Excess mortality in Europe coincides with peaks of COVID-19, influenza and respiratory syncytial virus (RSV), November 2023 to February 2024.

Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023-6 2024, preliminary results show a substantially increased rate of 95.3 (95% CI:  91.7-98.9) excess all-cause deaths per 100,000 person-years for all ages. This excess mortality is seen in adults aged 45 years and older, and coincides with widespread presence of COVID-19, influenza and respiratory syncytial virus (RSV) observed in many European countries during the 2023/24 winter season.

Historically High Excess Mortality During the COVID-19 Pandemic in Switzerland, Sweden, and Spain.

BACKGROUND: Excess mortality quantifies the overall mortality impact of a pandemic. Mortality data have been accessible for many countries in recent decades, but few continuous data have been available for longer periods. OBJECTIVE: To assess the historical dimension of the COVID-19 pandemic in 2020 for 3 countries with reliable death count data over an uninterrupted span of more than 100 years. DESIGN: Observational study. SETTING: Switzerland, Sweden, and Spain, which were militarily neutral and not involved in combat during either world war and have not been affected by significant changes in their territory since the end of the 19th century. PARTICIPANTS: Complete populations of these 3 countries. MEASUREMENTS: Continuous series of recorded deaths (from all causes) by month from the earliest available year (1877 for Switzerland, 1851 for Sweden, and 1908 for Spain) were jointly modeled with annual age group-specific death and total population counts using negative binomial and multinomial models, which accounted for temporal trends and seasonal variability of prepandemic years. The aim was to estimate the expected number of deaths in a pandemic year for a nonpandemic scenario and the difference in observed and expected deaths aggregated over the year. RESULTS: In 2020, the number of excess deaths recorded per 100 000 persons was 100 (95% credible interval [CrI], 60 to 135) for Switzerland, 75 (CrI, 40 to 105) for Sweden, and 155 (CrI, 110 to 195) for Spain. In 1918, excess mortality was 6 to 7 times higher. In all 3 countries, the peaks of monthly excess mortality in 2020 were greater than most monthly excess mortality since 1918, including many peaks due to seasonal influenza and heat waves during that period. LIMITATION: Historical vital statistics might be affected by minor completeness issues before the beginning of the 20th century. CONCLUSION: In 2020, the COVID-19 pandemic led to the second-largest infection-related mortality disaster in Switzerland, Sweden, and Spain since the beginning of the 20th century. PRIMARY FUNDING SOURCE: Foundation for Research in Science and the Humanities at the University of Zurich, Swiss National Science Foundation, and National Institute of Allergy and Infectious Diseases.

Estimating the Population Health Impact of Recently Introduced Modified Risk Tobacco Products: A Comparison of Different Approaches.

INTRODUCTION: Various approaches have been used to estimate the population health impact of introducing a Modified Risk Tobacco Product (MRTP). AIMS AND METHODS: We aimed to compare and contrast aspects of models considering effects on mortality that were known to experts attending a meeting on models in 2018. RESULTS: Thirteen models are described, some focussing on e-cigarettes, others more general. Most models are cohort-based, comparing results with or without MRTP introduction. They typically start with a population with known smoking habits and then use transition probabilities either to update smoking habits in the "null scenario" or joint smoking and MRTP habits in an "alternative scenario". The models vary in the tobacco groups and transition probabilities considered. Based on aspects of the tobacco history developed, the models compare mortality risks, and sometimes life-years lost and health costs, between scenarios. Estimating effects on population health depends on frequency of use of the MRTP and smoking, and the extent to which the products expose users to harmful constituents. Strengths and weaknesses of the approaches are summarized. CONCLUSIONS: Despite methodological differences, most modellers have assumed the increase in risk of mortality from MRTP use, relative to that from cigarette smoking, to be very low and have concluded that MRTP introduction is likely to have a beneficial impact. Further model development, supplemented by preliminary results from well-designed epidemiological studies, should enable more precise prediction of the anticipated effects of MRTP introduction. IMPLICATIONS: There is a need to estimate the population health impact of introducing modified risk nicotine-containing products for smokers unwilling or unable to quit. This paper reviews a variety of modeling methodologies proposed to do this, and discusses the implications of the different approaches. It should assist modelers in refining and improving their models, and help toward providing authorities with more reliable estimates.

Reduction in Exposure to Selected Harmful and Potentially Harmful Constituents Approaching Those Observed Upon Smoking Abstinence in Smokers Switching to the Menthol Tobacco Heating System 2.2 for 3 Months (Part 1).

INTRODUCTION: The Tobacco Heating System (THS) is a "heat-not-burn" tobacco product designed to generate significantly lower levels of harmful and potentially harmful constituents (HPHCs) and present lower risk of harm than cigarettes. This study assessed the exposure reduction to selected HPHCs in smokers switching to menthol Tobacco Heating System (mTHS) 2.2 compared with smokers continuing smoking menthol cigarettes (mCCs) and smoking abstinence (SA) for 5 days in a confined setting, followed by an 86-day ambulatory period. METHODS: A total of 160 healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Biomarkers of exposure to 16 HPHCs were measured in blood and 24-hour urine. Safety was monitored throughout the study. Information was also gathered on product evaluation, product use, subjective effects, and clinical risk markers (co-publication Part 2). RESULTS: Nicotine uptake was comparable in both exposure groups (mTHS:mCC ratio of 96% on day 90). On day 5, biomarker of exposure levels to other HPHCs were reduced by 51%-96% in the mTHS group compared with the mCC group, and these reductions were sustained for most biomarkers of exposure over ambulatory period. After 90 days of use, the level of satisfaction with mTHS and suppression of urge to smoke were comparable to mCC. CONCLUSION: Switching from mCCs to mTHS significantly reduced the exposure to HPHCs to levels approaching those observed in subjects who abstained from smoking for the duration of the study. IMPLICATIONS: This study compared the impact of switching to mTHS on biomarkers of exposure, relative to continued smoking or SA. TRIAL REGISTRATION: NCT01989156 (ClinicalTrials.gov).

Favorable Changes in Biomarkers of Potential Harm to Reduce the Adverse Health Effects of Smoking in Smokers Switching to the Menthol Tobacco Heating System 2.2 for 3 Months (Part 2).

INTRODUCTION: Tobacco Heating System (THS) 2.2, a candidate modified-risk tobacco product, aims at offering an alternative to cigarettes for smokers while substantially reducing the exposure to harmful and potentially harmful constituents found in cigarette smoke. METHODS: One hundred and sixty healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Subjects were randomized in a 2:1:1 ratio to menthol Tobacco Heating System 2.2 (mTHS), menthol cigarette, or smoking abstinence for 5 days in confinement and 86 subsequent ambulatory days. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents (reported in our co-publication, Part 1) and biomarkers of potential harm (BOPH). RESULTS: Compliance (protocol and allocated product exposure) was 51% and 18% in the mTHS and smoking abstinence arms, respectively, on day 90. Nonetheless, favorable changes in BOPHs of lipid metabolism (total cholesterol and high- and low-density cholesterol), endothelial dysfunction (soluble intercellular adhesion molecule-1), oxidative stress (8-epi-prostaglandin F2α), and cardiovascular risk factors (eg, high-sensitivity C-reactive protein) were observed in the mTHS group. Favorable effects in other BOPHs, including ones related to platelet activation (11-dehydrothromboxane B2) and metabolic syndrome (glucose), were more pronounced in normal weight subjects. CONCLUSIONS: The results suggest that the reduced exposure demonstrated when switching to mTHS is associated with overall improvements in BOPHs, which are indicative of pathomechanistic pathways underlying the development of smoking-related diseases, with some stronger effects in normal weight subjects. IMPLICATIONS: Switching to mTHS was associated with favorable changes for some BOPHs indicative of biological pathway alterations (eg, oxidative stress and endothelial dysfunction). The results suggest that switching to mTHS has the potential to reduce the adverse health effects of smoking and ultimately the risk of smoking-related diseases. Switching to mTHS for 90 days led to reductions in a number of biomarkers of exposure in smokers, relative to those who continued smoking cigarettes, which were close to those observed when stopping smoking (reported in our co-publication, Part 1). Initial findings suggest reduced levels of 8-epi-prostaglandin F2α and intercellular adhesion molecule 1, when switching to mTHS for 90 days. These changes are comparable to what is observed upon smoking cessation. In normal weight subjects, additional favorable changes were seen in 11-dehydrothromboxane B2, fibrinogen, homocysteine, hs-CRP, percentage of predicted forced expiratory volume in 1 second, systolic blood pressure, diastolic blood pressure, glucose, high-density lipoprotein, apolipoprotein A1, and triglycerides. TRIAL REGISTRATION: NCT01989156.

Using data on snus use in Sweden to compare different modelling approaches to estimate the population health impact of introducing a smoke-free tobacco product.

BACKGROUND: We have developed an approach for modelling the health impact of introducing new smoke-free tobacco products. We wished to compare its estimates with those of alternative approaches, when applied to snus, used in Sweden for many years. METHODS: Modelling was restricted to men aged 30-79 years for 1980-2009 and to four smoking-related diseases. Mortality data were extracted for Sweden and other European countries. Published data provided Swedish prevalence estimates for combinations of never/former/current smoking and snus use, and smoking prevalence estimates for other European countries. Approach 1 compares mortality in Sweden and in other countries with a smoking prevalence similar to Sweden's prevalence of combined smoking/snus use. Approaches 2 and 3 compare mortality in Sweden with hypothetical mortality had snus users smoked. Approach 3 uses our health impact model, individuals starting with the tobacco prevalence of Sweden in 1980. Tobacco histories during 30-year follow-up were then estimated using transition probabilities, with risk derived using a negative exponential model. Approach 2 uses annual tobacco prevalence estimates coupled with estimates of relative risk of current and former smokers regardless of history. The main applications of Approaches 2 and 3 assume that only smoking affects mortality, though sensitivity analyses using Approach 3 allow for risk to vary in snus users and dual users. RESULTS: Using Approach 2, estimated mortality increases in Sweden in 1980-2009 had snus not been introduced were: lung cancer 8786; COPD 1781; IHD 10,409; stroke 1720. The main Approach 3 estimates were similar (7931, 1969; 12,501; 1901). They decreased as risk in snus users and dual users increased. Approach 1 estimates differed wildly (77,762, 32,538; 77,438; 76,946), remaining very different following correction for differences between Sweden and the comparison countries in non-smoking-related disease mortality. CONCLUSIONS: Approach 1 is unreliable, accounting inadequately for non-tobacco factors affecting mortality. Approaches 2 and 3 provide reasonably similar approximate estimates of the mortality increase had snus not been available, but have differing advantages and disadvantages. Only Approach 3 considers tobacco history, but develops histories using tobacco transition probabilities, which is possibly less reliable than using estimated tobacco prevalences at each follow-up year.

Review of biomarkers to assess the effects of switching from cigarettes to modified risk tobacco products.

Context: One approach to reducing the harm caused by cigarette smoking, at both individual and population level, is to develop, assess and commercialize modified risk alternatives that adult smokers can switch to. Studies to demonstrate the exposure and risk reduction potential of such products generally involve the measuring of biomarkers, of both exposure and effect, sampled in various biological matrices.Objective: In this review, we detail the pros and cons for using several biomarkers as indicators of effects of changing from conventional cigarettes to modified risk products.Materials and methods: English language publications between 2008 and 2017 were retrieved from PubMed using the same search criteria for each of the 25 assessed biomarkers. Nine exclusion criteria were applied to exclude non-relevant publications.Results: A total of 8876 articles were retrieved (of which 7476 were excluded according to the exclusion criteria). The literature indicates that not all assessed biomarkers return to baseline levels following smoking cessation during the study periods but that nine had potential for use in medium to long-term studies.Discussion and conclusion: In clinical studies, it is important to choose biomarkers that show the biological effect of cessation within the duration of the study.

Effects of Switching to the Tobacco Heating System 2.2 Menthol, Smoking Abstinence, or Continued Cigarette Smoking on Biomarkers of Exposure: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 1).

Introduction: The menthol Tobacco Heating System 2.2 (mTHS) is a newly developed candidate modified-risk tobacco product intended to reduce exposure to the harmful and potentially harmful constituents (HPHCs) of conventional cigarette (CC) smoke. This study examined the impact of switching to mTHS on biomarkers of exposure to HPHCs relative to menthol CCs (mCCs) and smoking abstinence (SA). Methods: In this three-arm, parallel-group study, 160 Japanese adult smokers (23-65 years; smoking ≥10 mCCs per day) were randomized to mTHS (n = 78), mCC (n = 42), or SA (n = 40) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to HPHCs, human puffing topography, safety, and subjective effects of smoking measures. Results: After 5 days of product use, the concentrations of carboxyhemoglobin, 3-hydroxypropylmercapturic acid, monohydroxybutenyl mercapturic acid, and S-phenylmercapturic acid were 55%, 49%, 87%, and 89% lower (p < .001), respectively, in the mTHS group than in the mCC group. Other biomarkers of exposure (measured as secondary endpoints) were 50%-94% lower in the mTHS group than in the mCC group on day 5. These reductions in the mTHS group were maintained at day 90, similar to the SA group. Switching to mTHS was associated with changes in human puffing topography (shorter puff intervals and more frequent puffs). The urge-to-smoke and smoking satisfaction levels on day 90 were similar in the mTHS and the mCC groups. Conclusion: Switching from mCCs to mTHS significantly reduced exposure to HPHCs relative to continuing smoking mCCs with concentrations similar to those observed following SA in Japanese adult smokers. Implications: This randomized study compared the impact of switching to a modified-risk tobacco product candidate mTHS on biomarkers of exposure to HPHCs of cigarette smoke relative to continuing smoking cigarettes or abstaining from smoking in sequential confinement and ambulatory settings. The study showed that switching to mTHS was associated with significant biomarker reductions within 5 days in confinement, these reductions being maintained throughout the ambulatory setting up to day 90. The results provide evidence that switching to mTHS reduces real-life exposure to HPHCs in adult smokers.

Effects of Switching to the Menthol Tobacco Heating System 2.2, Smoking Abstinence, or Continued Cigarette Smoking on Clinically Relevant Risk Markers: A Randomized, Controlled, Open-Label, Multicenter Study in Sequential Confinement and Ambulatory Settings (Part 2).

Introduction: Modified-risk tobacco products are expected to reduce exposure to harmful and potentially harmful constituents of cigarette smoke, and ultimately reduce the health burden of smoking-related diseases. Clinically relevant risk markers of smoking-related diseases inform about the risk profile of new tobacco products in the absence of in-market epidemiological data. The menthol Tobacco Heating System 2.2 (mTHS) is a modified-risk tobacco product in development as an alternative to cigarettes (conventional cigarettes [CCs]). Methods: In this parallel-group study, Japanese adult smokers (23-65 years; ≥10 mCCs/day) were randomized to mTHS, menthol CCs (mCC), or smoking abstinence (SA) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents and clinically relevant risk markers of smoking-related diseases. Results: One-hundred and sixty participants were randomized to the mTHS (n = 78), mCC (n = 42), and SA (n = 40) groups. Switching to the mTHS was associated with reductions in biomarkers of exposure compared with continuing mCCs. Reductions in 8-epi-prostaglandin F2α (biomarker of oxidative stress), 11-dehydro-thromboxane B2 (biomarker of platelet activation), soluble intracellular adhesion molecule-1 (biomarker of endothelial function), and an increase in high-density lipoprotein cholesterol (biomarker of lipid metabolism) and forced expiratory volume in 1 second (biomarker of lung function) occurred in the mTHS group compared with the mCC group. The changes in the mTHS group approached those in the SA group. Conclusions: Switching from mCCs to mTHS was associated with improvements in clinically relevant risk markers linked to mechanistic pathways involved in smoking-related diseases. Implications: In this three-way randomized study, switching from menthol cigarettes to mTHS for 5 days in confinement and 85 days in ambulatory settings was associated with reductions in biomarkers of exposure to cigarette smoke, and changes were observed in clinically relevant biomarkers of oxidative stress (8-epi-prostaglandin F2α), platelet activity (11-dehydro-thromboxane B2), endothelial function (soluble intracellular adhesion molecule-1), lipid metabolism (high-density lipoprotein cholesterol) and lung function (forced expiratory volume in 1 second), similar to the SA group. The results suggest that switching to the mTHS has the potential to reduce the adverse health effects of conventional cigarettes.

Development and validation of a new instrument to measure perceived risks associated with the use of tobacco and nicotine-containing products.

BACKGROUND: Making tobacco products associated with lower risks available to smokers who would otherwise continue smoking is recognized as an important strategy towards addressing smoking-related harm. Predicting use behavior is an important major component of product risk assessment. In this context, risk perception is a possible factor driving tobacco product uptake and use. As prior to market launch real-world actual product use cannot be observed, assessing risk perception can provide predictive information. Considering the lack of suitable validated self-report instruments, the development of a new instrument was undertaken to quantify perceived risks of tobacco and nicotine-containing products by adult smokers, former smokers and never-smokers. METHODS: Initial items were constructed based on a literature review, focus groups and expert opinion. Data for scale formation and assessment were obtained through two successive US-based web surveys (n = 2020 and 1640 completers, respectively). Psychometric evaluation was based on Rasch Measurement Theory and Classical Test Theory. RESULTS: Psychometric evaluation supported the formation of an 18-item Perceived Health Risk scale and a 7-item Perceived Addiction Risk scale: item response option thresholds were ordered correctly for all items; item locations in each scale were spread out (coverage range 75-87%); scale reliability was supported by high person separation indices > 0.93, Cronbach's alpha > 0.98 and Corrected Item-Total Correlations > 0.88; and no differential item functioning was present. Construct validity evaluations met expectations through inter-scale correlations and findings from known-group comparisons. CONCLUSIONS: The Perceived Risk Instrument is a psychometrically robust instrument applicable for general and personal risk perception measurement, for use in different types of products (including cigarettes, nicotine replacement therapy, potential Modified Risk Tobacco Products), and for different smoking status groups (i.e., current smokers with and without intention to quit, former smokers, never smokers).

Estimating the population health impact of introducing a reduced-risk tobacco product into Japan. The effect of differing assumptions, and some comparisons with the U.S.

We estimated, using previously described methodology, the population health impact of introducing a reduced-risk tobacco product (RRP) into Japan. Various simulations were carried out to understand the impact on the population in different situations over a 20-year period from 1990. The overall reduction in tobacco-attributable deaths from lung cancer (LC), ischemic heart disease (IHD), stroke, and chronic obstructive pulmonary disease (COPD) for men and women combined was estimated to be 269,916 over the period if tobacco use disappeared completely at baseline. In contrast, reductions ranging from 167,041 to 232,519 deaths were estimated if the RRP totally replaced smoking at baseline (assuming that switching to it had an effect equivalent to 70%-90% of the effect of quitting). If, more plausibly, the RRP were introduced at baseline, with uptake rates consistent with the known uptake of the RRP IQOS®, the reductions would still be substantial (from 65,126 to 86,885 deaths). Expressed as a percentage of attributable deaths, these proportions are larger than those for the U.S., based on likely uptake rates. We discuss various limitations of the approach, though none should affect the conclusion that the introduction of an RRP into Japan will substantially reduce tobacco-related deaths.

Quantifying the risk-reduction potential of new Modified Risk Tobacco Products.

Quantitative risk assessment of novel Modified Risk Tobacco Products (MRTP) must rest on indirect measurements that are indicative of disease development prior to epidemiological data becoming available. For this purpose, a Population Health Impact Model (PHIM) has been developed to estimate the reduction in the number of deaths from smoking-related diseases following the introduction of an MRTP. One key parameter of the model, the F-factor, describes the effective dose upon switching from cigarette smoking to using an MRTP. Biomarker data, collected in clinical studies, can be analyzed to estimate the effects of switching to an MRTP as compared to quitting smoking. Based on transparent assumptions, a link function is formulated that translates these effects into the F-factor. The concepts of 'lack of sufficiency' and 'necessity' are introduced, allowing for a parametrization of a family of link functions. These can be uniformly sampled, thus providing different 'scenarios' on how biomarker-based evidence can be translated into the F-factor to inform the PHIM.

Reduced Exposure to Harmful and Potentially Harmful Smoke Constituents With the Tobacco Heating System 2.1.

INTRODUCTION: Heating rather than burning tobacco reduces levels of harmful and potentially harmful constituents, and consumer products using this approach aim to reduce exposure to tobacco toxicants. The Tobacco Heating System (THS) version 2.1 has been enhanced from earlier prototypes with an improved heat control and sensorial experience and thereby user acceptance. Exposure measurements are required to determine whether it may be possible to reduce the individual health risk compared to smoking combustible cigarettes (CCs). METHODS: This controlled clinical study randomly assigned 40 smokers to either a group continuing to use of their own CC brand (n = 20) or a group switching to THS 2.1 (n = 20) for 5 days. Biomarkers of exposure were measured at baseline and on day 1 through day 5. Product consumption, Human Puffing Topography, the occurrence of adverse events, and an assessment of subjective effects, such as smoking satisfaction and enjoyment of respiratory tract sensations, were also determined. RESULTS: The group of smokers who switched to THS 2.1 adapted their puffing behavior initially through longer puff duration and more puffs. During the duration of the study, total puff volume returned to baseline levels and the mean daily product consumption increased but with similar nicotine exposure compared to baseline CC use. Biomarkers of exposure to tobacco smoke toxicants which inform product risk assessment were significantly reduced with THS use compared to the CC group. THS 2.1 users experienced less reinforcing effects with THS 2.1 than with their own cigarette brand. CONCLUSIONS: THS 2.1 is a promising alternative to smoking CCs. Notwithstanding possible use adaption through consumption or puffing behavior, the exposure to harmful smoke constituents was markedly reduced with the new heated tobacco platform. IMPLICATIONS: Exposure markers to harmful and potentially harmful smoke constituents were lowered with the THS 2.1. Heating tobacco instead of burning can offer a potentially lower risk of delivering nicotine compared to CCs.

Nicotine pharmacokinetic profiles of the Tobacco Heating System 2.2, cigarettes and nicotine gum in Japanese smokers.

Two open-label randomized cross-over studies in Japanese smokers investigated the single-use nicotine pharmacokinetic profile of the Tobacco Heating System (THS) 2.2, cigarettes (CC) and nicotine replacement therapy (Gum). In each study, one on the regular and one on the menthol variants of the THS and CC, both using Gum as reference, 62 subjects were randomized to four sequences: Sequence 1: THS - CC (n = 22); Sequence 2: CC - THS (n = 22); Sequence 3: THS - Gum (n = 9); Sequence 4: Gum - THS (n = 9). Plasma nicotine concentrations were measured in 16 blood samples collected over 24 h after single use. Maximal nicotine concentration (Cmax) and area under the curve from start of product use to time of last quantifiable concentration (AUC0-last) were similar between THS and CC in both studies, with ratios varying from 88 to 104% for Cmax and from 96 to 98% for AUC0-last. Urge-to-smoke total scores were comparable between THS and CC. The THS nicotine pharmacokinetic profile was close to CC, with similar levels of urge-to-smoke. This suggests that THS can satisfy smokers and be a viable alternative to cigarettes for adult smokers who want to continue using tobacco.

Estimating the effect of differing assumptions on the population health impact of introducing a Reduced Risk Tobacco Product in the USA.

We use Population Health Impact Modelling to assess effects on tobacco prevalence and mortality of introducing a Reduced Risk Tobacco Product (RRP). Simulated samples start in 1990 with a US-representative smoking prevalence. Individual tobacco histories are updated annually until 2010 using estimated probabilities of switching between never/current/former smoking where the RRP is not introduced, with current users subdivided into cigarette/RRP/dual users where it is. RRP-related mortality reductions from lung cancer, IHD, stroke and COPD are derived from the histories and the assumed relative risks of the RRP. A basic analysis assumes a hypothetical RRP reduces effective dose 80% in users and 40% in dual users, with an uptake rate generating ∼10% RRP and ∼6% dual users among current users after 10 years. Sensitivity study changes in tobacco prevalence and mortality from varying effective doses, current smoking risks, quitting half-lives and rates of initiation, switching, re-initiation and cessation. They also study extreme situations (e.g. everyone using RRP), and investigate assumptions which might eliminate the RRP-related mortality reduction. The mortality reduction is proportional to the dose reduction, increasing rapidly with time of follow-up. Plausible increases in re-initiation or dual users' consumption, or decreased quitting by smokers would not eliminate the drop.

Evaluation of Biomarkers of Exposure in Smokers Switching to a Carbon-Heated Tobacco Product: A Controlled, Randomized, Open-Label 5-Day Exposure Study.

INTRODUCTION: Tobacco harm reduction aims to provide reduced risk alternatives to adult smokers who would otherwise continue smoking combustible cigarettes (CCs). This randomized, open-label, three-arm, parallel-group, single-center, short-term confinement study aimed to investigate the effects of exposure to selected harmful and potentially harmful constituents (HPHCs) of cigarette smoke in adult smokers who switched to a carbon-heated tobacco product (CHTP) compared with adult smokers who continued to smoke CCs and those who abstained from smoking for 5 days. METHODS: Biomarkers of exposure to HPHCs, including nicotine and urinary excretion of mutagenic material, were measured in 24-hour urine and blood samples in 112 male and female Caucasian smokers switching from CCs to the CHTP ad libitum use. Puffing topography was assessed during product use. RESULTS: Switching to the CHTP or smoking abstinence (SA) resulted in marked decreases from baseline to Day 5 in all biomarkers of exposure measured, including carboxyhemoglobin (43% and 55% decrease in the CHTP and SA groups, respectively). The urinary excretion of mutagenic material was also markedly decreased on Day 5 compared with baseline (89% and 87% decrease in the CHTP and SA groups, respectively). No changes in biomarkers of exposure to HPHCs or urinary mutagenic material were observed between baseline and Day 5 in the CC group. CONCLUSIONS: Our results provide clear evidence supporting a reduction in the level of exposure to HPHCs of tobacco smoke in smokers who switch to CHTP under controlled conditions, similar to that observed in SA. IMPLICATIONS: The reductions observed in biomarkers of exposure to HPHCs of tobacco smoke in this short-term study could potentially also reduce the incidence of cancer, cardiovascular and respiratory diseases in those smokers who switch to a heated tobacco product.

Comparison of the Pharmacokinetics of Nicotine Following Single and Ad Libitum Use of a Tobacco Heating System or Combustible Cigarettes.

INTRODUCTION: We aimed to compare the pharmacokinetics of nicotine between the heat-not-burn Tobacco Heating System 2.1 (THS 2.1) and combustible cigarettes (CCs). We also examined whether the subjective urge to smoke was associated with the pharmacokinetics of nicotine. METHODS: This open-label, randomized, two-period, two-sequence crossover study conducted in 28 healthy smokers assessed the pharmacokinetics of nicotine after single and ad libitum use of the THS 2.1 or CCs. During the 7-day confinement period, blood samples were drawn for pharmacokinetic analysis. Subjective effects related to THS 2.1 or CC use were assessed using the Questionnaire of Smoking Urges (QSU-Brief). RESULTS: The nicotine delivery rate was similar with the THS 2.1 and CCs after single and ad libitum use. The time to the maximum nicotine concentration was 8 minutes after single use of the THS 2.1 and CCs. The time to the peak concentration following ad libitum use was similar between the THS 2.1 and CCs. The maximum plasma nicotine concentration after single use of the THS 2.1 was 8.4 ng/mL, 70.3% of that obtained with CCs. A transient reduction from baseline in the urge to smoke of 40% was observed 15 minutes after the single use of both the THS 2.1 and CCs. The mean QSU-Brief total scores following single and ad libitum use were similar for the THS 2.1 and CCs. CONCLUSIONS: These results suggest that the THS 2.1 effectively delivers nicotine and achieves similar pharmacokinetic profiles to CCs. The THS 2.1 also reduced the urge to smoke similarly to CCs. IMPLICATIONS: Reducing exposure to toxicants and safer delivery of nicotine are among the strategies that may reduce the harm of smoking-related diseases. In the present study, we investigated the pharmacokinetics of nicotine and their effects on the urge to smoke using the THS 2.1. It was developed to replicate the ritual of smoking as closely as possible by providing nicotine in a way that mimics CC smoking, but limits pyrolysis and combustion by heating tobacco at a much lower temperature than CCs (heat-not-burn).

A Japanese cross-sectional multicentre study of biomarkers associated with cardiovascular disease in smokers and non-smokers.

We performed a cross-sectional, multicentre study in Japan to detect the differences in biomarkers of exposure and cardiovascular biomarkers between smokers and non-smokers. Several clinically relevant cardiovascular biomarkers differed significantly between smokers and non-smokers, including lipid metabolism (high-density lipoprotein cholesterol concentrations - lower in smokers), inflammation (fibrinogen and white blood cell count - both higher in smokers), oxidative stress (8-epi-prostaglandin F2α - higher in smokers) and platelet activation (11-dehydro-thromboxane B2 - higher in smokers) (p ≤ 0.0001). These results provide further evidence showing that cardiovascular biomarkers can discriminate smokers from non-smokers, and could be used to evaluate the risks associated with tobacco products.

A novel approach to assess the population health impact of introducing a Modified Risk Tobacco Product.

Based on the Food and Drug Administration's Modified Risk Tobacco Product (MRTP) Application draft guideline, Philip Morris International (PMI) has developed a Population Health Impact Model to estimate the reduction in the number of deaths over a period following the introduction of an MRTP. Such a model is necessary to assess the effect that its introduction would have on population health, given the lack of epidemiological data available prior to marketing authorization on any risks from MRTPs. The model is based on publicly available data on smoking prevalence and on the relationships between smoking-related disease-specific mortality and various aspects of the smoking of conventional cigarettes (CCs), together with an estimate of exposure from the MRTP relative to that from CCs, and allows the exploration of possible scenarios regarding the effect of MRTP introduction on the prevalence of CC and MRTP use, individually and in combination. By comparing mortality attributable in a scenario where the MRTP is introduced with one where it is not, the model can estimate the mortality attributable to CCs and the MRTP, as well as the reduction in the deaths attributable to the introduction of the MRTP.

Development and initial validation of a new self-report measure to assess perceived dependence on tobacco and nicotine products.

How nicotine is administered has evolved from cigarettes to various delivery systems. Assessing perceived dependence on nicotine-containing products now requires accounting for product specificity while allowing comparisons across products and users. This study aims to develop a new self-report measure to assess perceived dependence on tobacco and nicotine products (TNPs) among exclusive and poly-TNP users. A draft version of the new measure, the ABOUT-Dependence, was constructed based on literature review, qualitative research, and expert opinion. Data for scale formation and psychometric assessment was obtained through a US-based web survey (n = 2334) that included additional dependence measures for convergent validity assessment. Qualitative research confirmed a preliminary conceptual framework with seven sub-concepts. Following a cognitive debriefing, 19 items were considered to best represent the different sub-concepts. Psychometric findings supported a three-domain structure [i.e., behavioral impact (five items), signs and symptoms (five items), and extent/timing of use (two items)] and an overall total composite score. The data confirmed convergent and known-group validity, as well as test-retest reliability. The ABOUT-Dependence is a 12-item, psychometrically sound, self-report measure that may be used as a tool for research and further understanding of perceived dependence across the spectrum of TNP and TNP users.