Adjuvant use of melatonin for pain management in dysmenorrhea - a randomized double-blinded, placebo-controlled trial.

PURPOSE: Dysmenorrhea is a common, recurring, painful condition with a global prevalence of 71%. The treatment regime for dysmenorrhea includes hormonal therapies and NSAID, both of which are associated with side effects. A dose of 10 mg melatonin daily has previously been shown to reduce the level of pelvic pain in women with endometriosis. We chose to investigate how this regime, administered during the week of menstruation, would affect women with dysmenorrhea but without any signs of endometriosis, as adjuvant analgesic treatment. METHODS: Forty participants with severe dysmenorrhea were randomized to either melatonin or placebo, 20 in each group. Our primary outcome was pain measured with numeric rating scale (NRS); a difference of at least 1.3 units between the groups was considered clinically significant. Secondary outcomes were use of analgesics, as well as absenteeism and amount of bleeding. Mixed model was used for statistical analysis. RESULTS: Eighteen participants completed the study in the placebo group and 19 in the melatonin group. Mean NRS in the placebo group was 2.45 and 3.18 in the melatonin group, which proved to be statistically, although not clinically significant. CONCLUSION: This randomized, double-blinded, placebo-controlled trial could not show that 10 mg of melatonin given orally at bedtime during the menstrual week had better analgesic effect on dysmenorrhea as compared with placebo. However, no adverse effects were observed. CLINICAL TRIALS: NCT03782740 registered on 17 December 2018.

Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement.

Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS.

Perigestational alcohol consumption induces altered early placentation and organogenic embryo growth restriction by disruption of trophoblast angiogenic factors.

RESEARCH QUESTION: Maternal alcohol consumption produces fetal retardation and malformations, probably associated with placental defects. Does perigestational alcohol consumption up to organogenesis lead to abnormal placentation and embryo growth restriction by disrupting the vascular endothelial growth factor (VEGF) system in embryo-placental development? DESIGN: Female mice were treated with 10% ethanol in drinking water before and up to day 10 of gestation. Control mice received ethanol-free water. After treatment, the trophoblastic tissue, embryo growth and the angiogenic VEGF pathway were analysed. RESULTS: Female mice who had received treatment had resorbed and delayed implantation sites with poor ectoplacental cone development. Reduced trophoblastic area tissue from female mice who had received treatment had abnormal junctional zone and diminished labyrinthine vascularization. After treatment, the labyrinth had increased chorionic trophoblast proliferation, hypoxia inducible factor-1α immunoexpression but reduced apoptosis. The embryo growth was reduced concomitantly with low VEGF immunostaining but high endothelial nitric oxide synthase (eNOS) expression. In junctional and labyrinth of treated female mice, gene and protein immunoexpression of VEGF was reduced and the protein expression of FLT-1 increased compared with controls. Increased activation of kinase insert domain receptor receptor (phosphorylated KDR) and expression of eNOS were observed in placenta of treated female mice. Immunoexpression of metalloproteinase-9, however, was reduced in junctional zone but increased in labyrinth, compared with controls. CONCLUSIONS: These data reveal inadequate expression of VEGF/receptors and angiogenic eNOS and metalloproteinase factors related to abnormal early placentation after perigestational alcohol ingestion, providing insight into aetiological factors underlying early placentopathy associated with intrauterine growth restriction caused by maternal alcohol consumption.

Primed for addiction: A critical review of the role of microglia in the neurodevelopmental consequences of adolescent alcohol drinking.

Alcohol is one of the most widely used recreational substances worldwide, with drinking frequently initiated during adolescence. The developmental state of the adolescent brain makes it vulnerable to initiating alcohol use, often in high doses, and particularly susceptible to alcohol-induced brain changes. Microglia, the brain parenchymal macrophages, have been implicated in mediating some of these effects, though the role that these cells play in the progression from alcohol drinking to dependence remains unclear. Microglia are uniquely positioned to sense and respond to central nervous system insult, and are now understood to exhibit innate immune memory, or "priming," altering their future functional responses based on prior exposures. In alcohol use disorders (AUDs), the role of microglia is debated. Whereas microglial activation can be pathogenic, contributing to neuroinflammation, tissue damage, and behavioral changes, or protective, it can also engage protective functions, providing support and mediating the resolution of damage. Understanding the role of microglia in adolescent AUDs is complicated by the fact that microglia are thought to be involved in developmental processes such as synaptic refinement and myelination, which underlie the functional maturation of multiple brain systems in adolescence. Thus, the role microglia play in the impact of alcohol use in adolescence is likely multifaceted. Long-term sequelae may be due to a failure to recover from EtOH-induced tissue damage, altered neurodevelopmental trajectories, and/or persistent changes to microglial responsivity and function. Here, we review critically the literature surrounding the effects of alcohol on microglia in models of adolescent alcohol misuse. We attempt to disentangle what is known about microglia from other neuroimmune effectors, to which we apply recent discoveries on the role of microglia in development and plasticity. Considered altogether, these studies challenge assumptions that proinflammatory microglia drive addiction. Alcohol priming microglia and thereby perturbing their homeostatic roles in neurodevelopment, especially during critical periods of plasticity such as adolescence, may have more serious implications for the neuropathogenesis of AUDs in adolescents.

Gender moderates the association between acute alcohol intoxication and facial emotion recognition in a naturalistic field study setting.

BACKGROUND: Alcohol intoxication is associated with significant negative social consequences. Social information processing theory provides a framework for understanding how the accurate decoding and interpretation of social cues are critical for effective social responding. Acute intoxication has the potential to disrupt facial emotion recognition. If alcohol impairs the processing and interpretation of emotional cues, then the resultant behavioral responses may be less effective. The current study tested the association between alcohol intoxication and facial emotion recognition in a naturalistic field study of intoxicated participants. METHODS: 114 participants (59.4% men; Mage  = 24.2 years) who had been consuming alcohol were recruited in the downtown area of a mid-size town surrounded by several drinking establishments in the mid-southern United States. Participants were shown images depicting 5 facial displays of emotions (happy, sad, anger, disgust, and no emotion) portrayed by 1 male and 1 female actor per emotion and breath alcohol concentration (BrAC) was measured by the field breathalyzer test (M = 0.078%, SD = 0.052). RESULTS: BrAC was significantly negatively associated with emotion recognition accuracy when controlling for average alcohol use, B = -.35, t = -2.08, p < 0.05, F(3, 110) = 5.28, p < 0.01, R2  = 0.13. A significant BrAC × gender interaction was revealed, B = -0.39, t = -2.07, p = 0.04, ΔR2  = 0.033, p = 0.04, such that men (but not women) displayed a significant negative association between BrAC and emotion recognition accuracy. CONCLUSIONS: Acute intoxication was associated with impaired facial emotion recognition, particularly for men, in a field study context. Findings support and extend some previous experimental laboratory-based research and suggest that intoxication can impair the decoding stage of social information processing.

Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is caused by prenatal alcohol exposure (PAE), the intake of ethanol (C2 H5 OH) during pregnancy. Features of FASD cover a range of structural and functional defects including congenital heart defects (CHDs). Folic acid and choline, contributors of methyl groups to one-carbon metabolism (OCM), prevent CHDs in humans. Using our avian model of FASD, we have previously reported that betaine, another methyl donor downstream of choline, prevents CHDs. The CHD preventions are substantial but incomplete. Ethanol causes oxidative stress as well as depleting methyl groups for OCM to support DNA methylation and other epigenetic alterations. To identify more compounds that can safely and effectively prevent CHDs and other effects of PAE, we tested glutathione (GSH), a compound that regulates OCM and is known as a "master antioxidant." METHODS/RESULTS: Quail embryos injected with a single dose of ethanol at gastrulation exhibited congenital defects including CHDs similar to those identified in FASD individuals. GSH injected simultaneously with ethanol not only prevented CHDs, but also improved survival and prevented other PAE-induced defects. Assays of hearts at 8 days (HH stage 34) of quail development, when the heart normally has developed 4-chambers, showed that this single dose of PAE reduced global DNA methylation. GSH supplementation concurrent with PAE normalized global DNA methylation levels. The same assays performed on quail hearts at 3 days (HH stage 19-20) of development, showed no difference in global DNA methylation between controls, ethanol-treated, GSH alone, and GSH plus ethanol-treated cohorts. CONCLUSIONS: GSH supplementation shows promise to inhibit effects of PAE by improving survival, reducing the incidence of morphological defects including CHDs, and preventing global hypomethylation of DNA in heart tissues.

Jacobian Mapping Reveals Converging Brain Substrates of Disruption and Repair in Response to Ethanol Exposure and Abstinence in 2 Strains of Rats.

BACKGROUND: In a previous study using Jacobian mapping to evaluate the morphological effects on the brain of binge (4-day) intragastric ethanol (EtOH) on wild-type Wistar rats, we reported reversible thalamic shrinkage and lateral ventricular enlargement, but persistent superior and inferior colliculi shrinkage in response to binge EtOH treatment. METHODS: Herein, we used similar voxel-based comparisons of Magnetic Resonance Images collected in EtOH-exposed relative to control animals to test the hypothesis that regardless of the intoxication protocol or the rat strain, the hippocampi, thalami, and colliculi would be affected. RESULTS: Two experiments [binge (4-day) intragastric EtOH in Fisher 344 rats and chronic (1-month) vaporized EtOH in Wistar rats] showed similarly affected brain regions including retrosplenial and cingulate cortices, dorsal hippocampi, central and ventroposterior thalami, superior and inferior colliculi, periaqueductal gray, and corpus callosum. While most of these regions showed significant recovery, volumes of the colliculi and periaqueductal gray continued to show response to each proximal EtOH exposure but at diminished levels with repeated cycles. CONCLUSIONS: Given the high metabolic rate of these enduringly affected regions, the current findings suggest that EtOH per se may affect cellular respiration leading to brain volume deficits. Further, responsivity greatly diminished likely reflecting neuroadaptation to repeated alcohol exposure. In summary, this unbiased, in vivo-based approach demonstrating convergent brain systems responsive to 2 EtOH exposure protocols in 2 rat strains highlights regions that warrant further investigation in both animal models of alcoholism and in humans with alcohol use disorder.

Alcohol Use Disorder is Associated with Upregulation of MicroRNA-34a and MicroRNA-34c in Hippocampal Postmortem Tissue.

BACKGROUND: To investigate epigenetic mechanisms potentially involved in the cognitive decline associated with chronic alcohol intake, we evaluated the expressions of three micro-RNAs (miR-34a, -34b, and -34c) highly expressed in the hippocampus and involved in neuronal physiology and pathology. MiR-34a participates in functioning and survival of mature neurons; miR-34b is associated with Alzheimer-like disorders; and miR-34c is implicated in the memory impairment of Alzheimer disease in rodents and humans. METHODS: A total of 69 cases were selected from the Biobank for Aging Studies and categorized according to the absence (n = 50) or presence (n = 19) of alcohol use disorder (AUD). Cases presenting with neuropathological diagnoses of dementias were excluded. Total RNA was extracted from hippocampal paraffinized slices, complementary DNA was synthesized from miRs, and RT-qPCR was performed with TaqMan® assays. RESULTS: Higher expressions of miR-34a and miR-34c, but not of miR-34b, were found in the group with AUD in comparison with the group without AUD after adjustment for potential confounders (age, sex, body mass index, presence of hypertension, diabetes mellitus, smoking, and physical inactivity). CONCLUSIONS: Hippocampal upregulation of miR-34a and miR-34c may be involved in the cognitive decline associated with chronic alcohol consumption.

Effects of prenatal alcohol exposure on cognitive and behavioral development: Findings from a hierarchical meta-analysis of data from six prospective longitudinal U.S. cohorts.

BACKGROUND: Cognitive and behavioral sequelae of prenatal alcohol exposure (PAE) continue to be prevalent in the United States and worldwide. Because these sequelae are also common in other neurodevelopmental disorders, researchers have attempted to identify a distinct neurobehavioral profile to facilitate the differential diagnosis of fetal alcohol spectrum disorders (FASD). We used an innovative, individual participant meta-analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples. METHODS: Meta-analyses were performed on data from 2236 participants to examine effects of PAE (measured as oz absolute alcohol/day (AA/day)) on IQ, four domains of cognition function (learning and memory, executive function, reading achievement, and math achievement), sustained attention, and behavior problems, after adjusting for potential confounders using propensity scores. RESULTS: The effect sizes for IQ and the four domains of cognitive function were strikingly similar to one another and did not differ at school age, adolescence, or young adulthood. Effect sizes were smaller in the more middle-class Seattle cohort and larger in the three cohorts that obtained more detailed and comprehensive assessments of AA/day. PAE effect sizes were somewhat weaker for parent- and teacher-reported behavior problems and not significant for sustained attention. In a meta-analysis of five aspects of executive function, the strongest effect was on set-shifting. CONCLUSIONS: The similarity in the effect sizes for the four domains of cognitive function suggests that PAE affects an underlying component or components of cognition involving learning and memory and executive function that are reflected in IQ and academic achievement scores. The weaker effects in the more middle-class cohort may reflect a more cognitively stimulating environment, a different maternal drinking pattern (lower alcohol dose/occasion), and/or better maternal prenatal nutrition. These findings identify two domains of cognition-learning/memory and set-shifting-that are particularly affected by PAE, and one, sustained attention, which is apparently spared.

A review of the role of ethanol-induced adipose tissue dysfunction in alcohol-associated liver disease.

Alcohol-associated liver disease (AALD) encompasses a spectrum of liver diseases that includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis. The adverse effects of alcohol in liver and the mechanisms by which ethanol (EtOH) promotes liver injury are well studied. Although liver is known to be the primary organ affected by EtOH exposure, alcohol's effects on other organs are also known to contribute significantly to the development of liver injury. It is becoming increasingly evident that adipose tissue (AT) is an important site of EtOH action. Both AT storage and secretory functions are altered by EtOH. For example, AT lipolysis, stimulated by EtOH, contributes to chronic alcohol-induced hepatic steatosis. Adipocytes secrete a wide variety of biologically active molecules known as adipokines. EtOH alters the secretion of these adipokines from AT, which include cytokines and chemokines that exert paracrine effects in liver. In addition, the level of EtOH-metabolizing enzymes, in particular, CYP2E1, rises in the AT of EtOH-fed mice, which promotes oxidative stress and/or inflammation in AT. Thus, AT dysfunction characterized by increased AT lipolysis and free fatty acid mobilization and altered secretion of adipokines can contribute to the severity of AALD. Of note, moderate EtOH exposure results in AT browning and activation of brown adipose tissue which, in turn, can promote thermogenesis. In this review article, we discuss the direct effects of EtOH consumption in AT and the mechanisms by which EtOH impacts the functions of AT, which, in turn, increases the severity of AALD in animal models and humans.

Persistence of cerebellar ataxia during chronic ethanol exposure is associated with epigenetic up-regulation of Fmr1 gene expression in rat cerebellum.

BACKGROUND: Alcohol intoxication produces ataxia by affecting the cerebellum, which coordinates movements. Fragile X mental retardation (FMR) protein is a complex regulator of RNA and synaptic plasticity implicated in fragile X-associated tremor/ataxia syndrome, which features ataxia and increased Fmr1 mRNA expression resulting from epigenetic dysregulation of FMRP. We recently demonstrated that acute ethanol-induced ataxia is associated with increased cerebellar Fmr1 gene expression via histone modifications in rats, but it is unknown whether similar behavioral and molecular changes occur following chronic ethanol exposure. Here, we investigated the effects of chronic ethanol exposure on ataxia and epigenetically regulated changes in Fmr1 expression in the cerebellum. METHODS: Male adult Sprague-Dawley rats were trained on the accelerating rotarod and then fed with chronic ethanol or a control Lieber-DeCarli diet while undergoing periodic behavioral testing for ataxia during ethanol exposure and withdrawal. Cerebellar tissues were analyzed for expression of the Fmr1 gene and its targets using a real-time quantitative polymerase chain reaction assay. The epigenetic regulation of Fmr1 was also investigated using a chromatin immunoprecipitation assay. RESULTS: Ataxic behavior measured by the accelerating rotarod behavioral test developed during chronic ethanol treatment and persisted at both the 8-h and 24-h withdrawal time points compared to control diet-fed rats. In addition, chronic ethanol treatment resulted in up-regulated expression of Fmr1 mRNA and increased activating epigenetic marks H3K27 acetylation and H3K4 trimethylation at 2 sites within the Fmr1 promoter. Finally, measurement of the expression of relevant FMRP mRNA targets in the cerebellum showed that chronic ethanol up-regulated cAMP response element binding (CREB) Creb1, Psd95, Grm5, and Grin2b mRNA expression without altering Grin2a, Eaa1, or histone acetyltransferases CREB binding protein (Cbp) or p300 mRNA transcripts. CONCLUSIONS: These results suggest that epigenetic regulation of Fmr1 and subsequent FMRP regulation of target mRNA transcripts constitute neuroadaptations in the cerebellum that may underlie the persistence of ataxic behavior during chronic ethanol exposure and withdrawal.

Adjuvant use of melatonin for relieving symptoms of painful diabetic neuropathy: results of a randomized, double-blinded, controlled trial.

PURPOSE: The trial aimed to investigate the effectiveness of exogenous melatonin as an adjuvant to pregabalin for relief of pain in patients suffering from painful diabetic neuropathy (PDN). PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled trial was carried out between October 2019 and December 2020 in an outpatient specialty clinic in Iran. One-hundred-three type 2 diabetic patients suffering from PDN were randomized into either the melatonin group (n = 52) or the placebo group (n = 51). Besides pregabalin at a dose of 150 mg per day, patients started with melatonin or an identical placebo, at a dose of 3 mg/day at bedtime for 1 week, which was augmented to 6 mg/day for further 7 weeks. The primary outcomes were changes in mean NRS (numerical rating scale) pain score from baseline to endpoint and responder rate (patients with a reduction of 50% and higher in average pain score compared with baseline). Secondary endpoints were changes in mean NRS pain-related sleep-interference score, overall improvement evaluated by Patient and Clinical Global Impressions of Change (PGIC, CGIC), and impact of the intervention on patient's Health-related quality of life (QOL). All analyses were conducted on an Intention-to-Treat (ITT) analysis data set. RESULTS: At the study endpoint, treatment with melatonin resulted in a considerably higher reduction in the mean NRS pain score in comparison with placebo (4.2 ± 1.83 vs. 2.9 ± 1.56; P-value < 0.001). In terms of treatment responders, a greater proportion of melatonin-treated patients satisfied the responder criterion than placebo-treated patients (63.5% vs. 43.1%). Melatonin also reduced pain-related sleep interference scores more than did placebo (3.38 ± 1.49 vs. 2.25 ± 1.26; P-value < 0.001). Further, at the endpoint, more improvement was also seen in terms of PGIC, CGIC, and Health-related QOL in patients treated with melatonin than placebo. Melatonin was also well tolerated. CONCLUSION: The present results showed that melatonin as an adjunct therapy to pregabalin might be helpful for use in patients with PDN. However, confirmation of these results requires further studies.

Specialist alcohol inpatient treatment admissions and non-specialist hospital admissions for alcohol withdrawal in England: an inverse relationship.

AIMS: We assessed the relationship between specialist and non-specialist admissions for alcohol withdrawal since the introduction of the UK government Health and Social Care Act in 2012. METHODS: Using publicly available national data sets from 2009 to 2019, we compared the number of alcohol withdrawal admissions and estimated costs in specialist and non-specialist treatment settings. RESULTS: A significant negative correlation providing strong evidence of an association was observed between the fall in specialist and rise in non-specialist admissions. Significant cost reductions within specialist services were displaced to non-specialist settings. CONCLUSIONS: The shift in demand from specialist to non-specialist alcohol admissions due to policy changes in England should be reversed by specialist workforce investment to improve outcomes. In the meantime, non-specialist services and staff must be resourced and equipped to meet the complex needs of these service users.

Pharmacokinetics and Safety of Intravenous, Intravesical, Rectal, Transdermal, and Vaginal Melatonin in Healthy Female Volunteers: A Cross-Over Study.

INTRODUCTION: We aimed to investigate the pharmacokinetic properties and safety of melatonin administered by alternative routes of administration. METHODS: This study employed a cross-over design in healthy female volunteers. Twenty-five milligrams of melatonin was administered intravenously, intravesically, rectally, transdermally, and vaginally. Blood samples were collected at specified time points up to 24 h following intravenous, intravesical, rectal, and vaginal administration, and up to 48 h following transdermal administration. Plasma melatonin concentrations were determined by radioimmunoassay. Sedation was evaluated by a simple reaction-time test, and sleepiness was assessed by the Karolinska Sleepiness Scale. Adverse events were registered for each route of administration. RESULTS: Ten participants were included. We documented a mean (SD) time to maximal concentration of 51 (29) min for intravesical, 24 (20) min for rectal, 21 (8) h for transdermal, and 147 (56) min for vaginal administration. The mean (SD) elimination half-life was 47 (6) min for intravenous, 58 (7) min for intravesical, 60 (18) min for rectal, 14.6 (11.1) h for transdermal, and 129 (17) min for vaginal administration. The mean (SD) bioavailability was 3.6 (1.9)% for intravesical, 36.0 (28.6)% for rectal, 10.0 (5.7)% for transdermal, and 97.8 (31.7)% for vaginal administration. No significant changes in reaction times were observed following administration of melatonin by any of the administration routes. Increased tiredness was documented following transdermal administration only. No serious adverse effects were documented. CONCLUSION: Rectally and vaginally administered melatonin may serve as relevant alternatives to standard oral melatonin therapy. Transdermal delivery of melatonin displayed an extended absorption and can be applied if prolonged effects are intended. Intravesical administration displayed, as expected, a very limited bioavailability. Melatonin administered by these routes of administration was safe.

Successful implementation of managed alcohol programs in the San Francisco Bay Area during the COVID-19 crisis.

Background: The COVID-19 crisis presents new challenges and opportunities in managing alcohol use disorders, particularly for people unable to shelter in place due to homelessness or other reasons. Requiring abstinence for shelter engagement is impractical for many with severe alcohol use disorders and poses a modifiable barrier to self-isolation orders. Managed alcohol programs (MAPs) have successfully increased housing adherence for those with physical alcohol dependence in Canada, but to our knowledge, they have not been implemented in the United States. To avoid life-threatening alcohol withdrawal syndromes and to support adherence to COVID-19 self-isolation and quarantine orders, MAPs were piloted by the public health departments of San Francisco and Alameda counties. Development of MAPs: We describe implementation of a first-in-the-nation alcohol use disorder intervention of a MAP that emerged at three public health isolation settings within San Francisco and Alameda counties in California. All three interventions utilized a similar process to develop the protocol and implement the MAP that included identification of champions for system-level advocacy and engagement of stakeholders. Implementation of MAPs: We describe the creation and implementation of the distinct protocols. We provide examples of iterative changes to workflow processes and key lessons learned pertaining to protocol development, acceptability by stakeholders, alcohol procurement, documentation, and assessment. We discuss safety considerations, noting that there were no deaths or serious adverse events in any of the patients of the MAP during the 2-month implementation period. Conclusions: MAP pilots have been implemented in the US to aid adherence to isolation and quarantine setting guidelines. Lessons learned provide a foundation for their expansion as a recognized public health intervention for individuals with severe alcohol use disorders who are unable to stabilize within existing care systems. Based on the success of MAP implementation, efforts are under way to investigate alcohol management in homeless populations more broadly.

Different brain profiles in children with prenatal alcohol exposure with or without early adverse exposures.

Prenatal alcohol exposure (PAE) can alter brain development and impact mental health outcomes, and often occurs in conjunction with postnatal adversity (e.g., maltreatment). However, it is unclear how postnatal adverse exposures may moderate mental health and brain outcomes in children with PAE. T1-weighted and diffusion magnetic resonance imaging were obtained from 66 participants aged 7-16 years. Twenty-one participants had PAE and adverse postnatal exposures (PAE+), 12 had PAE without adverse postnatal exposures (PAE-), and 33 were age- and gender-matched controls unexposed to either prenatal alcohol or postnatal adversity. Internalizing and externalizing mental health symptoms were assessed using the Behavioral Assessment System for Children II, Parent-Rating Scale. ANCOVAs were used to compare mental health symptoms, limbic and prefrontal cortical volumes, and diffusion parameters of cortico-limbic white matter tracts between groups, and to assess brain-mental health relationships. Both PAE groups had worse externalizing behavior (higher scores) than controls. The PAE- group had lower fractional anisotropy (FA) in the bilateral cingulum and left uncinate fasciculus, and smaller volumes in the left anterior cingulate cortex than controls and the PAE+ group. The PAE- group also had higher mean diffusivity (MD) in the left uncinate than the PAE+ group, and smaller right anterior cingulate and superior frontal gyrus volumes than controls. These findings show different brain structure and mental health symptom profiles in children with PAE with and without postnatal adversity, highlighting the need to consider adverse postnatal exposures in individuals with PAE.

Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure.

BACKGROUND: Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status. METHODS: As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis. RESULTS: Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1ß, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-ß, IL-10, and IL-15 was associated with neurodevelopmental delay. CONCLUSIONS: Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.

RNA-Seq Analysis of Genetic and Transcriptome Network Effects of Dual-Trait Selection for Ethanol Preference and Withdrawal Using SOT and NOT Genetic Models.

BACKGROUND: Genetic factors significantly affect alcohol consumption and vulnerability to withdrawal. Furthermore, some genetic models showing predisposition to severe withdrawal are also predisposed to low ethanol (EtOH) consumption and vice versa, even when tested independently in naïve animals. METHODS: Beginning with a C57BL/6J × DBA/2J F2 intercross founder population, animals were simultaneously selectively bred for both high alcohol consumption and low acute withdrawal (SOT line), or vice versa (NOT line). Using randomly chosen fourth selected generation (S4) mice (N = 18-22/sex/line), RNA-Seq was employed to assess genome-wide gene expression in ventral striatum. The MegaMUGA array was used to detect genome-wide genotypic differences. Differential gene expression and the weighted gene co-expression network analysis were implemented as described elsewhere (Genes Brain Behav 16, 2017, 462). RESULTS: The new selection of the SOT and NOT lines was similar to that reported previously (Alcohol Clin Exp Res 38, 2014, 2915). One thousand eight hundred and sixteen transcripts were detected as differentially expressed between the lines. For genes more highly expressed in the SOT line, there was enrichment in genes associated with cell adhesion, synapse organization, and postsynaptic membrane. The genes with a cell adhesion annotation included 23 protocadherins, Mpdz and Dlg2. Genes with a postsynaptic membrane annotation included Gabrb3, Gphn, Grid1, Grin2b, Grin2c, and Grm3. The genes more highly expressed in the NOT line were enriched in a network module (red) with annotations associated with mitochondrial function. Several of these genes were module hub nodes, and these included Nedd8, Guk1, Elof1, Ndufa8, and Atp6v1f. CONCLUSIONS: Marked effects of selection on gene expression were detected. The NOT line was characterized by higher expression of hub nodes associated with mitochondrial function. Genes more highly expressed in the SOT aligned with previous findings, for example, Colville and colleagues (Genes Brain Behav 16, 2017, 462) that both high EtOH preference and consumption are associated with effects on cell adhesion and glutamate synaptic plasticity.

Para-limbic Structural Abnormalities Are Associated With Internalizing Symptoms in Children With Prenatal Alcohol Exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) is associated with a variety of structural abnormalities in the brain, including several within the para-limbic system. Children with PAE have higher rates of internalizing disorders, including depression and anxiety, which may be related to underlying limbic system anomalies. METHODS: Children aged 8 to 16 with PAE (n = 41) or without PAE (n = 36) underwent an magnetic resonance imaging of the brain and parents completed behavioral questionnaires about their children. Semi-automated procedures (FreeSurfer) were used to derive para-limbic volumes from T1-weighted anatomical images. RESULTS: There were significant group differences (PAE vs. nonexposed controls) in the caudate, hippocampus, and the putamen; children with PAE had smaller volumes in these regions even after controlling for total intracranial volume. A trend-level association was seen between caudate volume and internalizing symptoms in children with PAE; smaller caudate volumes (presumably reflecting less optimal neurodevelopment) were associated with higher levels of anxiety and depression symptoms in these children. CONCLUSIONS: Caudate structure may be disproportionately affected by PAE and may be associated with the later development of internalizing symptoms in those affected by PAE.

Efficacy and tolerability of DAAs in HCV-monoinfected and HCV/HIV-coinfected patients with psychiatric disorders.

BACKGROUND: Few data are available regarding the use of direct antiviral agents (DAAs) for chronic hepatitis C in psychiatric patients. The aim of the study is to assess safety and outcome of DAAs in patients with psychiatric comorbidities. METHODS: This retrospective, observational, single-centre study enrolled patients treated with psychiatric drugs who initiated DAAs between 2015 and 2018. Patients were classified into two groups: A (on anxiolitycs/antidepressant) and B (on antipsychotics). Week-12 sustained virological response (SVR-12) and adverse events (AEs) were evaluated. RESULTS: One hundred forty-four patients were included (A:101; B:43). Patients were 49.3% males, mean age 60 years (SD ± 13.5); 31.9% cirrhotic; 125 (86.8%) HCV-monoinfected and 19 (13.2%) HCV /HIV-coinfected. Twenty patients (13.8%) required a change of psychiatric therapy before initiation of DAA. Overall, SVR-12 was achieved in 88.2% of subjects in intention-to-treat(ITT)-analysis. Lower SVR rates were observed in group B vs A (79% vs 92%, p = 0.045) and in those changing psychiatric drugs vs others (8% vs 30%, p = 0.015). According to per-protocol (PP)-analysis, SVR-12 was achieved in 93/95 (97.9%) in group A versus 34/36 (94.4%) in group B (p = 0.30). At least one AE occurred in 60 patients (41.6%), including 10 severe AEs, leading to 3 discontinuations. AEs were more frequently reported in group A (p = 0.015). CONCLUSIONS: The study confirms effectiveness and safety of DAA-based treatment also in this special population, even if a careful evaluation of history and drug-drug interactions is warranted.