Tacrolimus-binding protein FKBP8 directs myosin light chain kinase-dependent barrier regulation and is a potential therapeutic target in Crohn's disease.

OBJECTIVE: Intestinal barrier loss is a Crohn's disease (CD) risk factor. This may be related to increased expression and enzymatic activation of myosin light chain kinase 1 (MLCK1), which increases intestinal paracellular permeability and correlates with CD severity. Moreover, preclinical studies have shown that MLCK1 recruitment to cell junctions is required for tumour necrosis factor (TNF)-induced barrier loss as well as experimental inflammatory bowel disease progression. We sought to define mechanisms of MLCK1 recruitment and to target this process pharmacologically. DESIGN: Protein interactions between FK506 binding protein 8 (FKBP8) and MLCK1 were assessed in vitro. Transgenic and knockout intestinal epithelial cell lines, human intestinal organoids, and mice were used as preclinical models. Discoveries were validated in biopsies from patients with CD and control subjects. RESULTS: MLCK1 interacted specifically with the tacrolimus-binding FKBP8 PPI domain. Knockout or dominant negative FKBP8 expression prevented TNF-induced MLCK1 recruitment and barrier loss in vitro. MLCK1-FKBP8 binding was blocked by tacrolimus, which reversed TNF-induced MLCK1-FKBP8 interactions, MLCK1 recruitment and barrier loss in vitro and in vivo. Biopsies of patient with CD demonstrated increased numbers of MLCK1-FKBP8 interactions at intercellular junctions relative to control subjects. CONCLUSION: Binding to FKBP8, which can be blocked by tacrolimus, is required for MLCK1 recruitment to intercellular junctions and downstream events leading to immune-mediated barrier loss. The observed increases in MLCK1 activity, MLCK1 localisation at cell junctions and perijunctional MLCK1-FKBP8 interactions in CD suggest that targeting this process may be therapeutic in human disease. These new insights into mechanisms of disease-associated barrier loss provide a critical foundation for therapeutic exploitation of FKBP8-MLCK1 interactions.

Improving engagement and retention to treatment within VHA PTSD specialty care: Evolution of an outpatient program design.

The Veteran's Health Administration (VA) and Department of Defense (DoD) posttraumatic stress disorder (PTSD) clinical practice guidelines (2017) recommend individual, trauma-focused therapy as the gold standard of treatment for PTSD (i.e., evidence-based practices [EBP]). Moreover, these guidelines encourage the use of individual shared decision-making (SDM) to increase engagement and completion of EBPs for PTSD in line with current literature. This study retrospectively evaluated three models of program design of a VA PTSD specialty clinic over the past 8 years. In line with previous literature, the study hypothesized that leveraging individualized SDM in the clinic design would lead to increased completion of EBPs for PTSD. Analyses indicated an impact as the models shifted from a group-based model to an individualized model. Specifically, as compared to veterans who completed a group-based design, a greater proportion of those enrolled in the clinic were more likely to complete an EBP. These results may suggest that individualized, patient-centered treatment planning may be related to patient engagement in EBPs for PTSD in contrast with group-based models. Other programmatic changes, such as changes in treatment options presented to patients, a movement to focus on EBPs for PTSD, and expanded clinic hours and telehealth options, possibly impacted veteran engagement and completion in EBPs. The study highlights the potential impacts of a changing patient population within the clinic over a relatively short period. The observations are discussed, and limitations are highlighted. The study shares the hope for additional randomized prospective studies of program designs. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The association between mentoring and training outcomes in junior doctors in medicine: an observational study.

OBJECTIVE: To determine quantitatively if a positive association exists between the mentoring of junior doctors and better training outcomes in postgraduate medical training within the UK. DESIGN: Observational study. PARTICIPANTS: 117 trainees from the East of England Deanery (non-mentored group) and the recently established Royal College of Physicians (RCP) Mentoring scheme (mentored group) who were core medical trainees (CMTs) between 2015 and 2017 completed an online survey. Trainees who received mentoring at the start of higher specialty training, incomplete responses and trainees who were a part of both the East of England deanery and RCP Mentoring scheme were excluded leaving 85 trainees in the non-mentored arm and 25 trainees in the mentored arm. Responses from a total of 110 trainees were analysed. MAIN OUTCOME MEASURES: Pass rates of the various components of the Membership of the Royal College of Physicians (MRCP) (UK) examination (MRCP Part 1, MRCP Part 2 Written and MRCP Part 2 PACES), pass rates at the Annual Review of Competency Progression (ARCP), trainee involvement in significant events, clinical incidents or complaints and trainee feedback on career progression and confidence. RESULTS: Mentored trainees reported higher pass rates of the MRCP Part 1 exam versus non-mentored trainees (84.0% vs 42.4%, p<0.01). Mentored international medical graduates (IMGs) reported higher pass rates than non-mentored IMGs in the MRCP Part 2 Written exam (71.4% vs 24.0%, p<0.05). ARCP pass rates in mentored trainees were observed to be higher than non-mentored trainees (95.8% vs 69.9%, p<0.05). Rates of involvement in significant events, clinical incidents and complaints in both groups did not show any statistical difference. Mentored trainees reported higher confidence and career progression. CONCLUSIONS: A positive association is observed between the mentoring of CMTs and better training outcomes. Further studies are needed to investigate the causative effects of mentoring in postgraduate medical training within the UK.

Effects of alcohol-induced working memory decline on alcohol consumption and adverse consequences of use.

RATIONALE: Alcohol use appears to decrease executive function acutely in a dose-dependent manner, and lower baseline executive function appears to contribute to problematic alcohol use. However, no studies, to our knowledge, have examined the relationship between individual differences in working memory (a subcomponent of executive function) after alcohol consumption and drinking behaviors and consequences. OBJECTIVES: The current study assessed the relationship between drinking behavior, alcohol-related consequences, and alcohol-induced changes in working memory (as assessed by Trail Making Test-B). METHOD: Participants recruited from the community (n = 41), 57.3 % male, mean age 39.2, took part in a three-session, within-subjects, repeated-measures design. Participants were administered a placebo, 0.4 g/kg, or 0.8 g/kg dose of alcohol. Working memory, past 30-day alcohol consumption, and consequences of alcohol use were measured at baseline; working memory was measured again after each beverage administration. RESULTS: Poorer working memory after alcohol administration (controlling for baseline working memory) was significantly associated with a greater number of drinks consumed per drinking day. Additionally, we observed a significant indirect relationship between the degree of alcohol-induced working memory decline and adverse consequences of alcohol use, which was mediated through greater average drinks per drinking day. CONCLUSIONS: It is possible that greater individual susceptibility to alcohol-induced working memory decline may limit one's ability to moderate alcohol consumption as evidenced by greater drinks per drinking day and that this results in more adverse consequences of alcohol use.

Executive Functioning in Alcohol Use Studies: A Brief Review of Findings and Challenges in Assessment.

There is a wealth of research about the links between executive functioning (EF) and alcohol use. However, difficulty may arise in interpreting findings because of the variability between studies regarding the specific components of EF measured, as well as the variability of tasks used to examine each EF construct. The current article considers each of these problems within the context of a literature review that focuses on two topics: (1) the efficacy of EF in predicting alcohol use and alcohol-related consequences, and (2) the effect of acute alcohol intoxication on EF task performance. An additional goal was to identify and describe commonly used EF measures with the intention of providing alcohol researchers information on the assessment of different EF domains. Our findings indicate that there is strong evidence supporting a relation between EF difficulties (particularly response inhibition and information updating) and alcohol use, with additional evidence of a significant interaction between EF and implicit associations on alcohol use. In contrast, research supporting a link between set shifting abilities and later alcohol use is scarce. Additionally, this review found evidence of alcohol acutely affecting many EF processes (particularly response inhibition). Overall, there is a need to replicate these findings with commonly used EF tasks (versus developing numerous tasks within individual laboratories) to better advance our understanding of the relation between EF and alcohol use.

Positive Psychotherapy for Smoking Cessation: A Pilot Randomized Controlled Trial.

OBJECTIVE: Greater depressive symptoms and low positive affect (PA) are associated with poor smoking cessation outcomes. Smoking cessation approaches that incorporate a focus on PA may benefit smokers trying to quit. The purpose of this study was to conduct a pilot randomized clinical trial to compare standard smoking cessation treatment (ST) with smoking cessation treatment that targets positive affect, termed positive psychotherapy for smoking cessation (PPT-S). METHOD: Smokers who were seeking smoking cessation treatment were assigned by urn randomization to receive, along with 8 weeks of nicotine replacement therapy, either ST (n = 31) or PPT-S (n = 35). Seven-day point prevalence smoking abstinence was biochemically confirmed at 8, 16, and 26 weeks. RESULTS: Compared to ST, a greater percentage of participants in PPT-S were abstinent at 8 weeks, 16 weeks, and 26 weeks, but these differences were nonsignificant. In a more statistically powerful longitudinal model, participants in PPT-S had a significantly higher odds of abstinence (adjusted odds ratio [AOR] = 2.75; 95% CI = 1.02, 7.42; p = .046) across follow-ups compared to those in ST. The positive effect of PPT-S was stronger for those higher in PA (OR = 6.69, 95% CI = 1.16, 38.47, p = .03). Greater use of PPT-S strategies during the initial 8 weeks of quitting was associated with a less steep decline in smoking abstinence rates over time (OR = 2.64, 95% CI = 1.06, 6.56, p =.04). CONCLUSION: This trial suggests substantial promise for incorporating PPT into smoking cessation treatment.

A field investigation of the effects of drinking consequences on young adults' readiness to change.

In the research on readiness to change (RTC) one's drinking, there has been little assessment of the influence of positive drinking consequences or other potential moderating variables. To address these limitations, we examined how young adults' RTC their alcohol consumption shortly following a drinking episode was associated with self-reported drinking consequences, as well as any potential moderating effects of gender and Breath Alcohol Concentration (BrAC). In street interviews outside bars, 238 young adults were administered questionnaires about their drinking, including a measure examining participants' current readiness to reduce their alcohol consumption. Within 72h of their drinking episode, 67 participants (36 males; entire sample Mage=20.90years, Range=18-26years) completed an online survey, once again measuring RTC as well as positive and negative drinking consequences. Consistent with our hypothesis, positive drinking consequences were negatively associated with participants' changes in RTC. Additionally, a three-way interaction of gender×BrAC×positive drinking consequences on RTC showed that females with low BrACs reported higher RTC scores when they had endorsed fewer positive drinking consequences. Interestingly, negative drinking consequences alone did not impact individuals' RTC. Because positive drinking consequences were a significantly better predictor of RTC than were negative drinking consequences, researchers are advised to examine both types of consequences in future studies. Finally, effective alcohol education programs for those who have never consumed alcohol as well as social drinkers should include consideration of the experience of positive outcomes.

Working Memory Moderates the Association Between Smoking Urge and Smoking Lapse Behavior After Alcohol Administration in a Laboratory Analogue Task.

INTRODUCTION: Lapses after smoking cessation often occur in the context of alcohol use, possibly because alcohol increases urge to smoke. Poor working memory, or alcohol-induced decrements in working memory, may influence this relationship by making it more difficult for an individual to resist smoking in the face of smoking urges. METHODS: Participants (n = 41) completed measures of working memory and urge to smoke before and after alcohol administration (placebo, 0.4 g/kg, and 0.8 g/kg, within subjects) and then participated in a laboratory analogue task in which smoking abstinence was monetarily incentivized. RESULTS: Working memory moderated the relationship between smoking urge and latency to smoke: for those with relatively poorer working memory, urge to smoke was more strongly and negatively associated with latency to smoke (i.e., higher urges were associated with shorter latency). CONCLUSIONS: Those with weak working memory may need additional forms of treatment to help them withstand smoking urges.

Ecological momentary assessment of acute alcohol use disorder symptoms: associations with mood, motives, and use on planned drinking days.

Several theories posit that alcohol is consumed both in relation to one's mood and in relation to different motives for drinking. However, there are mixed findings regarding the role of mood and motives in predicting drinking. Ecological momentary assessment (EMA) methods provide an opportunity to evaluate near real-time changes in mood and motives within individuals to predict alcohol use. In addition, endorsement of criteria of an alcohol use disorder (AUD) may also be sensitive to changes within subjects. The current study used EMA with 74 moderate drinkers who responded to fixed and random mood, motive, alcohol use, and AUD criteria prompts over a 21-day assessment period. A temporal pattern of daytime mood, evening drinking motivation, and nighttime alcohol use and acute AUD symptoms on planned drinking days was modeled to examine how these associations unfold throughout the day. The results suggest considerable heterogeneity in drinking motivation across drinking days. Additionally, an affect regulation model of drinking to cope with negative mood was observed. Specifically, on planned drinking days, the temporal association between daytime negative mood and the experience of acute AUD symptoms was mediated via coping motives and alcohol use. The current study found that motives are dynamic, and that changes in motives may predict differential drinking patterns across days. Further, the study provides evidence that emotion-regulation-driven alcohol involvement may need to be examined at the event level to fully capture the ebb and flow of negative affect motivated drinking.

Acute effects of low and high dose alcohol on smoking lapse behavior in a laboratory analogue task.

RATIONALE: Smoking lapses (i.e., returns to smoking after quitting) often occur following alcohol consumption with observational data suggesting greater quantities of alcohol lead to greater risk. However, a causal dose-dependent effect of alcohol consumption on smoking lapse behavior has not been established, and the mechanisms that might account for such an effect have not been tested. OBJECTIVES: In a within-subjects design, we examined the effects of low- (0.4 g/kg) and high-dose (0.8 g/kg) alcohol, relative to placebo, on smokers' ability to resist initiating smoking after acute smoking abstinence. METHODS: Participants were 100 heavy alcohol drinkers, smoking 10-30 cigarettes per day. Across three separate days, participants consumed placebo, low-dose, or high-dose alcohol following 3 h of smoking abstinence and, 35 min later, were offered the opportunity to smoke while resisting smoking was monetarily reinforced proportional to the amount of time delayed. RESULTS: Consistent with a dose-response effect, participants smoked 3.35 min (95 % confidence intervals (CI) [-7.09, 0.40], p = .08) earlier following low-dose alcohol and 6.36 min (95 % CI [-9.99, -2.73], p = .0006) earlier following high-dose alcohol compared to drinking a placebo beverage. Effects of dose on smoking behavior were partially mediated by increases in urge to smoke. There was no evidence that alcohol's effects on urge to smoke or ability to resist smoking were mediated through its stimulating or sedating effects. CONCLUSIONS: Alcohol can reduce the ability to resist smoking in a dose-dependent fashion, in part, due to its effect on increasing the intensity of smoking urges.

Positive Psychotherapy for Smoking Cessation: Treatment Development, Feasibility and Preliminary Results.

Low positive and high negative affect predict low rates of smoking abstinence among smokers making a quit attempt. Positive Psychotherapy can both increase positive affect and decrease negative affect and therefore may be a useful adjunct to behavioral smoking counseling. The purpose of the present study was to assess the feasibility and acceptability of a Positive Psychotherapy for Smoking Cessation (PPT-S) intervention that integrates standard smoking cessation counseling with nicotine patch and a package of positive psychology interventions. We delivered PPT-S to 19 smokers who were low in positive affect at baseline. Rates of session attendance and satisfaction with treatment were high, and most participants reported using and benefiting from the positive psychology interventions. Almost one-third of participants (31.6%) sustained smoking abstinence for 6 months after their quit date. Future studies to assess the relative efficacy of PPT-S compared to standard smoking cessation treatment are warranted.

Length of smoking deprivation moderates the effects of alcohol administration on urge to smoke.

Although smoking deprivation is often used in laboratory studies to induce urges to smoke cigarettes, the optimal length of deprivation has not been established. Previous research showed that overnight abstinence from cigarettes led to high baseline urge to smoke that potentially masked alcohol's acute effects on urge to smoke (Kahler et al., 2012). The current study examined whether alcohol's effects on smoking urge were more pronounced when a shorter length of smoking deprivation was used (i.e., 3h instead of overnight abstinence). Using a balanced placebo design for alcohol administration, we found that participants experienced a significant increase in self-reported urge to smoke when administered alcohol after a 3-h smoking deprivation (n=32), whereas this effect was smaller and nonsignificant when smokers were required to be abstinent overnight (n=96). Research on factors that heighten smoking urges may find stronger effects if a 3-h deprivation is used compared to using overnight abstinence.

Motivational interviewing versus brief advice for cigarette smokers in residential alcohol treatment.

Residential treatment for substance use disorders (SUD) provides opportunity for smoking intervention. A randomized controlled trial compared: (1) motivational interviewing (MI) to brief advice (BA), (2) in one session or with two booster sessions, for 165 alcoholics in SUD treatment. All received nicotine replacement (NRT). MI and BA produced equivalent confirmed abstinence, averaging 10% at 1 month, and 2% at 3, 6 and 12 months. However, patients with more drug use pretreatment (>22 days in 6 months) given BA had more abstinence at 12 months (7%) than patients in MI or with less drug use (all 0%). Boosters produced 16-31% fewer cigarettes per day after BA than MI. Substance use was unaffected by treatment condition or smoking cessation. Motivation to quit was higher after BA than MI. Thus, BA plus NRT may be a cost-effective way to reduce smoking for alcoholics with comorbid substance use who are not seeking smoking cessation.

Gender, history of alcohol use and number of drinks consumed predict craving among drinkers in a field setting.

To the extent that craving serves to compel excessive drinking, it would be important to predict the intensity of an individual's craving over the course of a drinking episode. Previous research indicates that regular alcohol use (measured by the AUDIT) and the number of drinks individuals have already consumed that evening independently predict craving to drink (Schoenmakers & Wiers, 2010). The current study aims to replicate those findings by testing whether these same variables predict craving to drink in a sample of 1320 bar patrons in a naturalistic setting. In addition, we extend those findings by testing whether regular alcohol use and self-reported number of drinks consumed interact to predict craving, and whether gender independently predicts craving or interacts with other variables to predict craving. Results indicate that for men, AUDIT score alone predicted craving, whereas for women, AUDIT score and number of drinks consumed interacted to predict craving, with craving highest among women with either high AUDIT scores or relatively high consumption levels. Our findings have implications for targeted intervention and prevention efforts, as women who have a history of harmful alcohol use and consume several drinks in an evening might be at the greatest risk for continued alcohol consumption.

Marijuana and self-regulation: examining likelihood and intensity of use and problems.

It is important to understand the individual differences that contribute to greater frequency or intensity of marijuana use, or greater frequency of experiencing marijuana-related problems. The current study examined several elements of behavioral and emotional self-regulation as predictors of the likelihood and intensity of both marijuana use and marijuana-related problems. As predicted, indices of behavioral self-regulation (self-control, sensation seeking) were better predictors of marijuana use, while indices of emotional self-regulation (affect, distress tolerance, and emotional instability) better predicted marijuana-related problems. Surprisingly, urgency was not related to use but was predictive of problems, and there were no significant interactions between behavioral and emotional self-regulation in predicting either use or problems. From these findings we conclude that while behavioral dysregulation may put individuals at risk for using marijuana, or using it more frequently, it is those individuals with difficulty in emotional self-regulation that are at risk for experiencing negative consequences as a result of their marijuana use. Clinically, these data are relevant; clinicians might focus more on addressing emotional regulation in order to lessen or eliminate the consequences of marijuana use.

Acute and chronic effects of alcohol on trail making test performance among underage drinkers in a field setting.

OBJECTIVE: Alcohol's effects on executive functioning are well documented. Research in this area has provided much information on both the acute and chronic effects of alcohol on processes such as working memory and mental flexibility. However, most research on the acute effects of alcohol is conducted with individuals older than 21 years of age. Using field recruitment methods can provide unique empirical data on the acute effects of alcohol on an underage population. METHOD: The current study examined the independent effects of acute alcohol intoxication (measured by breath alcohol content) and chronic alcohol use (measured by years drinking) on a test of visuomotor performance and mental flexibility (Trail Making Test) among 91 drinkers ages 18-20 years recruited from a field setting. RESULTS: Results show that breath alcohol predicts performance on Trails B, but not on Trails A, and that years drinking, above and beyond acute intoxication, predicts poorer performance on both Trails A and B. CONCLUSIONS: These data suggest that, independent of the acute effects of alcohol, chronic alcohol consumption has deleterious effects on executive functioning processes among underage drinkers. Our discussion focuses on the importance of these data in describing the effect of alcohol on adolescents and the potential for engaging in risky behavior while intoxicated.

Working memory and impulsivity predict marijuana-related problems among frequent users.

BACKGROUND: Although marijuana is the most commonly used illicit substance in the US, only a small portion of users go on to develop dependence, suggesting that there are substantial individual differences in vulnerability to marijuana-related problems among users. Deficits in working memory and high trait impulsivity are two factors that may place marijuana users at increased risk for experiencing related problems. METHODS: Using baseline data from an experimental study that recruited 104 frequent marijuana users (M=71.86% of prior 60 days, SD=22%), we examined the associations of working memory and trait impulsivity with marijuana-related problems. RESULTS: Lower working memory, as measured by Trail Making Test B, but not short-term memory capacity, predicted more marijuana-related problems. Higher trait impulsivity scores were independently associated with greater number of problems. CONCLUSIONS: Results suggest that marijuana users with reduced executive cognitive ability are more susceptible to developing problems related to their use. Trait impulsivity and executive working memory appear to be independent risk factors for experiencing marijuana-related problems.

[(3)H]Adenosine uptake in brainstem membranes of CD-1 mice lacking the adenosine A(2a) receptor.

Previous studies in our laboratory have demonstrated a decrease in [(3)H]nitrobenzylthioinosine binding sites in the brainstem of adenosine A(2a) receptor knockout mice, particularly in the brain nuclei involved in central control of cardiovascular function [Brain Research 877 (2000) 160]. The present study aimed to correlate this decrease, shown using autoradiography, with a functional change using a previously described method of [(3)H]adenosine uptake in a membrane preparation from the brainstem of wildtype CD - 1 and homozygous mutant mice lacking the adenosine A(2a) receptor. A statistically significant decrease was shown in the mean V(MAX) value obtained from homozygous mutant preparations (4.7 +/- 1.3 fmol/mg protein/20 s, P < 0.05, n = 4) compared to that obtained from wildtype controls (51.6 +/- 4.2 fmol/mg protein/20 s, n = 4). Competition studies using nucleoside uptake inhibitors showed a statistically significant increase in the log IC(50) values for dipyridamole (Wildtype: -4.3 +/- 0.2, Homozygous mutant: -8.3 +/- 0.4, n=5, P < 0.05) and dilazep (Wildtype: -3.9 +/- 0.8, Homozygous mutant: -8.3 +/- 0.8, n=5, P < 0.05) in the preparations using homozygous mutant tissue. The present study, in conjunction with the results of previous studies [Brain Research 877 (2000) 160], indicates that components of purinergic neurotransmission system have apparently adjusted in compensation for the lack of the A(2a) receptor.