An atlas of epithelial cell states and plasticity in lung adenocarcinoma.

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.

Dynamics for High-Sensitivity Detection of Free Radicals in Primary Bronchial Epithelial Cells upon Stimulation with Cigarette Smoke Extract.

Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is caused by chronic exposure to toxic particles and gases, such as cigarette smoke. Free radicals, which are produced during a stress response to toxic particles, play a crucial role in disease progression. Measuring these radicals is difficult since the complex mixture of chemicals within cigarette smoke interferes with radical detection. We used a new quantum sensing technique called relaxometry to measure free radicals with nanoscale resolution on cells from COPD patients and healthy controls exposed to cigarette smoke extract (CSE) or control medium. Epithelial cells from COPD patients display a higher free radical load than those from healthy donors and are more vulnerable to CSE. We show that epithelial cells of COPD patients are more susceptible to the damaging effects of cigarette smoke, leading to increased release of free radicals.

The paradox of the safer cigarette: understanding the pulmonary effects of electronic cigarettes.

Electronic cigarette (e-cigarette) use continues to rise globally. E-cigarettes have been presented as safer alternatives to combustion cigarettes that can mitigate the harm associated with tobacco products; however, the degree to which e-cigarette use itself can lead to morbidity and mortality is not fully defined. Herein we describe how e-cigarettes function; discuss the current knowledge of the effects of e-cigarette aerosol on lung cell cytotoxicity, inflammation, antipathogen immune response, mucociliary clearance, oxidative stress, DNA damage, carcinogenesis, matrix remodelling and airway hyperresponsiveness; and summarise the impact on lung diseases, including COPD, respiratory infection, lung cancer and asthma. We highlight how the inclusion of nicotine or flavouring compounds in e-liquids can impact lung toxicity. Finally, we consider the paradox of the safer cigarette: the toxicities of e-cigarettes that can mitigate their potential to serve as a harm reduction tool in the fight against traditional cigarettes, and we summarise the research needed in this underinvestigated area.

Warning Labels as a Public Health Intervention: Effects and Challenges for Tobacco, Cannabis, and Opioid Medications.

Warning labels help consumers understand product risks, enabling informed decisions. Since the 1966 introduction of cigarette warning labels in the United States, research has determined the most effective message content (health effects information) and format (brand-free packaging with pictures). However, new challenges have emerged. This article reviews the current state of tobacco warning labels in the United States, where legal battles have stalled pictorial cigarette warnings and new products such as electronic cigarettes and synthetic nicotine products pose unknown health risks. This article describes the emerging research on cannabis warnings; as more places legalize recreational cannabis, they are adopting lessons from tobacco warnings. However, its uncertain legal status and widespread underestimation of harms impede strict warning standards. The article also reviews opioid medication warning labels, suggesting that lessons from tobacco could help in the development of effective and culturally appropriate FDA-compliant opioid warning labels that promote safe medication use and increased co-dispensing of naloxone.

Comparative evaluation of cigarette smoke and a heated tobacco product on microglial toxicity, oxidative stress and inflammatory response.

BACKGROUND: Tobacco smoking is the leading cause of preventable death and disease worldwide, with over 8 million annual deaths attributed to cigarette smoking. This study investigates the impact of cigarette smoke and heated tobacco products (HTPs) on microglial function, focusing on toxicological profiles, inflammatory responses, and oxidative stress using ISO standard and clinically relevant conditions of exposure. METHODS: We assessed cell viability, reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial function, unfolded protein response, and inflammation in human microglial cells (HMC3) exposed to cigarette smoke, HTP aerosol or nicotine. RESULTS: Our findings show that cigarette smoke significantly reduces microglial viability, increases ROS formation, induces lipid peroxidation, and reduces intracellular glutathione levels. Cigarette smoke also alters the expression of genes involved in mitochondrial dynamics and biogenesis, leading to mitochondrial dysfunction. Additionally, cigarette smoke impairs the unfolded protein response, activates the NF-κB pathway, and induces a pro-inflammatory state characterized by increased TNF and IL-18 expression. Furthermore, cigarette smoke causes DNA damage and decreases the expression of the aging marker Klotho ß. In contrast, HTP, exhibited a lesser degree of microglial toxicity, with reduced ROS production, lipid peroxidation, and mitochondrial dysfunction compared to conventional cigarettes. CONCLUSION: These results highlight the differential toxicological profile of cigarette smoke and HTP on microglial cells, suggesting a potential harm reduction strategy for neurodegenerative disease for smokers unwilling or unable to quit.

Can switching from cigarettes to heated tobacco products reduce consequences of pulmonary infection?

RATIONALE: While tobacco industry data suggests that switching from combustible cigarettes to heated tobacco products (HTPs), like IQOS, may reduce the users' exposure to respiratory toxicants, it is not known if using HTPs impacts the outcomes of acute respiratory infections. OBJECTIVES: Does switching from cigarettes to HTPs improve responses to pulmonary infection. METHODS: We conducted experiments in which 3 groups of mice were pre-exposed to cigarette smoke for 8 weeks, followed by 8-week exposure to (1) HTPs (tobacco product switching), (2) air (smoking cessation), or (3) continued exposure to cigarette smoke. Pulmonary bacterial clearance and surrogate markers of lung damage were assessed as study outcomes. MAIN RESULTS: Significantly compromised clearance of bacteria from the lungs post-acute challenge occurred in both the switching group and in mice continuously exposed to cigarette smoke. Bacterial clearance, inflammatory T-cell infiltration into the lungs, and albumin leak improved at 12 h post-acute challenge in the switching group compared to mice continuously exposed to cigarette smoke. Bacterial clearance, total lung immune-cell infiltration, inflammatory T-cell infiltration into the lungs, the content of total proteins in the BAL, and albumin leak measured post-acute challenge were compromised in the switching group compared to mice in the cessation group. Switching from cigarettes to HTPs did not improve lung myeloperoxidase and neutrophil elastase levels (markers for lung inflammation and damage), which, however, were significantly reduced in the cessation group. CONCLUSIONS: This study reveals only a modest improvement in respiratory infection outcomes after switching exposure from cigarettes to HTPs and significantly compromised outcomes compared to a complete cessation of exposure to all tobacco products.

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.

Respiratory symptoms and outcomes among cigar smokers: findings from the Population Assessment of Tobacco and Health (PATH) study waves 2-5 (2014-2019).

BACKGROUND: The mechanisms by which cigarette smoking increases the risk of respiratory disease have been studied. However, less is known about risks of respiratory symptoms and outcomes associated with smoking cigars, and risks by cigar types have not been previously explored. The aim of this study was to examine associations between cigar use, including traditional cigars, cigarillos, filtered cigars, and dual cigar and cigarette use, and functionally important respiratory symptoms (FIRS), lifetime asthma diagnosis, uncontrolled asthma, and new cases of FIRS. METHODS: Data from Waves 2-5 (2014-19) of the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative longitudinal study, were analyzed in two ways. For cross-sectional analysis, the analytic sample included adults 18 and older at each wave, resulting in 44,040 observations. Separately, longitudinal analyses were assessed among adults 18 and older at Wave 2, resulting in 7,930 individuals. Both analyses excluded adults with chronic obstructive pulmonary disease (COPD) or non-asthma respiratory disease. RESULTS: Current established cigarillo smokers had higher odds of having FIRS (Adjusted odds ratio (AOR): 1.72; 95% CI: 1.08, 2.74) compared to never smokers of cigarillos and cigarettes, after adjusting for covariates. Current established filtered cigar smokers had higher odds of asthma diagnosis (AOR: 1.35; 95% CI: 1.10, 1.66) while current established dual smokers of filtered cigars and cigarettes had higher odds of uncontrolled asthma (AOR: 5.13; 95% CI: 1.75, 15.02) compared to never smokers of filtered cigars or cigarettes. Both current established cigar smokers and current established dual smokers of cigarettes and cigars had higher odds of new FIRS compared to never cigar or cigarette smokers (AORs: 1.62; 95% CI: 1.02, 2.60 for exclusive cigars and 2.55; 95% CI 1.57, 4.14 for dual smokers). CONCLUSIONS: This study provides evidence that cigar smokers or dual smokers of cigars and cigarettes have greater odds of FIRS, asthma, and uncontrolled asthma and that new incidence of FIRS is higher among any cigar smokers compared to never cigar or cigarette smokers. Understanding health impacts associated with cigar use provides information for supporting policy development, as well as for designing clinical interventions focused on smoking cessation for cigars.

Exploring the Cellular Impact of Size-Segregated Cigarette Aerosols: Insights into Indoor Particulate Matter Toxicity and Potential Therapeutic Interventions.

Exposure to anthropogenic aerosols has been associated with a variety of adverse health effects, increased morbidity, and premature death. Although cigarette smoke poses one of the most significant public health threats, the cellular toxicity of particulate matter contained in cigarette smoke has not been systematically interrogated in a size-segregated manner. In this study, we employed a refined particle size classification to collect cigarette aerosols, enabling a comprehensive assessment and comparison of the impacts exerted by cigarette aerosol extract (CAE) on SH-SY5Y, HEK293T, and A549 cells. Exposure to CAE reduced cell viability in a dose-dependent manner, with organic components having a greater impact and SH-SY5Y cells displaying lower tolerance compared to HEK293T and A549 cells. Moreover, CAE was found to cause increased oxidative stress, mitochondrial dysfunction, and increased levels of apoptosis, pyroptosis, and autophagy, leading to increased cell death. Furthermore, we found that rutin, a phytocompound with antioxidant potential, could reduce intracellular reactive oxygen species and protect against CAE-triggered cell death. These findings underscore the therapeutic potential of antioxidant drugs in mitigating the adverse effects of cigarette aerosol exposure for better public health outcomes.

Impact of switching from cigarette smoking to tobacco heating system use on biomarkers of potential harm in a randomized trial.

BACKGROUND: Smoking cessation reduces the risk of developing smoking-related diseases. Although smoking prevalence has declined, many continue smoking cigarettes. Switching completely to smoke-free alternatives like the Tobacco Heating System (THS) 2.2-a heated tobacco product for which there is evidence demonstrating significantly reduced formation and exposure to harmful chemicals compared to cigarettes-has the potential to reduce the harm caused by continuing to smoke cigarettes. METHODS: We conducted a 6-month clinical study (NCT02396381) with a 6-month extension (NCT02649556), initially randomizing 984 adult smokers to continue smoking or switch to THS (non-mentholated), of which 672 continued into the extension study. Endpoints were evaluated at baseline and at 3, 6, and 12 months. We longitudinally assessed biomarkers of potential harm (BoPHs) known to be reversible upon smoking cessation as indicators of pathways involved in the pathogenesis of cardiovascular or respiratory diseases and carcinogenicity. The need to cough and safety profile were also assessed. Impact on eight key BoPHs was used as a proxy to evaluate harm reduction potential. RESULTS: At 12 months, comparison of BoPH levels between the predominant THS use and cigarette smoking groups showed a positive effect in favor of switching, partially or in full, to THS. CONCLUSION: These results provide additional evidence of the harm reduction potential of THS for smokers who would otherwise continue smoking, but they need to be verified in long-term confirmatory studies. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT0264955. Date of registration: January 7, 2016 https://clinicaltrials.gov/ct2/show/NCT02649556.

Nicotine Delivery of a Menthol-Flavored Heat-not-Burn Tobacco Product During Directed Use.

INTRODUCTION: IQOS was authorized by the U.S. Food and Drug Administration (FDA) as a modified-risk tobacco product. We conducted a pharmacokinetic study evaluating the nicotine delivery and subjective effects of IQOS use among current menthol cigarette smokers to better understand if IQOS is an acceptable cigarette alternative in light of the proposed menthol cigarette ban. AIMS AND METHODS: Participants were adult smokers of >4 menthol cigarettes per day. After 14-hour nicotine abstinence, participants were provided an IQOS device and menthol heatstick to puff every 20 seconds for a total of 14 puffs. Blood samples were collected at baseline and during active use to calculate nicotine boost from baseline to peak concentration. Nicotine withdrawal symptoms were collected before and after IQOS use. In addition, a modified Product Evaluation Scale for IQOS was collected after use. RESULTS: Participants (n = 8) were a mean age of 43.9 years, 63% were female, 88% identified as White, and they smoked a mean of 17.1 menthol cigarettes per day. After IQOS use, the mean nicotine boost obtained was 15.96 ng/mL (SD = 6.91) (range 9.31 to 30.55 ng/mL). Most (75%) participants reported enjoying use of the product "a lot" or greater and more than half (62.5%) reported reduced cigarette cravings. Most participants reported no side effects after use; however, two experienced dry mouth, three experienced dizziness, one experienced throat irritation, and one experienced headache. CONCLUSION: We found that directed use (14 puffs) of menthol IQOS delivered a mean nicotine boost of 15.96 ng/mL which reduced craving for a cigarette. The majority of participants enjoyed use of IQOS and reported mild side effects. IMPLICATIONS: Menthol IQOS delivered a sufficient dose of nicotine perceived as satisfying by menthol cigarette smokers and it reduced craving with mild side effects. Menthol IQOS has potential to serve as a less harmful alternative for menthol cigarette smokers. The availability of modified risk products like IQOS should be considered by FDA's Comprehensive Plan for Tobacco and Nicotine Regulation.

Organic, Earth-Friendly Tobacco With a Charcoal Filter and Smooth Taste: A Randomized Experiment Testing Effects of Natural American Spirit's "Sky" Cigarette Advertising on Consumer Perceptions.

INTRODUCTION: The Natural American Spirit (NAS) brand has a history of marketing tactics that may convey reduced harm. While no longer allowed to use "additive-free" or natural descriptors (except in the brand name), it continues promoting potentially misleading attributes. This study examined perceptions of NAS's newer "Sky" style, promoted as organic tobacco with a charcoal filter. AIMS AND METHODS: In an online experiment, we randomized 1927 adult past 30-day tobacco or nicotine product users to one of six conditions showing Sky ads with different descriptors: (1) charcoal filter, (2) charcoal + organic, (3) charcoal + earth-friendly, (4) charcoal + smooth taste, (5) charcoal + all other descriptors, and (6) no-descriptor control (Sky ads without target descriptors). Product perceptions were compared by condition. Participants also reported perceived benefits of charcoal filters. RESULTS: Overall, 28% of participants indicated Sky is less harmful and 38% believed it exposes users to fewer chemicals. Participants in the "charcoal + organic," "charcoal + earth-friendly," and the all-descriptor conditions had higher odds of believing Sky reduces chemical exposure (respectively, 43%, 40%, and 42%), relative to the no-descriptor control. Fewer control participants endorsed beliefs that Sky has a "better filter" and is "more environmentally friendly". Many believed cigarettes with charcoal filters could confer benefits relative to other cigarettes, such as reducing chemical exposure, or being cleaner, purer or safer (though research on relative safety of charcoal filters in cigarettes is inconclusive). CONCLUSIONS: Sky marketing may promote misperceptions about product safety and composition, and ads using both charcoal and organic text may particularly reinforce them. IMPLICATIONS: This study examined the impact of new cigarette advertising promoting the use of charcoal filters and organic tobacco along with other suggestive claims ("environmentally friendly," "smooth taste") on tobacco users' perceptions of the advertised product-NAS Sky cigarettes. Our study provides new data about positive consumer perceptions of charcoal-filtered cigarettes, and results suggest that combinations of these marketing terms evoke perceptions about reduced harm and reduced exposure to harmful chemicals that may be misleading to the public. Our findings underscore a need for additional regulatory action regarding tobacco marketing that makes use of natural-themed marketing.

Effects of Modified Risk Tobacco Product Claims on Consumer Responses.

INTRODUCTION: US tobacco manufacturers can seek authorization from the US Food and Drug Administration (FDA) to market products using modified risk tobacco product (MRTP) claims. To inform regulatory decisions, we examined the impact of MRTP claim specificity and content, including whether the claims produced halo effects (ie, inferring health benefits beyond what is stated). AIMS AND METHODS: Participants were 3161 US adult cigarette smokers. Using a two (general vs. specific) × 2 (risk vs. exposure) plus independent control design, we randomized participants to view one message from these conditions: general risk claim (eg, "smoking-related diseases"), general exposure claim (eg, "chemicals in smoke"), specific risk claim (eg, "lung cancer"), specific exposure claim (eg, "arsenic"), or control. Claims described the benefits of completely switching from cigarettes to the heated tobacco product IQOS. RESULTS: MRTP claims of any sort elicited a higher willingness to try IQOS relative to control (d = 0.09, p = .043). Claims also elicited lower perceived risk of disease and exposure to harmful chemicals for completely switching from cigarettes to IQOS (d = -0.32 and -0.31) and partially switching (d = -0.25 and d = -0.26; all p < .05). Relative to specific MRTP claims, general MRTP claims led to lower perceived risk and exposure for complete switching (d = -0.13 and d = -0.16) and partial switching (d = -0.14 and d = -0.12; all p < .05). Risk and exposure MRTP claims had similar effects (all p > .05). DISCUSSION: MRTP claims led to lower perceived risk and exposure, and higher willingness to try IQOS. General claims elicited larger effects than specific claims. MRTP claims also promoted unintended halo effects (eg, lower perceived risk of disease and chemical exposure for partial switching). IMPLICATIONS: We found evidence that MRTP claims promoted health halo effects. In light of these findings, the FDA should require research on halo effects prior to authorization. Further, if an MRTP claim is authorized, FDA should require tobacco manufacturers to conduct post-market surveillance of how the claim affects consumer understanding, including partial switching perceived risk and exposure beliefs, as well as monitoring of dual-use behaviors.

Youth Exposure and Response to the FDA Health Warning Label on Electronic Cigarettes Packaging: Policy Implications.

INTRODUCTION: Youth represent a high-priority group for e-cigarette health communication. This study examined youth exposure to the Food and Drug Administration (FDA) e-cigarette warning label over 4 years and its association with change in youth harm perception and intention. AIMS AND METHODS: We pooled data from the 2018-2021 National Youth Tobacco Survey (age 10-17; n = 67 159). Participants were divided into four groups: never users (58.5%), susceptible nonusers (16.3%), former users (12.7%), and current users (12.5%). We examined the prevalence, time-trend, correlates, and association of youth exposure to the warning with addictiveness and harm perception, intention to use e-cigarettes, and intention to quit all tobacco products. RESULTS: Only 24.5% of youth were exposed to the warning. Exposure increased from 14.9% in 2018 to 30.8% in 2019, then declined to 25.2% in 2021. Hispanic (adjusted odds ratio (aOR) = 0.76 [95% CI = 0.641 to 0.89]) and non-Hispanic black current users (0.53 [0.40 to 0.69]) were less likely to be exposed to the warning than white current users. Youth exposure was positively associated with a higher perception of e-cigarette addictiveness (1.12 [1.04 to 1.19]) and intention to quit all tobacco products (1.28 [1.13 to 1.46]). However, exposure was negatively associated with harm perception (0.91 [0.85 to 0.96]) and the intention to use e-cigarettes among e-cigarette nonusers (2.38 [1.99 to 2.84]). CONCLUSIONS: The decline in youth exposure to the warning indicates wear-out effects. Strengthening the label by using compelling designs, adding themes on e-cigarette harm to youth, periodically rotating warning content, and using culturally tailored messaging may improve its impact on youth and address racial/ethnic disparities. IMPLICATIONS: The FDA e-cigarette label reached only 24.5% of youth, and exposure to the warning declined to indicate wear-out effects. Exposure was significantly lower among minorities. Exposure was associated with a higher perception of e-cigarette addictiveness and intention to quit all tobacco products. Still, it did not increase harm perception or reduce intention to use e-cigarettes among nonusers. Strengthening the label by using more compelling designs, including diverse themes focusing on e-cigarette harm relevant to youth, and periodically rotating warning content may improve its impact on youth. Continued surveillance of the implementation of e-cigarette policies is needed to ensure that they equally affect youth across racial/ethnic subpopulations.

What Can Current Biomarker Data Tell Us About the Risks of Lung Cancer Posed by Heated Tobacco Products?

INTRODUCTION: Heated tobacco products (HTPs) are marketed as less harmful alternatives to cigarettes, but the lung cancer risk of HTPs is unknown. In the absence of epidemiological data, assessing the risks of HTPs relies on biomarker data from clinical trials. This study examined existing biomarker data to determine what it tells us about the lung cancer risk posed by HTPs. AIMS AND METHODS: We identified all biomarkers of exposure and potential harm measured in HTP trials and evaluated their appropriateness based on ideal characteristics for measuring lung cancer risk and tobacco use. The effects of HTPs on the most appropriate biomarkers within cigarette smokers switched to HTPs and compared to continued cigarette smoking or cessation were synthesized. RESULTS: Sixteen out of eighty-two biomarkers (7 exposure and 9 potential harm) measured in HTP trials have been associated with tobacco use and lung cancer, dose-dependently correlated with smoking, modifiable upon cessation, measured within an appropriate timeframe, and had results published. Three of the exposure biomarkers significantly improved in smokers who switched to HTPs and were not significantly different from cessation. The remaining 13 biomarkers did not improve-in some instances worsening upon switching to HTPs-or were inconsistently affected across studies. There were no appropriate data to estimate the lung cancer risk of HTPs in non-smokers. CONCLUSIONS: The appropriateness of existing biomarker data in assessing lung cancer risk of HTPs, both relative to cigarettes and their absolute risk, is limited. Furthermore, findings on the most appropriate biomarkers were conflicting across studies and largely showed no improvement following a switch to HTPs. IMPLICATIONS: Biomarker data are fundamental to assessing the reduced risk potential of HTPs. Our evaluation suggests much of the existing biomarker data on HTPs is inappropriate for determining the risk of lung cancer posed by HTPs. In particular, there is a paucity of data on the absolute lung cancer risk of HTPs, which could be obtained from comparisons to smokers who quit and never smokers exposed to or using HTPs. There is an urgent need for further exploration of the lung cancer risks posed by HTPs, via clinical trials and, in the long-term, confirmation of these risks via epidemiological studies. However, careful consideration should be given to biomarker selection and study design to ensure both are appropriate and will provide valuable data.

Vuse Solo e-cigarettes do not provide net benefits to public health: a scientific analysis of FDA's marketing authorisation.

In October 2021, the US Food and Drug Administration (FDA) authorised marketing of RJ Reynolds Vapor Company's (RJR) Vuse Solo e-cigarette through FDA's Premarket Tobacco Product Application (PMTA) pathway. FDA concluded that RJR demonstrated Vuse products met the statutory standard of providing a net benefit to public health. A review of FDA's scientific justification reveals deficiencies: (1) not adequately considering Vuse's popularity with youth and evidence that e-cigarettes expanded the nicotine market and stimulate cigarette smoking; (2) trading youth addiction for unproven adult benefit without quantifying these risks and benefits; (3) not considering design factors that appeal to youth; (4) not addressing evidence that e-cigarettes used as consumer products do not help smokers quit and promote relapse in former smokers; (5) not discussing evidence that dual use is more dangerous than smoking; (6) narrowly focusing on the fact that e-cigarettes deliver lower levels of some toxicants without addressing direct evidence on adverse health effects; (7) downplaying significant evidence of other substantial harms; (8) not acting on FDA's own study showing no all-cause mortality benefit of reducing (but not stopping) cigarette use; and (9) improperly considering e-cigarettes' high abuse liability and potential for high youth addiction and undermining tobacco cessation. Because marketing these products is not appropriate for the protection of the public health, FDA should reconsider its Vuse marketing order as statutorily required and not use it as a template for other e-cigarette PMTAs. Policymakers outside the USA should anticipate that tobacco companies will use FDA's decision to try to weaken tobacco control regulation of e-cigarettes and promote their products.

The Scientific Basis for the Regulation of Flavors in Tobacco Products.

Effective tobacco policies are important for reducing the harm of tobacco use and can have a broad impact at the population level. This review provides an overview of how clinical science can inform tobacco policies with a focus on policies related to flavored tobacco products, using menthol cigarettes as an illustrative example. Specifically, this review summarizes the role of flavors in tobacco use and the history of regulation of flavored tobacco products by the US Food and Drug Administration (FDA), provides an overview of clinical research methods used to contribute to the scientific evidence to inform FDA tobacco policies, discusses key findings related to menthol tobacco products using these methods, and proposes future directions for clinical research. As the tobacco marketplace continues to evolve with new products and flavor chemicals, ongoing clinical science will be essential for establishing evidence-based policies to protect public health and reduce tobacco-related health disparities.

EAP and ECPCP urge ban on novel nicotine- (NNCPS) and non-nicotine-containing products (NNDS) to youth.

AIM: We want to verify the correlation between the increasing use of novel nicotine-containing products (NNCPs) and non-nicotine delivery products (NNDPs) among young individuals and the escalating negative health consequences, necessitating their prohibition. METHODS: We performed a comprehensive analysis of the most relevant literature about the utilisation of NNCPs and NNDPs among young individuals and their health effects. RESULTS: Despite being initially seen as less harmful alternatives, for smokers aiming to quit, these products have become more popular due to misleading marketing claims. Teenagers using NNCPs and NNDPs, despite having no smoking history, are more likely to transition to tobacco smoking. Consistent use can lead to health issues like pulmonary damage, asthma, and cardiovascular and ocular problems. CONCLUSION: The EAP and the ECPCP endorse the WHO's appeal to outlaw these hazardous products. They urge European governments to forbid the sale of NNCPs and NNDPs to children and adolescents in order to safeguard their well-being. They also propose specific recommendations (box 4) to support this cause.

Examining Perceptions of Uncertain Language in Potential E-Cigarette Warning Labels: Results from 16 Focus Groups with Adult Tobacco Users and Youth.

E-cigarette use among youth presents a public health risk. Yet, cigarette smokers who substantially reduce their smoking or switch completely from traditional combustible cigarettes could benefit. As science about e-cigarettes is continually emerging, any potential warnings are likely to contain uncertain language. Hedged verbiage may impact decision making. To assess reactions, we conducted 16 online focus groups; 8 with youth (n = 32, grouped by gender and by vaping experience) and 8 with adult tobacco users (n = 37, grouped by smokers, dual users of e-cigarettes and cigarettes, and former smokers who switched to e-cigarettes). Each focus group viewed and discussed 8 potential warnings messages. We conducted an inductive thematic analysis of the reactions to warning messages that contain uncertain language. Respondents' reactions were often negative, but varied based on specific usages of uncertainty, existing beliefs about uncertainty in law and science, and smoking/vaping use patterns that supported the use of uncertainty related to e-cigarettes. Many youth (and some adults) believed that uncertain language enabled audiences to minimize the likelihood of harm or interpreted it as meaning there are both healthy and unhealthy e-cigarettes. This qualitative study provides evidence that the use of types of uncertain language, the frequency of that use, and/or the selection of particular words in warnings, might not achieve the intended public health aims of increasing understanding of risk, deterring youth uptake, and/or facilitating a substantial switch from cigarettes. The use of certain types of uncertain language appears to have significant potential to bring unintended consequences. Suggestions for research and policy are included.

Use of cigarettes and heated tobacco products during pregnancy and maternal-fetal outcomes: a retrospective, monocentric study.

PURPOSE: To compare the effects of using heated tobacco products (HTP) or traditional cigarettes (C) on maternal and neonatal outcomes. METHODS: This is a retrospective, monocentric study conducted at San Marco Hospital from July 2021 to July 2022. We compared a cohort of pregnant patients who smoked HTP (HS), with pregnant women smoking cigarettes (CS), ex-smoker (ES) and non-smoker (NS) pregnant women. Biochemistry, ultrasound, and neonatal evaluations were performed. RESULTS: In total, 642 women were enrolled, of which 270 were NS, 114 were ES, 120 were CS, and 138 were HS. CS had the greatest weight gain and had more difficulty getting pregnant. Smokers and ES experienced more frequently threats of preterm labor, miscarriages, temporary hypertensive spikes, and higher rates of cesarean sections. Preterm delivery was more associated with CS and HS groups. CS and HS had lower awareness of the risks to which the mother and the fetus are exposed. CS were more likely to be depressed and anxious. Biochemical parameters did not show significant differences between the groups. CS had the greatest difference in days between the gestational age calculated based on the last menstrual period and the one based on the actual ultrasound age. The average percentile newborn weight range of CS was lower, as well as the mean 1st minute and the 5th minute Apgar scores. CONCLUSION: The comparison of the data obtained between CS and HS underlines the greater danger of C. Nevertheless, we do not recommend HTP because the maternal-fetal outcomes are not superimposable to the NS outcomes.