Effectiveness of contingency management using transdermal alcohol monitoring to reduce heavy drinking among driving while intoxicated (DWI) arrestees: A randomized controlled trial.

BACKGROUND: Driving while intoxicated (DWI) is a serious public health problem. However, treatment for DWI arrestees is not readily available. This study examines the effectiveness of a contingency management (CM) procedure using transdermal alcohol concentration (TAC) monitoring to reduce drinking among DWI arrestees. METHOD: The study participants were 216 DWI arrestees under pretrial and included both Mandated participants undergoing court-ordered TAC monitoring and Non-Mandated participants wearing a study-provided TAC monitor. Participants were randomly assigned to either a CM (Mandated = 35; Non-Mandated = 74) or a Control condition (Mandated = 37; Non-Mandated = 70) and completed the 8-week intervention. CM participants received $50/week for not exceeding a TAC of 0.02 g/dL during the previous week. Payments to Controls were yoked to the CM group. RESULTS: Among Non-Mandated participants, the probability of meeting the contingency was higher and remained stable (about 65%) over time in the CM group, whereas the probability was lower and declined in the Control group, widening the gaps in the probability between the study conditions (16.7%-24.1% greater in the CM group from visit 4 to 8, all p < 0.05). Among Mandated participants, the probability was not significantly different between conditions (p = 0.06-0.95). Furthermore, among Non-Mandated participants, the percentage of heavy drinking days remained low (9.16%-11.37%) in the CM group, whereas it was greater and increased over time (17.43%-26.59%) in the Control group. In Mandated participants, no significant differences in percent heavy drinking days were observed between conditions (p = 0.07-0.10). CONCLUSION: We found that contingency effects on alcohol use are more pronounced among frequent and heavy alcohol users, i.e., Non-Mandated DWI arrestees. However, for individuals whose drinking was already suppressed by existing contingencies (i.e., court-mandated TAC monitoring), our CM procedure did not produce additional reductions in drinking.

Virtual reality tour for first-time users of highly automated cars: Comparing the effects of virtual environments with different levels of interaction fidelity.

Research in aviation and driving has highlighted the importance of training as an effective approach to reduce the costs associated with the supervisory role of the human in automated systems. However, only a few studies have investigated the effect of training on highly automated driving. Moreover, available interactive trainings are mostly based on automated driving simulators and the application of immersive technology such as Virtual Reality (VR) as a low-cost training solution has not been widely adopted. In this study, we developed three types of familiarization tours (low-fidelity VR, high-fidelity VR, and video) to train first-time users of highly automated cars. Then, the effectiveness of these tours was investigated on automation trust and driving performance in several critical and non-critical transition tasks in four groups: control, video, low-fidelity VR, and high-fidelity VR. The results revealed the positive impact of the tours on trust and transition performance at the first time of measurement. Takeover quality only improved when practices were presented in high-fidelity VR. After three times of exposure to transition requests, trust and transition performance of all groups converged to those of the high-fidelity VR group, demonstrating that: a) experiencing takeover transition during the training may reduce costs associated with first critical takeover request in highly automated driving, b) the VR tour with high level of interaction fidelity was superior to other training methods, and c) untrained and less-trained drivers learned about automation after a few trials. Knowledge resulting from this research could help develop cost-effective solutions for automated driving training in dealerships and car rental centers.

Rheb1-Independent Activation of mTORC1 in Mammary Tumors Occurs through Activating Mutations in mTOR.

Mechanistic target of rapamycin complex 1 (mTORC1) is a master modulator of cellular growth, and its aberrant regulation is recurrently documented within breast cancer. While the small GTPase Rheb1 is the canonical activator of mTORC1, Rheb1-independent mechanisms of mTORC1 activation have also been reported but have not been fully understood. Employing multiple transgenic mouse models of breast cancer, we report that ablation of Rheb1 significantly impedes mammary tumorigenesis. In the absence of Rheb1, a block in tumor initiation can be overcome by multiple independent mutations in Mtor to allow Rheb1-independent reactivation of mTORC1. We further demonstrate that the mTOR kinase is indispensable for tumor initiation as the genetic ablation of mTOR abolishes mammary tumorigenesis. Collectively, our findings demonstrate that mTORC1 activation is indispensable for mammary tumor initiation and that tumors acquire alternative mechanisms of mTORC1 activation.

Electrostatic interactions modulate the differential aggregation propensities of IgG1 and IgG4P antibodies and inform charged residue substitutions for improved developability.

Native state aggregation is an important concern in the development of therapeutic antibodies. Enhanced knowledge of mAb native state aggregation mechanisms would permit sequence-based selection and design of therapeutic mAbs with improved developability. We investigated how electrostatic interactions affect the native state aggregation of seven human IgG1 and IgG4P mAb isotype pairs, each pair having identical variable domains that are different for each set of IgG1 and IgG4P constructs. Relative aggregation propensities were determined at pH 7.4, representing physiological conditions, and pH 5.0, representing commonly used storage conditions. Our work indicates that the net charge state of variable domains relative to the net charge state of the constant domains is predominantly responsible for the different native state aggregation behavior of IgG1 and IgG4P mAbs. This observation suggests that the global net charge of a multi domain protein is not a reliable predictor of aggregation propensity. Furthermore, we demonstrate a design strategy in the frameworks of variable domains to reduce the native state aggregation propensity of mAbs identified as being aggregation-prone. Importantly, substitution of specifically identified residues with alternative, human germline residues, to optimize Fv charge, resulted in decreased aggregation potential at pH 5.0 and 7.4, thus increasing developability.

A Direct Approach to Orthogonally Protected α-Amino Aldehydes.

O-Neopentyl-xanthate 19 bearing a masked α-amino aldehyde, with the two functional groups orthogonally protected, reacts cleanly with many functional alkenes. The radical addition-transfer furnishes densely functionalized adducts that can be further transformed into an array of amino-substituted carbocycles and heteroaromatics. They are also easily converted into imidazolones.

Development and psychometric properties of the Healthy Aging Activity Engagement Scale (HAAE).

OBJECTIVES: Accumulating research indicates that engaging in healthy lifestyle behaviors (e.g. exercise, cognitive and social engagement, stress reduction) can prevent illness and disability as people age and improve mental health. The Healthy Aging Activity Engagement (HAAE) scale was developed to holistically assess an individual's level of engagement in healthy aging behaviors across multiple health domains. METHODS: Participants were 275 healthy younger, midlife and older adults. Participants rated engagement in 38 healthy aging lifestyle behaviors over the past 7 days on a scale from 1 (strongly disagree) to 5 (strongly agree). RESULTS: Traditional measurement analysis and Rasch modelling techniques resulted in a 32-item scale with three subscales representing biologic health, social and cognitive strategies, and health safeguard behaviors. With the exception of the health safeguard subscale, the HAAE total score and subscales demonstrated good internal consistency, test-retest reliability, convergent and discriminant validity, and responsiveness to a program designed to promote engagement in healthy brain aging behaviors. DISCUSSION: With further validation, the HAAE may be useful for holistic clinical assessment of behaviors that promote healthy aging, support brain and mental health, and for treatment planning. Furthermore, the HAAE can be used to measure the outcome of multi-domain lifestyle interventions.

Strategies, Setbacks, and Successes in the Synthesis of (-)-Spiroleucettadine.

Various strategies toward the synthesis of the marine natural product (-)-spiroleucettadine are described. In the original strategy, a biomimetic inspired oxidation of a 2-imidazoline scaffold uncovered unexpected reactivity, where benzylic oxidation followed by a Baeyer-Villiger reaction was observed. The second generation approach examined oxidative dearomatization of the phenol ring system first, where a competing spirocyclization process was uncovered. Efforts to forge the scaffold via a carbocation mediated benzyl migration were unsuccessful. Highlights of the successful synthesis include two consecutive hypervalent iodine reactions: the first formed the spirocyclic center and the second facilitated installation of an acetate group at the C-5 position to allow for subsequent introduction of the methyl amine side chain.

Examining human behavior in video games: The development of a computational model to measure aggression.

Video games with violent content have raised considerable concern in popular media and within academia. Recently, there has been considerable attention regarding the claim of the relationship between aggression and video game play. The authors of this study propose the use of a new class of tools developed via computational models to allow examination of the question of whether there is a relationship between violent video games and aggression. The purpose of this study is to computationally model and compare the General Aggression Model with the Diathesis Mode of Aggression related to the play of violent content in video games. A secondary purpose is to provide a method of measuring and examining individual aggression arising from video game play. Total participants examined for this study are N = 1065. This study occurs in three phases. Phase 1 is the development and quantification of the profile combination of traits via latent class profile analysis. Phase 2 is the training of the artificial neural network. Phase 3 is the comparison of each model as a computational model with and without the presence of video game violence. Results suggest that a combination of environmental factors and genetic predispositions trigger aggression related to video games.

Total Synthesis of (-)-Spiroleucettadine.

One of a number of intriguing new alkaloids isolated from the Leucetta sp. sponge in 2004, spiroleucettadine displayed unique structural features on a restricted scaffold: a trans-fused 5,5-bicyclic ring system together with an amino hemiketal moiety. Attempts to synthesize the initially proposed structure failed, raising questions as to its veracity, and structure revision ensued in 2008; no successful synthetic approach has been reported to date. Herein, we describe the enantiospecific total synthesis of (-)-spiroleucettadine by a highly efficient biomimetic approach starting from l-tyrosine. One of two key hypervalent-iodine-mediated oxidation reactions forged the spirocyclic center, and the other enabled the installation of the methylamine side chain in the penultimate step. Our approach provides synthetic access to a new class of spiroannulated natural products and will enable future studies of the structure-biological-activity relationships of these antibacterial compounds.

Conditioned Stimulus Form Does Not Explain Failures to See Pavlovian-Instrumental-Transfer With Ethanol-Paired Conditioned Stimuli.

BACKGROUND: Pavlovian-Instrumental-Transfer (PIT) examines the effects of associative learning upon instrumental responding. Previous studies examining PIT with ethanol (EtOH)-maintained responding showed increases in responding following presentation of an EtOH-paired conditioned stimulus (CS). Recently, we conducted 2 studies examining PIT with an EtOH-paired CS. One of these found increases in responding, while the other did not. This less robust demonstration of PIT may have resulted from the form of the CS used, as we used a 120-second light stimulus as a CS, while the previous studies used either a 120-second auditory stimulus or a 10-second light stimulus. This study examined whether using conditions similar to our earlier study, but with either a 120-second auditory or a 10-second light stimulus as a CS, resulted in more robust PIT. We also examined the reliability of our previous failure to observe PIT. METHODS: Three experiments were conducted examining whether PIT was obtained using (i) a 120-second light stimulus, (ii) a 10-second light stimulus, or (iii) a 120-second auditory stimulus as CSs. RESULTS: We found PIT was not obtained using (i) a 120-second light stimulus as a CS, (ii) a 10-second light stimulus as a CS, or (iii) a 120-second auditory stimulus as a CS. CONCLUSIONS: These results suggest that CS form does not account for our earlier failure to see PIT. Rather, factors like rat strain or how EtOH drinking is induced may account for when PIT is or is not observed.

Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine.

Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.

Behavioral Impulsivity Does Not Predict Naturalistic Alcohol Consumption or Treatment Outcomes.

OBJECTIVE: The purpose of this study was to determine if behavioral impulsivity under multiple conditions (baseline, after alcohol consumption or after serotonin depletion) predicted naturalistic alcohol use or treatment outcomes from a moderation-based contingency management intervention. METHOD: The current data analysis pulls information from three phases of a large study: 1) Phase 1 examined baseline and the effects of alcohol use and serotonin depletion on three types of behavioral impulsivity: response initiation (IMT task), response inhibition (GoStop task), and delay discounting (SKIP task); 2) Phase 2 involved 28 days of naturalistic drinking; and 3) Phase 3 involved 3 months of contingency management. During phases 2 and 3 alcohol use was measured objectively using transdermal alcohol monitors. The results of each individual phase has been previously published showing that at a group level the effects of alcohol consumption on impulsivity were dependent on the component of impulsivity being measured and the dose of alcohol consumed but serotonin depletion had no effect on impulsivity, and that a moderation-based contingency management intervention reduced heavy drinking. RESULTS: The current analysis combining data from those who completed all three phases (n = 67) showed that impulsivity measured at baseline, after alcohol consumption, or after serotonin depletion did not predict naturalistic drinking or treatment outcomes from a moderation-based CM treatment. CONCLUSIONS: Contingency management interventions may prove to be an effective intervention for impulsive individuals, however, normal variations in measured impulsivity do not seem to relate to normal variations in drinking pattern or response to moderation-based contingency management.

The impact of diabetes mellitus on survival following resection and adjuvant chemotherapy for pancreatic cancer.

BACKGROUND: Diabetes mellitus is frequently observed in pancreatic cancer patients and is both a risk factor and an early manifestation of the disease. METHODS: We analysed the prognostic impact of diabetes on the outcome of pancreatic cancer following resection and adjuvant chemotherapy using individual patient data from three European Study Group for Pancreatic Cancer randomised controlled trials. Analyses were carried out to assess the association between clinical characteristics and the presence of preoperative diabetes, as well as the effect of diabetic status on overall survival. RESULTS: In total, 1105 patients were included in the analysis, of whom 257 (23%) had confirmed diabetes and 848 (77%) did not. Median (95% confidence interval (CI)) unadjusted overall survival in non-diabetic patients was 22.3 (20.8-24.1) months compared with 18.8 (16.9-22.1) months for diabetic patients (P=0.24). Diabetic patients were older, had increased weight and more co-morbidities. Following adjustment, multivariable analysis demonstrated that diabetic patients had an increased risk of death (hazard ratio: 1.19 (95% CI 1.01, 1.40), P=0.034). Maximum tumour size of diabetic patients was larger at randomisation (33.6 vs 29.7 mm, P=0.026). CONCLUSIONS: Diabetes mellitus was associated with increased tumour size and reduced survival following pancreatic cancer resection and adjuvant chemotherapy.

Examination of Variables That May Affect the Relationship Between Cognition and Functional Status in Individuals with Mild Cognitive Impairment: A Meta-Analysis.

The objective of this meta-analysis was to improve understanding of the heterogeneity in the relationship between cognition and functional status in individuals with mild cognitive impairment (MCI). Demographic, clinical, and methodological moderators were examined. Cognition explained an average of 23% of the variance in functional outcomes. Executive function measures explained the largest amount of variance (37%), whereas global cognitive status and processing speed measures explained the least (20%). Short- and long-delayed memory measures accounted for more variance (35% and 31%) than immediate memory measures (18%), and the relationship between cognition and functional outcomes was stronger when assessed with informant-report (28%) compared with self-report (21%). Demographics, sample characteristics, and type of everyday functioning measures (i.e., questionnaire, performance-based) explained relatively little variance compared with cognition. Executive functioning, particularly measured by Trails B, was a strong predictor of everyday functioning in individuals with MCI. A large proportion of variance remained unexplained by cognition.

Ethanol self-administration in mice under a second-order schedule.

Long Fixed-Interval (FI) schedules, particularly second-order schedules, can engender substantial responding before drug or ethanol delivery that is uninfluenced by the direct effects of the drug or ethanol. Thus, these schedules can be used to study the effects of medications upon drug- or ethanol-seeking, uninfluenced by the direct effects of the self-administered drug or ethanol. Long FI second-order schedules are frequently used in primates and occasionally in rats. Under second-order schedules, completion of one response requirement, e.g., a Fixed Ratio 10 (FR10:S), produces a brief stimulus presentation, e.g., a 1-s 80-dB 4-kHZ tone, and this FR10:S serves as the response unit under another schedule, e.g., an FI 1800-s. Thus, the first FR10 completed after 1800 s would result in delivery both of the tone and of reinforcement, e.g., 10 × 0.01 mL 16% (w/v) ethanol. To examine if such schedules could be effectively used in mice, which have advantages in neurobiological and genetic studies, we trained eight C57BL/6J mice to respond under the schedule just described. This schedule maintained substantial responding. The temporal pattern of behavior was typical of an FI schedule with responding accelerating across the interval. We also examined the effects of acute and chronic administration of fluvoxamine on this responding, and these were modest. Finally, we examined responding when alcohol and/or tone deliveries were withheld, and found that extinction occurred most rapidly when both were withheld. This work demonstrates that long FI schedules of ethanol delivery may be useful in studying ethanol seeking in mice.

Using Transdermal Alcohol Monitoring to Detect Low-Level Drinking.

BACKGROUND: Several studies demonstrate the utility of Alcohol Monitoring Systems' (AMS) transdermal alcohol concentration (TAC) monitor to objectively quantify drinking. AMS standard criteria (i.e., TAC >0.02 g/dl) used for drinking detection are deliberately conservative, but consequently only detect drinking equivalent to 5 or more standard drinks. Our study sought to characterize the sensitivity of TAC measurement to detect low-level drinking defined as the consumption of 1 to 3 beers. METHODS: Data were pooled from 3 studies giving controlled doses of 1, 2, 3, 4, and 5 Corona© beers (12 oz = 0.92 standard units) to 32 male and 29 female research volunteers wearing TAC monitors under controlled conditions. Analyses describe the sensitivity to detect drinking at various peak TAC thresholds beginning with any positive reading >0 g/dl, and then using TAC thresholds of 0.02 and 0.03 g/dl. RESULTS: Nearly 40% of participants drinking 1 beer did not have a positive TAC reading. However, positive TAC readings were observed in more than 95 and in 100% of participants drinking 2 and 3 or more beers, respectively. The probability of peak TAC detection was a positive function of the number of beers consumed and a negative function of the minimum TAC threshold for detection. Drinking was somewhat more likely to be detected in females than males drinking 2 to 5 beers, but not after 1 beer. Use of AMS standard criteria only reliably detected the consumption of 5 beers, and 45.9% of all occasions of drinking 1 to 3 beers were undetected using 0.02 g/dl as a threshold. CONCLUSIONS: Peak TAC levels between 0 and 0.02 g/dl must be considered to detect the low-level drinking of 1 to 3 standard drinks, and such thresholds are necessary when researchers and clinicians want to detect low-level drinking.

Relative potency of varenicline or fluvoxamine to reduce responding for ethanol versus food depends on the presence or absence of concurrently earned food.

BACKGROUND: Varenicline, a nicotinic partial agonist, selectively reduces ethanol (EtOH)- versus sucrose-maintained behavior when tested in separate groups, yet like the indirect agonist fluvoxamine, this selectively inverts when EtOH and food are concurrently available. METHODS: Here, we extend these findings by examining varenicline and fluvoxamine effects under a multiple concurrent schedule where food and EtOH are concurrently available in different components: Component 1 where the food fixed-ratio was 25 and Component 2 where the food fixed-ratio was 75. The EtOH fixed-ratio was always 5. Food-maintained responding predominated in Component 1, while EtOH-maintained responding predominated in Component 2. In a second experiment, varenicline effects were assessed under a multiple schedule where food, then EtOH, then again food were available in separate 5-minute components with fixed-ratios of 5 for each reinforcement. RESULTS: In the multiple concurrent schedule, varenicline was more potent at reducing food- versus EtOH-maintained responding in both components and reduced EtOH-maintained responding more potently during Component 1 (when food was almost never earned) than in Component 2 (where food was often earned). Fluvoxamine was similarly potent at reducing food- and EtOH-maintained responding. Under the multiple schedule, varenicline, like fluvoxamine, more potently decreases EtOH- versus food maintained responding when only food or EtOH is available in separate components. CONCLUSIONS: These results demonstrate that selective effects on drug- versus alternative-maintained behavior depend on the schedule arrangement, and assays in which EtOH or an alternative is the only programmed reinforcement may overestimate the selectivity of treatments to decrease EtOH self-administration. Thus selective effects obtained under one assay may not generalize to another. Better understanding the behavioral mechanisms responsible for these results may help to guide pharmaco-therapeutic development for substance use disorders.

Development and psychometric properties of the instrumental activities of daily living: compensation scale.

The Instrumental Activities of Daily Living - Compensation (IADL-C) scale was developed to capture early functional difficulties and to quantify compensatory strategy use that may mitigate functional decline in the aging population. The IADL-C was validated in a sample of cognitively healthy older adults (N=184) and individuals with mild cognitive impairment (MCI; N=92) and dementia (N=24). Factor analysis and Rasch item analysis led to the 27-item IADL-C informant questionnaire with four functional domain subscales (money and self-management, home daily living, travel and event memory, and social skills). The subscales demonstrated good internal consistency (Rasch reliability 0.80 to 0.93) and test-retest reliability (Spearman coefficients 0.70 to 0.91). The IADL-C total score and subscales showed convergent validity with other IADL measures, discriminant validity with psychosocial measures, and the ability to discriminate between diagnostic groups. The money and self management subscale showed notable difficulties for individuals with MCI, whereas difficulties with home daily living became more prominent for dementia participants. Compensatory strategy use increased in the MCI group and decreased in the dementia group.

Reinforcer magnitude and rate dependency: evaluation of resistance-to-change mechanisms.

Under many circumstances, reinforcer magnitude appears to modulate the rate-dependent effects of drugs such that when schedules arrange for relatively larger reinforcer magnitudes rate dependency is attenuated compared with behavior maintained by smaller magnitudes. The current literature on resistance to change suggests that increased reinforcer density strengthens operant behavior, and such strengthening effects appear to extend to the temporal control of behavior. As rate dependency may be understood as a loss of temporal control, the effects of reinforcer magnitude on rate dependency may be due to increased resistance to disruption of temporally controlled behavior. In the present experiments, pigeons earned different magnitudes of grain during signaled components of a multiple FI schedule. Three drugs, clonidine, haloperidol, and morphine, were examined. All three decreased overall rates of key pecking; however, only the effects of clonidine were attenuated as reinforcer magnitude increased. An analysis of within-interval performance found rate-dependent effects for clonidine and morphine; however, these effects were not modulated by reinforcer magnitude. In addition, we included prefeeding and extinction conditions, standard tests used to measure resistance to change. In general, rate-decreasing effects of prefeeding and extinction were attenuated by increasing reinforcer magnitudes. Rate-dependent analyses of prefeeding showed rate-dependency following those tests, but in no case were these effects modulated by reinforcer magnitude. The results suggest that a resistance-to-change interpretation of the effects of reinforcer magnitude on rate dependency is not viable.

Ethanol effects on multiple fixed-interval, fixed-ratio responding in mice with deletions of the serotonin transporter gene.

Serotonin transporter knockout (KO) mice self-administer less ethanol than either heterozygous or wild-type mice; however, the mechanistic basis for this difference remains unclear. Here we examine the possibility that ethanol more readily decreases responding in KO mice, thereby limiting ethanol self-administration. To examine whether KO mice were more sensitive to the response-decreasing effects of ethanol, we administered ethanol (0.2-3.2 g/kg) to mice responding under a multiple fixed-ratio 30-response, fixed-interval 300-s schedule of milk presentation. Ethanol decreased responding similarly in all three genotypes. Fixed-ratio responding tended to be decreased at lower doses than fixed-interval responding. The decreased level of ethanol self-administration in serotonin transporter KO mice is not explained by an increased sensitivity to the response-decreasing effects of ethanol in KO mice, as sensitivity to the response-decreasing effects of ethanol was similar in the KO, heterozygous, and wild-type mice.