Heterogeneity and other problems in a pooled analysis of snus use and mortality

A recent analysis of Swedish snus use and mortality combined eight Swedish datasets and found that exclusive Swedish male snus users have statistically significant increased mortality from all causes, cardiovascular diseases and other causes. These findings, from the Swedish Collaboration on Health Effects of Snus Use, are in sharp contrast with previous pooled results from the same group. The discrepant results may be indicative of unresolved statistical problems that haven’t been addressed by the collaboration authors in any of their studies. The most important problem is unresolved heterogeneity among the eight cohorts, which we describe in detail, and we show how the use of the random effects method by the authors was not sufficient. We explain why the tables in the article are uninformative, and we demonstrate why the exclusion of smokers in the analysis was not validated and eliminated important information. Finally, we strongly recommend some straightforward and easily implemented corrective measures.

Swedish snus use is associated with mortality: a pooled analysis of eight prospective studies

Background The health consequences of the use of Swedish snus, including its relationship with mortality, have not been fully established. We investigated the relationship between snus use and all-cause and cause-specific mortality (death due to cardiovascular diseases, cancer diseases and all other reasons, respectively) in a nationwide collaborative pooling project. Methods We followed 169 103 never-smoking men from eight Swedish cohort studies, recruited in 1978–2010. Shared frailty models with random effects at the study level were used in order to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of mortality associated with snus use. Results Exclusive current snus users had an increased risk of all-cause mortality (aHR 1.28, 95% CI 1.20–1.35), cardiovascular mortality (aHR 1.27, 95% CI 1.15–1.41) and other cause mortality (aHR 1.37, 95% CI 1.24–1.52) compared with never-users of tobacco. The risk of cancer mortality was also increased (aHR 1.12, 95% CI 1.00–1.26). These mortality risks increased with duration of snus use, but not with weekly amount. Conclusions Snus use among men is associated with increased all-cause mortality, cardiovascular mortality, with death from other causes and possibly with increased cancer mortality.

No association between moist oral snuff (snus) use and oral cancer: pooled analysis of nine prospective observational studies

Aims: Worldwide, smokeless-tobacco use is a major risk factor for oral cancer. Evidence regarding the particular association between Swedish snus use and oral cancer is, however, less clear. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess the association between snus use and oral cancer. Methods: A total of 418,369 male participants from nine cohort studies were followed up for oral cancer incidence through linkage to health registers. We used shared frailty models with random effects at the study level, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for confounding factors. Results: During 9,201,647 person-years of observation, 628 men developed oral cancer. Compared to never-snus use, ever-snus use was not associated with oral cancer (adjusted HR 0.90, 95% CI: 0.74, 1.09). There were no clear trends in risk with duration or intensity of snus use, although lower intensity use (⩽ 4 cans/week) was associated with a reduced risk (HR 0.65, 95% CI: 0.45, 0.94). Snus use was not associated with oral cancer among never smokers (HR 0.87, 95% CI: 0.57, 1.32). Conclusions: Swedish snus use does not appear to be implicated in the development of oral cancer in men.

Pharmacokinetic Comparison of a Novel Non-tobacco-Based Nicotine Pouch (ZYN) With Conventional, Tobacco-Based Swedish Snus and American Moist Snuff

Introduction The single-dose pharmacokinetics (PK) of a novel, non-tobacco-based nicotine pouch, ZYN, 3 and 6 mg, were compared with 8 mg General snus (part 1) and ZYN 8 mg was compared with 18 mg Longhorn moist snuff (part 2). The present study demonstrates the characteristics of three strengths of a novel tobacco-free oral snus, ZYN, viz. the extraction of nicotine from the oral cavity and its uptake into the systemic blood circulation. Comparison is made to Swedish General snus and American Longhorn moist snuff and from literature 4 mg Nicorette gum and mean of 13 brands of e-cigarettes. Aims and Methods A single-dose randomized crossover design was used. In vivo extraction and PK parameters were determined. Results Part 1. The AUCinf of ZYN 3 mg was 27% smaller than that of 8 mg General and the AUCinf of ZYN 6 mg was 34% larger than that of 8 mg General. Less nicotine was extracted from ZYN 3 mg (1.5 mg) and more from ZYN 6 mg (3.5 mg) than from 8 mg General (2.4 mg). The extracted fractions of nicotine for both ZYN products (56% and 59%) were significantly larger than for 8 mg General (32%). Results Part 2. Close to identical plasma nicotine curves, AUCinf and Cmax were found for ZYN 8 mg and Longhorn Natural 18 mg moist snuff. The extracted amount of nicotine from ZYN 8 mg (3.8 mg) was larger than the amount extracted from Longhorn Natural 18 mg (3.0 mg), but smaller than the extracted amount of nicotine from General 2 × 8 mg snus pouches (5.0 mg). The extracted fraction of nicotine for ZYN 8 mg (50%) was larger than for Longhorn Natural (19%) and General 2 × 8 mg snus pouches (33%). Conclusions The two higher doses of ZYN (6 and 8 mg) deliver nicotine as quickly and to a similar extent as existing smokeless products, with no significant adverse effects.

Activation of PI3K/Akt/NF-kB Signaling Mediates Swedish Snus Induced Proliferation and Apoptosis Evasion in the Rat Forestomach: Modulation by Blueberry

Background and Objective: The present study was undertaken to ascertain whether the modulatory effects of blueberries on cell proliferation induced by Swedish snus in the rat forestomach epithelium is mediated via abrogation of the PI3K/Akt/NFκB signaling axis that regulates cell fate decision. Methods: The transcript and protein expression of genes involved in cell cycle progression and apoptosis, as well as canonical PI3K/Akt/NF-κB signaling pathways, were analyzed by qRT-PCR, immunoblotting and ELISA. Expression profiling of noncoding RNAs (ncRNAs) that influence PI3K/Akt/NF-κB signaling was undertaken. TUNEL assay was performed using flow cytometry. Results: Administration of snus induced basal cell hyperplasia in the rat forestomach with increased cell proliferation and inhibition of apoptosis. This was associated with the activation of PI3K/Akt/NFκB signaling. Coadministration of blueberries significantly suppressed snus-induced hyperplasia. Analysis of the molecular mechanisms revealed that blueberries suppress the phosphorylation of Akt, NF-κB and IKKβ, prevent nuclear translocation of NF-κB and modulate the expression of microRNAs that influence PI3K/Akt/NF-κB signaling. Conclusion: Taken together, the results of the current study provide compelling evidence that blueberries exert significant protective effects against snus-induced soft tissue changes in the rat forestomach epithelium mediated by inhibiting key molecular players in the PI3K/Akt/NF-κB signaling axis. Long-term studies on the impact of snus exposure on various cellular processes, signaling pathways, and the interplay between genetic and epigenetic mechanisms are however warranted. The results of this investigation may contribute to the development of protection against soft tissue changes induced by smokeless tobacco in the human oral cavity.

Meningococcal carriage in Norwegian teenagers: strain characterisation and assessment of risk factors

Teenagers have a higher risk of invasive meningococcal disease (IMD) than the general population. This cross-sectional study aimed to characterise strains of Neisseria meningitidis circulating among Norwegian teenagers and to assess risk factors for meningococcal carriage. Oropharyngeal swabs were collected from secondary-school students in southeastern Norway in 2018–2019. Meningococcal isolates were characterised using whole genome sequencing. Risk factors for meningococcal carriage were assessed from questionnaire data. Samples were obtained from 2296 12–24-year-olds (majority 13–19-year-olds). N. meningitidis was identified in 167 (7.3%) individuals. The highest carriage rate was found among 18-year-olds (16.4%). Most carriage isolates were capsule null (40.1%) or genogroup Y (33.5%). Clonal complexes cc23 (35.9%) and cc198 (32.3%) dominated and 38.9% of carriage strains were similar to invasive strains currently causing IMD in Norway. Use of Swedish snus (smokeless tobacco) (OR 1.56, 95% CI 1.07–2.27), kissing >two persons/month (OR 2.76, 95% CI 1.49–5.10) and partying >10 times/3months (OR 3.50, 95% CI 1.45–8.48) were associated with carriage, while age, cigarette smoking, sharing of drinking bottles and meningococcal vaccination were not. The high meningococcal carriage rate among 18-year-olds is probably due to risk-related behaviour. Use of Swedish snus is possibly a new risk factor for meningococcal carriage. Almost 40% of circulating carriage strains have invasive potential.

LC-MS/MS Analysis of Sugars, Alditols, and Humectants in Smokeless Tobacco Products

SummaryGlobally, smokeless tobacco (ST) includes a wide array of chemically diverse products generally used in the oral cavity. Although ST has been widely investigated, this study was undertaken to determine the levels of sugars (mono- and di-saccharides), alditols, and humectants present in major ST categories/subcategories by using high performance liquid chromatography coupled with a triple quadrupole mass spectrometer (HPLC-MS/MS). The products studied included chewing tobacco (loose leaf, plug, twist), US moist snuff, Swedish snus, creamy snuff, dry snuff, dissolvable tobacco products, and tobacco-coated toothpicks. The highest mean sugar level was detected in chewing tobacco (9.3–27.5%, w/w), followed by dissolvable tobacco (2.1%); all other products were lower than 1%. Creamy snuff had the highest mean alditol levels (22.6%), followed by dissolvable tobacco (15.4%); all others had levels lower than 1%. The detected mean humectant levels ranged from non-detectable to 5.9%. This study demonstrates the broad chemical diversity among ST. This research may aid researchers and public health advocates investigating the exposures and risks of ST. [Beitr. Tabakforsch. Int. 28 (2019) 203–213]

Relative Risk Perceptions between Snus and Cigarettes in a Snus-Prevalent Society—An Observational Study over a 16 Year Period

Background: Most studies on perceived risks of smokeless tobacco products (SLT) have been conducted in the U.S., and the vast majority conclude that perceptions of the relative harmfulness of SLT versus cigarettes in the population are inconsistent with epidemiologically-based risk estimates, and typically conflated to that of cigarettes. We tested whether such inaccuracies also existed in Norway, where SLT-products are less toxic (Swedish snus) and SLT use is more prevalent than in the U.S. Methods: Over a 16 years period (2003–2018), 13,381 respondents (aged 16–79 years) answered questions about risk perceptions in Statistics Norway’s nationally representative survey of tobacco behavior. We applied an indirect measure of comparative harm where risk beliefs for eight nicotine products were assessed independently of other products and then compared the answers. The wording of the question was: “We will now mention a variety of nicotine products and ask you how harmful you think daily use of these are. Use a scale from 1 to 7, where 1 is slightly harmful and 7 is very harmful”. Mean scores with 95% confidence intervals were calculated. Results: The overall risk score for cigarettes was 6.48. The risk score for snus was 5.14–79.3% of the risk score of cigarettes. The relative risk scores for e-cigarettes (3.78) and NRT products (3.39) was 58.4% and 52.3% when compared to cigarettes. Perceptions of risk were stable over time. A strong association was observed between perceived risk of snus and having used snus in attempts to quit smoking. Conclusion: Perceptions of relative risk between snus and cigarettes is inconsistent with estimates from medical expert committees, which assess the overall health risk from use of Swedish snus to be minor when compared to the risk from smoking. Like the situation in the US, incorrect beliefs about SLT risks seem to be prevalent also in the snus-prevalent Norwegian setting. Accurate information on differential harms needs to be communicated. Future research should try to identify reasons why health authorities in the US and Scandinavia allow these well-documented misconceptions to persist.