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1.  A Randomized Placebo-controlled Trial to Test a Genetically-informed Biomarker ForPersonalizing Treatment for Tobacco Dependence 
The Lancet. Respiratory medicine  2015;3(2):131-138.
Summary
Background
There is substantial variability in therapeutic response and adverse effects with pharmacotherapies for tobacco dependence. Biomarkers to optimize treatment choice for individual smokers may improve treatment outcomes.Wetested whether a genetically-informed biomarker of nicotine clearance, the nicotine metabolite ratio (NMR; 3’hydroxycotinine/cotinine), predicts response to nicotine patch vs. varenicline for smoking cessation.
Methods
AnNMR-stratified multicenter, randomized, placebo-controlled clinical trial was conducted from November 2010-September 2013 at 4 sites. Treatment-seeking smokers (1246: 662 slow metabolizers; 584 normal metabolizers) were randomized to 11-weeks of nicotine patch (active patch + placebo pill), varenicline (active pill + placebo patch), or placebo (placebo pill + patch), plus behavioral counseling; an intent-to-treat analysis was conducted. Participants were followed for 12-months following the target quit date.The primary endpoint was biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT) to estimate the pharmacologic effect of treatment by NMR. Secondary outcomes were side-effects, withdrawal symptoms, and 6- and 12-month abstinence rates. ClinicalTrials.govregistration: NCT01314001
Findings
In the longitudinal model including all time points, the NMR-by-treatment interaction was significant (ratio of odds ratios (ORR)=1·96; CI=(1·11, 3·46); p=0·02). The results indicate that varenicline was more efficacious than nicotine patch for normal metabolizers, whilethe efficacy was equivalent for slow metabolizers. In cross-sectional analyses, the interaction was significant at EOT (ORR)=1·89; CI=(1·02, 3·45); p=0·04) andat 6-months (ORR=2·07; CI=(1·01, 4·22); p=0·05), but not at 12-months (p=0·14). An NMR-by-treatment interaction showed that slow (vs. normal) metabolizers reported greater overallside-effects severity with vareniclinevs. placebo (β−1·06; CI=(−2·08, −0·03); p=0·044).
Interpretation
Treating normal metabolizers with varenicline and slow metabolizers with nicotine patchmayoptimize quit rates while minimizing side-effects.
Funding
National Institutes of Health
doi:10.1016/S2213-2600(14)70294-2
PMCID: PMC4480925  PMID: 25588294
2.  Tracking Viable Circulating Tumor Cells (CTCs) in the Peripheral Blood of Non-Small Cell Lung Cancer Patients Undergoing Definitive Radiation Therapy: Pilot Study Results 
Cancer  2014;121(1):139-149.
Background
Assays identifying circulating tumor cells (CTC) allow noninvasive and sequential monitoring of the status of primary or metastatic tumors, potentially yielding clinically useful information. However, the effect of radiation therapy (RT) on CTC in patients with non-small cell lung cancer (NSCLC) to our knowledge has not been previously explored.
Methods
We describe here results of a pilot study of 30 NSCLC patients undergoing RT, from whom peripheral blood samples were assayed for CTC via an assay that identifies live cells, via an adenoviral probe that detects the elevated telomerase activity present in almost all cancer cells but not normal cells, and with validity of the assay confirmed with secondary tumor-specific markers. Patients were assayed prior to initiation of radiation (Pre-RT), during the RT treatment course, and/or after completion of radiation (Post-RT).
Results
The assay successfully detected CTC in the majority of patients, including 65% of patients prior to start of RT, and in patients with both EGFR wild type and mutation-positive tumors. Median counts in patients Pre-RT were 9.1 CTC/mL (range: undetectable - 571), significantly higher than the average Post-RT count of 0.6 CTC/mL (range: undetectable - 1.8) (p < 0.001). Sequential CTC counts were available in a subset of patients and demonstrated decreases after RT, except for a patient who subsequently developed distant failure.
Conclusions
These pilot data suggest that CTC counts appear to reflect response to RT for patients with localized NSCLC. Based on these promising results, we have launched a more comprehensive and detailed clinical trial.
doi:10.1002/cncr.28975
PMCID: PMC4270850  PMID: 25241991
Circulating tumor cells; non-small cell lung cancer; telomerase; assay; biomarkers
3.  Reinforcing value of smoking relative to physical activity and the effects of physical activity on smoking abstinence symptoms among young adults 
This study sought to evaluate whether individual differences in the reinforcing value of smoking relative to physical activity (RRVS) moderated the effects of physical activity on smoking abstinence symptoms in young adult smokers. The repeated measures within-subjects design included daily smokers (n=79) 18–26 years old. RRVS was measured with a validated behavioral choice task. On two subsequent visits, participants completed self-report measures of craving, withdrawal, mood, and affective valence before and after they engaged in passive sitting or a bout of physical activity. RRVS did not moderate any effects of physical activity (p’s > .05). Physical activity compared to passive sitting predicted decreased withdrawal symptoms (β=−5.23, CI= −6.93, −3.52; p<0.001), negative mood (β=−2.92, CI= −4.13, −1.72; p<0.001), and urge to smoke (β=−7.13, CI= −9.39, −4.86; p<0.001). Also, physical activity compared to passive sitting predicted increased positive affect (β=3.08, CI= 1.87, 4.28; p<0.001) and pleasurable feelings (β=1.07, CI= 0.58, 1.55; p<0.001), and greater time to first cigarette during the ad-libitum smoking period (β=211.76, CI= 32.54, 390.98; p=0.02). RRVS predicted higher levels of pleasurable feelings (β=0.22, CI= 0.01 – 0.43, p=0.045), increased odds of smoking versus remaining abstinent during the ad-libitum smoking period (β=0.04, CI= 0.01, 0.08; p=0.02), and reduced time to first cigarette (β=−163.00, CI = −323.50, −2.49; p=0.047). Regardless of the RRVS, physical activity produces effects that may aid smoking cessation in young adult smokers. However, young adult smokers who have a higher RRVS will be less likely to choose to engage physical activity, especially when smoking is an alternative.
doi:10.1037/pha0000051
PMCID: PMC4658299  PMID: 26348158
Smoking; physical activity; young adults; mood; affect; reinforcing value
4.  Reward and Affective Regulation in Depression-Prone Smokers 
Biological psychiatry  2014;76(9):689-697.
Background
There is a disproportionately high smoking prevalence among individuals who are prone to depression. While depression has been conceptualized as a disorder of dysregulated positive affect and disrupted reward processing, little research has been conducted to determine the role of smoking in these processes among depression-prone smokers.
Methods
Depression-prone smokers (DP+; n = 34) and smokers not depression-prone (DP-; n=49) underwent two laboratory sessions, once while smoking abstinent and once while smoking ad-libitum, to assess the relative reinforcing value of smoking and reward sensitivity. Using experience sampling methods, participants completed self-report measures of subjective reward, positive affect, and negative affect across three days while smoking as usual and three days while smoking abstinent.
Results
DP+ were two times more likely to work for cigarette puffs versus money in a progressive ratio, choice task (OR 2.05; CI 95% 1.04 to 4.06, p=0.039) compared to DP-. Reward sensitivity as measured by the signal detection task did not yield any significant findings. Mixed models regressions revealed a 3-way interaction (depression group, smoking phase, and time) for subjective reward, negative affect and positive affect. For all three of these outcomes, the slopes for DP- and DP+ differed significantly from each other (p's < 0.05), and the effect of smoking (vs. abstinence) over time was greater for DP+ than DP- smokers (p's <0.05).
Conclusions
These findings indicate that the effects of smoking on reward and positive affect regulation are specific to DP+ smokers and highlight novel targets for smoking cessation treatment in this population.
doi:10.1016/j.biopsych.2014.04.018
PMCID: PMC4186900  PMID: 24947541
Smoking; depression; positive affect; negative affect; reward regulation; reward sensitivity
5.  Age-Related Differences in Working Memory Deficits During Nicotine Withdrawal 
Addiction biology  2013;19(5):907-917.
Nicotine withdrawal is associated with subtle working memory deficits that predict subsequent relapse. We examined the neural substrates underlying these processes in treatment-seeking smokers, and explored the moderating influence of age on abstinence-induced alterations in brain activity and performance. Sixty-three smokers participated in two blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) scans while performing a visual N-back task on two separate occasions: smoking as usual and after 24 hours of biochemically confirmed abstinence (order counterbalanced). Abstinence (versus smoking) led to reduced accuracy, slower median correct response time, and reduced BOLD signal change in the 3 a priori regions of interest (ROIs): medial frontal/cingulate gyrus and right and left dorsolateral prefrontal cortex. Significant age x session effects were found for BOLD signal change in all three regions, as well as for withdrawal and craving; for all measures, abstinence effects were attenuated in smokers aged >50 years compared to those < 50 years old. These results suggest that abstinence effects on neurocognitive function may be more pronounced for younger smokers, and may indicate a new avenue for research exploring mechanisms underlying age differences in smoking cessation success.
doi:10.1111/adb.12051
PMCID: PMC3701751  PMID: 23496760
Addiction; cognition; fMRI; nicotine; withdrawal; age
6.  Guidelines on Statistical Reporting at Nicotine & Tobacco Research 
Nicotine & Tobacco Research  2015;17(11):1295-1296.
doi:10.1093/ntr/ntv131
PMCID: PMC4601527  PMID: 26079576
7.  The Association between Changes in Alternative Reinforcers and Short-term Smoking Cessation 
Drug and alcohol dependence  2014;138:67-74.
Background
While more than 50% of smokers make a serious quit attempt each year, less than 10% quit permanently. Evidence from studies of adolescent smoking and other substances of abuse suggest that alternative reinforcers, a construct of Behavioral Economic Theory, may contribute to the likelihood of smoking cessation in adults. This study examined the behavioral economics of smoking cessation within a smoking cessation clinical trial and evaluated how depressive symptoms and behavioral economic variables are associated with smoking cessation.
Methods
A sample of 469 smokers, enrolled in an effectiveness trial that provided counseling and 8 weeks of 21mg nicotine patches, was analyzed. Alternative reinforcers (substitute and complementary reinforcers) and depressive symptoms were examined in relation to 7-day point prevalence abstinence, verified with breath carbon monoxide, 8 weeks after the quit date.
Results
Controlling for covariates associated with cessation (nicotine dependence, age of smoking initiation, patch adherence), participants who were abstinent at week 8 showed significantly higher substitute reinforcers at all time-points, compared to those who were smoking (p’s < .05). Participants who were abstinent at week 8 showed lower complementary reinforcers and depressive symptoms at all time-points, compared to those who were smoking, but significant differences were confined to week 8 (p’s < .01). There was no significant interaction between alternative reinforcers and depressive symptoms across the eight weeks on week 8 abstinence.
Conclusions
These results support continued examination of Behavioral Economic Theory in understanding adult smoking cessation in order to inform future treatments and guidelines.
doi:10.1016/j.drugalcdep.2014.02.007
PMCID: PMC4030632  PMID: 24598122
smoking cessation; behavioral economics; alternative reinforcers; depression
8.  Long-term Nicotine Replacement Therapy 
JAMA internal medicine  2015;175(4):504-511.
IMPORTANCE
The US Food and Drug Administration adopted labeling for nicotine patches to allow use beyond the standard 8 weeks. This decision was based in part on data showing increased efficacy for 24 weeks of treatment. Few studies have examined whether the use of nicotine patches beyond 24 weeks provides additional therapeutic benefit.
OBJECTIVE
To compare 8 (standard), 24 (extended), and 52 (maintenance) weeks of nicotine patch treatment for promoting tobacco abstinence.
DESIGN, SETTING, AND PARTICIPANTS
We recruited 525 treatment-seeking smokers for a randomized clinical trial conducted from June 22, 2009, through April 15, 2014, through 2 universities.
INTERVENTIONS
Smokers received 12 smoking cessation behavioral counseling sessions and were randomized to 8, 24, or 52 weeks of nicotine patch treatment.
MAIN OUTCOMES AND MEASURES
The primary outcome was 7-day point prevalence abstinence, confirmed with breath levels of carbon monoxide at 6 and 12 months (intention to treat).
RESULTS
At 24 weeks, 21.7% of participants in the standard treatment arm were abstinent, compared with 27.2% of participants in the extended and maintenance treatment arms (χ 2 = 1.98; P = .17). In a multivariate model controlled for covariates, participants in the extended and maintenance treatment arms reported significantly greater abstinence rates at 24 weeks compared with participants in the standard treatment arm (odds ratio [OR], 1.70 [95% CI, 1.03-2.81]; P = .04), had a longer duration of abstinence until relapse (β = 21.30 [95% CI, 10.30-32.25]; P < .001), reported smoking fewer cigarettes per day if not abstinent (mean [SD], 5.8 [5.3] vs 6.4 [5.1] cigarettes per day; β = 0.43 [95% CI, 0.06-0.82]; P = .02), and reported more abstinent days (mean [SD], 80.5 [38.1] vs 68.2 [43.7] days; OR, 1.55 [95% CI, 1.06-2.26]; P = .02). At 52 weeks, participants in the maintenance treatment arm did not report significantly greater abstinence rates compared with participants in the standard and extended treatment arms (20.3% vs 23.8%; OR, 1.17 [95% CI, 0.69-1.98]; P = .57). Similarly, we found no difference in week 52 abstinence rates between participants in the extended and standard treatment arms (26.0% vs 21.7%; OR, 1.33 [95% CI, 0.72-2.45]; P = .36). Treatment duration was not associated with any adverse effects or adherence to the counseling regimen, but participants in the maintenance treatment arm reported lower adherence to the nicotine patch regimen compared with those in the standard and extended treatment arms (mean [SD], 3.94 [2.5], 4.61 [2.0], and 4.7 [2.4] patches/wk, respectively; F2,522 = 6.03; P = .003).
CONCLUSIONS AND RELEVANCE
The findings support the safety of long-term use of nicotine patch treatment, although they do not support efficacy beyond 24 weeks of treatment in a broad group of smokers.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01047527
doi:10.1001/jamainternmed.2014.8313
PMCID: PMC4410859  PMID: 25705872
9.  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
10.  A Double-Blind Placebo-Controlled Randomized Trial of Varenicline for Smokeless Tobacco Dependence in India 
Nicotine & Tobacco Research  2013;16(1):50-57.
Introduction:
The rate of smokeless tobacco use in India is 20%; its use causes serious health problems, and no trial has assessed behavioral or pharmacological treatments for this public health concern. This trial evaluated varenicline for treating smokeless tobacco dependence in India.
Methods:
This was a double-blind placebo-controlled randomized trial of varenicline (12 weeks, 1mg, twice per day) with 237 smokeless tobacco users in India. All participants received behavioral counseling. Outcomes included self-reported and biochemically verified abstinence at the end of treatment (EOT), lapse and recovery events, safety, and medication adherence.
Results:
Self-reported EOT abstinence was significantly greater for varenicline (43%) versus placebo (31%; adjusted odds ratio [AOR] = 2.6, 95% CI = 1.2–4.2, p = .009). Biochemically confirmed EOT abstinence was greater for varenicline versus placebo (25.2% vs. 19.5%), but this was not statistically different (AOR = 1.6, 95% CI = 0.84–3.1, p = .15). Compared with placebo, varenicline did not reduce the risk for a lapse (hazard ratio [HR] = 0.86, 95% CI = 0.69–1.1, p = .14), but it did increase the likelihood of recovery to abstinence (HR = 1.2, 95% CI = 1.02–1.4, p = .02). Greater adherence increased EOT cessation rates for varenicline (39% vs. 18%, p = .003) but not for placebo (28% vs. 14%, p = .06). There were no significant differences between varenicline and placebo in rate of side effects, serious adverse events, hypertension, or stopping or reducing medication.
Conclusions:
Varenicline is safe for treating smokeless tobacco dependence in India, and further examination of this medication for this important public health problem is warranted.
doi:10.1093/ntr/ntt115
PMCID: PMC3864491  PMID: 23946326
11.  Cognitive Deficits Specific to Depression-Prone Smokers During Abstinence 
Cigarette smoking is associated with a higher prevalence of depressive symptoms and individuals with elevated symptoms of depression have more difficulty quitting smoking. Depression is accompanied by cognitive deficits similar to those observed during nicotine withdrawal. Depressed smokers may smoke to alleviate these cognitive symptoms, which are exacerbated upon smoking abstinence. We hypothesized that following overnight abstinence, depression-prone smokers (DP+; past history and current depression symptoms; n = 34) would exhibit deficits in short-term and working memory, and experience greater attentional bias for affective stimuli, compared with smokers with no history or current symptoms of depression (DP−; n = 34). All participants underwent two laboratory sessions, once while smoking abstinent and once while smoking ad libitum (order counterbalanced, abstinence biochemically verified). Smokers completed measures of short-term memory (STM; word recognition task), working memory (N-back task), and attentional bias (Emotional Stroop task). The DP+ group showed declines in STM during abstinence compared with smoking, whereas the DP− group did not (interaction p = .02). There were small decrements in working memory accuracy during abstinence (p = .05), but this did not interact with depression status. During the Emotional Stroop task, the DP+ group showed an attentional bias toward positive versus neutral stimuli during abstinence compared with smoking (interaction p = .01). This study provides initial evidence that depressive symptoms may moderate abstinence-induced deficits in STM and shift attentional bias toward emotionally salient stimuli during abstinence. These cognitive changes may prompt relapse and may help identify novel targets for nicotine dependence treatment aimed at attenuating these deficits to improve cessation rates.
doi:10.1037/a0037072
PMCID: PMC4274744  PMID: 24932895
smoking; depression; memory; attentional bias; nicotine withdrawal
12.  Effects of tolcapone on working memory and brain activity in abstinent smokers: A proof-of-concept study 
Drug and alcohol dependence  2013;133(3):852-856.
Background
Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson’s disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers.
Methods
In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24 h of abstinence. Smokers were genotyped prospectively for the COMT val158met polymorphism for exploratory analysis.
Results
Compared to placebo, tolcapone modestly improved accuracy (p = 0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p = 0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo.
Conclusions
Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.
doi:10.1016/j.drugalcdep.2013.09.003
PMCID: PMC3960598  PMID: 24095246
Smoking; Nicotine; COMT; Tolcapone; fMRI; Working memory
13.  A Novel Recruitment Message to Increase Enrollment into a Smoking Cessation Treatment Program: Preliminary Results from a Randomized Triala 
Health communication  2011;26(8):735-742.
Most smokers do not utilize approved interventions for nicotine dependence, reducing the probability of cessation. Smoking cessation programs typically use recruitment messages emphasizing the health threats of smoking. Augmenting this threat message by describing the genetic aspects of nicotine addiction may enhance enrollment into a cessation program. During telephone recruitment, 125 treatment-seeking smokers were randomized to receive by phone either a standard threat message or a threat plus genetic prime message and were offered open-label varenicline and counseling. There was a greater rate of enrollment into the cessation program for the threat plus genetic prime participants (51.7%) vs. the threat-only participants (37.7%; p = .03). Smokers who self-identified from racial/ethnic minority groups were less likely to enroll in the cessation program (p = .01) vs. smokers who self-identified as Caucasian. These preliminary data suggest that a simple, affordable, and transportable communication approach enhances enrollment of smokers into a smoking cessation program. A larger clinical trial to evaluate a genetic prime message for improving recruitment into smoking cessation programs is warranted.
doi:10.1080/10410236.2011.566829
PMCID: PMC4243839  PMID: 21667366
14.  Comparison of Prior Authorization and Prospective Audit with Feedback for Antimicrobial Stewardship 
OBJECTIVE
Although prior authorization and prospective audit with feedback are both effective antimicrobial stewardship program (ASP) strategies, the relative impact of these approaches remains unclear. We compared these core ASP strategies at an academic medical center.
DESIGN
Quasi-experimental study.
METHODS
We compared antimicrobial use during the 24 months before and after implementation of an ASP strategy change. The ASP used prior authorization alone during the preintervention period, June 2007 through May 2009. In June 2009, many antimicrobials were unrestricted and prospective audit was implemented for cefepime, piperacillin/tazobactam, and vancomycin, marking the start of the postintervention period, July 2009 through June 2011. All adult inpatients who received more than or equal to 1 dose of an antimicrobial were included. The primary end point was antimicrobial consumption in days of therapy per 1,000 patient-days (DOT/1,000-PD). Secondary end points included length of stay (LOS).
RESULTS
In total, 55,336 patients were included (29,660 preintervention and 25,676 postintervention). During the preintervention period, both total systemic antimicrobial use (−9.75 DOT/1,000-PD per month) and broad-spectrum anti-gram-negative antimicrobial use (−4.00 DOT/1,000-PD) declined. After the introduction of prospective audit with feedback, however, both total antimicrobial use (+9.65 DOT/1,000-PD per month; P < .001) and broad-spectrum anti-gram-negative antimicrobial use (+4.80 DOT/1,000-PD per month; P < .001) increased significantly. Use of cefepime and piperacillin/tazobactam both significantly increased after the intervention (P = .03). Hospital LOS and LOS after first antimicrobial dose also significantly increased after the intervention (P = .016 and .004, respectively).
CONCLUSIONS
Significant increases in antimicrobial consumption and LOS were observed after the change in ASP strategy.
doi:10.1086/677624
PMCID: PMC4198070  PMID: 25111916
15.  Individual differences in positivity offset and negativity bias: Gender-specific associations with two serotonin receptor genes 
Individual differences in the evaluation of affective stimuli, such as the positivity offset and negativity bias may have a biological basis. We tested whether two SNPs (HTR2A; 102T>C and HTR1A; 1019C>G) related to serotonin receptor function, a biological pathway associated with affective regulation, were differentially related to positivity offset and negativity bias for males and females. Participants were 109 cigarette smokers who rated a series of affective stimuli to assess reactions to positive and negative pictures. Gender × genotype interactions were found for both SNPs. Males with the 102T allele showed a greater positivity offset than males with the 102C allele. For females, in contrast, the 1019C allele was associated with a greater positivity offset than the 1019G allele, whereas the 102T allele was associated with a greater negativity bias than the 102C allele. Identifying how gender differences may moderate the effect of serotonin receptor genes on affective information processing may provide insight into their role in guiding behavior and regulating affect.
doi:10.1016/j.paid.2013.04.009
PMCID: PMC3747009  PMID: 23976810
Cognitive Processes; Affect regulation; Negativity bias; Positivity bias; Gender; Serotonin receptor gene
16.  Detection of Brain Tumor Cells in the Peripheral Blood by a Telomerase Promoter-Based Assay 
Cancer research  2014;74(8):2152-2159.
Blood tests to detect circulating tumor cells (CTC) offer great potential to monitor disease status, gauge prognosis, and guide treatment decisions for patients with cancer. For patients with brain tumors, such as aggressive glioblastoma multiforme, CTC assays are needed that do not rely on expression of cancer cell surface biomarkers like epithelial cell adhesion molecules that brain tumors tend to lack. Here, we describe a strategy to detect CTC based on telomerase activity, which is elevated in nearly all tumor cells but not normal cells. This strategy uses an adenoviral detection system that is shown to successfully detect CTC in patients with brain tumors. Clinical data suggest that this assay might assist interpretation of treatment response in patients receiving radiotherapy, for example, to differentiate pseudoprogression from true tumor progression. These results support further development of this assay as a generalized method to detect CTC in patients with cancer.
doi:10.1158/0008-5472.CAN-13-0813
PMCID: PMC4144786  PMID: 24525740
17.  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
18.  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
19.  APOE ε4, an Alzheimer’s disease susceptibility allele, and smoking cessation 
The pharmacogenomics journal  2012;13(6):538-543.
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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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