The Epidemiology of Berry Consumption and Association of Berry Consumption with Diet Quality and Cardiometabolic Risk Factors in United States Adults: The National Health and Nutrition Examination Survey, 2003-2018.

BACKGROUND: Berries are rich in important nutrients and bioactive compounds, which could potentially contribute to maintenance of normal lipid and glucose profiles. OBJECTIVE: We reported the epidemiology of berry consumption and examined associations of berry consumption with diet quality [measured by Healthy Eating Index (HEI-2015)] and levels of cardiometabolic risk factors, including body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol (HDL cholesterol), glycated hemoglobin, and fasting biomarkers: triglycerides, low-density lipoprotein cholesterol (LDL cholesterol), glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). METHODS: We evaluated 33,082 adults (aged ≥20 y) using two 24-h diet recalls from National Health and Nutrition Examination Survey (2003-2018). Multivariable linear regression models were applied to examine the associations of total and individual berry intake with diet quality and cardiometabolic risk factors using appropriate sample weights. RESULTS: Approximately 25 % of the United States adults consumed berries (0.08 ± 0.003 cup-equivalents/d), representing ∼10 % of the daily mean total fruit intake. Among berry consumers, the mean intake of strawberries (0.31 ± 0.01 cup-equivalents) was higher than for other berries. Berry consumers had a significantly higher HEI-2015 score than nonconsumers (mean HEI-2015 score = 58.8 compared with 52.3, P < 0.0001). Berry consumers had significantly lower concentrations of cardiometabolic indices than nonconsumers, including BMI, WC, SBP, total cholesterol, LDL cholesterol, triglycerides, fasting insulin, HOMA-IR, and higher mean HDL cholesterol, after adjusting for sociodemographic, lifestyle, and dietary confounders (all P < 0.05). CONCLUSIONS: United States adult berry consumers had a higher diet quality and lower concentrations of cardiometabolic risk factors, suggesting a favorable role for berries in diets and cardiometabolic disease prevention in United States adult population.

Consumption of Berries and Flavonoids in Relation to Mortality in NHANES, 1999-2014.

BACKGROUND: Berries are foods that are abundant in nutrients, especially flavonoids, that promote good health; however, the effects of total berries on mortality are not well characterized. OBJECTIVES: We evaluated whether intakes of total berries and specific berry types including blueberries, strawberries, cranberries, flavonoids, and subclasses of flavonoids (anthocyanidins, flavonols, flavones, flavanones, flavan-3-ols, and isoflavones) in relation to mortality risk in United States adults. METHODS: A nationally representative sample of the United States adult population was obtained using data from the 1994-2014 NHANES (n = 37,232). Intake of berries was estimated using 24-h food recalls (1999-2014), and flavonoids intake was calculated using the matched USDA's expanded flavonoid database. Mortality outcomes based on 8 y of follow-up were obtained using linked death certificates. RESULTS: Compared with nonconsumers, the multivariable-adjusted hazard ratio for all-cause mortality was 0.79 [95% confidence intervals (CI): 0.7, 0.89] for any berry consumption, 0.86 (0.75, 0.99) for strawberry consumption 0.79 (0.66, 0.95) for blueberries, and 0.69 (0.51, 0.93) for cranberries. Compared with the lower median of intake, risk of all-cause mortality for greater intake was 0.85 (0.74, 0.97) for total flavonoids, 0.85 (0.76, 0.95) for anthocyanidins, 0.9 (0.82, 0.99) for flavan-3-ols, 0.89 (0.79, 0.9) for flavanols, and 0.89 (0.8, 0.99) for flavones. There was a dose-response relationship between intakes of total flavonoids, anthocyanidins, and flavones and lower all-cause mortality risks (Ptrend < 0.05). Risk for cardiometabolic mortality was 0.75 (0.58, 0.98) for berry consumers and 0.49 (0.25, 0.98) for cranberry consumers. For respiratory disease mortality, risk was 0.41 (0.2, 0.86), compared with blueberry nonconsumers. CONCLUSION: Higher intakes of berries and flavonoids were associated with a lower overall mortality risk in adult Americans. Few adults regularly consume berries, indicating that increased intake of berries and flavonoid-rich foods may be beneficial to health.

Free Radicals in Little Cigar Mainstream Smoke and the Potential Influence of Flavoring Chemicals on Free Radical Production.

Implementation of the Tobacco Control Act in 2009 banned characterizing flavors in cigarettes (except menthol and tobacco), but substitution has occurred by the continued availability of alternative flavored products (i.e., flavored little cigars). Little is known about how flavorants in noncigarette tobacco products impact human health. Thus, we investigated the impact of flavorants on free radical production in the mainstream smoke of little cigars. Gas- and particulate-phase free radical yields in mainstream smoke generated from 12 commercial little cigar brands and research little cigars and cigarettes were measured via electron paramagnetic resonance spectroscopy using the International Organization of Standardization (ISO) smoking protocol. Flavorants were extracted from unsmoked little cigars and analyzed by gas chromatography-mass spectroscopy. Gas- and particulate-phase radical yields from little cigars ranged from 13.5 to 97.6 and 0.453-1.175 nmol/unit, respectively. Comparatively, research cigarettes yielded an average of 4.9 nmol gas-phase radicals/unit and 0.292 nmol particulate-phase radicals/unit. From the products, 66 flavorants were identified, with each brand containing 4-24 individual flavorants. The free radical content was strongly correlated with the number of flavorants present in each cigar (r = 0.74, p = 0.01), indicating that highly flavored little cigars may produce higher levels of toxic free radicals. The presence of the flavorant ethyl methylphenylglycidate (strawberry) was associated with >2-fold higher levels of GP radicals (p = 0.001). Our results show that free radical delivery from little cigars is greater than that from research cigarettes and provide empirical evidence for the harmfulness of flavored tobacco products. Additionally, it demonstrates that flavorants present in combustible tobacco products can influence the levels of free radicals produced. Therefore, future tobacco product standards should consider little cigars.

Inhibition of Nicotine Metabolism by Cannabidiol (CBD) and 7-Hydroxycannabidiol (7-OH-CBD).

Cannabis-based products have experienced notable increases in co-usage alongside tobacco products. Several cannabinoids exhibit inhibition of a number of cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes, but few studies have examined their inhibition of enzymes involved in nicotine metabolism. The goal of the present study was to examine potential drug-drug interactions occurring in the nicotine metabolism pathway perpetrated by cannabidiol (CBD) and its active metabolite, 7-hydroxy-CBD (7-OH-CBD). The inhibitory effects of CBD and 7-OH-CBD were tested in microsomes from HEK293 cells overexpressing individual metabolizing enzymes and from human liver tissue. Assays with overexpressing microsomes demonstrated that CBD and 7-OH-CBD inhibited CYP-mediated nicotine metabolism. Binding-corrected IC50,u values for CBD inhibition of nicotine metabolism to cotinine and nornicotine, and cotinine metabolism to trans-3'-hydroxycotinine (3HC), were 0.27 ± 0.060, 0.23 ± 0.14, and 0.21 ± 0.14 µM, respectively, for CYP2A6; and 0.26 ± 0.17 and 0.029 ± 0.0050 µM for cotinine and nornicotine formation, respectively, for CYP2B6. 7-OH-CBD IC50,u values were 0.45 ± 0.18, 0.16 ± 0.08, and 0.78 ± 0.23 µM for cotinine, nornicotine, and 3HC formation, respectively, for CYP2A6, and 1.2 ± 0.44 and 0.11 ± 0.030 µM for cotinine and nornicotine formation, respectively, for CYP2B6. Similar IC50,u values were observed in HLM. Inhibition (IC50,u = 0.37 ± 0.06 µM) of 3HC to 3HC-glucuronide formation by UGT1A9 was demonstrated by CBD. Significant inhibition of nicotine metabolism pathways by CBD and 7-OH-CBD suggests that cannabinoids may inhibit nicotine metabolism, potentially impacting tobacco addiction and cessation.

Nighttime Waking to Smoke, Stress, and Nicotine Addiction.

INTRODUCTION: Up to one-half of cigarette smokers may wake up during the night and smoke. This behavior may result in greater likelihood of cessation failure, clinically relevant sleep difficulties, and a range of health issues. Whereas the scientific literature has often attributed this behavior to nicotine dependence, up to 85% of smokers who wake at night and smoke attribute this behavior to factors other than nicotine. This study examines the relations between nicotine dependence, psychological distress, perceived stress, and waking at night to smoke. METHODS: A total of 351 adult smokers from the Pennsylvania Adult Smoking Study (PASS) completed self-report surveys and provided saliva for the evaluation of cotinine values. Survey instruments included measures of nicotine addiction, perceived stress, a broad measure of global psychological distress, and a range of demographic factors. RESULTS: Logistic regression demonstrated that nicotine addiction, psychological distress, and perceived stress were all related to waking at night to smoke, but cotinine levels were not. Mediation models found that psychological distress had a direct relation to waking at night to smoke, even when considering nicotine addiction and other causes of sleep disturbances (e.g., apnea and chronic physical pain). Alternative moderation and mediation models were conducted but did not support other plausible associations between variables. CONCLUSIONS: Waking at night to smoke is likely the result of both nicotine dependence and psychological distress. Given that cotinine levels were not associated with waking at night, the mechanisms of how nicotine dependence may affect waking at night need further investigation.

Switching to Progressively Reduced Nicotine Content Cigarettes in Smokers With Low Socioeconomic Status: A Double-Blind Randomized Clinical Trial.

INTRODUCTION: The Food and Drug Administration issued an advanced notice of proposed rulemaking for setting a product standard for nicotine levels in cigarettes, with an emphasis on minimally or non-addicting very low nicotine content (VLNC). METHODS: A 33 week, two-arm, double-blind randomized trial conducted in Hershey, Pennsylvania, USA and Washington, DC, USA included adult daily cigarette smokers (≥5 cigarettes per day) with less than a college degree, and who had no plans to quit within the next six months. Participants were randomized to either reduced nicotine content (RNC) study cigarettes tapered every three weeks to a final VLNC (0.2 mg/cigarette) for six weeks or to usual nicotine content (UNC) study cigarettes (11.6 mg/cigarette). Outcomes included acceptability of study cigarettes measured by attrition (primary outcome), compliance, reduction in cigarette dependence and tobacco biomarkers, and post-intervention cessation. RESULTS: The RNC (n = 122) versus UNC (n = 123) group had higher attrition (adjusted Hazard Ratio 3.4; 95% confidence interval [CI] 1.99 to 5.81). At the end of the intervention, cotinine levels were 50% lower in the RNC group (mean group difference -137 ng/mL; 95% CI -172, -102). The RNC group smoked fewer CPD (-4.1; 95% CI -6.44, -1.75) and had lower carbon monoxide levels (-4.0 ppm; 95% CI -7.7, -0.4). Forty seven percent (29/62) of the RNC group were biochemically-confirmed compliant with smoking VLNC cigarettes (mean cotinine = 8.9 ng/ml). At three month follow-up, only compliant VLNC smokers quit with an assisted quit attempt (N = 6/22, 27%). CONCLUSIONS: This study supports a VLNC standard in cigarettes. IMPLICATIONS: Differential dropout and noncompliance indicate some smokers had difficulty transitioning to cigarettes with reduced nicotine. These smokers will benefit from supplemental nicotine in medicinal or noncombustible tobacco products if a nicotine reduction standard is established. Other smokers successfully transitioned to very low nicotine content cigarettes exclusively and substantially reduced their exposure to nicotine.

Characterizing nicotine exposure among a community sample of non-daily smokers in the United States.

BACKGROUND: Over one-quarter of all smokers in the United States identify as non-daily smokers and this number is projected to rise. Unlike daily smokers who typically maintain consistent levels of nicotine exposure with regular smoking, non-daily smokers have variable patterns of smoking that likely result in high intraindividual variability in nicotine intake. The current study aimed to characterize the weekly intraindividual variability in cotinine and identify smoking-related predictors in nondaily smokers. METHODS: An ecological momentary assessment of 60 non-daily smokers ages 24-57 years was conducted over a consecutive 7-day at-home protocol to log each smoking session, assessments of mood and social activity during smoking, and collection of daily saliva samples in a convenience sample from Pennsylvania, USA. Hierarchical linear regression analyses were conducted to determine the effects of smoking characteristics on total cotinine exposure measured by pharmacokinetic area under the curve and the range, maximum, and minimum cotinine values during the week controlling for demographic variables. RESULTS: The mean daily cotinine level was 119.2 ng/ml (SD = 168.9) with individual values that ranged from nondetectable to 949.6 ng/ml. Menthol predicted increased total cotinine levels (P < 0.05). Shorter time to the first cigarette of the day predicted significantly higher minimum (P < 0.05), maximum (P < 0.05), and total cotinine values (P < 0.05) after controlling for covariates. Negative emotions and social interactions with others were also significantly associated with higher cotinine metrics. There was no significant effect of the nicotine metabolite ratio. CONCLUSIONS: Our findings highlight the variability in nicotine exposure across days among non-daily smokers and point to the role of smoking context in nicotine exposure. The findings suggest the need to develop better assessment methods to determine health and dependence risk and personalized cessation interventions for this heterogeneous and growing group of smokers.

Free Radical and Nicotine Yields in Mainstream Smoke of Chinese Marketed Cigarettes: Variation with Smoking Regimens and Cigarette Brands.

Free radicals and nicotine are components of cigarette smoke that are thought to contribute to the development of smoking-induced diseases. China has the largest number of smokers in the world, yet little is known about the yields of tobacco smoke constituents in different Chinese brands of cigarettes. In this study, gas-phase and particulate-phase free radicals as well as nicotine yields were quantified in mainstream cigarette smoke from five popular Chinese brands and two research cigarettes (3R4F and 1R6F). Mainstream smoke was generated under International Organization of Standardization (ISO) and Canadian Intense (CI) smoking regimens using a linear smoking machine. Levels of free radicals and nicotine were measured by electron paramagnetic resonance spectroscopy (EPR) and gas chromatography with flame-ionization detection, respectively. Under the ISO puffing regimen, Chinese brand cigarettes produced an average of 3.0 ± 1.2 nmol/cig gas-phase radicals, 118 ± 44.7 pmol/cig particulate-phase radicals, and 0.6 ± 0.2 mg/cig nicotine. Under the CI puffing regimen, Chinese brand cigarettes produced an average of 5.6 ± 1.2 nmol/cig gas-phase radicals, 282 ± 92.1 pmol/cig particulate-phase radicals, and 2.1 ± 0.4 mg/cig nicotine. Overall, both gas- and particulate-phase free radicals were substantially lower compared to the research cigarettes under both regimens, whereas no significant differences were observed for nicotine levels. When Chinese brands were compared, the highest free radical and nicotine yields were found in "LL" and "BS" brands, while lowest levels were found in "YY". These results suggested that the lower radical delivery by Chinese cigarettes compared to United States reference cigarettes may be associated with reductions in oxidant-related harm.

Pharmacokinetic Profile of Spectrum Reduced Nicotine Cigarettes.

INTRODUCTION: Spectrum research cigarettes have been developed with varying nicotine content for use in studies evaluating the effects of a regulatory policy reducing the permissible nicotine content in cigarettes. This study aimed to characterize the nicotine pharmacokinetic profile of Spectrum cigarettes. METHODS: Twelve daily smokers attended four sessions and had blood nicotine, exhaled carbon monoxide, and subjective effects measured before and after smoking either a single cigarette of their preferred brand or high (10.9 mg/cigarette), medium (3.2 mg/cigarette), or low (0.2 mg/cigarette) nicotine content Spectrum research cigarettes, in a double-blind design with order counterbalanced. RESULTS: The boost in blood nicotine concentration was dose-dependent, with a boost of 0.3, 3.9, and 17.3 ng/mL for low-, medium-, and high-nicotine content Spectrum cigarettes. The high dose Spectrum had a similar nicotine boost to the "preferred brand" cigarettes (19 ng/mL). Subjects took longer puffs on the low nicotine cigarettes, but smoked these cigarettes faster than other cigarette types. High nicotine Spectrum cigarettes reduced the urge to smoke more than other cigarette types. CONCLUSIONS: This study shows that Spectrum research cigarettes produce blood nicotine absorption in a dose-dependent manner, and therefore, are appropriate for use in studies of nicotine reduction in cigarettes. IMPLICATIONS: This is the first study to determine the pharmacokinetic profile of Spectrum reduced nicotine content research cigarettes following an overnight abstinence. These data could provide evidence to regulatory agencies about the effects of reduced nicotine cigarettes when considering regulations on tobacco reduction.

Clinical trial recruitment of adult African American smokers from economically disadvantaged urban communities.

This investigation evaluated the effectiveness and challenges of multiple recruitment methods, described as proactive, reactive, and combination methods, among adult African American smokers (N = 527) from economically disadvantaged urban communities enrolled to test progressively reduced nicotine content investigational cigarettes. The study evaluated success using descriptive statistics to measure the volume of phone calls and percentage of eligible participants per method. Reactive and combination strategies effectively prompted participants to call about the study. Combination methods yielded the highest eligibility rates. Findings demonstrate the unique recruitment successes within this population across a range of recruitment methods and may inform improved methods to recruit and engage African Americans in clinical trials.

The Effect of Price on the Consumption of Reduced Nicotine Cigarettes.

BACKGROUND: Price affects the demand for cigarettes, indicating that smokers, perhaps especially lower income smokers, may choose low nicotine cigarettes (LNC) if they were commercially available and cost less than fully nicotinized conventional cigarettes. The present study tests the hypothesis that smokers will prefer purchasing LNCs at a lower price point than conventional cigarettes given a fixed budget. METHOD: A laboratory-based, within-subject, 3 (nicotine level) × 3 (price) factorial design provided smokers opportunities to purchase standard (0.7 per mg tobacco), moderately reduced (0.3 mg), and very low-nicotine (0.03 mg). Spectrum research cigarettes according to an escalating price structure (low-nicotine costing the least, high-nicotine costing the most) given a fixed, laboratory-provided "income." Participants were 20 overnight-abstinent smokers who previously smoked and rated each of the three cigarettes. RESULTS: Overall, smokers rated LNCs as less satisfying compared with standard nicotine cigarettes (SNC), t(18) = -5.40, p < .001. In the free-choice session, subjects were more likely to choose LNC that cost less compared with SNC that cost more, even after an 8-hour abstinence period, F(2, 19) = 4.32, p = .03. Those selecting LNC or moderate nicotine cigarettes after abstinence smoked more cigarettes per day, t(17) = 2.40, p = .03 and had higher dependence scores on the HONC, t(18) = 2.21, p = .04 that those selecting SNC. CONCLUSION: The results indicate that smokers' response to price points when purchasing cigarettes may extend to LNC if these were commercially available. Differential cigarette prices based on nicotine content may result in voluntary selection of less addicting products. IMPLICATIONS: The Food and Drug Administration has proposed a rule that would reduce nicotine content in commercially available cigarettes. However, it is not known how smokers may respond in an environment where products of differing nicotine content and of differing prices are available. This study demonstrates that price may be an important factor that could lead smokers to select reduced nicotine products voluntarily, even if those products are rated as inferior or less satisfying.

Reducing the Nicotine Content of Cigarettes: Effects in Smokers With Mental Health Conditions and Socioeconomic Disadvantages.

In this commentary, we review results from laboratory studies and randomized clinical trials that have examined the effects of very low-nicotine-content cigarette use in smokers with mental health conditions and socioeconomic disadvantages. On the basis of scientific evidence to date, we conclude that a reduced-nicotine standard for cigarettes would likely reduce cigarette smoking in these populations, without increasing psychiatric symptoms or compensatory smoking.

Characteristics of Adult Cigarette Smokers Who "Relight" and the Effects of Exposure to Tobacco Smoke Constituents.

INTRODUCTION: About half of smokers relight their cigarette, a habit that is a risk factor for chronic bronchitis and possibly lung cancer. Little is known about the characteristics of smokers who relight and their dependence on nicotine. It is unknown whether relighting affects exposure to tobacco smoke constituents. This study examined the characteristics of relighters of usual brand cigarettes and whether relighting affects exposure to selected tobacco smoke constituents. METHODS: We explored relighting status and frequency, using baseline data from 248 adult smokers participating in studies of reduced nicotine cigarettes in relation to demographic and cigarette characteristics, smoking behaviors, nicotine dependence, biomarkers of exposure (exhaled carbon monoxide, blood cotinine), and biomarkers of oxidative stress (ratio of oxidized/reduced glutathione). RESULTS: 69.4% (n = 172) of subjects reported relighting, and they relit an average of five cigarettes out of 20. Both relighters and non-relighters smoked a mean of 20 cigarettes per day (p = .6). Relighting was significantly associated with higher nicotine dependence, use of longer rod cigarettes, older age, lower income, and unemployment. There were no significant associations between relighting and blood cotinine, exhaled carbon monoxide or measures of oxidized/reduced blood glutathione. CONCLUSIONS: The majority of subjects were relighters, who had higher levels of nicotine dependence than non-relighters. Relighters had similar levels of plasma cotinine and exhaled carbon monoxide to non-relighters. IMPLICATIONS: No study has compared the cigarette characteristics and biomarkers of exposure of adult cigarette smokers who relight with those who do not. Relighting behavior was common in our sample and was associated with low income, not currently working, higher nicotine dependence, cigarette rod length, daily cigarette use years, and a lifetime history of depressed mood.

Socioeconomic differences in nicotine exposure and dependence in adult daily smokers.

BACKGROUND: Socioeconomic status (SES) is a major determinant of tobacco use but little is known whether SES affects nicotine exposure and the degree of nicotine dependence. METHODS: The Pennsylvania Adult Smoking Study is a cross-sectional study of smoke exposure and nicotine dependence among adults conducted in central Pennsylvania between June 2012 and April 2014. The study included several measures of SES, including assessments of education and household income, as well as occupation, home ownership, health insurance, household density and savings accounts. Measurements included saliva for the nicotine metabolites cotinine (COT), 3-'hydroxycotinine (3HC) and total metabolites (COT +3HC). Puffing behavior was determined using portable smoking topography devices. RESULTS: The income levels of lighter smokers (< 20 cigarettes per day) was $10,000 more than heavier smokers. Higher Fagerström Test for Nicotine Dependence scores were associated with lower income and job status, scores ranged from 5.4 in unemployed, 4.4 in blue-collar, and 3.8 in white-collar workers. In principal components analysis used to derive SES indicators, household income, number in household, and type of dwelling were the major SES correlates of the primary component. Job category was the major correlate of the second component. Lower SES predicted significantly higher adjusted total nicotine metabolite levels in the unemployed group. Job category was significantly associated with total daily puffs, with the highest level in the unemployed, followed by blue-collar workers, after adjustment for income. CONCLUSIONS: Among smokers, there was a relationship between lower SES and increased nicotine dependence, cigarettes per day and nicotine exposure, which varied by job type.

Nicotine dependence as an independent risk factor for atherosclerosis in the National Lung Screening Trial.

BACKGROUND: Atherosclerosis and COPD are systemic inflammatory diseases that share common risk factors including cigarette smoking. A high level of nicotine dependence is emerging as a recently identified risk factor for pulmonary impairment, chronic obstructive pulmonary disease and tobacco-related cancers. We hypothesized that nicotine dependence is associated with the risk of atherosclerosis in long-term cigarette smokers. METHODS: A nested case-control study was conducted within the National Lung Cancer Screening Trial- American College of Radiology Imaging Network. Cases were defined as having a new diagnosis of any type of atherosclerosis. Controls were matched on a 2:1 basis by age, sex, race, study center, smoking status, years of smoking, and frequency of smoking. Dependence was measured by the time to first cigarette after awakening (TTFC). RESULTS: The study included 166 cases and 286 controls. Compared to participants who smoked within 5 min after waking, the risk of atherosclerosis for participants who smoked an hour or more after waking was borderline non-significant (odds ratio = 0.49, 95% confidence intervals [CI] 0.23, 1.00). Findings were similar for men and women. For aortic atherosclerosis, the corresponding odds ratio was 0.24 (95% CI 0.08, 0.69). Hypertension was associated with an increased risk and body mass index was associated with a decreased risk of aortic atherosclerosis. The TTFC was unrelated to coronary atherosclerosis. CONCLUSIONS: Compared to smoking immediately after waking, delaying an hour or more reduces the risk of aortic atherosclerosis even among long-term heavy smokers. Possible mechanisms that explain this association are intensity of smoking, inflammation and oxidative stress, and elevated lipid levels.

Time to first cigarette of the day and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in adult regular and non-daily smokers: (NHANES) 2007-10.

As the number of regular smokers has decreased over the last decade, the prevalence of light (<10 cigarettes per day) and non-daily smokers has increased. As the FDA continues to develop regulations for tobacco products, understanding factors related to toxin exposure in all smokers is essential. The present study evaluated the relation between the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), as measured by its metabolite, and patterns of heavy smoking (>10 cigarettes per day), light smoking and non-daily smoking and the time to the first cigarette of the day (TTFC), a robust predictor of nicotine addiction, cessation failure, sleep disruption and other health indicators. Findings from a sample of 352 smokers suggest that among intermittent, non-daily and light daily smokers, TTFC of the day was associated with higher levels of NNK metabolite, an effect which was mediated by urinary cotinine levels, but not by the number of cigarettes smoked per day. This suggests these groups of smokers may be puffing each cigarette more intensely, thus increasing nicotine and toxin exposure, despite fewer overall cigarettes. These findings provide further information regarding toxicant exposure associated with lower-frequency smoking and has implications for future regulatory research approaches with lowered nicotine cigarettes and other tobacco products.

On meta- and mega-analyses for gene-environment interactions.

Gene-by-environment (G × E) interactions are important in explaining the missing heritability and understanding the causation of complex diseases, but a single, moderately sized study often has limited statistical power to detect such interactions. With the increasing need for integrating data and reporting results from multiple collaborative studies or sites, debate over choice between mega- versus meta-analysis continues. In principle, data from different sites can be integrated at the individual level into a "mega" data set, which can be fit by a joint "mega-analysis." Alternatively, analyses can be done at each site, and results across sites can be combined through a "meta-analysis" procedure without integrating individual level data across sites. Although mega-analysis has been advocated in several recent initiatives, meta-analysis has the advantages of simplicity and feasibility, and has recently led to several important findings in identifying main genetic effects. In this paper, we conducted empirical and simulation studies, using data from a G × E study of lung cancer, to compare the mega- and meta-analyses in four commonly used G × E analyses under the scenario that the number of studies is small and sample sizes of individual studies are relatively large. We compared the two data integration approaches in the context of fixed effect models and random effects models separately. Our investigations provide valuable insights in understanding the differences between mega- and meta-analyses in practice of combining small number of studies in identifying G × E interactions.

Ecological momentary assessment of smoking behaviors in native and converted intermittent smokers.

BACKGROUND AND OBJECTIVES: About 22% of adult smokers in the U.S. are intermittent cigarette smokers (ITS). ITS can be further classified as native ITS who never smoked daily and converted ITS who formerly smoked daily but reduced to intermittent smoking. Ecological momentary assessment (EMA) was conducted to determine the behaviors and experiences that are associated with the decision to smoke. METHODS: The study included 24 native ITS and 36 converted ITS (N = 60) from the Pennsylvania Adult Smoking Study. A baseline questionnaire, daily log, and an EMA smoking log that assessed emotions, activities, and smoking urges was filled out with each cigarette for 1 week to capture 574 smoking sessions. RESULTS: Both groups had very low levels of cigarette dependence. Both groups were more tempted to smoke in positive or negative situations than situations associated with habituation. EMA showed that the most common emotional state during smoking sessions was positive (47%), followed by negative (32%), neutral (16%), and mixed (5%) emotions. Smokers were more likely to smoke during activities of leisure (48%) than during performative duties (29%), social (16%) or interactive occasions (7%). Converted ITS were more likely to smoke alone compared to native ITS (p < .001). DISCUSSION AND CONCLUSIONS: ITS report minimal levels of dependence when captured on traditional scales of nicotine dependence, yet experience loss of autonomy and difficulty quitting. The majority of the ITS reported positive emotions and leisure activities while smoking, and smoked during the evening. SCIENTIFIC SIGNIFICANCE: The current paper identifies environmental and behavioral factors that are associated with smoking among ITS in real time. (Am J Addict 2018;27:131-138).

A two-site, two-arm, 34-week, double-blind, parallel-group, randomized controlled trial of reduced nicotine cigarettes in smokers with mood and/or anxiety disorders: trial design and protocol.

BACKGROUND: The U.S. Food and Drug Administration can set standards for cigarettes that could include reducing their nicotine content. Such a standard should improve public health without causing unintended serious consequences for sub-populations. This study evaluates the effect of progressive nicotine reduction in cigarettes on smoking behavior, toxicant exposure, and psychiatric symptoms in smokers with comorbid mood and/or anxiety disorders using a two-site, two-arm, double-blind, parallel group, randomized controlled trial (RCT) in four phases over 34 weeks. METHODS: Adult smokers (N = 200) of 5 or more cigarettes per day will be randomized across two sites (Penn State and Massachusetts General). Participants must have not had a quit attempt in the prior month, nor be planning to quit in the next 6 months, meet criteria for a current or lifetime unipolar mood and/or anxiety disorder based on the structured Mini-International Neuropsychiatric Interview, and must not have an unstable medical or psychiatric condition. After a week of smoking their own cigarettes, participants receive two weeks of Spectrum research cigarettes with usual nicotine content (11.6 mg). After this baseline period, participants will be randomly assigned to continue smoking Spectrum research cigarettes that contain either (a) Usual Nicotine Content (11.6 mg); or (b) Reduced Nicotine Content: the nicotine content per cigarette is progressively reduced from approximately 11.6 mg to 0.2 mg in five steps over 18 weeks. At the end of the randomization phase, participants will be offered the choice to either (a) quit smoking with assistance, (b) continue smoking free research cigarettes, or (c) return to purchasing their own cigarettes, for the final 12 weeks of the study. The primary outcome measure is blood cotinine; key secondary outcomes are: exhaled carbon monoxide, urinary total NNAL- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 1-hydroxypyrene, oxidative stress biomarkers including 8-isoprostanes, measures of psychiatric symptoms (e.g., depression, anxiety), smoking behavior and dependence (e.g., cigarette consumption, quit attempts), and health effects (e.g., blood pressure, respiratory symptoms). DISCUSSION: Results from this study will inform FDA on the potential effects of regulating the nicotine content of cigarettes and help determine whether smokers with mood and/or anxiety disorders can safely transition to significantly reduced nicotine content cigarettes. TRIAL REGISTRATION: TRN: NCT01928758 , registered August 21, 2013.

Comparison of Puff Volume With Cigarettes per Day in Predicting Nicotine Uptake Among Daily Smokers.

The role of inhalation behaviors as predictors of nicotine uptake was examined in the Pennsylvania Adult Smoking Study (2012-2014), a study of 332 adults whose cigarette smoking was measured in a naturalistic environment (e.g., at home) with portable handheld topography devices. Piecewise regression analyses showed that levels of salivary cotinine, trans-3'-hydroxycotinine, and total salivary nicotine metabolites (cotinine + trans-3'-hydroxycotinine) increased linearly up to a level of about 1 pack per day (20 cigarettes per day (CPD)) (P < 0.01). Total daily puff volume (TDPV; in mL) (P < 0.05) and total daily number of puffs (P < 0.05), but not other topographical measures, increased linearly with CPD up to a level of about 1 pack per day. The mean level of cotinine per cigarette did not change above 20 CPD and was 36% lower in heavy smokers (≥20 CPD) than in lighter smokers (<20 CPD) (15.6 ng/mL vs. 24.5 ng/mL, respectively; P < 0.01). Mediation models showed that TDPV accounted for 43%-63% of the association between CPD and nicotine metabolites for smokers of <20 CPD. TDPV was the best predictor of nicotine metabolite levels in light-to-moderate smokers (1-19 CPD). In contrast, neither CPD, total daily number of puffs, nor TDPV predicted nicotine metabolite levels above 20 CPD (up to 40 CPD). Finally, although light smokers are traditionally considered less dependent on nicotine, these findings suggest that they are exposed to more nicotine per cigarette than are heavy smokers due to more frequent, intensive puffing.