Smoking cessation is a process that unfolds over time and is characterized by intermittent lapses. Behavioral relapse prevention interventions commonly assume that lapse-relapse progression is driven by a set of psychological responses known as the Abstinence Violation Effect (AVE; Marlatt & Gordon, 1985), yet efforts to reduce the AVE have generally failed to affect clinical outcomes. We used parametric recurrent event survival analyses to better understand the dynamic relationship between a set of AVE responses to lapsing and subsequent lapse-relapse progression. Participants were 203 smokers who achieved abstinence and subsequently lapsed on one or more separate occasions. Using electronic diaries for ecological momentary assessment, participants responded to items assessing three core components of the AVE (internal attribution of self-blame for the lapse, abstinence self-efficacy and guilt) following a total of 1,001 smoking episodes in near real time. Contrary to hypothesis, neither self-blame, self-efficacy nor guilt following participants’ first lapse predicted relapse, and all three were overshadowed by responses to recurrent lapses that followed. Controlling for responses to their first lapse, responses to each additional lapse did prospectively predict lapse progression, such that drops in self-efficacy were associated with accelerated progression to a subsequent lapse (HR=1.09, CI=1.02–1.15), while increases in internal attributions of blame actually protected against lapsing (HR=0.98, CI=0.97–0.99). Treatment with nicotine patches slowed recurrent lapse progression (HR=0.58, CI=0.48–0.70), but this effect dissipated over multiple lapses, and was moderated by elevated ratings of post-lapse guilt (HR=1.08, CI=1.01–1.18), which predicted accelerated progression within the active patch group, while protecting against lapse in the placebo group. Results highlight the dynamic nature of lapse responses during smoking cessation, indicating that self-efficacy predicts progression from one lapse to the next, while attributions of self-blame and guilt did not influence progression as predicted by the RPM.
Smoking; lapse; relapse; abstinence violation effect
Smoking cessation trials generally record information on daily smoking behavior, but base analyses on measures of smoking status at the end of treatment (EOT). We present an alternative approach that analyzes the entire sequence of daily smoking status observations.
We analyzed daily abstinence data from a smoking cessation trial, using two longitudinal logistic regression methods: A mixed-effects (ME) model and a generalized estimating equations (GEE) model. We compared results to a standard analysis that takes as outcome abstinence status at EOT. We evaluated time-varying covariates (smoking history and time-varying drug effect) in the longitudinal analysis and compared ME and GEE approaches.
We observed some differences in the estimated treatment effect odds ratios across models, with narrower confidence intervals under the longitudinal models. GEE yields similar results to ME when only baseline factors appear in the model, but gives biased results when one includes time-varying covariates. The longitudinal models indicate that the quit probability declines and the drug effect varies over time. Both the previous day’s smoking status and recent smoking history predict quit probability, independently of the drug effect.
When analysing outcomes of studies from smoking cessation interventions, longitudinal models with multiple outcome data points, rather than just end of treatment, can makes efficient use of the data and incorporate time-varying covariates. The generalized estimating equations approach should be avoided when using time-varying predictors.
Generalized estimating equations; longitudinal analysis; mixed-effects model
Genome-wide association studies have linked single-nucleotide polymorphisms (SNPs) in the CHRNA5/A3/B4 gene cluster with heaviness of smoking. The nicotine metabolite ratio (NMR), a measure of the rate of nicotine metabolism, is associated with the number of cigarettes per day (CPD) and likelihood of cessation. We tested the potential interacting effects of these two risk factors on CPD.
Pretreatment data from three prior clinical trials were pooled for analysis. One thousand and thirty treatment seekers of European ancestry with genotype data for the CHRNA5/A3/B4 SNPs rs578776 and rs1051730 and complete data for NMR and CPD at pretreatment were included. Data for the third SNP, rs16969968, were available for 677 individuals. Linear regression models estimated the main and interacting effects of genotype and NMR on CPD.
We confirmed independent associations between the NMR and CPD as well as between the SNPs rs16969968 and rs1051730 and CPD. We did not detect a significant interaction between NMR and any of the SNPs examined.
This study demonstrates the additive and independent association of the NMR and SNPs in the CHRNA5/A3/B4 gene cluster with smoking rate in treatment-seeking smokers.
To evaluate the novel nanoparticle reconstituted bacteriochlorin e6 bisoleate low-density lipoprotein (r-Bchl-BOA-LDL) for its efficacy as a photodynamic therapy agent delivery system in xenografts of human hepatoblastoma G2 (HepG2) tumors.
Materials & methods
Bchl-BOA was encapsulated in the nanoparticle low-density lipoprotein (LDL), a native particle whose receptor’s overexpression is a cancer signature for a number of neoplasms. Evaluation of r-Bchl-BOA-LDL as a potential photosensitizer was performed using a tumor response and foot response assay.
Results & discussion
When compared with controls, tumor regrowth was significantly delayed at injected murine doses of 2 µmole/kg r-Bchl-BOA-LDL after illumination at fluences of 125, 150 or 175 J/cm2. Foot response assays showed that although normal tissue toxicity accompanied the higher fluences it was significantly reduced at the lowest fluence tested.
This research demonstrates that r-Bchl-BOA-LDL is an effective photosensitizer and a promising candidate for further investigation.
bacteriochlorophyll; low-density lipoprotein; nanoparticle; photodynamic therapy; xenograft hepatoma
Photodynamic therapy (PDT) with low light fluence rate has rarely been studied in protocols that use short drug–light intervals and thus deliver illumination while plasma concentrations of photosensitizer are high, creating a prominent vascular response. In this study, the effects of light fluence rate on PDT response were investigated using motexafin lutetium (10 mg/kg) in combination with 730 nm light and a 180-min drug–light interval. At 180 min, the plasma level of photosensitizer was 5.7 ng/μl compared to 3.1 ng/mg in RIF tumor, and PDT-mediated vascular effects were confirmed by a spasmodic decrease in blood flow during illumination. Light delivery at 25 mW/cm2 significantly improved long-term tumor responses over that at 75 mW/cm2. This effect could not be attributed to oxygen conservation at low fluence rate, because 25 mW/cm2 PDT provided little benefit to tumor hemoglobin oxygen saturation. However, 25 mW/cm2 PDT did prolong the duration of ischemic insult during illumination and was correspondingly associated with greater decreases in perfusion immediately after PDT, followed by smaller increases in total hemoglobin concentration in the hours after PDT. Increases in blood volume suggest blood pooling from suboptimal vascular damage; thus the smaller increases after 25 mW/cm2 PDT provide evidence of more widespread vascular damage, which was accompanied by greater decreases in clonogenic survival. Further study of low fluence rate as a means to improve responses to PDT under conditions designed to predominantly damage vasculature is warranted.
The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.
nicotine; smoking cessation; choline acetyltransferase ChAT; pharmacogenetics; addiction; Pharmacogenetics/Pharmacogenomics; Addiction & Substance Abuse; Clinical Pharmacology/Trials; Psychiatry & Behavioral Sciences; Nicotine; Smoking Cessation; choline acetyltransferase ChAT
To determine patient characteristics associated with isoniazid resistance in cases of tuberculous meningitis, we conducted a cross-sectional study by using data from the US National Tuberculosis Surveillance System during 1993–2005. Foreign-born patients were more likely to be infected with an isoniazid-resistant strain.
Tuberculosis and other mycobacteria; bacteria; meningitis; epidemiology; drug resistance; isoniazid resistance; United States; dispatch
The present study investigated demographic and psychosocial correlates of smoking status and predictors of smoking cessation among young adults, ages 18–30 years old. Young adults (n=294) completed a self-report survey regarding their health habits and smokers were offered the opportunity to enroll in a smoking cessation program. Substitute reinforcers were greater among ex-smokers compared to nontreatment seeking smokers, treatment seeking smokers who did participate in a smoking cessation program and treatment seeking smokers who did not subsequently participate in a smoking cessation program. Greater complementary reinforcers and delay discounting rates differentiated nontreatment seeking smokers from ex-smokers and treatment seeking smokers who subsequently attended a smoking cessation program. Nontreatment seekers were less likely to have higher depression symptoms than ex-smokers. Treatment seekers who did not attend a smoking cessation program tended to live in a household with another smoker, to not be college educated, and to be non-white. Young adult smokers who increased their substitute reinforcers across treatment were almost two times more likely to be quit at treatment end. These results highlight variables that may be important to consider in recruitment strategies and treatment components for smoking cessation interventions for young adult smokers.
Smoking; Young Adults; Depression; Reinforcers; Delay Discounting
Photodynamic therapy (PDT) can lead to the creation of heterogeneous, response-limiting hypoxia during illumination, which may be controlled in part through illumination fluence rate. In the present report we consider 1) regional differences in hypoxia, vascular response, and cell kill as a function of tumor depth and 2) the role of fluence rate as a mediator of depth-dependent regional intratumor heterogeneity. Intradermal RIF murine tumors were treated with Photofrin-PDT using surface illumination at an irradiance of 75 or 38 mW/cm2. Regional heterogeneity in tumor response was examined through comparison of effects in the surface vs. base of tumors, i.e. along a plane parallel to the skin surface and perpendicular to the incident illumination. 75 mW/cm2-PDT created significantly greater hypoxia in tumor bases relative to their surfaces. Increased hypoxia in the tumor base could not be attributed to regional differences in Photofrin concentration nor effects of fluence rate distribution on photochemical oxygen consumption, but significant depth-dependent heterogeneity in vascular responses and cytotoxic response were detected. At a lower fluence rate of 38 mW/cm2, no detectable regional differences in hypoxia or cytotoxic responses were apparent, and heterogeneity in vascular response was significantly less than that during 75 mW/cm2-PDT. This research suggests that the benefits of low-fluence-rate-PDT are mediated in part by a reduction in intratumor heterogeneity in hypoxic, vascular and cytotoxic responses.
photodynamic therapy; fluence rate; hypoxia; EF3; blood flow
The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry following eight weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 SNPs in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pre-treatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non treatment-seeking cohort, we utilized data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.
nicotine; smoking cessation; choline acetyltransferase ChAT; pharmacogenetics; addiction
Objective To determine whether initial isoniazid resistance is associated with death during the treatment of tuberculous meningitis.
Design Retrospective cohort study.
Setting National Tuberculosis Surveillance System at the Centers for Disease Control in the United States.
Participants Patients with a clinical diagnosis of tuberculous meningitis, reported to the National Tuberculosis Surveillance System between 1 January 1993 and 31 December 2005.
Main outcome measure All cause mortality during antituberculous treatment.
Results Between 1993 and 2005, 1896 patients had a clinical diagnosis of tuberculous meningitis and positive cultures from any site. In 123 (6%) of these patients, isoniazid resistance was present on initial susceptibility testing. The unadjusted association between initial isoniazid resistance and subsequent death among these 1896 patients did not reach statistical significance (odds ratio 1.38, 95% confidence interval 0.94 to 2.02). However, among 1614 patients with positive cerebrospinal fluid cultures, a significant unadjusted association was found between initial isoniazid resistance and subsequent death (odds ratio 1.61, 1.08 to 2.40). This association increased after adjustment for age, race, sex, and HIV status (odds ratio 2.07, 1.30 to 3.29).
Conclusions Isoniazid resistance on initial susceptibility testing was associated with subsequent death among cases of tuberculous meningitis with positive cerebrospinal fluid cultures. Randomised controlled trials are needed to evaluate the optimal empirical regimen for treating patients with tuberculous meningitis who are at high risk for both initial isoniazid resistance and poor clinical outcomes.
Although higher delay discounting rates have been linked to cigarette smoking, little is known about the stability of delay discounting, whether delay discounting promotes smoking acquisition, whether smoking contributes to impulsive choices, or if different relationships exist in distinct subgroups. This study sought to fill these gaps within a prospective longitudinal cohort study (N=947) spanning mid adolescence to young adulthood (age 15 to 21 years old). Smoking and delay discounting were measured across time. Covariates included peer and household smoking, academic performance, depression, novelty seeking, inattention and hyperactivity/impulsivity symptoms, and alcohol and marijuana use. The associated processes Latent Growth Curve Modeling (LGCM) with paths from the delay discounting level factor (baseline measure) and the trend factor (slope) to the smoking trend factor (slope) fit the data well, X2(19, n=947) = 15.37, p=.70, CFI=1.00, RMSEA=0, WRMR=.36. The results revealed that delay discounting did not change significantly across time. Baseline delay discounting had a significant positive effect on smoking trend (β=.08, z=2.16, p=.03). A standard deviation (SD=1.41) increase in baseline delay discounting resulted in an 11% increase (OR=1.11, 95% CI= 1.03, 1.23) in the odds of smoking uptake. The alternative path LCGM revealed that smoking did not significantly impact delay discounting (p’s > .05). Growth Mixture Modeling identified three smoking trajectories: nonsmokers, early/fast smoking adopters, and slow smoking progressors. Delay discounting was higher in the smoking versus nonsmoking trajectories, but did not discriminate between the smoking trajectories, despite different acquisition patterns. Delay discounting may provide a variable by which to screen for smoking vulnerability and help identify subgroups to target for more intensive smoking prevention efforts that include novel behavioral components directed toward aspects of impulsivity.
Delay discounting; smoking acquisition
Transdermal nicotine is widely used for smoking cessation, but only ~20% of smokers quit successfully with this medication. Interindividual variability in nicotine metabolism rate may influence treatment response. This study sought to validate, and extend in a larger sample, our previous finding that the ratio of plasma nicotine metabolites 3′-hydroxycotinine (3-HC)/cotinine, a measure of nicotine metabolism rate, predicts response to nicotine patch. A sample of 568 smokers was enrolled in a study that provided counseling and 8-weeks of 21mg nicotine patch. Pretreatment 3-HC/cotinine ratio was examined as a predictor of 7-day point prevalence abstinence, verified with breath carbon monoxide (CO), 8 weeks after the quit date. Controlling for sex, race, age, and nicotine dependence, smokers in the upper 3 quartiles of 3-HC/cotinine ratio (faster metabolizers) were ~50% less likely to be abstinent vs. smokers in the first quartile (slow metabolizers; 28% vs. 42%; OR=.54 [95% CI: .36–.82], p=.003). Among abstainers, plasma nicotine levels (assessed 1 week after treatment began) decreased linearly across the 3-HC/cotinine ratio (β = −3.38, t=−3.09, p<.05). These data support the value of the 3-HC/cotinine ratio as a biomarker to predict success with transdermal nicotine for smoking cessation.
nicotine; metabolism; tobacco; smoking; addiction
Nicotine deprivation symptoms, including fatigue and attentional deficits, predict relapse following smoking cessation. Modafinil (Provigil), a wakefulness medication shown to have efficacy for the treatment of cocaine addiction, was tested as a novel therapy for nicotine dependence in a double-blind placebo-controlled trial.
157 treatment-seeking smokers received brief smoking cessation counseling and were randomized to: 1) 8 weeks of modafinil (200mg/day), or 2) 8 weeks of placebo. The primary outcome was biochemically verified 7-day point prevalence abstinence at the end of treatment. Secondary outcomes included cigarette smoking rate and post-quit nicotine deprivation symptoms (e.g., negative affect, withdrawal).
In this interim study analysis, end of treatment (EOT) quit rates did not differ between treatment arms (42% for placebo vs. 34% for modafinil; OR = 0.67 [0.34 – 1.31], p = .24). Further, from the target quit date to EOT, the daily smoking rate was 44% higher among non-abstainers in the modafinil arm, compared to non-abstainers in the placebo arm (IRR = 1.44, CI95 = 1.09–1.89, p < .01). Modafinil-treated participants also reported greater increases in negative affect and withdrawal symptoms, vs. participants randomized to placebo (ps < .05).
These data do not support the use of modafinil for the treatment of nicotine dependence and, as a consequence, this trial was discontinued. Cigarette smoking should be considered when modafinil is prescribed, particularly among those with psychiatric conditions that have high comorbidity with nicotine dependence.
nicotine dependence; smoking cessation; addiction; modafinil
Pharmacogenetic clinical trials seek to identify genetic modifiers of treatment effects. When a trial has collected data on many potential genetic markers, a first step in analysis is to screen for evidence of pharmacogenetic effects by testing for treatment-by-marker interactions in a statistical model for the outcome of interest. This approach is potentially problematic because i) individual significance tests can be overly sensitive, particularly when sample sizes are large; and ii) standard significance tests fail to distinguish between markers that are likely, on biological grounds, to have an effect, and those that are not. One way to address these concerns is to perform Bayesian hypothesis tests (Berger 1985; Kass and Raftery 1995), which are typically more conservative than standard uncorrected frequentist tests, less conservative than multiplicity-corrected tests, and make explicit use of relevant biological information through specification of the prior distribution. In this article we use a Bayesian testing approach to screen a panel of genetic markers recorded in a randomized clinical trial of bupropion versus placebo for smoking cessation. From a panel of 59 single-nucleotide polymorphisms (SNPs) located on 11 candidate genes, we identify four SNPs (one each on CHRNA5 and CHRNA2 and two on CHAT) that appear to have pharmacogenetic relevance. Of these, the SNP on CHRNA5 is most robust to specification of the prior. An unadjusted frequentist test identifies seven SNPs, including these four, none of which remains significant upon correction for multiplicity. In a panel of 43 randomly selected control SNPs, none is significant by either the Bayesian or the corrected frequentist test.
Bayes factor; Bayesian hypothesis test; bupropion; importance sampling; pharmacogenomics; single-nucleotide polymorphism
This study explored whether functional genetic variants previously associated with nicotine dependence are associated with regional cerebral blood flow (rCBF) changes during nicotine abstinence (compared to satiety; smoking as usual). Thirteen smokers participating in a prior arterial spin labeled (ASL) perfusion MRI study were scanned on two occasions (after >12 hours abstinence vs. satiety) , and were genotyped for variants in the dopamine D2 receptor (DRD2-141 Ins/DelC; DRD2 C957T); a dopamine metabolizing enzyme (COMT val/val), and the mu opioid receptor (OPRM1 A118G). Significantly greater CBF increases were found in regions previously linked with cigarette cravings among carriers of the DelC variant of DRD2-141 and among the COMT val/val group. Smokers with TT genotypes for the DRD2 C957T exhibited less change in rCBF in abstinence relative to satiety, compared to those with CC or CT genotypes. Finally, smokers with OPRM1 AA genotypes showed significant increases in CBF in regions associated previously with cigarette cravings. While preliminary, these results suggest a neural mechanism through which these genetic variants may be linked with nicotine dependence, and provide further support for increased biological vulnerability in these subgroups of smokers.
perfusion MRI; nicotine; addiction; genetics
In a placebo-controlled bupropion smoking cessation trial, we examined blind integrity, the link between blind integrity and quit rates, and whether side effects and changes in nicotine withdrawal symptoms or mood were mechanisms through which blind integrity is threatened. At a 12-month follow-up, 498 participants indicated whether they thought they received bupropion, placebo, or were not sure. Potential mediators of treatment effects on treatment arm guess (i.e., side effects, withdrawal, and mood) were measured during treatment and 7-day point prevalence cessation was assessed at the end of treatment (EOT) and at 6- and 12-months post quit date. Overall, 55% of participants guessed their randomization correctly. Compared to guessing not sure, participants who guessed they were taking bupropion were more than twice as likely to have been randomized to bupropion. Similarly, participants who guessed placebo were twice as likely to have been randomized to placebo. Treatment arm guess was associated with quit rates. Including treatment arm guess with actual treatment arm in models of quit rates significantly reduced the odds ratio for bupropion efficacy at EOT and at 6- and 12-months post quit date. There was no evidence for mediation. In bupropion smoking cessation trials, blind failure may occur and participant guess about treatment arm assignment is associated with quit rates.
Study Blind; Bupropion; Smoking Cessation; Mediators; Blind Bias
Craving is a hallmark of drug dependence, including dependence on nicotine. Many studies have examined the neural substrates of cravings elicited by smoking-related cues. Less is known about the neural basis of unprovoked, abstinence-induced cravings, despite the contributions of such cravings to smoking relapse. To fill this gap, we used arterial spin labeled (ASL) perfusion MRI to characterize the neural substrates of abstinence-induced cravings to smoke. Fifteen chronic smokers were scanned during a resting state on two separate occasions: (1) smoking satiety and (2) abstinence (following ≥ 12 hours of smoking deprivation), in counterbalanced order. Smoking abstinence state (vs. satiety) was associated with increased cerebral blood flow (CBF) in anterior cingulate cortex (ACC)/medial orbitofrontal cortex (OFC) and left OFC. Abstinence-induced cravings to smoke were predicted by CBF increases (abstinence minus satiety) in: right OFC, right dorsolateral prefrontal cortex (DLPFC), occipital cortex, ACC, ventral striatum/nucleus accumbens, thalamus, amygdala, bilateral hippocampus, left caudate, and right insula. These data suggest that increased activation in the brain's visuospatial and reward circuitry underlies abstinence-induced cravings to smoke, and thereby, may be important in relapse.
Addiction; Cerebral Blood Flow; Cortex; Mesolimbic; Nicotine; Neuroimaging