.7% had moderate stress, and only 2.1% experienced severe stress. Multivariable logistic regression analysis revealed nine significant factors associated with students' stress levels (p ≤ 0.05). Particularly, medicine students exhibited a significantly higher level of moderate and severe stress (95% CI = 1.22-2.01), 1.57 times higher than preventive medicine students. Sixth-year students had a stress level 1.58 times higher (95% CI = 1.11-2.26) than first-year students. Students achieving excellent and very good academic performances in the last semester had a stress level 1.60 times higher (95% CI = 1.16-2.22) than students with average and lower academic performance. Students living at home had a stress level 1.73 times higher (95% CI = 1.05-2.84) than students living in their relatives' houses. Students who rarely or never had a part-time job during academic years had a stress level 1.70 times higher (95% CI = 1.31-2.20) than those who often or sometimes had a part-time job. Students with a family history of smoking addiction had a stress level 1.69 times higher (95% CI = 1.28-2.22) than students without such a family history. Students who rarely or never received concern and sharing from family had a stress level 7.41 times higher (95% CI = 5.07-10.84) than students who often or sometimes received concern and sharing from family. Students who were often or sometimes cursed by family had a stress level 2.04 times higher (95% CI = 1.09-3.81) than students who were rarely or never cursed by family. Students without close friends had a stress level 1.46 times higher (95% CI = 1.11-1.91) than students with close friends. Conclusions: The rates of mild and moderate stress levels were significantly higher than severe stress level among healthcare students. Research has provided scientific findings as the basis for determining risk factors and imposing solutions that aim to reduce the rate of stress in students. Therefore, it helps students overcome difficulties and enhance their physical and mental health.

Single cell transcriptomics reveals distinct transcriptional responses to oxycodone and buprenorphine by iPSC-derived brain organoids from patients with opioid use disorder.

The opioid epidemic represents a national crisis. Oxycodone is one of the most prescribed opioid medications in the United States, whereas buprenorphine is currently the most prescribed medication for opioid use disorder (OUD) pharmacotherapy. Given the extensive use of prescription opioids and the global opioid epidemic, it is essential to understand how opioids modulate brain cell type function at the single-cell level. We performed single nucleus RNA-seq (snRNA-seq) using iPSC-derived forebrain organoids from three male OUD subjects in response to oxycodone, buprenorphine, or vehicle for seven days. We utilized the snRNA-seq data to identify differentially expressed genes following drug treatment using the Seurat integrative analysis pipeline. We utilized iPSC-derived forebrain organoids and single-cell sequencing technology as an unbiased tool to study cell-type-specific and drug-specific transcriptional responses. After quality control filtering, we analyzed 25787 cells and identified sixteen clusters using unsupervised clustering analysis. Our results reveal distinct transcriptional responses to oxycodone and buprenorphine by iPSC-derived brain organoids from patients with OUD. Specifically, buprenorphine displayed a significant influence on transcription regulation in glial cells. However, oxycodone induced type I interferon signaling in many cell types, including neural cells in brain organoids. Finally, we demonstrate that oxycodone, but not buprenorphine activated STAT1 and induced the type I interferon signaling in patients with OUD. These data suggest that elevation of STAT1 expression associated with OUD might play a role in transcriptional regulation in response to oxycodone. In summary, our results provide novel mechanistic insight into drug action at single-cell resolution.

Technology-Facilitated Abuse Prevalence and Associations Among a Nationally Representative Sample of Young Men.

PURPOSE: We undertook a study to determine the prevalence and associations of technology-facilitated abuse (TFA)-insults, harassment, coercion, or threats carried out using digital tools such as smartphones and computers-among a US nationally representative sample of young men. METHODS: Analyses were based on 1,079 men aged 18 to 35 years who completed questionnaires during August and September of 2014 and reported ever having been in a romantic relationship. We used validated measures to assess demographics, health service use, mental health and substance use, and TFA delivered to and received from partners in the past year. We calculated survey-weighted descriptive statistics and conducted multinomial logistic regression analysis. RESULTS: Overall, 4.1% of men reported delivering TFA only, 8.0% receiving TFA only, and 25.6% both delivering and receiving TFA. Men were more likely to report only delivering TFA if they identified as Hispanic (adjusted odds ratio [AOR] = 2.72; 95% CI, 1.13 to 6.57), used marijuana (AOR = 1.31; 95% CI, 1.02 to 1.68), and used prescription opioids for nonmedical reasons (AOR 2.86; 95% CI, 1.48 to 5.54). Men were more likely to report only receiving TFA if they identified as Hispanic (AOR = 2.55; 95% CI, 1.01 to 6.43) and used prescription opioids for nonmedical reasons (AOR = 2.43; 95% CI, 1.34 to 4.39), whereas a primary care connection appeared protective (AOR = 0.43; 95% CI, 0.22 to 0.86). Men were more likely to report both delivering and receiving TFA if they identified as non-Hispanic Black (AOR = 2.83; 95% CI, 1.44 to 5.58), owned a smartphone (AOR = 1.80; 95% CI, 1.05 to 3.09), had ever had mental health care visits (AOR = 1.86; 95% CI, 1.16 to 2.98), misused alcohol (AOR = 1.10; 95% CI, 1.04 to 1.17), and used prescription opioids for nonmedical reasons (AOR = 1.79; 95% CI, 1.04 to 3.08). CONCLUSIONS: We found that TFA was prevalent among young men, with 1 in 25 reporting delivery only, 1 in 12 reporting receipt only, and 1 in 4 reporting both. Primary care physicians can consider assessing TFA among male patients and developing interventions to mitigate this behavior.VISUAL ABSTRACT.

State of the science: a scoping review of primary prevention of firearm injuries among children and adolescents.

Intentional and unintentional firearm injury is the second leading cause of death for youth, underscoring the need for effective primary prevention approaches that focus on increasing safe storage by caregivers and decreasing handling/carriage among youth. This article describes the state of the science for prevention of firearm injuries among children and adolescents. We applied PRISMA guidelines to present results from a scoping review using PubMed, Scopus, CINAHL, and CJ Abstracts for original research articles published between January 1, 1985 and March 1, 2018 in the U.S. focusing on primary screening or interventions for primary prevention of pediatric firearm injuries. In total, 46 articles met inclusion criteria: safe storage (23), screening (2), firearm handling/carriage/use (21). Across school, healthcare, and community settings, few evidenced-based programs exist, and data on firearm safety technologies are lacking. Programs have generally not employed rigorous designs, and/or assessed behavioral (e.g., carriage) or injury-related firearm outcomes. Evidenced-based prevention programs are needed to mitigate firearm morbidity and mortality among youth.

Adolescent sexual violence: Prevalence, adolescent risks, and violence characteristics.

The purpose of this research is to investigate peer-to-peer sexual violence victimization and perpetration among male and female adolescents in a large, racially and economically diverse, community-based sample. Using cross-sectional data over a four-year period (2009-2013) from a regional sample of middle school and high school students in southeastern Michigan, we examined the prevalence and correlates of peer-to-peer sexual violence victimization and perpetration among adolescents. 33.9% of males and 53.5% of females reported sexual violence victimization, while 22.8% of males and 12.6% of females reported sexual violence perpetration. The majority of peer-to-peer sexual victimization and perpetration occurred by someone of the opposite sex, however, same-sex victimization and perpetration were not uncommon. Substance use, depression, Attention Deficit Hyperactivity Disorder (ADHD), and conduct disorder were associated with peer-to-peer sexual violence (victimization or perpetration) for both males and females, with few differences in the patterns of associations by sex. These findings are an important step in better understanding the types of peer-to-peer sexual violence that adolescents experience and risk factors for both male and female youth.

Perceived Peer Behavior and Parental Support as Correlates of Marijuana Use: The Role of Age and Gender.

INTRODUCTION: Parental support and perceptions of peer behavior on substance use are well-studied, but precisely how their associations vary as a function of age, and how those age-specific patterns vary by gender, remain unknown components of the developmental process underlying substance use. METHODS: Using data from an 18-year longitudinal study of predominantly African-American students at high-risk for high school dropout in Flint, Michigan (baseline average age = 14.8 years), we examined longitudinal associations between past 30-day marijuana use and three self-reported variables: perceived friend drug use, perceived friend aggression, parental support. We used varying-coefficient regression models to semiparametrically estimate how covariate effects on past 30-day marijuana use vary smoothly as a function of age; gender differences in these age-specific coefficient trajectories were also tested. RESULTS: In the unadjusted tests, the risk-enhancing effect of perceived friend drug use decreased with age in both genders, but the effect of perceived friend aggression varied only in females; in both cases, gender differences were not significant. In males, parental support had protective effects that decreased with age. The effect of both parental support differed in females, with less protective baseline effects and no evidence of age-variation. Adjusted models simultaneously including both friend and parental variables produced qualitatively similar results. CONCLUSIONS: Prevention strategies focusing on social exposures may be more effective if they are age- and gender-specific. In particular, interventions focusing on perceived peer behaviors may be more appropriate during adolescence, and those involving parental relationships may be more appropriate for males.

Violent firearm-related conflicts among high-risk youth: An event-level and daily calendar analysis.

Firearm homicide is the leading cause of violence-related youth mortality. To inform prevention efforts, we analyzed event-level data to identify unique precursors to firearm conflicts. Youth (ages:14-24) seeking Emergency Department (ED) treatment for assault or for other reasons and reporting past 6-month drug use were enrolled in a 2-year longitudinal study. Time-line follow-back substance use/aggression modules were administered at baseline and each 6-month follow-up. Violent non-partner conflicts were combined across time-points. Regression analyzed: a)antecedents of firearm-related conflicts (i.e., threats/use) as compared to non-firearm conflicts; and b)substance use on conflict (vs. non-conflict) days for those engaged in firearm conflict. During the 24-months, we found that 421-youth reported involvement in violent non-partner conflict (n=829-conflicts;197-firearm/632-non-firearm). Among firearm conflicts, 24.9% involved aggression and 92.9% involved victimization. Retaliation was the most common motivation for firearm-aggression (51.0%), while "shot for no reason" (29.5%) and conflicts motivated by arguments over "personal belongings" (24.0%) were most common for firearm-victimization. Male sex (AOR=5.14), Black race (AOR=2.75), a ED visit for assault (AOR=3.46), marijuana use before the conflict (AOR=2.02), and conflicts motivated by retaliation (AOR=4.57) or personal belongings (AOR=2.28) increased the odds that a conflict involved firearms. Alcohol (AOR=2.80), marijuana (AOR=1.63), and prescription drugs (AOR=4.06) had a higher association with conflict (vs. non-conflict) days among youth reporting firearm conflict. Overall, we found that firearm conflicts are differentially associated with substance use and violence motivations. Addressing substance use, interrupting the cycle of retaliatory violence, and developing conflict resolution strategies that address escalation over infringement on personal belongings may aid in decreasing and preventing adolescent firearm violence.

Two-Year Trajectories of Sexual Risk Behaviors Among Drug-Using Adolescents and Emerging Adults in an Urban Community.

Among 14-24 year-olds who used drugs and were recruited from an emergency department, we examined 2-year trajectories of sexual risk behaviors. We hypothesized that those in higher risk trajectories would have more severe substance use, mental health concerns, and dating violence involvement at baseline. Analyses identified three behavioral trajectories. Individuals in the highest risk trajectory had a more severe profile of baseline alcohol use, marijuana use, dating violence involvement, and mental health problems. Future research will examine longitudinal differences in risk factors across trajectories. Understanding risk factors for sexual risk behavior trajectories can inform the delivery and tailoring of prevention interventions.

Diversion of ADHD Stimulants and Victimization Among Adolescents.

OBJECTIVE: To examine whether a recent prescription for stimulant medication is associated with peer victimization among youth with attention deficit/hyperactivity disorder (ADHD). METHODS: Data from 4,965 adolescents attending five public schools who completed an annual web survey over 4 years were used to examine recent stimulant medication prescription and self-reported frequent victimization. RESULTS: Adolescents with ADHD and recent stimulant prescription reported more victimization than those without ADHD, but similar to adolescents with ADHD and no recent prescription. Adolescents with ADHD and past 12-month diversion of their prescribed stimulants were at greatest risk of 12-month frequent victimization compared with adolescents without ADHD and adolescents with ADHD but no recent prescription. Youth approached to divert reported more victimization than youth not approached. Youth who diverted reported more victimization than those who did not divert. CONCLUSIONS: Close parent-prescriber collaboration is needed to ensure effective medical treatment for ADHD without greater risk for victimization and treatment failure.

Substance Use Among Sexual Minority Collegiate Athletes: A National Study.

BACKGROUND: The empirical research examining substance use among sexual minority collegiate athletes is sparse. Problematically, this group may be at a greater risk of substance use due to their marginalized status within the context of sport. OBJECTIVES: We examined different types of substance use during the past 30 days, and diagnosis of substance use disorders during the past 12 months, among sexual minority collegiate athletes. METHODS: This study uses data from college students for the fall semester between 2008 and 2012 from the American College Health Association-National College Health Assessment. RESULTS: Sexual minority collegiate athletes had greater odds of past 30-day cigarette use, past 30-day alcohol use, past 30-day marijuana use, and indicating being diagnosed or treated for a substance use disorder during the past 12 months when compared to either heterosexual collegiate athletes or heterosexual nonathletes, but had similar odds on these outcomes when compared to sexual minority nonathletes. Sexual minority collegiate athletes also had greater odds of binge drinking during the past 2 weeks when compared to either heterosexual nonathletes or sexual minority nonathletes, but had similar odds on this outcome when compared to heterosexual collegiate athletes. Additional analyses by gender reveal that male sexual minority athletes are at the greatest risk of being diagnosed or treated for a substance use disorder. CONCLUSIONS: Possible explanations as to why sexual minority collegiate athletes (particularly males) may be at a greater risk of substance use disorders could include the difficulty of trying to maintain an athletic identity within a social environment that is traditionally homophobic.

Substance use and violence among youth: a daily calendar analysis.

BACKGROUND: While researchers have identified factors that contribute to youth violence, less is known about the details of violent incidents. In addition, substance use has been linked to youth violence; however, little is known about actual substance use on days in which violence occurs. OBJECTIVE: This study examined reasons for peer violence and the association between substance use and violence using daily calendar-based analyses among at-risk urban youth. METHODS: Data were collected from Emergency Department (ED) patients (ages 14-24; n = 599; 59% male, 65% African American) who screened positive for substance use in the past 6 months. Daily data regarding past 30-day substance use and violence and reasons for violent incidents were obtained via semi-structured interviews. Multi-level multinomial regression models were conducted to test the associations between substance use and peer violence incidents (i.e., none, moderate and severe). RESULTS: Conflict over 'personal belongings' was a common reason for violence among males; 'jealousy'/'rumors' were common reasons among females. Moderate victimization was more likely to be reported on days in which participants reported alcohol and cocaine use. Severe victimization was more likely to be reported on days in which participants reported alcohol use. Moderate or severe aggression was more likely to be reported on days in which participants reported alcohol and non-medical sedative use. CONCLUSIONS: RESULTS suggest that youth violence prevention that addresses differential reasons for violence among males and females as well as substance use would be beneficial.

Dating violence among male and female youth seeking emergency department care.

STUDY OBJECTIVE: We determine prevalence and correlates of dating violence, dating victimization, and dating aggression among male and female patients aged 14 to 20 years seeking emergency department (ED) care. METHODS: This was a systematic sampling of subjects aged 14 to 20 years seeking care at a single large academic ED between September 2010 and March 2013. Participants completed a computerized, self-administered, cross-sectional survey of demographics, dating violence from physical abuse measures of the Conflict in Adolescent Dating Relationships Inventory, associated behaviors, and ED health service use. Separate analyses were conducted for male and female patients. RESULTS: Four thousand three hundred eighty-nine youths (86.1% participation rate) were screened, and 4,089 (mean age 17.5 years; 58% female patients) were eligible for analysis. Almost 1 in 5 female patients (n=215; 18.4%) and 1 in 8 male patients (n=212; 12.5%) reported past-year dating violence. Of female patients, 10.6% reported dating victimization and 14.6% dating aggression, whereas of male patients, 11.7% reported dating victimization and 4.9% reported dating aggression. Multivariate analyses showed that variables associated with any male dating violence were black race (adjusted odds ratio [AOR] 2.26; 95% CI 1.54 to 3.32), alcohol misuse (AOR 1.03; 95% CI 1.00 to 1.06), illicit drug use (AOR 2.38; 95% CI 1.68 to 3.38), and depression (AOR 2.13; 95% CI 1.46 to 3.10); any female dating violence was associated with black race (AOR 1.68; 95% CI 1.25 to 2.25), public assistance (AOR 1.64; 95% CI 1.28 to 2.09), grades D and below (AOR 1.62; 95% CI 1.07 to 2.43), alcohol misuse (AOR 1.04; 95% CI 1.02 to 1.07), illicit drug use (AOR 2.85; 95% CI 2.22 to 3.66), depression (AOR 1.86; 95% CI 1.42 to 2.44), and any past year ED visit for intentional injury (AOR 2.64; 95% CI 1.30 to 5.40). CONCLUSION: Nearly 1 of 6 male and female patients aged 14 to 20 years and seeking ED care report recent dating violence, and health disparities remain among this population. Dating violence was strongly associated with alcohol, illicit drug use, and depression and correlated with previous ED service use among female youths. ED interventions should consider addressing these associated health conditions, as well as improving screening protocols to address dating violence among male and female youths.

Ag-organic layered samples for optoelectronic applications: interface width and roughening using a 500 eV Cs+ probe in dynamic secondary ion mass spectrometry.

The performance of organic optoelectronic devices depends a lot on interface structure and width. Dynamic secondary ion mass spectrometry (SIMS) has been widely used to investigate interfaces in classical semiconductor devices and limitations are quite well understood. For low-energy dynamic SIMS on organic optoelectronic devices, sputter-induced diffusion processes and roughness formation have only been investigated sparsely. In this work we use low-energy dynamic SIMS depth profiling on metal-organic multilayered model samples with compositions similar to organic optoelectronic devices to investigate limitations in the calculation of interface widths due to sputter-induced roughness formation. The samples consist of silver and organic compounds (e.g., tris(8-hydroxyquinolinato) aluminum (Alq(3)) and metal phthalocyanines) sequentially deposited by thermal evaporation in vacuum onto a Si substrate. They are analyzed by a 500 eV Cs(+) primary ion beam. Surface roughness at the SIMS crater bottoms is characterized by AFM as a function of crater depth. We find that the roughness in SIMS craters is limited to approximately 1.5 nm, which is much smaller than the interface width of the as-deposited interfaces. Thus, for the studied organic-inorganic interfaces, low-energy dynamic SIMS can yield accurate information about interface morphology, allowing the study of its dependence on sample preparation conditions and its implication on device properties.

In response to community violence: coping strategies and involuntary stress responses among Latino adolescents.

Among poor, urban adolescents, high rates of community violence are a pressing public health concern. This study relies on a contextual framework of stress and coping to investigate how coping strategies and involuntary stress responses may both mediate and moderate the relation between exposure to community violence and psychological well-being. Our sample consists of 223 ninth grade Latino adolescents from poor, urban families. In response to community violence, these adolescents reported using an array of coping strategies as well as experiencing a number of involuntary stress responses; the most frequent coping responses were turning to religion and seeking social support. Hierarchical regression analyses demonstrated that involuntary stress responses mediated the relations between both witnessing or being victimized by violence and poorer psychological functioning, while coping strategies moderated these relations. These findings suggest that the negative psychological effects of exposure to community violence may, in part, be explained by involuntary stress responses, while religious-based coping may serve as a protective factor.

Deep Brain Stimulation for Substance Use Disorders? An Exploratory Qualitative Study of Perspectives of People Currently in Treatment.

OBJECTIVE: Although previous studies have discussed the promise of deep brain stimulation (DBS) as a possible treatment for substance use disorders (SUDs) and collected researcher perspectives on possible ethical issues surrounding it, none have consulted people with SUDs themselves. We addressed this gap by interviewing people with SUDs. METHODS: Participants viewed a short video introducing DBS, followed by a 1.5-hour semistructured interview on their experiences with SUDs and their perspective on DBS as a possible treatment option. Interviews were analyzed by multiple coders who iteratively identified salient themes. RESULTS: We interviewed 20 people in 12-step-based, inpatient treatment programs (10 [50%] White/Caucasian, 7 Black/African American [35%], 2 Asian [10%], 1 Hispanic/Latino [5%], and 1 [5%] Alaska Native/American Indian; 9 women [45%], 11 men [55%]). Interviewees described a variety of barriers they currently faced through the course of their disease that mirrored barriers often associated with DBS (stigma, invasiveness, maintenance burdens, privacy risks) and thus made them more open to the possibility of DBS as a future treatment option. CONCLUSIONS: Individuals with SUDs gave relatively less weight to surgical risks and clinical burdens associated with DBS than previous surveys of provider attitudes anticipated. These differences derived largely from their experiences living with an often-fatal disease and encountering limitations of current treatment options. These findings support the study of DBS as a treatment option for SUDs, with extensive input from people with SUDs and advocates.

Nonpartner Violence Perpetration Among Emerging Adults: Associations With Polysubstance Use and Trait Mindfulness.

Objective: Violence is a leading cause of death among individuals ages 18-25, with alcohol misuse consistently linked with violence perpetration. However, the association between polysubstance use and violence perpetration is less clear, despite the frequency of use of alcohol with other drugs. Additionally, protective factors such as mindfulness that may reduce violence perpetration among emerging adults have been understudied. This cross-sectional study examined the association between substance use, trait mindfulness, and violence perpetration outside of romantic relationships, utilizing a compensatory model of resilience. Methods: Data were drawn from a sample of 665 emerging adults ages 18-25, recruited from an urban Emergency Department (68% men). Participants self-administered a computer survey that assessed non-partner violence perpetration (NPV), alcohol use, marijuana use, prescription drug misuse, and trait mindfulness. Fifteen percent reported non-partner violence perpetration over the past six months. Results: Multivariate logistic regression tested associations between violence perpetration, substance use, trait mindfulness, and demographic characteristics. Results showed that alcohol use alone (OR= 3.04), prescription opioid use alone (OR = 3.58), alcohol and marijuana use (OR = 3.75), and use of all three substances (OR= 7.78) were positively associated with violence perpetration. Post-hoc contrasts demonstrated the polysubstance use significantly increased risk over single substance use. Trait mindfulness (OR= 0.97) was negatively associated with violence perpetration after controlling for substance use. Conclusions: Findings suggest that polysubstance use may increase risk for violence. Interventions that address polysubstance use, potentially including mindfulness, could reduce non-partner violence perpetration among emerging adults and requires further study.

Association Between Clinician-Level Factors and Patient Outcomes in Virtual and In-Person Outpatient Treatment for Substance Use Disorders: Multilevel Analysis.

BACKGROUND: The use of virtual treatment services increased dramatically during the COVID-19 pandemic. Unfortunately, large-scale research on virtual treatment for substance use disorder (SUD), including factors that may influence outcomes, has not advanced with the rapidly changing landscape. OBJECTIVE: This study aims to evaluate the link between clinician-level factors and patient outcomes in populations receiving virtual and in-person intensive outpatient services. METHODS: Data came from patients (n=1410) treated in a virtual intensive outpatient program (VIOP) and an in-person intensive outpatient program (IOP), who were discharged between January 2020 and March 2021 from a national treatment organization. Patient data were nested by treatment providers (n=58) examining associations with no-shows and discharge with staff approval. Empathy, comfort with technology, perceived stress, resistance to change, and demographic covariates were examined at the clinician level. RESULTS: The VIOP (ß=-5.71; P=.03) and the personal distress subscale measure (ß=-6.31; P=.003) were negatively associated with the percentage of no-shows. The VIOP was positively associated with discharges with staff approval (odds ratio [OR] 2.38, 95% CI 1.50-3.76). Clinician scores on perspective taking (ß=-9.22; P=.02), personal distress (ß=-9.44; P=.02), and male clinician gender (ß=-6.43; P=.04) were negatively associated with in-person no-shows. Patient load was positively associated with discharge with staff approval (OR 1.04, 95% CI 1.02-1.06). CONCLUSIONS: Overall, patients in the VIOP had fewer no-shows and a higher rate of successful discharge. Few clinician-level characteristics were significantly associated with patient outcomes. Further research is necessary to understand the relationships among factors such as clinician gender, patient load, personal distress, and patient retention.

Epigenetic regulation of GABA catabolism in iPSC-derived neurons: The molecular links between FGF21 and histone methylation.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) analogs have been tested as potential therapeutics for substance use disorders. Prior research suggests that FGF21 administration might affect alcohol consumption and reward behaviors. Our recent report showed that plasma FGF21 levels were positively correlated with alcohol use in patients with alcohol use disorder (AUD). FGF21 has a short half-life (0.5-2 h) and crosses the blood-brain barrier. Therefore, we set out to identify molecular mechanisms for both the naïve form of FGF21 and a long-acting FGF21 molecule (PF-05231023) in induced pluripotent stem cell (iPSC)-derived forebrain neurons. METHODS: We performed RNA-seq in iPSC-derived forebrain neurons treated with naïve FGF21 or PF-05231023 at physiologically relevant concentrations. We obtained plasma levels of FGF21 and GABA from our previous AUD clinical trial (n = 442). We performed ELISA for FGF21 in both iPSC-derived forebrain neurons and forebrain organoids. We determined protein interactions using co-immunoprecipitation. Finally, we applied ChIP assays to confirm the occupancy of REST, EZH2 and H3K27me3 by FGF21 using iPSC-derived forebrain neurons with and without drug exposure. RESULTS: We identified 4701 and 1956 differentially expressed genes in response to naïve FGF21 or PF-05231023, respectively (FDR < 0.05). Notably, 974 differentially expressed genes overlapped between treatment with naïve FGF21 and PF-05231023. REST was the most important upstream regulator of differentially expressed genes. The GABAergic synapse pathway was the most significant pathway identified using the overlapping genes. We also observed a significant positive correlation between plasma FGF21 and GABA concentrations in AUD patients. In parallel, FGF21 and PF-05231023 significantly induced GABA levels in iPSC-derived neurons. Finally, functional genomics studies showed a drug-dependent occupancy of REST, EZH2, and H3K27me3 in the promoter regions of genes involved in GABA catabolism which resulted in transcriptional repression. CONCLUSIONS: Our results highlight a significant role in the epigenetic regulation of genes involved in GABA catabolism related to FGF21 action. (The ClinicalTrials.gov Identifier: NCT00662571).

Adaptive interventions for alcohol misuse and violent behaviors among adolescents and emerging adults in the emergency department: A sequential multiple assignment randomized controlled trial protocol.

Alcohol use and violent behaviors among youth are associated with morbidity and mortality. An emergency department (ED) visit provides an opportunity to initiate prevention efforts. Despite promising findings from our single session SafERteens brief intervention (BI), impact is limited by modest effect sizes, with data lacking on optimal boosters to enhance effects. This paper describes the protocol for a sequential, multiple assignment, randomized trial (SMART). Adolescents and emerging adults (ages 14-20) in the ED screening positive for alcohol use and violent behaviors (physical aggression) were randomly assigned to: 1) SafERteens BI + Text Messaging (TM), or 2) SafERteens BI + remote Health Coach (HC). Participants completed weekly surveys over 8 weeks after the ED visit to tailor intervention content and measure mechanisms of change. At one-month, intervention response/non-response is determined (e.g., binge drinking or violent behaviors). Responders are re-randomized to continued intervention condition (e.g., maintenance) or minimized condition (e.g., stepped down). Non-responders are re-randomized to continued condition (e.g., maintenance), or intensified condition (e.g., stepped up). Outcomes were measured at 4 and 8 months, including primary outcomes of alcohol consumption and violence, with secondary outcomes of alcohol consequences and violence consequences. Although the original goal was to enroll 700 participants, COVID-19 impacts on research diminished recruitment in this trial (enrolled n = 400). Nonetheless, the proposed SMART is highly innovative by blending real-time assessment methodologies with adaptive intervention delivery among teens with comorbid alcohol misuse and violent behaviors. Findings will inform the content and timing booster interventions to alter risk behavior trajectories. Trial Registration:ClinicalTrials.govNCT03344666. University of Michigan # HUM00109156.