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1.  Effect of active smoking on the human bronchial epithelium transcriptome 
BMC Genomics  2007;8:297.
Background
Lung cancer is the most common cause of cancer-related deaths. Tobacco smoke exposure is the strongest aetiological factor associated with lung cancer. In this study, using serial analysis of gene expression (SAGE), we comprehensively examined the effect of active smoking by comparing the transcriptomes of clinical specimens obtained from current, former and never smokers, and identified genes showing both reversible and irreversible expression changes upon smoking cessation.
Results
Twenty-four SAGE profiles of the bronchial epithelium of eight current, twelve former and four never smokers were generated and analyzed. In total, 3,111,471 SAGE tags representing over 110 thousand potentially unique transcripts were generated, comprising the largest human SAGE study to date. We identified 1,733 constitutively expressed genes in current, former and never smoker transcriptomes. We have also identified both reversible and irreversible gene expression changes upon cessation of smoking; reversible changes were frequently associated with either xenobiotic metabolism, nucleotide metabolism or mucus secretion. Increased expression of TFF3, CABYR, and ENTPD8 were found to be reversible upon smoking cessation. Expression of GSK3B, which regulates COX2 expression, was irreversibly decreased. MUC5AC expression was only partially reversed. Validation of select genes was performed using quantitative RT-PCR on a secondary cohort of nine current smokers, seven former smokers and six never smokers.
Conclusion
Expression levels of some of the genes related to tobacco smoking return to levels similar to never smokers upon cessation of smoking, while expression of others appears to be permanently altered despite prolonged smoking cessation. These irreversible changes may account for the persistent lung cancer risk despite smoking cessation.
doi:10.1186/1471-2164-8-297
PMCID: PMC2001199  PMID: 17727719
2.  Relation between smoking history and gene expression profiles in lung adenocarcinomas 
BMC Medical Genomics  2012;5:22.
Background
Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers’ lung carcinomas remain to a large extent unclear.
Methods
Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets.
Results
Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking.
Conclusions
Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history.
doi:10.1186/1755-8794-5-22
PMCID: PMC3447685  PMID: 22676229
Lung cancer; Smoking; Gene expression analysis; Adenocarcinoma; EGFR; Never-smokers; Immune response
3.  Characterizing the Impact of Smoking and Lung Cancer on the Airway Transcriptome Using RNA-Seq 
Cigarette smoke creates a molecular field of injury in epithelial cells that line the respiratory tract. We hypothesized that transcriptome sequencing (RNA-Seq) will enhance our understanding of the field of molecular injury in response to tobacco smoke exposure and lung cancer pathogenesis by identifying gene expression differences not interrogated or accurately measured by microarrays. We sequenced the high-molecular-weight fraction of total RNA (>200 nt) from pooled bronchial airway epithelial cell brushings (n = 3 patients per pool) obtained during bronchoscopy from healthy never smoker (NS) and current smoker (S) volunteers and smokers with (C) and without (NC) lung cancer undergoing lung nodule resection surgery. RNA-Seq libraries were prepared using 2 distinct approaches, one capable of capturing non-polyadenylated RNA (the prototype NuGEN Ovation RNA-Seq protocol) and the other designed to measure only polyadenylated RNA (the standard Illumina mRNA-Seq protocol) followed by sequencing generating approximately 29 million 36 nt reads per pool and approximately 22 million 75 nt paired-end reads per pool, respectively. The NuGEN protocol captured additional transcripts not detected by the Illumina protocol at the expense of reduced coverage of polyadenylated transcripts, while longer read lengths and a paired-end sequencing strategy significantly improved the number of reads that could be aligned to the genome. The aligned reads derived from the two complementary protocols were used to define the compendium of genes expressed in the airway epithelium (n = 20,573 genes). Pathways related to the metabolism of xenobiotics by cytochrome P450, retinol metabolism, and oxidoreductase activity were enriched among genes differentially expressed in smokers, whereas chemokine signaling pathways, cytokine–cytokine receptor interactions, and cell adhesion molecules were enriched among genes differentially expressed in smokers with lung cancer. There was a significant correlation between the RNA-Seq gene expression data and Affymetrix microarray data generated from the same samples (P < 0.001); however, the RNA-Seq data detected additional smoking- and cancer-related transcripts whose expression was were either not interrogated by or was not found to be significantly altered when using microarrays, including smoking-related changes in the inflammatory genes S100A8 and S100A9 and cancer-related changes in MUC5AC and secretoglobin (SCGB3A1). Quantitative real-time PCR confirmed differential expression of select genes and non-coding RNAs within individual samples. These results demonstrate that transcriptome sequencing has the potential to provide new insights into the biology of the airway field of injury associated with smoking and lung cancer. The measurement of both coding and non-coding transcripts by RNA-Seq has the potential to help elucidate mechanisms of response to tobacco smoke and to identify additional biomarkers of lung cancer risk and novel targets for chemoprevention.
doi:10.1158/1940-6207.CAPR-11-0212
PMCID: PMC3694393  PMID: 21636547
4.  Comparison of Proteomic and Transcriptomic Profiles in the Bronchial Airway Epithelium of Current and Never Smokers 
PLoS ONE  2009;4(4):e5043.
Background
Although prior studies have demonstrated a smoking-induced field of molecular injury throughout the lung and airway, the impact of smoking on the airway epithelial proteome and its relationship to smoking-related changes in the airway transcriptome are unclear.
Methodology/Principal Findings
Airway epithelial cells were obtained from never (n = 5) and current (n = 5) smokers by brushing the mainstem bronchus. Proteins were separated by one dimensional polyacrylamide gel electrophoresis (1D-PAGE). After in-gel digestion, tryptic peptides were processed via liquid chromatography/ tandem mass spectrometry (LC-MS/MS) and proteins identified. RNA from the same samples was hybridized to HG-U133A microarrays. Protein detection was compared to RNA expression in the current study and a previously published airway dataset. The functional properties of many of the 197 proteins detected in a majority of never smokers were similar to those observed in the never smoker airway transcriptome. LC-MS/MS identified 23 proteins that differed between never and current smokers. Western blotting confirmed the smoking-related changes of PLUNC, P4HB1, and uteroglobin protein levels. Many of the proteins differentially detected between never and current smokers were also altered at the level of gene expression in this cohort and the prior airway transcriptome study. There was a strong association between protein detection and expression of its corresponding transcript within the same sample, with 86% of the proteins detected by LC-MS/MS having a detectable corresponding probeset by microarray in the same sample. Forty-one proteins identified by LC-MS/MS lacked detectable expression of a corresponding transcript and were detected in ≤5% of airway samples from a previously published dataset.
Conclusions/Significance
1D-PAGE coupled with LC-MS/MS effectively profiled the airway epithelium proteome and identified proteins expressed at different levels as a result of cigarette smoke exposure. While there was a strong correlation between protein and transcript detection within the same sample, we also identified proteins whose corresponding transcripts were not detected by microarray. This noninvasive approach to proteomic profiling of airway epithelium may provide additional insights into the field of injury induced by tobacco exposure.
doi:10.1371/journal.pone.0005043
PMCID: PMC2664466  PMID: 19357784
5.  Impact of Scotland's Smoke-Free Legislation on Pregnancy Complications: Retrospective Cohort Study 
PLoS Medicine  2012;9(3):e1001175.
An analysis of pregnancy data for the whole of Scotland demonstrates a reduction in small-for-gestational-age births and preterm delivery since the introduction of legislation banning smoking in enclosed public spaces.
Background
Both active smoking and environmental tobacco smoke exposure are associated with pregnancy complications. In March 2006, Scotland implemented legislation prohibiting smoking in all wholly or partially enclosed public spaces. The aim of this study was to determine the impact of this legislation on preterm delivery and small for gestational age.
Methods and Findings
We conducted logistic regression analyses using national administrative pregnancy data covering the whole of Scotland. Of the two breakpoints tested, 1 January 2006 produced a better fit than the date when the legislation came into force (26 March 2006), suggesting an anticipatory effect. Among the 716,941 eligible women who conceived between August 1995 and February 2009 and subsequently delivered a live-born, singleton infant between 24 and 44 wk gestation, the prevalence of current smoking fell from 25.4% before legislation to 18.8% after legislation (p<0.001). Three months prior to the legislation, there were significant decreases in small for gestational age (−4.52%, 95% CI −8.28, −0.60, p = 0.024), overall preterm delivery (−11.72%, 95% CI −15.87, −7.35, p<0.001), and spontaneous preterm labour (−11.35%, 95% CI −17.20, −5.09, p = 0.001). In sub-group analyses, significant reductions were observed among both current and never smokers.
Conclusions
Reductions were observed in the risk of preterm delivery and small for gestational age 3 mo prior to the introduction of legislation, although the former reversed partially following the legislation. There is growing evidence of the potential for tobacco control legislation to have a positive impact on health.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The risks of smoking during pregnancy, both on mother and fetus, are well established: women who smoke during pregnancy are more likely to have a miscarriage. Smoking can cause placental problems, such as placental abruption, which can result in heavy bleeding during pregnancy, which is dangerous for both mother and baby. Other dangers of smoking during pregnancy include the baby being born too early (premature birth), the baby being below average weight (small for gestational age), birth defects, and infant death. Because of the serious damage to health caused by smoking, in 2005, under the auspices of the World Health Organization, countries adopted the Framework Convention on Tobacco Control to protect present and future generations from the devastating health, social, environmental, and economic consequences of tobacco consumption and exposure to tobacco smoke. Article 8 of the treaty obliges member states who have ratified the treaty—168 so far—to protect all people from exposure to tobacco smoke in indoor workplaces, public transport, and indoor public places. As a result, many countries around the world have banned smoking in public places.
Why Was This Study Done?
Scotland was the first country in the United Kingdom to ban smoking in public places, which was implemented as part of the Smoking, Health and Social Care (Scotland) Bill on 26 March 2006. Previous studies have shown that the introduction of the legislation led directly to a reduction in smoking and also a reduction in environmental tobacco smoke exposure in adults and children. Furthermore, the Scottish legislation has been accompanied by significant reductions in both cardiovascular and respiratory disease. Because of the known risks of smoking during pregnancy, the researchers wanted to investigate whether the change in policy on smoking in public places had positive benefits on the health of mothers and babies. They evaluated this by measuring the rates of preterm delivery and small for gestational age before and after the Scottish legislation went into effect.
What Did the Researchers Do and Find?
The researchers collected information on preterm delivery and small for gestational age in all single babies born live at 22–44 weeks gestation between 1 January 1996 and 31 December 2009 by using the Scottish Morbidity Record (SMR2), which collects relevant information on all women discharged from Scottish maternity hospitals, including maternal and infant characteristics and pregnancy complications. The researchers categorized preterm delivery into mild, moderate, and extreme depending on how much before 37 weeks the baby was born. They defined small for gestational age as the smallest 10% (below the 10th centile) for sex-specific birth weight at delivery, and very small for gestational age as the smallest 3% (below the 3rd centile), for all deliveries in Scotland over the study period. As some people may have stopped smoking in anticipation of the smoking ban, in their statistical model, the researchers included two possible breakpoints for the effect of the legislation—the actual date of implementation and 1 January 2006.
The researchers found that of the 716,968 pregnancies (the number eligible for inclusion in the study), 99.9% of women had their smoking status recorded, and among these 23.9% were current smokers, 57.6% never smokers, and 8.7% former smokers. However, following implementation of the legislation the researchers noted that there was a significant reduction in current smokers to 18.8%. In their statistical model, the researchers found that following 1 January 2006, there was a significant drop in overall preterm deliveries, which remained after adjustment for potential confounding factors. Likewise, there was a significant decrease in the number of infants born small, and very small, for gestational age after 1 January 2006. Furthermore, the researchers found that these significant reductions occurred in both mothers who smoked and those who had never smoked.
What Do These Findings Mean?
These findings suggest that the introduction of national, comprehensive smoke-free legislation in Scotland was associated with significant reductions in preterm delivery and babies being born small for gestational age. These findings are plausible and add to the growing evidence of the wide-ranging health benefits of smoke-free legislation, and support the adoption of such legislation in other countries that have yet to implement smoking bans.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001175.
More information is available on the World Health Organization's Framework Convention for Tobacco Control
More information on the Smoking, Health and Social Care (Scotland) Bill is available
The US Centers for Disease Control and Prevention has more information about the risks of smoking in pregnancy, as does the UK National Health Service's smokefree web page
NHS Health Scotland has a website that summarises all the studies to date evaluating the Scottish smoke-free legislation
doi:10.1371/journal.pmed.1001175
PMCID: PMC3295815  PMID: 22412353
6.  Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium 
BMC Genomics  2008;9:259.
Background
Cigarette smoking is a leading cause of preventable death and a significant cause of lung cancer and chronic obstructive pulmonary disease. Prior studies have demonstrated that smoking creates a field of molecular injury throughout the airway epithelium exposed to cigarette smoke. We have previously characterized gene expression in the bronchial epithelium of never smokers and identified the gene expression changes that occur in the mainstem bronchus in response to smoking. In this study, we explored relationships in whole-genome gene expression between extrathorcic (buccal and nasal) and intrathoracic (bronchial) epithelium in healthy current and never smokers.
Results
Using genes that have been previously defined as being expressed in the bronchial airway of never smokers (the "normal airway transcriptome"), we found that bronchial and nasal epithelium from non-smokers were most similar in gene expression when compared to other epithelial and nonepithelial tissues, with several antioxidant, detoxification, and structural genes being highly expressed in both the bronchus and nose. Principle component analysis of previously defined smoking-induced genes from the bronchus suggested that smoking had a similar effect on gene expression in nasal epithelium. Gene set enrichment analysis demonstrated that this set of genes was also highly enriched among the genes most altered by smoking in both nasal and buccal epithelial samples. The expression of several detoxification genes was commonly altered by smoking in all three respiratory epithelial tissues, suggesting a common airway-wide response to tobacco exposure.
Conclusion
Our findings support a relationship between gene expression in extra- and intrathoracic airway epithelial cells and extend the concept of a smoking-induced field of injury to epithelial cells that line the mouth and nose. This relationship could potentially be utilized to develop a non-invasive biomarker for tobacco exposure as well as a non-invasive screening or diagnostic tool providing information about individual susceptibility to smoking-induced lung diseases.
doi:10.1186/1471-2164-9-259
PMCID: PMC2435556  PMID: 18513428
7.  Genetic Variation and Antioxidant Response Gene Expression in the Bronchial Airway Epithelium of Smokers at Risk for Lung Cancer 
PLoS ONE  2010;5(8):e11934.
Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. As a first step in applying functional genomic analysis to population studies, we have examined the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer. We assessed global gene expression in histologically normal airway epithelial cells obtained at bronchoscopy from smokers who developed lung cancer (SC, n = 20), smokers without lung cancer (SNC, n = 24), and never smokers (NS, n = 8). Functional enrichment analysis showed that the NRF2-mediated, antioxidant response element (ARE)-regulated genes, were significantly lower in SC, when compared with expression levels in SNC. Importantly, we found that the expression of MAFG (a binding partner of NRF2) was correlated with the expression of ARE genes, suggesting MAFG levels may limit target gene induction. Bioinformatically we identified single nucleotide polymorphisms (SNPs) in putative ARE genes and to test the impact of genetic variation, we genotyped these putative regulatory SNPs and other tag SNPs in selected NRF2 pathway genes. Sequencing MAFG locus, we identified 30 novel SNPs and two were associated with either gene expression or lung cancer status among smokers. This work demonstrates an analysis approach that integrates bioinformatics pathway and transcription factor binding site analysis with genotype, gene expression and disease status to identify SNPs that may be associated with individual differences in gene expression and/or cancer status in smokers. These polymorphisms might ultimately contribute to lung cancer risk via their effect on the airway gene expression response to tobacco-smoke exposure.
doi:10.1371/journal.pone.0011934
PMCID: PMC2914741  PMID: 20689807
8.  Threshold of Biologic Responses of the Small Airway Epithelium to Low Levels of Tobacco Smoke 
Rationale: Epidemiologic data demonstrate that individuals exposed to low levels of tobacco smoke have decrements in lung function and higher risk for lung disease compared with unexposed individuals. Although this risk is small, low-level tobacco smoke exposure is so widespread, it is a significant public health concern.
Objectives: To identify biologic correlates of this risk we hypothesized that, compared with unexposed individuals, individuals exposed to low levels of tobacco smoke have biologic changes in the small airway epithelium, the site of the first abnormalities associated with smoking.
Methods: Small airway epithelium was obtained by bronchoscopy from 121 individuals; microarrays were used to assess genome-wide gene expression; urine nicotine and cotinine were used to categorize subjects as “nonsmokers,” “active smokers,” and “low exposure.” Gene expression data were used to determine the threshold and induction half maximal level (ID50) of urine nicotine and cotinine at which the small airway epithelium showed abnormal responses.
Measurements and Main Results: There was no threshold of urine nicotine without a small airway epithelial response, and only slightly above detectable urine cotinine threshold with a small airway epithelium response. The ID50 for nicotine was 25 ng/ml and for cotinine it was 104 ng/ml.
Conclusions: The small airway epithelium detects and responds to low levels of tobacco smoke with transcriptome modifications. This provides biologic correlates of epidemiologic studies linking low-level tobacco smoke exposure to lung health risk, identifies the genes most sensitive to tobacco smoke, and defines thresholds at which the lung epithelium responds to low levels of tobacco smoke.
doi:10.1164/rccm.201002-0294OC
PMCID: PMC3029938  PMID: 20693378
threshold; exposure; dose-dependant; ID50
9.  Effects of smoking and smoking cessation on human serum metabolite profile: results from the KORA cohort study 
BMC Medicine  2013;11:60.
Background
Metabolomics helps to identify links between environmental exposures and intermediate biomarkers of disturbed pathways. We previously reported variations in phosphatidylcholines in male smokers compared with non-smokers in a cross-sectional pilot study with a small sample size, but knowledge of the reversibility of smoking effects on metabolite profiles is limited. Here, we extend our metabolomics study with a large prospective study including female smokers and quitters.
Methods
Using targeted metabolomics approach, we quantified 140 metabolite concentrations for 1,241 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) human cohort at two time points: baseline survey conducted between 1999 and 2001 and follow-up after seven years. Metabolite profiles were compared among groups of current smokers, former smokers and never smokers, and were further assessed for their reversibility after smoking cessation. Changes in metabolite concentrations from baseline to the follow-up were investigated in a longitudinal analysis comparing current smokers, never smokers and smoking quitters, who were current smokers at baseline but former smokers by the time of follow-up. In addition, we constructed protein-metabolite networks with smoking-related genes and metabolites.
Results
We identified 21 smoking-related metabolites in the baseline investigation (18 in men and six in women, with three overlaps) enriched in amino acid and lipid pathways, which were significantly different between current smokers and never smokers. Moreover, 19 out of the 21 metabolites were found to be reversible in former smokers. In the follow-up study, 13 reversible metabolites in men were measured, of which 10 were confirmed to be reversible in male quitters. Protein-metabolite networks are proposed to explain the consistent reversibility of smoking effects on metabolites.
Conclusions
We showed that smoking-related changes in human serum metabolites are reversible after smoking cessation, consistent with the known cardiovascular risk reduction. The metabolites identified may serve as potential biomarkers to evaluate the status of smoking cessation and characterize smoking-related diseases.
doi:10.1186/1741-7015-11-60
PMCID: PMC3653729  PMID: 23497222
metabolic network; metabolomics; molecular epidemiology; smoking; smoking cessation
10.  Current and Former Smoking and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(9):e1001515.
In a meta-analysis of 32 observational studies involving 3,966,184 participants and 35,151 events, Suhua Wu and colleagues found that current, ever, and former smoking was associated with risk of venous thromboembolism.
Please see later in the article for the Editors' Summary
Background
Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose–response relationship exists.
Methods and Findings
We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09–1.25) for ever smokers, 1.23 (95% CI 1.14–1.33) for current smokers, and 1.10 (95% CI 1.03–1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%–11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%–8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24–1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%–12.3%) for ever smoking, 5.8% (95% CI 3.6%–8.2%) for current smoking, and 2.7% (95% CI 0.8%–4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4–26.7) cases per 100,000 person-years.
Conclusions
Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Blood normally flows throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. Occasionally, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep within the body, usually in a leg, is called deep vein thrombosis (DVT) and can cause pain, swelling, and redness in the affected limb. DVT can be treated with drugs that stop the blood clot from getting larger (anticoagulants) but, if left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are collectively known as venous thromboembolism (VTE). Risk factors for VTE include having an inherited blood clotting disorder, oral contraceptive use, prolonged inactivity (for example, during a long-haul plane flight), and having surgery. VTEs are present in about a third of all people who die in hospital and, in non-bedridden populations, about 10% of people die within 28 days of a first VTE event.
Why Was This Study Done?
Some but not all studies have reported that smoking is also a risk factor for VTE. A clear demonstration of a significant association (a relationship unlikely to have occurred by chance) between smoking and VTE might help to reduce the burden of VTE because smoking can potentially be reduced by encouraging individuals to quit smoking and through taxation policies and other measures designed to reduce tobacco consumption. In this systematic review and meta-analysis, the researchers examine the link between smoking and the risk of VTE in the general population and investigate whether heavy smokers have a higher risk of VTE than light smokers. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 32 observational studies (investigations that record a population's baseline characteristics and subsequent disease development) that provided data on smoking and VTE. Together, the studies involved nearly 4 million participants and recorded 35,151 VTE events. Compared with never smokers, ever smokers (current and former smokers combined) had a relative risk (RR) of developing VTE of 1.17. That is, ever smokers were 17% more likely to develop VTE than never smokers. For current smokers and former smokers, RRs were 1.23 and 1.10, respectively. Analysis of only studies that adjusted for body mass index (a measure of body fat and a known risk factor for conditions that affect the heart and circulation) yielded a slightly higher RR (1.30) for current smokers compared with never smokers. For ever smokers, the population attributable fraction (the proportional reduction in VTE that would accrue in the population if no one smoked) was 8.7%. Notably, the risk of VTE increased by 10.2% for every additional ten cigarettes smoked per day and by 6.1% for every additional ten pack-years. Thus, an individual who smoked one pack of cigarettes per day for 40 years had a 26.7% higher risk of developing VTE than someone who had never smoked. Finally, smoking was associated with an absolute risk increase of 24.3 cases of VTE per 100,000 person-years.
What Do These Findings Mean?
These findings indicate that cigarette smoking is associated with a statistically significant, slightly increased risk for VTE among the general population and reveal a dose-relationship between smoking and VTE risk. They cannot prove that smoking causes VTE—people who smoke may share other unknown characteristics (confounding factors) that are actually responsible for their increased risk of VTE. Indeed, these findings identify body mass index as a potential confounding factor that might affect the accuracy of estimates of the association between smoking and VTE risk. Although the risk of VTE associated with smoking is smaller than the risk associated with some well-established VTE risk factors, smoking is more common (globally, there are 1.1 billion smokers) and may act synergistically with some of these risk factors. Thus, smoking behavior should be considered when screening individuals for VTE and in the prevention of first and subsequent VTE events.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001515.
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolism), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, and on pulmonary embolism; SmokeFree is a website provided by the UK National Health Service that offers advice on quitting smoking
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
The World Health Organization provides information about the dangers of tobacco (in several languages)
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and the dangers of smoking (in English and Spanish)
doi:10.1371/journal.pmed.1001515
PMCID: PMC3775725  PMID: 24068896
11.  Associations Between Initial Water Pipe Tobacco Smoking and Snus Use and Subsequent Cigarette Smoking Results From a Longitudinal Study of US Adolescents and Young Adults 
JAMA pediatrics  2015;169(2):129-136.
IMPORTANCE
Many adolescents and young adults use alternative tobacco products, such as water pipes and snus, instead of cigarettes.
OBJECTIVE
To assess whether prior water pipe tobacco smoking and snus use among never smokers are risk factors for subsequent cigarette smoking.
DESIGN, SETTING, AND PARTICIPANTS
We conducted a 2-wave national longitudinal study in the United States among 2541 individuals aged 15 to 23 years old. At baseline (October 25, 2010, through June 11, 2011), we ascertained whether respondents had smoked cigarettes, smoked water pipe tobacco, or used snus. At the 2-year follow-up (October 27, 2012, through March 31, 2013), we determined whether baseline non–cigarette smokers had subsequently tried cigarette smoking, were current (past 30 days) cigarette smokers, or were high-intensity cigarette smokers. We fit multivariable logistic regression models among baseline non–cigarette smokers to assess whether baseline water pipe tobacco smoking and baseline snus use were associated with subsequent cigarette smoking initiation and current cigarette smoking, accounting for established sociodemographic and behavioral risk factors. We fit similarly specified multivariable ordinal logistic regression models to assess whether baseline water pipe tobacco smoking and baseline snus use were associated with high-intensity cigarette smoking at follow-up.
EXPOSURES
Water pipe tobacco smoking and the use of snus at baseline.
MAIN OUTCOMES AND MEASURES
Among baseline non–cigarette smokers, cigarette smoking initiation, current (past 30 days) cigarette smoking at follow-up, and the intensity of cigarette smoking at follow-up.
RESULTS
Among 1596 respondents, 1048 had never smoked cigarettes at baseline, of whom 71 had smoked water pipe tobacco and 20 had used snus at baseline. At follow-up, accounting for behavioral and sociodemographic risk factors, baseline water pipe tobacco smoking and snus use were independently associated with cigarette smoking initiation (adjusted odds ratios: 2.56; 95% CI, 1.46-4.47 and 3.73; 95% CI, 1.43-9.76, respectively), current cigarette smoking (adjusted odds ratios: 2.48; 95% CI, 1.01-6.06 and 6.19; 95% CI, 1.86-20.56, respectively), and higher intensity of cigarette smoking (adjusted proportional odds ratios: 2.55; 95% CI, 1.48-4.38 and 4.45; 95% CI, 1.75-11.27, respectively).
CONCLUSIONS AND RELEVANCE
Water pipe tobacco smoking and the use of snus independently predicted the onset of cigarette smoking and current cigarette smoking at follow-up. Comprehensive Food and Drug Administration regulation of these tobacco products may limit their appeal to youth and curb the onset of cigarette smoking.
doi:10.1001/jamapediatrics.2014.2697
PMCID: PMC4388043  PMID: 25485959
12.  Smoking and high-risk mammographic parenchymal patterns: a case-control study 
Breast Cancer Research  1999;2(1):59-63.
Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern. Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to the mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results are still strongly suggestive. The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate that smoking is a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It appears that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
Introduction:
Overall, epidemiological studies [1,2,3,4] have reported no substantial association between cigarette smoking and the risk of breast cancer. Some studies [5,6,7] reported a significant increase of breast cancer risk among smokers. In recent studies that addressed the association between breast cancer and cigarette smoking, however, there was some suggestion of a decreased risk [8,9,10], especially among current smokers, ranging from approximately 10 to 30% [9,10]. Brunet et al [11] reported that smoking might reduce the risk of breast cancer by 44% in carriers of BRCA1 or BRCA2 gene mutations. Wolfe [12] described four different mammographic patterns created by variations in the relative amounts of fat, epithelial and connective tissue in the breast, designated N1, P1, P2 and DY. Women with either P2 or DY pattern are considered at greater risk for breast cancer than those with N1 or P1 pattern [12,13,14,15]. There are no published studies that assessed the relationship between smoking and mammographic parenchymal patterns.
Aims:
To evaluate whether mammographic parenchymal patterns as classified by Wolfe, which have been positively associated with breast cancer risk, are affected by smoking. In this case-control study, nested within the European Prospective Investigation on Cancer in Norfolk (EPIC-Norfolk) cohort [16], the association between smoking habits and mammographic parenchymal patterns are examined. The full results will be published elsewhere.
Methods:
Study subjects were members of the EPIC cohort in Norwich who also attended the prevalence screening round at the Norwich Breast Screening Centre between November 1989 and December 1997, and were free of breast cancer at that screening. Cases were defined as women with a P2/DY Wolfe's mammographic parenchymal pattern on the prevalence screen mammograms. A total of 203 women with P2/DY patterns were identified as cases and were individually matched by date of birth (within 1 year) and date of prevalence screening (within 3 months) with 203 women with N1/P1 patterns who served as control individuals.
Two views, the mediolateral and craniocaudal mammograms, of both breasts were independently reviewed by two of the authors (ES and RW) to determine the Wolfe mammographic parenchymal pattern.
Considerable information on health and lifestyle factors was available from the EPIC Health and Lifestyle Questionnaire [16]. In the present study we examined the subjects' personal history of benign breast diseases, menstrual and reproductive factors, oral contraception and hormone replacement therapy, smoking, and anthropometric information such as body mass index and waist:hip ratio.
Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by conditional logistic regression [17], and were adjusted for possible confounding factors.
Results:
The characteristics of the cases and controls are presented in Table 1. Cases were leaner than controls. A larger percentage of cases were nulliparous, premenopausal, current hormone replacement therapy users, had a personal history of benign breast diseases, and had had a hysterectomy. A larger proportion of controls had more than three births and were current smokers.
Table 2 shows the unadjusted and adjusted OR estimates for Wolfe's high-risk mammographic parenchymal patterns and smoking in the total study population and in postmenopausal women separately. Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern (OR 0.37, 95% CI 0.14-0.94). Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results were still strongly suggestive. There was no interaction between cigarette smoking and body mass index.
Discussion:
In the present study we found a strong inverse relationship between current smoking and high-risk mammographic parenchymal patterns of breast tissue as classified by Wolfe [12]. These findings are not completely unprecedented; Greendale et al [18] found a reduced risk of breast density in association with smoking, although the magnitude of the reduction was unclear. The present findings suggest that this reduction is large.
Recent studies [9,10] have suggested that breast cancer risk may be reduced among current smokers. In a multicentre Italian case-control study, Braga et al [10] found that, relative to nonsmokers, current smokers had a reduced risk of breast cancer (OR 0.84, 95% CI 0.7-1.0). These findings were recently supported by Gammon et al [9], who reported that breast cancer risk in younger women (younger than 45 years) may be reduced among current smokers who began smoking at an early age (OR 0.59, 95% CI 0.41-0.85 for age 15 years or younger) and among long-term smokers (OR 0.70, 95% CI 0.52-0.94 for those who had smoked for 21 years or more).
The possible protective effect of smoking might be due to its anti-oestrogenic effect [1,2,19]. Recently there has been renewed interest in the potential effect of smoking on breast cancer risk, and whether individuals may respond differently on the basis of differences in metabolism of bioproducts of smoking [20,21]. Different relationships between smoking and breast cancer risk have been suggested that are dependent on the rapid or slow status of acetylators of aromatic amines [20,21]. More recent studies [22,23], however, do not support these findings.
The present study design minimized the opportunity for bias to influence the findings. Because subjects were unaware of their own case-control status, the possibility of recall bias in reporting smoking status was minimized. Systematic error in the assessment of mammograms was avoided because reading was done without knowledge of the risk factor data. Furthermore, the associations observed are unlikely to be explained by the confounding effect of other known breast cancer risk factors, because we adjusted for these in the analysis. We did not have information on passive smoking status, however, which has recently been reported to be a possible confounder [5,6,21,24].
The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate smoking as a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It seems that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
PMCID: PMC13911  PMID: 11056684
mammography; screening; smoking; Wolfe's parenchymal patterns
13.  Tobacco Smoke, Indoor Air Pollution and Tuberculosis: A Systematic Review and Meta-Analysis 
PLoS Medicine  2007;4(1):e20.
Background
Tobacco smoking, passive smoking, and indoor air pollution from biomass fuels have been implicated as risk factors for tuberculosis (TB) infection, disease, and death. Tobacco smoking and indoor air pollution are persistent or growing exposures in regions where TB poses a major health risk. We undertook a systematic review and meta-analysis to quantitatively assess the association between these exposures and the risk of infection, disease, and death from TB.
Methods and Findings
We conducted a systematic review and meta-analysis of observational studies reporting effect estimates and 95% confidence intervals on how tobacco smoking, passive smoke exposure, and indoor air pollution are associated with TB. We identified 33 papers on tobacco smoking and TB, five papers on passive smoking and TB, and five on indoor air pollution and TB. We found substantial evidence that tobacco smoking is positively associated with TB, regardless of the specific TB outcomes. Compared with people who do not smoke, smokers have an increased risk of having a positive tuberculin skin test, of having active TB, and of dying from TB. Although we also found evidence that passive smoking and indoor air pollution increased the risk of TB disease, these associations are less strongly supported by the available evidence.
Conclusions
There is consistent evidence that tobacco smoking is associated with an increased risk of TB. The finding that passive smoking and biomass fuel combustion also increase TB risk should be substantiated with larger studies in future. TB control programs might benefit from a focus on interventions aimed at reducing tobacco and indoor air pollution exposures, especially among those at high risk for exposure to TB.
Evidence from a number of studies suggest that tobacco smoking, environmental tobacco smoke, and indoor air pollution from biomass fuels is associated with an increased risk of tuberculosis.
Editors' Summary
Background.
Tobacco smoking has been identified by the World Health Organization as one of the leading causes of death worldwide. Smokers are at higher risk than nonsmokers for a very wide variety of illnesses, many of which are life-threatening. Inhaling tobacco smoke, whether this is active (when an individual smokes) or passive (when an individual is exposed to cigarette smoke in their environment) has also been associated with tuberculosis (TB). Many people infected with the TB bacterium never develop disease, but it is thought that people infected with TB who also smoke are far more likely to develop the symptoms of disease, and to have worse outcomes when they do.
Why Was This Study Done?
The researchers were specifically interested in the link between smoking and TB. They wanted to try to work out the overall increase in risk for getting TB in people who smoke, as compared with people who do not smoke. In this study, the researchers wanted to separately study the risks for different types of exposure to smoke, so, for example, what the risks were for people who actively smoke as distinct from people who are exposed to smoke from others. The researchers also wanted to calculate the association between TB and exposure to indoor pollution from burning fuels such as wood and charcoal.
What Did the Researchers Do and Find?
In carrying out this study, the researchers wanted to base their conclusions on all the relevant information that was already available worldwide. Therefore they carried out a systematic review. A systematic review involves setting out the research question that is being asked and then developing a search strategy to find all the meaningful evidence relating to the particular question under study. For this systematic review, the researchers wanted to find all published research in the biomedical literature that looked at human participants and dealt with the association between active smoking, passive smoking, indoor air pollution and TB. Studies were included if they were published in English, Russian, or Chinese, and included enough data for the researchers to calculate a number for the increase in TB risk. The researchers initially found 1,397 research studies but then narrowed that down to 38 that fit their criteria. Then specific pieces of data were extracted from each of those studies and in some cases the researchers combined data to produce overall calculations for the increase in TB risk. Separate assessments were done for different aspects of “TB risk,” namely, TB infection, TB disease, and mortality from TB. The data showed an approximately 2-fold increase in risk of TB infection among smokers as compared with nonsmokers. The researchers found that all studies evaluating the link between smoking and TB disease or TB mortality showed an association, but they did not combine these data together because of wide potential differences between the studies. Finally, all studies looking at passive smoking found an association with TB, as did some of those examining the link with indoor air pollution.
What Do These Findings Mean?
The findings here show that smoking is associated with an increased risk of TB infection, disease, and deaths from TB. The researchers found much more data on the risks for active smoking than on passive smoking or indoor air pollution. Tobacco smoking is increasing in many countries where TB is already a problem. These results therefore suggest that it is important for health policy makers to further develop strategies for controlling tobacco use in order to reduce the impact of TB worldwide.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040020
The World Health Organization (WHO)'s Tobacco Free Initiative provides resources on research and policy related to tobacco control, its network of initiatives, and other relevant information
WHO also has a tuberculosis minisite
The US National Library of Medicine's MedLinePlus provides a set of links and resources about smoking, including news, overviews, recent research, statistics, and others
The Health Consequences of Smoking: A Report of the Surgeon General provides information on the health consequences of smoking
Tobacco Country Profiles provides information on smoking in different countries
doi:10.1371/journal.pmed.0040020
PMCID: PMC1769410  PMID: 17227135
14.  Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival 
PLoS ONE  2008;3(2):e1651.
Background
Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure.
Methodology/Principal Findings
We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change >1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p = 0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers.
Conclusions/Significance
Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers.
doi:10.1371/journal.pone.0001651
PMCID: PMC2249927  PMID: 18297132
15.  Lung Cancer Occurrence in Never-Smokers: An Analysis of 13 Cohorts and 22 Cancer Registry Studies  
PLoS Medicine  2008;5(9):e185.
Background
Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions.
Methods and Findings
We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40–69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking.
Conclusions
These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.
Michael Thun and colleagues pooled and analyzed comprehensive data on lung cancer incidence and death rates among never-smokers to examine what factors other than active smoking affect lung cancer risk.
Editors' Summary
Background.
Every year, more than 1.4 million people die from lung cancer, a leading cause of cancer deaths worldwide. In the US alone, more than 161,000 people will die from lung cancer this year. Like all cancers, lung cancer occurs when cells begin to divide uncontrollably because of changes in their genes. The main trigger for these changes in lung cancer is exposure to the chemicals in cigarette smoke—either directly through smoking cigarettes or indirectly through exposure to secondhand smoke. Eighty-five to 90% of lung cancer deaths are caused by exposure to cigarette smoke and, on average, current smokers are 15 times more likely to die from lung cancer than lifelong nonsmokers (never smokers). Furthermore, a person's cumulative lifetime risk of developing lung cancer is related to how much they smoke, to how many years they are a smoker, and—if they give up smoking—to the age at which they stop smoking.
Why Was This Study Done?
Because lung cancer is so common, even the small fraction of lung cancer that occurs in lifelong nonsmokers represents a large number of people. For example, about 20,000 of this year's US lung cancer deaths will be in never-smokers. However, very little is known about how age, sex, or race affects the incidence (the annual number of new cases of diseases in a population) or death rates from lung cancer among never-smokers. A better understanding of the patterns of lung cancer incidence and death rates among never-smokers could provide useful information about the factors other than cigarette smoke that increase the likelihood of not only never-smokers, but also former smokers and current smokers developing lung cancer. In this study, therefore, the researchers pooled and analyzed a large amount of information about lung cancer incidence and death rates among never smokers to examine what factors other than active smoking affect lung cancer risk.
What Did the Researchers Do and Find?
The researchers analyzed information on lung cancer incidence and/or death rates among nearly 2.5 million self-reported never smokers (men and women) from 13 large studies investigating the health of people in North America, Europe, and Asia. They also analyzed similar information for women taken from cancer registries in ten countries at times when very few women were smokers (for example, the US in the late 1930s). The researchers' detailed statistical analyses reveal, for example, that lung cancer death rates in African Americans and in Asians living in Korea and Japan (but not among Asians living in the US) are higher than those in people of the European continental ancestry group. They also show that men have higher death rates from lung cancer than women irrespective of racial group, but that women aged 40–59 years have a slightly higher incidence of lung cancer than men of a similar age. This difference disappears at older ages. Finally, an analysis of lung cancer incidence and death rates at different times during the past 70 years shows no evidence of an increase in the lung cancer burden among never smokers over time.
What Do These Findings Mean?
Although some of the findings described above have been hinted at in previous, smaller studies, these and other findings provide a much more accurate picture of lung cancer incidence and death rates among never smokers. Most importantly the underlying data used in these analyses are now freely available and should provide an excellent resource for future studies of lung cancer in never smokers.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050185.
The US National Cancer Institute provides detailed information for patients and health professionals about all aspects of lung cancer and information on smoking and cancer (in English and Spanish)
Links to other US-based resources dealing with lung cancer are provided by MedlinePlus (in English and Spanish)
Cancer Research UK provides key facts about the link between lung cancer and smoking and information about all other aspects of lung cancer
doi:10.1371/journal.pmed.0050185
PMCID: PMC2531137  PMID: 18788891
16.  Environmental tobacco smoke exposure in the home and worksite and health effects in adults: results from the 1991 National Health Interview Survey 
Tobacco Control  1997;6(4):296-305.
OBJECTIVE: To determine the effect of environmental tobacco smoke (ETS) exposure in the home and worksite on the health of adults in the United States. DESIGN: Cross-sectional survey. SETTING: Nationally representative population. PARTICIPANTS: 43,732 adults who completed the Health Promotion and Disease Prevention supplement in the 1991 National Health Interview Survey. MAIN OUTCOME MEASURES: Rate of restricted activity, bed confinement, and work absence in the two weeks preceding the survey and self-reported health status among adults with and without exposure to ETS. RESULTS: We found that only 20.2% of never- smokers and 23.1% of former smokers reported exposure to ETS at home or work, whereas 87.2% of current smokers reported exposure to ETS. Among never-smokers, after adjusting for covariates, people who were exposed to ETS were more likely to report one or more days of restricted activity (relative risk (RR) = 1.27, 95% confidence interval (CI) = 1.10 to 1.46), one or more days of bed confinement (RR = 1.43, 95% CI = 1.19 to 1.73), and one or more days of work absence (RR = 1.33, 95% CI = 1.05 to 1.73) in the two weeks before the survey than were people without such exposure. We detected smaller trends for one or more days of restricted activity among current and former smokers (RR = 1.16, 95% CI = 0.97 to 1.40; and RR = 1.11, 95% CI = 0.82 to 1.51), one or more days of bed confinement among current smokers (RR = 1.34, 95% CI = 0.95 to 1.88), and one or more days of work absence among former smokers (RR = 1.13, 95% CI = 0.84 to 1.50) in the two weeks before the survey than among people without such exposure, although the CIs were wide and chance cannot be excluded as an explanation for these findings. Never- smokers (RR = 1.47, 95% CI = 1.34 to 1.62), former smokers (RR = 1.22, 95% CI = 1.07 to 1.39) and current smokers (RR = 1.31, 95% CI = 1.10 to 1.56) exposed to ETS were all more likely to report a less than very good health status than were people without such exposure. CONCLUSIONS: This study demonstrates that never-smoking adults exposed to ETS report more acute health effects than unexposed, never-smoking adults, and suggests similar findings in current and former smoking adults. 



PMCID: PMC1759596  PMID: 9583627
17.  SIRT1 pathway dysregulation in the smoke-exposed airway epithelium and lung tumor tissue 
Cancer research  2012;72(22):5702-5711.
Cigarette smoke produces a molecular “field of injury” in epithelial cells lining the respiratory tract. However, the specific signaling pathways that are altered in the airway of smokers and the signaling processes responsible for the transition from smoking-induced airway damage to lung cancer remain unknown. In this study, we use a genomic approach to study the signaling processes associated with tobacco smoke exposure and lung cancer. First, we developed and validated pathway-specific gene expression signatures in bronchial airway epithelium that reflect activation of signaling pathways relevant to tobacco-exposure including ATM, BCL2, GPX1, NOS2, IKBKB, and SIRT1. Using these profiles and four independent gene expression datasets, we found that SIRT1 activity is significantly up-regulated in cytologically normal bronchial airway epithelial cells from active smokers compared to non-smokers. In contrast, this activity is strikingly down-regulated in non-small cell lung cancer. This pattern of signaling modulation was unique to SIRT1, and down-regulation of SIRT1 activity is confined to tumors from smokers. Decreased activity of SIRT1 was validated using genomic analyses of mouse models of lung cancer and biochemical testing of SIRT1 activity in patient lung tumors. Together, our findings indicate a role of SIRT1 in response to smoke and a potential role in repressing lung cancer. Further, our findings suggest that the airway gene-expression signatures derived in this study can provide novel insights into signaling pathways altered in the “field of inury” induced by tobacco smoke and thus may impact strategies for prevention of tobacco-related lung cancer.
doi:10.1158/0008-5472.CAN-12-1043
PMCID: PMC4053174  PMID: 22986747
18.  The association between active smoking, smokeless tobacco, secondhand smoke exposure and insufficient sleep 
Sleep medicine  2010;12(1):7-11.
Background
Studies have shown that cigarette smoking is associated with sleep disorders in the general population. But studies examining the association between smokeless tobacco use, secondhand smoke exposure and insufficient rest/sleep are limited.
Methods
We examined the association between smoking, smokeless tobacco use (n=83,072), secondhand smoke exposure (n=28,557) and insufficient rest/sleep among adults aged ≥20 years in the state-based 2008 Behavioral Risk Factor Surveillance System. Exposure to secondhand smoke was defined as >1 day of exposure to cigarette smoking either at home or in the workplace in the preceding 7 days. Insufficient rest/sleep was defined as not getting enough rest/sleep everyday in the preceding 30 days.
Results
Compared to never smokeless tobacco users, the odds ratio (OR; 95% confidence interval [CI]) of insufficient rest/sleep was 1.16 (1.00–1.36) and 1.74 (1.37–2.22) among former and current users. Compared to non-smokers/non-smokeless tobacco users, the OR (95% CI) of insufficient rest/sleep for those who were both current smokers and current smokeless tobacco users was 2.21 (1.66–2.94). Regarding secondhand smoke exposure among non-smokers, those with second-hand smoke exposure had higher odds for insufficient rest/sleep than those without. In contrast, the odds of insufficient rest/sleep were similar among current smokers with or without secondhand smoke exposure.
Conclusions
In a multiethnic sample of US adults, compared to non-smokers/non-smokeless tobacco users, those who were both current smokers and current smokeless tobacco users had twice the odds of insufficient sleep. Secondhand smoke exposure was associated with insufficient rest/sleep among non-smokers.
doi:10.1016/j.sleep.2010.09.002
PMCID: PMC3056485  PMID: 21144798
Smokeless tobacco; secondhand smoke; insufficient sleep; BRFSS
19.  Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts 
PLoS Medicine  2014;11(4):e1001631.
Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia.
Please see later in the article for the Editors' Summary
Background
Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.
Methods and Findings
We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.
Conclusions
Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 5 million smokers die from tobacco-related diseases. Tobacco smoking is a major risk factor for cardiovascular disease (conditions that affect the heart and the circulation), respiratory disease (conditions that affect breathing), lung cancer, and several other types of cancer. All told, tobacco smoking kills up to half its users. The ongoing global “epidemic” of tobacco smoking and tobacco-related diseases initially affected people living in the US and other Western countries, where the prevalence of smoking (the proportion of the population that smokes) in men began to rise in the early 1900s, peaking in the 1960s. A similar epidemic occurred in women about 40 years later. Smoking-related deaths began to increase in the second half of the 20th century, and by the 1990s, tobacco smoking accounted for a third of all deaths and about half of cancer deaths among men in the US and other Western countries. More recently, increased awareness of the risks of smoking and the introduction of various tobacco control measures has led to a steady decline in tobacco use and in smoking-related diseases in many developed countries.
Why Was This Study Done?
Unfortunately, less well-developed tobacco control programs, inadequate public awareness of smoking risks, and tobacco company marketing have recently led to sharp increases in the prevalence of smoking in many low- and middle-income countries, particularly in Asia. More than 50% of men in many Asian countries are now smokers, about twice the prevalence in many Western countries, and more women in some Asian countries are smoking than previously. More than half of the world's billion smokers now live in Asia. However, little is known about the burden of tobacco-related mortality (deaths) in this region. In this study, the researchers quantify the risk of total and cause-specific mortality associated with tobacco use among adults aged 45 years or older by undertaking a pooled statistical analysis of data collected from 21 Asian cohorts (groups) about their smoking history and health.
What Did the Researchers Do and Find?
For their study, the researchers used data from more than 1 million participants enrolled in studies undertaken in Bangladesh, India, mainland China, Japan, the Republic of Korea, Singapore, and Taiwan (which together account for 71% of Asia's total population). Smoking prevalences among male and female participants were 65.1% and 7.1%, respectively. Compared with never-smokers, ever-smokers had a higher risk of death from any cause in pooled analyses of all the cohorts (adjusted hazard ratios [HRs] of 1.44 and 1.48 for men and women, respectively; an adjusted HR indicates how often an event occurs in one group compared to another group after adjustment for other characteristics that affect an individual's risk of the event). Compared with never smoking, ever smoking was associated with a higher risk of death due to cardiovascular disease, cancer (particularly lung cancer), and respiratory disease among Asian men and among East Asian women. Moreover, the researchers estimate that, in the countries included in this study, tobacco smoking accounted for 15.8% of all deaths among men and 3.3% of deaths among women in 2004—a total of about 1.5 million deaths, which scales up to 2 million deaths for the population of the whole of Asia. Notably, in 2004, tobacco smoking accounted for 60.5% of lung-cancer deaths among Asian men and 16.7% of lung-cancer deaths among East Asian women.
What Do These Findings Mean?
These findings provide strong evidence that tobacco smoking is associated with a substantially raised risk of death among adults aged 45 years or older throughout Asia. The association between smoking and mortality risk in Asia reported here is weaker than that previously reported for Western countries, possibly because widespread tobacco smoking started several decades later in most Asian countries than in Europe and North America and the deleterious effects of smoking take some years to become evident. The researchers note that certain limitations of their analysis are likely to affect the accuracy of its findings. For example, because no data were available to estimate the impact of secondhand smoke, the estimate of deaths attributable to smoking is likely to be an underestimate. However, the finding that nearly 45% of the global deaths from active tobacco smoking occur in Asia highlights the urgent need to implement comprehensive tobacco control programs in Asia to reduce the burden of tobacco-related disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001631.
The World Health Organization provides information about the dangers of tobacco (in several languages) and about the WHO Framework Convention on Tobacco Control, an international instrument for tobacco control that came into force in February 2005 and requires parties to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes; its 2013 report on the global tobacco epidemic is available
The US Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use
The UK National Health Services Choices website provides information about the health risks associated with smoking
MedlinePlus has links to further information about the dangers of smoking (in English and Spanish)
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001631
PMCID: PMC3995657  PMID: 24756146
20.  F2RL3 Methylation as a Biomarker of Current and Lifetime Smoking Exposures 
Environmental Health Perspectives  2013;122(2):131-137.
Background: Recent genome-wide DNA methylation studies have found a pronounced difference in methylation of the F2RL3 gene (also known as PAR-4) in blood DNA according to smoking exposure. Knowledge on the variation of F2RL3 methylation by various degrees of smoking exposure is still very sparse.
Objectives: We aimed to assess dose–response relationships of current and lifetime active smoking exposure with F2RL3 methylation.
Methods: In a large population-based study, we quantified blood DNA methylation at F2RL3 for 3,588 participants using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Associations of smoking exposure with methylation intensity were examined by multiple linear regression, controlling for potential confounding factors and paying particular attention to dose–response patterns with respect to current and lifetime smoking exposure as well as time since cessation of smoking.
Results: F2RL3 methylation intensity showed a strong association with smoking status (p < 0.0001), which persisted after controlling for potential confounding factors. Clear inverse dose–response relationships with F2RL3 methylation intensity were seen for both current intensity and lifetime pack-years of smoking. Among former smokers, F2RL3 methylation intensity increased gradually from levels close to those of current smokers for recent quitters to levels close to never smokers for long-term (> 20 years) quitters.
Conclusions: F2RL3 methylation is a promising biomarker for both current and long-term past tobacco exposure, and its predictive value for smoking-related diseases warrants further exploration.
Citation: Zhang Y, Yang R, Burwinkel B, Breitling LP, Brenner H. 2014. F2RL3 methylation as a biomarker of current and lifetime smoking exposures. Environ Health Perspect 122:131–137; http://dx.doi.org/10.1289/ehp.1306937
doi:10.1289/ehp.1306937
PMCID: PMC3915264  PMID: 24273234
21.  Derivation of a bronchial genomic classifier for lung cancer in a prospective study of patients undergoing diagnostic bronchoscopy 
BMC Medical Genomics  2015;8:18.
Background
The gene expression profile of cytologically-normal bronchial airway epithelial cells has previously been shown to be altered in patients with lung cancer. Although bronchoscopy is often used for the diagnosis of lung cancer, its sensitivity is imperfect, especially for small and peripheral suspicious lesions. In this study, we derived a gene expression classifier from airway epithelial cells that detects the presence of cancer in current and former smokers undergoing bronchoscopy for suspect lung cancer and evaluated its sensitivity to detect lung cancer among patients from an independent cohort.
Methods
We collected bronchial epithelial cells (BECs) from the mainstem bronchus of 299 current or former smokers (223 cancer-positive and 76 cancer-free subjects) undergoing bronchoscopy for suspected lung cancer in a prospective, multi-center study. RNA from these samples was run on gene expression microarrays for training a gene-expression classifier. A logistic regression model was built to predict cancer status, and the finalized classifier was validated in an independent cohort from a previous study.
Results
We found 232 genes whose expression levels in the bronchial airway are associated with lung cancer. We then built a classifier based on the combination of 17 cancer genes, gene expression predictors of smoking status, smoking history, and gender, plus patient age. This classifier had a ROC curve AUC of 0.78 (95% CI, 0.70-0.86) in patients whose bronchoscopy did not lead to a diagnosis of lung cancer (n = 134). In the validation cohort, the classifier had a similar AUC of 0.81 (95% CI, 0.73-0.88) in this same subgroup (n = 118). The classifier performed similarly across a range of mass sizes, cancer histologies and stages. The negative predictive value was 94% (95% CI, 83-99%) in subjects with a non-diagnostic bronchoscopy.
Conclusion
We developed a gene expression classifier measured in bronchial airway epithelial cells that is able to detect lung cancer in current and former smokers who have undergone bronchoscopy for suspicion of lung cancer. Due to the high NPV of the classifier, it could potentially inform clinical decisions regarding the need for further invasive testing in patients whose bronchoscopy is non diagnostic.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-015-0091-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12920-015-0091-3
PMCID: PMC4434538  PMID: 25944280
22.  The Epithelial Cell in Lung Health and Emphysema Pathogenesis 
Cigarette smoking is the primary cause of the irreversible lung disease emphysema. Historically, inflammatory cells such as macrophages and neutrophils have been studied for their role in emphysema pathology. However, recent studies indicate that the lung epithelium is an active participant in emphysema pathogenesis and plays a critical role in the lung’s response to cigarette smoke. Tobacco smoke increases protease production and alters cytokine expression in isolated epithelial cells, suggesting that these cells respond potently even in the absence of a complete inflammatory program. Tobacco smoke also acts as an immunosuppressant, reducing the defense function of airway epithelial cells and enhancing colonization of the lower airways. Thus, the paradigm that emphysema is strictly an inflammatory-cell based disease is shifting to consider the involvement of resident epithelial cells. Here we review the role of epithelial cells in lung development and emphysema. To better understand tobacco-epithelial interactions we performed microarray analyses of RNA from human airway epithelial cells exposed to smoke extract for 24 hours. These studies identified differential regulation of 425 genes involved in diverse biological processes, such as apoptosis, immune function, cell cycle, signal transduction, proliferation, and antioxidants. Some of these genes, including VEGF, glutathione peroxidase, IL-13 receptor, and cytochrome P450, have been previously reported to be altered in the lungs of smokers. Others, such as pirin, cathepsin L, STAT1, and BMP2, are shown here for the first time to have a potential role in smoke-associated injury. These data broaden our understanding of the importance of epithelial cells in lung health and cigarette smoke-induced emphysema.
PMCID: PMC2721228  PMID: 19662102
Epithelium; cytokine; inflammation; tobacco; microarray; apoptosis; alveolar; development; vitamins; antioxidants
23.  Health, Health Inequality, and Cost Impacts of Annual Increases in Tobacco Tax: Multistate Life Table Modeling in New Zealand 
PLoS Medicine  2015;12(7):e1001856.
Background
Countries are increasingly considering how to reduce or even end tobacco consumption, and raising tobacco taxes is a potential strategy to achieve these goals. We estimated the impacts on health, health inequalities, and health system costs of ongoing tobacco tax increases (10% annually from 2011 to 2031, compared to no tax increases from 2011 [“business as usual,” BAU]), in a country (New Zealand) with large ethnic inequalities in smoking-related and noncommunicable disease (NCD) burden.
Methods and Findings
We modeled 16 tobacco-related diseases in parallel, using rich national data by sex, age, and ethnicity, to estimate undiscounted quality-adjusted life-years (QALYs) gained and net health system costs over the remaining life of the 2011 population (n = 4.4 million). A total of 260,000 (95% uncertainty interval [UI]: 155,000–419,000) QALYs were gained among the 2011 cohort exposed to annual tobacco tax increases, compared to BAU, and cost savings were US$2,550 million (95% UI: US$1,480 to US$4,000). QALY gains and cost savings took 50 y to peak, owing to such factors as the price sensitivity of youth and young adult smokers. The QALY gains per capita were 3.7 times greater for Māori (indigenous population) compared to non-Māori because of higher background smoking prevalence and price sensitivity in Māori. Health inequalities measured by differences in 45+ y-old standardized mortality rates between Māori and non-Māori were projected to be 2.31% (95% UI: 1.49% to 3.41%) less in 2041 with ongoing tax rises, compared to BAU. Percentage reductions in inequalities in 2041 were maximal for 45–64-y-old women (3.01%). As with all such modeling, there were limitations pertaining to the model structure and input parameters.
Conclusions
Ongoing tobacco tax increases deliver sizeable health gains and health sector cost savings and are likely to reduce health inequalities. However, if policy makers are to achieve more rapid reductions in the NCD burden and health inequalities, they will also need to complement tobacco tax increases with additional tobacco control interventions focused on cessation.
Using a multistate life table modeling approach, Frederieke van der Deen and colleagues estimate the potential impact of annual increases in tobacco tax on health and health inequalities in New Zealand.
Editors' Summary
Background
Worldwide, approximately 21% of the population aged 15 and above smoke cigarettes and other tobacco products. However, tobacco is a killer. Half of all tobacco users die because of cancer, lung disease, heart disease, or another tobacco-related disease. Tobacco caused 100 million deaths in the 20th century; if current trends continue, it could cause a many more deaths in the 21st century. In response to this global tobacco epidemic, individual countries are considering how to reduce or even end tobacco consumption (the “tobacco endgame”), and international bodies have drawn up various tobacco control directives. The World Health Organization, for example, has developed an international instrument for tobacco control called the Framework Convention on Tobacco Control (FCTC). Countries that are party to the FCTC agree to implement a wide range of measures designed to reduce tobacco use. For example, they agree to implement bans on tobacco advertising, promotion, and sponsorship and to protect people from tobacco smoke exposure in public spaces and indoor workplaces.
Why Was This Study Done?
An important tobacco control measure is the implementation of taxation policies aimed at reducing tobacco consumption, promoting cessation, and preventing young people from taking up smoking. But less is known about the impact on population health, health inequality (higher rates of illness and death in specific parts of the population), and health system costs of annual tobacco tax increases, a strategy that is being used or considered by many countries. Here, the researchers estimate the impact of annual tobacco tax increases compared with no tax increases in New Zealand using a mathematical approach called multistate life table modeling. In New Zealand, a country that collects data on disease incidence and mortality by sociodemographic status and has implemented annual tobacco taxation increases since 2010, there are marked health inequalities between indigenous Māori (15% of the population) and non-Māori residents. Smoking is a major cause of these existing health inequalities (as in many other countries)—33% of Māori smoke compared to 14% of New Zealand Europeans. A life table shows, for each age, the probability that a person of that age will die before his or her next birthday.
What Did the Researchers Do and Find?
The researchers estimated quality-adjusted life-years (QALYs; a measure of disease burden that includes both the quantity and quality of life lived) gained and net health system costs over the remaining life of New Zealand’s 2011 population exposed to annual 10% tobacco tax increases or to no tax increases by modeling 16 tobacco-related diseases in parallel using national data on all-cause mortality and morbidity (illness). Compared to the 2011 population exposed to no tax increases, 260,000 QALYs were gained among the population exposed to annual tax increases from 2011 to 2031 and followed up for the remainder of their lives. The net health system cost savings associated with this intervention were estimated at US$2,550 million over the remainder of the 2011 population’s life. Both the health gains and cost savings began to accrue immediately but took five decades to peak. The QALY gains per capita associated with annual tobacco tax increases were 3.7-fold higher for Māori than for non-Māori because of higher smoking levels and price sensitivity among Māori (the tobacco purchasing behavior of Māori is affected more by the price of tobacco than non-Māori because they have less disposable income). Finally, projected health inequalities measured by the difference in mortality rates among Māori and non-Māori aged 45+ y were 2.3% lower in 2041 with ongoing tax rises than with no tax rises.
What Do These Findings Mean?
These findings suggest that in New Zealand (and probably in other similar populations), ongoing tobacco tax increases should deliver sizeable health gains and health system cost savings and should modestly reduce health inequalities. Notably, the health gains and cost savings will not peak for several decades because smoking is more common among younger age groups and the tobacco tax effect is greater among young people (who have limited disposable income) but young people do not benefit maximally from reduced rates of tobacco-related diseases for many decades. As with all modeling studies, the accuracy of these findings depends on the assumptions built into the model and the data fed into it. Overall, however, these findings support the use of annual increases of tobacco tax as a way to improve population health, save health system costs, and reduce health inequalities but suggest that policy makers will need to introduce other tobacco control interventions focused on smoking cessation among middle-age to older smokers if they want to achieve more rapid reductions in tobacco-related diseases and health inequalities.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001856.
The World Health Organization provides information about the dangers of tobacco (in several languages), about FCTC, and about tobacco control economics; its 2013 report on the global tobacco epidemic is available
The United States Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use
The United Kingdom National Health Services website provides information about the health risks associated with smoking
The UK campaigning public health not-for profit organization Action on Smoking and Health (ASH) provides detailed information on tobacco taxation
Information about tobacco control in New Zealand is available
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001856
PMCID: PMC4517929  PMID: 26218517
24.  Preventing smoking during pregnancy: the importance of maternal knowledge of the health hazards and of the treatment options available*  
Jornal Brasileiro de Pneumologia  2015;41(2):175-181.
OBJECTIVE:
To examine the pattern of tobacco use and knowledge about tobacco-related diseases, as well as to identify popular types of electronic media, in pregnant women, in order to improve strategies for the prevention or cessation of smoking among such women.
METHODS:
A cross-sectional study involving 61 pregnant women, seen at primary care clinics and at a university hospital, in the city of Botucatu, Brazil. For all subjects, we applied the Hospital Anxiety and Depression Scale. For subjects with a history of smoking, we also applied the Fagerström Test for Nicotine Dependence, and we evaluated the level of motivation to quit smoking among the current smokers.
RESULTS:
Of the 61 pregnant women evaluated, 25 (40.9%) were smokers (mean age, 26.4 ± 7.4 years), 24 (39.3%) were former smokers (26.4 ± 8.3 years), and 12 (19.8%) were never-smokers (25.1 ± 7.2 years). Thirty-nine women (63.9%) reported exposure to passive smoking. Of the 49 smokers/former smokers, 13 (26.5%) were aware of the pulmonary consequences of smoking; only 2 (4.1%) were aware of the cardiovascular risks; 23 (46.9%) believed that smoking does not harm the fetus or newborn infant; 21 (42.9%) drank alcohol during pregnancy; 18 (36.7%) reported increased cigarette consumption when drinking; 25 (51.0%) had smoked flavored cigarettes; and 12 (24.5%) had smoked a narghile. Among the 61 pregnant women evaluated, television was the most widely available and favorite form of electronic media (in 85.2%), as well as being the form most preferred (by 49.2%).
CONCLUSIONS:
Among pregnant women, active smoking, passive smoking, and alternative forms of tobacco consumption appear to be highly prevalent, and such women seem to possess little knowledge about the consequences of tobacco use. Educational programs that include information about the consequences of all forms of tobacco use, employing new and effective formats tailored to this particular population, should be developed, in order to promote smoking prevention and cessation among pregnant women. Further samples to explore regional and cultural adaptations should be evaluated.
doi:10.1590/S1806-37132015000004482
PMCID: PMC4428855  PMID: 25972970
Pregnancy; Health knowledge, attitudes, practice; Smoking; Mass media; Smoking cessation; Primary prevention
25.  Systemic Inflammatory Response to Smoking in Chronic Obstructive Pulmonary Disease: Evidence of a Gender Effect 
PLoS ONE  2014;9(5):e97491.
Background
Tobacco smoking is the main risk factor of chronic obstructive pulmonary disease (COPD) but not all smokers develop the disease. An abnormal pulmonary and systemic inflammatory response to smoking is thought to play a major pathogenic role in COPD, but this has never been tested directly.
Methods
We studied the systemic biomarker and leukocyte transcriptomic response (Affymetrix microarrays) to smoking exposure in 10 smokers with COPD and 10 smokers with normal spirometry. We also studied 10 healthy never smokers (not exposed to smoking) as controls. Because some aspects of COPD may differ in males and females, and the inflammatory response to other stressors (infection) might be different in man and women, we stratified participant recruitment by sex. Differentially expressed genes were validated by q-PCR. Ontology enrichment was evaluated and interaction networks inferred.
Results
Principal component analysis identified sex differences in the leukocyte transcriptomic response to acute smoking. In both genders, we identified genes that were differentially expressed in response to smoking exclusively in COPD patients (COPD related signature) or smokers with normal spirometry (Smoking related signature), their ontologies and interaction networks.
Conclusions
The use of an experimental intervention (smoking exposure) to investigate the transcriptomic response of peripheral leukocytes in COPD is a step beyond the standard case-control transcriptomic profiling carried out so far, and has facilitated the identification of novel COPD and Smoking expression related signatures which differ in males and females.
doi:10.1371/journal.pone.0097491
PMCID: PMC4022517  PMID: 24830457

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