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OBJECTIVE: Active patient involvement in promoting quality and safety is a priority for healthcare. We investigated how dental patients perceive their role as partners in promoting quality and safety across various dental care settings. METHODS: Focus group sessions were conducted at three dental practice settings: an academic dental center, a community dental clinic, and a large group private practice, from October 2018-July 2019. Patients were recruited through flyers or word-of-mouth invitations. Each session lasted 2.5 h and patients completed a demographic and informational survey at the beginning. Audio recordings were transcribed, and a hybrid thematic analysis was performed by two independent reviewers using Dedoose. RESULTS: Forty-seven participants took part in eight focus group sessions; 70.2% were females and 38.3% were aged 45-64 years. Results were organized into three major themes: patients overall perception of dental quality and safety; patients reaction to an adverse dental event; and patients role in promoting quality and safety. Dental patients were willing to participate in promoting quality and safety by careful provider selection, shared decision-making, self-advocacy, and providing post-treatment provider evaluations. Their reactions towards adverse dental events varied based on the type of dental practice setting. Some factors that influenced a patients overall perception of dental quality and safety included provider credentials, communication skills, cleanliness, and durability of dental treatment. CONCLUSION: The type of dental practice setting affected patients desire to work as partners in promoting dental quality and safety. Although patients acknowledged having an important role to play in their care, their willingness to participate depended on their relationship with their provider and their perception of provider receptivity to patient feedback.

BACKGROUND: Preventable medical errors in hospital settings are the third leading cause of deaths in the United States. However, less is known about harm that occurs in patients in outpatient settings, where the majority of care is delivered. We do not know the likelihood that a patient sitting in a dentist chair will experience harm. Additionally, we do not know if patients of certain race, age, sex, or socioeconomic status disproportionately experience iatrogenic harm. METHODS: We initiated the Dental Practice Study (DPS) with the aim of determining the frequency and types of adverse events (AEs) that occur in dentistry on the basis of retrospective chart audit. This article discusses the 6-month pilot phase of the DPS during which we explored the feasibility and efficiency of our multistaged review process to detect AEs. RESULTS: At sites 1, 2, and 3, respectively, 2 reviewers abstracted 21, 11, and 23 probable AEs, respectively, from the 100 patient charts audited per site. At site 2, a third reviewer audited the same 100 charts and found only 1 additional probable AE. Of the total 56 probable AEs (from 300 charts), the expert panel confirmed 9 AE cases. This equals 3 AEs per 100 patients per year. Patients who experienced an AE tended to be male and older and to have undergone more procedures within the study year. CONCLUSIONS: This article presents an overview of the DPS. It describes the methods used and summarizes the results of its pilot phase. To minimize threats to dental patient safety, a starting point is to understand their basic epidemiology, both in terms of their frequency and the extent to which they affect different populations.

Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen.

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule implicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring, -neutral, or -avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphorylated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug's reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA.

The tremendous diversity of Hymenoptera is commonly attributed to the evolution of parasitoidism in the last common ancestor of parasitoid sawflies (Orussidae) and wasp-waisted Hymenoptera (Apocrita). However, Apocrita and Orussidae differ dramatically in their species richness, indicating that the diversification of Apocrita was promoted by additional traits. These traits have remained elusive due to a paucity of sawfly genome sequences, in particular those of parasitoid sawflies. Here, we present comparative analyses of draft genomes of the primarily phytophagous sawfly Athalia rosae and the parasitoid sawfly Orussus abietinus. Our analyses revealed that the ancestral hymenopteran genome exhibited traits that were previously considered unique to eusocial Apocrita (e.g., low transposable element content and activity) and a wider gene repertoire than previously thought (e.g., genes for CO2 detection). Moreover, we discovered that Apocrita evolved a significantly larger array of odorant receptors than sawflies, which could be relevant to the remarkable diversification of Apocrita by enabling efficient detection and reliable identification of hosts.

Posttraumatic stress disorder (PTSD) and alcohol use disorder commonly co-occur. Little is known about how symptoms of one affect subsequent week symptoms of the other during the course of integrated treatment for both disorders. The sample included 107 veterans who were randomized to receive either Concurrent Treatment of PTSD and Substance Use Disorder Using Prolonged Exposure (COPE; an exposure-based trauma focused treatment) or Seeking Safety (SS; a present-focused coping skills-based treatment) and completed measures of PTSD and alcohol use at every other session. Multilevel models estimated the prospective associations between PTSD and alcohol use during treatment. Results indicated that greater PTSD symptom severity was associated with greater future alcohol use (b = 0.20, p = .024), and greater alcohol use was associated with greater future PTSD symptom severity (b = 0.13, p = .003). The effect size for PTSD symptoms to future alcohol use was larger than the reciprocal relationship. When using lagged PTSD severity to predict future drinking, results revealed that clinically significant differences in PTSD severity levels were associated with comparably large differences in drinking. Treatment condition did not moderate the effect of PTSD symptom severity on alcohol use (or the reciprocal relationship). Findings lend support to the mutual maintenance model of addiction. Integrated treatments that treat both PTSD and alcohol use may be preferential to sequential model of care where individuals are expected to achieve abstinence or reduced use prior to receiving trauma-focused treatment. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

ObjectivesAlcohol and cannabis remain the substances most widely used by adolescents. Better understanding of the dynamic relationship between trajectories of substance use in relation to neuropsychological functioning is needed. The aim of this study was to examine the different impacts of within- and between-person changes in alcohol and cannabis use on neuropsychological functioning over multiple time points.MethodsHierarchical linear modeling examined the effects of alcohol and cannabis use on neuropsychological functioning over the course of 14 years in a sample of 175 adolescents (aged 12-15 years at baseline).ResultsTime-specific fluctuations in alcohol use (within-person effect) predicted worse performance across time on the Wechsler Abbreviated Scale of Intelligence Block Design subtest (B = -.05, SE = .02, p = .01). Greater mean levels of percent days of cannabis use across time (between-person effect) were associated with an increased contrast score between Delis-Kaplan Executive Function System Color Word Inhibition and Color Naming conditions (B = .52, SE = .14, p < .0001) and poorer performance over time on Block Design (B = -.08, SE = .04, p = .03). Neither alcohol and/nor cannabis use over time was associated with performance in the verbal memory and processing speed domains.ConclusionsGreater cumulative cannabis use over adolescence may be linked to poorer inhibitory control and visuospatial functioning performance, whereas more proximal increases in alcohol consumption during adolescence may drive alcohol-related performance decrements in visuospatial functioning. Results from this prospective study add to the growing body of literature on the impact of alcohol and cannabis use on cognition from adolescent to young adulthood.

The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress, and glutamate transmission within this region has been implicated in the neurobiology of alcoholism. Herein, we used a combination of immunoblotting, neuropharmacological and transgenic procedures to investigate the role for metabotropic glutamate receptor 5 (mGlu5) signaling within the BNST in excessive drinking. We discovered that mGlu5 signaling in the BNST is linked to excessive alcohol consumption in a manner distinct from behavioral or neuropharmacological endophenotypes that have been previously implicated as triggers for heavy drinking. Our studies demonstrate that, in male mice, a history of chronic binge alcohol-drinking elevates BNST levels of the mGlu5-scaffolding protein Homer2 and activated extracellular signal-regulated kinase (ERK) in an adaptive response to limit alcohol consumption. Male and female transgenic mice expressing a point mutation of mGlu5 that cannot be phosphorylated by ERK exhibit excessive alcohol-drinking, despite greater behavioral signs of alcohol intoxication and reduced anxiety, and are insensitive to local manipulations of signaling in the BNST. These transgenic mice also show selective insensitivity to alcohol-aversion and increased novelty-seeking, which may be relevant to excessive drinking. Further, the insensitivity to alcohol-aversion exhibited by male mice can be mimicked by the local inhibition of ERK signaling within the BNST. Our findings elucidate a novel mGluR5-linked signaling state within BNST that plays a central and unanticipated role in excessive alcohol consumption.SIGNIFICANCE STATEMENT The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress and alcohol, and glutamate transmission within BNST is implicated in the neurobiology of alcoholism. The present study provides evidence that a history of excessive alcohol drinking increases signaling through the metabotropic glutamate receptor 5 (mGlu5) receptor within the BNST in an adaptive response to limit alcohol consumption. In particular, disruption of mGlu5 phosphorylation by extracellular signal-regulated kinase within this brain region induces excessive alcohol-drinking, which reflects a selective insensitivity to the aversive properties of alcohol intoxication. These data indicate that a specific signaling state of mGlu5 within BNST plays a central and unanticipated role in excessive alcohol consumption.

Recent studies suggest that closely related species can accumulate substantial genetic and phenotypic differences despite ongoing gene flow, thus challenging traditional ideas regarding the genetics of speciation. Baboons (genus Papio) are Old World monkeys consisting of six readily distinguishable species. Baboon species hybridize in the wild, and prior data imply a complex history of differentiation and introgression. We produced a reference genome assembly for the olive baboon (Papio anubis) and whole-genome sequence data for all six extant species. We document multiple episodes of admixture and introgression during the radiation of Papio baboons, thus demonstrating their value as a model of complex evolutionary divergence, hybridization, and reticulation. These results help inform our understanding of similar cases, including modern humans, Neanderthals, Denisovans, and other ancient hominins.

IntroductionAdults with alcohol dependence (AD) have exceptionally high smoking rates and poor smoking cessation outcomes. Discovery of factors that predict reduced smoking among AD smokers may help improve treatment. This study examined baseline predictors of smoking quantity among AD smokers in a pharmacotherapy trial for smoking cessation.MethodsThe sample includes male, AD smokers (N = 129) with 1-32 months of alcohol abstinence who participated in a 12-week trial of medication (topiramate vs. placebo) and adjunct counseling with 6 months of follow-up. Baseline measures of nicotine dependence, AD severity, psychopathology, motivation to quit smoking, and smoking-related cognitions were used to predict smoking quantity (cigarettes per day) at post-treatment and follow-up.ResultsOverall, the sample had statistically significant reductions in smoking quantity. Greater nicotine dependence (Incidence rate ratios (IRRs) = 0.82-0.90), motivation to quit (IRRs = 0.65-0.85), and intrinsic reasons for quitting (IRRs = 0.96-0.98) predicted fewer cigarettes/day. Conversely, greater lifetime AD severity (IRR = 1.02), depression severity (IRRs = 1.05-1.07), impulsivity (IRRs = 1.01-1.03), weight-control expectancies (IRRs = 1.10-1.15), and childhood sexual abuse (IRRs = 1.03-1.07) predicted more cigarettes/day.ConclusionsSmokers with AD can achieve large reductions in smoking quantity during treatment, and factors that predict smoking outcomes in the general population also predict greater smoking reductions in AD smokers. Treatment providers can use severity of nicotine dependence and AD, motivation to quit, smoking-related cognitions, and severity of depression to guide treatment and improve outcomes among AD smokers.

BackgroundPrevious studies have suggested that varenicline, an α4β2 nicotinic receptor partial agonist, and α7 nicotinic receptor full agonist, may be effective for the treatment of methamphetamine (MA) dependence due to dopaminergic effects, relief of glutamatergic and cognitive dysfunction, and activation of nicotinic cholinergic systems. This study aimed to determine if varenicline (1 mg BID) resulted in reduced methamphetamine use compared to placebo among treatment-seeking MA-dependent volunteers.MethodsTreatment-seeking MA-dependent volunteers were randomized to varenicline 1 mg twice daily (n = 27) or placebo (n = 25) and cognitive behavioral therapy for 9 weeks. The primary outcomes were the proportion of participants achieving end-of-treatment-abstinence (EOTA, MA-negative urine specimens during weeks 8 and 9) and the treatment effectiveness score (TES, number of MA-negative urine specimens) for varenicline versus placebo.ResultsThere was no significant difference in EOTA between varenicline (15%, 4/27) and placebo (20%, 5/25; p = 0.9). There was some suggestion that urinary confirmed medication compliance corresponded with EOTA in the varenicline condition, though it did not reach statistical significance, OR = 1.57 for a 100 ng/ml increase in urine varenicline, p = 0.10, 95% CI (0.99, 3.02). There was no significant difference in mean TES in the varenicline condition (8.6) compared to the placebo condition (8.1), and treatment condition was not a statistically significant predictor of TES, IRR = 1.01, p = 0.9, 95% CI (0.39, 2.70).ConclusionsThe results of this study indicate that 1 mg varenicline BID was not an effective treatment for MA dependence among treatment-seeking MA-dependent volunteers.

The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.

The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.

Substance use (SU) and sleep problems appear interrelated, but few studies have examined the influence of adolescent sleep patterns on development of SU disorders. This study prospectively examined the influence of sleep habits on subsequent SU in youth who later transitioned into heavy drinking. At time 1 (T1), participants (n = 95) were substance-naive 12- to 14-year-olds. Path-analytic models examined whether the effects of T1 risk factors (familial SU disorder, inhibition control, and externalizing and internalizing traits) on time 3 (M = 19.8 years old) tobacco, alcohol, and cannabis were mediated by time 2 (M = 15.1 years old) sleep chronotype, daytime sleepiness, and erratic sleep/wake behaviors. Significant direct path effects of T1 risk factors and time 2 sleep behaviors on time 3 SU were found, Ps

IntroductionAlcohol hangover experiences in young adulthood have been shown to predict more subsequent alcohol problems. Hangover susceptibility appears to be partially heritable and related to family history of alcohol use disorders. However, very little is known about the developmental course of these associations and whether they are accounted for by an individual's drinking history. The goal of this study is to investigate the prospective and unique relationships between family history of alcohol use disorders, severity of alcohol hangover experiences in adolescence, and later alcohol use and related problems measured over 13years.MethodsParticipants were first assessed on family history at age 12-14, prior to initiating drinking, and re-assessed annually on hangover severity, drinks per drinking day (DPDD), and alcohol-related problems throughout the 13-year follow-up period (n=205; 59% male).ResultsIn mixed effects negative binomial regression models, greater family history density scores predicted more future DPDD (Incidence Rate Ratio [IRR]=1.19, p=0.04), alcohol problems (IRR=1.64, p=0.05), and future hangover severity (IRR=1.24; p=0.01). In turn, greater hangover severity predicted more future DPDD (IRR=1.03; p=0.002) and alcohol problems (IRR=1.12, p

ObjectiveTo evaluate the temperature distribution among moderately preterm (MPT, 29-33 weeks) and extremely preterm (EPT, 37.5°C (4.2% vs 6.2%). For EPT infants in 2012-2013 compared with 2002-2003, the percentage of temperatures between 36.5°C and 37.5°C more than doubled and the percentage of temperatures >37.5°C more than tripled. Admission temperature was inversely associated with in-hospital mortality.ConclusionsLow and high admission temperatures are more frequent among EPT than MPT infants. Compared with a decade earlier, fewer EPT infants experience low admission temperatures but more have elevated temperatures. In spite of a change in distribution of NICU admission temperature, an inverse association between temperature and mortality risk persists.

BackgroundThe duplication of genes can occur through various mechanisms and is thought to make a major contribution to the evolutionary diversification of organisms. There is increasing evidence for a large-scale duplication of genes in some chelicerate lineages including two rounds of whole genome duplication (WGD) in horseshoe crabs. To investigate this further, we sequenced and analyzed the genome of the common house spider Parasteatoda tepidariorum.ResultsWe found pervasive duplication of both coding and non-coding genes in this spider, including two clusters of Hox genes. Analysis of synteny conservation across the P. tepidariorum genome suggests that there has been an ancient WGD in spiders. Comparison with the genomes of other chelicerates, including that of the newly sequenced bark scorpion Centruroides sculpturatus, suggests that this event occurred in the common ancestor of spiders and scorpions, and is probably independent of the WGDs in horseshoe crabs. Furthermore, characterization of the sequence and expression of the Hox paralogs in P. tepidariorum suggests that many have been subject to neo-functionalization and/or sub-functionalization since their duplication.ConclusionsOur results reveal that spiders and scorpions are likely the descendants of a polyploid ancestor that lived more than 450 MYA. Given the extensive morphological diversity and ecological adaptations found among these animals, rivaling those of vertebrates, our study of the ancient WGD event in Arachnopulmonata provides a new comparative platform to explore common and divergent evolutionary outcomes of polyploidization events across eukaryotes.

Background and aimsBuprenorphine-naloxone (BUP-NLX) can be used to manage prescription opioid addiction among persons with chronic pain, but post-treatment relapse is common and difficult to predict. This study estimated whether changes in pain over time and pain volatility during BUP-NLX maintenance would predict opioid use during the taper BUP-NLX taper.DesignSecondary analysis of a multi-site clinical trial for prescription opioid addiction, using data obtained during a 12-week BUP-NLX stabilization and 4-week BUP-NLX taper.SettingCommunity clinics affiliated with a national clinical trials network in 10 US cities.ParticipantsSubjects with chronic pain who entered the BUP-NLX taper phase (n = 125) with enrollment occurring from June 2006 to July 2009 (52% male, 88% Caucasian, 31% married).MeasurementsOutcomes were weekly biologically verified and self-reported opioid use from the 4-week taper phase. Predictors were estimates of baseline severity, rate of change and volatility in pain from weekly self-reports during the 12-week maintenance phase.FindingsControlling for baseline pain and treatment condition, increased pain [odds ratio (OR) = 2.38, P = 0.02] and greater pain volatility (OR = 2.43, P = 0.04) predicted greater odds of positive opioid urine screen during BUP-NLX taper. Increased pain (IRR = 1.40, P = 0.04) and greater pain volatility [incidence-rate ratio (IRR) = 1.66, P = 0.009] also predicted greater frequency of self-reported opioid use.ConclusionsAdults with chronic pain receiving out-patient treatment with buprenorphine-naloxone (BUP-NLX) for prescription opioid addiction have an elevated risk for opioid use when tapering off maintenance treatment. Those with relative persistence in pain over time and greater volatility in pain during treatment are less likely to sustain abstinence during BUP-NLX taper.

ObjectiveBabor's A/B typology characterizes alcohol-dependence subtypes, which differ across multiple defining variables; however, differences in cigarette smoking and cessation between these subtypes have not been previously investigated. Topiramate reduces heavy drinking and has separately been found to help non-alcohol-dependent individuals quit smoking. This study tested the hypothesis that topiramate's effects on smoking would be moderated by alcohol-dependence subtype, and explored craving as a mediator of this response.MethodOne hundred twenty-nine abstinent alcohol-dependent outpatient male smokers participated in this 12-week, randomized controlled trial comparing topiramate (maximum dosage 200 mg/day) with placebo, both with brief counseling, for smoking cessation. Participants were followed for 24 weeks following end of treatment.ResultsOf the 125 participants with sufficient subtyping data, k-means cluster analysis categorized 52 (42%) as Type A alcoholics and 73 (58%) as Type B. Types A and B did not differ on baseline smoking characteristics, urges to smoke, or smoking consequence scores. Longitudinal mixed-effects regression indicated that the effect of treatment on smoking was moderated by the Type × Time interaction. Specifically, during the nontreatment follow-up phase, Type B's treated with topiramate had relative suppressed levels of smoking compared with placebo-treated Type B's. This moderating effect of the Type × Time interaction was mediated by intention to smoke and craving related to relief of negative affect.ConclusionsType B alcoholics demonstrated suppressed levels of smoking in response to topiramate treatment as compared with placebo, but only during the nontreatment follow-up phase. This effect was mediated, in part, through intention to smoke and craving to smoke to relieve negative affect. Our findings extend other studies demonstrating a differential medication response by alcoholism subtype.

BackgroundAlcohol and nicotine dependence frequently co-occur, and quitting smoking might enhance long-term alcohol abstinence. Topiramate appears to help non-alcohol-dependent individuals quit smoking, and our pilot work suggested efficacy only in men. It also prevents relapse to alcohol in recently detoxified alcoholics. We evaluated topiramate in abstinent alcohol-dependent men to assess whether this medication (i) promotes smoking cessation and (ii) prevents alcohol and other drug relapse in the context of smoking cessation treatment.MethodsOne hundred and twenty-nine alcohol-abstinent (mean ~6 months) alcohol-dependent male smokers (80% with other substance use disorders) participated in this 12-week randomized, double blind, parallel group comparison of topiramate (up to 200 mg/d) and placebo with a 24-week nontreatment follow-up period. The study was carried out sequentially at 2 academic centers in the Midwest and Southern California between March 23, 2009 and November 20, 2014. All participants received manual-guided smoking cessation counseling combined with medication-focused compliance enhancement therapy. Randomization was block designed by the research pharmacist in a 1:1 ratio. Participants, investigators, and research personnel were masked to treatment assignment. The primary smoking end point was biochemically confirmed 4-week continuous abstinence from smoking during weeks 9 to 12, while the secondary end point was relapse to any drinking or drug use during the entire 36-week evaluation period. Logistic regression was used to determine the effects of topiramate on quitting smoking and alcohol relapse, controlling for relevant covariates. The trial is registered at ClinicalTrials.gov (number NCT00802412) and is now closed.ResultsOnly a small proportion (7.9%) of topiramate-treated participants were able to quit smoking, and this cessation rate was similar to placebo (10.6%; odds ratio = 1.60; 95% confidence interval 0.4, 6.5; p = 0.51). Roughly 30% of the sample had a documented relapse to drinking or drug use during the study, and these rates were similar in the topiramate (20/63; 31.8%) and placebo groups (18/66; 27.3%; p = 0.58). Results of a longitudinal logistic regression model examining time to any alcohol relapse revealed no medication effect.ConclusionsTopiramate at a daily dosage of up to 200 mg per day, combined with smoking cessation and medication adherence counseling, had no effects on smoking cessation or the prevention of alcohol or drug relapse in male smokers who were in early or sustained full remission from alcohol and motivated to make a quit attempt. Alternative approaches for treating this high-risk, dually dependent population are needed.

PurposeTo examine the associations between substance use and antisocial behavior trajectories and seven risky behaviors over time.MethodData were collected from a high-risk sample of adolescents followed into young adulthood. Five trajectory classes, identified based on dual development of substance use and antisocial behavior symptoms, were used to predict three risky driving and four risky sexual behaviors.ResultsIn this high-risk sample (n=530), participants reported notably high overall rates of reckless driving (55.5%) and unprotected sex under the influence (44.8%) in the past year. Risky behaviors that are typically of low base rates in population-based studies were also elevated, with 8.8% reporting past-year driving under the influence (DUI) charge, 17.6% reporting lifetime sexually transmitted infection (STI), and 10.4% reporting lifetime injection drug use. The Dual Chronic class had the highest levels of all seven risky behaviors, and were 3-4 times more likely to report risky driving, lifetime STI, and injection drug use than the Relatively Resolved class. Rates of past-year reckless driving and DUI were elevated among classes with persistent antisocial behavior, whereas rates of DUI, DUI charge, and unprotected sex under the influence were elevated among classes with persistent substance use.ConclusionsYoung adults with persistent co-occurring substance use and antisocial behavior engage in multiple very costly risky behaviors. Differential associations between risky behaviors and trajectory classes highlight the need for targeted interventions.

Adolescence is a period marked by increases in risk taking, sensation seeking, and emotion dysregulation. Neurobiological models of adolescent development propose that lagging development in brain regions associated with affect and behavior control compared to regions associated with reward and emotion processing may underlie these behavioral manifestations. Cross-sectional studies have identified several functional brain networks that may contribute to risk for substance use and psychopathology in adolescents. Determining brain structure measures that prospectively predict substance use and psychopathology could refine our understanding of the mechanisms that contribute to these problems, and lead to improved prevention efforts. Participants (N = 265) were healthy substance-naïve adolescents (ages 12-14) who underwent magnetic resonance imaging and then were followed annually for up to 13 years. Cortical thickness and surface area measures for three prefrontal regions (dorsolateral prefrontal cortex, inferior frontal gyrus, and orbitofrontal cortex) and three cortical regions from identified functional networks (anterior cingulate cortex, insular cortex, and parietal cortex) were used to predict subsequent binge drinking, externalizing symptoms, and internalizing symptoms. Thinner dorsolateral prefrontal cortex and inferior frontal cortex in early adolescence predicted more binge drinking and externalizing symptoms, respectively, in late adolescence (ps < .05). Having a family history of alcohol use disorder predicted more subsequent binge drinking and externalizing symptoms. Thinner parietal cortex, but not family history, predicted more subsequent internalizing symptoms (p < .05). This study emphasizes the temporal association between maturation of the salience, inhibition, and executive control networks in early adolescence and late adolescent behavior outcomes. Our findings indicate that developmental variations in these brain regions predate behavioral outcomes of substance use and psychopathology, and may therefore serve as prospective biomarkers of vulnerability.

BackgroundThe circulatory pathway for particles deposited outside of blood capillaries has not been well characterized for non-traditionally-delivered chemotherapeutics.Materials and methodsBlood and lymph pharmacokinetics of docetaxel (5 mg/kg) and carboplatin (14 and 28 mg/kg) following subcutaneous (s.c.) versus intravenous (i.v.) delivery were determined in a rodent model with catheterizations of both the thoracic lymphatic duct and jugular vein for prolonged synchronous blood and lymph sampling.ResultsSubcutaneous docetaxel demonstrates preferential lymphatic accumulation based on the area under the time-concentration curve (AUC0-24h) whereas i.v. docetaxel resulted in a greater plasma maximum concentration measured (Cmax). The apparent elimination half-life (t1/2) in lymph for docetaxel is greater following i.v. or s.c. delivery compared to t1/2 in blood. Carboplatin demonstrates a dose-dependent increase in plasma Cmax regardless of delivery route; the total carboplatin exposure over 24 h in lymph and plasma are comparable.ConclusionSubcutaneous docetaxel achieves lymphatic accumulation greater than that of i.v. delivery.

Iron is an essential micronutrient for healthy brain function and development. Because of the importance of iron in the brain, iron deficiency results in widespread and lasting effects on behavior and cognition. We measured iron in the basal ganglia of young children using a novel MRI method, quantitative susceptibility mapping, and examined the association of brain iron with age and cognitive performance. Participants were a community sample of 39 young children recruited from pediatric primary care who were participating in a 5-year longitudinal study of child brain development and anxiety disorders. The children were ages 7 to 11years old (mean age: 9.5years old) at the time of the quantitative susceptibility mapping scan. The differential abilities scale was administered when the children were 6years old to provide a measure of general intelligence and verbal (receptive and expressive), non-verbal, and spatial performance. Magnetic susceptibility values, which are linearly related to iron concentration in iron-rich areas, were extracted from regions of interest within iron-rich deep gray matter nuclei from the basal ganglia, including the caudate, putamen, substantia nigra, globus pallidus, and thalamus. Controlling for scan age, there was a significant positive association between iron in the basal ganglia and spatial IQ, with this effect being driven by iron in the right caudate We also replicated previous findings of a significant positive association between iron in the bilateral basal ganglia and age. Our finding of a positive association between spatial IQ and mean iron in the basal ganglia, and in the caudate specifically, suggests that iron content in specific regions of the iron-rich deep nuclei of the basal ganglia influences spatial intelligence. This provides a potential neurobiological mechanism linking deficits in spatial abilities reported in children who were severely iron deficient as infants to decreased iron within the caudate.

Despite numerous clinical trials no efficacious medications for methamphetamine (MA) have been identified. Neuroinflammation, which has a role in MA-related reward and neurodegeneration, is a novel MA pharmacotherapy target. Ibudilast inhibits activation of microglia and pro-inflammatory cytokines and has reduced MA self-administration in preclinical research. This study examined whether ibudilast would reduce subjective effects of MA in humans.Adult, non-treatment seeking, MA-dependent volunteers (N=11) received oral placebo, moderate ibudilast (40 mg), and high-dose ibudilast (100mg) via twice-daily dosing for 7 days each in an inpatient setting. Following infusions of saline, MA 15 mg, and MA 30 mg participants rated 12 subjective drug effects on a visual analog scale (VAS).As demonstrated by statistically-significant ibudilast × MA condition interactions (p

Major depressive disorder (MDD) is a prevalent and frequently comorbid psychiatric disorder. This study evaluates the development of depressive symptoms, MDD diagnosis, and suicidal ideation in a high-risk sample (N=524) diagnosed with conduct disorder (CD) and substance use disorder (SUD) symptoms as youth and re-assessed approximately 6.5 years later. Dual trajectory classes of both alcohol and other drug use (AOD) and antisocial behavior (ASB), previously identified using latent class growth analyses (LCGA), were used to predict depression outcomes. The Dual Chronic, Increasing AOD/Persistent ASB, and Decreasing Drugs/Persistent ASB classes had higher past-week depression scores, more past-year MDD symptoms, and were more likely to have past-year MDD than the Resolved class. The Dual Chronic and Decreasing Drugs/Persistent ASB classes also had more past-year MDD symptoms than the Persistent AOD/Adolescent ASB class. Youth at highest risk for developing or maintaining depression in adulthood had the common characteristic of persistent antisocial behavior. This suggests young adulthood depression is associated more with persistent antisocial behavior than with persistent substance use in comorbid youth. As such, interventions targeting high-risk youth, particularly those with persistent antisocial behavior, are needed to help reduce the risk of severe psychosocial consequences (including risk for suicide) in adulthood.

The combination of prescription opioid dependence and chronic pain is increasingly prevalent and hazardous to public health. Variability in pain may explain poor prescription opioid addiction treatment outcomes in persons with chronic pain. This study examined pain trajectories and pain volatility in patients with chronic pain receiving treatment for prescription opioid addiction. We conducted secondary analyses of adults with chronic pain (n = 149) who received buprenorphine/naloxone (BUP/NLX) and counseling for 12 weeks in an outpatient, multisite clinical trial. Good treatment outcome was defined as urine-verified abstinence from opioids at treatment endpoint (Week 12) and during at least 2 of the previous 3 weeks. Pain severity significantly declined over time during treatment (b = -0.36, p < .001). Patients with greater pain volatility were less likely to have a good treatment outcome (odds ratio = 0.55, p < .05), controlling for baseline pain severity and rate of change in pain over time. A 1 standard deviation increase in pain volatility was associated with a 44% reduction in the probability of endpoint abstinence. The significant reduction in subjective pain during treatment provides observational support for the analgesic effects of BUP/NLX in patients with chronic pain and opioid dependence. Patients with greater volatility in subjective pain during treatment have increased risk of returning to opioid use by the conclusion of an intensive treatment with BUP/NLX and counseling. Future research should examine underlying mechanisms of pain volatility and identify related therapeutic targets to optimize interventions for prescription opioid addiction and co-occurring chronic pain.

BackgroundResearch grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction.MethodsSecondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N=353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use.ResultsObtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR=1.30, p

AimsThis study explored whether the density of family history (FH) of substance use disorders relates to post-treatment substance use outcomes in adolescents, with the primary aim of determining whether FH exerts a relatively stronger influence on longer-term outcomes.MethodThe present investigation examined adolescents (ages 12-18, n=366) from two independent samples who were treated for alcohol/substance use disorder (ASUD) and re-assessed during the eight years following treatment with identical methodology. Primary substance use outcomes were assessed at 1, 2, 4, 6, and 8 years post-treatment and included total drinks, days using marijuana, and days using other drugs.ResultsIn hierarchical linear models there were significant FH density×linear time interactions for total drinks (z=12.75, p

BackgroundOral naltrexone is an efficacious medication for treatment of alcohol dependence, but small effect sizes and variability in outcomes suggest the presence of person-level moderators of naltrexone response. Identification of contextual or psychosocial moderators may assist in guiding clinical recommendations. Given the established importance of social networks in drinking outcomes, as well as the potential effects of naltrexone in reducing cue reactivity which may be especially important among those with more heavy drinkers and more alcohol cues in their networks, we examined pretreatment social network variables as potential moderators of naltrexone treatment effects in the COMBINE study.MethodsThe sample included all COMBINE study participants in medication conditions with full data on the Important People Inventory (IPI) and covariates at intake (N = 1,197). The intake IPI assessed whether participants had any frequent drinkers in their network and the average frequency of contact with these drinkers. The effects of treatment condition, pretreatment network variables, and their interactions on percent heavy drinking days were tested in hierarchical linear models, controlling for demographics and baseline clinical covariates.ResultsIn treatment conditions involving medical management and combined behavioral intervention (CBI), the effects of active naltrexone on heavy drinking were significantly greater for individuals with frequent drinkers in their network (z = -2.66, p

Proximal personal and environmental factors typically predict outcomes of treatment for alcohol or drug dependence (AODD), but longitudinal treatment studies have rarely examined these factors in adults with co-occurring psychiatric disorders. In adults with AODD and major depression, the aims of this study were to: (a) disaggregate person-and time-level components of network substance use and self-efficacy, (b) examine their prospective effects on posttreatment alcohol/drug use, and (c) examine whether residential environment moderated relations between these proximal factors and substance use outcomes. Veterans (N = 201) enrolled in a trial of group psychotherapy for AODD and independent MDD completed assessments every 3 months during 1 year of posttreatment follow-up. Outcome variables were percent days drinking (PDD) and using drugs (PDDRG). Proximal variables included abstinence self-efficacy and social network drinking and drug use. Self-efficacy and network substance use at the person-level prospectively predicted PDD (ps < .05) and PDDRG (ps < .05). Within-person, time-level effects of social networks predicted future PDD (ps < .05) but not PDDRG. Controlled environments moderated person-level social network effects (ps < .05), such that greater time in controlled settings attenuated the association between a heavier drinking/using network and posttreatment drinking and drug use. Both individual differences and time-specific fluctuations in proximal targets of psychosocial interventions are related to posttreatment substance use in adults with co-occurring AODD and MDD. More structured environmental settings appear to alleviate risk associated with social network substance use, and may be especially advised for those who have greater difficulty altering social networks during outpatient treatment.

Accurate gene model annotation of reference genomes is critical for making them useful. The modENCODE project has improved the D. melanogaster genome annotation by using deep and diverse high-throughput data. Since transcriptional activity that has been evolutionarily conserved is likely to have an advantageous function, we have performed large-scale interspecific comparisons to increase confidence in predicted annotations. To support comparative genomics, we filled in divergence gaps in the Drosophila phylogeny by generating draft genomes for eight new species. For comparative transcriptome analysis, we generated mRNA expression profiles on 81 samples from multiple tissues and developmental stages of 15 Drosophila species, and we performed cap analysis of gene expression in D. melanogaster and D. pseudoobscura. We also describe conservation of four distinct core promoter structures composed of combinations of elements at three positions. Overall, each type of genomic feature shows a characteristic divergence rate relative to neutral models, highlighting the value of multispecies alignment in annotating a target genome that should prove useful in the annotation of other high priority genomes, especially human and other mammalian genomes that are rich in noncoding sequences. We report that the vast majority of elements in the annotation are evolutionarily conserved, indicating that the annotation will be an important springboard for functional genetic testing by the Drosophila community.

ObjectiveNeurocognitive impairment has not consistently predicted substance use treatment outcomes but has been linked to proximal mediators of outcome. These indirect effects have not been examined in adults with substance dependence and co-occurring psychiatric disorders. We examined mediators and moderators of the effects of neurocognitive impairment on substance use among adults in treatment for alcohol or drug dependence and major depression (MDD).MethodParticipants were veterans (N = 197, mean age = 49.3 years, 90% male, 75% Caucasian) in a trial of 2 group interventions for alcohol/drug dependence and MDD. Measures examined here included intake neurocognitive assessments and percent days drinking (PDD), percent days using drugs (PDDRG), self-efficacy, 12-step affiliation, and depressive symptoms measured every 3 months from intake to the 18-month follow-up.ResultsGreater intake neurocognitive impairment predicted lower self-efficacy, lower 12-step affiliation, and greater depression severity, and these time-varying variables mediated the effects of impairment on future PDD and PDDRG. The prospective effects of 12-step affiliation on future PDD were greater for those with greater neurocognitive impairment. Impairment also interacted with depression to moderate the effects of 12-step affiliation and self-efficacy on PDD. Adults with greater impairment and currently severe depression had the strongest associations between 12-step affiliation/self-efficacy and future drinking.ConclusionsGreater neurocognitive impairment may lead to poorer outcomes from group therapy for alcohol/drug dependence and MDD due to compromised change in therapeutic processes. Distal factors such as neurocognitive impairment can interact with dynamic risk factors to modulate the association between therapeutic processes and future drinking outcomes.

Despite the fact that binge alcohol drinking (intake resulting in blood alcohol concentrations (BACs) 80 mg% within a 2-h period) is the most prevalent form of alcohol-use disorders (AUD), a large knowledge gap exists regarding how this form of AUD influences neural circuits mediating alcohol reinforcement. The present study employed integrative approaches to examine the functional relevance of binge drinking-induced changes in glutamate receptors, their associated scaffolding proteins and certain signaling molecules within the central nucleus of the amygdala (CeA). A 30-day history of binge alcohol drinking (for example, 4-5 g kg(-1) per 2 h(-1)) elevated CeA levels of mGluR1, GluN2B, Homer2a/b and phospholipase C (PLC) β3, without significantly altering protein expression within the adjacent basolateral amygdala. An intra-CeA infusion of mGluR1, mGluR5 and PLC inhibitors all dose-dependently reduced binge intake, without influencing sucrose drinking. The effects of co-infusing mGluR1 and PLC inhibitors were additive, whereas those of coinhibiting mGluR5 and PLC were not, indicating that the efficacy of mGluR1 blockade to lower binge intake involves a pathway independent of PLC activation. The efficacy of mGluR1, mGluR5 and PLC inhibitors to reduce binge intake depended upon intact Homer2 expression as revealed through neuropharmacological studies of Homer2 null mutant mice. Collectively, these data indicate binge alcohol-induced increases in Group1 mGluR signaling within the CeA as a neuroadaptation maintaining excessive alcohol intake, which may contribute to the propensity to binge drink.

Among substance-dependent individuals, comorbid major depressive disorder (MDD) is associated with greater severity and poorer treatment outcomes, but little research has examined mediators of posttreatment substance use outcomes within this population. Using latent growth curve models, the authors tested relationships between individual rates of change in 12-step involvement and substance use, utilizing posttreatment follow-up data from a trial of group Twelve-Step Facilitation (TSF) and integrated cognitive-behavioral therapy (ICBT) for veterans with substance dependence and MDD. Although TSF patients were higher on 12-step affiliation and meeting attendance at end-of-treatment as compared with ICBT, they also experienced significantly greater reductions in these variables during the year following treatment, ending at similar levels as ICBT. Veterans in TSF also had significantly greater increases in drinking frequency during follow-up, and this group difference was mediated by their greater reductions in 12-step affiliation and meeting attendance. Patients with comorbid depression appear to have difficulty sustaining high levels of 12-step involvement after the conclusion of formal 12-step interventions, which predicts poorer drinking outcomes over time. Modifications to TSF and other formal 12-step protocols or continued therapeutic contact may be necessary to sustain 12-step involvement and reduced drinking for patients with substance dependence and MDD.