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1.  Is a Cancer Diagnosis a Teachable Moment for the Patient’s Relative who Smokes? 
Cancer causes & control : CCC  2013;24(7):1339-1346.
Purpose
This study examined a cancer diagnosis, vs. orthopedic surgery, as a teachable moment for recruiting smokers and treating nicotine dependence among patients’ relatives.
Methods
Cancer patients and, for comparison, orthopedic patients at the University of Pennsylvania Health System were approached for referrals of relatives for a smoking cessation program, which involved behavioral counseling and nicotine patches. Primary outcomes were rate of program enrollment and rate of smoking abstinence. Potential mediators of smoking cessation were explored (e.g., treatment adherence, depression, anxiety). Two-hundred thirty four relatives (113 cancer, 121 orthopedic) were considered eligible for the cessation program and comprised the study sample.
Results
Relatives of oncology patients were significantly more likely to enroll in the smoking cessation program, vs. orthopedic relatives (75% vs. 60%; OR=1.96, 95% CI: 1.07-3.61, p=.03) but they were not significantly more likely to remain in the program (61% vs. 52%) or quit smoking (19% vs. 26%; p’s > .05). Compared to orthopedic relatives, oncology relatives showed significantly lower nicotine patch adherence and significantly greater levels of negative affect and depression and anxiety symptoms during treatment (p’s < .05). Further, orthopedic relatives, compared to oncology relatives, showed a greater reduction in the perceived benefits of smoking (p=.06), which was significantly associated with abstinence (p=.02).
Conclusions
While a family member’s cancer diagnosis may serve as a teachable moment for a smoker to enroll in a smoking cessation treatment program, high levels of psychological distress and perceptions of the benefits of smoking and low levels of treatment adherence may undermine successful abstinence among this population.
doi:10.1007/s10552-013-0212-2
PMCID: PMC3676691  PMID: 23605220
Teachable moment; cancer; smoking cessation
2.  The First Seven Days of a Quit Attempt Predicts Relapse: Validation of a Measure for Screening Medications for Nicotine Dependence 
Journal of addiction medicine  2013;7(4):249-254.
Objectives
There is a critical need for the development of novel treatments for nicotine dependence. Since the majority of smokers who make a quit attempt fail within seven days, medication screening procedures which focus on this early cessation period may provide an indicator of treatment efficacy. To establish the clinical validity of this paradigm, it is critical to demonstrate the association of early abstinence with longer-term abstinence. We tested the number of days abstinent during the first week following the target quit date (TQD) as a predictor of point-prevalence abstinence in three independent pharmacotherapy trials for nicotine dependence.
Methods
This was a secondary data analysis of three randomized clinical trials: a placebo-controlled trial of transdermal nicotine (n=545); an open-label nicotine replacement therapy (patch vs. spray) trial (n=566); and a bupropion placebo-controlled trial (n=538). In separate logistic regression models, the maximum number of consecutive days of abstinence during the first week following the TQD was used to predict biochemically-verified 7-day point prevalence abstinence at end-of-treatment and six months post-TQD.
Results
Across the three trials, number of days abstinent significantly predicted abstinence at end-of-treatment and six months (ORs>1.4, ps<0.0001). Likewise, not having any lapse during the first week predicted abstinence at end-of-treatment and six months (ORs>4.7, ps<0.0001).
Conclusions
The first week of abstinence was highly predictive of end-of-treatment and long-term abstinence. Medication screening procedures which focus on this early abstinence period (i.e., six or seven days of consecutive abstinence) represent a valid tool for assessing the presence of a signal for medication efficacy.
doi:10.1097/ADM.0b013e31829363e1
PMCID: PMC3737394  PMID: 23669629
Smoking cessation; nicotine dependence; medication screening; relapse
3.  APOE ε4, an Alzheimer’s disease susceptibility allele, and smoking cessation 
The pharmacogenomics journal  2012;13(6):10.1038/tpj.2012.49.
Possessing an APOE ε4 allele, advanced age, and smoking are risk factors for Alzheimer’s disease and cognitive decline. Deficits in cognitive function also increase risk for smoking relapse. Data from 917 adult smokers of European ancestry were pooled across three randomized trials of smoking cessation. We examined whether smokers who carry at least one ε4 allele (n=252) have more difficulty quitting smoking compared to noncarriers (n=665), and whether age moderated this association. The genotype by age interaction was significant for 7-day point-prevalence abstinence rates (p=0.04) and time to 7-day failure (p=0.03). Among smokers over age 60, ε4 carriers were less likely to quit (OR=0.27, p=0.018) and relapsed more quickly (HR=3.38, p=0.001) compared to noncarriers. The genotype association with relapse was non-significant among younger smokers. An increased understanding of the underlying pathophysiological mechanisms of this association could facilitate the development of targeted therapies for smokers with increased risk for cognitive decline.
doi:10.1038/tpj.2012.49
PMCID: PMC3604077  PMID: 23247396
smoking; smoking cessation; relapse; nicotine; cognition; APOE
4.  Assessing the fit of parametric cure models 
Biostatistics (Oxford, England)  2012;14(2):340-350.
Survival data can contain an unknown fraction of subjects who are “cured” in the sense of not being at risk of failure. We describe such data with cure-mixture models, which separately model cure status and the hazard of failure among non-cured subjects. No diagnostic currently exists for evaluating the fit of such models; the popular Schoenfeld residual (Schoenfeld, 1982. Partial residuals for the proportional hazards regression-model. Biometrika 69, 239–241) is not applicable to data with cures. In this article, we propose a pseudo-residual, modeled on Schoenfeld's, to assess the fit of the survival regression in the non-cured fraction. Unlike Schoenfeld's approach, which tests the validity of the proportional hazards (PH) assumption, our method uses the full hazard and is thus also applicable to non-PH models. We derive the asymptotic distribution of the residuals and evaluate their performance by simulation in a range of parametric models. We apply our approach to data from a smoking cessation drug trial.
doi:10.1093/biostatistics/kxs043
PMCID: PMC3695652  PMID: 23197383
Accelerated failure time; Long-term survivors; Proportional hazards; Residual analysis
5.  High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine: A Proof of Concept Placebo-Controlled Trial 
Nicotine & Tobacco Research  2012;15(2):348-354.
Introduction:
Smokers with a faster rate of nicotine metabolism, estimated using the ratio of 3′-hydroxycotinine (3-HC) to cotinine, have lower plasma nicotine levels and are more likely to relapse with 21 mg nicotine patch therapy, than smokers with slower rates of nicotine metabolism. Thus, faster metabolizers of nicotine may require a higher nicotine patch dose to achieve cessation.
Methods:
This proof of concept randomized placebo-controlled trial evaluated the efficacy and safety of 8 weeks of 42 mg transdermal nicotine versus 21 mg, among 87 fast metabolizers of nicotine (3-HC/cotinine ≥ 0.18).
Results:
After 1 week of treatment, an intent-to-treat (ITT) analysis showed that participants treated with 42 mg nicotine had significantly higher expired-air carbon monoxide (CO)-confirmed 24-hr abstinence (75% vs. 58.1%; OR = 3.21; 95% CI: 1.12–9.24, p = .03) but not 7-day abstinence (50% vs. 34.9%; OR = 2.02; 95% CI: 0.82–4.94, p = .13). After 8 weeks of treatment, ITT analysis showed that participants treated with 42 mg nicotine had marginally higher rates of CO-confirmed 24-hr abstinence (45.5% vs. 30.2%; OR = 2.32; 95% CI: 0.92–5.92, p = .08) but not 7-day abstinence (29.6% vs. 23.3%; OR = 1.52, 95% CI: 0.57–4.07, p = .41). Percent nicotine and cotinine replacement were significantly greater for 42 mg nicotine versus 21 mg (p < .005). There were no significant differences between treatment arms in the frequency of severe side effects and serious adverse events or blood pressure during treatment (p > .10).
Conclusions:
Further examination of the efficacy of 42 mg nicotine patch therapy for fast metabolizers of nicotine is warranted.
doi:10.1093/ntr/nts129
PMCID: PMC3545715  PMID: 22589423
6.  Diffusion of an evidence-based smoking cessation intervention through Facebook: a randomised controlled trial study protocol 
BMJ Open  2014;4(1):e004089.
Introduction
Online social networks represent a potential mechanism for the dissemination of health interventions including smoking cessation; however, which elements of an intervention determine diffusion between participants is unclear. Diffusion is frequently measured using R, the reproductive rate, which is determined by the duration of use (t), the ‘contagiousness’ of an intervention (β) and a participant's total contacts (z). We have developed a Facebook ‘app’ that allows us to enable or disable various components designed to impact the duration of use (expanded content, proactive contact), contagiousness (active and passive sharing) and number of contacts (use by non-smoker supporters). We hypothesised that these elements would be synergistic in their impact on R, while including non-smokers would induce a ‘carrier’ state allowing the app to bridge clusters of smokers.
Methods and analysis
This study is a fractional factorial, randomised control trial of the diffusion of a Facebook application for smoking cessation. Participants recruited through online advertising are randomised to 1 of 12 cells and serve as ‘seed’ users. All user interactions are tracked, including social interactions with friends. Individuals installing the application that can be traced back to a seed participant are deemed ‘descendants’ and form the outcome of interest. Analysis will be conducted using Poisson regression, with event count as the outcome and the number of seeds in the cell as the exposure.
Results
The results will be reported as a baseline R0 for the reference group, and incidence rate ratio for the remainder of predictors.
Ethics and Dissemination
This study uses an abbreviated consent process designed to minimise barriers to adoption and was deemed to be minimal risk by the Institutional Review Board (IRB). Results will be disseminated through traditional academic literature as well as social media. If feasible, anonymised data and underlying source code are intended to be made available under an open source license.
ClinicalTrials.gov registration number
NCT01746472.
doi:10.1136/bmjopen-2013-004089
PMCID: PMC3902462  PMID: 24448847
Internet; Smoking Cessation; Diffusion; Dissemination; RCT
7.  Efficacy of Extended Duration Transdermal Nicotine Therapy: A Randomized Trial 
Annals of internal medicine  2010;152(3):144-151.
Background: Tobacco dependence is a chronic, relapsing condition that may require extended treatment.
Objective: To assess whether extended transdermal nicotine therapy increases abstinence from tobacco more than standard duration therapy in adult smokers.
Design: Parallel randomized placebo-controlled trial from September 2004 to February 2008 (small block randomization scheme, not stratified). Study participants and all research personnel except for the database manager were blinded to randomization. (NCT00364156)
Setting: Academic center.
Participants: 568 adult smokers.
Intervention: Participants were randomized to: standard (8 weeks 21mg Nicoderm CQ, 16 weeks placebo) or extended (24 weeks 21mg Nicoderm CQ) therapy.
Measurements: The primary outcome was biochemically-verified point prevalence abstinence at weeks 24 and 52. Secondary outcomes were continuous and prolonged abstinence, lapse and recovery events, cost/additional quitter, and side effects and adherence.
Results: At 24 weeks, extended therapy produced higher rates of point prevalence abstinence (31.6% versus 20.3%; Odds Ratio [OR] = 1.81 [1.23-2.66], p = 0.002), prolonged abstinence (41.5% versus 26.9%; OR = 1.97 [1.38-2.82] p = 0.001), and continuous abstinence (19.2% versus 12.6%; OR = 1.64 [1.04-2.60] p = 0.032), versus standard therapy. Extended therapy reduced the risk for a lapse (Hazard Ratio [HR] = 0.77 [0.63-0.95], p = 0.013) and increased the chances of recovery from lapses (HR = 1.47 [1.17-1.84], p = 0.001). Time to relapse was slower with extended versus standard therapy (HR = 0.50 [0.35-0.73], p < 0.001). At week 52, extended therapy produced higher quit rates for prolonged abstinence only (p = 0.027). There were no group differences in side effects and adverse events at the extended treatment phase assessment.
Limitations: The generalizability of the findings may be limited because participants were treatment-seeking smokers without medical comorbidity and differences in adherence across treatment arms were detected.
Conclusion: Compared to 8 weeks of transdermal nicotine, 24 weeks of transdermal nicotine increased biochemically-confirmed point prevalence abstinence and continuous abstinence at week 24, reduced the risk of smoking lapses, and increased the likelihood of post-lapse recovery to abstinence.
doi:10.7326/0003-4819-152-3-201002020-00005
PMCID: PMC3782858  PMID: 20124230
8.  Photodynamic Therapy of Disseminated Non-Small Cell Lung Carcinoma in a Murine Model 
Lasers in surgery and medicine  2011;43(7):663-675.
Background and Objective
Photodynamic therapy (PDT) of thoracic malignancies involving the pleural surfaces is an active area of clinical investigation. The present report aims to characterize a model for PDT of disseminated non-small cell lung carcinoma grown orthotopically in nude mice, and to evaluate PDT effect on tumor and normal tissues.
Study Design
H460 human non-small cell lung carcinoma (NSCLC) cells were injected percutaneously into the thoracic cavity of nude mice. HPPH-PDT (1 mg/kg, 24 h) was performed via the interstitial delivery (150 mW/cm) of 661 nm light to the thoracic cavity at fluences of 25-200 J/cm.
Results
H460 tumors exhibited exponential growth within the thoracic cavity consisting of diffuse, gross nodular disease within 9 days after intrathoracic injection. Tumor volume, measured by magnetic resonance imaging (MRI), was highly correlated with the aggregate tumor mass extracted from the corresponding animal. Intrathoracic PDT at fluences of ≥ 50 J/cm produced significant decreases in tumor burden as compared to untreated controls, however mortality increased with rising fluence. Accordingly, 50 J/cm was selected for MRI studies to measure intra-animal PDT effects. Tumor distribution favored the ventral (vs. dorsal), caudal (vs. cranial), and right (vs. left) sides of the thoracic cavity by MRI; PDT did not change this spatial pattern despite an overall effect on tumor burden. Histopathology revealed edema and fibrin deposition within the pulmonary interstitium and alveoli of the PDT-treated thoracic cavity, as well as occasional evidence of vascular disruption. Prominent neutrophil infiltration with a concomitant decline in the lymphocyte compartment was also noted in the lung parenchyma within 24 hours after PDT.
Conclusion
HPPH-PDT of an orthotopic model of disseminated NSCLC is both feasible and effective using intracavitary light delivery. We establish this animal model, together with the treatment and monitoring approaches, as novel and valuable methods for the pre-clinical investigation of intrathoracic PDT of disseminated pleural malignancies.
doi:10.1002/lsm.21102
PMCID: PMC3676899  PMID: 22057494
HPPH; Photochlor®; 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a; interstitial illumination; magnetic resonance imaging; non-small cell lung carcinoma; photodynamic therapy; pleural malignancy
9.  µ-opioid Receptor Availability in the Amygdala is Associated with Smoking for Negative Affect Relief 
Psychopharmacology  2012;222(4):701-708.
Rationale
The perception that smoking relieves negative affect contributes to smoking persistence. Endogenous opioid neurotransmission, and the µ-opioid receptor (MOR) in particular, plays a role in affective regulation and is modulated by nicotine.
Objectives
We examined the relationship of µ-opioid receptor binding availability in the amygdala to the motivation to smoke for negative affect relief and to the acute effects of smoking on affective responses.
Methods
Twenty-two smokers were scanned on two separate occasions after overnight abstinence using [11C]carfentanil positron emission tomography imaging: after smoking a nicotine-containing cigarette and after smoking a denicotinized cigarette. Self-reports of smoking motives were collected at baseline, and measures of positive and negative affect were collected pre- and post- cigarette smoking.
Results
Higher MOR availability in the amygdala was associated with motivation to smoke to relieve negative affect. However, MOR availability was unrelated to changes in affect after smoking either cigarette.
Conclusions
Increased MOR availability in amygdala may underlie the motivation to smoke for negative affective relief. These results are consistent with previous data highlighting the role of µ-opioid receptor neurotransmission in smoking behavior.
doi:10.1007/s00213-012-2673-5
PMCID: PMC3670416  PMID: 22389047
Smoking motivation; µ-opioid receptor; amygdala; affect regulation
10.  Pharmacogenetic Association of the Galanin Receptor (GALR1) SNP rs2717162 with Smoking Cessation 
Neuropsychopharmacology  2012;37(7):1683-1688.
Galanin modulates dopaminergic neurotransmission in the mesolimbic dopamine system, thereby influencing the rewarding effects of nicotine. Variants in the galanin receptor 1 (GALR1) gene have been associated with retrospective craving severity and heaviness of smoking in prior research. We investigated pharmacogenetic associations of the previously studied GALR1 polymorphism, rs2717162, in 1217 smokers of European ancestry who participated in one of three pharmacogenetic smoking cessation clinical trials and were treated with nicotine patch (n=623), nicotine nasal spray (n=189), bupropion (n=213), or placebo (n=192). The primary endpoint was abstinence (7-day point prevalence, biochemically confirmed) at the end of treatment. Cravings to smoke were assessed on the target quit day (TQD). The longitudinal regression model revealed a significant genotype by treatment interaction (P=0.03). There was a reduced odds of quitting success with the presence of at least one minor (C) allele in the bupropion-treated group (OR=0.43; 95% CI=0.22–0.77; P=0.005) but equivalent quit rates by genotype in the nicotine-replacement therapy groups. This genotype by treatment interaction was reproduced in a Cox regression model of time to relapse (P=0.04). In the bupropion trial, smokers carrying the C allele also reported more severe TQD cravings. Further research to identify functional variants in GALR1 and to replicate pharmacogenetic associations is warranted.
doi:10.1038/npp.2012.13
PMCID: PMC3358736  PMID: 22373943
nicotine; addiction; craving; pharmacogenetics; galanin receptor; behavioral science; neurogenetics; pharmacogenetics / pharmacogenomics; psychiatry & behavioral sciences; nicotine; addiction; craving; pharmacogenetics; galanin receptor 1
11.  Tumor Vascular Microenvironment Determines Responsiveness to Photodynamic Therapy 
Cancer Research  2012;72(8):2079-2088.
The efficacy of photodynamic therapy (PDT) depends upon the delivery of both photosensitizing drug and oxygen. In this study, we hypothesized that local vascular microenvironment is a determinant of tumor response to PDT. Tumor vascularization and its basement membrane (collagen) were studied as a function of supplementation with basement membrane matrix (Matrigel) at the time of tumor cell inoculation. Effects on vascular composition with consequences to tumor hypoxia, photosensitizer uptake and PDT response were measured. Matrigel-supplemented tumors developed more normalized vasculature, composed of smaller and more uniformly-spaced blood vessels than their unsupplemented counterparts, but these changes did not affect tumor oxygenation or PDT-mediated direct cytotoxicity. However, PDT-induced vascular damage increased in Matrigel-supplemented tumors, following an affinity of the photosensitizer Photofrin for collagen-containing vascular basement membrane coupled with increased collagen content in these tumors. The more highly-collagenated tumors demonstrated more vascular congestion and ischemia after PDT, along with a higher probability of curative outcome that was collagen dependent. In the presence of photosensitizer-collagen localization, PDT effects on collagen were evidenced by a decrease in its association with vessels. Together, our findings demonstrate that photosensitizer localization to collagen increases vascular damage and improves treatment efficacy in tumors with greater collagen content. The vascular basement membrane is thus identified to be a determinant of therapeutic outcome in PDT of tumors.
doi:10.1158/0008-5472.CAN-11-3744
PMCID: PMC3328659  PMID: 22374982
collagen; photodynamic therapy; microenvironment; normalization; vasculature
12.  Extended Duration Therapy with Transdermal Nicotine may Attenuate Weight Gain Following Smoking Cessation 
Addictive Behaviors  2011;37(4):565-568.
Aim
People who quit smoking often gain 11–12 pounds, on average, which can frequently lead to a relapse to smoking. This study evaluated whether extended vs. standard duration treatment with nicotine patch helps those able to quit smoking to reduce cessation-induced weight gain and explored nicotine patch adherence as a mediator of treatment effects.
Design and Setting
We examined data from a completed randomized placebo-controlled clinical trial of extended (24 weeks) vs. standard (8 weeks plus 16 weeks of placebo) transdermal nicotine patch therapy. Changes in measured weight over 24 weeks were compared across the two treatment arms, controlling for gender, baseline smoking rate, and previous weight. Adherence to patch use was assessed using self-report of daily use over 24 weeks.
Participants
139 clinical trial participants who were confirmed to be abstinent at weeks 8 and 24.
Findings
Compared to participants who received 8 weeks of nicotine patch therapy, participants who received 24 weeks of treatment showed significantly less weight gain from pre-treatment to week 24 (β = −4.76, 95% CI: −7.68 to −1.84, p = .002) and significantly less weight gain from week 8 to week 24 (β = −2.31, 95% CI: −4.39 to −0.23, p = .03). Extended treatment increased patch adherence which, in turn, reduced weight gain; patch adherence accounted for 20% of the effect of treatment arm on weight gain.
Conclusion
Compared to 8 weeks of transdermal nicotine therapy, 24 weeks of patch treatment may help to reduce the weight gain that is typical among smokers who are able to achieve abstinence from tobacco use. Extended treatment increased nicotine patch adherence which, in turn, reduced weight gain.
doi:10.1016/j.addbeh.2011.12.009
PMCID: PMC3288882  PMID: 22244706
13.  Relapse dynamics during smoking cessation: Recurrent abstinence violation effects and lapse-relapse progression 
Journal of Abnormal Psychology  2011;121(1):187-197.
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.
doi:10.1037/a0024451
PMCID: PMC3296289  PMID: 21787035
Smoking; lapse; relapse; abstinence violation effect
14.  Statistical Analysis of Daily Smoking Status in Smoking Cessation Clinical Trials 
Addiction (Abingdon, England)  2011;106(11):2039-2046.
Aims
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1111/j.1360-0443.2011.03519.x
PMCID: PMC3197211  PMID: 21631623
Generalized estimating equations; longitudinal analysis; mixed-effects model
15.  Association of the Nicotine Metabolite Ratio and CHRNA5/CHRNA3 Polymorphisms With Smoking Rate Among Treatment-Seeking Smokers 
Nicotine & Tobacco Research  2011;13(6):498-503.
Introduction:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1093/ntr/ntr012
PMCID: PMC3103715  PMID: 21385908
16.  Evaluation of bacteriochlorophyll-reconstituted low-density lipoprotein nanoparticles for photodynamic therapy efficacy in vivo 
Nanomedicine (London, England)  2011;6(3):475-487.
Aim
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.
Conclusion
This research demonstrates that r-Bchl-BOA-LDL is an effective photosensitizer and a promising candidate for further investigation.
doi:10.2217/nnm.11.8
PMCID: PMC3137792  PMID: 21542686
bacteriochlorophyll; low-density lipoprotein; nanoparticle; photodynamic therapy; xenograft hepatoma
17.  Increasing Damage to Tumor Blood Vessels during Motexafin Lutetium-PDT through Use of Low Fluence Rate 
Radiation research  2010;174(3):331-340.
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.
doi:10.1667/RR2075.1
PMCID: PMC2995951  PMID: 20726728
18.  Proactive recruitment predicts participant retention to end of treatment in a secondhand smoke reduction trial with low-income maternal smokers 
Improving smoking intervention trial retention in underserved populations remains a public health priority. Low retention rates undermine clinical advancements that could reduce health disparities. To examine the effects of recruitment strategies on participant retention among 279 low-income, maternal smokers who initiated treatment in a 16-week behavioral counseling trial to reduce child secondhand smoke exposure (SHSe). Participants were recruited using either reactive strategies or methods that included proactive strategies. Logistic regression analysis was used to test associations among retention and recruitment method in the context of other psychosocial and sociodemographic factors known to relate to retention. Backwards stepwise procedures determined the most parsimonious solution. Ninety-four percent of participants recruited with proactive + reactive methods were retained through end of treatment compared to 74.7% of reactive-recruited participants. Retention likelihood was five times greater if participants were recruited with proactive + reactive strategies rather than reactive recruitment alone (odds ration [OR] = 5.36; confidence interval [CI], 2.31–12.45). Greater knowledge of SHS consequences (OR = 1.58; CI, 1.07–2.34) was another significant factor retained in the final LR model. Proactive recruitment may improve retention among underserved smokers in behavioral intervention trials. Identifying factors influencing retention may improve the success of recruitment strategies in future trials, in turn, enhancing the impact of smoking interventions.
doi:10.1007/s13142-011-0059-6
PMCID: PMC3717634  PMID: 24073063
Retention; Recruitment; Underserved; Secondhand smoke
19.  Convergent Evidence that Choline Acetyltransferase Gene Variation is Associated with Prospective Smoking Cessation and Nicotine Dependence 
Neuropsychopharmacology  2010;35(6):1374-1382.
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.
doi:10.1038/npp.2010.7
PMCID: PMC2855736  PMID: 20147892
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
20.  Isoniazid-Resistant Tuberculous Meningitis, United States, 1993–2005 
Emerging Infectious Diseases  2011;17(3):539-542.
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.
doi:10.3201/eid1703.101715
PMCID: PMC3166033  PMID: 21392454
Tuberculosis and other mycobacteria; bacteria; meningitis; epidemiology; drug resistance; isoniazid resistance; United States; dispatch
21.  Young Adult Smoking: What factors differentiate ex-smokers, smoking cessation treatment seekers and nontreatment seekers? 
Addictive behaviors  2009;34(12):1036-1041.
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.
doi:10.1016/j.addbeh.2009.06.012
PMCID: PMC2743450  PMID: 19619948
Smoking; Young Adults; Depression; Reinforcers; Delay Discounting
22.  Fluence Rate-Dependent Intratumor Heterogeneity in Physiologic and Cytotoxic Responses to Photofrin Photodynamic Therapy 
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.
doi:10.1039/b9pp00004f
PMCID: PMC2834171  PMID: 20024165
photodynamic therapy; fluence rate; hypoxia; EF3; blood flow
23.  Convergent Evidence that Choline Acetyltransferase Gene Variation is Associated with Prospective Smoking Cessation and Nicotine Dependence 
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.
doi:10.1038/npp.2010.7
PMCID: PMC2855736  PMID: 20147892
nicotine; smoking cessation; choline acetyltransferase ChAT; pharmacogenetics; addiction
24.  Isoniazid resistance and death in patients with tuberculous meningitis: retrospective cohort study 
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.
doi:10.1136/bmj.c4451
PMCID: PMC2938884  PMID: 20819874
25.  Does delay discounting play an etiological role in smoking or is it a consequence of smoking? 
Drug and alcohol dependence  2009;103(3):99-106.
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.
doi:10.1016/j.drugalcdep.2008.12.019
PMCID: PMC2743449  PMID: 19443136
Delay discounting; smoking acquisition

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