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.