Multicenter experience with valve-in-valve transcatheter aortic valve replacement compared with primary, native valve transcatheter aortic valve replacement.

BACKGROUND: Valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) offers an alternative to reoperative surgical aortic valve replacement. The short- and intermediate-term outcomes after ViV TAVR in the real world are not entirely clear. PATIENTS AND METHODS: A multicenter, retrospective analysis of a consecutive series of 121 ViV TAVR patients and 2200 patients undergoing primary native valve TAVR from 2012 to 2017 at six medical centers. The main outcome measures were in-hospital mortality, 30-day mortality, stroke, myocardial infarction, acute kidney injury, and pacemaker implantation. RESULTS: ViV patients were more likely male, younger, prior coronary artery bypass graft, "hostile chest," and urgent. 30% of the patients had Society of Thoracic Surgeons risk score <4%, 36.3% were 4%-8% and 33.8% were >8%. In both groups many patients had concomitant coronary artery disease. Median time to prosthetic failure was 9.6 years (interquartile range: 5.5-13.5 years). 82% of failed surgical valves were size 21, 23, or 25 mm. Access was 91% femoral. After ViV, 87% had none or trivial aortic regurgitation. Mean gradients were <20 mmHg in 54.6%, 20-29 mmHg in 30.6%, 30-39 mmHg in 8.3% and ≥40 mmHg in 5.87%. Median length of stay was 4 days. In-hospital mortality was 0%. 30-day mortality was 0% in ViV and 3.7% in native TAVR. There was no difference in in-hospital mortality, postprocedure myocardial infarction, stroke, or acute kidney injury. CONCLUSION: Compared to native TAVR, ViV TAVR has similar peri-procedural morbidity with relatively high postprocedure mean gradients. A multidisciplinary approach will help ensure patients receive the ideal therapy in the setting of structural bioprosthetic valve degeneration.

Estimating the public health impact had tobacco-free nicotine pouches been introduced into the US in 2000.

BACKGROUND: For smokers not intending to quit, switching to a reduced-risk nicotine product should be healthier than continuing smoking. We estimate the health impact, over the period 2000-2050, had the nicotine pouch ZYN hypothetically been introduced into the US in 2000. ZYN's toxicant profile and method of use is like that for Swedish snus, a product with known health effects much less than smoking. METHODS: Our modelling approach is similar to others developed for estimating potential effects of new tobacco products. It starts with a simulated cohort of 100,000 individuals in the year 2000 subdivided by age, sex, and smoking status (including years since quitting). They are followed annually accounting for births, net immigrations, deaths and product use changes, with follow-up carried out in the Base Case (ZYN not introduced) and Modified Case (ZYN introduced). Using informed assumptions about initiation, quitting and switching rates, distributions of the population over time are then constructed for each Case, and used to estimate product mortality based on assumptions about the relative risk according to product use. RESULTS: Whereas in both Base and Modified Cases, the prevalence of any current product use is predicted to decline from about 22% to 10% during follow-up, in the Modified Case about 25% of current users use ZYN by 2050, about a quarter being dual users and the rest ZYN-only users. Over the 50 years, deaths at ages 35-84 from product use among the 100,000 are estimated as 249 less in the Modified than the Base Case, equivalent to about 700,000 less in the whole US. Sensitivity analyses varying individual parameter values confirm the benefits of switching to ZYN, which increase as either the switching rate to ZYN increases or the initiation rate of ZYN relative to smoking increases. Even assuming the reduction in excess mortality risk using ZYN use is 20% of that from smoking rather than the 3.5% assumed in the main analyses, the reduction in product-related deaths would still be 213, or about 600,000 in the US. CONCLUSIONS: Although such model-based estimates involve uncertainties, the results suggest that introducing ZYN could substantially reduce product-related deaths.

Estimating the reduction in US mortality if cigarettes were largely replaced by e-cigarettes.

BACKGROUND: Recent estimates indicated substantially replacing cigarettes by e-cigarettes would, during 2016-2100, reduce US deaths and life-years lost (millions) by 6.6 and 86.7 (Optimistic Scenario) and 1.6 and 20.8 (Pessimistic). To provide additional insight we use alternative modelling based on a shorter period (1991-2040), four main smoking-associated diseases, deaths aged 30-79 years, and a full product history. We consider variations in: assumed effective dose of e-cigarettes versus cigarettes (F); their relative quitting rate (Q); proportions smoking after 10 years (X); and initiation rate (I) of vaping, relative to smoking. METHODS: We set F = 0.05, X = 5%, Q = 1.0 and I = 1.0 (Main Scenario) and F = 0.4, X = 10%, Q = 0.5 and I = 1.5 (Pessimistic Scenario). Sensitivity Analyses varied Main Scenario parameters singly; F from 0 to 0.4, X 0.01% to 15%, and Q and I 0.5 to 1.5. To allow comparison with prior work, individuals cannot be dual users, re-initiate, or switch except from cigarettes to e-cigarettes. RESULTS: Main Scenario reductions were 2.52 and 26.23 million deaths and life-years lost; Pessimistic Scenario reductions were 0.76 and 8.31 million. These were less than previously, due to the more limited age-range and follow-up, and restriction to four diseases. Reductions in deaths (millions) varied most for X, from 3.22 (X = 0.01%) to 1.31 (X = 15%), and F, 2.74 (F = 0) to 1.35 (F = 0.4). Varying Q or I had little effect. CONCLUSIONS: Substantial reductions in deaths and life-years lost were observed even under pessimistic assumptions. Estimates varied most for X and F. These findings supplement literature indicating e-cigarettes can importantly impact health challenges from smoking.

Awareness and preparedness of healthcare workers against the first wave of the COVID-19 pandemic: A cross-sectional survey across 57 countries.

BACKGROUND: Since the COVID-19 pandemic began, there have been concerns related to the preparedness of healthcare workers (HCWs). This study aimed to describe the level of awareness and preparedness of hospital HCWs at the time of the first wave. METHODS: This multinational, multicenter, cross-sectional survey was conducted among hospital HCWs from February to May 2020. We used a hierarchical logistic regression multivariate analysis to adjust the influence of variables based on awareness and preparedness. We then used association rule mining to identify relationships between HCW confidence in handling suspected COVID-19 patients and prior COVID-19 case-management training. RESULTS: We surveyed 24,653 HCWs from 371 hospitals across 57 countries and received 17,302 responses from 70.2% HCWs overall. The median COVID-19 preparedness score was 11.0 (interquartile range [IQR] = 6.0-14.0) and the median awareness score was 29.6 (IQR = 26.6-32.6). HCWs at COVID-19 designated facilities with previous outbreak experience, or HCWs who were trained for dealing with the SARS-CoV-2 outbreak, had significantly higher levels of preparedness and awareness (p<0.001). Association rule mining suggests that nurses and doctors who had a 'great-extent-of-confidence' in handling suspected COVID-19 patients had participated in COVID-19 training courses. Male participants (mean difference = 0.34; 95% CI = 0.22, 0.46; p<0.001) and nurses (mean difference = 0.67; 95% CI = 0.53, 0.81; p<0.001) had higher preparedness scores compared to women participants and doctors. INTERPRETATION: There was an unsurprising high level of awareness and preparedness among HCWs who participated in COVID-19 training courses. However, disparity existed along the lines of gender and type of HCW. It is unknown whether the difference in COVID-19 preparedness that we detected early in the pandemic may have translated into disproportionate SARS-CoV-2 burden of disease by gender or HCW type.

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.

Further investigation of gateway effects using the PATH study.

Background: Interest exists in whether youth e-cigarette use ("vaping") increases risk of initiating cigarette smoking. Using Waves 1 and 2 of the US PATH study we reported that adjustment for vaping propensity using Wave 1 variables explained about 80% of the unadjusted relationship. Here we use data from Waves 1 to 3 to avoid over-adjustment if Wave 1 vaping affected variables recorded then. Methods: Our main analysis M1 concerned Wave 2 never smokers who never vaped by Wave 1, linking Wave 2 vaping to Wave 3 smoking initiation, adjusting for Wave 1 predictors. We conducted sensitivity analyses that: excluded Wave 1 other tobacco product users; included other product use as an extra predictor; or considered propensity for smoking or any tobacco use, rather than vaping. We also conducted analyses that: adjusted for propensity as derived originally; ignored Wave 1 data; used exact age (not previously available) as a confounder rather than grouped age; attempted residual confounding adjustment by modifying predictor values using data recorded later; or considered interactions with age. Results: In M1, adjustment removed about half the excess OR (i.e. OR-1), the unadjusted OR, 5.60 (95% CI 4.52-6.93), becoming 3.37 (2.65-4.28), 3.11 (2.47-3.92) or 3.27 (2.57-4.16), depending whether adjustment was for propensity as a continuous variable, as quintiles, or for the variables making up the propensity score. Many factors had little effect: using grouped or exact age; considering other products; including interactions; or using predictors of smoking or tobacco use rather than vaping. The clearest conclusion was that analyses avoiding over-adjustment explained about half the excess OR, whereas analyses subject to over-adjustment explained about 80%. Conclusions: Although much of the unadjusted gateway effect results from confounding, we provide stronger evidence than previously of some causal effect of vaping, though some doubts still remain about the completeness of adjustment.

Investigating the effect of e-cigarette use on quitting smoking in adults aged 25 years or more using the PATH study.

Background: The evidence on harms and benefits of e-cigarettes partly concerns whether their use encourages smokers to quit.  We addressed this using data from the nationally representative PATH study, with detailed accounting for potential confounding variables. Methods: We considered adults aged 25+.  Our original analyses, reported in version 1 of this paper, used data for Waves 1 to 3, separate analyses considering Waves 1 to 2, 2 to 3 and 1 to 3.  These related baseline ever e-cigarette use (or e-product use at Wave 2) to quitting at follow-up, adjusting for confounders derived from 55 candidates.  Sensitivity analyses omitted ever other product users, linked quitting to current e-cigarette use, and used values of some predictors modified using follow-up data.  Additional analyses used data for Waves 1 to 4, separately considering sustained, delayed and temporary quitting during Waves 1 to 3, 2 to 4 and 1 to 4.  Sensitivity analyses considered 30-day quitting, restricted attention to smokers attempting to quit, and considered ever smokeless tobacco or snus use. Results: In the original analyses, unadjusted odds ratios (ORs) of quitting smoking for ever e-cigarette use were 1.29 (95% CI 1.01-1.66), 1.52 (1.26-1.83) and 1.47 (1.19-1.82) for the Wave 1 to 2, 2 to 3, and 1 to 3 analyses.  These reduced after adjustment, to 1.23 (0.94-1.61), 1.51 (1.24-1.85) and 1.39 (1.11-1.74).  Quitting rates remained elevated in users in all sensitivity analyses.  The additional analyses found associations of e-cigarette use with sustained, delayed and temporary quitting, associations little affected by considering 30-day quitting, and only slightly reduced restricting attention to quit attempters.  Ever use of smokeless tobacco or snus also predicted increased quitting.   Conclusions: As does most evidence from clinical trials, other analyses of PATH, and other epidemiological studies, our results suggest using e-cigarettes helps adult smokers to quit.

Methodological steps used by authors of systematic reviews and meta-analyses of clinical trials: a cross-sectional study.

BACKGROUND: The quality of systematic reviews and meta-analyses (SR/MAs) depends on the extent of the methods used. We investigated the methodological steps used by authors of SR/MAs of clinical trials via an author survey. METHODS: We conducted an email-based cross-sectional study by contacting corresponding authors of SR/MAs that were published in 2015 and 2016 and retrieved through the PubMed database. The 27-item questionnaire was developed to study the methodological steps used by authors when conducting a SR/MA and the demographic characteristics of the respondent. Besides the demographic characteristics, methodological questions regarding the source, extraction and synthesis of data were included. RESULTS: From 10,292 emails sent, 384 authors responded and were included in the final analysis. Manual searches were carried out by 69.2% of authors, while 87.3% do updated searches, 49.2% search grey literature, 74.9% use the Cochrane tool for risk of bias assessment, 69.8% assign more than two reviewers for data extraction, 20.5% use digital software to extract data from graphs, 57.9% use raw data in the meta-analysis, and 43.8% meta-analyze both adjusted and non-adjusted data. There was a positive correlation of years of experience in conducting of SR/MAs with both searching grey literature (P = 0.0003) and use of adjusted and non-adjusted data (P = 0.006). CONCLUSIONS: Many authors still do not carry out many of the vital methodological steps to be taken when performing any SR/MA. The experience of the authors in SR/MAs is highly correlated with use of the recommended tips for SR/MA conduct. The optimal methodological approach for researchers conducting a SR/MA should be standardized.

Updating the evidence relating smoking bans to incidence of heart disease.

In our latest update of the evidence on smoking bans and heart disease we summarize 59 studies. We take account of the underlying trends in incidence rates as far as possible by using control data in eight studies, and by adjustment based on observed trends in cases pre- and post-ban in 40 studies, being unable to make an adjustment in the remaining 11 studies. Overall, based on 62 independent estimates from the 59 studies, we estimate that bans reduce incidence by 5.0% (95% CI 3.2-6.8%), though this estimate reduces to 2.9% (0.01-5.6%) when we exclude regional estimates where national estimates are available, and studies where trend adjustment is not possible. For 25 of the studies, quadratic rather than linear adjustment is possible, but this hardly affects the overall estimates. Ban effects are somewhat greater when the pre-ban period studied is relatively short, and in smaller studies. We compare our findings with those in other recent reviews, one of which totally ignored underlying trends and results from control populations. We discuss reasons why we believe there is likely to be a true small effect of smoking bans, and weaknesses in the data which preclude reaching any very confident conclusion.

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.

Modeling the Population Health Impact of Introducing a Modified Risk Tobacco Product into the U.S. Market.

Philip Morris International (PMI) has developed the Population Health Impact Model (PHIM) to quantify, in the absence of epidemiological data, the effects of marketing a candidate modified risk tobacco product (cMRTP) on the public health of a whole population. Various simulations were performed to understand the harm reduction impact on the U.S. population over a 20-year period under various scenarios. The overall reduction in smoking attributable deaths (SAD) over the 20-year period was estimated as 934,947 if smoking completely went away and between 516,944 and 780,433 if cMRTP use completely replaces smoking. The reduction in SADs was estimated as 172,458 for the World Health Organization (WHO) 2025 Target and between 70,274 and 90,155 for the gradual cMRTP uptake. Combining the scenarios (WHO 2025 Target and cMRTP uptake), the reductions were between 256,453 and 268,796, depending on the cMRTP relative exposure. These results show how a cMRTP can reduce overall population harm additionally to existing tobacco control efforts.

Tar level of cigarettes smoked and risk of smoking-related diseases.

BACKGROUND: Opinions differ on the relationship between tar level and risk of smoking-related disease. However, except for lung cancer, few reviews have evaluated the epidemiological evidence. Here the relationship of tar level to risk of the four main smoking-related diseases is considered. METHODS: Papers comparing risk of lung cancer, COPD, heart disease or stroke in smokers of lower and higher tar yield cigarettes were identified from reviews and searches, relative risk estimates being extracted comparing the lowest and highest tar groups. Meta-analyses investigated heterogeneity by various study characteristics. RESULTS: Twenty-six studies were identified, nine of prospective design and 17 case-control. Two studies grouped cigarettes by nicotine rather than tar. Seventeen studies gave results for lung cancer, 16 for heart disease, five for stroke and four for COPD. Preferring relative risks adjusted for daily amount smoked, where adjusted and unadjusted estimates were available, combined estimates for lowest versus highest tar (or nicotine) groups were 0.78 (95% confidence interval 0.70-0.88) for lung cancer, 0.86 (0.81-0.91) for heart disease, 0.77 (0.62-0.95) for stroke and 0.81 (0.65-1.02) for COPD. Lower risks were generally evident in subgroups by publication period, gender, study design, location and extent of confounder adjustment. Estimates were similar preferring data unadjusted for amount smoked or excluding nicotine-based estimates. CONCLUSIONS: Despite evidence that smokers substantially compensate for reduced cigarette yields, the results clearly show lower risks in lower tar smokers. Limitations of the evidence are discussed, but seem unlikely to affect this conclusion.

Epidemiological evidence relating environmental smoke to COPD in lifelong non-smokers: a systematic review.

Background: Some evidence suggests environmental tobacco smoke (ETS) might cause chronic obstructive pulmonary disease (COPD). We reviewed available epidemiological data in never smokers. Methods: We identified epidemiological studies providing estimates of relative risk (RR) with 95% confidence interval (CI) for various ETS exposure indices. Confounder-adjusted RRs for COPD were extracted, or derived using standard methods. Meta-analyses were conducted for each exposure index, with tests for heterogeneity and publication bias. For the main index (spouse ever smoked or nearest equivalent), analyses investigated variation in RR by location, publication period, study type, sex, diagnosis, study size, confounder adjustment, never smoker definition, and exposure index definition. Results: Twenty-eight relevant studies were identified; nine European or Middle Eastern, nine Asian, eight American and two from multiple countries. Five were prospective, seven case-control and 16 cross-sectional. The COPD definition involved death or hospitalisation in seven studies, GOLD stage 1+ criteria in twelve, and other definitions in nine. For the main index, random-effects meta-analysis of 33 heterogeneous (p<0.001) estimates gave a RR of 1.20 (95%CI 1.08-1.34). Higher estimates for females (1.59,1.16-2.19, n=11) than males (1.29,0.94-1.76, n=7) or sexes combined (1.10,0.99-1.22, n=15 where sex-specific not available), and lower estimates for studies of 150+ cases (1.08,0.97-1.20, n=13) partly explained the heterogeneity. Estimates were higher for Asian studies (1.34,1.08-1.67, n=10), case-control studies (1.55,1.04-2.32, n=8), and COPD mortality or hospitalisation (1.40,1.12-1.74, n=11). Some increase was seen for severer COPD (1.29,1.10-1.52, n=7). Dose-response evidence was heterogeneous. Evidence for childhood (0.88,0.72-1.07, n=2) and workplace (1.12,0.77-1.64, n=4) exposure was limited, but an increase was seen for overall adulthood exposure (1.20,1.03-1.39, n=17). We discuss study weaknesses that may bias estimation of the association of COPD with ETS. Conclusions: Although the evidence suggests ETS increases COPD, study weaknesses and absence of well-designed large studies precludes reliable inference of causality. More definitive evidence is required.

The relationship of cigarette smoking in Japan to lung cancer, COPD, ischemic heart disease and stroke: A systematic review.

Background:  To present up-to-date meta-analyses of evidence from Japan relating smoking to major smoking-related diseases.  Methods:  We restricted attention to lung cancer, chronic obstructive pulmonary disease (COPD), ischemic heart disease (IHD) and stroke, considering relative risks (RRs) for current and ex-smokers relative to never smokers.  Evidence by amount smoked and time quit was also considered.  For IHD and stroke only, studies had to provide age-adjusted RRs, with age-specific results considered.  For each disease we extended earlier published databases to include more recent studies.  Meta-analyses were conducted, with random-effects RRs and tests of heterogeneity presented.  Results:  Of 40 studies, 26 reported results for lung cancer and 7 to 9 for each other disease.  For current smoking, RRs (95%CIs) were lung cancer 3.59 (3.25-3.96), COPD 3.57 (2.72-4.70), IHD 2.21 (1.96-2.50) and stroke 1.40 (1.25-1.57).  Ex-smoking RRs were lower.  Data for lung cancer and IHD showed a clear tendency for RRs to rise with increasing amount smoked and decrease with increasing time quit.  Dose-response data were unavailable for COPD and unclear for stroke, where the association was weaker.  Conclusions:  Compared to studies in other Asian and Western countries, current smoking RRs were quite similar for IHD and stroke.  The comparison is not clear for COPD, where the Japanese data, mainly from cross-sectional studies, is limited.  For lung cancer, the RRs are similar to those in other Asian countries, but substantially lower than in Western countries.  Explanations for this are unclear, but less accurate reporting of smoking by Japanese may contribute to the difference.

Considerations related to vaping as a possible gateway into cigarette smoking: an analytical review.

Background: Toxicant levels are much lower in e-cigarettes than cigarettes. Therefore, introducing e-cigarettes into the market seems likely to reduce smoking-related diseases (SRD). However, vaping might provide a gateway into cigarette smoking for those who otherwise would never have smoked, a concern fuelled by cohort studies showing vaping predicts subsequent smoking initiation in young people. Methods: In this discussion paper, we consider various aspects of the gateway issue in youths. We provide a descriptive critical review of results from prospective studies relating to the gateway effect and the extent to which the studies considered other potential confounding variables associated with smoking initiation. We then estimate the effects of omitting a confounding variable, or misclassifying it, on the association between vaping and subsequent smoking initiation, and determine how the prevalence of smoking might be affected by any true gateway effects of vaping. Finally, we examine trends in e-cigarette and smoking prevalence in youths based on national surveys. Results: First, we demonstrate that although studies report that vaping significantly predicts smoking initiation following adjustment for various other predictors, the sets of predictors considered are quite incomplete. Furthermore, no study considered residual confounding arising from inaccurate measurement of predictors. More precise adjustment may substantially reduce the association. Second, we show any true gateway effect would likely affect smoking prevalence only modestly. Third, we show smoking prevalence in U.S. and U.K. youths in 2014-2016 declined somewhat faster than predicted by the preceding trend; a substantial gateway effect suggests the opposite. Finally, we argue that even if some gateway effect exists, introducing e-cigarettes still likely reduces SRDs. Conclusions: Given that the existence of any true gateway effect in youth is not yet clearly demonstrated the population health impact of introducing e-cigarettes is still likely to be beneficial.

The relationship of snus use to diabetes and allied conditions.

A recent meta-analysis reported smoking to be associated with a 37% higher risk of type 2 diabetes in current smokers, rising to a 57% increase in heavy smokers, which declines on quitting. If the increase results from nicotine exposure, it is possible that using Swedish moist snuff ("snus"), which provides at least equivalent nicotine doses, might also increase diabetes risk. Following a recent publication reporting pooled results from five cohorts, we present a detailed meta-analysis of data from 18 studies. Based on covariate-adjusted estimates, no significant increased risk was seen in never smokers with RRs (95% CIs) of 1.08 (0.86-1.34), 0.93 (0.79-1.11) and 1.05 (0.94-1.18) for current, former and ever snus users. Significant increases were also not seen in the whole population, the corresponding RR estimates being 1.18 (0.94-1.48), 0.69 (0.49-0.96) and 0.95 (0.81-1.11). Nor was there an association of snus use with related endpoints, such as impaired glucose tolerance. However, dose-response analyses showed a relationship, with the highest levels of snus exposure associated with a diabetes RR of 1.65 (1.25-2.18) in never smokers. The evidence relating snus to type 2 diabetes is somewhat limited, requiring further studies to confirm any possible relationship.

Investigation into the risk of ultra-low tar cigarettes and lung cancer.

We present analyses relating cigarette type to lung cancer based on a case-control study in five European countries. The analyses involved 3561 cases and 2301 controls with diseases not associated with smoking. Subjects completed a detailed questionnaire, including a lifetime smoking history. Analyses included never smokers, and those who smoked for at least 80% of the "critical period" from 2 to 20 years before diagnosis, ignoring those who ever smoked pipes or cigars, or chewed tobacco. The main analysis compares risk in those who, in the critical period, smoked ultra-low tar (ULT) cigarettes (machine yield ≤3 mg tar/cigarette) for 8 + years, with those who only smoked full flavour (FF) cigarettes (≥10 mg tar/cigarette). After adjustment for sex, age, country, education, age of starting smoking, mean cigarette consumption and mean tar level 21-50 years before interview, the odds ratio (OR) was 0.73 (95% confidence interval (CI) 0.50-1.06). Other analyses showed a modest, not statistically significant, reduction in risk with tar reduction. Risk in ULT smokers for 8 + years was substantially higher than in never smokers (OR 16.27, 95% CI 10.14-26.09). The study was prematurely terminated due to cost overrun, limiting the power to detect an association. More evidence is needed, particularly on lifetime ULT smoking.

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.

Environmental Tobacco Smoke Exposure and Risk of Stroke in Never Smokers: An Updated Review with Meta-Analysis.

OBJECTIVES: The study aimed to review the epidemiological evidence relating environmental tobacco smoke exposure to stroke in never smokers. METHODS: The study is similar to our review in 2006, with searches extended to March 2016. RESULTS: Twelve further studies were identified. A total of 28 studies varied considerably in design, exposure indices used, and disease definition. Based on 39 sex-specific estimates and the exposure index current spousal exposure (or nearest equivalent), the meta-analysis gave an overall fixed-effect relative risk estimate of 1.23 (95% confidence interval: 1.16-1.31), with significant (P < .05) heterogeneity. There was no significant heterogeneity by sex, continent, fatality, disease end point, or degree of adjustment for potential confounding factors. Relative risks were less elevated in prospective studies (1.15, 1.06-1.24) than in case-control studies (1.44, 1.22-1.60) or cross-sectional studies (1.40, 1.21-1.61). They also varied by publication year, but with no trend. A significant increase was not seen in studies that excluded smokers of any tobacco (1.07, .97-1.17), but was seen for studies that included pipe- or cigar-only smokers, occasional smokers, or long-term former smokers. No elevation was seen for hemorrhagic stroke. Relative risk estimates were similar using ever rather than current exposure, or total rather than spousal exposure. Eleven studies provided dose-response estimates, the combined relative risk for the highest exposure level being 1.56 (1.37-1.79). Many studies have evident weaknesses, recall bias, and particularly publication bias being major concerns. CONCLUSIONS: Although other reviewers inferred a causal relationship, we consider the evidence does not conclusively demonstrate this. We repeat our call for publication of data from existing large prospective studies.

A systematic review of possible serious adverse health effects of nicotine replacement therapy.

We conducted a systematic literature review to identify and critically evaluate studies of serious adverse health effects (SAHEs) in humans using nicotine replacement therapy (NRT) products. Serious adverse health effects refer to adverse events, leading to substantial disruption of the ability to conduct normal life functions. Strength of evidence evaluations and conclusions were also determined for the identified SAHEs. We evaluated 34 epidemiological studies and clinical trials, relating NRT use to cancer, reproduction/development, CVD, stroke and/or other SAHEs in patients, and four meta-analyses on effects in healthy populations. The overall evidence suffers from many limitations, the most significant being the short-term exposure (≤12 weeks) and follow-up to NRT product use in most of the studies, the common failure to account for changes in smoking behaviour following NRT use, and the sparse information on SAHEs by type of NRT product used. The only SAHE from NRT exposure we identified was an increase in respiratory congenital abnormalities reported in one study. Limited evidence indicated a lack of effect between NRT exposure and SAHEs for CVD and various reproduction/developmental endpoints. For cancer, stroke and other SAHEs, the evidence was inadequate to demonstrate any association with NRT use. Our conclusions agree with recent statements from authoritative bodies.