Leveraging information from secondary endpoints to enhance dynamic borrowing across subpopulations.

Randomized trials seek efficient treatment effect estimation within target populations, yet scientific interest often also centers on subpopulations. Although there are typically too few subjects within each subpopulation to efficiently estimate these subpopulation treatment effects, one can gain precision by borrowing strength across subpopulations, as is the case in a basket trial. While dynamic borrowing has been proposed as an efficient approach to estimating subpopulation treatment effects on primary endpoints, additional efficiency could be gained by leveraging the information found in secondary endpoints. We propose a multisource exchangeability model (MEM) that incorporates secondary endpoints to more efficiently assess subpopulation exchangeability. Across simulation studies, our proposed model almost uniformly reduces the mean squared error when compared to the standard MEM that only considers data from the primary endpoint by gaining efficiency when subpopulations respond similarly to the treatment and reducing the magnitude of bias when the subpopulations are heterogeneous. We illustrate our model's feasibility using data from a recently completed trial of very low nicotine content cigarettes to estimate the effect on abstinence from smoking within three priority subpopulations. Our proposed model led to increases in the effective sample size two to four times greater than under the standard MEM.

Tobacco Exposures are Associated With Healthcare Utilization and Healthcare Costs in Pregnant Persons and Their Newborn Babies.

INTRODUCTION: Identifying healthcare utilization and costs associated with active and passive smoking during pregnancy could help improve health management strategies. AIMS AND METHODS: Data are from the Newborn Epigenetics STudy (NEST), a birth cohort enrolled from 2005 to 2011 in Durham and adjacent counties in North Carolina, United States. Participants included those for whom prenatal serum samples were assayed and for whom administrative data were obtainable (N = 1045). Zero-inflated poisson regression models were used to assess associations between cotinine, adjusted for covariates (eg, race and ethnicity, age at delivery, cohabitation status, and education), and health care utilization outcomes. Generalized linear regression models were used to estimate average total charges. Simulation models were conducted to determine the economic benefits of reducing secondhand smoke and smoking during pregnancy. RESULTS: Increasing levels of cotinine were positively associated with parent's number of emergency department (ED) visits (coefficient[b] = 0.0012, standard error [SE] = 0.0002; p < .001), the number of ICU hours (b = 0.0079, SE = 0.0025; p = .002), time spent in the ICU (b = 0.0238, SE = 0.0020, p < .001), and the number of OP visits (b = 0.0003, SE = 0.0001; p < .001). For infants, higher cotinine levels were associated with higher number of ED (b = 0.0012, SE = 0.0004; p = .005), ICU (b = 0.0050, SE = 0.001; p < .001), and OP (b = 0.0006, SE = 0.0002; p < .001) visits and longer time spent in the ED (b = 0.0025, SE = 0.0003; p < .001), ICU (b = 0.0005, SE = 0.0001; p < .001), and IP (b = 0.0020, SE = 0.0002; p < .001). Simulation results showed that a 5% reduction in smoking would correspond to a potential median cost savings of $150 533 from ED visits of parents and infants. CONCLUSIONS: Our findings highlight the importance of smoke exposure cessation during pregnancy to reduce health care utilization and costs for both parents and infants. IMPLICATIONS: This study reinforces the importance of reducing smoking and secondhand smoke exposure during pregnancy. Focusing on expanding cessation services to this group could help reduce morbidities observed within this population. Furthermore, there is the potential for healthcare cost savings to healthcare systems, especially for those with high delivery numbers. These cost savings are represented by potential reductions in ED, OP, and ICU hours and visits.

Modeling the Effects of Policies that Restrict Tobacco Retail Outlets on Prenatal Smoke Exposure and Perinatal Health Care Utilization.

Tobacco retail outlet (TRO) density has been associated with increased cotinine levels in pregnant persons and their children. As such, the higher densities of TROs may represent higher levels of active smoking during pregnancy. The purpose of this study is to simulate the reduction in cotinine (a biomarker of smoke exposure) and health care utilization that could occur in pregnant persons under enactment of several candidate TRO reduction policy recommendations. Using existing retail outlet data from the state of North Carolina and from the Newborn Epigenetic Study (NEST), the present study created hypothetical policy-informed datasets of TROs that a) limited the number of TROs to the same density as the 2014 San Francisco (SF) policy (Policy 1), b) set the minimum distance to 500 feet between TROs from a school and from other TROs (Policy 2), c) restricted the types of TROs to exclude pharmacies (Policy 3), and d) a combination of Policies 1-3 (Policy 4). We estimated the effects of each policy individually and in a separate model with their combined effects in terms of the reduction on cotinine levels and health care utilization, as measured by number of visits to the emergency department (ED). We found that the hypothetical policies were likely to be effective in reducing maternal cotinine and ED visits, with the majority of the mothers in the dataset demonstrating reductions in these outcomes after implementation of the policies. We found that Policy 1 led to moderate reductions in TRO exposure for the majority of the sample as well as stratified by race/ethnicity. Additionally, Policy 4 had slightly larger estimated effects than Policy 1, but could be more onerous to implement in practice. Overall, we identified evidence supporting the efficacy of TRO reduction strategies that could impact smoke exposure during pregnancy in our diverse sample in North Carolina.

Smoking Quit Attempts and Associated Factors Among Rural Adults Who Smoke Daily in the US.

INTRODUCTION: Rural American communities are heavily affected by tobacco-related health disparities. This study aims to evaluate the prevalence of quit attempts (QA) and factors that promote or impede QA among rural adults who smoke daily. METHODS: Data from Wave 5 of the Population Assessment of Tobacco and Health study were analyzed. Multivariable logistic regression was used to identify factors associated with quit attempt. Backwards selection was used to identify variables included in the final model with statistical significance set at p <0.05. RESULTS: Among 1,610 rural adults who smoked daily, the prevalence of a quit attempt in the past 12 months was 25.6% (95% CI: 23.2, 28.2). Factors associated with greater QA odds: having greater education (aOR = 1.35, 95% CI: 1.03, 1.77), e-cigarette use (aOR=1.35 95% CI: 1.03, 1.80), disapproval of smoking from friends/family (aOR= 1.46, 95% CI: 1.09-1.94), greater frequency of thinking about the harm of tobacco (aOR = 1.48, 95% CI: 1.28, 1.71), fair/poor physical health (aOR=1.31, 95% CI: 1.00, 1.70), and being advised to quit by a doctor (aOR =1.63 , 95% CI:1.25, 2.13). Smokeless tobacco use (aOR = 0.67, 95% CI: 0.47, 0.96) and greater cigarettes per day (aOR = 0.67, 95% CI: 0.47, 0.96) were associated with QA lower odds. CONCLUSION: Only 1 in 4 rural adults who smoke made a past year quit attempt. Interventions that promote provider advice to quit smoking, tobacco health harms, and normative beliefs may increase quit attempts in rural communities. IMPLICATIONS: Along with higher smoking rates and lower quitting attempts, rural communities face limited access to programs, medication, and health care professionals as tools to help them quit smoking. Public Health initiatives should focus on developing cultural sensitivity training targeting health care professionals to advise patients to quit smoking and the role of multiple tobacco products use. Furthermore, given the low rates of smoking quitting attempts future mixed methods research is needed to inform policies and interventions targeted at eliminating tobacco-related health disparities.

Older age is associated with greater misperception of the relative health risk of e-cigarettes and cigarettes among US adults who smoke.

INTRODUCTION: The prevalence of cigarette smoking among adults aged ≥55 has remained stagnant over the past decade. National data modelling suggests no reduction in cigarette smoking prevalence attributable to e-cigarette use in the USA among people aged ≥45. Misperceptions about the absolute risks (ie, cigarettes are not harmful) and relative risks (ie, e-cigarettes are more harmful than cigarettes) of tobacco products may contribute to sustained smoking prevalence and hesitancy to switch from cigarettes to e-cigarettes among older adults. METHODS: Participants reported cigarette use (n=8072) at Wave 5 (2018-2019) of the Population Assessment of Tobacco and Health Study. Weighted multivariable logistic regressions included six age categories (independent variable) and cigarette and e-cigarette risk perceptions (outcomes). Additional models assessed the associations between dichotomous age (≥55 vs 18-54), risk perceptions and an interaction term (independent variables) with past 12-month quit attempts and past-month e-cigarette use (outcomes). RESULTS: Adults aged ≥65 were less likely than adults aged 18-24 to rate cigarettes as very/extremely harmful (p<0.05). Odds of rating e-cigarettes as more harmful than cigarettes among adults aged 55-64 and ≥65 were 1.71 (p<0.001) and 1.43 (p=0.024) greater than for adults aged 18-24. This misperception was negatively associated with past-month e-cigarette use and was stronger among adults aged ≥55 (p<0.001) than adults aged <55 (p<0.001). DISCUSSION: Adults aged ≥55 are more likely to have misperceptions about the absolute and relative risks of tobacco products, which may contribute to continued smoking. Health communications targeting this age group could modify beliefs about the perceived harms of tobacco products.

Feasibility, Acceptability, and Preliminary Efficacy of a Gamified Mobile Health Contingency Management Intervention for PrEP Adherence Among Black MSM.

Oral HIV pre-exposure prophylaxis (PrEP) is effective at preventing HIV. However, low adherence is common and undermines these protective effects. This is particularly relevant for groups with disproportionately higher rates of HIV, including Black men who have sex with men (MSM). The current study tested the feasibility, acceptability, and preliminary efficacy of a gamified mobile health contingency management intervention for PrEP adherence-called mSMART (Mobile App-Based Personalized Solutions for Medication Adherence of Rx Pill Tool). Fifteen Black MSM already prescribed PrEP in the community completed baseline and follow-up assessments separated by 8 weeks of using mSMART. Regarding feasibility, there was no study attrition, no mSMART functional difficulties that significantly interfered with use, and a mean rate of 82% daily mSMART use. Acceptability ratings were in the moderately to extremely satisfied range for factors such as willingness to recommend mSMART to others and user-friendliness, and in the low range for ratings on difficulty learning how to use mSMART. Scores on a system usability measure were in the acceptable range for 73% of the sample. Qualitative analysis of follow-up interviews identified individual components of mSMART that could be modified in future iterations to make it more engaging. PrEP composite adherence scores from biomarkers indicated an improvement from baseline to follow-up with a medium effect size, as well as a decrease in the number of perceived barriers to medication adherence. Findings indicate a future efficacy trial is needed to examine the effects of this gamified mobile health contingency management intervention on PrEP adherence.

Multiple Tobacco Product Use Conceptual Framework: A 2021 Update on Evidence.

INTRODUCTION: One-third of adults in the United States who use tobacco regularly use two or more types of tobacco products. As the use of e-cigarettes and other noncombusted tobacco products increases-making multiple tobacco product (MTP) use increasingly common-it is essential to evaluate the complex factors that affect product use. AIMS AND METHODS: In this update to our 2019 conceptual framework, we review and evaluate recent literature and expand the model to include ways in which MTP use may be affected by market factors such as the introduction of new products and socioenvironmental factors like marketing and advertising. RESULTS AND CONCLUSIONS: MTP use patterns are complex, dynamic, and multiply determined by factors at the level of individuals, products, situations or contexts, and marketplace. Substitution, or using one product with the intent of decreasing use of another, and complementarity, or using multiple products for different reasons or purposes, explain patterns in MTP use. Moreover, substitution and complementarity may inform our understanding of how market changes targeted at one product, for instance, new product standards, bans, product pricing, and taxation, affect consumption of other tobacco products. New data from natural experiments and novel laboratory-based techniques add additional data and expand the framework. IMPLICATIONS: A substantial proportion of people who use tobacco use more than one product. This review synthesizes and evaluates recent evidence on the diverse factors that affect MTP use in addition to expanding our framework. Our review is accompanied by suggested research questions that can guide future study.

Preliminary Evaluation of Short-Term Abstinence Effects Among Never-Smoking Experienced Users of Modern Electronic Cigarettes.

INTRODUCTION: ECIG use has increased among non-smokers, with the potential negative consequence of developing nicotine dependence. ECIG users report withdrawal symptoms upon abstinence, though the significance of these symptoms has been questioned. This preliminary study aimed to characterize the early timecourse of ECIG withdrawal under forced abstinence. METHODS: Fifteen never-smoking ECIG users completed two conditions whereby participants either abstained from ECIG use (abstinence) or used their own ECIG (ad lib) for 3 h. Puff topography in this latter condition was measured via video observation. Outcome measures included heart rate, subjective ratings of withdrawal, cognitive performance, and choice behavior. RESULTS: Heart rate was lower during abstinence compared to ad lib use (F = 12.60, p < .01, ƞp2 = 0.47). Higher levels of craving (F = 4.98, p < .05, ƞp2 = 0.26) and lower levels of nicotine effects (e.g., dizzy, F = 4.62, p < .05, ƞp2 = 0.36) were reported during abstinence compared to ad lib use. Interaction effects were observed for both factors of the Questionnaire of Smoking Urges: Brief (Fs > 3.56, ps < .05, ƞp2s = 0.21-0.27), with factor scores increasing from baseline to 90 min in the abstinent condition only. Inhibitory control was impaired at 120 min in the abstinent condition only (F = 7.51, p < .05, ƞp2 = 0.50). CONCLUSIONS: Never-smoking ECIG users experienced aversive withdrawal symptoms within 2-3 h of abstinence. Future work should include other control conditions, such as placebo ECIGs or nicotine replacement therapy, and biomarkers of nicotine exposure, as well as examine withdrawal as a function of device type. IMPLICATIONS: Never-smoking ECIG users experience some aversive nicotine withdrawal symptoms within two to three hours of abstinence. Relative to ad lib ECIG use, abstinence decreased heart rate and inhibitory control, as well as increased subjective ratings of withdrawal such as craving and intention to vape. Those same symptoms might be suppressed by self-administration of ECIGs. Experiencing withdrawal upon abstinence may indicate that ECIGs can cause dependence without a history of other tobacco use.

Prediction of Smoking Risk From Repeated Sampling of Environmental Images: Model Validation.

BACKGROUND: Viewing their habitual smoking environments increases smokers' craving and smoking behaviors in laboratory settings. A deep learning approach can differentiate between habitual smoking versus nonsmoking environments, suggesting that it may be possible to predict environment-associated smoking risk from continuously acquired images of smokers' daily environments. OBJECTIVE: In this study, we aim to predict environment-associated risk from continuously acquired images of smokers' daily environments. We also aim to understand how model performance varies by location type, as reported by participants. METHODS: Smokers from Durham, North Carolina and surrounding areas completed ecological momentary assessments both immediately after smoking and at randomly selected times throughout the day for 2 weeks. At each assessment, participants took a picture of their current environment and completed a questionnaire on smoking, craving, and the environmental setting. A convolutional neural network-based model was trained to predict smoking, craving, whether smoking was permitted in the current environment and whether the participant was outside based on images of participants' daily environments, the time since their last cigarette, and baseline data on daily smoking habits. Prediction performance, quantified using the area under the receiver operating characteristic curve (AUC) and average precision (AP), was assessed for out-of-sample prediction as well as personalized models trained on images from days 1 to 10. The models were optimized for mobile devices and implemented as a smartphone app. RESULTS: A total of 48 participants completed the study, and 8008 images were acquired. The personalized models were highly effective in predicting smoking risk (AUC=0.827; AP=0.882), craving (AUC=0.837; AP=0.798), whether smoking was permitted in the current environment (AUC=0.932; AP=0.981), and whether the participant was outside (AUC=0.977; AP=0.956). The out-of-sample models were also effective in predicting smoking risk (AUC=0.723; AP=0.785), whether smoking was permitted in the current environment (AUC=0.815; AP=0.937), and whether the participant was outside (AUC=0.949; AP=0.922); however, they were not effective in predicting craving (AUC=0.522; AP=0.427). Omitting image features reduced AUC by over 0.1 when predicting all outcomes except craving. Prediction of smoking was more effective for participants whose self-reported location type was more variable (Spearman ρ=0.48; P=.001). CONCLUSIONS: Images of daily environments can be used to effectively predict smoking risk. Model personalization, achieved by incorporating information about daily smoking habits and training on participant-specific images, further improves prediction performance. Environment-associated smoking risk can be assessed in real time on a mobile device and can be incorporated into device-based smoking cessation interventions.

Not Quite the Rule, But No Longer the Exception: Multiple Tobacco Product Use and Implications for Treatment, Research, and Regulation.

The patterns of tobacco product use in the United States have changed during the past several decades. Currently, a large proportion of tobacco users report using multiple tobacco products (MTPs). The prevalence of MTP use varies significantly by cigarette smoking frequency, as well: nearly half (46.9%) of all non-daily smokers report using other tobacco products within the past 30 days. Despite this, much of extant tobacco dependence treatment efforts, tobacco regulatory science research, and tobacco product research, in general, has focused largely on single product use (ie, cigarette smoking). To effectively design interventions and model the potential impact of regulations on tobacco products aimed at reducing tobacco use, as well as effectively study tobacco users, it is essential to consider actual use patterns in the population of tobacco users. Implications: MTP use is increasingly common in the United States. This commentary highlights the impact that MTP use has for efforts to treat tobacco dependence, tobacco regulatory science efforts, as well as on tobacco research, in general.

Very Low Nicotine Content Cigarettes Disrupt the Feedback Loop of Affective States and Smoking Behavior.

INTRODUCTION: Smoking to reduce negative affect has been identified as a key motivational feature of tobacco use. Our recent work suggests that smoking very low nicotine content (VLNC) cigarettes reduces the relationship between negative affect and smoking behavior over a 6-week period. Here, we sought to extend our findings by evaluating whether a gradual or immediate approach to switching to VLNC cigarettes led to a differential reduction in the relationship between affect and smoking behavior over a longer (20-week) period. AIMS AND METHODS: Participants (n = 1250) were adult smokers from 10 US sites randomized to one of three groups: gradual nicotine reduction (15.5, 11.7, 5.2, 2.4, and 0.4 mg of nicotine per gram of tobacco [mg/g]), immediate nicotine reduction (0.4 mg/g), or standard nicotine content cigarettes (15.5 mg/g; control), for 20 weeks. We examined whether the relationship between affect-both negative and positive-and cigarettes per day differed as a function of reduction group. RESULTS: We found that both negative and positive affect were associated with cigarette consumption in the control group, but not in the gradual or immediate reduction groups across the 20 weeks of exposure. CONCLUSIONS: Our results extend previous findings that switching to VLNC cigarettes disrupts the relationship between affect and cigarette consumption by showing that either gradually or immediately reducing cigarette nicotine content achieves this disruption. These findings provide further evidence that switching to VLNC cigarettes reduces nicotine-related reinforcement of cigarette smoking. IMPLICATIONS: These findings support the notion that switching to very low nicotine content cigarettes reduces the association between affect and smoking behavior, and that either a gradual or immediate nicotine reduction approach achieves this reduction. This provides further evidence that switching to very low nicotine content cigarettes weakens reinforcement mechanisms associated with nicotine dependence.

The Effects of Nicotine and Tobacco Use on Brain Reward Function: Interaction With Nicotine Dependence Severity.

INTRODUCTION: This study investigated the effects of nicotine/tobacco on neural activation during performance of a monetary incentive delay task. AIMS AND METHODS: Prior to each scan, nonsmokers received nicotine or placebo nasal spray, and smokers were smoking satiated or 24-hour withdrawn. During the scan, participants made timed responses to reward-related cues and received feedback. Parameter estimates from cue- and feedback-related activation in medial prefrontal regions and the nucleus accumbens were extracted and underwent within- and between-group analyses. Smokers' nicotine dependence severity was included as a continuous predictor variable for neural activation. RESULTS: Among smokers (n = 21), withdrawal decreased cue-related activation in the supplementary motor area and ventromedial prefrontal cortex, and the difference in activation (satiety > withdrawal) in these regions negatively correlated with nicotine dependence severity (Fagerström Test for Nicotine Dependence). Among nonsmokers (n = 22), nicotine increased the difference in nucleus accumbens activation between rewarded and nonrewarded feedback phases. Tobacco withdrawal and acute nicotine also had widespread effects on activation throughout the brain during the feedback phase. CONCLUSIONS: Acute nicotine in nonsmokers may have increased the salience of feedback information, but produced few effects on reward-related activation overall, perhaps reflecting nicotine's modest, indirect effects on reward processing. Conversely, tobacco withdrawal decreased activation compared with satiety, and this difference between conditions correlated with nicotine dependence severity. This suggests that as smokers become more dependent on nicotine, tobacco withdrawal has a more pronounced effect on reward processing. IMPLICATIONS: Relative to the acute effects of nicotine in nonsmokers, withdrawal from daily tobacco use had more significant effects on reward-related brain activation. This study suggests that the effects of tobacco withdrawal on reward-related brain function interact with subjects' level of nicotine dependence severity. These are potentially important sources of variability that could contribute to smoking cessation outcomes.

A Conceptual Framework for Understanding Multiple Tobacco Product Use and the Impact of Regulatory Action.

INTRODUCTION: Over 35% of the adult tobacco-using population regularly use more than one tobacco product. Although rates of tobacco use in the United States have declined over the last decade, rates of multiple tobacco product (MTP) have either remained stable (among adults) or increased (among youth). METHODS: In this paper, we review the literature and propose a framework for understanding both MTP use and how regulatory actions on any single tobacco product (STP) may influence the use of other tobacco products. RESULTS AND CONCLUSIONS: Within the framework, Product, Person, and Context/Situational factors (and their interactions) influence product cross-substitution and thus patterns of use of MTPs. In addition, we propose that Context/Situation effects specifically increase the complexity of MTP-use patterns resulting in "dynamic complementarity" in addition to substitution-like relationships between tobacco products. Experimentation with, and use of, various tobacco products results in reinforcement histories that affect which products are used, in what contexts, and by whom, which in turn has downstream impacts on toxicant exposure and health. We conclude our analysis with an examination of how regulation of STPs can have impacts on the use of other STP and MTP use and provide research questions for further examining MTP use. IMPLICATIONS: Though rates of tobacco use have declined in the United States, over 35% of the adult tobacco-using population regularly uses more than one tobacco product. This paper provides a framework for understanding MTP use and how regulatory actions on any STP may influence the use of other tobacco products. We conclude our analysis by providing research questions for further examining MTP use.

Using Neuroscience to Inform Tobacco Control Policy.

INTRODUCTION: Techniques employed in the field of neuroscience, such as eye tracking, electroencephalography, and functional magnetic resonance imaging, have been important in informing our understanding of the cognitive mechanisms underlying tobacco smoking. These techniques are now increasingly being used to investigate the likely impact of tobacco control policies. AIMS AND METHODS: In this narrative review, we outline the value of these methodological approaches in answering policy-relevant tobacco control research questions, with a particular focus on their use in examining the impact of standardized cigarette packaging and health warnings. We also examine the limitations of these methodologies and provide examples of how they can be used to answer other policy-relevant questions. RESULTS: We argue that neuroscience techniques can provide more objective evidence of the impacts of policy measures, allow investigation where it is not possible to conduct behavioral manipulations, and facilitate a deeper understanding of the cognitive mechanisms underlying the impacts of tobacco control policies such as standardized packaging, health warnings, point-of-sale displays, and mass media campaigns. CONCLUSIONS: Rather than replacing more traditional methods of examining tobacco control measures, such as observational experiments, surveys, and questionnaires, neuroscience techniques can complement and extend these methods. IMPLICATIONS: Neuroscience techniques facilitate objective examination of the mechanisms underlying the impacts of tobacco control measures. These techniques can therefore complement and extend other methodologies typically used in this field, such as observational experiments, surveys, and questionnaires.

Combined Smoking Cues Enhance Reactivity and Predict Immediate Subsequent Smoking.

Introduction: Cue reactivity (CR) research has reliably demonstrated robust cue-induced responding among smokers exposed to common proximal smoking cues (eg, cigarettes, lighter). More recent work demonstrates that distal stimuli, most notably the actual environments in which smoking previously occurred, can also gain associative control over craving. In the real world, proximal cues always occur within an environment; thus, a more informative test of how cues affect smokers might be to present these two cue types simultaneously. Methods: Using a combined-cue counterbalanced CR paradigm, the present study tested the impact of proximal (smoking and neutral) + personal environment (smoking and nonsmoking places) pictorial cues, on smokers' subjective and behavioral CR; as well as the extent to which cue-induced craving predicts immediate subsequent smoking in a within-subjects design. Results: As anticipated, the dual smoking cue combination (ProxS + EnvS) led to the greatest cue-induced craving relative to the other three cue combinations (ProxS + EnvN, ProxN + EnvS, and ProxN ± EnvN), ps < .004. Dual smoking cues also led to significantly shorter post-trial latencies to smoke, ps < .01. Overall CR difference score (post-trial craving minus baseline craving) was predictive of subsequent immediate smoking indexed by: post-trial latency to smoke [B = -2.69, SE = 9.02; t(143) = -2.98, p = .003]; total puff volume [B = 2.99, SE = 1.13; t(143) = 2.65, p = .009]; and total number of puffs [B = .053, SE = .027; t(143) = 1.95, p = .05]. Conclusions: The implications of these findings for better understanding the impact of cues on smoking behavior and cessation are discussed. Implications: This novel cue reactivity study examined smokers' reactivity to combined proximal and distal smoking cues. Exposure to a combination of two smoking cues (proximal and environment) led to the greatest increases in cue-induced craving and smoking behavior compared to all other cue combinations. Further, the overall magnitude of cue-induced craving was found to significantly predict immediate subsequent smoking. This work provides new insight on how exposure to various cues and cue combinations directly affect smokers' craving and actual smoking behavior, as well as the relationship between those two indices of reactivity.

Anticipated Effects of Nicotine Reduction on Youth Smoking Initiation and Maintenance.

This commentary summarizes emerging findings on the potential impact of a nicotine reduction policy on youth and young adults. We conclude that: (1) adolescent smokers and nonsmokers alike are likely to be less sensitive to reinforcement from very low nicotine content (VLNC) cigarettes compared with adults; (2) reducing nicotine in cigarettes to 0.4 mg/g would reduce the abuse potential of cigarettes in adolescents and young adults; (3) findings to date do not support concerns that nicotine reduction leads to compensatory smoking in young smokers; and (4) if the scope of a reduced nicotine product standard were applied to all combusted tobacco products, that would likely maximize public health benefit of this policy.

The Impact of Gradual and Immediate Nicotine Reduction on Subjective Cigarette Ratings.

BACKGROUND: A recent clinical trial showed that an immediate transition to very low nicotine content (VLNC) cigarettes, compared with a gradual transition, produced greater reductions in smoking behavior, smoke exposure, and dependence. However, there was less compliance with the instruction to smoke only VLNC cigarettes in the immediate versus gradual reduction condition. The goal of this study was to test whether nicotine reduction method alters subjective ratings of VLNC cigarettes, and whether subjective ratings mediate effects of nicotine reduction method on smoking behavior, smoke exposure, dependence, and compliance. METHODS: This is a secondary analysis of a randomized trial conducted across 10 sites in the United States. Smokers (n = 1250) were randomized to either a control condition, or to have the nicotine content of their cigarettes reduced immediately or gradually to 0.04 mg nicotine/g of tobacco during a 20-week study period. Participants completed the modified Cigarette Evaluation Questionnaire (mCEQ). RESULTS: After Week 20, the immediate reduction group scored significantly lower than the gradual reduction group on multiple subscales of the mCEQ (ps < .001). The Satisfaction subscale of the mCEQ mediated the impact of nicotine reduction method on smoke exposure, smoking behavior, dependence, compliance, and abstinence. Other subscales also mediated a subset of these outcomes. CONCLUSIONS: An immediate reduction in nicotine content resulted in lower product satisfaction than a gradual reduction, suggesting that immediate reduction further reduces cigarette reward value. This study will provide the Food and Drug Administration with information about the impact of nicotine reduction method on cigarette reward value. IMPLICATIONS: These data suggest that an immediate reduction in nicotine content will result in greater reductions in cigarette satisfaction than a gradual reduction, and this reduction in satisfaction is related to changes in smoking behavior and dependence.

Correlates of support for a nicotine-reduction policy in smokers with 6-week exposure to very low nicotine cigarettes.

BACKGROUND: The US Food and Drug Administration recently issued an advanced notice of proposed rule-making for reducing the nicotine content in cigarettes to a minimally addictive level. Very little is known about whether use of very low nicotine content (VLNC) cigarettes affects support for a nicotine reduction policy. OBJECTIVE: This study examined the effects of using VLNC versus usual brand (UB) cigarettes on support for a nicotine reduction policy and determined whether participant characteristics and responses to VLNC cigarettes were associated with policy support. METHODS: Participants from a cigarette trial who were assigned to either 0.4 mg nicotine/g tobacco research cigarettes or their UB for 6 weeks were asked about their support for the policy. χ2 tests were used to compare support for the policy between cigarette conditions and logistic regression analyses were conducted to assess covariates associated with policy support. FINDINGS: Policy support did not differ by condition. After 6 weeks of using VLNC cigarettes, 50% of participants supported the policy, 26% opposed and 24% responded 'Don't Know'. Support was higher among those adherent to smoking only VLNC cigarettes (65%) compared with those who were non-adherent (44%). Older participants and those interested in quitting had increased odds of support. Cigarette satisfaction, perceived harm and perceived nicotine content were not significantly associated with support. CONCLUSIONS: Smoking VLNC cigarettes did not affect support for a nicotine reduction policy. Understanding predictors of policy support and opposition will help public health officials to maximise the public health acceptance and impact of this policy (ClinicalTrials.gov Identifier: NCT01681875 Post-Results).

Young adult dual combusted cigarette and e-cigarette users' anticipated responses to hypothetical e-cigarette market restrictions.

Introduction: The aim of this exploratory study was to assess young adult dual e-cigarette (EC) and combusted cigarette (CC) users' anticipated responses to hypothetical market restrictions regarding key EC characteristics. Methods: Data came from 240 young adult dual EC and CC users recruited via Amazon Mechanical Turk in June 2017. Descriptive statistics were used to report sociodemographic, CC smoking, and EC use characteristics. McNemar's chi-square tests and chi-square tests were used to assess differences between groups in terms of anticipated responses to hypothetical EC market restrictions. Results: Hypothetical regulations resulted in reported intentions to reduce EC use and increase CC use; the greatest impact was found for restrictions regarding e-liquid nicotine content, followed by flavor and ability to modify EC devices. Moreover, individuals reporting use of flavored e-liquid, high nicotine content e-liquid, and customizable EC were most likely to report intentions to reduce EC use and increase CC use. Conclusions: This work provides preliminary evidence that restrictive regulations regarding key EC characteristics may increase intentions to increase CC use among young adult dual EC and CC users.

Randomized Trial of Reduced-Nicotine Standards for Cigarettes.

BACKGROUND: The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. METHODS: We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. RESULTS: A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups. CONCLUSIONS: In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875.).