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Background: Remnant Cholesterol (RC) has emerged as a significant risk factor for cardiovascular disease. However, the factors influencing RC levels remain incompletely understood. This research investigates smoking-a major modifiable risk factor-to elucidate its impact on RC levels and examine the mediating role of inflammation in this relationship., Methods: Using NHANES data from 1999 to 2018, this study analyzed the association between serum cotinine levels (a biomarker of smoking intensity) and RC in 8,829 participants aged 20 years and older. Through complex sampling design and adjustment for multiple covariables, we examined both linear and nonlinear relationships using linear regression models, restricted cubic splines (RCS), and subgroup analyses. Additionally, mediation analyses evaluated the role of inflammatory markers-neutrophils (NEU), monocytes (MON), lymphocytes (LYM), and platelets (PLT)-in this association., Results: The high cotinine exposure group demonstrated significantly elevated RC levels (β = 2.256, 95% CI: 1.401-3.112, p < 0.001) compared to the no/minimal exposure group. This positive association was particularly pronounced in females (p for interaction < 0.05). Restricted cubic spline analysis demonstrated a nonlinear, N-shaped relationship (p for nonlinearity < 0.05), with RC levels reaching their peak at cotinine concentrations of approximately 172 ng/mL. In the mediation analysis, inflammatory markers showed significant mediating effects: NEU (28%), LYM (14.1%), PLT (9.5%), and MON (6.9%) of the total effect., Conclusion: A significant positive association exists between cotinine and RC levels, moderated by sex. Inflammatory markers, particularly NEU, partially mediate this association., Competing Interests: Declarations. Ethics approval and consent to participate: This research complied with the Helsinki Declaration and used NHANES data which has undergone ethical review by NCHS. As a secondary analysis of this approved dataset following STROBE guidelines, no additional ethical approval was required. Consent for publication: Written informed consent for publication was obtained from all participants. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Herpes simplex virus (HSV) infections, primarily caused by HSV-1 and HSV-2, are prevalent worldwide and carry significant health implications. The impact of tobacco use on HSV infections, however, remains underexplored. This cross-sectional study utilized the National Health and Nutrition Examination Survey (NHANES) database (2009-2016) to investigate the link between Tobacco use and HSV infections among U.S. adults. Smoking status, volume, and serum cotinine levels were analyzed, alongside demographic and behavioral factors. Propensity score matching (PSM) was employed to adjust for confounders such as sexual behavior. Our study involved 5693 participants to explore the relationship between tobacco use and HSV infection. We found that smokers, particularly current smokers, have a significantly increased risk of both HSV-1 and HSV-2 infections compared to non-smokers. Specifically, the adjusted odds ratio (OR) for HSV-1 in current smokers was 1.36 (95% CI: 1.16-1.59, p < 0.001), and for HSV-2, it was 2.37 (95% CI: 1.88-3, p < 0.001). The risk escalates with the intensity of smoking. Elevated serum cotinine levels correlated with an increased risk of HSV infection (HSV-1:1.13 [95% CI:1.09-1.18, p < 0.001]; HSV-2:1.33 [95% CI:1.25-1.41, p < 0.001]). After PSM for factors such as age, gender, sexual behavior, and condom use, these associations remained significant. Tobacco use is significantly associated with an increased risk of HSV infections, highlighting the importance of reducing tobacco exposure in public health strategies against HSV. Further, longitudinal studies are warranted to establish causality and explore underlying mechanisms., (© 2024 Wiley Periodicals LLC.)

Background: Fractional exhaled nitric oxide (FeNO) is a marker of type 2 airway inflammation. Tobacco exposure can lower FeNO levels. However, the effect of acute tobacco exposure on FeNO in patients with chronic obstructive pulmonary disease (COPD) is unclear. This study aimed to investigate the relationship of acute tobacco exposure with FeNO and eosinophils in COPD patients., Methods: This retrospective cohort study included 445 patients with COPD based on the 2007-2012 National Health and Nutrition Examination Survey. Serum cotinine levels were examined to assess environmental tobacco smoke exposure. The patients were divided into five groups based on cotinine levels: Q1 (first quintile), Q2 (second quintile), Q3 (third quintile), Q4 (fourth quintile) and Q5 (fifth quintile). Logistic regression models and linear logistic regression models were used to evaluate the relationship between serum cotinine and FeNO and EOS levels., Results: Approximately 16.5 % (75/445) of the participants had elevated FeNO (>25 bbp). In the unadjusted model, COPD patients with the lowest quintile of serum cotinine levels (0.011-0.0185 ng/mL) had higher FeNO levels compared to those with the highest quintile (≥309 ng/mL) (odds ratios (OR), 5.86 [2.11-16.20]). These findings remained consistent even after adjusting for covariates of demographics, lifestyle, diabetes, coronary heart disease, tumours, hypertension, using oral or inhaled steroids within 2 days, asthma and respiratory symptoms within 7 days. Furthermore, a standard deviation increase of ln-transformed cotinine levels was associated with decreased FeNO levels (OR, 0.45 [0.33, 0.60]). No significant correlation was observed betweenserum cotinine and blood eosinophils. After high extents of tobacco exposure, no correlation was found between FeNO and eosinophils. Our findings indicate that high cotinine levels are associated with decreased FeNO in COPD patients but not with blood eosinophils. This reveals that smoking may affect FeNO levels in patients with COPD, whereas it does not appear to influence blood eosinophil levels., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The aim of designing this clinical trial is to investigate the impact of a nicotine-rich diet with/without protein redistribution on the motor indices of patients with Parkinson's disease (PD)., Methods: We randomly divided 45 patients (age > 50) with PD into three groups including: nicotine-rich diet (20 µg per day) group (group N; n = 15), nicotine-rich diet with protein redistribution group (group N + P; n = 15), and control group (group C; n = 15). In all group, the diet was isocaloric, and participants received six meals and snacks. After 12 weeks, the Unified Parkinson's Disease Rating Scale part III (UPDRS), serum alpha-synuclein levels, serum apolipoprotein A1, serum cotinine, and anthropometric parameters were measured in the three groups before and 12 weeks after the beginning of the study., Results: All of the enrolled patients completed the study. The UPDRS score was improved by 1.47 and 1.95 units in the N and N + P groups compared to the placebo (P < 0.001). On the other hand, effect size of N and N + P diets for α-synuclein were -52.82 and -175.85, respectively. The differences were significant compared to the control group (P < 0.05). Also, the effect of the both diets on serum cotinine compared to the control group was significant (P < 0.05). Although the effect size for UPDRS, α-synuclein, and cotinine in N + P diet were higher than N group, the differences were not statistically significant (P > 0.05). Also, the obtained results showed that there were no significant effects on anthropometric variables and serum levels of Apolipoprotein A1 in diet-receiving groups (P > 0.05)., Conclusions: The results of our study indicated that nicotine consumption in an isocaloric diet, while preventing a decrease in anthropometric indices, leads to improvements in motor indices and a reduction in alpha-synuclein levels. Additional and larger controlled trials are required to validate these findings., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mohammad Hassan Javanbakht reports financial support was provided by Tehran University of Medical Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Smoking has been recognized as a contributing factor to frailty in older adults. Nevertheless, it remains uncertain whether the degree of smoking has a discernible impact on frailty among older smokers. This cross-sectional study was conducted to investigate the correlation between serum cotinine levels, a biomarker reflecting tobacco exposure, and the presence of frailty within a nationally representative cohort of older adults., Method: A total of 1626 individuals aged ≥ 60 who identified as smokers were included in the analysis. Participants were selected based on self-reported current smoking status. According to the Fried Phenotype, frailty is assessed through five dimensions: unintentional weight loss, slow walking speed, weakness, self-reported exhaustion, and low physical activity. Participants with three or more of these conditions were categorized as frailty, those with at least one but less than three as pre-frailty, and those with none as robust. Multinomial logistic regression models were employed to explore the relationship between serum cotinine level quartiles, with the lowest quartile as the reference group, and the various frailty statuses, with robustness as the reference category. These models were adjusted for covariates, including age, sex, race/ethnicity, alcohol drinking, daily protein intake, systolic blood pressure, serum albumin level, depressive symptoms, and cognitive function. The data used for this analysis were sourced from the National Health and Nutrition Examination Survey for the years 2011 to 2014., Results: The median age of the participants was 69.0 years. The majority were male (62.2%) and non-Hispanic White (49.0%). The distribution of frailty statuses among the participants revealed that the highest proportion had pre-frailty (50.7%), followed by robustness (41.1%), and frailty (8.2%). Multinomial logistic regression showed that participants in the 4 th quartile of serum cotinine level exhibited a higher probability of pre-frailty versus robustness (Odds ratio [OR] 1.599, 95% confidence interval [CI] 1.017, 2.513, P = 0.042). Participants in the 3 rd quartile of serum cotinine level had higher odds of frailty versus robustness (OR 2.403, 95% CI 1.125, 5.134, P = 0.024). Moreover, participants whose serum cotinine levels were higher than the literature cutoffs (≥ 15 ng/ml) were more likely to be pre-frail (Odds ratio [OR] 1.478, 95% confidence interval [CI] 1.017, 2.150, P = 0.035) or frail (Odds ratio [OR] 2.141, 95% confidence interval [CI] 1.054, 4.351, P = 0.041)., Conclusions: A higher serum cotinine level is linked to an elevated probability of pre-frailty and frailty among older smokers. Initiatives geared towards assisting older smokers in reducing or quitting their smoking habits might possibly play a crucial role in preventing pre-frailty and frailty., (© 2024. The Author(s).)

This study examined the associations between tobacco smoking and serum cotinine levels, an objective biochemical measure of tobacco smoke exposure, with markers of inflammation, i.e., interferon-gamma (IFN-γ), interleukin 10 (IL-10), interleukin 2 (IL-2) and tumour necrosis factor-alpha (TNF-α) in people living with HIV (PLWH).These specific markers were selected because of their hypothesised associations with smoking, PLWH and their outcomes. In a random sample of ≥ 18-year-old PLWH receiving care at 17 public healthcare facilities across the Western Cape Province in South Africa, data collection included self-reported smoking history, and serum levels of cotinine and selected inflammatory markers. The inflammatory marker data were log transformed because of the skewedness of their distribution. Linear regression models (1) adjusted for age and gender, and (2) fully adjusted for age, gender, current alcohol use, body mass index and CD4 counts were used to examine the associations between smoking tobacco or serum cotinine and inflammatory markers. Level of significance was p < 0.05. Among 749 PLWH who were mainly women (79%), the mean age was 38.5 (8.9) years and similar when stratified by smoking status. Serum cotinine levels exhibited a striking discrepancy, with a median of 154 ng/mL among current smokers, in stark contrast to the consistent median values of 10 ng/mL observed among past and never smokers. In regression models adjusted for age and gender, current smoking and frequent smoking were associated with lower IL-2 but higher TNF-α. Log-cotinine exhibited associations with IFN-γ, IL-10, and TNF-α, while cotinine levels ≥ 10 ng/mL compared to < 10 ng/mL were associated with higher IFN-γ and TNF-α. In fully adjusted models, log-cotinine and cotinine levels ≥ 10 ng/mL displayed significant associations with higher IFN-γ and lower IL-2. This study underscores the importance of investigating the interplay between smoking tobacco or serum cotinine levels with pro-inflammatory cytokines in PLWH. It signals the need for comprehensive research to unravel the potential synergistic impacts of smoking tobacco and HIV infection on chronic inflammation and immune dysregulation, shedding light on critical avenues for intervention and management strategies., (© 2024. The Author(s).)

Background: Asthma is an airway inflammatory disease driven by multiple factors with a high incidence in children and adolescents. Environmental tobacco smoke exposure (TSE) and diet are inducing factors for asthma. The potential of omega-3 polyunsaturated fatty acids (PUFAs) to alleviate asthma symptoms by their anti-inflammatory effects has been explored. However, to date, no studies have explored the effect of dietary PUFAs intake on the asthma in children and adolescents exposed to tobacco smoke., Objective: We aimed to examine the effect of dietary PUFAs intake on the current asthma in children and adolescents exposed to tobacco smoke., Methods: Data of this cross-sectional were extracted from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Children and adolescents with serum cotinine concentration ≥ 0.05 ng/mL were defined to exposed to tobacco smoke. Dietary PUFAs intake information were obtained from 24 h recall interview. The weighted univariate and multivariate were utilized to explore the effect of PUFAs on the association of asthma and TSE, with adjusted odds ratios (AORs) and 95% confidence intervals (CIs). These moderating effects were further explored based on the age, gender and body mass index (BMI) and sedentary time., Results: Totally, 7981 eligible children and adolescents were included, with the mean age of 11.96 ± 0.06 years old. Of whom, 1.024 (12.83%) had current asthma. After adjusted all covariates, we found children and adolescents with TSE had high occurrence of current asthma (AOR = 1.2, 95% CI 1.03-1.63); We also found omega-3 PUFAs intake (P for interaction = 0.010), not omega-6 PUFAs (P for interaction = 0.546), has a moderating effect on the association of TSE and current asthma. Moreover, we further observed that children and adolescents with TSE and low omega-3 PUFAs intake had high occurrence of current asthma (AOR = 1.58, 95% CI 1.19-2.10), while no significant association was found in children and adolescents with high omega-3 PUFAs intake (all P > 0.05). This moderating effect was more prominent in children and adolescents aged ≤ 12 years old (AOR = 1.62, 95% CI 1.06-2.47), girls (AOR = 2.14, 95% CI 1.15-3.98), overweight (AOR = 1.87, 95% CI 1.01-3.47) and sedentary time > 6 h (AOR = 1.96, 95% CI 1.00-3.86)., Conclusion: We found dietary omega-3 PUFAs plays a moderating effect on the association of asthma and TSE in children and adolescents, especially in children and adolescents aged ≤ 12 years, girls, overweight or sedentary time > 6 h. This moderating effect suggested higher omega-3 intake has potential benefits in decreasing the occurrence of asthma in children and adolescents who exposed to tobacco smoke., (© 2024. The Author(s).)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This cross-sectional survey aims to determine whether cotinine exposure would enhance the relationship between blood manganese (Mn) and non-alcoholic fatty liver disease (NAFLD) in children using the NHANES database. Restricted cubic spline (RCS) and logistic regression analyses were adopted to determine the potential relationship. Besides, we tested the robustness of the results by performing trend tests and subgroup analyses. The study finally enrolled 866 children aged 18 years and below. Blood Mn was linearly linked to NAFLD and the risk of NAFLD was increased with the blood Mn elevation (P < 0.05). There was a notable relationship between blood Mn and NAFLD in crude model 1, which was still significant upon adjustment of all the identified covariates (all P < 0.05). Under Mn exposure, the cotinine-exposed group had a higher risk of NAFLD than the cotinine-unexposed group. In conclusion, blood Mn level is an independent risk factor for pediatric NAFLD, and cotinine exposure can enhance this relationship to some degree. Therefore, reducing cotinine exposure may alleviate detrimental consequences related to exposure to heavy metals in children., (© 2024. The Author(s).)

Background: Recent studies suggested that the combination of tobacco smoke exposure (TSE) and dietary nutrients intake may be related to a higher or lower risk of hypertension. However, the relationship between dietary magnesium (Mg) intake, TSE and the odds of hypertension remain unclear. This study aimed to evaluate the association of TSE, dietary Mg intake and the odds of hypertension among children and adolescents., Method: Data of this study were extracted from the National Health and Nutrition Examination Surveys (NHANES) 2007-2018. Dietary Mg intake was calculated as the average of two days of dietary and supplementations intake. Serum cotinine concertation ≥ 0.05 µg/L or at least one-person smoking in the household was considered as exposing to the tobacco smoke. The weighted univariate and multivariate logistic regression models were utilized to explore the associations of dietary Mg intake, TSE and the odds of hypertension among children and adolescents with the evaluation index of odds ratio (ORs) and 95% confidence intervals (CIs). Subgroup analyses based on different age, gender and overweight were further assessed these associations., Results: A total of 7,122 children and adolescents aged 8-17 years old and with the blood pressure measurement were included. Of which, 948 (13.31%) had hypertension. After adjusting all covariates, we observed children and adolescents exposed to tobacco smoke was related to higher odds of hypertension (OR = 1.34, 95%CI: 1.01-1.78); children and adolescents not reached the dietary Mg references intakes was related to higher odds of hypertension (OR = 1.48, (95%CI: 1.11-1.97); compared to children and adolescents non-TSE and reached the DRIs of Mg, those not reached the DRIs of Mg and exposed to tobacco smoke have the highest odds of hypertension (OR = 1.94, 95%CI: 1.30-2.89, P for trend = 0.002). These associations of dietary Mg intake, TSE and hypertension remain robust after the stratified analysis based on age, gender and overweight was conducted., Conclusion: Our findings suggested there were a robust association between dietary Mg intake, TSE and hypertension in children and adolescents. Those children and adolescents with deficiency dietary Mg intake and exposed to tobacco smoke may have the high odds of hypertension. More restrictions on smoking as well as Mg supplementation in the prevention and treatment of hypertension among children and adolescents might be justified., (© 2024. The Author(s).)

The relationship between smoking and testosterone levels in adult males remains a topic of ongoing debate. Serum cotinine is considered a reliable marker of both smoking intensity and exposure to tobacco smoke. Therefore, we aim to examine the association between serum cotinine levels and total testosterone concentrations in adult males using data from the U.S. National Health and Nutrition Examination Survey (NHANES) database. Our study assessed the relationship between serum cotinine and total testosterone using weighted linear regression models and subgroup analysis. A fully adjusted model with smooth curve fitting was employed to investigate the potential nonlinear association between serum cotinine and total testosterone. Threshold effects were analyzed to identify the inflection point between serum cotinine and total testosterone. Indeed, a total of 7797 participants were included in our study. After adjusting for potential confounding variables, the findings indicate a positive association between serum cotinine levels and total testosterone levels (β: 0.05, 95%CI: 0.02, 0.09). Furthermore, applying smoothed curve fitting analysis and threshold effects, an inflection point was detected at a serum cotinine level of 487 ng/ml. Above this threshold, total testosterone levels declined with increasing serum cotinine levels. In conclusion, the findings of our study suggest a positive association between elevated serum cotinine levels and total testosterone levels in adult men. However, it is essential to note that this association may be reversed at excessively high serum cotinine concentrations., (© 2024. The Author(s).)

This study was to assess the individual effects of serum copper levels and environmental tobacco exposure and their joint effects on the risk of overweight and obesity among children and adolescents of 6 to 19 year olds. We analyzed cross-sectional data from 1849 children and adolescents participating in the National Health and Nutrition Examination Survey (NHANES) collected between 2011 and 2016. Environmental tobacco exposure was determined by cotinine levels. The serum copper level was divided into < median group and ≥ median groups according to the median of 109.81 µg/dL. The outcome was overweight/obese in children and adolescents. Weighted multinomial multivariate logistic regression models were used to assess the association of serum copper and cotinine levels, with the risk of overweight/obesity, and the joint effects on the risk of overweight and obesity among children and adolescents. The subgroup analyses based on age, gender, and household smoking status were conducted. Among 1849 children and adolescents, 332 children and adolescents had overweight BMI, and 450 children and adolescents had obese BMI. Higher serum copper levels were associated with the risk of obesity in children and adolescents (odds ratio (OR) 2.96, 95% confidence interval (CI) 1.39-6.31, P = 0.006). A positive association between increasing levels of cotinine levels and the risk of overweight (OR 1.83, 95% CI 1.16-2.87, P = 0.010) and obesity (OR 2.56, 95% CI 1.03-6.40, P = 0.044) in children and adolescents was observed. A remarkable association was found between higher serum copper in combination with higher cotinine levels and the risk of overweight (OR 3.23, 95% CI 1.19-8.83, P = 0.023) and obesity (OR 8.76, 95% CI 2.14-35.87, P = 0.003) in children and adolescents. The subgroup analyses revealed positive associations between high serum copper levels in combination with high cotinine levels and overweight and obesity in children and adolescents aged ≥ 12 years, of female sex, and without smoking family members. There may exist a joint effect of serum copper levels and environmental tobacco exposure on overweight/obesity among children and adolescents. These findings offer an insight that early weight control and reduction of tobacco exposure and the detection of serum copper levels may be important in reducing the risk of obesity in children., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: This study aimed to assess the role of the rs16969968 variant of nicotinic receptor alpha-5 subunit in regulating smoking behavior and nicotine intake in response to nicotine manipulations among dependent smokers in a naturalistic environment., Aims and Methods: Sixty-nine adults (19 females) smoking 10 or more cigarettes per day (CPD) were asked to complete four 2-week study phases during which they smoked exclusively one of two types of Spectrum nicotine research cigarettes (FTC nicotine yield 0.8 and 1.6 mg, respectively), their usual brand of cigarettes, or their usual brand of cigarettes while wearing a 21-mg nicotine patch. Measurements included rs16969968 genotype, number of CPD, smoking topography, and plasma cotinine., Results: Compared to controls (G/G carriers), A allele carriers reported smoking 4 to 5 more CPD across all conditions (all ps < .05). Mean total smoke volume per day and cotinine were greater in A allele carriers than in controls (ps = .05, .046, respectively). No significant genotype differences were found in smoking compensation indices for the switch from medium to high-nicotine-yield cigarettes. Nicotine patch-induced reductions in cigarettes smoked per day and total smoke volume per day showed significant interactions between genotype and pre-patch levels, with heavier smokers showing greater effects of genotype (p = .052 and p = .006, respectively)., Conclusions: Results suggest that the rs16969968 variants regulate the heaviness of smoking primarily by their impact on daily numbers of cigarettes smoked, but no genotype differences were found in smoking compensation after switching from medium to high-nicotine cigarettes., Implications: The differences in daily cigarette consumption between rs16969968 risk-allele carriers and controls are shown to be consistent regardless of manipulations of cigarette nicotine content and transdermal nicotine supplementation and markedly greater among dependent smokers than those observed in the general smoker populations. G/G allele carriers, relative to A allele carriers, appeared to be more sensitive to the nicotine patch manipulation, reducing their smoking to a greater extent. These findings support continued efforts in the development of personalized intervention strategies to reduce the rs16969968-conveyed genetic propensity for heavy smoking., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Sex and gender differences play a crucial role in health and disease outcomes. This study used data from the National Health and Nutrition Examination Survey to explore how environmental exposures affect health-related traits differently in males and females. We utilized a sex-stratified phenomic environment-wide association study (PheEWAS), which allowed the identification of associations across a wide range of phenotypes and environmental exposures. We examined associations between 272 environmental exposures, including smoking-related exposures such as cotinine levels and smoking habits, and 58 clinically relevant blood phenotypes, such as serum albumin and homocysteine levels. Our analysis identified 119 sex-specific associations. For example, smoking-related exposures had a stronger impact on increasing homocysteine, hemoglobin, and hematocrit levels in females while reducing serum albumin and bilirubin levels and increasing c-reactive protein levels more significantly in males. These findings suggest mechanisms by which smoking exposure may pose higher cardiovascular risks and greater induced hypoxia for women, and greater inflammatory and immune responses in men. The results highlight the importance of considering sex differences in biomedical research. Understanding these differences can help develop more personalized and effective health interventions and improve clinical outcomes for both men and women., (© 2024. The Author(s).)

The association between tobacco smoke exposure and sleep has been widely discussed, but the correlation between serum cotinine levels and sleep health outcomes in adolescents has not been well described. This study aimed to further evaluate the association between serum cotinine levels and sleep health outcomes in adolescents using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. This cross-sectional study included participants aged 16-19 years from the NHANES 2005-2018. A weighted multivariate logistic regression model was used for the primary analysis. A restricted cubic spline (RCS) model was employed to investigate the non-linear association between serum cotinine levels and trouble sleeping. Subgroup analyses based on population characteristics were also conducted. In total, 2630 participants were included, which are representative of the 11.5 million US adolescents. Higher serum cotinine levels (≥ 3 ng/ml) were significantly associated with trouble sleeping in the fully adjusted model (odds ratio [OR] 1.817). The RCS model revealed a non-linear relationship between serum cotinine levels and trouble sleeping. Subgroup analyses indicated that this relationship was consistent and stable across various population characteristics. Serum cotinine levels are associated with sleep health outcomes in adolescents, with high serum cotinine levels being linked to increased trouble sleeping and longer or shorter sleep duration., (© 2024. The Author(s).)

Background: Smoking is associated with an increased risk of HPV infection. However, the use of e-cigarettes and marijuana, number of cigarettes, and serum cotinine concentrations in relation with HPV (6, 11, 16, 18) and high-risk HPV (16 or 18) infections in underserved and understudied populations remain poorly understood., Methods: Data included 687 males and 664 females among whom 489 were White, 375 were Black and 342 were Hispanics from the NHANES 2013-2016 with HPV and high-risk HPV infections. Smoking history included current and past smokers, number of cigarettes, use of e-cigarettes, marijuana, and serum cotinine levels. Weighted multivariable-adjusted logistic regression models were conducted., Results: High-risk HPV infection was associated with current smoking history plus ≥ 20 cigarettes/day (OR=1.92, 95 % CI=1.09, 3.37) in the overall population. E-cigarettes use (5 days) was positively associated with high-risk HPV infection (OR=2.43, 95 % CI=1.13, 5.22) in the overall population, with similar findings with e-cigarette (past 30 days) among women and Whites., Conclusion: High number of cigarettes, e-cigarette usage and marijuana were associated with HPV and high-risk HPV infections in the overall population. Most of these associations remained significant when stratified by gender and race/ethnicity. Increasing use of e-cigarettes and marijuana in these population warrants further investigation for the prevention of HPV infection and related cancers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Environmental tobacco smoke (ETS) exposure has been shown to be associated with a variety of diseases, but evidence regarding the association between it and urinary incontinence (UI) is limited. Cotinine, a metabolite of nicotine in the human body, can more accurately quantify the level of human exposure to tobacco smoke. The study utilized data from seven survey cycles (2007-March 2020 Pre-pandemic) of the National Health and Nutrition Examination Survey (NHANES) program. Weighted multivariable logistic regression analysis, subgroup analysis, interaction tests, smooth curve fitting, and threshold effect models were used to analyze the relationship between serum cotinine and UI. Additionally, a 1:1 nearest neighbor propensity score matching (PSM) method was employed to minimize the impact of confounding factors. Before and after PSM, serum cotinine levels were higher in individuals with UI than those without (P < 0.05). Both before and after PSM, UI was positively correlated with serum cotinine levels, with a significantly increased risk of urinary incontinence when serum cotinine levels were in the Q3 range (before PSM: OR = 1.89, 95% CI = 1.59-2.24; after PSM: OR = 1.60, 95% CI = 1.28-2.00). Smooth curve fitting before and after PSM showed an approximate J-shaped non-linear dose-response relationship between log-transformed serum cotinine levels and UI. This study indicates that among American adults, there is a positive relationship between serum cotinine levels and UI, which is also significant in self-reported non-smoking populations. Therefore, reducing exposure to environmental tobacco smoke (e.g., avoiding second-hand smoke) in work and daily life may help alleviate the occurrence of UI, and serum cotinine levels have the potential to be a tool for predicting the degree of risk of developing UI., (© 2024. The Author(s).)

Introduction: Cigarette smoking remains the leading preventable cause of disease and death. Nicotine is the primary reinforcing ingredient in cigarettes sustaining addiction. Cotinine is the major metabolite of nicotine that produces a myriad of neurobehavioral effects. Previous studies showed that cotinine-supported self-administration in rats and rats with a history of cotinine self-administration exhibited relapse-like drug-seeking behavior, suggesting that cotinine may also be reinforcing. To date, whether cotinine may contribute to nicotine reinforcement remains unknown. Nicotine metabolism is mainly catalyzed by hepatic CYP2B1/2 enzymes in rats and methoxsalen is a potent CYP2B1/2 inhibitor., Aims and Methods: The study examined nicotine metabolism, self-administration, and locomotor activity. The hypothesis is that methoxsalen inhibits nicotine self-administration and cotinine replacement attenuates the inhibitory effects of methoxsalen in male rats., Results: Methoxsalen decreased plasma cotinine levels following a subcutaneous nicotine injection. Repeated daily methoxsalen treatments reduced the acquisition of nicotine self-administration, leading to fewer nicotine infusions, lower nicotine intake, and lower plasma cotinine levels. However, methoxsalen did not alter the maintenance of nicotine self-administration despite a significant reduction of plasma cotinine levels. Cotinine replacement by mixing cotinine with nicotine for self-administration dose-dependently increased plasma cotinine levels and enhanced the acquisition of self-administration. Neither basal nor nicotine-induced locomotor activity was altered by methoxsalen., Conclusions: These results indicate that methoxsalen inhibition of cotinine formation impaired the acquisition of nicotine self-administration, and cotinine replacement attenuated the inhibitory effects of methoxsalen on the acquisition of self-administration, suggesting that cotinine may contribute to the initial development of nicotine reinforcement., Implications: Smoking cessation medications targeting nicotine's effects are only moderately effective, making it imperative to better understand the mechanisms of nicotine misuse. Methoxsalen inhibited nicotine metabolism to cotinine and impaired the acquisition of nicotine self-administration. Cotinine replacement restored plasma cotinine and attenuated the methoxsalen inhibition of nicotine self-administration in rats. These results suggest that (1) the inhibition of nicotine metabolism may be a viable strategy in reducing the development of nicotine reinforcement, (2) methoxsalen may be translationally valuable, and (3) cotinine may be a potential pharmacological target for therapeutic development given its important role in the initial development of nicotine reinforcement., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Asthma is a common non-communicable disease in children, and airway inflammation is the main pathological change of asthma. Tobacco smoke exposure (TSE) can cause systematic inflammation and oxidative stress, which may further aggravate the progression of asthma. Dietary antioxidants can relieve the inflammation and oxidative stress in human body. This study aims to assess the effect of overall antioxidant capacity of dietary intake, evaluating by dietary antioxidant quality score (DAQS), in the association between TSE and childhood asthma., Methods: Data of this cross-sectional study were extracted from the National Health and Nutrition Examination Surveys (NHANES) 2007-2018. DAQS was calculated based on the daily dietary intake of selenium, zinc, magnesium, vitamin A, C and E. TSE was measured by serum cotinine concentration. The weighted univariate and multivariate logistic regression models were employed to evaluate the role of DAQS in the association between TSE and asthma among children and adolescents. Subgroup analysis was conducted to further evaluate the association based on gender., Results: Totally 11,026 children and adolescents were included, of whom 1,244 (11.28%) had asthma. After adjusted all covariates, TSE was associated with the high odds of childhood asthma (OR = 1.26, 95%CI = 1.05-1.52). Among children exposed to tobacco smoke, those with higher DAQS level (OR = 1.15, 95%CI: 0.88-1.50) had a reduced risk of asthma compared with those children with lower DAQS level (OR = 1.43, 1.08-1.89), especially among girls (OR = 1.42, 95%CI: 0.93-2.17)., Conclusion: High DAQS may have a moderating effect on asthma in children; that is, the higher DAQS, the lower the odds of asthma in children who exposed to tobacco smoke. Our study provides a reference for developing more targeted strategies for prevention and treatment of asthma in children., (© 2024. The Author(s).)

Purpose: Recently, the detrimental effect of cigarette smoking on muscle metabolism has attracted much attention, but the relationship between cigarette smoking and muscle mass is poorly understood. Thus, this study investigated the association between exposure to cigarette smoke, defined based on serum cotinine, and muscle mass in the US population., Methods: We utilized National Health and Nutrition Examination Survey (NHANES) data between 2011 and 2018 for analysis. Data on serum cotinine, muscle mass (quantified by appendicular skeletal muscle mass index, ASMI), and covariates were extracted and analyzed. Weighted multivariate linear regression analyses and smooth curve fittings were performed to investigate the association between serum cotinine and ASMI. Subgroup analyses were stratified by gender, race and smoking status. When nonlinearity was detected, the threshold effects were analyzed using a two-piecewise linear regression model., Results: In total, 8004 participants were included for analysis. The serum level of cotinine was negatively associated with ASMI in the fully adjusted model. Furthermore, comparing participants in the highest vs. the lowest tertile of serum cotinine, we found that ASMI decreased by 0.135 Kg/m 2 . In subgroup analysis stratified by gender and race, the association between serum cotinine and ASMI remained significant in all genders and races. In addition, the association remained significant among current and former smokers, but not among those who never smoked. Smooth curve fittings showed nonlinear relationships between serum cotinine and ASMI, with the inflection points identified at 356 ng/mL., Conclusions: Our study revealed that serum cotinine was negatively related to muscle mass. This finding improves our understanding of the deleterious effects of cigarette smoking on muscle mass and highlights the importance of smoking cessation for muscle health., (© 2024. The Author(s).)

Exposure to tobacco smoke (ETS) is one of the main risk factors for cardiovascular disease (CVD). Renalase is a protein that may play a role in the pathogenesis of CVD. The aim of the study was to assess the relationship between ETS and serum renalase concentration. A group of 109 patients was recruited for this study (49.7 ± 14.7 years). In accordance with the questionnaire, patients were divided into the following subgroups: subgroup A- declaring themselves active smokers (n = 36), subgroup B- declaring themselves non-smokers and exposed to environmental tobacco smoke (n = 35), subgroup C- declaring themselves non-smokers and not exposed to environmental tobacco smoke (n = 38). The same patients were divided based on cotinine concentration into the following subgroups: subgroup D- active smokers (n = 42), subgroup E- non-smokers exposed to environmental tobacco smoke (n = 66), and subgroup F- non-smokers not exposed to environmental tobacco smoke (n = 1). Serum cotinine concentration and serum renalase concentration were measured using ELISA tests. Serum renalase concentration was statistically significantly higher in subgroup C than in subgroups A and B and in subgroup E and F than in D. There was a negative correlation between serum cotinine concentration and serum renalase concentration (r = -0.41, p < 0.05). Regression analysis showed that higher BMI, higher diastolic blood pressure, coronary artery disease and higher serum cotinine concentration are independent risk factors of lower serum renalase concentration. The questionnaire method of assessing exposure to tobacco smoke was characterized by high sensitivity, but only moderate specificity, especially in terms of assessing environmental exposure to tobacco smoke. In summary, the study showed an independent relationship between exposure to tobacco smoke and lower serum renalase concentration., (© 2024. The Author(s).)

Tobacco smoke exposure has been demonstrated to impede bone remodeling and diminish bone density, yet research regarding its correlation with parathyroid hormone (PTH) remains limited. This study aims to investigate the relationship between tobacco smoke exposure and serum PTH levels in adults aged 20 years and older. This study included 7,641 participants from two cycles of the National Health and Nutrition Examination Survey (NHANES, United States, 2003- 2006). Reflect tobacco smoke exposure through serum cotinine levels, and use an adjusted weighted multivariate linear regression model to test the independent linear relationship between serum cotinine and PTH. Stratified analysis was conducted to validate the sensitivity of the conclusions. Smooth curve fitting and threshold effect analysis were performed to assess the non-linear relationship. After comprehensive adjustment using weighted multivariate regression analysis, a negative correlation was found between serum cotinine and PTH levels. The interaction p-values in subgroup analyses were all greater than 0.05. Moreover, smooth curve fitting indicated a non-linear relationship between serum cotinine and PTH, with a turning point observed. Our research indicates that tobacco smoke exposure is negatively correlated and independent of serum parathyroid hormone levels, indicating that long-term tobacco smoke exposure may lead to parathyroid dysfunction in adults., (© 2024. The Author(s).)

Understanding the combined effects of risk factors on all-cause mortality is crucial for implementing effective risk stratification and designing targeted interventions, but such combined effects are understudied. We aim to use survival-tree based machine learning models as more flexible nonparametric techniques to examine the combined effects of multiple physiological risk factors on mortality. More specifically, we (1) study the combined effects between multiple physiological factors and all-cause mortality, (2) identify the five most influential factors and visualize their combined influence on all-cause mortality, and (3) compare the mortality cut-offs with the current clinical thresholds. Data from the 1999-2014 NHANES Survey were linked to National Death Index data with follow-up through 2015 for 17,790 adults. We observed that the five most influential factors affecting mortality are the tobacco smoking biomarker cotinine, glomerular filtration rate (GFR), plasma glucose, sex, and white blood cell count. Specifically, high mortality risk is associated with being male, active smoking, low GFR, elevated plasma glucose levels, and high white blood cell count. The identified mortality-based cutoffs for these factors are mostly consistent with relevant studies and current clinical thresholds. This approach enabled us to identify important cutoffs and provide enhanced risk prediction as an important basis to inform clinical practice and develop new strategies for precision medicine., (© 2024. The Author(s).)

Importance: With the prevalence of e-cigarette use (vaping) increasing worldwide, there are concerns about children's exposure to secondhand vapor., Objective: To compare nicotine absorption among children who are (1) exposed to secondhand tobacco smoke only or (2) exposed to secondhand vapor only with (3) those exposed to neither., Design, Setting, and Participants: The US Continuous National Health and Nutrition Examination Survey (NHANES) is a repeat cross-sectional survey. Participants are interviewed in their homes and, several days after, visit a mobile examination center to provide biological specimens. This study uses data from a nationally representative sample of US households from 2017 to 2020. Participants were children aged 3 to 11 years with serum cotinine levels incompatible with current firsthand nicotine use (ie, <15 μg/L). The final analysis was conducted on January 9, 2024., Exposures: Reported exposure to secondhand smoke or vapor indoors in the past 7 days (only secondhand smoke, only secondhand vapor, or neither). Covariates included age, sex, ethnicity, family income, body weight, and height., Main Outcomes and Measures: The primary outcome was serum cotinine concentration, an objective biomarker of nicotine absorption. Geometric mean cotinine levels and 95% CIs were calculated using log-normal tobit regression, accounting for the complex survey design and weights., Results: The mean (SD) age of the 1777 children surveyed was 7.4 (2.6) years, 882 (49.6%) were female, and 531 (29.9%) had family incomes below the poverty level. Nicotine absorption, as indexed by serum cotinine level, was highest among children only exposed to secondhand smoke (0.494 μg/L μg/L; 95% CI, 0.386-0.633 μg/L), followed by those exposed only to secondhand vapor (0.081 μg/L; 95% CI, 0.048-0.137 μg/L), equating to 83.6% (95% CI, 71.5%-90.5%; P < .001) lower nicotine absorption. Among children with no reported secondhand exposure, the geometric mean cotinine level was 0.016 μg/L (95% CI, 0.013-0.021 μg/L), or 96.7% (95% CI, 95.6%-97.6%; P < .001) lower than for those with exposure to secondhand smoke. Results were similar after covariate adjustment., Conclusions and Relevance: In this cross-sectional study of US children, nicotine absorption was much lower in children who were exposed to secondhand vapor vs secondhand smoke, but higher than in those exposed to neither. These findings suggest that switching from smoking to vaping indoors may substantially reduce, but not eliminate, children's secondhand exposure to nicotine and other noxious substances.

Transdermal nicotine patches (TNPs), administering nicotine into the bloodstream through skin, have been widely used as nicotine replacement therapy, and exposure to nicotine can be detected by measurement of plasma cotinine concentration. In animal studies, nicotine treatment could increase the number of endothelial progenitor cells (EPCs), but the effect of TNPs on circulating EPCs and their activity in humans remained unclear. This study aimed to explore the influence of TNPs on circulating EPCs with surface markers of CD34, CD133, and/or KDR, and colony-forming function plus migration activity of early EPCs derived from cultured peripheral blood mononuclear cells before and after TNP treatments in young healthy nonsmokers. In parallel, pulse wave analysis (PWA) was applied to evaluate the vascular effect of TNP treatments. Twenty-one participants (25.8 ± 3.6 years old, 10 males) used TNP (nicotine: 4.2 mg/day) for 7 consecutive days. During the treatment, the CD34 + EPCs progressively increased in number. In addition, the number of EPCs positive for CD34/KDR, CD133, and CD34/CD133 were also increased on day 7 of the treatment. Furthermore, the early EPC colony-forming function and migration activity were increased with the plasma cotinine level positively correlating with change in colony-forming unit number. PWA analyses on day 7, compared with pretreatment, did not show significant change except diastolic pressure time index, which was prolonged and implied potential vascular benefit. In conclusion, 7-day TNP treatments could be a practical strategy to enhance angiogenesis of circulating EPCs to alleviate tissue ischemia without any hemodynamic concern., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background and Aim: The impact of environmental chemical exposure on blood pressure (BP) is well-established. However, the relationship between secondhand smoke exposure (SHSE) and mortality in hypertensive patients in the general population remains unclear., Methods and Results: This cohort study included US adults in the National Health and Nutrition Examination Survey from 2007 to 2018. All-cause mortality and cause-specific mortality outcomes were determined by associating them with the National Death Index records. Cox proportional risk models were used to estimate hazard ratios (HRs) for all-cause mortality and cardiovascular disease (CVD) mortality, and 95% confidence intervals (CIs) for SHSE. The cohort included 10,760 adult participants. The mean serum cotinine level was 0.024 ng/mL. During a mean follow-up period of 76.9 months, there were 1729 deaths, including 469 cardiovascular disease deaths recorded. After adjusting for lifestyle factors, BMI, hypertension duration, medication use, and chronic disease presence, the highest SHSE was significantly associated with higher all-cause and CVD mortality., Conclusions: This study demonstrates that higher SHSE is significantly associated with higher all-cause mortality and CVD mortality. Further research is necessary to elucidate the underlying mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Introduction: Smoking is a public health threat because of its well-described link to increased oxidative stress-related diseases including peripheral vascular disease and coronary artery disease. Tobacco use has been linked to risk of inpatient trauma morbidity including acute respiratory distress syndrome; however, its mechanistic effect on comprehensive metabolic heterogeneity has yet to be examined., Methods: Plasma was obtained on arrival from injured patients at a Level 1 trauma center and analyzed with modern mass spectrometry-based metabolomics. Patients were stratified by nonsmoker, passive smoker, and active smoker by lower, interquartile, and upper quartile ranges of cotinine intensity peaks. Patients were substratified by high injury/high shock (Injury Severity Score, ≥15; base excess, <-6) and compared with healthy controls. p Value of <0.05 following false discovery rate correction of t test was considered significant., Results: Forty-eight patients with high injury/high shock (7 nonsmokers [15%], 25 passive smokers [52%], and 16 active smokers [33%]) and 95 healthy patients who served as controls (30 nonsmokers [32%], 43 passive smokers [45%], and 22 active smokers [23%]) were included. Elevated metabolites in our controls who were active smokers include enrichment in chronic inflammatory and oxidative processes. Elevated metabolites in active smokers in high injury/high shock include enrichment in the malate-aspartate shuttle, tyrosine metabolism, carnitine synthesis, and oxidation of very long-chain fatty acids., Conclusion: Smoking promotes a state of oxidative stress leading to mitochondrial dysfunction, which is additive to the inflammatory milieu of trauma. Smoking is associated with impaired mitochondrial substrate utilization of long-chain fatty acids, aspartate, and tyrosine, all of which accentuate oxidative stress following injury. This altered expression represents an ideal target for therapies to reduce oxidative damage toward the goal of personalized treatment of trauma patients., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Dose-response and nonlinear relationships of cigarette exposure with sleep disturbances and depression are warranted, and the potential mechanism of sex hormones in such associations remains unclear., Methods: Cigarette exposure, trouble sleeping, and depression were assessed by standard questionnaires, and the levels of cotinine and sex steroid hormones were determined among 9900 adults from the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression, logistic regression, and mediation models were conducted to evaluate the associations between smoking, sex steroid hormones, trouble sleeping, and depression., Results: With never smokers as a reference, current smokers had a higher prevalence of trouble sleeping (OR = 1.931, 95% CI: 1.680, 2.219) and depression (OR = 2.525, 95% CI: 1.936, 3.293) as well as testosterone level (β = 0.083, 95% CI: 0.028, 0.140). Pack-years of smoking and cigarettes per day were positively associated with the prevalence of trouble sleeping and depression as well as testosterone level (P trend <0.05). The restricted cubic spline model showed linear relationships of cotinine with trouble sleeping, depression, and testosterone. The positive associations of cigarettes per day with trouble sleeping and depression were greater in females than that in males (P modification <0.05). However, the potential role of sex hormones was not observed in the association of cotinine with trouble sleeping or depression (P mediation >0.05)., Conclusion: Smoking may induce sex hormone disturbance and increase the risk of sleep problems and depression symptoms, and ceasing smoking may reduce the risk of such complications., (© 2024. The Author(s).)

In this study, we developed a method for determining cotinine and 3-hydroxycotinine in human serum and established a methodology for an in-depth study of tobacco exposure and health. After the proteins in the human serum samples were precipitated with acetonitrile, they were separated on a ZORBAX SB-Phenyl column with a mobile phase of methanol encompassing 0.3% formic acid-water encompassing 0.15% formic acid. The measurement was performed on an API5500 triple quadrupole mass spectrometer in the multiple reaction monitoring mode. Cotinine, 3-hydroxycotinine, and cotinine-d3 isotope internal standards were held for 2.56 minutes, 1.58 minutes, and 2.56 minutes, respectively. In serum, the linear range was 0.05 to 500 ng·mL-1 for cotinine and 0.50 to 1250 ng·mL-1 for 3-hydroxycotinine. The lower limit of quantification (LLOQ) was 0.05 ng·mL-1 and 0.5 ng·mL-1 for cotinine and 3-hydroxycotinine, respectively. The intra-day and inter-day relative standard deviations were <11%, and the relative errors were within ± 7%. Moreover, the mean extraction recoveries of cotinine and 3-hydroxycotinine were 98.54% and 100.24%, respectively. This method is suitable for the rapid determination of cotinine and 3-hydroxycotinine in human serum because of its rapidity, sensitivity, strong specificity, and high reproducibility. The detection of cotinine levels in human serum allows for the identification of the cutoff value, providing a basis for differentiation between smoking and nonsmoking populations., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Smoking is an environmental factor that differentially impacts Crohn's disease (CD) and ulcerative colitis (UC). The mechanism of impact of smoking on disease risk and clinical outcomes remains to be established., Methods: This study used a prospective cohort of patients with CD or UC. Self-reported smoking status was validated using serum cotinine measurement. We profiled methylation changes in peripheral blood using the Illumina Methylation BeadChip. Transcriptomic profiling was performed on ileal and colonic tissue using an Illumina TruSeq platform. We compared the methylation and transcriptional changes in current, former, and never smokers stratified by disease type., Results: Our cohort included 200 patients with CD or UC with methylation profiles and 160 with transcriptomic data. The mean serum cotinine level was higher in current compared with former or never smokers. Epigenetic changes common to both CD and UC included hypomethylation at AHRR. Smoking-associated MGAT3 hypomethylation was associated with severe disease course only in UC, while IER3 hypomethylation was associated with worse course only in CD. Smoking downregulated several inflammatory pathways in UC. Current smoking in CD but not in UC was associated with upregulation of several genes mediating Paneth cell function. Genes with opposite direction of effects in CD and UC include HSD3B2 and GSTA1., Conclusions: Our findings suggest both common and differential effects of cigarette smoking on CD and UC. Paneth cell dysfunction may mediate adverse impact of smoking on CD. Bile acid and oxidative stress pathways may be relevant for the differential effect of smoking on CD and UC., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Environmental tobacco smoke exposure (ETSE) was race/ethnicity-specific, but how the race/ethnicity-specific ETSE has changed over time, diverging or converging, remains unclear. We examined ETSE trends by race/ethnicity in US children aged 3-11 years., Methods: We analyzed the data of 9678 children who participated in the biennial National Health and Nutrition Examination Surveys, 1999-2018. ETSE was defined as serum cotinine ≥ 0.05 ng/ml, with ≥ 1 ng/ml as heavy exposure. For trend description, adjusted biennial prevalence ratios (abiPR: the ratio associated with a 2-year increase in time) were estimated by race/ethnicity. The prevalence ratios between races/ethnicities were used to quantify ethnoracial differences in different survey periods. Analyses were performed in 2021., Results: The overall ETSE prevalence was cut by almost half, from 61.59% (95% confidence interval = 56.55%, 66.62%) in the 1999-2004 survey to 37.61% (33.90%, 41.31%) in 2013-2018, exceeding the national 2020 health target (47.0%). However, the decrease occurred unequally between races/ethnicities. Heavy ETSE declined significantly in white [abiPR = 0.80 (0.74, 0.86)] and Hispanic children [0.83 (0.74, 0.93)], but insignificantly in black children [0.97 (0.92, 1.03)]. Consequently, the adjusted prevalence ratio between black children and white children increased from 0.82 (0.47, 1.44) in 1999-2004 to 2.73 (1.51, 4.92) in 2013-2018 for heavy ETSE. Hispanic children remained at the lowest risk throughout the study period., Conclusion: Overall ETSE prevalence was cut by half between 1999 and 2018. However, due to uneven declines, the gaps between black children and others have expanded in heavy ETSE. Special vigilance is needed in preventive medicine practice with black children., (© 2023. W. Montague Cobb-NMA Health Institute.)

Introduction: Smoking is a cause of nonalcoholic fatty liver disease (NAFLD), but the dose-response relationship between secondhand smoke exposure (SHS) and NAFLD is unclear. This study sought to determine the relationship between SHS and NAFLD risk among adult nonsmokers in the United States., Aims and Methods: Data from 7412 adult nonsmokers aged ≥20 years who participated in the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016 were used in this study. SHS was defined as a nonsmoker with a serum cotinine concentration of 0.05-10.00 ng/mL. NAFLD was identified using the U.S. fatty liver index (USFLI), hepatic steatosis index (HSI), and fatty liver index (FLI). Weighted multivariable logistic regression and restricted cubic spline models were applied to evaluate the relationship between SHS and NAFLD risk., Results: The participants had a weighted mean age of 49.2 years, and 55.5% were female. SHS was associated with NAFLD (odds ratio [OR] 1.22; 95% confidence interval CI: 1.05 to 1.42), showing a linear dose-response relationship (natural log of cotinine level: OR 1.10, 95% CI: 1.05 to 1.17). Sensitivity analyses using different NAFLD definitions (HSI: OR 1.21, 95% CI: 1.01 to 1.46; FLI: OR 1.26, 95% CI: 1.06 to 1.49), excluding participants taking hepatotoxic drugs, and propensity score-adjusted analysis yielded similar results. The association between SHS and NAFLD was consistent in analyses stratified by age, sex, and race/ethnicity., Conclusions: Among this nationally representative sample of U.S. adults, SHS had a linear dose-response relationship with the risk of NAFLD, suggesting that measures to lower SHS might lower NAFLD risk., Implications: This study assessed the association between secondhand smoke exposure and the risk of nonalcoholic fatty liver disease (NAFLD) using data from 7412 adult nonsmokers aged 20 years or older who participated in the United States NHANES between 2007 and 2016. Secondhand smoke exposure was measured using serum cotinine levels. Three different noninvasive indexes were used to measure NAFLD. Secondhand smoke exposure was associated with an increased risk of NAFLD, with a linear dose-response relationship. The results of sensitivity analyses and subgroup analyses were consistent., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: There has been a resurgence in nicotine inhalation in adolescents due to the popularity and availability of Electronic Nicotine Delivery Systems (ENDS). Almost five times as many US high-school seniors inhale nicotine vapor daily compared with those who smoke tobacco. This study was conducted to determine the impact of repeated adolescent vapor inhalation of nicotine on behavior in adulthood., Methods: Male and female Sprague-Dawley rats were exposed to 30-minute sessions of ENDS vapor inhalation, twice daily, from post-natal day (PND) 31-40. Conditions included vapor from the propylene glycol (PG) vehicle or nicotine (30 mg/mL in the PG). Animals were assessed for effects of nicotine on open field (PND 74-105) and wheel activity (PND 126-180) and for volitional exposure to nicotine vapor (PND 285-395). Plasma nicotine and cotinine were assessed in separate groups of male and female Wistar and Sprague-Dawley rats after a single nicotine inhalation session., Results: Group mean plasma nicotine ranged from 39 to 59 ng/mL post-session with minimal strain differences detected. Adolescent nicotine exposure enhanced sensitivity to the locomotor stimulating effects of nicotine (0.1-0.8 mg/kg, s.c.) in an open field in female rats, but didn't change the effects of nicotine on wheel activity. Female rats exposed to nicotine (30 mg/mL) vapor as adolescents responded more vigorously than PG-exposed females to nicotine vapor in a fixed ratio 5 challenge., Conclusions: Repeated adolescent nicotine vapor inhalation leads to enhanced liability for volitional exposure to nicotine vapor in adulthood in female rats, but minimal change in spontaneous locomotor behavior., Implications: These results show that adolescent vaping of nicotine can lead to lasting sensitization to the effects of nicotine in adulthood, including volitional responding for nicotine vapor. Demonstration of this in a controlled animal model establishes causality in a manner not possible from longitudinal evidence in human populations. These findings further highlight the importance of decreasing adolescent nicotine exposure to e-cigarettes to reduce consumption in adulthood., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Nicotine and tobacco use remain high both globally and in the United States, contributing to large health care expenditures. With a rise in e-cigarette use, it is important to have clinically relevant models of inhaled nicotine exposure., Aims and Methods: This study aims to extend prior preclinical nicotine inhalation animal data to females and provide both behavior and serum pharmacokinetics. We tested two inhalation doses of nicotine (24 mg/mL and 59 mg/ mL) and compared these to injected doses (0.4 mg/kg and 1 mg/kg). In addition, we assessed locomotor behavior after the same doses. Blood was collected at 10- and 120-minutes post-administration. We assessed nicotine and cotinine serum concentrations by LC-MS/MS., Results: Showed that while nicotine serum concentrations for the respective high and low-dose administrations were similar between both routes of administration, the route had differential effects on locomotor behavior. Inhaled nicotine showed a dose-dependent decrease in locomotor activity while injected doses showed the opposite trend., Conclusions: Our results indicate that the route of administration is an important factor when establishing preclinical models of nicotine exposures. Given that the overall use of e-cigarettes in vulnerable populations is on the rise, our study provides important behavioral and pharmacokinetic information to advance our currently limited understanding of the effects of nicotine vapor exposure., Implications: This study highlights behavioral differences between different routes of administration of similar doses of nicotine. Using a low and high dose of nicotine, we found that nicotine serum concentrations were similar between the different routes of administration. Our results indicate that different routes of administration have opposing effects on locomotor activity. These findings provide important implications for future behavioral models., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Tobacco exposure is known to be associated with a higher prevalence and incidence of liver diseases. Cotinine, a metabolite of nicotine, is a typical indicator of tobacco exposure. However, the relationship of serum cotinine levels with hepatic steatosis and liver fibrosis remains controversial and these relationships need more research to explored in American teenagers. Cross-sectional data included 1433 participants aged 12-19 from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020 were thoroughly used for this study. The linear relationships between serum cotinine levels and the Liver Stiffness Measurement (LSM) and Controlled Attenuation Parameter (CAP) were examined using multiple linear regression models. Subgroup analysis, interaction tests, and nonlinear interactions were also carried out. Serum cotinine levels > 2.99 ng/ml [β = 0.41 (0.07, 0.76), p = 0.018] and 0.05-2.99 ng/ml [β = 0.24 (0.00, 0.49), p = 0.048] showed a significant positive connection with LSM in multivariate linear regression analysis when compared to serum cotinine levels ≤ 0.05 ng/ml (p for trend = 0.006). Moreover, we discovered an inverted U-shaped association of log2-transformed cotinine with LSM with an inflection point of 4.53 using a two-stage linear regression model. However, according to multiple regression analysis, serum cotinine and CAP did not significantly correlate (p = 0.512). In conclusion, this study demonstrated that smoking cessation and keep away from secondhand smoking may beneficial for liver health in American teenagers., (© 2024. The Author(s).)

Objective: To estimate the association between secondhand smoke (SHS) exposure and serum sex hormone concentrations in female adults (never smokers and former smokers)., Design: Cross-sectional analysis., Setting: US National Health and Nutrition Examination Survey, 2013-2016., Outcome Measures: Serum sex hormone measures included total testosterone (TT) and oestradiol (E2), sex hormone-binding globulin (SHBG), the ratio of TT and E2 and free androgen index (FAI). Isotope dilution-liquid chromatography tandem mass spectrometry was used to measure serum TT and E2. SHBG was measured using immunoassay. The ratio of TT and E2 and FAI were calculated. SHS exposure was defined as serum cotinine concentration of 0.05-10 ng/mL., Participants: A total of 622 female participants aged ≥20 years were included in the analysis., Results: For never smokers, a doubling of serum cotinine concentration was associated with a 2.85% (95% CI 0.29% to 5.47%) increase in TT concentration and a 6.29% (95% CI 0.68% to 12.23%) increase in E2 in fully adjusted models. The never smokers in the highest quartile (Q4) of serum cotinine level exhibited a 10.30% (95% CI 0.78% to 20.72%) increase in TT concentration and a 27.75% (95% CI 5.17% to 55.17%) increase in E2 compared with those in the lowest quartile (Q1). For former smokers, SHBG was reduced by 4.36% (95% CI -8.47% to -0.07%, p for trend=0.049) when the serum cotinine level was doubled, and the SHBG of those in Q4 was reduced by 17.58% (95% CI -31.33% to -1.07%, p for trend=0.018) compared with those in Q1., Conclusion: SHS was associated with serum sex hormone concentrations among female adults. In never smokers, SHS was associated with increased levels of TT and E2. In former smokers, SHS was associated with decreased SHBG levels., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While smoking is widely acknowledged as a risk factor for rheumatoid arthritis (RA), the connection between secondhand smoke (SHS) exposure and RA in never-smoking adults remains limited and inconsistent. This study aims to explore and quantify this association using serum cotinine levels. We conducted a cross-sectional study with 14,940 adults who self-report as never smokers, using National Health and Nutrition Examination Survey data from 1999 to 2018. Based on previous literature, SHS exposure was categorized into four groups according to serum cotinine levels. Compared to individuals in the unexposed group (serum cotinine < 0.05 ng/mL), the adjusted odds ratio (OR) for RA was 1.37 (95% CI 1.14-1.64, p = 0.001) in the low exposure group (serum cotinine at 0.05 to 0.99 ng/mL) after adjusting for covariates. However, no significant association was found in the moderate exposure group (serum cotinine at 1 to 10 ng/mL) or the heavy exposure group (serum cotinine ≥ 10 ng/mL). Furthermore, we detected a non-linear, positively saturated correlation between the cotinine levels after log2 transformation and RA, with a turning point at approximately - 2.756 ng/mL (OR = 1.163, 95% CI 1.073-1.261, p = 0.0002). The stability of the results was confirmed by subgroup analysis., (© 2024. The Author(s).)

Background: Manganese (Mn) plays a significant role in both human health and global industries. Epidemiological studies of exposed populations demonstrate a dose-dependent association between Mn and neuromotor effects ranging from subclinical effects to a clinically defined syndrome. However, little is known about the relationship between early life Mn biomarkers and adolescent postural balance., Objectives: This study investigated the associations between childhood and adolescent Mn biomarkers and adolescent postural balance in participants from the longitudinal Marietta Communities Actively Researching Exposures Study (CARES) cohort., Methods: Participants were recruited into CARES when they were 7-9 y old, and reenrolled at 13-18 years of age. At both time points, participants provided samples of blood, hair, and toenails that were analyzed for blood Mn and lead (Pb), serum cotinine, hair Mn, and toenail Mn. In adolescence, participants completed a postural balance assessment. Greater sway indicates postural instability (harmful effect), whereas lesser sway indicates postural stability (beneficial effect). Multivariable linear regression models were conducted to investigate the associations between childhood and adolescent Mn biomarkers and adolescent postural balance adjusted for age, sex, height-weight ratio, parent/caregiver intelligence quotient, socioeconomic status, blood Pb, and serum cotinine., Results: CARES participants who completed the adolescent postural balance assessment ( n = 123 ) were 98% White and 54% female and had a mean age of 16 y (range: 13-18 y). In both childhood and adolescence, higher Mn biomarker concentrations were significantly associated with greater adolescent sway measures. Supplemental analyses revealed sex-specific associations; higher childhood Mn biomarker concentrations were significantly associated with greater sway in females compared with males., Discussion: This study found childhood and adolescent Mn biomarkers were associated with subclinical neuromotor effects in adolescence. This study demonstrates postural balance as a sensitive measure to assess the association between Mn biomarkers and neuromotor function. https://doi.org/10.1289/EHP13381.

This study assessed changes in biomarkers of exposure (BoE) after 5 days of completely or partially switching to an electronic nicotine delivery system (ENDS) use, compared with continued use of combustible cigarettes and smoking abstinence among Chinese adult smokers. A randomized, open-label, parallel-arm study was conducted among Chinese adult smokers who were naive ENDS users. Forty-six subjects were randomized to 4 study groups (n = 11-12 per group): exclusive ENDS use, dual use of ENDS and cigarettes, exclusive cigarettes use, and smoking abstinence. Subjects were confined in clinic for 5 consecutive days and product use was ad libitum. Nicotine and its metabolites (cotinine and 3-hydroxycotinine), and BoEs (AAMA, CEMA, HEMA, HMPMA, 3-HPMA, SPMA, exhaled CO, and exhaled NO) were measured. Withdrawal symptom was measured using MNWS throughout the 5-day period. Six urine BoEs of volatile organic compounds decreased by 55.1-84.1% in the exclusive ENDS use group, which is similar to the smoking abstinence group (67.2-87.4%). The level of decrease was 56.8-70.4% in the dual use group and 10.7-39.0% in the cigarettes group. Urine total nicotine exposure had a non-significant increase in the exclusive ENDS use group, and plasma nicotine and cotinine showed a trend of increasing day by day. After completely or partially switching to ENDS use among Chinese smokers, exposure to selected toxicants were significantly decreased. The results of this study add to the body of evidence that exposure to toxic substance decreased among smokers after complete or partial switch from combustible cigarettes to ENDS use. As part of transition to experienced ENDS use, this study found that smokers of the initial stage who have no prior ENDS experience may increase nicotine intake after switching to ENDS use., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Objective: We aimed to (1) compare serum cotinine with self-report for ascertaining smoking status among reproductive-aged women; (2) estimate the relative odds of adverse cardiovascular (CV) outcomes among women by smoking status; (3) assess whether the association between adverse pregnancy outcomes (APOs) and CV outcomes varies by smoking status., Study Design: We conducted a cross-sectional study of the nuMoM2b Heart Health Study. Women attended a study visit 2 to 7 years after their first pregnancy. The exposure was smoking status, determined by self-report and by serum cotinine. Outcomes included incident chronic hypertension (HTN), metabolic syndrome (MetS), and dyslipidemia. Multivariable logistic regression estimated odds ratios (ORs) for each outcome by smoking status., Results: Of 4,392 women with serum cotinine measured, 3,610 were categorized as nonsmokers, 62 as secondhand smoke exposure, and 720 as smokers. Of 3,144 women who denied tobacco smoke exposure, serum cotinine was consistent with secondhand smoke exposure in 48 (1.5%) and current smoking in 131 (4.2%) After adjustment for APOs, smoking defined by serum cotinine was associated with MetS (adjusted OR [aOR] = 1.52, 95% confidence interval [CI]: 1.21, 1.91) and dyslipidemia (aOR = 1.28, 95% CI: 1.01, 1.62). When stratified by nicotine exposure, nonsmokers with an APO in their index pregnancy had higher odds of stage 1 (aOR = 1.64, 95% CI: 1.32, 2.03) and stage 2 HTN (aOR = 2.92, 95% CI: 2.17, 3.93), MetS (aOR = 1.76, 95% CI: 1.42, 2.18), and dyslipidemia (aOR = 1.55, 95% CI: 1.25, 1.91) relative to women with no APO. Results were similar when smoking exposure was defined by self-report., Conclusion: Whether determined by serum cotinine or self-report, smoking is associated with subsequent CV outcomes in reproductive-aged women. APOs are also independently associated with CV outcomes in women., Key Points: · Cotinine was detected in 5.7% of reported nonsmokers.. · Smoking and APOs were independently associated with CV health.. · Smoking was associated with MetS and dyslipidemia.., Competing Interests: H.N.S. reports grants from National Institutes of Health during the conduct of the study.B.M. reports grants from National Institutes of Health during the conduct of the study.M.K.H. reports grants from National Institute of Child Health and Human Development during the conduct of the study.C.B.P. reports grants from National Institutes of Health/National Heart, Lung, and Blood Institute during the conduct of the study.S.H. reports grants from National Heart, Lung, and Blood Institute, grants from Eunice Kennedy Shriver National Institute of Child Health and Human Development during the conduct of the study.R.B.M. reports grants from National Institutes of Health/National Heart, Lung, and Blood Institute during the conduct of the study.L.H.T. reports grants from American Association of Obstetricians and Gynecologists Foundation Scholar Award, from null, outside the submitted work., (Thieme. All rights reserved.)

Introduction: We assessed tobacco smoke exposure (TSE) levels based on private and public locations of TSE according to race and ethnicity among US school-aged children ages 6-11 years and adolescents ages 12-17 years., Aims and Methods: Data were from 5296 children and adolescents who participated in the National Health and Nutrition Examination Survey (NHANES) 2013-2018. Racial and ethnic groups were non-Hispanic white, black, other or multiracial, and Hispanic. NHANES assessed serum cotinine and the following TSE locations: homes and whether smokers did not smoke indoors (home thirdhand smoke [THS] exposure proxy) or smoked indoors (secondhand [SHS] and THS exposure proxy), cars, in other homes, restaurants, or any other indoor area. We used stratified weighted linear regression models by racial and ethnic groups and assessed the variance in cotinine levels explained by each location within each age group., Results: Among 6-11-year-olds, exposure to home THS only and home SHS + THS predicted higher log-cotinine among all racial and ethnic groups. Non-Hispanic white children exposed to car TSE had higher log-cotinine (β = 1.64, 95% confidence interval [CI] = 0.91% to 2.37%) compared to those unexposed. Non-Hispanic other/multiracial children exposed to restaurant TSE had higher log-cotinine (β = 1.13, 95% CI = 0.23% to 2.03%) compared to those unexposed. Among 12-17-year-olds, home SHS + THS exposure predicted higher log-cotinine among all racial and ethnic groups, except for non-Hispanic black adolescents. Car TSE predicted higher log-cotinine among all racial and ethnic groups. Non-Hispanic black adolescents with TSE in another indoor area had higher log-cotinine (β = 2.84, 95% CI = 0.85% to 4.83%) compared to those unexposed., Conclusions: TSE location was uniquely associated with cotinine levels by race and ethnicity. Smoke-free home and car legislation are needed to reduce TSE among children and adolescents of all racial and ethnic backgrounds., Implications: Racial and ethnic disparities in TSE trends have remained stable among US children and adolescents over time. This study's results indicate that TSE locations differentially contribute to biochemically measured TSE within racial and ethnic groups. Home TSE significantly contributed to cotinine levels among school-aged children 6-11 years old, and car TSE significantly contributed to cotinine levels among adolescents 12-17 years old. Racial and ethnic differences in locations of TSE were observed among each age group. Study findings provide unique insight into TSE sources, and indicate that home and car smoke-free legislation have great potential to reduce TSE among youth of all racial and ethnic backgrounds., (Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2022.)

Objectives. To test the efficacy of Babies Living Safe and Smokefree (BLiSS), a multilevel intervention initiated in a citywide safety net health system to improve low-income maternal smokers' abstinence and reduce child tobacco smoke exposure. Methods. This randomized controlled trial in Philadelphia, Pennsylvania (2015-2020), recruited low-income maternal smokers who received a brief smoking intervention (Ask, Advise, Refer [AAR]) from nutrition professionals in the Special Supplemental Nutrition Program for Women, Infants, and Children before randomization to (1) a multilevel intervention (AAR + multimodal behavioral intervention [MBI]; n = 199) or (2) an attention control intervention (AAR + control; n = 197). Results. AAR + MBI mothers had significantly higher 12-month bioverified abstinence rates than did AAR + control mothers (odds ratio [OR] = 9.55; 95% confidence interval [CI] = 1.54, 59.30; P  = .015). There were significant effects of time (b = -0.15; SE = 0.04; P  < .001) and condition by time (b = -0.19; SE = 0.06; P  < .001) on reported child exposure favoring AAR + MBI, but no group difference in child cotinine. Presence of other residential smokers was related to higher exposure. Higher baseline nicotine dependence was related to higher child exposure and lower abstinence likelihood at follow-up. Conclusions. The multilevel BLiSS intervention was acceptable and efficacious in a population that experiences elevated challenges with cessation. Public Health Implications. BLiSS is a translatable intervention model that can successfully improve efforts to address the persistent tobacco-related burdens in low-income communities. Trial Registration. Clinical Trials.gov identifier: NCT02602288. ( Am J Public Health . 2022;112(3):472-481. https://doi.org/10.2105/AJPH.2021.306601).

The routine techniques currently applied for the determination of nicotine and its major metabolites, cotinine, and trans -3'-hydroxycotinine, in biological fluids, include spectrophotometric, immunoassays, and chromatographic techniques. The aim of this study was to develop, and compare two new chromatographic methods high-performance liquid chromatography coupled to triple quadrupole mass spectrometry (HPLC-QQQ-MS/MS), and RP-HPLC enriched with chaotropic additives, which would allow reliable confirmation of tobacco smoke exposure in toxicological and epidemiological studies. The concentrations of analytes were determined in human plasma as the sample matrix. The methods were compared in terms of the linearity, accuracy, repeatability, detection and quantification limits (LOD and LOQ), and recovery. The obtained validation parameters met the ICH requirements for both proposed procedures. However, the limits of detection (LOD) were much better for HPLC-QQQ-MS/MS (0.07 ng mL -1 for trans -3'-hydroxcotinine; 0.02 ng mL -1 for cotinine; 0.04 ng mL -1 for nicotine) in comparison to the RP-HPLC-DAD enriched with chaotropic additives (1.47 ng mL -1 for trans -3'-hydroxcotinine; 1.59 ng mL -1 for cotinine; 1.50 ng mL -1 for nicotine). The extraction efficiency (%) was concentration-dependent and ranged between 96.66% and 99.39% for RP-HPLC-DAD and 76.8% to 96.4% for HPLC-QQQ-MS/MS. The usefulness of the elaborated analytical methods was checked on the example of the analysis of a blood sample taken from a tobacco smoker. The nicotine, cotinine, and trans -3'-hydroxycotinine contents in the smoker's plasma quantified by the RP-HPLC-DAD method differed from the values measured by the HPLC-QQQ-MS/MS. However, the relative errors of measurements were smaller than 10% (6.80%, 6.72%, 2.04% respectively).

Nicotine is a highly addictive substance and harmful to the developing foetus. However, few studies have investigated the transporter mechanism responsible for regulating the transfer of nicotine across the blood-placental interface. A multiple in-vivo microdialysis system coupled to ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was developed to monitor simultaneously nicotine and cotinine in the blood, placenta, foetus, and amniotic fluid of pregnant rats. The pharmacological mechanism of nicotine transfer across the placenta was investigated by co-administering corticosterone, an inhibitor of organic cation transporters (OCTs) that partly mediate the exchange of nicotine across the placenta. The results revealed that intravenously administered nicotine (1 mg/kg) was rapidly metabolised to cotinine with a transformation ratio (AUC cotinine /AUC nicotine ) of 0.67 ± 0.08, 0.21 ± 0.05, 0.25 ± 0.12, 0.31 ± 0.05 in maternal blood, placenta, amniotic fluid, and foetus, respectively. The tissue transformation ratios (AUC tissue /AUC blood ) were 0.83 ± 0.16, 0.65 ± 0.17, 0.57 ± 0.13 for nicotine, and 0.25 ± 0.06, 0.24 ± 0.12, 0.26 ± 0.04 for cotinine at placenta, amniotic fluid and foetus, respectively. Following the co-administration of corticosterone (2 mg/kg), the tissue transformation ratio of nicotine was significantly reduced in the placenta but was significantly increased in the foetus. Levels of cotinine were not significantly altered by the administration of corticosterone. These findings implicate OCT in mediating the transfer of nicotine across the blood-placenta barrier. Understanding the mechanism of nicotine transfer through the placenta may inform therapeutic strategies to lessen the exposure of the developing foetus to nicotine in the maternal bloodstream., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Smoking increases systemic inflammation and circulating endothelin-1 (ET-1), both of which contribute to an elevated risk of cardiovascular disease (CVD). The present study sought to test the hypothesis that a 12-week smoking cessation intervention would contribute to a long-term reduction in circulating ET-1, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). 30 individuals participated in a 12-week evidence-based smoking cessation program at Augusta University. Serum cotinine, plasma inflammatory cytokines, and plasma ET-1 were determined at baseline, immediately after the 12-week cessation program (end of treatment, EOT), and 12-months (12M) following the cessation program. Serum cotinine was significantly reduced (p < 0.001) at EOT and 12M following the smoking cessation program. Compared to BL (7.0 ± 1.6 pg/mL), TNF-α was significantly reduced at EOT (6.3 ± 1.5 pg/mL, p = 0.001) and 12M (5.2 ± 2.7 pg/mL, p < 0.001). ET-1 was significantly lower at EOT (1.9 ± 0.6 pg/mL, p = 0.013) and at 12M (2.0 ± 0.8 pg/mL, p = 0.091) following smoking cessation compared with BL (2.3 ± 0.6 pg/mL). BL concentrations of cotinine were significantly associated with basal ET-1 (r = 0.449, p = 0.013) and the change in cotinine at 12M following smoking cessation was significantly associated with the change in plasma ET-1 at 12M (r = 0.457, p = 0.011). Findings from the present pilot investigation demonstrate that a 12-week smoking cessation program reduces circulating concentrations of ET-1 and TNF-α for at least a year. The reduction in serum cotinine was associated with the decrease in circulating ET-1. The attenuation in ET-1 and inflammation may in part, contribute to the lower risk of CVD that is observed with smoking cessation., (© 2021. The Author(s).)

Background: Fractional exhaled nitric oxide (FeNO) can objectively guide clinical practice in the assessment, diagnosis, and treatment of eosinophilic airway inflammation. FeNO values may be affected by current smoking, but the role of tobacco smoke exposure (TSE) is understudied., Objective: This study investigated the associations between biochemically validated and self-reported TSE and FeNO levels among U.S. nonsmoking adolescents without asthma., Methods: National Health and Nutrition Examination Survey 2007-2012 data were used. TSE was assessed via serum cotinine and self-reported measures. We assessed FeNO continuously and using cutpoints of >35 ppb and >50 ppb to indicate likely eosinophilic inflammation in children and adults, respectively. We conducted linear and logistic regression adjusting for potential covariates., Results: Overall, 34.0% of adolescents had low cotinine (0.05-2.99 ng/ml), 6.2% had high cotinine (≥3.00 ng/ml), and 11.9% had home TSE. Compared to adolescents with no/minimal cotinine, adolescents with high cotinine were at reduced odds to have FeNO >35 ppb (adjusted odds ratio [aOR] = 0.54, 95%CI = 0.43,0.69). Adolescents with low cotinine had lower FeNO values (β = -2.05, 95%CI = -3.61,-0.49), and were also at decreased odds to have FeNO >35 ppb (aOR = 0.74, 95%CI = 0.66,0.83) and FeNO >50 ppb (aOR = 0.62, 95%CI = 0.53,0.72). Adolescents with home TSE were at reduced odds to have FeNO >50 ppb (aOR = 0.72, 95%CI = 0.57,0.91) than adolescents without home TSE. Adolescents with a higher number of cigarettes/day smoked inside their home were at reduced odds to have FeNO >35 ppb (OR = 0.98, 95%CI = 0.97,0.99) and FeNO >50 ppb (OR = 0.98, 95%CI = 0.96,0.99)., Conclusions: TSE was associated with decreased FeNO levels. The addition of TSE may be clinically important when interpreting thresholds for FeNO., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Understanding implications of passive smoke exposure during pregnancy is an important public health issue under the Developmental Origins of Health and Disease paradigm. In a prospective cohort of low-risk non-smoking pregnant women (NICHD Fetal Growth Studies-Singletons, 2009-2013, N = 2055), the association between first trimester passive smoke exposure and neonatal size was assessed by race/ethnicity. Plasma biomarker concentrations (cotinine, nicotine) assessed passive smoke exposure. Neonatal anthropometric measures included weight, 8 non-skeletal, and 2 skeletal measures. Linear regression evaluated associations between continuous biomarker concentrations and neonatal anthropometric measures by race/ethnicity. Cotinine concentrations were low and the percent above limit of quantification varied by maternal race/ethnicity (10% Whites; 14% Asians; 15% Hispanics; 49% Blacks). The association between cotinine concentration and infant weight differed by race/ethnicity (Pinteraction = 0.034); compared to women of the same race/ethnicity, per 1 log-unit increase in cotinine, weight increased 48g (95%CI -44, 139) in White and 51g (95%CI -81, 183) in Hispanic women, but decreased -90g (95%CI -490, 309) in Asian and -93g (95%CI -151, -35) in Black women. Consistent racial/ethnic differences and patterns were found for associations between biomarker concentrations and multiple non-skeletal measures for White and Black women (Pinteraction<0.1). Among Black women, an inverse association between cotinine concentration and head circumference was observed (-0.20g; 95%CI -0.38, -0.02). Associations between plasma cotinine concentration and neonatal size differed by maternal race/ethnicity, with increasing concentrations associated with decreasing infant size among Black women, who had the greatest biomarker concentrations. Public health campaigns should advocate for reducing pregnancy exposure, particularly for vulnerable populations., Competing Interests: NG and DH are employed by a commercial company: The Prospective Group. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have declared that no additional competing interests exist.

E-cigarettes, which deliver vaporized nicotine, have dramatically risen in popularity in recent years, despite many unanswered questions about safety, efficacy in reducing dependence, and overall impact on public health. Other factors, such as sex, also play an important role in determining behavioral and neurochemical responses to drugs of abuse. In these studies, we sought to develop a protocol for vaporized e-cigarette nicotine self-administration in rats, as a foundation to better understand the differing effects of nicotine exposure routes on behavior and physiological function. We report a novel method that elicits robust nicotine vapor self-administration in male and female rats. Our findings indicate that 5-mg/ml nicotine vape solution provides a high level of consistency in lever-pressing behavior for both males and females. Moreover, in male rats, we find that such e-cigarette nicotine vapor induces similar blood levels of nicotine's main metabolite, cotinine, as that found with intravenous nicotine self-administration. Therefore, the breathing pattern during vapor exposure in males leads to similar levels of titrated nicotine intake as with intravenous nicotine self-administration. Interestingly, a differential effect was found in the females, in which the same conditions of vapor exposure led to decreased cotinine levels with vapor compared to intravenous self-administration. Finally, differences in nicotine-mediated locomotion provide further support of the physiological effects of e-cigarette vapor inhalation. Taken together, our findings reveal important sex differences in nicotine intake based on the route of exposure, and we further establish a protocol for nicotine vapor self-administration in rats., (© 2021 Society for the Study of Addiction.)

Introduction: Women who smoke during pregnancy have a reduced risk of preeclampsia. The mechanism of this association is poorly understood. Preeclampsia is an anti-angiogenic and inflammatory state. Transforming growth factor beta 1 (TGF-β1) is a multi-functional anti-inflammatory cytokine that activates membrane bound endoglin on endothelial cells causing a myriad of vascular actions including vasorelaxation. The objective of the study was to determine serum levels of cytokines, angiogenic factors, placental growth factor (PlGF), TGF-β-1 and anti-angiogenic factors, soluble endoglin (sEng) and soluble vascular endothelial growth factor 1 (sVEGFR1) in smoking and non-smoking pregnant women., Methods: Using enzyme-linked immunosorbent and multiplex assays we prospectively analyzed serum levels of PIGF, TGF-β1, sEng, sVEGFR1 and cytokines in normotensive pregnant smokers and non-smokers. Exclusion criteria included maternal hypertension, autoimmune disorders, rupture of membranes, evidence of labor and drug use., Results: There were 59 women in the smoking and 66 in the non-smoking group. Compared to non-smoking mothers. maternal age was lower in smoking mothers with no significant difference in other demographic variables. There was no difference in levels of cytokines, anti-angiogenic factors and PlGF between the two groups. Median TGF-β1 levels were significantly higher in the smoking group (8120 pg/mL vs 6040 pg/mL, p < 0.001) and remained significant after controlling for confounders. TGF-β1 levels correlated positively with cotinine levels in the smoking group., Conclusions: We speculate that higher TGF-β1 levels may explain the reduced incidence of preeclampsia in mothers who smoke by being available for action on maternal endothelium even after inactivation by circulating maternal sEng., (Copyright © 2021 Elsevier B.V. All rights reserved.)

New nicotine delivery products are gaining market share. For evaluation of their characteristics, toxicokinetic investigations are in current research focus. For reliable determination of blood plasma levels of nicotine and its main metabolites cotinine and trans-3'-hydroxycotinine, a quantitation method based on LC-ESI-MS/MS was developed and validated. Addition of isotope labeled internal standards prior to rapid sample preparation using protein precipitation with methanol was chosen for sample preparation. Different stationary phases were tested and phenyl-hexyl separation was found to be superior to HILIC, C18, and C8 stationary phases. Ion suppression effects caused by hydrophilic early eluting matrix were eliminated by the adjustment of an adequate retention utilizing a phenyl-hexyl separation stationary phase. Exchange of acetonitrile as organic mobile phase by methanol and elevation of pH value of aqueous mobile phase containing 5 mM NH 4 Ac to 4.50 improved the chromatographic resolution. The limits of quantitation for nicotine, cotinine, and hydroxycotinine were 0.15, 0.30, and 0.40 ng/mL, respectively. Linearity was proven by matrix matched calibration for the whole working range from 0.50 ng/mL to 35.0 ng/mL for nicotine and from 6.00 to 420 ng/mL for cotinine and hydroxycotinine (Mandel's fitting test with R 2  > 0.995). Quality control samples at four different levels (0.50, 1.50, 17.5, 28.0 ng/mL for nicotine and 6.00, 18.0, 210, 336 ng/mL for cotinine and hydroxycotinine) in plasma were analyzed six times on three days. Mean accuracies ranged from 87.7% to 105.8% for nicotine, from 90.3% to 102.9% for cotinine, and from 99.9% to 109.9% for hydroxycotinine. Intra- and inter-day precisions (RSD %) were below 15% for all analytes (<20% for LLOQ). As proof of concept, the method was successfully applied to a real plasma sample from a cigarette smoking volunteer., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)