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The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute–designated and 18 emerging centers. Among these 82 respondents, non-Hispanic White individuals comprised 79% of center directors, 82% of deputy directors, 72% of associate directors, and 72% of program leaders. Women are underrepresented in all leadership roles (ranging from 16% for center directors to 45% for associate directors). Although the limited gender, ethnic, and racial diversity of center directors and perhaps deputy directors is less surprising, the demographics of current research program leaders and associate directors exposes a substantial lack of diversity in the traditional cancer center senior leadership pipeline. Sole reliance on the cohort of current center leaders and leadership pipeline is unlikely to produce the diversity in cancer center leadership needed to facilitate the ability of those centers to address the needs of the diverse populations they serve. Informed by these data, this commentary describes some best practices to build a pipeline of emerging leaders who are representative of the diverse populations served by these institutions and who are well positioned to succeed.

PURPOSE Machine learning (ML) algorithms that incorporate routinely collected patient-reported outcomes (PROs) alongside electronic health record (EHR) variables may improve prediction of short-term mortality and facilitate earlier supportive and palliative care for patients with cancer. METHODS We trained and validated two-phase ML algorithms that incorporated standard PRO assessments alongside approximately 200 routinely collected EHR variables, among patients with medical oncology encounters at a tertiary academic oncology and a community oncology practice. RESULTS Among 12,350 patients, 5,870 (47.5%) completed PRO assessments. Compared with EHR- and PRO-only algorithms, the EHR + PRO model improved predictive performance in both tertiary oncology (EHR + PRO v EHR v PRO: area under the curve [AUC] 0.86 [0.85-0.87] v 0.82 [0.81-0.83] v 0.74 [0.74-0.74]) and community oncology (area under the curve 0.89 [0.88-0.90] v 0.86 [0.85-0.88] v 0.77 [0.76-0.79]) practices. CONCLUSION Routinely collected PROs contain added prognostic information not captured by an EHR-based ML mortality risk algorithm. Augmenting an EHR-based algorithm with PROs resulted in a more accurate and clinically relevant model, which can facilitate earlier and targeted supportive care for patients with cancer.

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking‐related disease risk. The heritability of the NMR is 60–80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30–35%. Rare variants (minor allele frequency

Why do people discount future rewards? Multiple theories in psychology argue that one reason is that future events are imagined less vividly than immediate events, thereby diminishing their perceived value. Here we provide neuroscientific evidence for this proposal. First, we construct a neural signature of the vividness of prospective thought, using an fMRI dataset where the vividness of imagined future events is orthogonal to their valence by design. Then, we apply this neural signature in two additional fMRI datasets, each using a different delay-discounting task, to show that neural measures of vividness decline as rewards are delayed farther into the future.

Women harboring mutations in breast cancer susceptibility genes are at increased lifetime risk of developing breast cancer and are faced with decisions about risk management, including whether to undergo high-risk screening or risk-reducing mastectomy (RRM). National guidelines recommend BRCA1 or BRCA2 mutation carriers consider RRM, but that carriers of moderate penetrance mutations (e.g., ATM or CHEK2) should be managed based on family history. We aimed to investigate determinants of decision for RRM, and hypothesized that mutation status, age, family history, partner status, and breast cancer would impact RRM decision making.We performed a retrospective study assessing RRM decisions for 279 women.Women with BRCA and moderate penetrance gene mutations, a personal history of breast cancer, or a first degree relative with a history of breast cancer were more likely to undergo RRM. Breast cancer status and age showed an interaction effect such that women with breast cancer were less likely to undergo RRM with increasing age.Although national guidelines do not recommend RRM for moderate penetrance carriers, the rates of RRM for this population approached those for BRCA mutation carriers. Further insights are needed to better support RRM decision-making in this population.

The Nicotine Metabolite Ratio (NMR; 3-hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in nonsmokers, former smokers, or intermittent smokers, for example, in evaluating tobacco-related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation. We previously created a CYP2A6 weighted genetic risk score (wGRS) for European (EUR)-ancestry populations by incorporating independent signals from genome-wide association studies to capture a larger proportion of NMR variation. However, CYP2A6 genetic architecture is unique to ancestral populations. In this study, we developed and replicated an African-ancestry (AFR) wGRS, which captured 30-35% of the variation in NMR. We demonstrated model robustness against known environmental sources of NMR variation. Furthermore, despite the vast diversity within AFR populations, we showed that the AFR wGRS was consistent between different US geographical regions and unaltered by fine AFR population substructure. The AFR and EUR wGRSs can distinguish slow from normal metabolizers in their respective populations, and were able to reflect unique smoking cessation pharmacotherapy outcomes previously observed for the NMR. Additionally, we evaluated the utility of a cross-ancestry wGRS, and the capacity of EUR, AFR, and cross-ancestry wGRSs to predict the NMR within stratified or admixed AFR-EUR populations. Overall, our findings establish the clinical benefit of applying ancestry-specific wGRSs, demonstrating superiority of the AFR wGRS in AFRs.

Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3 ' hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained similar to 38% of NMR variation, a substantial increase from the similar to 20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3 ' hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.

Background: Cancer centers are expected to engage communities and reduce the burden of cancer in their catchment areas. However, the extent to which cancer centers adequately reach the entire US population is unknown. Methods: We surveyed all members of the Association of American Cancer Institutes (N = 102 cancer centers) to document and map each cancer center's primary catchment area. Catchment area descriptions were aggregated to the county level. Catchment area coverage scores were calculated for each county and choropleths generated representing coverage across the US. Similar analyses were used to overlay US population density, cancer incidence, and cancer-related mortality compared with each county's cancer center catchment area coverage. Results: Roughly 85% of US counties were included in at least one cancer center's primary catchment area. However, 15% of US counties, or roughly 25 million Americans, do not reside in a catchment area. When catchment area coverage was integrated with population density, cancer incidence, and cancer-related mortality metrics, geographical trends in both over- and undercoverage were apparent. Conclusions: Geographic gaps in cancer center catchment area coverage exist and may be propagating cancer disparities. Efforts to ensure coverage to all Americans should be a priority of cancer center leadership. Impact: This is the first known geographic analysis and interpretation of the primary catchment areas of all US-based cancer centers and identifies key geographic gaps important to target for disparities reduction. See related commentary by Lieberman-Cribbin and Taioli, p. 949

Background As Asian American breast cancer incidence rises, it is necessary to investigate the origins of differential breast cancer outcomes among Asian ethnic subgroups. This study aimed to examine disparities in delays of breast cancer surgery among Asian ethnic subgroups. Methods We obtained California Cancer Registry data on female breast cancer diagnoses and treatment from 2012 to 2017. Our main independent variable was patient race and ethnicity, including 6 Asian ethnic subgroups. Dependent variables included time to surgical treatment for breast cancer and receipt of surgical treatment within 30 and 90 days of diagnosis. We conducted multivariable logistic regression to determine the odds of receiving surgery within 30 and 90 days of diagnosis and multivariable Cox proportional hazards regression to determine the risk of prolonged time to surgery. Results In our cohort of 93 168 breast cancer patients, Hispanic (odds ratio [OR] = 0.86, 95% confidence interval [CI] = 0.82 to 0.89) and non-Hispanic Black (OR = 0.83, 95% CI = 0.78 to 0.88) patients were statistically significantly less likely than non-Hispanic White patients to receive surgery within 30 days of breast cancer diagnosis, whereas Asian Indian or Pakistani (OR = 1.23, 95% CI = 1.09 to 1.40) and Chinese (OR = 1.30, 95% CI = 1.20 to 1.40) patients were statistically significantly more likely to receive surgery within 30 days of diagnosis. Conclusions This large, population-based retrospective cohort study of female breast cancer patients is the first, to our knowledge, to demonstrate that time to surgical treatment is not equal for all Asians. Distinct differences among Asian ethnic subgroups suggest the necessity of further investigating breast cancer treatment patterns to fully understand and target disparities in breast cancer treatment.

Introduction Varenicline is the most efficacious smoking cessation treatment; however, long-term cessation rates tend to be Methods We conducted a genome-wide association study of nausea incidence at 1 week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF)≥10% were considered. Results Fifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (odds ratio [OR] = 2.61 for A vs. G allele; 95% confidence interval [CI] = 1.65,4.15; p = 2.1e-7; MAF = 48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (p = .56; n = 181) or placebo (p = .59; n = 174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n = 74) versus males (20.9%; n = 115) (p = .001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (p for sex*genotype interaction = .36). Future studies in larger samples are required to test the robustness of this finding. Conclusions Variation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation. Implications Varenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an important cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.

Nicotine dependence (ND) has a heritability rate of ∼50%, suggesting genetic factors contribute to underlying mechanisms. Here, we aimed to examine variants within both mtDNA and the nuclear genome to determine if mitochondrial genes are associated with ND. A total of 129 mtDNA SNPs and 1136 nuclear-encoded mitochondrial genes in a sample of N = 374 Caucasians were selected for analysis. Age of onset of first, occasional, and daily smoking and Fagerström Test for Nicotine Dependence were used as outcomes for the analysis. Linear regression was used to test common variants. Gene analyses were performed using MAGMA. One nuclear mitochondrial SNP, rs78417112 found in the HSD17B4 gene, was significantly associated with the age of onset of occasional smoking. Additionally, one nuclear mitochondrial gene, PRKACA, was significantly associated with age of onset of both first and occasional smoking. Replication testing of the mtDNA m.1700TC SNP, nominally associated with age of onset of daily smoking, was available in the PNAT2 clinical trial (N = 930 Caucasians). A meta-analysis showed this SNP was associated with age of onset of daily smoking (p-value = 0.004). Overall, the findings suggest mitochondrial genetic variation may contribute to variability in smoking phenotypes, although replication in larger samples is required.

Nicotine is inactivated by the polymorphic CYP2A6 enzyme to cotinine and then to 3′hydroxycotinine. The Nicotine Metabolite Ratio (NMR; 3′hydroxycotinine/cotinine) is a heritable nicotine metabolism biomarker, varies with sex and ancestry, and influences smoking cessation and disease risk. We conducted sex-stratified genome-wide association studies of the NMR in European American (EA) and African American (AA) smokers (NCT01314001, NCT00666978). In EA females (n = 389) and males (n = 541), one significant (P CYP2A6 (intronic), for C vs. T: females: beta = 0.67, P = 7.5e−22, 21.8% variation explained; males: beta = 0.75, P = 1.2e−37, 26.1% variation explained). In AA females (n = 503) and males (n = 352), the top variant was found on chromosome 19 but differed by sex (females: rs11878604, CYP2A6 (~ 16 kb 3′), for C vs. T: beta = − 0.71, P = 6.6e−26, 16.2% variation explained; males: rs3865454, CYP2A6 (~ 7 kb 3′), for G vs. T: beta = 0.64, P = 1.9e−19, 18.9% variation explained). In AA females, a significant region was found on chromosome 12 (top variant: rs12425845: P = 5.0e−9, TMEM132C (~ 1 Mb 5′), 6.1% variation explained) which was not significant in AA males. In AA males, significant regions were found on chromosomes 6 (top variant: rs9379805: P = 4.8e−9, SLC17A2 (~ 8 kb 5′), 8.0% variation explained) and 16 (top variant: rs77368288: P = 3.5e−8, ZNF469 (~ 92 kb 5′), 7.1% variation explained) which were not significant in AA females. Further investigation of these associations outside of chromosome 19 is required, as they did not replicate. Understanding how sex and ancestry influence nicotine metabolism genetics may improve personalized approaches for smoking cessation and risk prediction for tobacco-related diseases.

Racial/ethnic disparities in breast cancer outcomes may be related to quality of care and reflected in emergency department (ED) visits following primary treatment. We examined racial/ethnic variation in ED visits following breast cancer surgery. Using linked data from the California Cancer Registry and California Office of Statewide Health Planning and Development, we identified 151,229 women diagnosed with stage 0-III breast cancer between 2005 and 2013 who received surgical treatment. Differences in odds of having at least one breast cancer-related ED visit within 90 days post-surgery were estimated with logistic regression controlling for clinical and sociodemographic variables. Secondary analyses examined health care-related moderators of disparities. Hispanics and non-Hispanic (NH) Blacks had an increased likelihood of having an ED visit within 90 days of surgery compared to NH Whites [OR = 1.11 (1.04–1.18), p = 0.0016; OR = 1.38 (1.27–1.50), p

BACKGROUND: Variation in CYP2A6 activity influences tobacco smoking behaviors and smoking-related health outcomes. Plasma Nicotine Metabolite Ratio (NMR) is a robust phenotypic biomarker of CYP2A6 activity and nicotine clearance. In urine, the NMR has been calculated as a ratio of free trans-3’-hydroxycotinine to free cotinine (NMR(F/F)), total trans-3’-hydroxycotinine to free cotinine (NMR(T/F)), or total trans-3’-hydroxycotinine to total cotinine (NMR(T/T)). We evaluated these three urinary NMR versions relative to plasma NMR and nicotine clearance and elucidated mechanisms of discrepancies among them. METHODS: Baseline plasma and urine biomarker data were available from two smoking cessation clinical trials and one nicotine pharmacokinetic study (total N=768). NMRs were compared using Pearson correlations, linear regressions and ANOVA analyses. UGT2B10 and UGT2B17 were genotyped. RESULTS: Urinary NMR(T/F) was the most highly related to plasma NMR (R(2)=0.70, P urinary NMR(T/F) > NMR(F/F) > NMR(T/T) (R(2)=0.41>0.37>0.35>0.25 respectively). CONCLUSION: Urinary NMR(T/F) followed by NMR(F/F) are the best urinary alternatives to plasma NMR or nicotine clearance. NMR(T/T) has the least utility as it is influenced substantially by variation in cotinine glucuronidation. IMPACT: This work highlighted the variation in urinary NMRs, and identified mechanisms for disparities among them, which facilitates their use in predicting smoking-related outcomes.

Background Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate‐risk pathogenic variants (PVs). Methods Study participants (N = 1264) were counseled and tested with a 25‐ or 28‐gene panel and completed a 3‐month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA). Results The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non‐Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non–English‐speaking. The genetic test results were as follows: 7% had a high‐risk PV, 6% had a moderate‐risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of “never,” “rarely,” or only “sometimes” reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high‐ and moderate‐risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High‐ and moderate‐risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences. Conclusions In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds. Lay Summary Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate‐risk pathogenic variants (mutations) and among carriers of variants of uncertain significance.This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% “never,” “rarely,” or only “sometimes” reacted negatively to results.Somewhat higher uncertainty and distress were identified among carriers of high‐ and moderate‐risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result.Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results., Multigene panel tests for hereditary cancer have become widespread despite concerns that carriers of moderate‐risk pathogenic variants or uncertain variants could have adverse psychological reactions. This large cohort study of patients undergoing panel testing has found that the psychological response is favorable, regardless of genetic test results.

OBJECTIVE: Addressing tobacco use among HIV+ smokers is a priority. Lack of knowledge about how HIV+ smokers respond to tobacco use treatments limits our ability to effectively treat this population of smokers. METHOD: Using data from two clinical trials that provided 12 weeks of varenicline and behavioral counseling, one with smokers with HIV (n=89) and one with smokers without HIV (n=179), we used mixed logistic regression modeling to compare point-prevalence abstinence rates and adherence to the initial target quit date (TQD) and Cox regression for repeated outcomes to evaluate lapse and recovery dynamics between the groups. RESULTS: 60% of HIV− smokers refrained from smoking at the TQD while only 33% of HIV+ smokers did (OR=0.32, 95% CI: 0.18-0.56, p

Background: The opioid crisis has reached epidemic proportions, yet risk of persistent opioid use following curative intent surgery for cancer and factors influencing this risk are not well understood. Methods: We used electronic health record data from 3,901 adult patients who received a prescription for an opioid analgesic related to hysterectomy or large bowel surgery from January 1, 2013, through June 30, 2018. Patients with and without a cancer diagnosis were matched on the basis of demographic, clinical, and procedural variables and compared for persistent opioid use. Results: Cancer diagnosis was associated with greater risk for persistent opioid use after hysterectomy [18.9% vs. 9.6%; adjusted OR (aOR), 2.26; 95% confidence interval (CI), 1.38–3.69; P = 0.001], but not after large bowel surgery (28.3% vs. 24.1%; aOR 1.25; 95% CI, 0.97–1.59; P = 0.09). In the cancer hysterectomy cohort, persistent opioid use was associated with cancer stage (increased rates among those with stage III cancer compared with stage I) and use of neoadjuvant or adjuvant chemotherapy; however, these factors were not associated with persistent opioid use in the large bowel cohort. Conclusions: Patients with cancer may have an increased risk of persistent opioid use following hysterectomy. Impact: Risks and benefits of opioid analgesia for surgical pain among patients with cancer undergoing hysterectomy should be carefully considered.

INTRODUCTION: Adherence to pharmacotherapies for tobacco dependence, such as varenicline, is necessary for effective treatment. The relationship between varenicline adherence, determined by commonly used indirect (i.e., self-reported pill counts) and infrequently used direct (i.e., varenicline levels) methods, and abstinence outcomes have not been previously examined, nor has their impact on the outcomes of a genetically randomized clinical trial been assessed. METHODS: At Week 1 following target quit date, self-reported pill count and salivary varenicline levels were obtained from participants (N=376) in a smoking cessation clinical trial (NCT01314001). Point-prevalence abstinence was biochemically-verified by salivary cotinine at Week 1 and by exhaled carbon monoxide at Week 1, end-of-treatment, 6 and 12 months following treatment. Blood nicotine metabolite ratio (NMR) was obtained at baseline. RESULTS: Adherent individuals based on varenicline levels were significantly more likely to be abstinent than non-adherent individuals at Week 1 (odds ratios [ORs] 1.92–3.16, p’s≤ .006), end-of-treatment (OR=2.53, p=.004), and six months following treatment (OR=2.30, p=.03). In contrast, pill counts did not consistently predict abstinence. Including direct measures of adherence enhanced the association between rate of nicotine metabolism (NMR) and end-of-treatment abstinence; normal metabolizers (NMR≥0.31) were significantly more likely than slow metabolizers (NMR

INTRODUCTION:While adherence to medication in smoking cessation clinical trials is strongly associated with clinical outcome, very few studies have evaluated the validity of pill count as a measure of adherence relative to a biological assay, and evaluated a broad range of correlates of adherence. METHODS:In a smoking cessation clinical trial of varenicline, we compared pill counts collected over 4 different time periods to varenicline salivary levels taken after 2weeks of treatment, as well as evaluated predictors of adherence to varenicline. RESULTS:Using a binary measure of adherence based on salivary varenicline levels, adherence was higher among older, white, and more educated participants. Relative to 3, 7, and 14-day pill count, 12-week pill count was the only significant measure able to discriminate adherence as defined by salivary varenicline levels (assessed by area under the receiver operating characteristic curve; AUC=0.59, p=0.004). Seventy-two percent of participants who indicated adherence on 12-week pill count were classified as adherent based on varenicline saliva levels (sensitivity=0.80; specificity=0.40). There was modest variability in the relationship between 12-week pill count and varenicline levels across race and rate of nicotine metabolism. Lastly, General Estimating Equation models demonstrated that longitudinal changes in withdrawal, craving, negative and positive affect, and side effect count and severity were not related to adherence based on salivary varenicline levels. CONCLUSIONS:These results indicate that 12-week pill count was the best, albeit a relatively weak, measure of varenicline adherence; additional factors associated with treatment adherence need to be identified.

Increased preference for immediate over delayed and for risky over certain rewards has been associated with unhealthy behavioral choices. Motivated by evidence that enhanced cognitive control can shift choice behavior away from immediate and risky rewards, we tested whether training executive cognitive function could influence choice behavior and brain responses. In this randomized controlled trial, 128 young adults (71 male, 57 female) participated in 10 weeks of training with either a commercial web-based cognitive training program or web-based video games that do not specifically target executive function or adapt the level of difficulty throughout training. Pre- and post-training, participants completed cognitive assessments and functional magnetic resonance imaging (fMRI) during performance of validated decision-making tasks: delay discounting (choices between smaller rewards now vs. larger rewards in the future) and risk sensitivity (choices between larger riskier rewards vs. smaller certain rewards). Contrary to our hypothesis, we found no evidence that cognitive training influences neural activity during decision-making, nor did we find effects of cognitive training on measures of delay discounting or risk sensitivity. Participants in the commercial training condition improved with practice on the specific tasks they performed during training, but participants in both conditions showed similar improvement on standardized cognitive measures over time. Moreover, the degree of improvement was comparable to that observed in individuals who were reassessed without any training whatsoever. Commercial adaptive cognitive training appears to have no benefits in healthy young adults above those of standard video games for measures of brain activity, choice behavior, or cognitive performance. Registry: NCT01252966, www.clinicaltrials.gov SIGNIFICANCE STATEMENT Engagement of neural regions and circuits important in executive cognitive function can bias behavioral choices away from immediate rewards. Activity in these regions may be enhanced through adaptive cognitive training. Commercial brain training programs claim to improve a broad range of mental processes; however, evidence for transfer beyond trained tasks is mixed. We undertook the first randomized controlled trial of the effects of commercial adaptive cognitive training (Lumosity®) on neural activity and decision-making in young adults (N = 128), compared to an active control (playing online video games). We found no evidence for relative benefits of cognitive training with respect to changes in decision-making behavior or brain response, or for cognitive task performance beyond those specifically trained.

BACKGROUND: Adherence to nicotine patches relates to cessation. This is the first study to examine the validity of self-reported nicotine patch adherence relative to saliva cotinine. METHODS: We used data from 198 clinical trial participants who received 11 weeks of nicotine patches, self-reported patch use, had saliva cotinine 1-week after the start of treatment assessed, and were not smoking when saliva was collected (CO≤6). Self-reported patch adherence was defined as: 3-day (before saliva collection), 7-day (before saliva collection), 3-week use (7 days before, and 14 days after, saliva collection), and 11-week use (7 days before, and 10 weeks after, saliva collection). Analyses, including receiver operating characteristic curves, considered differences in nicotine metabolism. Sensitivity, specificity and positive (PPV) and negative predictive value (NPV) assessed optimal cotinine cut-point for adherence. RESULTS: Self-reported 7-day (r=0.13) and 3-week (r=0.13) patch use marginally correlated with week 1 cotinine (p’s=0.08) but not 3-day or 11-week. Significant area under the curve (AUC) values of 0.67 (95%CI: 0.55–0.79) and 0.72 (95%CI: 0.57–0.88) were found using 7-day self-report for the overall sample and for slow metabolizers (p’s

Introduction By improving our understanding of the neurobiological mechanisms underlying addiction, neuroimaging research is helping to identify new targets for personalized treatment interventions. When trying to quit, smokers with larger electrophysiological responses to cigarette-related, compared with pleasant, stimuli (“C > P”) are more likely to relapse than smokers with the opposite brain reactivity profile (“P > C”). Aim and Method The goal was to (1) build a classification algorithm to identify smokers characterized by P > C or C > P neuroaffective profiles and (2) validate the algorithm’s classification outcomes in an independent data set where we assessed both smokers’ electrophysiological responses at baseline and smoking abstinence during a quit attempt. We built the classification algorithm applying discriminant function analysis on the event-related potentials evoked by emotional images in 180 smokers. Results The predictive validity of the classifier showed promise in an independent data set that included new data from 177 smokers interested in quitting; the algorithm classified 111 smokers as P > C and 66 as C > P. The overall abstinence rate was low; 15 individuals (8.5% of the sample) achieved CO-verified 12-month abstinence. Although individuals classified as P > C were nearly 2.5 times more likely to be abstinent than smokers classified as C > P (12 vs. 3, or 11% vs. 4.5%), this result was nonsignificant, preliminary, and in need of confirmation in larger trials. Conclusion These results suggest that psychophysiological techniques have the potential to advance our knowledge of the neurobiological underpinnings of nicotine addiction and improve clinical applications. However, larger sample sizes are necessary to reliably assess the predictive ability of our algorithm. Implications We assessed the clinical relevance of a neuroimaging-based classification algorithm on an independent sample of smokers enrolled in a smoking cessation trial and found those with the tendency to attribute more relevance to rewards than cues were nearly 2.5 times more likely to be abstinent than smokers with the opposite brain reactivity profile (11% vs. 4.5%). Although this result was not statistically significant, it suggests our neuroimaging-based classification algorithm can potentially contribute to the development of new precision medicine interventions aimed at treating substance use disorders. Regardless, these findings are still preliminary and in need of confirmation in larger trials.

Author(s): Peng, Annie R; Swardfager, Walter; Benowitz, Neal L; Ahluwalia, Jasjit S; Lerman, Caryn; Nollen, Nicole L; Tyndale, Rachel F | Abstract: Background and aimsVarenicline effectiveness may be related to the level of adherence, which might be reduced by adverse effects such as nausea. The aim of the study was to test a possible effect of nausea on smoking cessation outcomes mediated by adherence.DesignMediation path analysis.SettingMultiple sites within Canada and the United States.ParticipantsTreatment-seeking smokers receiving varenicline from two smoking cessation clinical trials: Quit2Live (NCT01836276; n = 449) and Pharmacogenetics of Nicotine Addiction Treatment (PNAT) (NCT01314001; n = 421).MeasurementsNausea severity was collected through self-report and adherence was biologically assessed using varenicline concentrations (Quit2Live, plasma sample at week 4; PNAT, saliva sample at week 2). In Quit2Live, the end-points were cotinine-verified abstinence at weeks 4, 12 and 26. In PNAT, the end-points were carbon monoxide-verified abstinence at weeks 2, 12 and 26.FindingsEarly nausea was not directly associated with abstinence [odds ratio (OR) ranging from 0.73-1.28; P ≥ 0.26]. However early nausea was indirectly associated with lower cessation rates at multiple timepoints (ORs ranging from 0.92-0.94; 95% CI between 0.83-0.99) in a relationship mediated by reduced varenicline adherence (assessed by plasma varenicline concentrations) in the primary trial (Quit2Live). This relationship between nausea, adherence and cessation was similar in direction but weaker in effect size (ORs ranging from 0.98-0.99; 95% CI between 0.90-1.03) in a secondary trial (PNAT), where adherence was assessed using salivary varenicline concentrations.ConclusionsThese data suggest that early nausea during varenicline treatment may be indirectly associated with lower likelihood of smoking cessation through reducing varenicline adherence. Differences in robustness between the trials may be due to the different biological matrices (plasma vs. saliva) and/or timing used to assess varenicline adherence. The results of the first study suggest that improved management of early nausea during varenicline treatment may positively impact smoking cessation success through increasing varenicline adherence.

Across many studies, ventromedial prefrontal cortex (vmPFC) activity has been found to correlate with subjective value during value-based decision-making. Recently, however, vmPFC has also been shown to reflect a hexagonal gridlike code during navigation through physical and conceptual space, and such gridlike codes have been proposed to enable value-based choices between novel options. Here, we first show that, in theory, a hexagonal gridlike code can in some cases mimic vmPFC activity previously attributed to subjective value, raising the possibility that the subjective value correlates previously observed in vmPFC may have actually been a misconstrued gridlike signal. We then compare the two accounts empirically, using fMRI data from a large number of subjects performing an intertemporal choice task. We find clear and unambiguous evidence that subjective value is a better description of vmPFC activity in this task than a hexagonal gridlike code. In fact, we find no significant evidence at all for a hexagonal gridlike code in vmPFC activity during intertemporal choice. This result limits the generality of gridlike modulation as description of vmPFC activity. We suggest that vmPFC may flexibly switch representational schemes so as to encode the most relevant information for the current task.

Background Subjective stress is a well-documented predictor of early smoking relapse, yet our understanding of stress and tobacco use is limited by reliance on self-reported measures of stress. We utilized a validated functional neuroimaging paradigm to examine whether stress exposure during early abstinence alters objective measures of brain function. Methods Seventy-five participants underwent blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) during the Montreal Imaging Stress Task (MIST) on two occasions: once during smoking satiety and once following biochemically confirmed 24-hour abstinence (order counterbalanced). The primary outcome measure was brain response during stress (vs. control) blocks of the MIST, assessed using whole-brain analysis corrected for multiple comparisons using clusters determined by Z ≥ 3.1. Results Abstinence (vs. satiety) was associated with significantly increased activation in the left inferior frontal gyrus, a brain region associated with inhibitory control. Abstinence-induced change in brain response to stress was positively associated with change in self-reported stress. Conclusions This study provides objective evidence that the brain response to stress is altered during the first 24 hours of a quit attempt compared to smoking satiety. Implications These results point to the potential value of inoculating smokers with stress management training prior to a quit attempt.

The nicotine metabolite ratio (NMR), a genetically informed biomarker of rate of nicotine metabolism, has been validated as a tool to select the optimal treatment for individual smokers, thereby improving treatment outcomes. This review summarizes the evidence supporting the development of the NMR as a biomarker of individual differences in nicotine metabolism, the relationship between the NMR and smoking behavior, the clinical utility of using the NMR to personalize treatments for smoking cessation, and the potential mechanisms that underlie the relationship between NMR and smoking cessation. We conclude with a call for additional research necessary to determine the ultimate benefits of using the NMR to personalize treatments for smoking cessation. These future directions include measurement and other methodologic considerations, disseminating this approach to at-risk subpopulations, expanding the NMR to evaluate its efficacy in predicting treatment responses to e-cigarettes and other noncigarette forms of nicotine, and implementation science including cost-effectiveness analyses. See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention

Background and aims Deficits in cognitive function are observed during nicotine withdrawal and present a challenge to successful smoking cessation. This clinical trial evaluated a cognitive exercise training (CT) program to improve smoking cessation rates. Methods Adult treatment-seeking smokers (n = 213) were randomized to receive nicotine patch therapy and 12 weeks of either computerized CT or computerized relaxation (control) training. Smoking status was biochemically verified at the end of treatment and 6-month follow-up. Results Quit rates did not differ by treatment arm at either time-point, nor were there effects on withdrawal symptoms or smoking urges. Reaction time for emotion recognition and verbal interference tasks showed improvement in the CT group. When including only successful quitters, improvements in recognition memory, verbal interference accuracy, and attention switching error rate were also observed in the CT group, while commission errors on the continuous performance task decreased in the control group. Conclusions Despite modest changes in cognitive performance, these results do not support the efficacy of computerized cognitive training as an adjunctive therapy for smoking cessation.

Background Inherited differences in the rate of metabolism of nicotine, the addictive chemical in tobacco, affect smoking behavior and quitting success. The nicotine metabolite ratio (3′-hydroxycotinine/cotinine) is a reliable measure of nicotine clearance and a well-validated predictive biomarker of response to pharmacotherapy. To clarify the mechanisms underlying these associations, we investigated the neural responses to smoking cues in normal and slow nicotine metabolizers. Methods Treatment-seeking smokers ( N = 69; 30 slow metabolizers and 39 normal metabolizers) completed a visual cue reactivity task during functional magnetic resonance imaging on two separate occasions: once during smoking satiety and once after 24 hours of smoking abstinence. Results In whole-brain analysis, normal (compared with slow) metabolizers exhibited heightened abstinence-induced neural responses to smoking cues in the left caudate, left inferior frontal gyrus, and left frontal pole. These effects were more pronounced when extreme groups of slow and normal metabolizers were examined. Greater activation in the left caudate and left frontal pole was associated with abstinence-induced subjective cravings to smoke. Conclusions Inherited differences in rate of nicotine elimination may drive neural responses to smoking cues during early abstinence, providing a plausible mechanism to explain differences in smoking behaviors and response to cessation treatment. Normal metabolizers may benefit from adjunctive behavioral smoking cessation treatments, such as cue exposure therapy.

INTRODUCTION The decrease in smoking rates in North America has plateaued, underscoring the need for new approaches to treat nicotine dependence. Inter-individual differences in smoking behavior result, in part, from variation in the rate of CYP2A6-mediated nicotine metabolism. A phenotypic measure of CYP2A6 activity is the nicotine metabolite ratio (NMR), the ratio of 3'hydroxycotinine/cotinine. The NMR is associated with smoking cessation. However, the NMR is also associated with genetic (eg, CYP2A6 genotype) and other (eg, sex and ethnicity) factors. Here we aimed to determine if previously identified non-CYP2A6 sources of variation in the NMR mitigated the association between the NMR and short-term abstinence. METHODS The NMR was determined from blood samples collected at intake from daily smokers aged 18-65. Biochemically-verified point prevalence abstinence (exhaled carbon monoxide level ≤ 8 ppm) was measured at 1 week following the target quit date in participants from a smoking cessation clinical trial (NCT01314001). Analyses were restricted to N = 462 blacks and N = 693 whites in the intent-to-treat sample. RESULTS Lower NMR (

Background The ability to exert self-control over temptation is a fundamental component of smoking behavior change. Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) has been shown to modulate cognitive control circuits. Although prior studies show that stimulation reduces cigarette craving and self-reported smoking, effects on ability to resist smoking have not been investigated directly. Objectives We assessed effects of a single 20-minute session of 1.0 mA anodal stimulation over the left DLPFC with cathodal stimulation over the right supra-orbital area (vs. sham stimulation) on ability to resist smoking in a validated smoking lapse paradigm. Methods Twenty-five participants completed two tDCS sessions (active and sham stimulation) in a within-subject, double-blind, randomized and counterbalanced order with a 2-week washout period. Following overnight abstinence, participants received tDCS in the presence of smoking related cues; they had the option to smoke at any time or receive $1 for every 5 minutes they abstained. After 50 minutes, they participated in a 1 hour ad libitum smoking session. Primary and secondary outcomes were time to first cigarette and cigarette consumption, respectively. Results In multiple regression models, active tDCS (compared to sham) significantly increased latency to smoke (p = 0.02) and decreased the total number of cigarettes smoked (p = 0.014) during the session. Conclusion These findings suggest that acute anodal stimulation over the left DLPFC (with cathodal stimulation over the right supra-orbital area) can improve ability to resist smoking, supporting the therapeutic potential of tDCS for smoking cessation treatment.

The nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine’s metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome-wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European-ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine-d2/(nicotine-d2 + cotinine-d2)). CYP2A6 genotypes and the NMR were assessed in European-ancestry participants. The wGRS training set included N = 933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N = 196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory-based pharmacokinetic study (N = 92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P < 0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ = 0.70 and ρ = 0.79, respectively; P < 0.001), and to one another (ρ = 0.82; P < 0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC = 0.79; P < 0.001), and to replicate previous NMR-stratified cessation outcomes showing unique treatment outcomes between metabolizer groups. CLINICAL TRIAL REGISTRATIONS: NCT01314001 and NCT01836276.

IMPORTANCE The US Food and Drug Administration (FDA) has announced its intention to reduce the nicotine content in combustible cigarettes but must base regulation on public health benefits. Fast nicotine metabolizers may be at risk for increased smoking following a national nicotine reduction policy. We hypothesized that using reduced nicotine content (RNC) cigarettes would be associated with increases in smoking behaviors and exposure among smokers with a fast—but not slow—nicotine-metabolite ratio (NMR). OBJECTIVES To examine the association of RNC cigarettes with smoking behaviors and biomarkers of exposure and to compare these associations in fast and slow metabolizers of nicotine based on the NMR. DESIGN, SETTING, AND PARTICIPANTS A 35-day, 3-period, within-participant nonrandomized clinical trial was conducted at an academic medical center in Philadelphia, Pennsylvania. A 5-day baseline period using the smokers’ preferred brand of cigarettes was followed by 2 consecutive 15-day periods using free investigational RNC cigarettes. A total of 100 daily, non–treatment-seeking, nonmenthol cigarette smokers (59 fast, 41 slow metabolizers) were recruited from December 24, 2013, to December 2, 2015. Data analysis was performed from December 12, 2016, to January 3, 2018. INTERVENTIONS Two 15-day periods using cigarettes containing 5.2 mg (RNC1) and 1.3 mg (RNC2) of nicotine per gram of tobacco. MAIN OUTCOMES AND MEASURES Smoking behaviors (number of cigarettes per day [CPD], total puff volume) and biomarkers of exposure (carbon monoxide [CO], urine total nicotine equivalents [TNE], and 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]). RESULTS Smokers (73 [73.0%] men; 74 [74.0%] white; mean [SD] age, 43.02 [12.13] years; mean [SD] CPD, 17.31 [5.72]) consumed 2.62 (95% CI, 1.54–3.70) more CPD during the RNC1 period vs their preferred brand during baseline (P < .001) and approximated baseline CPD during the RNC2 period (mean difference, 0.96 [95% CI, −0.36 to 2.28]; P = .24). Additional outcome measures were lower during both RNC periods vs baseline (total puff volume, mean [95% CI]: RNC1, 537 mL [95% CI, 479–595 mL]; RNC2, 598 mL [95% CI, 547–649 mL] vs baseline, 744 mL [95% CI, 681–806 mL]; TNE, mean [95% CI]: RNC1, 30.9 nmoL/mg creatinine [95% CI, 26.0–36.6 nmoL/mg]; RNC2, 22.8 nmoL/mg creatinine [95% CI, 17.8–29.0 nmoL/mg] vs baseline, 54.6 nmoL/mg creatinine [95% CI, 48.1–62.1 nmoL/mg]; and NNAL, mean [95% CI]: RNC1, 229 pg/mg creatinine [95% CI, 189–277 pg/mg]; RNC2, 190 pg/mg creatinine [95% CI, 157–231 pg/mg] vs baseline, 280 pg/mg creatinine [95% CI, 231–339 pg/mg]; all P < .001). Carbon monoxide measures were similar across study periods (CO boost [SD], RNC1, 4.6 ppm [4.1–5.1 ppm]; RNC2, 4.2 ppm [3.7–4.6 ppm]; and baseline, 4.4 ppm [3.8–4.9 ppm]). The RNC cigarette associations did not differ by NMR. CONCLUSIONS AND RELEVANCE Both RNC cigarettes were associated with decreased puffing and urinary biomarker exposure but not with decreased daily cigarette consumption or CO levels. The NMR did not moderate associations at the nicotine levels tested, suggesting that fast metabolizers may not be at greater risk of increasing use or exposure from these products should the FDA mandate an RNC standard for cigarettes.

Smokers attempting to quit often attribute smoking relapse to negative affect, craving, and other nicotine withdrawal symptoms. In addition, there is evidence that smoking relapse can increase these symptoms, particularly negative affect. To address this issue, we analyzed data from an 11-week smoking cessation clinical trial in which smokers (n = 1,246) were randomized to receive either nicotine replacement therapy (NRT), varenicline, or placebo, combined with behavioral counseling. Using cross-lagged analyses, we examined the temporal bidirectional relationships between self-reported measures of affect, craving, and composite withdrawal symptoms and biochemically verified smoking abstinence. The relative strength of these temporal relationships was examined by comparing the explained variances of the models. The results showed that higher negative affect, craving, and composite withdrawal symptoms increased the likelihood of subsequent smoking relapse, and that smoking relapse led to subsequent increases in these same symptoms. A comparison of the explained variances found symptom predicting subsequent relapse models to be stronger than those where relapse predicted subsequent symptoms. Although the explained variance findings generally support a negative reinforcement conceptualization of nicotine dependence, the bidirectional relationship between symptoms and smoking relapse suggests that struggling with quitting smoking leads to significant negative affect, craving, and other withdrawal symptoms that do not quickly resolve. These findings highlight the importance of addressing specific symptoms within the context of smoking cessation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

BACKGROUND: Transcranial direct current stimulation (tDCS) has been shown to improve measures of executive cognitive function and reduce cigarette consumption. Studies conducted to date have been small, and the results are mixed. METHODS: This randomized, double-blind, parallel arm clinical trial tested the effects of active anodal tDCS targeted to the left dorsolateral prefrontal cortex (versus sham) on 7-day smoking cessation in 106 treatment-seeking smokers. Participants received three sessions of sham (n = 35), 1mA (n = 35), or 2mA (n = 36) tDCS in the context of a validated smoking lapse paradigm then received brief smoking cessation counseling and completed a monitored quit attempt. The primary outcome was total number of days of abstinence confirmed via exhaled carbon monoxide. RESULTS: During the quit period, there were no effects of dose group on days of abstinence (sham, M (SD): 2.5 days (±2.5); 1mA: 2.5 days (±2.5); 2mA: 2.4 days (±2.3); β = −0.08; p = 0.76) or on change in daily smoking rate (sham, M (SD): −12.6 CPD (±4.8); 1mA: −11.8 CPD (±4.4); 2mA: −11.7 CPD (±5.3); β = 0.42, p = 0.49), nor were there effects of dose group on latency to smoke or number of cigarettes smoked during the smoking lapse paradigm. Side effects of tDCS were generally mild (

Background Understanding the mechanisms behind exerting self-control may reveal why health behaviors are resistant to change. Activity in the right inferior frontal gyrus (rIFG) plays a role in self-control processes and may be modulated using transcranial direct current stimulation (tDCS). Objective In this early phase behavioral research study, we investigated whether anodal stimulation over the rIFG with cathodal stimulation over the left IFG (versus sham) reduced chocolate consumption. Methods Twenty-three healthy females (ages 18–35) completed two tDCS sessions (2.0 mA vs. sham; order counterbalanced) in a within-subject, double-blind, randomized design with a 4-week washout. Participants were self-reported “chocolate cravers” and restrained eaters. Self-report assessments on disinhibited eating were completed at intake. Delay discounting and inhibitory control were assessed at the remaining visits. During stimulation, participants completed an inhibitory control training task (chocolate go/no-go task) and were randomized to the chocolate no-go condition (inhibit all responses to chocolate cues) or the control condition (inhibit responses to chocolate cues on half the trials). Following stimulation, participants completed a 15-min chocolate “taste test” with chocolate rating forms. Afterwards, staff measured the remaining chocolate to determine total consumption. Results Contrary to our hypotheses, active tDCS significantly increased chocolate consumption vs. sham (mean = 43.2 vs. 32.2, p=0.005) in both task conditions, but had no effect on chocolate ratings (ps > 0.05). Higher delay discounting and self-reported disinhibited eating predicted greater consumption (ps Conclusions The results suggest widespread activation of the prefrontal cortex may reduce the ability to resist chocolate. Our data highlights important methodological considerations for conducting tDCS studies to target health behaviors.

Summary Risk tolerance, the degree to which an individual is willing to tolerate risk in order to achieve a greater expected return, influences a variety of financial choices and health behaviors. Here we identify intrinsic neural markers for risk tolerance in a large (n = 108) multimodal imaging dataset of healthy young adults, which includes anatomical and resting-state functional MRI and diffusion tensor imaging. Using a data-driven approach, we found that higher risk tolerance was most strongly associated with greater global functional connectivity (node strength) of and greater gray matter volume in bilateral amygdala. Further, risk tolerance was positively associated with functional connectivity between amygdala and medial prefrontal cortex and negatively associated with structural connectivity between these regions. These findings show how the intrinsic functional and structural architecture of the amygdala, and amygdala-medial prefrontal pathways, which have previously been implicated in anxiety, are linked to individual differences in risk tolerance during economic decision making.

Introduction FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. Methods Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. Results We found that SORBS2 on 4q35 (p = 4.05 × 10−8), BG182718 on 11q22 (p = 1.02 × 10−8), and AA333164 on 14q21 (p = 4.11 × 10−9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. Conclusions Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. Implications Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

Background: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3′-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. Methods: Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland–Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. Results: Measures of plasma NMR were in strong agreement between methods according to Bland–Altman analysis (ratios, 0.82–1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62–1.71) and less strongly correlated (Pearson r values of 0.66–0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR. Conclusions: Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site. Impact: Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies. Cancer Epidemiol Biomarkers Prev; 24(8); 1239–46. ©2015 AACR.

Background: Total nicotine equivalents (TNE), the sum of nicotine and metabolites in urine, is a valuable tool for evaluating nicotine exposure. Most methods for measuring TNE involve two-step enzymatic hydrolysis for indirect quantification of glucuronide metabolites. Here, we describe a rapid, low-cost direct LC/MS assay. Methods: In 139 smokers' urine samples, Bland–Altman, correlation, and regression analyses were used to investigate differences in quantification of nicotine and metabolites, TNE, and nicotine metabolite ratio (NMR) between direct and indirect LC/MS methods. DNA from a subset (n = 97 smokers) was genotyped for UGT2B10*2 and UGT2B17*2, and the known impact of these variants was evaluated using urinary ratios determined by the direct versus indirect method. Results: The direct method showed high accuracy (0%–9% bias) and precision (3%–14% coefficient of variation) with similar distribution of nicotine metabolites to literary estimates and good agreement between the direct and indirect methods for nicotine, cotinine, and 3-hydroxycotinine (ratios 0.99–1.07), but less agreement for their respective glucuronides (ratios 1.16–4.17). The direct method identified urinary 3HC+3HC-GLUC/COT as having the highest concordance with plasma NMR and provided substantially better estimations of the established genetic impact of glucuronidation variants compared with the indirect method. Conclusions: Direct quantification of nicotine and metabolites is less time-consuming and less costly, and provides accurate estimates of nicotine intake, metabolism rate, and the impact of genetic variation in smokers. Impact: Lower cost and maintenance combined with high accuracy and reproducibility make the direct method ideal for smoking biomarker, NMR, and pharmacogenomics studies. Cancer Epidemiol Biomarkers Prev; 27(8); 882–91. ©2018 AACR.

OBJECTIVES Smoking patterns and cessation rates vary widely across smokers and can be influenced by variation in rates of nicotine metabolism [i.e. cytochrome P450 2A6 (CYP2A6), enzyme activity]. There is high heritability of CYP2A6-mediated nicotine metabolism (60-80%) owing to known and unidentified genetic variation in the CYP2A6 gene. We aimed to identify and characterize additional genetic variants at the CYP2A6 gene locus. METHODS A new CYP2A6-specific sequencing method was used to investigate genetic variation in CYP2A6. Novel variants were characterized in a White human liver bank that has been extensively phenotyped for CYP2A6. Linkage and haplotype structure for the novel single nucleotide polymorphisms (SNPs) were assessed. The association between novel five-SNP diplotypes and nicotine metabolism rate was investigated. RESULTS Seven high-frequency (minor allele frequencies ≥6%) noncoding SNPs were identified as important contributors to CYP2A6 phenotypes in a White human liver bank (rs57837628, rs7260629, rs7259706, rs150298687 (also denoted rs4803381), rs56113850, rs28399453, and rs8192733), accounting for two times more variation in in-vitro CYP2A6 activity relative to the four established functional CYP2A6 variants that are frequently tested in Whites (CYP2A6*2, *4, *9, and *12). Two pairs of novel SNPs were in high linkage disequilibrium, allowing us to establish five-SNP diplotypes that were associated with CYP2A6 enzyme activity (rate of nicotine metabolism) in-vitro in the liver bank and in-vivo among smokers. CONCLUSION The novel five-SNP diplotype may be useful to incorporate into CYP2A6 genotype models for personalized prediction of nicotine metabolism rate, cessation success, and response to pharmacotherapies.

Introduction We previously reported poor associations between salivary varenicline and pill counts, and a substantial overestimation of adherence by pill counts in “Measures and predictors of varenicline adherence in the treatment of nicotine dependence” (Peng et al., 2017). We have since conducted supplementary analyses characterizing, and then excluding, individuals with established inaccurate pill count recall. Methods Based on published varenicline pharmacokinetics (including drug levels, and the long half-life) and our detection limits, conservatively we should be able to detect varenicline in anyone who took at least one pill during the 48 h prior to saliva collection; thus, those reporting 1 or more pills in this time frame but who had undetectable salivary varenicline were deemed to have inaccurate pill count recall. Correlations between pill counts and salivary varenicline, and Receiver Operating Characteristics curve analyses were conducted following exclusion of participants with inaccurate pill count recall. Results Nearly 20% of our participants (N = 67/376) had inaccurate self-reported pill counts. These participants were younger, non-white, lower income, and unmarried (evaluated using chi-square or Mann-Whitney U test). Following exclusion of these individuals, the correlations between salivary varenicline and pill count improved and the area under the curve (AUC) of pill counts for discriminating adherence improved modestly. Conclusion When the 20% of individuals with inaccurate pill count recall were excluded, an improved association between self-reported pill count and salivary varenicline was observed, albeit still weak. A substantial overestimation of adherence by pill counts relative to salivary varenicline is still observed even after exclusion of almost 20% of the group having established inaccurate reporting suggesting that these individuals, with identifiable inaccuracies, were only part of the overestimation of adherence.

Background: Impulsivity is a core deficit in attention deficit hyperactivity disorder (ADHD). Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) has been shown to modulate cognitive control circuits and could enhance DLPFC activity, leading to improved impulse control in ADHD. Objective: Hypothesis: We predicted 2.0 mA anodal stimulation (tDCS) versus sham stimulation applied over the left DLPFC would improve Conners Continuous Performance Task (CPT) scores. Our secondary hypothesis predicted that stop signal task (SST) reaction time (SSRT) would decrease with tDCS (versus sham). Methods: Thirty-seven participants completed two periods of three tDCS (or sham) sessions two weeks apart in a within-subject, double-blind, counterbalanced order. Participants performed a fractal N-back training task concurrent with tDCS (or sham) stimulation. Participants completed the CPT and SST at the beginning of treatment (baseline), at the end of the treatment, and at a 3-day post-stimulation follow-up. Results: There was a significant stimulation condition by session interaction for CPT false positive scores (χ2 = 15.44, p 0.05). There was no significant stimulation condition by session interaction effect on CPT true positive errors or response time (ps > 0.05). No significant change in SSRT performance was observed (p > 0.05). Conclusion: These findings suggest that stimulation of the left DLPFC with tDCS can improve impulsivity symptoms in ADHD, supporting the therapeutic potential for tDCS in adult ADHD patients.

Brief abstinence from smoking impairs cognition, particularly executive function, and this has a role in relapse to smoking. This study examined whether working memory-related brain activity predicts subsequent smoking relapse above and beyond standard clinical and behavioral measures. Eighty treatment-seeking smokers completed two functional magnetic resonance imaging sessions (smoking satiety vs 24 h abstinence challenge) during performance of a visual N-back task. Brief counseling and a short-term quit attempt followed. Relapse during the first 7 days was biochemically confirmed by the presence of the nicotine metabolite cotinine. Mean percent blood oxygen level-dependent (BOLD) signal change was extracted from a priori regions of interest: bilateral dorsolateral prefrontal cortex (DLPFC), medial frontal/cingulate gyrus, posterior cingulate cortex (PCC), and ventromedial prefrontal cortex. Signal from these brain regions and additional clinical measures were used to model outcome status, which was then validated with resampling techniques. Relapse to smoking was predicted by increased withdrawal symptoms, decreased left DLPFC and increased PCC BOLD percent signal change (abstinence vs smoking satiety). Receiver operating characteristic analysis demonstrated 81% area under the curve using these predictors, a significant improvement over the model with clinical variables only. The combination of abstinence-induced decreases in left DLPFC activation and reduced suppression of PCC may be a prognostic marker for poor outcome, specifically early smoking relapse.

Background: The ratio of 3′hydroxycotinine to cotinine, or nicotine metabolite ratio (NMR), is strongly associated with CYP2A6 genotype, CYP2A6-mediated nicotine and cotinine metabolism, and nicotine clearance. Higher NMR (faster nicotine clearance) is associated retrospectively with heavier smoking and lower cessation rates. Methods: NMR as a predictive biomarker of cessation outcomes is being investigated (NCT01314001). In addition to strong CYP2A6 genetic influences on NMR, demographic and hormonal factors alter NMR. Here, we analyzed, for the first time together, these sources of variation on NMR in smokers screened for this clinical trial (N = 1,672). Results: Participants (mean age = 45.9) were 65.1% Caucasian, 34.9% African American, and 54.8% male. Mean NMR (SD) was higher in Caucasians versus African Americans [0.41 (0.20) vs. 0.33 (0.21); P < 0.001], and in females versus males [0.41 (0.22) vs. 0.37 (0.20); P < 0.001]. Among females, birth control pill use (N = 17) and hormone replacement therapy (N = 14) were associated with 19.5% (P = 0.09) and 29.3% (P = 0.06) higher mean NMR, respectively, albeit nonsignificantly. BMI was negatively associated with NMR (Rho = −0.14; P < 0.001), whereas alcohol use (Rho = 0.11; P < 0.001) and cigarette consumption (Rho = 0.12; P < 0.001) were positively associated with NMR. NMR was 16% lower in mentholated cigarette users (P < 0.001). When analyzed together in a linear regression model, these predictors (each ≤2%) accounted for Conclusions: Although these factors significantly affected NMR, they contributed little (together Impact: Thus, when using NMR, for example, to prospectively guide smoking cessation therapy, these sources of variation are unlikely to cause NMR misclassification. Cancer Epidemiol Biomarkers Prev; 23(9); 1773–82. ©2014 AACR.

Initial screening of new medications for potential efficacy (i.e., Food and Drug Administration (FDA) early phase 2), such as in aiding smoking cessation, should be efficient in identifying which drugs do, or do not, warrant more extensive (and expensive) clinical testing.This focused review outlines our research on development, evaluation, and validation of an efficient crossover procedure for sensitivity in detecting medication efficacy for smoking cessation. First-line FDA-approved medications of nicotine patch, varenicline, and bupropion were tested as model drugs, in three separate placebo-controlled studies. We also tested specificity of our procedure in identifying a drug that lacks efficacy, using modafinil.This crossover procedure showed sensitivity (increased days of abstinence) during week-long "practice" quit attempts with each of the active cessation medications (positive controls) versus placebo, but not with modafinil (negative control) versus placebo, as hypothesized. Sensitivity to medication efficacy signal was observed only in smokers high in intrinsic quit motivation (i.e., already preparing to quit soon) and not smokers low in intrinsic quit motivation, even if monetarily reinforced for abstinence (i.e., given extrinsic motivation).A crossover procedure requiring less time and fewer subjects than formal trials may provide an efficient strategy for a go/no-go decision whether to advance to subsequent phase 2 randomized clinical trials with a novel drug. Future research is needed to replicate our results and evaluate this procedure with novel compounds, identify factors that may limit its utility, and evaluate its applicability to testing efficacy of compounds for treating other forms of addiction.

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.

Bupropion may aid tobacco abstinence by quickly relieving symptoms of nicotine withdrawal, perhaps including impaired cognitive performance. We examined whether bupropion would attenuate abstinence-induced cognitive deficits on the first day of a brief quit attempt, when smokers are most likely to relapse.Smokers (N=24) with high quit interest were recruited for within-subjects cross-over test of bupropion vs placebo on ability to abstain during separate short-term practice quit smoking attempts. After introduction to working memory (N-back) and sustained attention (continuous performance task; CPT) tasks during the pre-quit smoking baseline, performance on these tasks was assessed after abstaining overnight (CO10 ppm) on the first day of each quit attempt, while on bupropion and on placebo.Compared to placebo, bupropion after abstinence improved correct response times for working memory (p=.01 for medication by memory load interaction) and for one measure of sustained attention (numbers, but not letters; p.05).Bupropion may attenuate some features of impaired cognitive performance due to withdrawal on the first day of a quit attempt. Future studies could examine whether this effect of bupropion contributes to its efficacy for longer-term smoking cessation.

Anti-smoking public service announcements (PSAs) often include smoking-related cues; however, visual drug cues can trigger acute cravings that may impede cognitive processing of the anti-smoking message. This experiment evaluated effects of smoking cues in PSAs on smoking urges, immediate smoking behavior, and persuasion measures in daily smokers.Three-hundred and eighteen non-treatment seeking smokers completed a single laboratory session during which they viewed sets of PSAs differentiated by presence of smoking cues (central to the PSA's argument, peripheral, or no cues) and argument strength (high versus low). After viewing the PSAs, participants completed self-report measures of smoking urges, attitudes toward quitting, self-efficacy, and intentions to quit smoking. Smoking behavior was recorded during a 1-h ad libitum smoking period immediately following PSA viewing and assessment.There was a significant positive effect of argument strength on attitudes toward quitting smoking (p=0.012). There were no main effects of smoking cues or smoking cue by argument strength interactions on any of the outcome measures.Visual smoking cues in PSAs do not increase urges to smoke, nor is there evidence that the inclusion of such cues impedes the recall or persuasive effects of anti-smoking arguments.

Addiction to nicotine and the ability to quit smoking are influenced by genetic factors. We used functional genomic approaches (chromatin immunoprecipitation (ChIP) and whole-genome sequencing) to identify cAMP response element-binding protein (CREB) targets following chronic nicotine administration and withdrawal (WD) in rodents. We found that chronic nicotine and WD differentially modulate CREB binding to the gene for neuregulin 3 (NRG3). Quantitative analysis of saline, nicotine and nicotine WD in two biological replicates corroborate this finding, with NRG3 increases in both mRNA and protein following WD from chronic nicotine treatment. To translate these data for human relevance, single-nucleotide polymorphisms (SNPs) across NRG3 were examined for association with prospective smoking cessation among smokers of European ancestry treated with transdermal nicotine in two independent cohorts. Individual SNP and haplotype analysis support the association of NRG3 SNPs and smoking cessation success. NRG3 is a neural-enriched member of the epidermal growth factor family, and a specific ligand for the receptor tyrosine kinase ErbB4, which is also upregulated following nicotine treatment and WD. Mice with significantly reduced levels of NRG3 or pharmacological inhibition of ErbB4 show similar reductions in anxiety following nicotine WD compared with control animals, suggesting a role for NRG3 in nicotine dependence. Although the function of the SNP in NRG3 in humans is not known, these data suggest that Nrg3/ErbB4 signaling may be an important factor in nicotine dependence.

Background: Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine, and carcinogen exposure. However, a given cotinine level may not represent the same tobacco exposure; for example, African-Americans have higher cotinine levels than Caucasians after controlling for exposure. Methods: Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. Because CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal was measured in nonsmoking Caucasians (Study 1, n = 181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n = 163). Results: Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P = 0.01), or 1.39 and 1.12 in males and females (P = 0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by 25% or more in CYP2A6 reduced metabolizers (≈2-fold between some genotypes) and in males. Conclusions: In people with slower relative to faster CYP2A6 activity, cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure. Impact: Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e., African-Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels), or between the sexes. Cancer Epidemiol Biomarkers Prev; 22(4); 708–18. ©2013 AACR.