The information capacity of adolescent alcohol consumption indicators along a continuum of severity: A cross-national comparison of sixteen Central and Eastern European countries

Background

Because there is high variability among European countries in prevalence levels of various alcohol consumption measures, the informational value of adolescent's alcohol consumption indicators is uncertain. The present study aimed to examine information capacity and measurement invariance of different alcohol consumption indicators in adolescents from countries of the former Soviet (Eastern) Bloc in Central and Eastern Europe (CEE).

Methods

Data were collected in 16 CEE countries, as part of the 2013/2014 wave of the Health Behavior in School-aged Children study. Data from adolescents (age 15) who reported having consumed alcohol at least once in their lifetime were analyzed. Four binary items selected for analysis measured the presence or absence of alcohol consumption in the last 30 days, lifetime drunkenness, weekly drinking frequency, and binge drinking on a typical occasion. Multiple group confirmatory factor analysis and item response theory analysis were used to examine the data.

Results

In most of the included countries, alcohol consumption in the last 30 days and lifetime drunkenness were indicative at lower severity levels, while binge drinking and weekly drinking frequency were informative at higher levels of alcohol use severity. A low proportion of the estimated intercepts and factor loadings were noninvariant, which indicated approximate cross-national invariance of these indicators.

Conclusions

Adolescent alcohol consumption indicators are informative for different severity levels and enable cross-nationally invariant measurement. However, different indicators suggested the presence of diverging drinking cultures in the CEE regions, with the highest discrimination capacity at the lower and higher ends of the continuum of alcohol use severity.

     

Age at First Alcohol Use as a Possible Risk Factor for Adolescent Acute Alcohol Intoxication Hospital Admission in the Netherlands

Background

The primary objective of this study is to determine whether age at first alcohol use is a determinant for adolescent acute alcohol intoxication characteristics, such as age at first acute alcohol intoxication and blood alcohol concentration (BAC) at hospital admission. Around the world, as in the Netherlands, a key aim of alcohol policy is to postpone the age at first alcohol use. This is based on cohort studies that indicate a relationship between a younger age at first alcohol use and subsequent adult alcohol use disorders.

Methods

This study was conducted using a cohort of data comprising individuals under 18 years of age. Data were collected between 2007 and 2017 by the Dutch Pediatric Surveillance System (NSCK) in order to monitor trends in admissions for acute alcohol intoxication. Multivariate linear regression analyses were used to determine the association between age at first alcohol use and acute alcohol intoxication characteristics, such as age at first acute alcohol intoxication and BAC at admission.

Results

This study indicates that among adolescents admitted for acute alcohol intoxication, adolescents who started drinking at ≤ 14 years of age are significantly more often female, lower educated, and raised in nontraditional family structures than adolescents who started drinking between 15 and 18 years of age. Multiple linear regression analyses indicated that age at first alcohol use, corrected for covariates, significantly predicted the age at acute alcohol intoxication and BAC at admission. The association between age at first alcohol use and age at intoxication was also found to be clinically relevant.

Conclusions

Although causation cannot be implied based on the results of these analyses, the results of this study suggest that interventions delaying the age at first alcohol use could be successful in increasing the average age that adolescents are admitted to the hospital for acute alcohol intoxication.

     

Is talk cheap? Correspondence between self-attributions about changes in drinking and longitudinal changes in drinking during the 2019 coronavirus pandemic

Background

There are concerns that the coronavirus disease 2019 (COVID-19) pandemic may increase drinking, but most accounts to date are cross-sectional studies of self-attributions about alcohol-related impacts and the accuracy of those perceptions has not been investigated. The current study examined the correspondence between self-attributions of pandemic-related changes in drinking and longitudinally-measured changes in drinking and alcohol-related consequences in a sample of emerging adults.

Methods

In an existing ongoing longitudinal study on alcohol misuse (≥1 heavy episodic drinking day/month) in emerging adults, 473 individuals (M_age = 23.8; 41.7% male) received a supplemental assessment from June 17th to July 1st, 2020, during public health restrictions in Ontario, Canada. These intrapandemic data were matched to the most recent assessment prior to the pandemic (~8 months earlier). Self-attributions about changes in drinking were assessed globally (i.e., increases/decreases/no change) and with higher resolution questions clarifying the magnitude of changes.

Results

Global self-attributions about changes in drinking substantively paralleled longitudinal changes in weekly drinking days (DD). In the longitudinal data, individuals’ who self-reported increases in drinking exhibited significant increases; individuals’ who self-reported decreases exhibited significant decreases; and individuals who self-reported no change exhibited nonsignificant changes. Higher resolution items likewise revealed longitudinal patterns of weekly drinking that were substantively consistent with self-attributions. Heavy DD and alcohol-related consequences exhibited similar patterns, but only individuals who self-reported large increases in drinking exhibited increases on these outcomes. Individuals who reported large increases in drinking also exhibited significant increases in depression and posttraumatic stress disorder symptoms.

Conclusions

Self-attributions about drinking closely corresponded to longitudinal changes in drinking, supporting the validity of self-attributions in population-level surveys, particularly in young adults. Notably, a subgroup was identified that exhibited pronounced increases for all alcohol-related outcomes and concurrent increases in internalizing psychopathology.

     

Longitudinal assessment of drinking changes during the pandemic: The 2021 COVID-19 follow-up study to the 2019 to 2020 National Alcohol Survey

Background

Surveys of changes in drinking during the COVID-19 pandemic have primarily relied on retrospective self-report. Further, most such surveys have not included detailed measures of alcohol use patterns, such as beverage-specific consumption, nor measures of alcohol use disorder (AUD) symptoms that would allow a comprehensive understanding of changes in alcohol use.

Methods

Data from 1819 completed interviews from the N14C follow-up survey to the 2019 to 2020 National Alcohol Survey (N14) were conducted between January 30 and March 28, 2021. Questions on alcohol use from the Graduated Frequency series, beverage-specific quantity and frequency, and DSM-5 AUD items were asked in both surveys and used to estimate changes from pre-pandemic drinking to drinking during the pandemic. Analyses focus on changes in these measures over time and comparisons between key subgroups defined by gender, race/ethnicity, and age.

Results

Key findings include particularly large increases in drinking and AUD for African Americans and women, reduced drinking and heavy drinking prevalence among men and White respondents, and a concentration of increased drinking and AUD among respondents aged 35 to 49. Increases in alcohol use were found to be driven particularly by increases in drinking frequency and the consumption of spirits.

Conclusions

Results confirm prior findings of overall increases and subgroup-specific changes, and importantly, provide detailed information on the patterns of change across major socio-demographic subgroups. Substantial increases in the prevalence of DSM-5 moderate to severe AUDs are a novel finding that is of particular concern.

     

Association of Prenatal Alcohol Exposure and Offspring Depression: A Negative Control Analysis of Maternal and Partner Consumption

Background

Previous research has suggested that intrauterine alcohol exposure is associated with a variety of adverse outcomes in offspring. However, few studies have investigated its association with offspring internalizing disorders in late adolescence.

Methods

Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we investigated the associations of maternal drinking in pregnancy with offspring depression at age 18 and 24 (n = 13,480). We also examined partner drinking as a negative control for intrauterine exposure for comparison.

Results

Offspring of mothers that consumed any alcohol at 18 weeks gestation were at increased risk of having a diagnosis of depression (fully adjusted model: OR 1.17, 95% CI 1.02 to 1.34), but there was no clear evidence of association between partners’ alcohol consumption at 18 weeks gestation during pregnancy and increased risk of offspring depression (fully adjusted model: OR 0.87, 95% CI 0.74 to 1.01). Postestimation tests found a positive difference between the association of maternal and partner alcohol use on offspring depression, showing a stronger association for maternal compared with partner alcohol use (OR 1.41, CI 1.07 to 1.84).

Conclusions

Maternal drinking in pregnancy was associated with increased risk of offspring depression at age 18. Residual confounding may explain this association, but the negative control comparison of paternal drinking provides some evidence that it may be causal, and this warrants further investigation.

     

COVID-19 impacts on drinking and mental health in emerging adults: Longitudinal changes and moderation by economic disruption and sex

Background

There are significant concerns that the COVID-19 pandemic may have negative effects on substance use and mental health, but most studies to date are cross-sectional. In a sample of emerging adults, over a two-week period during the pandemic, the current study examined: (1) changes in drinking-related outcomes, depression, anxiety, and posttraumatic stress disorder and (2) differences in changes by sex and income loss. The intra-pandemic measures were compared to pre-pandemic measures.

Methods

Participants were 473 emerging adults (M_age = 23.84; 41.7% male) in an existing longitudinal study on alcohol misuse who were assessed from June 17 to July 1, 2020, during acute public health restrictions in Ontario, Canada. These intra-pandemic data were matched to participant pre-pandemic reports, collected an average of 5 months earlier. Assessments included validated measures of drinking, alcohol-related consequences, and mental health indicators.

Results

Longitudinal analyses revealed significant decreases in heavy drinking and adverse alcohol consequences, with no moderation by sex or income loss, but with substantial heterogeneity in changes. Significant increases in continuous measures of depression and anxiety were present, both of which were moderated by sex. Females reported significantly larger increases in depression and anxiety. Income loss >50% was significantly associated with increases in depression.

Conclusions

During the initial phase of the pandemic, reductions in heavy drinking and alcohol consequences were present in this sample of emerging adults, perhaps due to restrictions on socializing. In contrast, there was an increase in internalizing symptoms , especially in females, highlighting disparities in the mental health impacts of the pandemic.

     

Changes in Alcohol Use and Drinking Context due to the COVID-19 Pandemic: A Multimethod Study of College Student Drinkers

Background

In spring 2020, U.S. universities closed campuses to limit the transmission of COVID-19, resulting in an abrupt change in residence, reductions in social interaction, and in many cases, movement away from a heavy drinking culture. The present mixed-methods study explores COVID-19-related changes in college student drinking. We characterize concomitant changes in social and location drinking contexts and describe reasons attributed to changes in drinking.

Methods

We conducted two studies of the impact of the COVID-19 pandemic on drinking behavior, drinking context, and reasons for both increases and decreases in consumption among college students. Study 1 (qualitative) included 18 heavy-drinking college students (M_age = 20.2; 56% female) who completed semi-structured interviews. Study 2 (quantitative) included 312 current and former college students who reported use of alcohol and cannabis (M_age = 21.3; 62% female) and who completed an online survey.

Results

In both studies, COVID-19-related increases in drinking frequency were accompanied by decreases in quantity, heavy drinking, and drunkenness. Yet, in Study 2, although heavier drinkers reduced their drinking, among non-heavy drinkers several indices of consumption increased or remained stable . Both studies also provided evidence of reductions in social drinking with friends and roommates and at parties and increased drinking with family. Participants confirmed that their drinking decreased due to reduced social opportunities and/or settings, limited access to alcohol, and reasons related to health and self-discipline. Increases were attributed to greater opportunity (more time) and boredom and to a lesser extent, lower perceived risk of harm and to cope with distress.

Conclusion

This study documents COVID-19-related changes in drinking among college student drinkers that were attributable to changes in context, particularly a shift away from heavy drinking with peers to lighter drinking with family. Given the continued threat of COVID-19, it is imperative for researchers, administrators, and parents to understand these trends as they may have lasting effects on college student drinking behaviors.

     

Multifactorial Genetic and Environmental Hedgehog Pathway Disruption Sensitizes Embryos to Alcohol-Induced Craniofacial Defects

Background

Prenatal alcohol exposure (PAE) is perhaps the most common environmental cause of human birth defects. These exposures cause a range of structural and neurological defects, including facial dysmorphologies, collectively known as fetal alcohol spectrum disorders (FASD). While PAE causes FASD, phenotypic outcomes vary widely. It is thought that multifactorial genetic and environmental interactions modify the effects of PAE. However, little is known of the nature of these modifiers. Disruption of the Hedgehog (Hh) signaling pathway has been suggested as a modifier of ethanol teratogenicity. In addition to regulating the morphogenesis of craniofacial tissues commonly disrupted in FASD, a core member of the Hh pathway, Smoothened, is susceptible to modulation by structurally diverse chemicals. These include environmentally prevalent teratogens like piperonyl butoxide (PBO), a synergist found in thousands of pesticide formulations.

Methods

Here, we characterize multifactorial genetic and environmental interactions using a zebrafish model of craniofacial development.

Results

We show that loss of a single allele of shha sensitized embryos to both alcohol- and PBO-induced facial defects. Co-exposure of PBO and alcohol synergized to cause more frequent and severe defects. The effects of this co-exposure were even more profound in the genetically susceptible shha heterozygotes.

Conclusions

Together, these findings shed light on the multifactorial basis of alcohol-induced craniofacial defects. In addition to further implicating genetic disruption of the Hh pathway in alcohol teratogenicity, our findings suggest that co-exposure to environmental chemicals that perturb Hh signaling may be important variables in FASD and related craniofacial disorders.

     

Phosphatidylethanol as Blood Biomarker of Alcohol Consumption in Early Pregnancy: An Observational Study in 4,067 Pregnant Women

Background

The teratogenic effects of alcohol are well documented, but there is a lack of screening methods to detect alcohol use during pregnancy. Phosphatidylethanol 16:0/18:1 (PEth) is a specific and sensitive biomarker reflecting alcohol intake up to several weeks after consumption. The aim of this study was to investigate the prevalence of positive PEth values as an indicator of early prenatal alcohol exposure in a general population of pregnant women.

Methods

Rhesus typing is routinely performed in Norway in all pregnancies around gestational week 12. Rhesus-negative women have an additional test taken around week 24. Blood samples submitted to St. Olav University Hospital in Trøndelag, Norway, for Rhesus typing during the period September 2017 to October 2018 were collected. A total of 4,533 whole blood samples from 4,067 women were analyzed for PEth (limit of quantification of 0.003 µM).

Results

Fifty-eight women had a positive PEth sample. Of these, 50 women were positive around gestational week 12, 3 women were positive around week 24, and in 5 cases, the timing was unknown. There were no significant differences in proportions of women with positive PEth values related to age, or rural versus urban residency.

Conclusion

In an unselected pregnant population in Norway, 1.4% had a positive PEth sample around gestational week 12, whereas 0.4% had a positive sample around week 24. The use of PEth as an alcohol biomarker should be further investigated as a diagnostic tool in the antenatal setting.

     

Effects of prenatal alcohol and delta-9-tetrahydrocannabinol exposure via electronic cigarettes on motor development

Background

Prenatal alcohol exposure can lead to a wide range of neurological and behavioral deficits, including alterations in motor domains. However, much less is known about the effects of prenatal cannabis exposure on motor development, despite cannabis being the most consumed illicit drug among women. Cannabis use among pregnant women has become increasingly popular given the widespread perception that consumption is safe during pregnancy. Moreover, alcohol and cannabis are commonly used together, even among pregnant women. Yet few studies have explored the potential consequences of combined prenatal exposure on behavioral domains.

Methods

Using our previously established model, during gestational days 5 to 20, four groups of pregnant Sprague–Dawley rats were exposed to vaporized alcohol, delta-9-Tetrahydrocannabinol (THC) via electronic (e-) cigarettes, the combination of alcohol and THC, or a vehicle. Following birth, offspring were tested on early sensorimotor development, adolescent motor coordination, and adolescent activity levels.

Results

Prenatal THC e-cigarette exposure delayed sensorimotor development early in life and impaired motor coordination later in early adolescence; combined prenatal alcohol and THC exposure did not have additive effects on sensorimotor development. However, combined prenatal exposure produced hyperactivity among male offspring.

Conclusions

Prenatal cannabis exposure may lead to impaired motor skills throughout early development and combined exposure with alcohol during gestation may lead to hyperactivity in early adolescence. These findings have important implications for informing pregnant women of the risks to the fetus associated with prenatal cannabis exposure, with and without alcohol, and could influence public policy.

     

Stigmatization of people with alcohol use disorders: An updated systematic review of population studies

Background

We summarize research on the public stigmatization of persons with alcohol use disorder (AUD) in comparison with other mental health conditions and embed the results into a conceptual framework of the stigma process.

Methods

We conducted a systematic search using Embase, MEDLINE, PubMed and PsycINFO (via Ovid), and Web of Science for population-based studies on the public stigma in AUD and at least 1 other mental health condition, published between October 1, 2010 and December 20, 2020, thus including all studies published since the last systematic review on this topic. The study is registered with PROSPERO (registration number: CRD42020173054).

Results

We identified 20,561 records, of which 24 met the inclusion criteria, reporting results from 16 unique studies conducted in 9 different countries. Compared to substance-unrelated mental disorders, persons with AUD were generally less likely to be considered mentally ill, while they were perceived as being more dangerous and responsible for their condition. Further, the public desire for social distance was consistently higher for people with AUD. We found no consistent differences in the public stigma toward persons with AUD in comparison with other substance use disorders.

Conclusion

The stigmatization of persons with AUD remains comparatively high and is distinct from that of other substance-unrelated disorders.

     

Estimated Prevalence of Harmful Alcohol Consumption in Pregnant and Nonpregnant Women in Saxony-Anhalt (NorthEast Germany) Using Biomarkers

Background

Alcohol consumption is commonly accepted in Western societies and is a known risk factor in pregnancy, which could lead to fetal alcohol spectrum disorders (FASDs). Prevalence of alcohol consumption during pregnancy is mostly unknown. Prevalence estimates in publications based on questionnaires are limited by possible underreporting due to social stigmatization. The aim of this study was to estimate the prevalence of harmful alcohol consumption in a large cohort of pregnant women using different biomarkers related to alcohol consumption and compare the findings with those of non-pregnant women

Methods

Routine parameters known to be influenced by alcohol consumption (γ-glutamyltransferase, GGT; carbohydrate-deficient transferrin, CDT/%CDT; mean corpuscular/cell volume, MCV; combined parameter of GGT and %CDT, GGT-CDT) were analyzed in serum samples of 2,182 pregnant women and 743 non-pregnant, age-matched females. Data were tested for (i) differences between pregnant and non-pregnant women and (ii) changes across the 3 trimesters of pregnancy.

Results

Prevalence rates differ greatly according to the parameter and cutoff, which reflects the limitations of assessing alcohol consumption with biomarkers. The prevalence of harmful alcohol consumption on the basis of a single or several elevated parameters was 13.8% (95% CI: 12.4 to 15.2) in pregnant women and 18.6% (95% CI: 15.8 to 21.4) in non-pregnant women, though 85.0% of the elevated measurements were attributable to an isolated elevation in %CDT only. Using GGT-CDT as the parameter with the highest specificity according to the literature, the estimated prevalence of harmful alcohol consumption in pregnancy is 0.5% (95% CI: 0.2 to 0.7).

Conclusion

Estimated prevalence rates differ greatly with respect to the biomarkers and cutoffs used. The use of CDT/%CDT alone appears to overestimate harmful alcohol consumption during pregnancy.

     

Emotion differentiation in early recovery from alcohol use disorder: Associations with in-the-moment affect and 3-month drinking outcomes

Background

Early recovery from alcohol use disorder (AUD) is commonly associated with high levels of negative affect, stress, and emotional vulnerability, which confer significant relapse risk. Emotion differentiation—the ability to distinguish between discrete emotions—has been shown to predict relapse after treatment for a drug use disorder, but this relationship has not been explored in individuals recovering from AUD.

Methods

The current study used thrice daily random and up to thrice daily self-initiated ecological momentary assessment surveys (N = 42, observations = 915) to examine whether 1) moments of high affective arousal are characterized by momentary differences in emotion differentiation among individuals in the first year of a current AUD recovery attempt, and 2) individuals’ average emotion differentiation would predict subsequent alcohol use measured by the timeline follow-back over a 3-month follow-up period.

Results

Multilevel models showed that moments (Level 1) of higher-than-average negative affect (p < 0.001) and/or stress (p = 0.033) were characterized by less negative emotion differentiation, while moments of higher-than-average positive affect were characterized by greater positive emotion differentiation (p < 0.001). At the between-person level (Level 2), participants with higher stress overall had lower negative emotion differentiation (p = 0.009). Linear regression showed that average negative, but not positive, emotion differentiation was inversely associated with percent drinking days over the subsequent 3-month follow-up period (p = 0.042). Neither form of average emotion differentiation was associated with drinking quantity.

Conclusions

We found that for individuals in early AUD recovery, affective states are associated with acute shifts in the capacity for emotion differentiation. Further, we found that average negative emotion differentiation prospectively predicts subsequent alcohol use.

     

Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy

Background

There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no “spontaneous improvement” prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD.

Methods

We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis.

Results

Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months).

Conclusions

Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.

     

Resting state functional connectivity as a predictor of brief intervention response in adults with alcohol use disorder: A preliminary study

Background

Brief interventions for alcohol use disorder (AUD) are generally efficacious, albeit with variability in response. Resting state functional connectivity (rsFC) may characterize neurobiological indicators that predict the response to brief interventions and is the focus of the current investigation.

Materials and Methods

Forty-six individuals with AUD (65.2% female) completed a resting state functional magnetic resonance imaging (fMRI) scan immediately followed by a brief intervention aimed at reducing alcohol consumption. Positive clinical response was defined as a reduction in alcohol consumption by at least one World Health Organization (WHO) risk drinking level at 3-month follow-up. rsFC was analyzed using seed-to-voxel analysis with seed regions from four networks: salience network, reward network, frontoparietal network, and default mode network.

Results

At baseline, responders had greater rsFC between the following seed regions in relation to voxel-based clusters than non-responders: (i) anterior cingulate cortex (ACC) in relation to left postcentral gyrus and right supramarginal gyrus (salience network); (ii) right posterior parietal cortex in relation to right ventral ACC (salience network); (iii) right interior frontal gyrus (IFG) pars opercularis in relation to right cerebellum and right occipital fusiform gyrus (frontoparietal); and (iv) right primary motor cortex in relation to left thalamus (default mode). Lower rsFC in responders vs. nonresponders was seen between the (i) right rostral prefrontal cortex in relation to left IFG pars triangularis (frontoparietal); (ii) right IFG pars triangularis in relation to right cerebellum (frontoparietal); (iii) right IFG pars triangularis in relation to right frontal eye fields and right angular gyrus (frontoparietal); and (iv) right nucleus accumbens in relation to right orbital frontal cortex and right insula (reward).

Conclusions

Resting state functional connectivity in the frontoparietal, salience, and reward networks predicts the response to a brief intervention in individuals with AUD and could reflect greater receptivity or motivation for behavior change.

     

Prevalence of fetal alcohol spectrum disorder in Greater Manchester,UK: An active case ascertainment study

Background

Despite high levels of prenatal alcohol exposure in the UK, evidence on the prevalence of fetal alcohol spectrum disorders (FASD) is lacking. This paper reports on FASD prevalence in a small sample of children in primary school.

Methods

A 2-phase active case ascertainment study was conducted in 3 mainstream primary schools in Greater Manchester, UK. Schools were located in areas that ranged from relatively deprived to relatively affluent. Initial screening of children aged 8–9 years used prespecified criteria for elevated FASD risk (small for age; special educational needs; currently/previously in care; significant social/emotional/mental health symptoms). Screen-positive children were invited for detailed ascertainment of FASD using gold standard measures that included medical history, facial dysmorphology, neurological impairment, executive function, and behavioral difficulties.

Results

Of 220 eligible children, 50 (23%) screened positive and 12% (26/220) proceeded to Phase 2 assessment. Twenty had a developmental disorder, of whom 4 had FASD and 4 were assessed as possible FASD. The crude prevalence rate of FASD in these schools was 1.8% (95% CI: 1.0%, 3.4%) and when including possible cases was 3.6% (2.1%, 6.3%). None of these children had previously been identified with a developmental diagnosis.

Conclusions

FASD was found to be common in these schools and most of these children's needs had not previously been identified. A larger, more definitive study that uses a random sampling technique stratified by deprivation level to select schools is needed to make inferences regarding the population prevalence of FASD.

     

2-Arachidonoylglycerol-mediated endocannabinoid signaling modulates mechanical hypersensitivity associated with alcohol withdrawal in mice

Background

Alcohol use disorder (AUD) commonly occurs in patients with chronic pain, and a major barrier to achieving abstinence and preventing relapse is the emergence of hyperalgesia during alcohol withdrawal. Elucidating novel therapeutic approaches to target hyperalgesia associated with alcohol withdrawal could have important implications for treating AUD. Here, we examined the role of 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid (eCB) signaling in the regulation of hyperalgesia associated with alcohol withdrawal in mice. We tested the hypothesis that pharmacological augmentation of 2-AG signaling could reduce hyperalgesia during withdrawal.

Methods

Male and female C57BL/6J mice were tested during withdrawal from a continuous access two-bottle choice (2BC) paradigm to investigate how eCB signaling modulates mechanical and thermal sensitivity during withdrawal. Mice were pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184 to elevate levels of 2-AG. Rimonabant or AM630 were given to block CB₁ and CB₂ receptor activity, respectively. DO34 was given to reduce 2-AG by inhibiting the 2-AG synthetic enzyme diacylglycerol lipase (DAGL).

Results

After 72 h of withdrawal, male and female mice exhibited increased mechanical, but not thermal, hypersensitivity, which normalized by 7 days. This effect was reversed by pretreatment with JZL184. The effects of JZL184 were prevented by coadministration of either the CB₁ or the CB₂ antagonist. DO34, Rimonabant, and AM630 exacerbated mechanical hypersensitivity during alcohol withdrawal, causing an earlier onset and persistent hypersensitivity even 1 week into withdrawal.

Conclusions

Our findings demonstrate the critical role of 2-AG signaling in the bidirectional regulation of mechanical sensitivity during alcohol withdrawal, with enhancement of 2-AG levels reducing sensitivity, and inhibition of 2-AG signaling exacerbating sensitivity. These data suggest that 2-AG augmentation represents a novel approach to the treatment of alcohol withdrawal-associated hyperalgesia and AUD in patients with comorbid pain disorders.

     

Novel Ethanol-Sensitive Mutants Identified in an F3 Forward Genetic Screen

Background

Fetal alcohol spectrum disorders (FASD) collectively refer to all deleterious outcomes due to prenatal alcohol exposures. Alterations to the face are common phenotypes in FASD. While alcohol exposure is the underlying cause of FASD, many variables modify the outcomes of such exposures. Genetic risk is one such variable, yet we still have a limited understanding of the nature of the genetic loci mediating susceptibility to FASD.

Methods

We employed ENU-based random mutagenesis in zebrafish to identify mutations that enhanced the teratogenicity of ethanol (EtOH). F3 embryos obtained from 126 inbred F2 families were exposed to 1% EtOH in the medium (approximately 41 mM tissue levels). Zebrafish stained with Alcian Blue and Alizarin Red were screened for qualitative alterations to the craniofacial skeleton between 4 and 7 days postfertilization (dpf).

Results

In all, we recovered 6 EtOH-sensitive mutants, 5 from the genetic screen itself and one as a background mutation in one of our wild-type lines. Each mutant has a unique EtOH-induced phenotype relative to the other mutant lines. All but 1 mutation appears to be recessive in nature, and only 1 mutant, au29, has apparent craniofacial defects in the absence of EtOH. To validate the genetic screen, we genetically mapped au29 and found that it carries a mutation in a previously uncharacterized gene, si:dkey-88l16.3.

Conclusions

The phenotypes of these EtOH-sensitive mutants differ from those in previous characterizations of gene–EtOH interactions. Thus, each mutant is likely to provide novel insights into EtOH teratogenesis. Given that most of these mutants only have craniofacial defects in the presence of EtOH and our mapping of au29, it is also likely that many of the mutants will be previously uncharacterized. Collectively, our findings point to the importance of unbiased genetic screens in the identification, and eventual characterization, of risk alleles for FASD.

     

Impact of Long-Term Alcohol Consumption and Relapse on Genome-Wide DNA Methylation Changes in Alcohol-Dependent Subjects: A Longitudinal Study

Background

Genetic factors play an important role in the development and maintenance of alcohol use disorder (AUD). Significant and widespread differences in methylation levels of multiple regions within the genome have been reported between AUD patients and healthy controls in large epigenome-wide association studies (EWASs). Also, within patient populations, methylation changes over time (both during and after withdrawal) have been identified as sensitive indicators for disease activity. The detection of changes in methylation levels is a powerful tool to further explore and understand the biological correlates and underpinnings of AUD. Although there is strong and convincing evidence for differences in methylation of various sites between AUD patients and controls, only few studies assessed changes within patients over longer periods of time while taking into account alcohol consumption, relapse, and abstinence. So far, the longest period assessed as a within-subject design using EWASs was 4 weeks.

Methods

Here, we investigated changes in whole-genome methylation levels within a sample of 69 detoxified AUD patients over a period as long as 12 months for the first time, comparing patients that relapsed within the follow-up period to those that remained abstinent.

Results

Whole-genome methylation patterns of individual CpG sites over time did not differ between abstinent and relapsing patients. However, there was a negative association between global mean methylation at the 12-month follow-up and alcohol consumption within our sample.

Conclusion

Although the present study represents the largest study of methylation levels in a sample of AUD patients with a follow-up period of 1 year and accounting for alcohol consumption and relapse to date, the sample size might still not be large enough to detect genome-wide significant effects. Therefore, large-scale, long-term studies with AUD subjects are needed to determine the utility of DNA methylation for the assessment and monitoring of persons with alcohol use disorders.

     

Genes regulating levels of ω-3 long-chain polyunsaturated fatty acids are associated with alcohol use disorder and consumption,and broader externalizing behavior in humans

Background

Individual variation in the physiological response to alcohol is predictive of an individual's likelihood to develop alcohol use disorder (AUD). Evidence from diverse model organisms indicates that the levels of long-chain polyunsaturated omega-3 fatty acids (ω-3 LC-PUFAs) can modulate the behavioral response to ethanol and therefore may impact the propensity to develop AUD. While most ω-3 LC-PUFAs come from diet, humans can produce these fatty acids from shorter chain precursors through a series of enzymatic steps. Natural variation in the genes encoding these enzymes has been shown to affect ω-3 LC-PUFA levels. We hypothesized that variation in these genes could contribute to the susceptibility to develop AUD.

Methods

We identified nine genes (FADS1, FADS2, FADS3, ELOVL2, GCKR, ELOVL1, ACOX1, APOE, and PPARA) that are required to generate ω-3 LC-PUFAs and/or have been shown or predicted to affect ω-3 LC-PUFA levels. Using both set-based and gene-based analyses we examined their association with AUD and two AUD-related phenotypes, alcohol consumption, and an externalizing phenotype.

Results

We found that the set of nine genes is associated with all three phenotypes. When examined individually, GCKR, FADS2, and ACOX1 showed significant association signals with alcohol consumption. GCKR was significantly associated with AUD. ELOVL1 and APOE were associated with externalizing.

Conclusions

Taken together with observations that dietary ω-3 LC-PUFAs can affect ethanol-related phenotypes, this work suggests that these fatty acids provide a link between the environmental and genetic influences on the risk of developing AUD.