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Background and Aims: Treatment of depression-related psychological factors related to smoking behavior may improve rates of cessation among adults with major depressive disorder (MDD). This study measured the efficacy and safety of 12 weeks of behavioral activation for smoking cessation (BASC), varenicline and their combination., Design, Setting, Participants: This study used a randomized, placebo-controlled, 2 × 2 factorial design comparing BASC versus standard behavioral treatment (ST) and varenicline versus placebo, taking place in research clinics at two urban universities in the United States. Participants comprised 300 hundred adult smokers with current or past MDD., Interventions: BASC integrated behavioral activation therapy and ST to increase engagement in rewarding activities by reducing avoidance, withdrawal and inactivity associated with depression. ST was based on the 2008 PHS Clinical Practice Guideline. Both treatments consisted of eight 45-min sessions delivered between weeks 1 and 12. Varenicline and placebo were administered for 12 weeks between weeks 2 and 14., Measurements: Primary outcomes were bioverified intent-to-treat (ITT) 7-day point-prevalence abstinence at 27 weeks and adverse events (AEs)., Findings: No significant interaction was detected between behavioral treatment and pharmacotherapy at 27 weeks (χ 2 (1)  = 0.19, P = 0.67). BASC and ST did not differ (χ 2 (1)  = 0.43, P = 0.51). Significant differences in ITT abstinence rates (χ 2 (1)  = 4.84, P = 0.03) emerged among pharmacotherapy arms (16.2% for varenicline, 7.5% for placebo), with results favoring varenicline over placebo (rate ratio = 2.16, 95% confidence interval = 1.08, 4.30). All significant differences in AE rates after start of medication were higher for placebo than varenicline., Conclusion: A randomized trial in smokers with major depressive disorder found that varenicline improved smoking abstinence versus placebo at 27 weeks without elevating rates of adverse events. Behavioral activation for smoking cessation did not outperform standard behavioral treatment, with or without adjunctive varenicline therapy., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Crigler-Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine-diphosphate-glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1-modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first-in-human studies, a quantitative systems pharmacology (QSP) model was developed. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First-in-human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels., (© 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Smoking cessation treatment should be an important aspect of cancer care. In this study, we evaluated whether cancer-related disease factors adversely influence smoking cessation treatment., Methods: Smokers with cancer (within 5 years of diagnosis, any tumor site) were recruited for an ongoing trial of varenicline for smoking cessation. Disease factors, assessed at baseline, included tumor site, cancer treatment, time since diagnosis, and health-related quality of life. Medication adherence was defined by 132 of 165 pills taken and counseling adherence was defined by 4 of 4 behavioral counseling sessions attended. Abstinence was bioverified at Week 12. Using logistic regression analysis, we assessed the relationship between disease factors and 12-week medication adherence, counseling adherence, and abstinence., Results: Of 144 participants, 56% were medication adherent, 74% were counseling adherent, and 39% were abstinent. Health-related quality of life predicted medication adherence (OR: 1.08, 95% CI, 1.01-1.16, P = .019, d = 0.20) but not counseling adherence or 12-week abstinence. Tumor site, cancer treatment, and time since diagnosis did not predict any smoking cessation treatment outcomes., Conclusions: Cancer-related disease factors did not predict cancer survivors' engagement or success in smoking cessation treatment. Findings support National Comprehensive Cancer Network Clinical Practice guidelines that recommend smoking cessation treatment for all smokers with cancer, regardless of time since diagnosis., (Copyright © 2017 John Wiley & Sons, Ltd.)

The nicotine metabolite ratio (NMR) has been shown to predict response to the transdermal nicotine patch, such that faster nicotine metabolism is associated with a lower abstinence rate. Menthol cigarette use, versus nonmenthol cigarette use, slows nicotine metabolism and therefore may attenuate the effect of NMR on smoking abstinence. In this study, we evaluated whether cigarette type (menthol vs. nonmenthol) modified the association between NMR and short-term abstinence. This was a secondary analysis examining treatment in the first 8 weeks of 21 mg/day nicotine patch therapy in a completed clinical trial (n = 474). Menthol cigarette use was based on self-report. NMR was defined dichotomously (0 = fast, 1 = slow) to distinguish between fast (≥0.47) versus slow NMR. Using logistic regression analysis, we tested whether cigarette type moderated the association between NMR and bioverified 7-day point prevalence abstinence at Week 8. Covariates include nicotine dependence, age, race, and gender. Three hundred two participants reported smoking menthol cigarettes, of which 234 (77%) were classified as slow NMR. Among the 172 nonmenthol smokers, 136 were classified as slow NMR (79%). Contrary to our expectations, the NMR ×Cigarette Type interaction effect on abstinence was not significant (odds ratio [OR] = 0.91, p = .86). Excluding the interaction variable, fast NMR was associated with decreased likelihood of abstinence (OR = 0.55, p = .03), but menthol cigarette use was not (OR = 1.15, p = .56). Further exploration of risk factors among menthol cigarette smokers, especially among racially diverse and light smokers, could clarify the association between menthol cigarette use and poorer smoking outcomes. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Introduction: Anhedonia has been recognized as a major risk factor for smoking persistence. Potential gender differences in the effect of anhedonia on smoking cessation have not been studied. Using data from a completed clinical trial of maintenance nicotine patch therapy, we hypothesized that gender would moderate the effect of anhedonia on short-term abstinence, such that anhedonic women would be less likely to achieve abstinence., Methods: Participants (N = 525; 50% female, 48.2% Black/African American, average age: 46 years) received 21mg/day nicotine patch and four brief behavior counseling sessions over 8 weeks. Participants were classified at baseline using the Snaith-Hamilton Pleasure Scale as anhedonic (scores > 2) or hedonic (scores ≤ 2). Bioverified 7-day point prevalence abstinence was measured at week 8. Using logistic regression analysis, we tested the interaction of anhedonia by gender predicting abstinence, adjusting for age, race, nicotine dependence, and baseline depressive symptomatology., Results: Seventy participants (13%) were classified as anhedonic. Men were more likely to be anhedonic than women (16.6% vs. 10.2%, p = .03). Contrary to our hypothesis, the interaction of anhedonic status (hedonic vs. anhedonic) by gender was nonsignificant (p = .18). There was a main effect of hedonic capacity, such that anhedonia predicted abstinence, odds ratio = 3.24, 95% confidence interval = 1.39-7.51, p = .006., Conclusion: Both male and female anhedonic smokers were more likely to be abstinent, which contrasts with prior research indicating that anhedonia is a risk factor for difficulty quitting. This unexpected finding may be explained by a possible selective benefit of nicotine patch therapy, which has been observed in some studies to have antidepressant effects., Implications: This is the first study to examine whether the association between pretreatment anhedonia and smoking cessation differs by gender. For both women and men, anhedonia was associated with a greater likelihood of abstinence after 8 weeks of treatment with 21mg/day nicotine patch and behavior counseling. Our findings indicate that the association between anhedonia and smoking cessation is not as clear as has been assumed and may depend in part on the type of treatment delivered., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

History of major depression is increasingly being measured in smoking cessation trials using brief screening scales, typically only 1-2 items, despite that their validity has not been fully established. The aim of this study was to evaluate the positive predictive value (PPV) of a 4-item screening scale of lifetime major depressive episode (MDE). Current (n = 475), former (n = 401), and never (n = 646) smokers were asked about a history of depressed mood and anhedonia lasting several days or longer. Endorsers of either depressed mood or anhedonia were then asked about whether the symptom(s) lasted most of the day nearly every day for two weeks or longer. Symptom endorsers, regardless of symptom duration, were administered the depression module of the Composite International Diagnostic Interview. Eight hundred and thirty-five (54.9%) participants had no history of either screening symptom, 296 (20.9%) had a history of depressed mood and/or anhedonia < 2 weeks, and 369 (24.2%) had a history of depressed mood and/or anhedonia ≥ 2 weeks. PPV of depressed mood and/or anhedonia ≥ 2 weeks was high (84.8%) for detecting lifetime MDE, as compared to only 23.9% for symptom(s) <2 weeks. PPV did not vary by either smoking status or gender. This 4-item screening scale has high predictive value in detecting lifetime MDE. Smoking cessation trials that do not require a history of depressed mood and/or anhedonia for two weeks or longer may overestimate rates of lifetime MDE and confound tests of the association between depression and treatment outcome., ((c) 2011 APA, all rights reserved.)

Boundary value formulations are presented for exact and efficient sensitivity analysis, with respect to model parameters and initial conditions, of different classes of oscillating systems. Methods for the computation of sensitivities of derived quantities of oscillations such as period, amplitude and different types of phases are first developed for limit-cycle oscillators. In particular, a novel decomposition of the state sensitivities into three parts is proposed to provide an intuitive classification of the influence of parameter changes on period, amplitude and relative phase. The importance of the choice of time reference, i.e., the phase locking condition, is demonstrated and discussed, and its influence on the sensitivity solution is quantified. The methods are then extended to other classes of oscillatory systems in a general formulation. Numerical techniques are presented to facilitate the solution of the boundary value problem, and the computation of different types of sensitivities. Numerical results are verified by demonstrating consistency with finite difference approximations and are superior both in computational efficiency and in numerical precision to existing partial methods.

Processes that repeat in time, such as the cell cycle, the circadian rhythm, and seasonal variations, are prevalent in biology. Mathematical models can represent our knowledge of the underlying mechanisms, and numerical methods can then facilitate analysis, which forms the foundation for a more integrated understanding as well as for design and intervention. Here, the intracellular molecular network responsible for the mammalian circadian clock system was studied. A new formulation of detailed sensitivity analysis is introduced and applied to elucidate the influence of individual rate processes, represented through their parameters, on network functional characteristics. One of four negative feedback loops in the model, the Per2 loop, was uniquely identified as most responsible for setting the period of oscillation; none of the other feedback loops were found to play as substantial a role. The analysis further suggested that the activity of the kinases CK1delta and CK1varepsilon were well placed within the network such that they could be instrumental in implementing short-term adjustments to the period in the circadian clock system. The numerical results reported here are supported by previously published experimental data.