Muscular remodeling and anteroposterior patterning during tapeworm segmentation.

BACKGROUND: Tapeworms are parasitic flatworms that independently evolved a segmented body plan, historically confounding comparisons with other animals. Anteroposterior (AP) patterning in free-living flatworms and in tapeworm larvae is associated with canonical Wnt signaling and positional control genes (PCGs) are expressed by their musculature in regionalized domains along the AP axis. Here, we extend investigations of PCG expression to the adult of the mouse bile-duct tapeworm Hymenolepis microstoma, focusing on the growth zone of the neck region and the initial establishment of segmental patterning. RESULTS: We show that the adult musculature includes new, segmental elements that first appear in the neck and that the spatial patterns of Wnt factors are consistent with expression by muscle cells. Wnt factor expression is highly regionalized and becomes AP-polarized in segments, marking them with axes in agreement with the polarity of the main body axis, while the transition between the neck and strobila is specifically demarcated by the expression domain of a Wnt11 paralog. CONCLUSION: We suggest that segmentation could originate in the muscular system and participate in patterning the AP axis through regional and polarized expression of PCGs, akin to the gene regulatory networks employed by free-living flatworms and other animals.

Measuring the utility of brief psychological intervention in psychiatric hospitals: A call for change.

OBJECTIVE: Despite the known importance of regularly monitoring progress when delivering psychological interventions, this is not mandated or seemingly even common practice on Australian inpatient psychiatric wards. Barriers for why this might be the case are described, an argument made to rise above them, and a call for research in this area is made. CONCLUSIONS: Failure to find ways to collect, analyse and be transparent with data around brief inpatient psychological interventions can diminish treatment outcomes and leaves us open to criticism as a profession.

Impaired Decision-Making and Skin Conductance Responses Are Associated with Reward and Punishment Sensitivity in Individuals with Severe Alcohol Use Disorder.

INTRODUCTION: Individuals with alcohol use disorder (AUD) have difficulties regulating alcohol consumption, despite adverse drinking-related consequences. This may be due to incapacity incorporating previous negative feedback from drinking, resulting in impaired decision-making. METHODS: We assessed whether decision-making is impaired in participants with AUD related to severity of AUD, indexed by severe negative drinking consequences using the Drinkers Inventory of Consequences (DrInC) and reward and punishment sensitivity with the Behavioural Inhibition System Behavioural Activation System (BIS BAS) scales. 36 treatment-seeking alcohol-dependent participants completed the Iowa gambling task (IGT) with skin conductance responses (SCRs) measured continuously as an index of somatic autonomic arousal to evaluate impaired expectancy of negative outcomes. RESULTS: Two-thirds of the sample showed behavioural impairment during the IGT, with greater AUD severity related to worse performance. BIS moderated IGT performance according to severity of AUD, with increased anticipatory SCRs for those with fewer reported DrInC severe consequences. Participants with more DrInC severe consequences showed IGT deficits and reduced SCRs regardless of BIS scores. BAS-Reward was associated with increased anticipatory SCRs to disadvantageous deck choices among those with lower AUD severity, while SCRs did not differ related to AUD severity for reward outcomes. DISCUSSION: Effective decision-making in the IGT and adaptive somatic responses were moderated by punishment sensitivity contingent on severity of AUD in these drinkers, with impairments in expectancy to negative outcomes from risky choices, including reduced somatic responses, resulting in poor decision-making processes that may help explain impaired drinking and worse drinking-related consequences.

Spatiotemporal Trends Spanning Three Decades Show Toxic Levels of Chemical Contaminants in Marine Mammals.

Despite their ban and restriction under the 2001 Stockholm Convention, persistent organic pollutants (POPs) are still widespread and pervasive in the environment. Releases of these toxic and bioaccumulative chemicals are ongoing, and their contribution to population declines of marine mammals is of global concern. To safeguard their survival, it is of paramount importance to understand the effectiveness of mitigation measures. Using one of the world's largest marine mammals strandings data sets, we combine published and unpublished data to examine pollutant concentrations in 11 species that stranded along the coast of Great Britain to quantify spatiotemporal trends over three decades and identify species and regions where pollutants pose the greatest threat. We find that although levels of pollutants have decreased overall, there is significant spatial and taxonomic heterogeneity such that pollutants remain a threat to biodiversity in several species and regions. Of individuals sampled within the most recent five years (2014-2018), 48% of individuals exhibited a concentration known to exceed toxic thresholds. Notably, pollutant concentrations are highest in long-lived, apex odontocetes (e.g., killer whales (Orcinus orca), bottlenose dolphins (Tursiops truncatus), and white-beaked dolphins (Lagenorhynchus albirostris)) and were significantly higher in animals that stranded on more industrialized coastlines. At the present concentrations, POPs are likely to be significantly impacting marine mammal health. We conclude that more effective international elimination and mitigation strategies are urgently needed to address this critical issue for the global ocean health.

Unintentional drug-related deaths in people with mental illness in NSW Australia, 2012-2016: a retrospective cohort study.

PURPOSE: People with mental illness are a vulnerable and stigmatised group with poor health outcomes including greater premature mortality. This study aimed to investigate trends and rates of change in unintentional drug-related deaths for people with mental illness, describe types of medicines involved, and identify populations at risk in a cohort from New South Wales, Australia. METHODS: Features of unintentional drug-related deaths for people with mental illness between 2012 and 2016 were identified in a retrospective review of data from the National Coronial Information System. RESULTS: A total of 495 unintentional drug-related deaths were identified (1.6 deaths/100,000 population), showing an upward trend (p < 0.01). The most common substance involved was diazepam in both genders (males 135/319, 42%, female 76/176, 43%) and more than one contributory drug was included in 80% of cases. Between 2012 and 2016, amphetamine-related deaths showed the highest increase (3.2-fold), followed by codeine (2.5-fold) and quetiapine (2.5-fold). Males (RR 1.8, 95% CI 1.5-2.2) and people aged 35-44 (RR 1.7, CI 1.3-2.2) were more likely to die from unintentional drug-related deaths compared with the reference (females and people aged 25-34). CONCLUSION: This study found that the drugs commonly involved in deaths are also the drugs commonly used by and prescribed to people with mental illness. There were also significant differences between gender, age group, and marital status in the trend and rate of unintentional drug-related deaths for people with mental illness. A multifaceted approach encompassing both pharmaceutical prescribing and targeted public health messaging is required to inform intervention and prevention strategies.

The relationship between brain structure and general psychopathology in preadolescents.

BACKGROUND: An emerging body of literature has indicated that broad, transdiagnostic dimensions of psychopathology are associated with alterations in brain structure across the life span. The current study aimed to investigate the relationship between brain structure and broad dimensions of psychopathology in the critical preadolescent period when psychopathology is emerging. METHODS: This study included baseline data from the Adolescent Brain and Cognitive Development (ABCD) Study® (n = 11,875; age range = 9-10 years; male = 52.2%). General psychopathology, externalizing, internalizing, and thought disorder dimensions were based on a higher-order model of psychopathology and estimated using Bayesian plausible values. Outcome variables included global and regional cortical volume, thickness, and surface area. RESULTS: Higher levels of psychopathology across all dimensions were associated with lower volume and surface area globally, as well as widespread and pervasive alterations across the majority of cortical and subcortical regions studied, after adjusting for sex, race/ethnicity, parental education, income, and maternal psychopathology. The relationships between general psychopathology and brain structure were attenuated when adjusting for cognitive functioning. There were no statistically significant relationships between psychopathology and cortical thickness in this sample of preadolescents. CONCLUSIONS: The current study identified lower cortical volume and surface area as transdiagnostic biomarkers for general psychopathology in preadolescence. Future research may focus on whether the widespread and pervasive relationships between general psychopathology and brain structure reflect cognitive dysfunction that is a feature across a range of mental illnesses.

Relationship between clinician-level attributes and implementation outcomes from the Pathways to Comorbidity Care training program.

BACKGROUND: The process of determining the best strategy for increasing the uptake of evidence-based practice might be improved through an understanding of relevant clinician-level factors. The Pathways to Comorbidity Care (PCC) training program (Louie E, et al., J Dual Diagnosis 17:304-12, 2021) aimed to facilitate integrated management of comorbid drug and alcohol and mental disorders amongst drug and alcohol clinicians. We hypothesised that uptake of integrated management of comorbidity following the implementation of the PCC program would be associated with clinician-level: (i) demographics (gender, education, experience), (ii) attitudes (evidence-based practice, therapist manuals, counselling self-efficacy), and (iii) organisational readiness to change. METHODS: Twenty clinicians participated in the 9-month PCC training program. Attitudes towards evidence-based practices and psychotherapist manuals, self-efficacy, and organisational readiness to change, along with demographics, were measured at baseline. At follow-up, change in Comorbidity Practice (CoP) scores related to integrated comorbidity management were obtained using a file audit checklist and categorised into high (at least 60% increase in CoP), medium or low (a decrease of - 20% or less in CoP). Clinician-level characteristics were examined across the implementation categories. RESULTS: There were no significant differences found between implementation groups on sociodemographic variables (p's > 0.30), attitudes to evidence-based practices, attitudes to therapist manuals, and self-efficacy (p's > 0.52). The high implementation group demonstrated significantly higher scores on leadership practices aspect of organisational readiness to change relative to the low and medium implementation group ((F(2, 16) = 3.63, p = 0.05; Cohen's d = .31) but not on the other subscales (p's > 0.07). CONCLUSIONS: Confidence that leadership will play a positive role in the implementation process may improve effectiveness of comorbidity training programs for drug and alcohol clinicians. On the other hand, contrary to our hypothesis, counselling self-efficacy, evidence-based practice attitudes, attitudes towards therapist manuals, gender, education and experience were not distinguishing factors.

New Australian guidelines for the treatment of alcohol problems: an overview of recommendations.

OF RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 2: Screening and assessment for unhealthy alcohol use Screening Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). Quantity-frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient's needs (Level D). Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence Acamprosate is recommended to help maintain abstinence from alcohol (Level A). Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues Screen women and men for domestic abuse (Level C). Consider child protection assessments for caregivers with alcohol use disorder (GPP). Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups Use an appropriate method, such as the "teach-back" technique, to assess the need for language and health literacy support (Level C). Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people All new patients aged over 50 years should be screened for harmful alcohol use (Level D). Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment Cognitive impairment may impair engagement with treatment (Level A). Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). SUMMARY OF KEY RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A).

The structure of psychopathology and association with poor sleep, self-harm, suicidality, risky sexual behavior, and low self-esteem in a population sample of adolescents.

There is a growing body of evidence highlighting the presence of a single general dimension of psychopathology that can account for multiple associations across mental and substance use disorders. However, relatively little evidence has emerged regarding the validity of this model with respect to a range of factors that have been previously implicated across multiple disorders. The current study utilized a cross-sectional population survey of adolescents (n = 2,003) to examine the extent to which broad psychopathology factors account for specific associations between psychopathology and key validators: poor sleep, self-harm, suicidality, risky sexual behavior, and low self-esteem. Confirmatory factor models, latent class models, and factor mixture models were estimated to identify the best structure of psychopathology. Structural equation models were then estimated to examine the broad and specific associations between each psychopathology indicator and the validators. A confirmatory factor model with three lower-order factors, representing internalizing, externalizing, and psychotic-like experiences, and a single higher-order factor evidenced the best fit. The associations between manifest indicators of psychopathology and validators were largely nonspecific. However, significant and large direct effects were found between several pairwise associations. These findings have implications for the identification of potential targets for intervention and/or tailoring of prevention programs.

Randomised controlled trial of integrated cognitive behavioural treatment and motivational enhancement for comorbid social anxiety and alcohol use disorders.

OBJECTIVE: Alcohol use disorder and social anxiety disorder are interconnected disorders that commonly co-occur. We report the first trial to assess whether integrated treatment for social anxiety and alcohol use disorder comorbidity improves outcomes relative to standard alcohol-focussed treatment. METHOD: Participants were recruited to a randomised controlled trial, and randomly allocated to one of two treatments, Integrated (n = 61) or Control (alcohol-focussed; n = 56). Assessment and treatment session were conducted at two sites in Sydney, Australia. Inclusion criteria were as follows: (1) clinical diagnosis of social anxiety disorder and (2) Diagnosis or sub-clinical symptoms of alcohol use disorder. Diagnoses were determined according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.). All participants (n = 117) received 10 sessions of cognitive behavioural treatment and motivational enhancement. The Integrated treatment simultaneously targeted social anxiety disorder, alcohol use disorder and the connections between these disorders. The Control treatment focussed on alcohol use disorder only. Outcomes were assessed at 6-month follow-up, with interim assessments at post-treatment and 3 months. Primary outcomes were social anxiety disorder severity (composite Social Phobia Scale and Social Interaction Anxiety Scale), alcohol use disorder severity (standard drinks per day and Severity of Alcohol Dependence Questionnaire) and quality of life (Short-Form Health survey) was assessed to capture the combined impairment of social anxiety and alcohol use disorder comorbidity. RESULTS: At 6-month follow-up, both conditions showed significant reductions in social anxiety and alcohol use disorder symptoms, and improved quality of life. There was no evidence of between-condition differences for alcohol outcomes, with mean consumption reduced by 5.0 (0.8) and 5.8 (1.0) drinks per day following Alcohol and Integrated treatments, respectively. Integrated treatment achieved greater improvements in social anxiety symptoms (mean difference = -14.9, 95% confidence interval = [-28.1, -1.6], d = 0.60) and quality of life (mean difference = 7.6, 95% confidence interval = [1.2, 14.0], d = 0.80) relative to alcohol-focused treatment. CONCLUSION: These results suggest that integrated social anxiety and alcohol use disorder treatment enhances quality of life and social anxiety disorder symptom improvement, but not alcohol outcomes, compared to treatment focussed on alcohol use disorder alone.

Complete representation of a tapeworm genome reveals chromosomes capped by centromeres, necessitating a dual role in segregation and protection.

BACKGROUND: Chromosome-level assemblies are indispensable for accurate gene prediction, synteny assessment, and understanding higher-order genome architecture. Reference and draft genomes of key helminth species have been published, but little is yet known about the biology of their chromosomes. Here, we present the complete genome of the tapeworm Hymenolepis microstoma, providing a reference quality, end-to-end assembly that represents the first fully assembled genome of a spiralian/lophotrochozoan, revealing new insights into chromosome evolution. RESULTS: Long-read sequencing and optical mapping data were added to previous short-read data enabling complete re-assembly into six chromosomes, consistent with karyology. Small genome size (169 Mb) and lack of haploid variation (1 SNP/3.2 Mb) contributed to exceptionally high contiguity with only 85 gaps remaining in regions of low complexity sequence. Resolution of repeat regions reveals novel gene expansions, micro-exon genes, and spliced leader trans-splicing, and illuminates the landscape of transposable elements, explaining observed length differences in sister chromatids. Syntenic comparison with other parasitic flatworms shows conserved ancestral linkage groups indicating that the H. microstoma karyotype evolved through fusion events. Strikingly, the assembly reveals that the chromosomes terminate in centromeric arrays, indicating that these motifs play a role not only in segregation, but also in protecting the linear integrity and full lengths of chromosomes. CONCLUSIONS: Despite strong conservation of canonical telomeres, our results show that they can be substituted by more complex, species-specific sequences, as represented by centromeres. The assembly provides a robust platform for investigations that require complete genome representation.

Implementation of a Multi-Modal Training Program for the Management of Comorbid Mental Disorders in Drug and Alcohol Settings: Pathways to Comorbidity Care (PCC).

OBJECTIVES: We aimed to evaluate the impact of the Pathways to Comorbidity Care (PCC) training program for alcohol and other drugs (AOD) clinicians to improve the management of comorbidity. METHODS: A controlled before-and-after study using PCC training was conducted across 6 matched sites in Australia including 35 clinicians. Controls received standard workplace training. PCC training included seminar presentations, workshops conducted by local "clinical champions," individual clinical supervision, and access to an online information portal. We examined (a) identification (screening, assessment) and treatment (treatment, referral) of comorbidity in practice (N = 10 clinical files per clinician), (b) self-efficacy, knowledge, and attitudes of clinicians. RESULTS: Significant improvements were observed in the PCC group but not the control sites with regards to the rate of clinical files showing identification of comorbidity (+50% v -12% change from baseline, respectively; [X2 (1, N = 340) = 35.29, p = .01] with only a trend for improvements in the rate of files demonstrating treatment of comorbidity [X2 (1, N = 340) = 10.45, p = .06]. There were significant improvements in the PCC relative to the control group for clinician self-efficacy, F(1,33) = 6.40, p = .02 and knowledge and attitudes of comorbidity monitoring, F(1,33) = 8.745, p = .01. CONCLUSIONS: The PCC training package may help improve identification of comorbidity, self-efficacy, and attitudes toward screening and monitoring of comorbidity in drug and alcohol settings.

Acceptability and Co-Development of an Online Cognitive Bias Modification Intervention for Emerging Adults With Hazardous Alcohol Use and Social Anxiety: A Mixed Methods Study.

BACKGROUND: Approach bias modification (ApBM) and interpretation bias modification (IBM) are two promising adjunct treatments for alcohol use and social anxiety, respectively. However, the acceptability of combining ApBM and IBM into one program for people who experience both of these disorders is unknown. The present study describes the codevelopment of a new, hybrid ApBM + IBM program and provides insight into the perceptions of acceptability from service providers and emerging adults. METHODS: Service providers (n = 14) and emerging adults aged 18 to 25 years with lived experience of hazardous alcohol use and heightened social anxiety (n = 15) were recruited via online advertisements and through existing networks. All participants were shown a beta version of the program and asked to complete qualitative and quantitative questions to ascertain feedback on the program's acceptability and suggestions for improvement. RESULTS: Themes emerged relating to the ApBM + IBM program's quality and usefulness, appropriateness, motivation and engagement, and potential clinical value. The program was well received and deemed acceptable for the target age group. It was rated particularly highly with regard to the overall quality and ease of use. Emerging adults had fewer suggestions for how the intervention might be revised; however, there were suggestions from both groups regarding the need for a compelling rationale at the outset of treatment and a suggestion to include a motivational interviewing and psychoeducational-based module prior to the first training session, to increase user buy-in and engagement. CONCLUSIONS: The current findings reflect positively on the acceptability of a hybrid ApBM + IBM for emerging adults with co-occurring hazardous alcohol use and social anxiety. Service providers and emerging adults identified a number of ways to improve the design and implementation of the program, which will likely improve adherence to, and outcomes of, the intervention when added as an adjunct to treatment as usual.

Baclofen modulates cardiovascular responses to appetitive cues in treatment-seeking alcohol use disorder individuals.

OBJECTIVE: To assess whether baclofen-treated alcohol dependent participants show different subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task compared to placebo, and whether these responses are associated with prospective drinking outcomes. METHODS: Forty-two alcohol dependent participants (placebo: n = 12, low-dose baclofen [30 mg/day] n = 18, high-dose baclofen [75 mg/day]: n = 12) completed an alcohol cue reactivity task, whereby water and alcohol beverage cues were presented, with subsequent recovery periods, and subjective alcohol craving and psychophysiological indices (skin conductance; cardiovascular measures: heart rate, high-frequency heart rate variability) were recorded. RESULTS: High-dose baclofen-treated participants showed both overall cue reactivity to water and alcohol cues and greater recovery effects during recovery periods, revealed by high-frequency heart rate variability, when compared to low-dose- and placebo-treated participants. There were no medication effects on subjective craving. In high-dose baclofen participants only, there was a predictive effect of lower baseline heart rate variability and fewer post-test percentage of heavy drinking days. CONCLUSION: There was a dose-specific rescuing effect of high-dose baclofen on the dynamic modulation of cardiovascular responses to eliciting cues. Investigation of treatment responses using psychophysiological techniques may elucidate baclofen's mechanisms of action, and identify subgroups amenable to treatment.

Brain GABA levels are reduced in alcoholic liver disease: A proton magnetic resonance spectroscopy study.

BACKGROUND AND AIMS: Baclofen, a selective γ-aminobutyric acid (GABA)B receptor agonist, has emerged as a potential treatment for alcohol use disorder with much unexplained variation in response to treatment efficacy and dose regimen. Several positive studies include patients with alcoholic liver disease (ALD) and/or history of heavy drinking. The aim of this paper was to examine the association of cortical GABA+ concentration with severity of liver disease (including markers of liver injury) and other clinical characteristics in alcohol patients. METHODS: Proton magnetic resonance spectroscopy (1 H-MRS), from the parietal lobe, was analyzed to yield absolute concentration of GABA in 24 alcohol-dependent individuals. Diagnosis of ALD, markers of liver injury, severity of liver disease (Model for End-Stage Liver Disease [MELD]), and alcohol history were assessed. Covariates included concurrent medication, age, and recent alcohol consumption. RESULTS: Multiple linear regression revealed that GABA+ concentration was significantly predicted by MELD scores (F = 5.02, R2  = 0.59, P = 0.01; MELD: B = -0.63, P = 0.02), when controlling for covariates concurrent medication, age, and recent alcohol consumption. CONCLUSION: Severity of ALD is associated with lower cortical concentrations of GABA+. These results may explain variations in response to the GABAB agonist, baclofen, in the alcohol-dependent population.

Psychological therapies for the prevention of migraine in adults.

BACKGROUND: Migraine is a common neurological problem associated with the highest burden amongst neurological conditions in terms of years lived with disability. Medications can be used as prophylaxis or rescue medicines, but are costly and not always effective. A range of psychological interventions have been developed to manage migraine. OBJECTIVES: The objective was to evaluate the efficacy and adverse events of psychological therapies for the prevention of migraine in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL from their inception until July 2018, and trials registries in the UK, USA, Australia and New Zealand for randomised controlled trials of any psychological intervention for adults with migraine. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of a psychological therapy for people with chronic or episodic migraine, with or without aura. Interventions could be compared to another active treatment (psychological or medical), an attention-placebo (e.g. supportive counselling) or other placebo, routine care, or waiting-list control. We excluded studies where fewer than 15 participants completed each arm. DATA COLLECTION AND ANALYSIS: We extracted study characteristics and outcome data at post-treatment and the longest available follow-up. We analysed intervention versus control comparisons for the primary outcome of migraine frequency. We measured migraine frequency using days with migraines or number of migraine attacks measured in the four weeks after treatment. In addition, we analysed the following secondary outcomes: responder rate (the proportion of participants with a 50% reduction in migraine frequency between the four weeks prior to and the four weeks after treatment); migraine intensity; migraine duration; migraine medication usage; mood; quality of life; migraine-related disability; and proportion of participants reporting adverse events during the treatment. We included these variables, where available, at follow-up, the timing of which varied between the studies. We used the GRADE approach to judge the quality of the evidence. MAIN RESULTS: We found 21 RCTs including 2482 participants with migraine, and we extracted meta-analytic data from 14 of these studies. The majority of studies recruited participants through advertisements, included participants with migraine according to the International Classification of Headache Disorders (ICHD) criteria and those with and without aura. Most intervention arms were a form of behavioural or cognitive-behavioural therapy. The majority of comparator arms were no treatment, routine care or waiting list. Interventions varied from one 20-minute session to 14 hours of intervention. No study had unequivocally low risk of bias; all had at least one domain at high risk of bias, and 20 had two to five domains at high risk. Reporting of randomisation procedures and allocation concealment were at high or unclear risk of bias. We downgraded the quality of evidence for outcomes to very low, due to very serious limitations in study quality and imprecision. Reporting in trials was poor; we found no preregistrations stipulating the outcomes, or demonstrating equivalent expectations between groups. Few studies reported our outcomes of interest, most only reported outcomes post treatment; follow-up data were sparse.Post-treatment effectsWe found no evidence of an effect of psychological interventions for migraine frequency in number of migraines or days with migraine (standardised mean difference (SMD) -0.02, 95% confidence interval (CI) -0.17 to 0.13; 4 studies, 681 participants; very low-quality evidence).The responder rate (proportion of participants with migraine frequency reduction of more than 50%) was greater for those who received a psychological intervention compared to control: 101/186 participants (54%) with psychological therapy; 37/152 participants (24%) with control (risk ratio (RR) 2.21, 95% CI 1.63 to 2.98; 4 studies, 338 participants; very low-quality evidence). We found no effect of psychological therapies on migraine intensity (SMD -0.13, 95% CI -0.28 to 0.02; 4 studies, 685 participants). There were no data for migraine duration (hours of migraine per day). There was no effect on migraine medication usage (SMD -0.06, 95% CI -0.35 to 0.24; 2 studies, 483 participants), mood (mean difference (MD) 0.08, 95% CI -0.33 to 0.49; 4 studies, 432 participants), quality of life (SMD -0.02, 95% CI -0.30 to 0.26; 4 studies, 565 participants), or migraine-related disability (SMD -0.67, 95% CI -1.34 to 0.00; 6 studies, 952 participants). The proportion of participants reporting adverse events did not differ between those receiving psychological treatment (9/107; 8%) and control (30/101; 30%) (RR 0.16, 95% CI 0.00 to 7.85; 2 studies, 208 participants). Only two studies reported adverse events and so we were unable to draw any conclusions.We rated evidence from all studies as very low quality.Follow-upOnly four studies reported any follow-up data. Follow-ups ranged from four months following intervention to 11 months following intervention. There was no evidence of an effect on any outcomes at follow-up (very low-quality evidence). AUTHORS' CONCLUSIONS: This review identified 21 studies of psychological interventions for the management of migraine. We did not find evidence that psychological interventions affected migraine frequency, a result based on four studies of primarily brief treatments. Those who received psychological interventions were twice as likely to be classified as responders in the short term, but this was based on very low-quality evidence and there was no evidence of an effect of psychological intervention compared to control at follow-up. There was no evidence of an effect of psychological interventions on medication usage, mood, migraine-related disability or quality of life. There was no evidence of an effect of psychological interventions on migraine frequency in the short-term or long-term. In terms of adverse events, we were unable to draw conclusions as there was insufficient evidence. High and unclear risk of bias in study design and reporting, small numbers of participants, performance and detection bias meant that we rated all evidence as very low quality. Therefore, we conclude that there is an absence of high-quality evidence to determine whether psychological interventions are effective in managing migraine in adults and we are uncertain whether there is any difference between psychological therapies and controls.

Clinical Predictors of Response to Baclofen in the Treatment of Alcohol use Disorder: Results from the BacALD Trial.

AIM: To examine clinical predictors of treatment response to baclofen in patients with alcohol use disorder (AUD). METHODS: Data from a randomised controlled trial (RCT) (N = 104), in which AUD patients received placebo or baclofen (30 mg/day or 75 mg/day) for 12 weeks, were analysed to determine predictive effects of the following four clinical characteristics: alcoholic liver disease (ALD), baseline alcohol consumption, craving and anxiety. Treatment outcomes included: (i) time to lapse and (ii) time to relapse. RESULTS: For both outcome measures, baclofen, irrespective of dose, was more effective when alcohol consumption was higher at baseline. Relative to placebo, baclofen increased time to first lapse in patients with higher baseline alcohol consumption (HR = 0.459, 95% CI = 0.219-0.962, P < 0.05). Similarly, baclofen increased time to first relapse in patients with higher alcohol consumption at baseline (HR = 0.360, 95% CI = 0.168-0.772, P < 0.05). There were no predictive effects of other baseline characteristics on time to lapse nor time to relapse. Directly comparing high dose of baclofen (75 mg/day) with low dose of baclofen (30 mg/day) revealed no differences with regards to predictors of baclofen response. CONCLUSION: Baclofen, relative to placebo, was more effective when alcohol consumption was higher at baseline.

Systematic Reviews of Mindfulness and Acceptance and Commitment Therapy for Alcohol Use Disorder: Should we be using Third Wave Therapies?

AIMS: Third wave therapies have shown efficacy for treating emotional disorders and potential for treating substance use disorders. There is developing interest in whether they can more specifically be used for treating alcohol use disorders (AUDs). We were interested in whether third wave therapies have value alongside current evidence-based psychosocial treatments for AUDs. METHOD: We conducted systematic reviews of third wave therapies for AUDs. We searched PsycINFO, Embase and Medline for peer reviewed journal articles where mindfulness or Acceptance and Commitment Therapy (ACT) were used to treat adults with AUDs or alcohol use that caused impairment. RESULTS: We identified 11 studies where mindfulness was used for treating AUDs and 6 where ACT was used for AUDs. The studies identified included RCTs, non-randomized controlled studies and uncontrolled studies. We found preliminary support that both third wave therapies are better than no treatment, treatments of minimal efficacy, as well as some evidence they are comparable to effective psychosocial treatments for AUDs. CONCLUSIONS: We conclude ACT and mindfulness provide an alternative to existing treatments, particularly for patients who have not responded to, or have disengaged from, standard treatments. We also found some evidence ACT and mindfulness are useful for comorbid mental health conditions. Yet while these results are promising, further research is needed to determine their utility, ideally employing randomized-controlled designs, larger clinical samples and longer follow-ups. Furthermore, few studies in this review directly compared third wave therapies to first line treatments, making it difficult to determine their relative efficacy.

Executive Functioning Moderates Responses to Appetitive Cues: A Study in Severe Alcohol Use Disorder and Alcoholic Liver Disease.

AIM: To examine subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task, and its relation to alcoholic liver disease and assess whether executive functioning is associated with appropriate regulation of cue-elicited responses in individuals with severe alcohol use disorder (AUD). METHODS: Seventeen treatment-seeking alcoholic liver disease patients and a control group of treatment-seeking severe AUD participants completed neuropsychological executive functioning measures (Stroop task; Trail-making test) and the cue reactivity task, whereby control (water) and alcohol beverage cues were presented, followed by respective recovery periods. Subjective alcohol craving and heart rate variability were recorded across the task. RESULTS: Overall cue reactivity and consequent recovery after cue offset during the cue reactivity task was observed, and alcoholic liver disease participants demonstrated a reduced overall recovery effect. Better Stroop performance related to greater overall and alcohol-specific cue reactivity within the control AUD group, and alcoholic liver disease participants showed dysfunctional activity regardless of executive functioning performance. No group differences in recovery effects according to executive functioning performance were seen. CONCLUSION: Among patients with AUD, having alcoholic liver disease seems to reduce overall regulation of responses to eliciting cues. Executive functioning moderated the magnitude of responses during cue exposures in our AUD sample overall; having alcoholic liver disease did not appear to affect regulation related to executive functioning during recovery.

Cue Exposure Therapy for Alcohol Use Disorders: What Can Be Learned from Exposure Therapy for Anxiety Disorders?

Background: Cue Exposure Therapy (CET) has shown efficacy for treating alcohol use disorders (AUDs). Exposure therapy is highly effective for treating anxiety. Both techniques involve repeated, controlled exposures to alcohol or fear-related stimuli. Objectives: We considered the mechanisms of CET for AUDs by comparing it to exposure therapy for anxiety. Method: We conducted a narrative review contrasting theoretical literature examining the mechanisms of CET versus exposure therapy for anxiety. We reviewed RCTs and acute laboratory paradigms examining CET for AUDs. We considered common areas of emerging research, including the use of d-Cycloserine (DCS) and virtual reality (VR). Results: We found evidence that exposure therapy and CET at least partially achieve their effects through extinction learning. We found evidence that CET for AUDs is effective, with comparable benefits to other effective psychosocial treatments. DCS and VR have shown some limited success for augmenting CET for AUDs, so further research is needed to determine their value. Conclusions: There are theoretical and practical similarities between exposure to fear cues and cues of addiction, especially regarding extinction learning. However, these processes are also unique, particularly regarding the differing motivational properties of fear versus reward-related stimuli. We propose that unlike exposure for anxiety, CET takes effect by increasing self-control with each unreinforced exposure. We consider reasons for CET's limited use for AUDs, including its lower acceptability to clients and clinicians. We also note the limited evidence for CET for other substance use disorders, highlighting the need for continued investigation into its mechanisms and efficacy.