Rapid, efficient and activation-neutral gene editing of polyclonal primary human resting CD4+ T cells allows complex functional analyses.

CD4+ T cells are central mediators of adaptive and innate immune responses and constitute a major reservoir for human immunodeficiency virus (HIV) in vivo. Detailed investigations of resting human CD4+ T cells have been precluded by the absence of efficient approaches for genetic manipulation limiting our understanding of HIV replication and restricting efforts to find a cure. Here we report a method for rapid, efficient, activation-neutral gene editing of resting, polyclonal human CD4+ T cells using optimized cell cultivation and nucleofection conditions of Cas9-guide RNA ribonucleoprotein complexes. Up to six genes, including HIV dependency and restriction factors, were knocked out individually or simultaneously and functionally characterized. Moreover, we demonstrate the knock in of double-stranded DNA donor templates into different endogenous loci, enabling the study of the physiological interplay of cellular and viral components at single-cell resolution. Together, this technique allows improved molecular and functional characterizations of HIV biology and general immune functions in resting CD4+ T cells.

Isoproterenol improves hemodynamics and right ventricle-pulmonary artery coupling after heart transplantation.

Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol (Iso) has chronotropic, inotropic, and vasodilatory properties, which might improve right ventricle function in this setting. We aimed to investigate the hemodynamic effects of isoproterenol on patients with post-HT RVF. We conducted a 1-yr retrospective observational study including patients receiving isoproterenol (Iso) and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively three times: no isoproterenol, low doses: 0.025 µg/kg/min, and high doses: 0.05 µg/kg/min (henceforth, respectively, called no Iso, low Iso, and high Iso). From June 2022 to June 2023, 25 patients, median [interquartile range (IQR) 25-75] age 54 [38-61] yr, were included. Before isoproterenol was introduced, all patients received dobutamine, and 15 (60%) were on venoarterial extracorporeal membrane oxygenation (VA-ECMO). Isoproterenol significantly increased heart rate from 84 [77-99] (no Iso) to 91 [88-106] (low Iso) and 102 [90-122] beats/min (high Iso, P < 0.001). Similarly, cardiac index rose from 2.3 [1.4-3.1] to 2.7 [1.8-3.4] and 3 [1.9-3.7] L/min/m2 (P < 0.001) with a concomitant increase in indexed stroke volume (28 [17-34] to 31 [20-34] and 33 [23-35] mL/m2, P < 0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance (PVR) tended to decrease from 2.9 [1.4-3.6] to 2.3 [1.3-3.5] wood units (WU), P = 0.06. Right ventricular ejection fraction/systolic pulmonary artery pressure (sPAP) evaluating right ventricle-pulmonary artery (RV-PA) coupling increased after isoproterenol from 0.8 to 0.9 and 1%·mmHg-1 (P = 0.001). In conclusion, in post-HT RVF, isoproterenol exhibits chronotropic and inotropic effects, thereby improving RV-PA coupling and resulting in a clinically relevant increase in the cardiac index.NEW & NOTEWORTHY This study offers a detailed and comprehensive hemodynamic investigation at the bedside, illustrating the favorable impact of isoproterenol on right ventricular-pulmonary arterial coupling and global hemodynamics. It elucidates the physiological effects of an underused inotropic strategy in a critical clinical scenario. By enhancing cardiac hemodynamics, isoproterenol has the potential to expedite right ventricular recovery and mitigate primary graft dysfunction, thereby reducing the duration of mechanical support and intensive care unit stay posttransplantation.

Association between cigar use, with and without cigarettes, and incident diagnosed COPD: a longitudinal cohort study.

BACKGROUND: While regular cigar smoking is believed to carry similar health risks as regular cigarette smoking, the impact of cigar use, alone or in combination with cigarettes, on obstructive pulmonary disease (COPD) has not been well characterized. The purpose of this study was to examine the prospective association between exclusive and dual cigar and cigarette use and incident self-reported diagnosed COPD. METHODS: This study used data from Waves 1-5 (2013-2019) of the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative survey of U.S. adults. Longitudinal data from adults aged 40 to 79 at Wave 1, without a pre-existing COPD diagnosis who participated at follow-up interview were analyzed. A time-varying current tobacco exposure, lagged by one wave and categorized as: (a) never/non-current use; (b) exclusive cigar use; (c) exclusive cigarette use; and (d) dual cigar/cigarette use. Multivariable models adjusted for demographics (age, sex, race or ethnicity, education), clinical risk factors (asthma, obesity), and smoking-related confounders (second-hand smoke exposure, other combustible tobacco product use, e-cigarette use, time since quitting, cigarette pack-years). The incidence of self-reported diagnosed COPD was estimated using discrete-time survival models, using a general linear modeling (GLM) approach with a binomial distribution and a complementary log-log link function. RESULTS: The analytic sample consisted of 9,556 adults with a mean (SD) age of 56 (10.4), who were predominately female (52.8%) and Non-Hispanic White (70.8%). A total of 906 respondents reported a diagnosis of COPD at follow-up. In the fully adjusted model, exclusive cigar use (adjusted hazard ratio (aHR) = 1.57, 95% CI: 0.77, 3.21) was not associated with increased COPD risk compared to non-use, while exclusive cigarette use (aHR = 1.48, 95% CI: 1.13, 1.93) and dual cigar/cigarette use (aHR = 1.88, 95% CI: 1.24, 2.85) were. CONCLUSIONS: Exclusive cigarette use and dual cigar/cigarette use were associated with diagnosed incident COPD. These results suggest that cigars, when used in combination with cigarettes, may be associated with poorer COPD health outcomes. Dual use may promote a higher likelihood of inhaling cigar smoke, and future research would benefit from examining whether inhalation of cigar smoke increases COPD risk.

The prevalence and mortality risks of PRISm and COPD in the United States from NHANES 2007-2012.

BACKGROUND: We estimated the prevalence and mortality risks of preserved ratio impaired spirometry (PRISm) and chronic obstructive pulmonary disease (COPD) in the US adult population. METHODS: We linked three waves of pre-bronchodilator spirometry data from the US National Health and Nutritional Examination Survey (2007-2012) with the National Death Index. The analytic sample included adults ages 20 to 79 without missing data on age, sex, height, BMI, race/ethnicity, and smoking status. We defined COPD (GOLD 1, 2, and 3-4) and PRISm using FEV1/FVC cut points by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). We compared the prevalence of GOLD stages and PRISm by covariates across the three waves. We estimated adjusted all-cause and cause-specific mortality risks by COPD stage and PRISm using all three waves combined. RESULTS: Prevalence of COPD and PRISm from 2007-2012 ranged from 13.1%-14.3% and 9.6%-10.2%, respectively. We found significant differences in prevalence by sex, age, smoking status, and race/ethnicity. Males had higher rates of COPD regardless of stage, while females had higher rates of PRISm. COPD prevalence increased with age, but not PRISm, which was highest among middle-aged individuals. Compared to current and never smokers, former smokers showed lower rates of PRISm but higher rates of GOLD 1. COPD prevalence was highest among non-Hispanic White individuals, and PRISm was notably higher among non-Hispanic Black individuals (range 31.4%-37.4%). We found associations between PRISm and all-cause mortality (hazard ratio [HR]: 2.3 95% CI: 1.9-2.9) and various cause-specific deaths (HR ranges: 2.0-5.3). We also found associations between GOLD 2 (HR: 2.1, 95% CI: 1.7-2.6) or higher (HR: 4.2, 95% CI: 2.7-6.5) and all-cause mortality. Cause-specific mortality risk varied within COPD stages but typically increased with higher GOLD stage. CONCLUSIONS: The prevalence of COPD and PRISm remained stable from 2007-2012. Greater attention should be paid to the potential impacts of PRISm due to its higher prevalence in minority groups and its associations with mortality across various causes including cancer.

Birth-cohort patterns of e-cigarette and other tobacco use among adolescents in the US.

BACKGROUND: E-cigarette use has increased considerably among US adolescents. While many studies have described cross-sectional prevalence trends of youth e-cigarette use, less is known about cohort or generational initiation and use patterns. METHODS: We used data from the US National Youth Tobacco Survey (NYTS) from 2014 to 2022 and age-period-cohort models to analyze age-specific patterns of e-cigarette use initiation and prevalence by cohort and calendar. For comparison, we also examined initiation and prevalence for cigarettes, cigars, and smokeless tobacco, using NYTS data from 1999 to 2022. RESULTS: Age-specific e-cigarette initiation and prevalence varied considerably by calendar year and birth cohort. There was a rapid increase in e-cigarette initiation and prevalence starting with the 1995 birth cohort, peaking with the 2005 birth cohort, and showing signs of decline with more recent cohorts. In contrast, there were substantial continuous reductions in cigarette, cigar, and smokeless use initiation and prevalence by birth cohort. While the reductions in cigarette smoking started with the 1980s birth cohorts, cigar and smokeless initiation and prevalence did not decrease until the 1990-1995 cohorts. CONCLUSIONS: Despite their recent emergence, e-cigarette use has varied considerably across US adolescent cohorts. After early increases, e-cigarette use and initiation peaked with the 2005 birth cohort. These patterns are in contrast with the continuous decreases by cohort in cigarette, cigar, and smokeless use and initiation. As the tobacco product landscape continues to evolve, it will be essential to monitor patterns of use of adolescent and young adult cohorts as they age into adulthood.

Cross-state Border Nicotine Vaping Products Purchase - Early Evidence from State Emergency Sales Restrictions in 2019.

INTRODUCTION: While retail sales and retailer inspection studies generally indicate high compliance with state sales restrictions on Nicotine Vaping Products (NVPs) within the restricted area, studies using survey data generally indicate that most users could readily continue gaining access to restricted NVPs. Our study bridges a gap in the current literature and investigates the potential role of cross-state border purchases to evade state emergency NVP sales restrictions in 2019. METHODS: The study sample was restricted to NVP sales from the states neighboring Massachusetts (MA), Rhode Island (RI), and Washington (WA), three states that implemented all NVP or flavored NVP sales restrictions in 2019. Among these neighboring states, the 2019 weekly county-level NVP sales by flavors (tobacco, mint/menthol, and other flavors) were compiled using Nielsen Scanner data. A quasi-experimental, comparison group pre-post study design was used to study the impacts of NVP sales restrictions on cross-state border NVP purchases. RESULTS: Weekly NVP sales for border counties significantly increased in response to the MA, RI, and WA bans for tobacco flavored (56%, 45%, 14%, respectively), menthol/mint flavored (51%, 2%, 41%, respectively), and other flavored (79%, 3%, 4%, respectively) products, compared to sales for non-border counties (all p-values <0.01). CONCLUSIONS: Our study identified significant cross-state border NVP purchases in all studied states to circumvent NVP emergency sales restrictions in response to the EVALI outbreak. Policymakers should factor in these purchasing behaviors to evade sales restrictions when evaluating any future potential policies at the state or local levels. IMPLICATIONS: While retail sales data and retailer inspections indicate high compliance with Nicotine Vaping Product (NVP) flavor sales restrictions from major retail outlets, survey data obtain mixed findings on the effects of sales restrictions on vaping behaviors. Our study identified a significant increase in cross-state border NVP purchases to circumvent NVP sales restrictions in 2019, consistent across all three settings of Massachusetts, Rhode Island, and Washington. Policymakers should factor in these cross-state border NVP purchases in response to sales restrictions when evaluating any future potential NVP sales restrictions.

The Potential Impact of Oral Nicotine Pouches on Public Health: A Scoping Review.

INTRODUCTION: Oral nicotine pouches (ONPs) are a new class of nicotine products. This scoping review summarizes evidence on ONPs and explores their potential public health impact. AIMS AND METHODS: We conducted a structured literature search for empirical studies across three electronic databases through January 10, 2024. Outcomes included ONP product characteristics, use patterns, beliefs and perceptions, toxicity, and marketing and sales. RESULTS: Sixty-two studies were included, 17 were industry-funded. Most studies were from the United States. While large variations across studies were observed in ONP youth prevalence estimates, nationally representative U.S. studies find current use at 1.5% and lifetime use below 2.5% through 2023. Between 35% and 42% of U.S. adolescents and young adults have heard of ONPs, and 9-21% of tobacco-naïve youth were susceptible to trying them. U.S. adult-use estimates varied widely (0.8%-3% current; 3%-16% lifetime use) and were limited to populations with a history of tobacco use. The chemical composition of ONPs suggests fewer harmful/potentially harmful compounds at lower levels than cigarettes and smokeless tobacco (SLT), except formaldehyde. Industry-funded studies find substantially less cytotoxicity compared to cigarettes and suggest that higher nicotine-strength ONPs can deliver nicotine at levels comparable to or higher than SLT or cigarettes, although with slower nicotine release than cigarettes. Evidence on the cytotoxicity of ONPs relative to SLT is mixed. CONCLUSIONS: ONPs appear to be less toxic than cigarettes and deliver comparable nicotine, presenting an alternative for combustible product users, although key data are mainly available from industry-funded studies. Data from independent research is critically needed. Industry marketing of ONPs may encourage initiation in youth and situational and dual use in adults. IMPLICATIONS: The review provides an initial assessment of the potential role of ONPs in harm reduction and aims to determine unintended consequences of their use (youth uptake and dual-use) and identify populations that disproportionately use the product. This information is essential for tobacco regulatory bodies in determining the net public health impact of nicotine pouches.

The Public Health Impact of a Ban on Flavored Cigars: A Decision-Theoretic Policy Framework.

INTRODUCTION: Half of adult cigar users report flavored cigars as their usual brand. The FDA proposed prohibiting "all characterizing flavors in cigars" and "menthol… in cigarettes." We provide evidence on cigar and cigarette transitions and a framework to assess the impact of a U.S. flavored cigar ban. METHODS: Using PATH Waves 1-4, we estimated use patterns and annual transitions among flavored cigars, non-flavored cigars, cigarettes, and among adults aged 18-34 and aged 35+. We also consider ENDS-related transitions. We developed a decision-theoretic framework for examining the impact of a flavored cigar ban alone, and the impact of a flavored cigar with a menthol cigarette ban with and without a non-tobacco flavored ENDS ban. RESULTS: Cigar users exhibited less stable use than cigarette users, with a large portion of cigar users switching to cigarette use each year. Past studies provide limited information on transitions between cigar and ENDS use. Our policy framework suggests that imposing a flavored cigar ban alone may be partially undermined by the substitution of menthol cigarettes for flavored cigars. While adding a menthol cigarette to a flavored cigar ban is expected to improve public health, a simultaneously implemented ENDS may offset some of the gains. DISCUSSION: Our analysis suggests the information necessary to gauge the public health impact of a cigar flavor ban alone and with flavor bans on cigarettes and ENDS. Further research is needed on ENDS vis-a'-vis cigar use, and the impact of enforcement and non-flavor-related policies on flavor ban effectiveness. IMPLICATIONS: Unlike menthol cigarette use and menthol bans, flavored cigar use and flavored cigar bans have received minimal attention. Transitions from cigars, especially dual and flavored use, are generally common compared to cigarettes. Our policy framework suggests important public health impacts. A flavored cigar ban absent a menthol cigarette ban may be partially undermined by the substitution of menthol cigarettes for flavored cigars. Adding a menthol cigarette ban is expected to offset such substitution and improve public health. However, simultaneously adding an ENDS with a flavored cigar and menthol cigarette ban may reduce the public health impact of a menthol cigarette and cigar flavor ban since flavored cigar users would be less able to substitute a lower-risk alternative.

Evaluating trends in cigarette and HTP use in Japan and measurement issues in the National Health and Nutrition Survey.

INTRODUTION: Studies have reported that the rapid rise in heated tobacco product (HTP) sales in Japan accompanied an accelerated decline in cigarette sales. However, these studies do not distinguish whether those who previously smoked cigarettes became dual users with HTPs (smoking fewer cigarettes) or instead switched completely to HTPs. If HTPs present lower health risks than cigarettes, replacing cigarettes with HTPs is more likely to improve public health than cigarette users continuing as dual users. METHODS: To evaluate the role of HTP introduction relative to smoking prevalence, we examine trends in cigarette prevalence as related to trends in HTP use using Japan's National Health and Nutrition Survey (NHNS) from 2011 to 2019. We develop measures of relative changes in smoking prevalence use by age and gender in the pre-HTP and post-HTP periods. We then analyse prevalence data by year using joinpoint regression to statistically distinguish changes in trend. RESULTS: Compared with the pre-HTP 2011-2014 period, cigarette prevalence decreased more rapidly during the post-HTP 2014-2017 period, particularly among younger age groups. However, the changing format of NHNS questions limits our ability to determine the impact on smoking prevalence, particularly after 2017. CONCLUSIONS: While suggesting that HTPs helped some people who smoke to quit smoking, this study also shows the difficulties in eliciting accurate survey responses about product use and distinguishing the impact of a potentially harm-reducing product in an environment subject to rapidly evolving patterns of use.

IL-6 enhances CD4 cell motility by sustaining mitochondrial Ca2+ through the noncanonical STAT3 pathway.

Interleukin 6 (IL-6) is known to regulate the CD4 T cell function by inducing gene expression of a number of cytokines through activation of Stat3 transcription factor. Here, we reveal that IL-6 strengthens the mechanics of CD4 T cells. The presence of IL-6 during activation of mouse and human CD4 T cells enhances their motility (random walk and exploratory spread), resulting in an increase in travel distance and higher velocity. This is an intrinsic effect of IL-6 on CD4 T-cell fitness that involves an increase in mitochondrial Ca2+ Although Stat3 transcriptional activity is dispensable for this process, IL-6 uses mitochondrial Stat3 to enhance mitochondrial Ca2+-mediated motility of CD4 T cells. Thus, through a noncanonical pathway, IL-6 can improve competitive fitness of CD4 T cells by facilitating cell motility. These results could lead to alternative therapeutic strategies for inflammatory diseases in which IL-6 plays a pathogenic role.

Leveraging Data Locality in Quantum Convolutional Classifiers.

Quantum computing (QC) has opened the door to advancements in machine learning (ML) tasks that are currently implemented in the classical domain. Convolutional neural networks (CNNs) are classical ML architectures that exploit data locality and possess a simpler structure than a fully connected multi-layer perceptrons (MLPs) without compromising the accuracy of classification. However, the concept of preserving data locality is usually overlooked in the existing quantum counterparts of CNNs, particularly for extracting multifeatures in multidimensional data. In this paper, we present an multidimensional quantum convolutional classifier (MQCC) that performs multidimensional and multifeature quantum convolution with average and Euclidean pooling, thus adapting the CNN structure to a variational quantum algorithm (VQA). The experimental work was conducted using multidimensional data to validate the correctness and demonstrate the scalability of the proposed method utilizing both noisy and noise-free quantum simulations. We evaluated the MQCC model with reference to reported work on state-of-the-art quantum simulators from IBM Quantum and Xanadu using a variety of standard ML datasets. The experimental results show the favorable characteristics of our proposed techniques compared with existing work with respect to a number of quantitative metrics, such as the number of training parameters, cross-entropy loss, classification accuracy, circuit depth, and quantum gate count.

Longitudinal associations between exclusive, dual, and polytobacco use and asthma among US youth.

Little is known about the respiratory health effects of dual (two products) and polytobacco (three or more products) use among youth in the United States. Thus, we followed a longitudinal cohort of youth into adulthood using data from Waves 1-5 (2013-2019) of the Population Assessment of Tobacco and Health Study, examining incident asthma at each follow-up (Waves 2-5). We classified past 30-day tobacco use as 1) no products (never/former use), 2) exclusive cigarettes, 3) exclusive electronic nicotine delivery systems (ENDS), 4) exclusive other combustible (OC) tobacco products (cigars, hookah, pipe), 5) dual cigarettes/OC and ENDS, 6) dual cigarettes and OCs, and 7) polytobacco use (cigarettes, OCs, and ENDS). Using discrete time survival models, we analyzed the incidence of asthma across Waves 2-5, predicted by time-varying tobacco use lagged by one wave, and adjusted for potential baseline confounders. Asthma was reported by 574 of the 9141 respondents, with an average annual incidence of 1.44% (range 0.35% to 2.02%, Waves 2-5). In adjusted models, exclusive cigarette use (HR: 1.71, 95% CI: 1.11-2.64) and dual cigarette and OC use (HR: 2.78, 95% CI: 1.65-4.70) were associated with incident asthma compared to never/former use, while exclusive ENDS use (HR: 1.50, 95% CI: 0.92-2.44) and polytobacco use (HR: 1.95, 95% CI: 0.86-4.44) were not. To conclude, youth who use cigarettes with or without OCs had higher risk of incident asthma. Further longitudinal studies on the respiratory health effects of ENDS and dual/polytobacco use are needed as products continue to evolve.

Associations Between E-cigarette Use and E-cigarette Flavors With Cigarette Smoking Quit Attempts and Quit Success: Evidence From a U.S. Large, Nationally Representative 2018-2019 Survey.

INTRODUCTION: Although many studies have examined the association between e-cigarette use and smoking cessation, fewer have considered the impact of e-cigarette flavors on cessation outcomes. This study extends previous studies by examining the effects of e-cigarette use and e-cigarette flavors on quit attempts and quit success of smoking. AIMS AND METHODS: We used data from the 2018-2019 Tobacco Use Supplement-Current Population Survey (TUS-CPS) survey. Multivariate logistic regression analyses were used to investigate the associations between flavored e-cigarette use with quit attempts and quit success of smoking among individuals who smoked 12 months ago. Two current e-cigarette use definitions were used in these logistic regression analyses; currently use every day or some days versus 20+ days in the past 30 days. RESULTS: Compared to those not using e-cigarettes, current every day or someday e-cigarette use with all nontobacco flavors had an adjusted odds ratio (AOR) of 2.9 (95% CI: 2.4 to 3.5) for quit attempts and 1.7 (95% CI: 1.3 to 2.2) for quit success. 20+ days e-cigarette use with flavors had stronger associations with quit attempts (AOR = 4.2, 95% CI: 3.1 to 5.5) and quit success (AOR = 4.0, 95% CI: 2.9 to 5.4). E-cigarette users with nontobacco flavors were more likely to succeed in quitting compared to those exclusively using non-flavored or tobacco-flavored e-cigarettes. Menthol or mint flavor users had slightly higher odds of quit attempts and success than users of other nontobacco flavors. CONCLUSIONS: E-cigarette use is positively associated with both making smoking quit attempts and quit success. Those using flavored e-cigarettes, particularly menthol or mint, are more likely to quit successfully. IMPLICATIONS: E-cigarette use is positively associated with both making a quit attempt and quit success, and those using flavored e-cigarettes are more likely to successfully quit smoking, with no statistically significant differences between the use of menthol or mint-flavored e-cigarettes versus the use of other nontobacco flavored products. This suggests that the potential for e-cigarettes to help people who currently smoke quit could be maintained with the availability of menthol or mint-flavored e-cigarettes, even if other nontobacco flavored products, which are associated with e-cigarette use among youth, were removed from the market.

The Longitudinal Association Between Cigarette Coupon Receipt and Short-term Smoking Cessation Among US Adults.

INTRODUCTION: To help offset the increased price of cigarettes and promote brand loyalty, tobacco companies distribute coupons, particularly to price-sensitive consumers. Few studies, however, have examined the longitudinal association between coupon receipt and smoking cessation. AIMS AND METHODS: Using adult data from waves 1-5 (2013-2019) of the Population Assessment of Tobacco and Health Study, we examined the longitudinal association between coupon receipt and short-term smoking cessation. Multivariable discrete-time survival models were fit to an unbalanced person-period dataset for adult respondents (≥18 years) with current established smoking status at baseline (person n = 9472, risk period n = 29 784). Short-term smoking cessation was measured as discontinued cigarette use (no past 30-day cigarette use at follow-up) and self-reported complete quitting. Coupon receipt was measured as a time-varying exposure, measured in the wave preceding the outcome. Tobacco dependence and time-varying cigarette use intensity were controlled as potential confounders. Effect modification by age, sex, race-ethnicity, and education was assessed by examining interaction terms. RESULTS: We found that adults who received a coupon were 19% less likely to quit smoking compared to adults who did not receive a coupon, adjusting for covariates (adjusted hazard rate [aHR]: 0.81, 95% CI: 0.74-0.89). None of the interaction terms were statistically significant, suggesting that the association between coupon receipt and short-term smoking cessation may not differ across the sociodemographic groups that we examined. CONCLUSIONS: Taken together, our results reveal that coupon receipt reduces the likelihood of short-term smoking cessation, and that this association does not differ by age, sex, race-ethnicity, or education. IMPLICATIONS (97/100): Tobacco companies distribute coupons for tobacco products to price-sensitive customers in the United States, and these coupons can be particularly effective in partly offsetting the impact of a tax increases and promoting brand loyalty. This study provides longitudinal evidence that coupon receipt is associated with a decrease in short-term smoking cessation among US adults who smoke cigarettes after adjusting for covariates and tobacco-related confounders. The findings from this study suggest that coupons are an effective tool for tobacco companies to prevent adults who smoke from quitting, and a national ban on coupons may help to facilitate smoking cessation.

Potential Implications for Tobacco Industry Transformation of the Acquisition of Swedish Match by Philip Morris International.

Philip Morris International's recent purchase of Swedish Match may prove to be a vital tobacco industry development. We focus on PMIs potential progress in moving from primarily selling cigarettes toward primarily selling noncombustible nicotine delivery products (NCNDPs). We also consider the potential contribution of the acquisition to industry transformation whereby other cigarette firms may potentially move toward primarily selling NCNDPs. We examine the potential impact on noncombustible nicotine delivery product use, including nicotine pouches (a major Swedish Match product), e-cigarettes, heated tobacco products, and, most importantly, on sales of the industry's staple, combustible cigarettes. We focus on the United States as a special case, where PMI is limited from entering the cigarette market. Implications: Philip Morris International's purchase of Swedish Match and policies regarding nicotine pouches (NPs) have been overlooked in the tobacco control literature. The acquisition indicates the importance of the NP market to the largest nonstate-owned tobacco company. The acquisition has the potential through pricing and marketing tactics to either encourage or discourage the use of NPs, e-cigarettes, heated tobacco products, and most importantly cigarettes. Due to its inability to sell cigarettes in the United States, PMI will have incentives to use its alternative nicotine delivery products, including its newly acquired NPs, to reduce the sale of cigarettes by other companies. However, the potential effects in other countries, where PMI does sell cigarettes, are less clear. Monitoring and analyzing tobacco company acquisitions is essential to studying future transitions in using different kinds of tobacco products, especially from cigarettes to lower-risk alternative nicotine delivery products.

The Australia Smoking and Vaping Model: The Potential Impact of Increasing Access to Nicotine Vaping Products.

BACKGROUND: We model the potential impact of relaxing current nicotine vaping product (NVP) restrictions on public health in Australia. AIMS AND METHODS: A Restricted NVP Scenario was first developed to project current smoking and vaping rates, where a U.S. smoking model was calibrated to recent Australian trends. To model less restrictive NVP policies, a Permissive NVP Scenario applied rates of switching from smoking to vaping, initiation into NVP and cigarette use, and cessation from smoking and vaping based on U.S. trends. The model measures vaping risk relative to the excess mortality rate of smoking. The public health impacts are measured as the difference between smoking- and vaping-attributable deaths (SVADs) and life years lost (LYLs) in the Restricted and Permissive NVP Scenarios. Sensitivity analysis is conducted regarding the NVP excess risk and other factors. RESULTS: Assuming an NVP excess risk of 5% that of smoking, 104.2 thousand SVADs (7.7% reduction) and 2.05 million LYLs (17.3% reduction) are averted during 2017-2080 in the Permissive NVP Scenario compared to the Restricted NVP Scenario. Assuming 40% NVP excess risk, 70 thousand SVADs and 1.2 million LYLs are averted. The impact is sensitive to the rate at which smokers switch to NVPs and quit smoking, and relatively insensitive to the smoking initiation and NVP initiation and cessation rates. CONCLUSIONS: The model suggests the potential for public health gains to be achieved by relaxing NVP access regulations. However, the model would benefit from better information regarding the impact of NVPs on smoking under a relaxation of current restrictions. IMPLICATIONS: Australia has implemented a strong array of cigarette-oriented policies, but has restricted access to NVPs. The Smoking and Vaping Model offers a framework for modeling hypothetical policy scenarios. The Australian model shows the potential for public health gains by maintaining cigarette-oriented policies while relaxing the current restrictive NVP policy. Modeling results under a permissive NVP policy are particularly sensitive to the estimated rates of smoking cessation and switching to vaping, which are not well established and will likely depend on past and future cigarette-oriented policies and the specific NVP policies implemented in Australia.

Do Tobacco Companies Have an Incentive to Promote "Harm Reduction" Products?: The Role of Competition.

INTRODUCTION: Some cigarette companies have started to talk about replacing cigarettes with less harmful alternatives, which might include nicotine vaping products (NVPs), heated tobacco products (HTPs), and oral nicotine delivery products. We consider market competition as a primary driver of whether cigarette companies follow through on their stated intentions. AIMS AND METHODS: We focus on the behavior of cigarette companies in the United States. We compare competition in the pre- and post-2012 time periods, analyze the impact of the growth in NVPs on smoking prevalence and cigarette company profits, and examine the potential future role of competition. RESULTS: Since 2006, consumers have broadened their use of non-combustible nicotine delivery products (NCNDPs) to include, inter alia, NVPs, HTPs, and oral nicotine pouches. U.S. cigarette companies have acquired major stakes in each of these product categories which corresponds to a period of rapidly declining adult smoking prevalence, especially among younger adults (ages 18-24 years). The shifting dynamics of the nicotine product marketplace are also reflected in cigarette company stock prices. While cigarette companies are likely to promote HTPs and nicotine delivery products over NVPs, their incentives will be directly related to competition from independent firms, which in turn will depend on government regulation. CONCLUSIONS: Although cigarette companies will back alternatives to combusted tobacco when threatened by competition, the prospects for their lasting conversion to NCNDPs will depend on the extent of such competition, which will be influenced by government regulation of tobacco products. IMPLICATIONS: Regulations that limit competition from independent firms while also protecting cigarette company profits risk slowing or even reversing recent declines in smoking, especially among youth and young adults. Regulations that reduce the appeal and addictiveness of combusted tobacco products, such as higher cigarette taxes or a reduced nicotine standard, will encourage smokers to quit and/or switch to less harmful non-combusted forms of tobacco. The regulation of non-combustible nicotine delivery products and cigarettes should be proportionate to their relative risks, so that smokers have incentives to switch from combustibles to safer alternatives, and cigarette companies have incentives to promote safer products.

Are the Relevant Risk Factors Being Adequately Captured in Empirical Studies of Smoking Initiation? A Machine Learning Analysis Based on the Population Assessment of Tobacco and Health Study.

INTRODUCTION: Cigarette smoking continues to pose a threat to public health. Identifying individual risk factors for smoking initiation is essential to further mitigate this epidemic. To the best of our knowledge, no study today has used machine learning (ML) techniques to automatically uncover informative predictors of smoking onset among adults using the Population Assessment of Tobacco and Health (PATH) study. AIMS AND METHODS: In this work, we employed random forest paired with Recursive Feature Elimination to identify relevant PATH variables that predict smoking initiation among adults who have never smoked at baseline between two consecutive PATH waves. We included all potentially informative baseline variables in wave 1 (wave 4) to predict past 30-day smoking status in wave 2 (wave 5). Using the first and most recent pairs of PATH waves was found sufficient to identify the key risk factors of smoking initiation and test their robustness over time. The eXtreme Gradient Boosting method was employed to test the quality of these selected variables. RESULTS: As a result, classification models suggested about 60 informative PATH variables among many candidate variables in each baseline wave. With these selected predictors, the resulting models have a high discriminatory power with the area under the specificity-sensitivity curves of around 80%. We examined the chosen variables and discovered important features. Across the considered waves, two factors, (1) BMI, and (2) dental and oral health status, robustly appeared as important predictors of smoking initiation, besides other well-established predictors. CONCLUSIONS: Our work demonstrates that ML methods are useful to predict smoking initiation with high accuracy, identifying novel smoking initiation predictors, and to enhance our understanding of tobacco use behaviors. IMPLICATIONS: Understanding individual risk factors for smoking initiation is essential to prevent smoking initiation. With this methodology, a set of the most informative predictors of smoking onset in the PATH data were identified. Besides reconfirming well-known risk factors, the findings suggested additional predictors of smoking initiation that have been overlooked in previous work. More studies that focus on the newly discovered factors (BMI and dental and oral health status,) are needed to confirm their predictive power against the onset of smoking as well as determine the underlying mechanisms.

Cigarette Prices and Disparities in Cessation in the United States.

INTRODUCTION: Achieving cessation in people with established smoking patterns remains a challenge. Increasing cigarette prices has been one of the most effective strategies for lowering smoking rates. It remains unclear how effective it has been in encouraging cessation among adults in recent years and how the effectiveness varies by sociodemographic characteristics. METHODS: Using repeated cross-sectional data collected by the Tobacco Use Supplement of the Current Population Survey, we investigate the relationship between cigarette prices and cessation from 2003 to 2019 in adults 25+. We examine the associations between price and cessation in the population overall and by sex, race/ethnicity, and socioeconomic status. RESULTS: We found mixed support for associations between greater local prices and cessation. Unadjusted models showed that greater local prices were associated with greater odds of cessation, but the associations did not persist after controlling for sociodemographic characteristics. The associations did not significantly differ by respondent characteristics. Sensitivity analysis using alternative specifications and retail state price as the main predictor showed similar results. Sensitivity analysis with controls for e-cigarette use in the 2014-2019 period showed that greater local price was associated with cessation among adults with less than a high school degree. When stratified by year of data collection, results show that greater local prices were associated with cessation after 2009. CONCLUSIONS: Overall, the study adds to the conflicting evidence on the effectiveness of increasing prices on smoking cessation among adults with established smoking patterns. IMPLICATIONS: Higher cigarette prices have been one of the most effective tools for lowering smoking prevalence. It remains unclear how effective they are in encouraging adults with established smoking patterns to quit. Results show that greater local prices were associated with higher odds of cessation, but the association did not persist after sociodemographic adjustment. In a sensitivity analysis, greater local price was associated with cessation among people with less than a high school degree in models controlling for e-cigarette use. We also found evidence that greater local price was associated with cessation after 2009. More comprehensive smoke-free coverage was also associated with greater odds of cessation. The study's results highlight that encouraging cessation among adults with an established smoking pattern remains a challenging policy problem even when cigarette prices rise.

Longitudinal Associations Between Exclusive and Dual Use of Electronic Nicotine Delivery Systems and Cigarettes and Self-Reported Incident Diagnosed Cardiovascular Disease Among Adults.

INTRODUCTION: The cardiovascular health effects of electronic nicotine delivery systems (ENDS) use are not well characterized, making it difficult to assess ENDS as a potential harm reduction tool for adults who use cigarettes. AIMS AND METHODS: Using waves 1-5 of the Population Assessment of Tobacco and Health Study (2013-2019), we analyzed the risk of self-reported incident diagnosed myocardial infarction (MI; 280 incident cases) and stroke (186 incident cases) associated with ENDS and/or cigarette use among adults aged 40 + using discrete time survival models. We employed a time-varying exposure lagged by one wave, defined as exclusive or dual established use of ENDS and/or cigarettes every day or some days, and controlled for demographics, clinical factors, and past smoking history. RESULTS: The analytic samples (MI = 11 031; stroke = 11 076) were predominantly female and non-Hispanic White with a mean age of 58 years. At baseline, 14.2% of respondents exclusively smoked cigarettes, 0.6% exclusively used ENDS, and 1.0% used both products. Incident MI and stroke were rare during follow-up (< 1% at each wave). Compared to no cigarette or ENDS use, exclusive cigarette use increased the risk of MI (aHR 1.99, 95% CI = 1.40-2.84) and stroke (aHR 2.26, 95% CI = 1.51-3.39), while exclusive ENDS use (MI: aHR 0.61, 95% CI = 0.12-3.04; stroke: aHR 1.74, 95% CI = 0.55-5.49) and dual use (MI: aHR 1.84, 95% CI = 0.64-5.30; stroke: aHR 1.12, 95% CI = 0.33-3.79) were not significantly associated with the risk of either outcome. CONCLUSIONS: Compared to non-use, exclusive cigarette use was associated with an increased risk of self-reported incident diagnosed cardiovascular disease over a 5-year period, while ENDS use was not associated with a statistically significant increase in the outcomes. IMPLICATIONS: Existing literature on the health effects of ENDS use has important limitations, including potential reverse causation and improper control for cigarette smoking. We accounted for these issues by using a prospective design and adjusting for current and former smoking status and cigarette pack-years. In this context, we did not find that ENDS use was associated with a statistically significant increase in self-reported incident diagnosed myocardial infarction or stroke over a 5-year period. While more studies are needed, this analysis provides an important foundation and key methodological considerations for future research on the health effects of ENDS use.