Selective Reduction of Socioeconomic Disparities in the Experimental Tobacco Marketplace: Effects of Cigarette and E-cigarette Flavor Restrictions.

INTRODUCTION: Cigarette smoking accounts for >30% of the socioeconomic gap in life expectancy. Flavored restrictions claim to promote equity; however, no previous studies have compared the effect of cigarette and e-cigarette flavor restrictions among individuals who smoke with lower and higher socioeconomic status (SES). AIMS AND METHODS: In a between-group within-subject design, individuals with lower (n = 155) and higher (n = 125) SES completed hypothetical purchasing trials in the experimental tobacco marketplace (ETM). Conditions were presented in a 2 × 2 factorial design (cigarette flavors restricted or unrestricted and e-cigarette flavors restricted or unrestricted) with increasing cigarette prices across trials. RESULTS: Results show (1) SES differences in cigarette, e-cigarette, and NRT purchases under unrestricted policies, with lower SES showing higher cigarette demand and lower e-cigarette and NRT substitution than higher SES, (2) cigarette restrictions decreased cigarette and increased NRT purchases among lower SES, but no significant changes among higher SES, (3) decreased SES differences in cigarette demand under cigarette restrictions, but persistence under e-cigarette restrictions or their combination, (4) persistence of SES differences in e-cigarette purchases when all restrictions were enforced, and (5) waning of SES differences in NRT purchasing under all restrictions. CONCLUSIONS: Flavor restrictions differentially affected individuals based on SES. Within-group comparisons demonstrated restrictions significantly impacted lower SES, but not higher SES. Between-group comparisons showed SES differences in cigarette purchasing decreased under cigarette restrictions, but persisted under e-cigarette-restrictions or their combination. Additionally, SES differences in NRT substitution decreased under flavor restrictions. These findings highlight the utility of the ETM to investigate SES disparities. IMPLICATIONS: With increasing trends of socioeconomic differences in smoking prevalence and cessation rates, smoking-related health disparities are expected to continue to widen. Restricting menthol flavor in cigarettes while enhancing the availability and affordability of NRT have the potential to alleviate SES disparities in tobacco use, therefore, positively impacting health equity. However, this effect may depend on flavor availability in other tobacco products.

Impact of Standardized Multidisciplinary Critical Care Training on Confidence with Critical Illness and Attitudes Towards Interprofessional Education and Multidisciplinary Care.

INTRODUCTION: The Fundamental Critical Care Support Course (FCCS) is a standardized multidisciplinary program designed to educate participants on the basics of identification and management of patients with critical illness. Our objective was to evaluate the effect of FCCS participation on confidence in the assessment and management of critically ill patients and attitudes towards multidisciplinary education and interprofessional care in a multidisciplinary group of participants. METHODS: Participants enrolled in the FCCS course from May 2018 to November 2019 were solicited to participate in a series of surveys evaluating their course experience and confidence in critical care. Attitudes towards multidisciplinary education and interprofessional care were evaluated using the Student Perceptions of Interprofessional Clinical Education-Revised Instrument version 2 (SPICE-R2) tool. A prospective pre- and post-design with a self-report survey including retrospective pre-training assessment and a 3-month follow-up was conducted. Statistical analysis was performed using descriptive statics and non-parametric methods. RESULTS: 321 (97.9%) of the course participants enrolled in the study and completed the confidence survey and SPICE-R2 tool pre-course. Nurses (113, 35.4%) and physicians (110, 34.4%) made up the largest groups of participants, although physician assistants and paramedics were also well represented. Confidence in recognition and management of critical illness significantly improved across all studied domains after course completion, with the mean total confidence score improving from 32.96 pre-course to 41.10 post-course, P < 0.001. Attitudes towards multidisciplinary education and interprofessional care also improved (mean score 41.37 pre-course vs 42.71 post-course, P < 0.001), although pre-course numbers were higher than expected which limited the significance to only certain domains. DISCUSSION: In a multidisciplinary group, completion of FCCS training led to increased confidence in all aspects of critical illness measured. A modest increase in attitudes regarding multidisciplinary education and interprofessional care was also demonstrated. Further study is needed to assess whether this increased confidence translates to improvements in patient care and outcomes.

The phenotype of recovery XI: associations of sleep quality and perceived stress with discounting and quality of life in substance use recovery.

PURPOSE: Sleep and stress show an interdependent relationship in physiology, and both are known risk factors for relapse in substance use disorder (SUD) recovery. However, sleep and stress are often investigated independently in addiction research. In this exploratory study, the associations of sleep quality and perceived stress with delay discounting (DD), effort discounting (ED), and quality of life (QOL) were examined concomitantly to determine their role in addiction recovery. DD has been proposed as a prognostic indicator of SUD treatment response, ED is hypothesized to be relevant to the effort to overcome addiction, and QOL is an important component in addiction recovery. METHOD: An online sample of 118 individuals recovering from SUDs was collected through the International Quit and Recovery Registry. Exhaustive model selection, using the Bayesian Information Criterion to determine the optimal multiple linear model, was conducted to identify variables (i.e., sleep quality, perceived stress, and demographics) contributing to the total variance in DD, ED, and QOL. RESULTS: After model selection, sleep was found to be significantly associated with DD. Stress was found to be significantly associated with psychological health, social relationships, and environment QOL. Both sleep and stress were found to be significantly associated with physical health QOL. Neither sleep nor stress was supported as an explanatory variable of ED. CONCLUSION: Together, these findings suggest sleep and stress contribute uniquely to the process of addiction recovery. Considering both factors when designing interventions and planning for future research is recommended.

Illegal Experimental Tobacco Marketplace II: effects of vaping product bans - findings from the 2020 International Tobacco Control Project.

SIGNIFICANCE: Restrictive e-cigarette policies may increase purchases from illegal sources. The Illegal Experimental Tobacco Marketplace (IETM) allows examination of how restrictions impact illegal purchases. We investigated (1) the effect of a vaping ban, total flavour vaping ban and partial flavour vaping ban on the probability of purchasing illegal vaping products among different regulatory environments (USA, Canada and England) and tobacco user types (cigarette smokers, dual users and e-cigarette users); and (2) the relation between ban endorsement and illegal purchases. METHODS: Participants (N=459) from the International Tobacco Control Survey rated their support of bans and chose to purchase from a hypothetical legal experimental tobacco marketplace or IETM under control and the three ban conditions. RESULTS: In total, 25% of cigarette smokers, 67% of dual users and 79% of e-cigarette users made IETM purchases. Cross-country comparisons depicted dual users from Canada (OR: 19.8), and e-cigarette users from the USA (OR: 12.9) exhibited higher illegal purchases odds than the same user type in England. Within-country comparisons showed e-cigarette and dual users are more likely to purchase from the IETM than cigarette smokers in the most restrictive condition, with the largest effects in e-cigarette users (England-OR: 1722.6, USA-OR: 22725.3, Canada-OR: 6125.0). Increased opposition towards partial or total flavour ban was associated with increased IETM purchasing in the corresponding condition. CONCLUSIONS: Vaping restrictions may shift users' preference to the illegal marketplace in a regulatory environment. Evidence of the IETM generalisability in a geographically dispersed sample enhances its utility in tobacco regulatory science.

Antagonism between the RNA-binding protein Musashi1 and miR-137 and its potential impact on neurogenesis and glioblastoma development.

RNA-binding proteins (RBPs) and miRNAs are critical gene expression regulators that interact with one another in cooperative and antagonistic fashions. We identified Musashi1 (Msi1) and miR-137 as regulators of a molecular switch between self-renewal and differentiation. Msi1 and miR-137 have opposite expression patterns and functions, and Msi1 is repressed by miR-137. Msi1 is a stem-cell protein implicated in self-renewal while miR-137 functions as a proneuronal differentiation miRNA. In gliomas, miR-137 functions as a tumor suppressor while Msi1 is a prooncogenic factor. We suggest that the balance between Msi1 and miR-137 is a key determinant in cell fate decisions and disruption of this balance could contribute to neurodegenerative diseases and glioma development. Genomic analyses revealed that Msi1 and miR-137 share 141 target genes associated with differentiation, development, and morphogenesis. Initial results pointed out that these two regulators have an opposite impact on the expression of their target genes. Therefore, we propose an antagonistic model in which this network of shared targets could be either repressed by miR-137 or activated by Msi1, leading to different outcomes (self-renewal, proliferation, tumorigenesis).

The Illegal Experimental Tobacco Marketplace I: Effects of Vaping Product Bans.

OBJECTIVES: Banning vaping products may have unintended outcomes, such as increased demand for illegal products. This study experimentally examined the effects of a vaping ban and a flavored vaping ban on the probability of purchasing illicit vaping products, and factors affecting purchasing from a hypothetical illegal marketplace. METHODS: A crowdsourced sample of exclusive cigarette smokers, exclusive e-cigarette users, and frequent dual users (n = 150) completed hypothetical purchasing trials in an Experimental Tobacco Marketplace under three conditions (no ban, vaping ban, and flavored vaping ban). Participants chose to purchase in a hypothetical legal experimental tobacco marketplace (LETM) or illegal experimental tobacco marketplace (IETM). Vaping products were available in each marketplace depending on the condition. Other tobacco products were always available in the LETM. A hypothetical illicit purchase task with five fine amounts assessed the effect of monetary penalties. RESULTS: Participants from all groups were more likely to purchase from the IETM when product availability in the LETM was more restricted, with e-cigarette users being most affected. The likelihood of purchasing illegal products was systematically decreased as monetary penalties associated with the IETM increased, with e-cigarette users showing greater persistence in defending their illicit purchases. CONCLUSIONS: Restricting vaping products from the marketplace may shift preference towards purchasing vaping products in the illegal marketplace. Nevertheless, penalties imposed on consumer's behavior might be effective in preventing illicit trade. The IETM is a methodological extension that supports the utility and flexibility of the ETM as a framework for understanding the impact of different tobacco regulatory policies. IMPLICATIONS: This study suggests that limiting or banning vaping products as a possible strategy to reduce the adverse effects of vaping products could result in some tobacco-users seeking banned products from illegal sources. Monetary fines were shown to reduce illegal purchases. Therefore, policymakers should consider implementing strategies that may mitigate illegal purchases.

Attenuating loss of cardiac conduction during no-flow ischemia through changes in perfusate sodium and calcium.

Myocardial ischemia leads to conduction slowing, cell-to-cell uncoupling, and arrhythmias. We previously demonstrated that varying perfusate sodium (Na+) and calcium (Ca2+) attenuates conduction slowing and arrhythmias during simulated ischemia with continuous perfusion. Cardioprotection was selectively associated with widening of the perinexus, a gap junction adjacent nanodomain important to ephaptic coupling. It is unknown whether perfusate composition affects the perinexus or ischemic conduction during nonsimulated ischemia, when coronary flow is reduced or halted. We hypothesized that altering preischemic perfusate composition could facilitate perinexal expansion and attenuate conduction slowing during global ischemia. To test this hypothesis, ex vivo guinea pig hearts (n = 49) were Langendorff perfused with 145 or 153 mM Na+ and 1.25 or 2.0 mM Ca2+ and optically mapped during 30 min of no-flow ischemia. Altering Na+ and Ca2+ did not substantially affect baseline conduction. Increasing Na+ and decreasing Ca2+ both lowered pacing thresholds, whereas increasing Ca2+ narrowed perinexal width (Wp). A least squares mean estimate revealed that reduced perfusate Na+ and Ca2+ resulted in the most severe conduction slowing during ischemia. Increasing Na+ alone modestly attenuated conduction slowing, yet significantly delayed the median time to conduction block (10 to 16 min). Increasing both Na+ and Ca2+ selectively widened Wp during ischemia (22.7 vs. 15.7 nm) and attenuated conduction slowing to the greatest extent. Neither repolarization nor levels of total or phosphorylated connexin43 correlated with conduction slowing or block. Thus, perfusate-dependent widening of the perinexus preserved ischemic conduction and may be an adaptive response to ischemic stress.NEW & NOTEWORTHY Conduction slowing during acute ischemia creates an arrhythmogenic substrate. We have shown that extracellular ionic concentrations can alter conduction by modulating ephaptic coupling. Here, we demonstrate increased extracellular sodium and calcium significantly attenuate conduction slowing during no-flow ischemia. This effect was associated with selective widening of the perinexus, an intercalated disc nanodomain and putative cardiac ephapse. These findings suggest that acute changes in ephaptic coupling may serve as an adaptive response to ischemic stress.

A Machine-Learning Approach to Predicting Smoking Cessation Treatment Outcomes.

AIMS: Most cigarette smokers want to quit smoking and more than half make an attempt every year, but less than 10% remain abstinent for at least 6 months. Evidence-based tobacco use treatment improves the likelihood of quitting, but more than two-thirds of individuals relapse when provided even the most robust treatments. Identifying for whom treatment is effective will improve the success of our treatments and perhaps identify strategies for improving current approaches. METHODS: Two cohorts (training: N = 90, validation: N = 71) of cigarette smokers enrolled in group cognitive-behavioral therapy (CBT). Generalized estimating equations were used to identify baseline predictors of outcome, as defined by breath carbon monoxide and urine cotinine. Significant measures were entered as candidate variables to predict quit status. The resulting decision trees were used to predict cessation outcomes in a validation cohort. RESULTS: In the training cohort, the decision trees significantly improved on chance classification of smoking status following treatment and at 6-month follow-up. The first split of all decision trees, which was delay discounting, significantly improved on chance classification rates in both the training and validation cohort. Delay discounting emerged as the single best predictor of group CBT treatment response with an average baseline discount rate of ln(k) = -7.1, correctly predicting smoking status of 80% of participants at posttreatment and 81% of participants at follow-up. CONCLUSIONS: This study provides a first step toward personalized care for smoking cessation though future work is needed to identify individuals that are likely to be successful in treatments beyond group CBT. IMPLICATIONS: This study provides a first step toward personalized care for smoking cessation. Using a novel machine-learning approach, baseline measures of clinical and executive functioning are used to predict smoking cessation outcomes following group CBT. A decision point is recommended for the single best predictor of treatment outcomes, delay discounting, to inform future research or clinical practice in an effort to better allocate patients to treatments that are likely to work.

Willing to Work But Not to Wait: Individuals with Greater Alcohol Use Disorder Show Increased Delay Discounting Across Commodities and Less Effort Discounting for Alcohol.

BACKGROUND: Delay discounting refers to the devaluation of a reward given increasing delays to delivery. Similarly, effort discounting refers to the devaluation of a reward given increasing effort required to obtain it. Individuals with substance use disorder show higher rates of delay discounting, exacerbating short-term positive reinforcement at the expense of long-term consequences. This study explores how effort discounting compares to delay discounting behavior among alcohol users as well as how these preferences change between monetary and alcohol rewards. METHODS: A total of 100 participants completed an online survey through Amazon Mechanical Turk. Participant alcohol use was evaluated using DSM-5 and the Alcohol Use Disorders Identification Test criteria. All participants completed 4 randomized discounting tasks involving delay or effort discounting, in which the reward was money or alcohol. A follow-up experiment (n = 423) added the alcohol purchase task to assess alcohol valuation. RESULTS: Individuals with greater alcohol use disorder (AUD) severity discounted future money and alcohol significantly more than those with less AUD. However, individuals meeting more DSM-5 criteria were only willing to perform more effort for alcohol. The follow-up experiment replicated these findings and demonstrated that individuals with greater AUD also showed an increased valuation of alcohol and alcohol value-mediated effort discounting. CONCLUSIONS: These results suggest that individuals with greater AUD were less willing to wait for money or alcohol. While all participants were willing to work for money regardless of AUD severity, individuals with greater AUD showed increased valuation of alcohol drinks and were willing to exert more effort to obtain alcohol. Together, these results paint a picture of individuals with increased AUD as both more impulsive and willing to work to obtain alcohol, contributing to our understanding of decision making among individuals who abuse substances.

XTalkDB: a database of signaling pathway crosstalk.

Analysis of signaling pathways and their crosstalk is a cornerstone of systems biology. Thousands of papers have been published on these topics. Surprisingly, there is no database that carefully and explicitly documents crosstalk between specific pairs of signaling pathways. We have developed XTalkDB (http://www.xtalkdb.org) to fill this very important gap. XTalkDB contains curated information for 650 pairs of pathways from over 1600 publications. In addition, the database reports the molecular components (e.g. proteins, hormones, microRNAs) that mediate crosstalk between a pair of pathways and the species and tissue in which the crosstalk was observed. The XTalkDB website provides an easy-to-use interface for scientists to browse crosstalk information by querying one or more pathways or molecules of interest.

GraphSpace: stimulating interdisciplinary collaborations in network biology.

SUMMARY: Networks have become ubiquitous in systems biology. Visualization is a crucial component in their analysis. However, collaborations within research teams in network biology are hampered by software systems that are either specific to a computational algorithm, create visualizations that are not biologically meaningful, or have limited features for sharing networks and visualizations. We present GraphSpace, a web-based platform that fosters team science by allowing collaborating research groups to easily store, interact with, layout and share networks. AVAILABILITY AND IMPLEMENTATION: Anyone can upload and share networks at http://graphspace.org. In addition, the GraphSpace code is available at http://github.com/Murali-group/graphspace if a user wants to run his or her own server. CONTACT: murali@cs.vt.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Episodic future thinking reduces delay discounting and cigarette demand: an investigation of the good-subject effect.

Episodic future thinking (EFT), an intervention involving mental simulation of future events, has been shown to reduce both delay discounting and cigarette self-administration. In the present study, we extended these findings by showing that EFT in a web-based sample of smokers reduces delay discounting and intensity of demand for cigarettes (ad libitum consumption) in a hypothetical purchase task. No effect was observed on elasticity of demand (sensitivity to price) or cigarette craving. We also explored whether demand characteristics (specifically, the "good-subject" effect) might be responsible for observed effects. EFT participants were significantly better able than control participants to discern the experimental hypothesis. However, EFT participants were not better than controls at identifying whether they had been assigned to the experimental group and, likewise, showed no differences in attitudes about the experiment and experimenter. Importantly, effects of EFT on delay discounting and demand remained significant even when controlling for measures of demand characteristics, indicating that EFT's effects are independent of participants' perceptions about the experiment.

Xtalk: a path-based approach for identifying crosstalk between signaling pathways.

MOTIVATION: Cells communicate with their environment via signal transduction pathways. On occasion, the activation of one pathway can produce an effect downstream of another pathway, a phenomenon known as crosstalk. Existing computational methods to discover such pathway pairs rely on simple overlap statistics. RESULTS: We present Xtalk, a path-based approach for identifying pairs of pathways that may crosstalk. Xtalk computes the statistical significance of the average length of multiple short paths that connect receptors in one pathway to the transcription factors in another. By design, Xtalk reports the precise interactions and mechanisms that support the identified crosstalk. We applied Xtalk to signaling pathways in the KEGG and NCI-PID databases. We manually curated a gold standard set of 132 crosstalking pathway pairs and a set of 140 pairs that did not crosstalk, for which Xtalk achieved an area under the receiver operator characteristic curve of 0.65, a 12% improvement over the closest competing approach. The area under the receiver operator characteristic curve varied with the pathway, suggesting that crosstalk should be evaluated on a pathway-by-pathway level. We also analyzed an extended set of 658 pathway pairs in KEGG and to a set of more than 7000 pathway pairs in NCI-PID. For the top-ranking pairs, we found substantial support in the literature (81% for KEGG and 78% for NCI-PID). We provide examples of networks computed by Xtalk that accurately recovered known mechanisms of crosstalk. AVAILABILITY AND IMPLEMENTATION: The XTALK software is available at http://bioinformatics.cs.vt.edu/~murali/software. Crosstalk networks are available at http://graphspace.org/graphs?tags=2015-bioinformatics-xtalk. CONTACT: ategge@vt.edu, murali@cs.vt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

miR-124, -128, and -137 Orchestrate Neural Differentiation by Acting on Overlapping Gene Sets Containing a Highly Connected Transcription Factor Network.

The ventricular-subventricular zone harbors neural stem cells (NSCs) that can differentiate into neurons, astrocytes, and oligodendrocytes. This process requires loss of stem cell properties and gain of characteristics associated with differentiated cells. miRNAs function as important drivers of this transition; miR-124, -128, and -137 are among the most relevant ones and have been shown to share commonalities and act as proneurogenic regulators. We conducted biological and genomic analyses to dissect their target repertoire during neurogenesis and tested the hypothesis that they act cooperatively to promote differentiation. To map their target genes, we transfected NSCs with antagomiRs and analyzed differences in their mRNA profile throughout differentiation with respect to controls. This strategy led to the identification of 910 targets for miR-124, 216 for miR-128, and 652 for miR-137. The target sets show extensive overlap. Inspection by gene ontology and network analysis indicated that transcription factors are a major component of these miRNAs target sets. Moreover, several of these transcription factors form a highly interconnected network. Sp1 was determined to be the main node of this network and was further investigated. Our data suggest that miR-124, -128, and -137 act synergistically to regulate Sp1 expression. Sp1 levels are dramatically reduced as cells differentiate and silencing of its expression reduced neuronal production and affected NSC viability and proliferation. In summary, our results show that miRNAs can act cooperatively and synergistically to regulate complex biological processes like neurogenesis and that transcription factors are heavily targeted to branch out their regulatory effect.

Cross-commodity delay discounting of alcohol and money in alcohol users.

Despite real-world implications, the pattern of delay discounting in alcohol users when the commodities now and later differ has not been well characterized. In this study, 60 participants on Amazon's Mechanical Turk completed the Alcohol Use Disorder Identification Test (AUDIT) to assess severity of use and completed four delay discounting tasks between hypothetical, equivalent amounts of alcohol and money available at five delays. The tasks included two cross-commodity (alcohol now-money later and money now-alcohol later) and two same-commodity (money now-money later and alcohol now-alcohol later) conditions. Delay discounting was significantly associated with clinical cutoffs of the AUDIT for both of the cross-commodity conditions but not for either of the same-commodity delay discounting tasks. The cross-commodity discounting conditions were related to severity of use wherein heavy users discounted future alcohol less and future money more. The change in direction of the discounting effect was dependent on the commodity that was distally available suggesting a distinctive pattern of discounting across commodities when comparing light and heavy alcohol users.

Associations between delay discounting and unhealthy behaviors in substance use recovery.

BACKGROUND: Research on delay discounting (DD) is mixed on whether DD is a domain-specific component related to specific behaviors or a domain-general process that cuts across various behaviors. A pivotal group to test the associations between DD and unhealthy behaviors is individuals in recovery from substance use disorders (SUD), as they are moving away from a disorder toward a healthier state. METHODS: Individuals in SUD recovery (n = 317) completed the Temptation Scale, the Health Behaviors Questionnaire, and an Adjusting Delay Discounting Task. An exhaustive model space search was performed using linear regression to examine associations between DD with temptation, engagement in unhealthy behaviors, and the total number of unhealthy behaviors participants engage in. We also tested whether remission status is associated with the total number of unhealthy behaviors participants engage in. RESULTS: Results revealed that DD was positively associated with poor eating (p<.001), physical inactivity (p=.003), financial irresponsibility (p<.001), risky behaviors (p<.001), lack of personal development goals (p<.001), lack of household savings (p=.004), and lack of health behaviors (p=.003). DD was also positively associated with the total number of unhealthy behaviors participants engage in (p<.001). Participants who were not in remission engaged in more unhealthy behaviors compared to those who were in remission (p<.001). CONCLUSION: In a sample of individuals in recovery from SUD, DD is not domain-specific and undergirds engagement in several maladaptive health behaviors that can negatively impact recovery. Thus, DD can be a target for interventions aiming to reduce other maladaptive behaviors in SUD recovery.

Latent profiles of regulatory flexibility in alcohol use disorder: Associations with delay discounting and symptoms of depression, anxiety, and stress.

BACKGROUND: Regulatory flexibility (RF) involves three distinct components of self-regulation: context sensitivity, repertoire, and feedback responsiveness. Subgroups based on differences in RF have been identified in a general sample and are differentially associated with symptoms of anxiety and depression. However, potential RF profiles have not been examined in individuals with substance use disorders. This study examined RF subtypes in individuals with alcohol use disorder (AUD) and their associations with psychosocial outcomes (i.e., depression, anxiety, and stress) and delay discounting (a core feature of addiction). METHODS: Individuals (n = 200) with an Alcohol Use Disorders Identification Test score of >16 (mean = 24.12 (±6.92)) were recruited from Amazon Mechanical Turk (mean = 37.26 years old (±11.41); 94 (47%) women). Participants completed the Context Sensitivity Index, the Flexible Regulation of Emotional Expression Scale, and the Coping Flexibility Scale to assess RF. Participants also completed an Adjusting Amount Delay Discounting Task and the Depression, Anxiety, and Stress Scale (DASS-21). Latent profile analyses (LPA) were used to identify patterns in RF deficits. Kruskal-Wallis and Dunn's tests were performed to examine differences in discounting rates and symptoms of depression, anxiety, and stress across RF profiles. RESULTS: The LPA revealed a 2-profile characterization, including (1) context sensitive regulators (CSR; n = 39) and (2) moderate flexibility regulators (MFR; n = 161). CSR demonstrated significantly lower symptoms of depression (p = 0.004), anxiety (p < 0.001), and stress (p < 0.001) than MFR. CSR also displayed significantly lower AUDIT scores (p = 0.031). CONCLUSIONS: Findings illustrate that among individuals with moderate-severe AUD, those high in context sensitivity coupled with moderate abilities in repertoire and feedback responsiveness have fewer symptoms of depression, anxiety, and stress. Together, context sensitivity may be an important and protective component of RF among individuals with AUD.

Selective regulation of chemosensitivity in glioblastoma by phosphatidylinositol 3-kinase beta.

Resistance to chemotherapies such as temozolomide is a major hurdle to effectively treat therapy-resistant glioblastoma. This challenge arises from the activation of phosphatidylinositol 3-kinase (PI3K), which makes it an appealing therapeutic target. However, non-selectively blocking PI3K kinases PI3Kα/ß/δ/γ has yielded undesired clinical outcomes. It is, therefore, imperative to investigate individual kinases in glioblastoma's chemosensitivity. Here, we report that PI3K kinases were unequally expressed in glioblastoma, with levels of PI3Kß being the highest. Patients deficient of O6-methylguanine-DNA-methyltransferase (MGMT) and expressing elevated levels of PI3Kß, defined as MGMT-deficient/PI3Kß-high, were less responsive to temozolomide and experienced poor prognosis. Consistently, MGMT-deficient/PI3Kß-high glioblastoma cells were resistant to temozolomide. Perturbation of PI3Kß, but not other kinases, sensitized MGMT-deficient/PI3Kß-high glioblastoma cells or tumors to temozolomide. Moreover, PI3Kß-selective inhibitors and temozolomide synergistically mitigated the growth of glioblastoma stem cells. Our results have demonstrated an essential role of PI3Kß in chemoresistance, making PI3Kß-selective blockade an effective chemosensitizer for glioblastoma.

Understanding family-level decision-making when seeking access to acute surgical care for children: Protocol for a cross-sectional mixed methods study.

BACKGROUND: There is limited understanding of how social determinants of health (SDOH) impact family decision-making when seeking surgical care for children. Our objectives of this study are to identify key family experiences that contribute to decision-making when accessing surgical care for children, to confirm if family experiences impact delays in care, and to describe differences in family experiences across populations (race, ethnicity, socioeconomic status, rurality). METHODS: We will use a prospective, cross-sectional, mixed methods design to examine family experiences during access to care for children with appendicitis. Participants will include 242 parents of consecutive children (0-17 years) with acute appendicitis over a 15-month period at two academic health systems in North Carolina and Virginia. We will collect demographic and clinical data. Parents will be administered the Adult Responses to Children's Symptoms survey (ARCS), the child and parental forms of the Adverse Childhood Experiences (ACE) survey, the Accountable Health Communities Health-Related Social Needs Screening Tool, and Single Item Literacy Screener. Parallel ARCS data will be collected from child participants (8-17 years). We will use nested concurrent, purposive sampling to select a subset of families for semi-structured interviews. Qualitative data will be analyzed using thematic analysis and integrated with quantitative data to identify emerging themes that inform a conceptual model of family-level decision-making during access to surgical care. Multivariate linear regression will be used to determine association between the appendicitis perforation rate and ARCS responses (primary outcome). Secondary outcomes include comparison of health literacy, ACEs, and SDOH, clinical outcomes, and family experiences across populations. DISCUSSION: We expect to identify key family experiences when accessing care for appendicitis which may impact outcomes and differ across populations. Increased understanding of how SDOH and family experiences influence family decision-making may inform novel strategies to mitigate surgical disparities in children.

Utility of the 5-trial adjusting delay task in screening for high delay discounting rates: A cohort study of individuals reporting harmful alcohol and tobacco use.

High delay discounting (DD) rates are associated with several health conditions, including addiction. Investigators interested in the modulation of DD rates may be interested in screening for individuals with high DD rates within substance-using samples. The adjusting delay discounting task (ADT) is a brief DD rate measure suitable for screening purposes, but how performance on this task is related to more granular DD measures (e.g., adjusting amount task; AAT) in individuals who use substances is unknown. This study investigated the relationship between DD rates measured by the ADT and AAT to assess the utility of the ADT in screening for high discounting rates in individuals who use tobacco and alcohol. Participants (N = 488) were screened for high discounting rates, ln(k) ≥ -4.3118, using the ADT. Subsequently, participants completed the AAT. Linear regressions were conducted to understand the relationship between the ADT and AAT DD rates. Separate analyses between the total, high-quality and low-quality samples were conducted. Significant relationships between the ADT and AAT were found for the total (p < .001), high-quality (p < .001), and low-quality samples (p < .001). Although the ADT overestimated DD rates on the AAT by 2.49, 2.29, and 2.97 units in the total, high-quality, and low-quality samples, the ADT accurately identified individuals with high discounting rates. Specifically, 71% of the total sample, 80% of the high-quality sample, and 66% of the low-quality sample maintained a high DD rate on the AAT. These results demonstrate that ADT can be used as a quick, accurate screening tool to identify high discounting rates in individuals who use substances. (PsycInfo Database Record (c) 2023 APA, all rights reserved).