Internalized Stigma Measurement in Substance Use Treatment Settings: A Narrative Review.

Stigma relating to substance use disorders is one of the many barriers to enrolling in substance use treatment. Stigma is also related to poorer substance use treatment outcomes, yet few studies of substance use and substance use treatment outcomes include measures of stigma. Stigma is a multi-level experience occurring as a result of discrimination within a systematic power structure promoting inequities among marginalized populations. Several domains of stigma are manifested among individuals seeking treatment for a substance use disorder, with internalized stigma being the most commonly measured. The current paper is a narrative review of measures that have been developed to measure internalized stigma related to substance use in treatment settings. Measures of stigma (n=8) in substance use treatment settings were identified using PubMed and PsycINFO databases. The review identified various strengths of existing measures, including a broad range of measures with mostly excellent internal consistency. The review also identified limitations including the general lack of consideration for multiple domains and intersecting forms of stigma, samples with limited racial and ethnic diversity, and the lack of assessments of polysubstance use. The development of measures of stigma that assess multiple domains of stigma and that are tested in a wide range of substance use treatment settings with racially and ethnically diverse participants is needed. This is of particular importance because stigma remains a crucial barrier to successful initiation and completion of substance use treatment.

Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis.

BACKGROUND: Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It is characterized by a diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems. Studies have so far largely failed to identify genetic associations, the mechanisms behind the disease, or any common pathophysiology with other conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that present with similar symptoms. METHODS: We used a combinatorial analysis approach to identify combinations of genetic variants significantly associated with the development of long COVID and to examine the biological mechanisms underpinning its various symptoms. We compared two subpopulations of long COVID patients from Sano Genetics' Long COVID GOLD study cohort, focusing on patients with severe or fatigue dominant phenotypes. We evaluated the genetic signatures previously identified in an ME/CFS population against this long COVID population to understand similarities with other fatigue disorders that may be triggered by a prior viral infection. Finally, we also compared the output of this long COVID analysis against known genetic associations in other chronic diseases, including a range of metabolic and neurological disorders, to understand the overlap of pathophysiological mechanisms. RESULTS: Combinatorial analysis identified 73 genes that were highly associated with at least one of the long COVID populations included in this analysis. Of these, 9 genes have prior associations with acute COVID-19, and 14 were differentially expressed in a transcriptomic analysis of long COVID patients. A pathway enrichment analysis revealed that the biological pathways most significantly associated with the 73 long COVID genes were mainly aligned with neurological and cardiometabolic diseases. Expanded genotype analysis suggests that specific SNX9 genotypes are a significant contributor to the risk of or protection against severe long COVID infection, but that the gene-disease relationship is context dependent and mediated by interactions with KLF15 and RYR3. Comparison of the genes uniquely associated with the Severe and Fatigue Dominant long COVID patients revealed significant differences between the pathways enriched in each subgroup. The genes unique to Severe long COVID patients were associated with immune pathways such as myeloid differentiation and macrophage foam cells. Genes unique to the Fatigue Dominant subgroup were enriched in metabolic pathways such as MAPK/JNK signaling. We also identified overlap in the genes associated with Fatigue Dominant long COVID and ME/CFS, including several involved in circadian rhythm regulation and insulin regulation. Overall, 39 SNPs associated in this study with long COVID can be linked to 9 genes identified in a recent combinatorial analysis of ME/CFS patient from UK Biobank. Among the 73 genes associated with long COVID, 42 are potentially tractable for novel drug discovery approaches, with 13 of these already targeted by drugs in clinical development pipelines. From this analysis for example, we identified TLR4 antagonists as repurposing candidates with potential to protect against long term cognitive impairment pathology caused by SARS-CoV-2. We are currently evaluating the repurposing potential of these drug targets for use in treating long COVID and/or ME/CFS. CONCLUSION: This study demonstrates the power of combinatorial analytics for stratifying heterogeneous populations in complex diseases that do not have simple monogenic etiologies. These results build upon the genetic findings from combinatorial analyses of severe acute COVID-19 patients and an ME/CFS population and we expect that access to additional independent, larger patient datasets will further improve the disease insights and validate potential treatment options in long COVID.

Measuring Readiness to Change Substance Use, Alcohol Use, and Cannabis Use: An Experimental Manipulation of Cognitive Effort.

Background: The Transtheoretical Model supports that readiness to change should predict actual substance-related behavior change. This relationship is surprisingly modest. Across several behavioral domains, individuals tend to have unrealistic expectations regarding the amount of effort and time required to successfully change one's behaviors, dubbed the False Hope Syndrome. Objectives: Based on False Hope Syndrome, we expect the standard method of measuring self-reported readiness to change is overestimated. To test this hypothesis, we experimentally manipulated level of cognitive effort prior to completing readiness to change measures. College students from a large southwestern university who reported using substances in the past 30 days (n = 345) were recruited from a psychology department participant pool and randomized to one of three conditions: 1) standard, low effort condition, 2) medium effort condition (selected likes/dislikes of substance use and negative consequences of changing one's use), and 3) high effort condition (also provided written responses to how they would handle difficult situations related to changing their substance use). We conducted one-way ANOVAs with Tukey post-hoc comparisons to examine differences on three measures of readiness to change: the University of Rhode Island Change Assessment (URICA) scale as well as readiness and motivation rulers. Results: Contrary to our hypothesis, all significant statistical tests supported higher cognitive effort conditions reporting higher readiness to change. Although effect sizes were modest, higher cognitive effort appeared to increase self-reported readiness to change substance use. Conclusions: Additional work is needed to test how self-reported readiness to change relates to actual behavior change when assessed under the different effort conditions.

Utility of the Brief Young Adult Alcohol Consequences Questionnaire to Identify College Students At-Risk for Alcohol Related Problems: Relative Operating Characteristics across Seven Countries.

Background: It is important to identify students who would benefit from early interventions to reduce harmful drinking patterns and associated consequences. the Brief Young Adult Alcohol Consequences Questionnaire (B-YAACQ) could be particularly useful as a screening tool in university settings. Objectives. The present study examined the utility of the B-YAACQ to distinguish among students at-risk for problematic alcohol use as measured by the AUDIT. Objectives: The present study examined the utility of the B-YAACQ to distinguish among students at-risk for problematic alcohol use as measured by the AUDIT. Methods: A sample of 6382 students (mean age=20.28, SD=3.75, 72.2% females) from seven countries (i.e., U.S., Canada, South-Africa, Spain, Argentina, Uruguay, England) completed the B-YAACQ, the AUDIT and different measures of alcohol use. Results: ROC analyses suggested that a cutoff score of 5 maximized the YAACQ's discrimination utility to differentiate between students at low versus moderate/high risk in the total sample and across countries (except in Canada, where the cutoff was 4). In addition, a cutoff of 7 differentiated between students at low/moderate versus high risk in the total sample, while cutoffs of 10, 9, 8 and 7 differentiate between students at low/moderate versus high risk in Uruguay, U.S and Spain (10), Argentina (9), England (8), and Canada and South-Africa (7), respectively. Students classified at the three risk levels (i.e., low, moderate and high) differed in age (i.e., a younger age was associated with higher risk) and drinking patters (i.e., higher drinking frequency, quantity, binge drinking and AUDIT and B-YAACQ scores in the higher risk groups). Conclusions: This study suggest that the B-YAACQ is a useful tool to identify college students at-risk for experiencing problematic patterns of alcohol use.

Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis.

During apoptosis, pro-apoptotic BAX and BAK are activated, causing mitochondrial outer membrane permeabilisation (MOMP), caspase activation and cell death. However, even in the absence of caspase activity, cells usually die following MOMP Such caspase-independent cell death is accompanied by inflammation that requires mitochondrial DNA (mtDNA) activation of cGAS-STING signalling. Because the mitochondrial inner membrane is thought to remain intact during apoptosis, we sought to address how matrix mtDNA could activate the cytosolic cGAS-STING signalling pathway. Using super-resolution imaging, we show that mtDNA is efficiently released from mitochondria following MOMP In a temporal manner, we find that following MOMP, BAX/BAK-mediated mitochondrial outer membrane pores gradually widen. This allows extrusion of the mitochondrial inner membrane into the cytosol whereupon it permeablises allowing mtDNA release. Our data demonstrate that mitochondrial inner membrane permeabilisation (MIMP) can occur during cell death following BAX/BAK-dependent MOMP Importantly, by enabling the cytosolic release of mtDNA, inner membrane permeabilisation underpins the immunogenic effects of caspase-independent cell death.

Measurement invariance of the University of Rhode Island Change Assessment Scale in Project MATCH: An exploratory structural equation modeling approach.

BACKGROUND: Progression through the stages of change is a proposed mechanism underlying the effects of treatment for alcohol use disorder (AUD). However, examining stages of change as a mechanism of treatment effects requires that the measure be invariant across patient subgroups, treatment conditions, and time. In this study, we examined measurement invariance of the University of Rhode Island Change Assessment Scale (URICA) in Project MATCH using an exploratory structural equation modeling (ESEM) approach. METHODS: We conducted a secondary analysis of data from Project MATCH (N = 1726; Mage  = 40.2, SD = 10.9; 75.7% male; 80% non-Hispanic white), a multisite randomized clinical trial that tested three AUD treatments: Motivational Enhancement Therapy, Cognitive-Behavioral Therapy, or Twelve-Step Facilitation. Participants completed the 24-item URICA for assessing the stages of change in relation to drinking at baseline and post-treatment (3 months after baseline). RESULTS: A 4-factor ESEM provided a good fit to the data and a better fit to the data than a conventional 4-factor confirmatory factor analysis model. Further, the URICA demonstrated scalar invariance across each patient subgroup at baseline (sex, ethnicity, marital status, education, and parental history of AUD) and treatment condition at follow-up. However, the URICA was not longitudinally invariant as the metric model resulted in a significant decrement in model fit. CONCLUSIONS: Measurement invariance of the URICA over time was not supported. Longitudinally invariant measures of the stages of change are needed to test the proposal that progression through the stages explains treatment effects.

A ß-NMR study of the depth, temperature, and molecular-weight dependence of secondary dynamics in polystyrene: Entropy-enthalpy compensation and dynamic gradients near the free surface.

We investigated the depth, temperature, and molecular-weight (MW) dependence of the γ-relaxation in polystyrene glasses using implanted 8Li+ and ß-detected nuclear magnetic resonance. Measurements were performed on thin films with MW ranging from 1.1 to 641 kg/mol. The temperature dependence of the average 8Li spin-lattice relaxation time (T1 avg) was measured near the free surface and in the bulk. Spin-lattice relaxation is caused by phenyl ring flips, which involve transitions between local minima over free-energy barriers with enthalpic and entropic contributions. We used transition state theory to model the temperature dependence of the γ-relaxation, and hence T1 avg. There is no clear correlation of the average entropy of activation (Δ‡S̄) and enthalpy of activation (Δ‡H̄) with MW, but there is a clear correlation between Δ‡S̄ and Δ‡H̄, i.e., entropy-enthalpy compensation. This results in the average Gibbs energy of activation, Δ‡G, being approximately independent of MW. Measurements of the temperature dependence of T1 avg as a function of depth below the free surface indicate the inherent entropic barrier, i.e., the entropy of activation corresponding to Δ‡H̄ = 0, has an exponential dependence on the distance from the free surface before reaching the bulk value. This results in Δ‡G near the free surface being lower than the bulk. Combining these observations results in a model where the average fluctuation rate of the γ-relaxation has a "double-exponential" depth dependence. This model can explain the depth dependence of 1/T1 avg in polystyrene films. The characteristic length of enhanced dynamics is ∼6 nm and approximately independent of MW near room temperature.

Examining Cross-Country and Sex Differences on a Comprehensive Assessment of Protective Behavioral Strategies for Alcohol.

OBJECTIVE: Use of protective behavioral strategies (PBS) has been associated with reduced alcohol-related harms among college students. However, most of this research has been conducted among U.S. samples. The present study examines the use of PBS in an international context. METHOD: Participants (n = 1512) were recruited from universities in Spain (n = 298), Argentina (n = 439), and the U.S. (n = 775) to determine if there are differences in PBS use across countries and/or across sex. Further, we examined whether the association between PBS use and negative consequences differ across country and sex. RESULTS: We found that U.S. students reported the most frequent use of Stopping/Limiting Drinking PBS (M = 3.32, SD = 1.23) compared to Argentine (M = 2.89, SD = 0.97) and Spanish (M = 2.83, SD = 0.94) students. Argentine students reported the least frequent use of Serious Harm Reduction PBS (M = 4.57, SD = 0.99) compared to U.S. (M = 5.09, SD = 0.98) and Spanish (M = 5.03, SD = 0.78) students. Elastic net regression analyses stratified by country indicated most individual PBS predicted decreased negative alcohol-related consequences, although two items consistently predicted increased consequences and we observed some variability in the most predictive specific strategies in each country. Across each subscale and for 32 of 40 individual items, females reported more frequent use of PBS than males (ps<.05). CONCLUSIONS: From the perspective of developing and adapting interventions, we recommend the cultural context in which PBS are used is taken into account. Although future work is needed to delineate cultural factors underlying the country-level differences we found, these findings have implications for the most promising PBS to target for college students in each country.

Fleet's Geode: A Breakthrough Sensor for Real-Time Ambient Seismic Noise Tomography over DtS-IoT.

As most of the outcropping and shallow mineral deposits have been found, new technology is imperative to finding the hidden critical mineral deposits required to transition to renewable energy. One such new technique, called ambient seismic noise tomography, has shown promise in recent years as a low-cost, low environmental impact method that can image under cover and at depth. Wireless and compact nodal seismic technology has been instrumental to enable industry applications of ambient noise tomography, but these devices are designed for the active seismic reflection method and do not have the required sensitivity at low frequencies for ambient noise tomography, and real-time data transmission in remote locations requires significant infrastructure to be installed. In this paper, we show the development and testing of the Geode-a real-time seismic node purpose-built by Fleet Space Technologies for ambient seismic noise tomography on exploration scales. We discuss the key differences between current nodal technology and the Geode and show results of a field trial where the performance of the Geode is compared with a commercially popular nodal geophone. The use of a 2 Hz high sensitivity geophone and low noise digitiser results in an instrument noise floor that is more than 30 dB lower below 5 Hz than nodes that are commonly used in the industry. The increased sensitivity results in signal-to-noise ratios in the cross-correlation functions in the field trial that are more than double that of commercially available nodal geophone at low frequencies. When considering the full bandwidth of retrievable correlations in our study, using the Geode would reduce the required recording time from 75 h to 32 h to achieve an average signal-to-noise ratio in the cross-correlation functions of 10. We also discuss the integration of a real-time direct-to-satellite Internet of Things (DtS-IoT) modem in the Geode, which, together with edge processing of seismic data directly on the Geode, enables us to image the subsurface in real-time. During the field trial, the Geodes successfully transmitted more than 90% of the available preprocessed data packets. The Geode is compact enough so that several devices can be carried and installed by one field technician, whilst the array of stations do not require a base station to transmit data to the cloud for further processing. We believe this is the future of passive seismic surveys and will result in faster and more dynamic seismic imaging capabilities analogous to the medical imaging community, increasing the pace at which new mineral deposits are discovered.

Magnesium(II)-ATP Complexes in 1-Ethyl-3-Methylimidazolium Acetate Solutions Characterized by 31 Mg ß-Radiation-Detected NMR Spectroscopy.

The complexation of MgII with adenosine 5'-triphosphate (ATP) is omnipresent in biochemical energy conversion, but is difficult to interrogate directly. Here we use the spin- 1/2 ß-emitter 31 Mg to study MgII -ATP complexation in 1-ethyl-3-methylimidazolium acetate (EMIM-Ac) solutions using ß-radiation-detected nuclear magnetic resonance (ß-NMR). We demonstrate that (nuclear) spin-polarized 31 Mg, following ion-implantation from an accelerator beamline into EMIM-Ac, binds to ATP within its radioactive lifetime before depolarizing. The evolution of the spectra with solute concentration indicates that the implanted 31 Mg initially bind to the solvent acetate anions, whereafter they undergo dynamic exchange and form either a mono- (31 Mg-ATP) or di-nuclear (31 MgMg-ATP) complex. The chemical shift of 31 Mg-ATP is observed up-field of 31 MgMg-ATP, in accord with quantum chemical calculations. These observations constitute a crucial advance towards using ß-NMR to probe chemistry and biochemistry in solution.

Reduced Endothelial Leptin Signaling Increases Vascular Adrenergic Reactivity in a Mouse Model of Congenital Generalized Lipodystrophy.

The adipokine leptin, which is best-known for its role in the control of metabolic function, is also a master regulator of cardiovascular function. While leptin has been approved for the treatment of metabolic disorders in patients with congenital generalized lipodystrophy (CGL), the effects of chronic leptin deficiency and the treatment on vascular contractility remain unknown. Herein, we investigated the effects of leptin deficiency and treatment (0.3 mg/day/7 days) on aortic contractility in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-, model of CGL) and their wild-type control (gBscl2+/+), as well as in mice with selective deficiency in endothelial leptin receptor (LepREC-/-). Lipodystrophy selectively increased vascular adrenergic contractility via NO-independent mechanisms and induced hypertrophic vascular remodeling. Leptin treatment and Nox1 inhibition blunted adrenergic hypercontractility in gBscl2-/- mice, however, leptin failed to rescue vascular media thickness. Selective deficiency in endothelial leptin receptor did not alter baseline adrenergic contractility but abolished leptin-mediated reduction in adrenergic contractility, supporting the contribution of endothelium-dependent mechanisms. These data reveal a new direct role for endothelial leptin receptors in the control of vascular contractility and homeostasis, and present leptin as a safe therapy for the treatment of vascular disease in CGL.

Understanding alcohol harm reduction behaviors from the perspective of self-determination theory: A research agenda.

The evidence for the efficacy of harm reduction approaches to harmful alcohol use has accumulated over the past 30 years. Self-determination theory (SDT; Ryan and Deci 2017) offers a useful framework for understanding why people engage in alcohol harm reduction behaviors, as well as for delineating active ingredients of harm reduction interventions and individual characteristics that influence response to intervention. In the current paper, we sought to advance a research agenda for applying SDT to alcohol harm reduction behaviors. Specifically, we provide specific examples of the utility of SDT in advancing research on alcohol harm reduction behaviors and provide recommendations for future studies to address issues related to measurement, generalizability, temporal directionality, and causal relationships in examining the constructs of SDT and alcohol harm reduction behaviors. We also suggest that future research apply SDT to advance the understanding of how, why, and for whom harm reduction interventions are most effective. Finally, we provide recommendations for how SDT could potentially be applied to develop novel alcohol interventions.

The Addictions Neuroclinical Assessment Negative Emotionality Domain Among Treatment-Seekers with Alcohol Use Disorder: Construct Validity and Measurement Invariance.

BACKGROUND: The Addictions Neuroclinical Assessment (ANA), a framework for measuring heterogeneity in alcohol use disorder (AUD), focuses on 3 domains that reflect neurobiological dysfunction in addiction and correspond to the cycles of addiction: executive function, incentive salience, and negative emotionality. Kwako and colleagues (Am J Psychiatry 176:744, 2019) validated a 3-factor model of the ANA with neuropsychological and self-report indicators among treatment-seekers and non-treatment-seekers with and without AUD. The present analysis replicated and extended these findings in a treatment-seeking sample, focusing on the negative emotionality domain. METHODS: Participants (n = 563; 58.8% male; mean age = 34.3) were part of a multisite prospective study of individuals entering AUD treatment. We examined the factor structure of the negative emotionality domain at the baseline, 6-month follow-up, and 12-month follow-up assessments. The Beck Depression Inventory, Beck Anxiety Inventory, State-Trait Anger Expression Inventory-Trait Anger Subscale, and 3 Drinker Inventory of Consequences items assessing negative affective consequences were indicators in the model. RESULTS: Results indicated that a 1-factor model was an excellent fit at all assessments and that the negative emotionality domain was time and gender invariant. Furthermore, negative emotionality was associated with drinking patterns and reasons for alcohol use (i.e., drinking because of negative emotions and urges/withdrawal) at all assessments. CONCLUSIONS: This analysis provides evidence for the construct validity and measurement invariance of the ANA negative emotionality domain among AUD treatment-seekers. Future studies are needed to evaluate prospective associations between negative emotionality and specific treatment modalities, and whether individuals with greater negative emotionality are more likely to respond to treatment that targets drinking to relieve negative affective states.

Can Alcohol Use Disorder Recovery Include Some Heavy Drinking? A Replication and Extension up to 9 Years Following Treatment.

BACKGROUND: Recent research indicates some individuals who engage in heavy drinking following treatment for alcohol use disorder fare as well as those who abstain with respect to psychosocial functioning, employment, life satisfaction, and mental health. The current study evaluated whether these findings replicated in an independent sample and examined associations between recovery profiles and functioning up to 6 years later. METHODS: Data were from the 3-year and 7- to 9-year follow-ups of subsamples initially recruited for the COMBINE study (3-year follow-up: n = 694; 30.1% female, 21.0% non-White; 7- to 9-year follow-up: n = 127; 38.9% female, 27.8% non-White). Recovery at 3 years was defined by latent profile analyses including measures of health functioning, quality of life, employment, alcohol consumption, and cannabis and other drug use. Functioning at the 7- to 9-year follow-up was assessed using single items of self-rated general health, hospitalizations, and alcohol consumption. RESULTS: We identified 4 profiles at the 3-year follow-up: (i) low-functioning frequent heavy drinkers (13.9%), (ii) low-functioning infrequent heavy drinkers (15.8%), (iii) high-functioning heavy drinkers (19.4%), and (iv) high-functioning infrequent drinkers (50.9%). At the 7- to 9-year follow-up, the 2 high-functioning profiles had the best self-rated health, and the high-functioning heavy drinking profile had significantly fewer hospitalizations than the low-functioning frequent heavy drinking profile. CONCLUSIONS: Previous findings showing heterogeneity in recovery outcomes were replicated. Most treatment recipients functioned well for years after treatment, and a subset who achieved stable recovery engaged in heavy drinking and reported good health outcomes up to 9 years after treatment. Results question the long-standing emphasis on drinking practices as a primary outcome, as well as abstinence as a recovery criterion in epidemiologic and treatment outcome research and among stakeholder groups and funding/regulatory agencies. Findings support an expanded recovery research agenda that considers drinking patterns, health, life satisfaction, and functioning.

General Method for Determining Redox Potentials without Electrolyte.

A novel method to determine redox potentials without electrolyte is presented. The method is based on a new ability to determine the dissociation constant, K°d, for ion pairs formed between any radical anion and any inert electrolyte counterion. These dissociation constants can be used to determine relative shifts of redox potential as a function of electrolyte concentration, connecting referenced potentials determined with electrochemistry (with 0.1 M electrolyte) to electrolyte-free values. Pulse radiolysis created radical anions enabling determination of equilibrium constants for electron transfer between anions of donor and acceptor molecules as a function of electrolyte concentration in THF. The measurements determined "composite equilibrium constants", KeqC, which contain information about the dissociation constant for the electrolyte cations, X+, with the radical anions of both the donor, K°d(D-•,X+) and the acceptor, K°d(A-•,X+). Dissociation constants were obtained for a selection of radical anions with tetrabutylammonium (TBA+). The electrolyte was found to shift the reduction potentials of small molecules 1-methylpyrene and trans-stilbene by close to +130 mV whereas oligo-fluorenes and polyfluorenes experienced shifts of only (+25 ± 6) mV due to charge delocalization weakening the ion pair. These shifts for reduction of aromatic hydrocarbon molecules are smaller than shifts of +232 and +451 mV seen previously for benzophenone radical anion with TBA+ and Na+ respectively where the charge on the radical anion is localized largely on one C═O bond, thus forming a more tightly bound ion pair.

The Relationship between Negative Affect and Alcohol and Marijuana Use Outcomes among Dual Users.

Background: Past research with college students has found that substance use motives, particularly coping motives, mediate the relationship between negative affect and alcohol- and marijuana-related outcomes. Objectives: This study aimed to investigate substance use motives of dual users of both substances (past 30-day use; not necessarily simultaneous use) and identify any mediation effects that are either common to both substances or substance-specific. Methods: The majority of dual users (n = 2,034) identified as being White, non-Hispanic (63.8%), female (69.08%), and reported a mean age of 20.24 (SD = 3.16) years. To test study aims, path models were conducted such that negative affect (stress, depressive and anxiety symptoms) were independently modeled as predictors of substance use outcomes (i.e. quantity and consequences) via substance use motives. Results: All three negative affect symptoms were indirectly related to both alcohol and marijuana consequences via coping motives, such that higher negative affect was associated with higher coping motives; which in turn were positively associated with consequences. Substance-specific effects were also found: (a) stress was indirectly related to both alcohol and marijuana use quantity via enhancement motives, (b) depressive/anxiety symptoms were indirectly related to alcohol use quantity via enhancement motives, and (c) all three negative affect symptoms were indirectly related to both marijuana use quantity and negative consequences via expansion motives. Conclusions: Findings suggests that dual users of alcohol and marijuana with negative affect symptoms engage in substance use for similar reasons as single substance users with negative affect symptoms. Intervention efforts should examine ways to replace substance-related coping and expansion methods with non-substance-related methods.

Post-traumatic stress and marijuana outcomes: The mediating role of marijuana protective behavioral strategies.

Background: The present study investigated the mediating role of protective behavioral strategies for marijuana (PBSM) on the relationship between posttraumatic stress disorder (PTSD) and marijuana outcomes (i.e. marijuana use frequency, marijuana use quantity, cannabis use disorder (CUD) symptoms, and marijuana-related problems). Methods: Participants were 1,107 traditional age college students (Mage = 20.26, SD = 3.32; 66.5% White, non-Hispanic; 68.8% female), who reported consuming marijuana at least once in the last 30 days and completed measures of PTSD symptoms, PBSM, and marijuana-related outcomes. Results: PBSM significantly mediated the positive relationships between PTSD symptoms and both CUD symptoms and marijuana-related problems. More specifically, PTSD symptoms were negatively associated with PBSM, which in turn was negatively associated with marijuana use frequency and marijuana use quantity, which were in turn positively associated with CUD symptoms and marijuana-related problems. Conclusion: Taken together, the associations between higher PTSD symptoms and greater experience of CUD symptoms and marijuana-related problems may occur because students use fewer PBSM and thus engage in larger quantity and frequency of marijuana use. These findings lend support to the utility of targeting PBSM as a harm reduction effort for students with PTSD symptoms who use marijuana.

Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex.

Astrocytes serve many functions in the human brain, many of which focus on maintenance of homeostasis. Astrocyte dysfunction in Tuberous Sclerosis Complex (TSC) has long been appreciated with activation of the mTORC1 signaling pathway resulting in gliosis and possibly contributing to the very frequent phenotype of epilepsy. We hypothesized that aberrant expression of the astrocyte protein aquaporin-4 (AQP4) may be present in TSC and contribute to disease pathology. Characterization of AQP4 expression in epileptic cortex from TSC patients demonstrated a diffuse increase in AQP4. To determine if this was due to exposure to seizures, we examined Aqp4 expression in mouse models of TSC in which Tsc1 or Tsc2 inactivation was targeted to astrocytes or glial progenitors, respectively. Loss of either Tsc1 or Tsc2 from astrocytes resulted in a marked increase in Aqp4 expression which was sensitive to mTORC1 inhibition with rapamycin. Our findings in both TSC epileptogenic cortex and in a variety of astrocyte culture models demonstrate for the first time that AQP4 expression is dysregulated in TSC. The extent to which AQP4 contributes to epilepsy in TSC is not known, though the similarities in AQP4 expression between TSC and temporal lobe epilepsy supports further studies targeting AQP4 in TSC.

Fronto-limbic white matter microstructure, behavior, and emotion regulation in survivors of pediatric brain tumor.

PURPOSE: After treatment, pediatric brain tumor survivors (PBTS) face emotional and behavioral challenges, perhaps due to tumor or treatment-related changes in brain structures involved in emotion regulation, including those with fronto-limbic connections. We hypothesized that relative to healthy controls (HCs), PBTS would exhibit greater difficulties with behavior and emotional functioning, and display reduced mean fractional anisotropy (mFA) in white matter tracts with fronto-limbic connections including the cingulum bundle (CB), inferior fronto-occipital fasciculus (IFOF), and uncinate fasciculus (UF). We further predicted that mFA would account for variance in the relationship between group and emotional/behavioral outcome. METHODS: Eleven 8-16 year old PBTS and 14 HCs underwent MRI, including diffusion tensor imaging to assess white matter microstructure. Tractography quantified mFA of selected tracts. Parents rated children's emotional and behavioral functioning. RESULTS: Compared to HCs, caregivers of PBTS reported poorer behavioral regulation and greater internalizing and externalizing symptoms. Relative to HCs, PBTS had lower mFA within the bilateral CB, IFOF, and UF (ds = 0.59-1.15). Across groups, several medium-to-large correlations linked tract mFA and increased internalizing, externalizing, and poor behavioral regulation. Tract mFA also accounted for significant variance in the group-outcome association. CONCLUSIONS: Reduced mFA in fronto-limbic associated tracts may be associated with reduced behavioral regulation following pediatric brain tumor. PBTS with treatment known to impact white matter may be most susceptible. Research with larger, longitudinal samples should clarify this relationship, allow for multiple mediators across time, and consider factors like tumor and treatment type.

The Relationship Between Social Anxiety and Alcohol and Marijuana Use Outcomes Among Concurrent Users: A Motivational Model of Substance Use.

BACKGROUND: College students with more social anxiety symptoms are particularly vulnerable to problematic alcohol and marijuana use given their susceptibility for elevated anxiety symptoms in social settings combined with the normative nature of substance use. Existing research has established substance use as coping motivated for these students when examining alcohol and marijuana use problems separately. The next step is to determine whether students with more social anxiety who use both substances do so for similar or different reasons. The current study tested a comprehensive (i.e., all variables in the same model) motivational model of alcohol/marijuana use in a sample of college students from 10 universities across the United States who endorsed both past-month alcohol and marijuana use. METHODS: College students were recruited through psychology department participant pools and completed an online survey assessing mental health symptoms, substance use motives, and substances use behaviors. Current sample comprised concurrent alcohol/marijuana users (n = 2,034), 29.6% of whom endorsed clinically indicated levels of social anxiety and nearly one-fourth exceeded the cutoff for hazardous drinking (23.2%) and hazardous marijuana use (21.9%). RESULTS: Across both substances, coping motives significantly mediated the positive relationship between social anxiety symptoms and substance use problems. Unique to alcohol, conformity motives mediated the association between social anxiety symptoms and alcohol-related problems. CONCLUSIONS: Taken together, students with more social anxiety who are focused on anxiety management may use either alcohol or marijuana; however, these students may experience more alcohol-related problems when drinking to fit in with peers.