NOT PEER REVIEWED The study conducted in England by Petrescu and colleagues [1] concludes that there is a "potential for e-cigarette adverts to undermine tobacco control efforts by reducing a potential barrier (i.e. beliefs about harm) to occasional smoking". Clearly it is important to keep monitoring the impact of advertising, particularly on children, and this research paper is a welcome contribution. However, it is important to put this in context.

The most recent survey of smoking among children in England found the lowest recorded smoking rates among youth aged 11-15 since records began in 1982.[2] It's worth noting that rates have continued to fall since e- cigarette use and marketing of products began to take off in Great Britain after 2010.[3][4] In 2010, 5% of 11-15 year olds were regular smokers falling to 3% in 2014. Also, in 2010 27% had ever tried smoking, falling to 18% in 2014.

So it doesn't appear that e-cigarette advertising in England has had an impact so far on the number of children trying smoking, or becoming regular smokers. Furthermore from May 2016 all cross border advertising including TV, radio, internet and newspaper advertising has been banned throughout the European Union, thereby limiting advertising to that with local impact.

It should also be noted that in the UK e-cigarette manufacturers are required to adhere to strict rules on advertising content.[5] These rules specify in particular that advertisers must ensure ads do not target, feature or appeal to children; that they do not confuse e-cigarettes with tobacco products; that they do not mislead with regard to product ingredients.

In jurisdictions where e-cigarette ads are unregulated and resemble tobacco promotion, it's reasonable to assume that they could affect children's perceptions of both e-cigarettes and smoking. This study underlines the need to monitor e-cigarette marketing but the potential risks that e-cigarette advertisements are undermining tobacco control efforts in England are likely to be over-stated.

[1] D C Petrescu, M Vasiljevic, J K Pepper, K M Ribisl, T M Marteau. What is the impact of adverts on children's perceptions of tobacco smoking? Tobacco Control published online 6 Sept. 2016. Doi: 10.1136/tobaccocontrol-2016-052940

[2] Smoking, drinking and drug use among young people in England in 2014. Health & Social Care Information Centre, 2015.

[3] ASH Fact sheet. Use of electronic cigarettes (vapourisers) among adults in Great Britain. ASH, 2016

[4] De Andrade M et al. The marketing of e-cigarettes in the UK. Cancer Research UK, 2013. https://www.cancerresearchuk.org/sites/default/files/cruk_marketing_of_electronic_cigs_nov_2013.pdf

[5] Committee on Advertising Practice. https://www.cap.org.uk/Advice-Training-on-the-rules/Advice-Online- Database/Electronic-cigarettes.aspx#.V86Snf_6uvE

Conflict of Interest:

None declared

NOT PEER REVIEWED In the last decade, electronic cigarettes (EC) have become increasingly popular in particular among smokers. Most EC users choose to use nicotine containing liquids (electronic nicotine delivery system, ENDS); these ENDS can be considered as similar to nicotine replacement therapies. Among the several questions EC use raises, one is of major importance: Are EC a smoking cessation aid and if yes to what extent compared to existing pharmacotherapies such as nicotine replacement therapies, varenicline or bupropion? Several systematic reviews tried to approach the role of EC as a smoking cessation aid. As of today, only two randomized trials assessed the efficacy of EC with controversial results (1,2). As an editorial (3) and the last systematic review (4) concluded, because of the absence of well- designed and sufficiently powered randomized, controlled, head-to-head therapeutic trials the current accumulation of data originating essentially from observational studies does not allow us to make any conclusion as to EC's therapeutic efficacy in smoking cessation. Manzoli et al. (5, 6) assessed abstinence from tobacco cigarettes or tobacco and electronic cigarettes ('any product') in a prospective cohort study. They included at baseline EC only users, individuals using tobacco cigarettes and EC (dual use) and those using only tobacco cigarettes. They reported the 12-month (5) and 24-month (6) results in two separate papers the latter published online in the June 2016 issue of Tobacco Control. For both papers, the analyses were restricted to individuals whose data were available at 12 or 24 months (completers). This study raises the question whether observational studies assessing efficacy should be analyzed similarly to randomized efficacy trials for which the gold standard approach is the intent-to treat-analysis (ITT) (7) which defines the population submitted to the main data analysis. Table 1. https://docs.google.com/document/d/1RM5mvK1s85N1iZZ_kKiHkKiMsS1SVl4YMPTj6ALHvS8/edit?usp=sharing compares Manzoli et al. results for the 12-month and 24-month abstinence outcomes (5,6). For all baseline categories, completers' abstinence rates are higher than abstinence rates of the baseline population that we can call here as the "ITT" population i.e. of all individuals included. Of particular interest is that EC only users had higher tobacco cigarettes but not 'any product' abstinence rates both at 12 and 24 months than the two other groups. The (unadjusted) "ITT" tobacco cigarettes abstinence rates are 42% and 40.8 % versus the completers abstinence rates of 61.9% and 61.1 % at 12 and 24 months, respectively; all higher than among dual users or tobacco cigarette only users suggesting that EC can be an aid to quit smoking. Unfortunately, both papers report only confounder adjusted odds ratios for completers and not for the "ITT" population. Observational studies looking for treatment efficacy could be analyzed like randomized efficacy trials (8,9) to narrow the gap between randomized clinical trials and observational data (8). Non-ITT, usually completer analyses, aim to estimate the effect of treatments received as opposed to treatments assigned under the ITT approach and by this exclude all factors contributing to non-completion of the trial (lost to follow up, adverse events, discontinuation for any reasons). The advantage of the ITT analysis is that it evaluates the true treatment effect which is the sum of the biological effects, positive or negative such as adverse events, and study adherence. The limitation of the ITT analysis of randomized efficacy trials is the underestimation of efficacy because of non- treatment related confounders (e.g. lost to follow-up for moving to another city). On the other hand, completer analysis overestimates efficacy by ignoring e.g. discontinuation because of adverse events and cannot, therefore, help to assess the benefit/risk ratio of a given intervention. Until results of high-quality, large-scale, comparative, randomized trials of EC' efficacy will be available, data of well conducted prospective observational studies as that of Manzoli at al. (5,6) could estimate EC's efficacy by analyzing "ITT" data and not completers' data while adjusting for all available and potential confounders. Thus, in the Manzoli et al. study (5,6) adjusted "ITT" population abstinence rates would have provided more convincing results about EC's efficacy as an aid for smoking cessation than completers' adjusted abstinence rates. REFERENCES 1. Caponnetto P, Campagna D, Cibella F, et al. EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized control design study. PLoS One. 2013 Jun 24;8(6):e66317. doi: 10.1371/journal.pone.0066317. Print 2013. 2. Bullen C, Howe C, Laugesen M, et al. Electronic cigarettes for smoking cessation: a randomised controlled trial. Lancet. 2013 Nov 16;382(9905):1629-37. doi: 10.1016/S0140-6736(13)61842-5. Epub 2013 Sep 9. 3. Bernstein SL. Electronic cigarettes: more light, less heat needed. Lancet Respir Med. 2016; Feb;4(2):85-7. doi: 10.1016/S2213-2600(16)00010- 2. Epub 2016 Jan 14 4. Malas M, van der Tempel J, Schwartz R, et al. Electronic Cigarettes for Smoking Cessation: A Systematic Review. Nicotine Tob Res. 2016 Apr 25. pii: ntw119. [Epub ahead of print] Review. 5. Manzoli L, Flacco ME, Fiore M, et al. , Electronic cigarettes efficacy and safety at 12 months: Cohort Study. PLoS One. 2015 Jun 10;10(6):e0129443. doi: 10.1371/journal.pone.0129443. eCollection 2015. 6. Manzoli L, Flacco ME, Ferrante M, et al. Cohort study of electronic cigarette use: effectiveness and safety at 24 months. Tob Control. 2016 Jun 6. pii: tobaccocontrol-2015-052822. doi: 10.1136/tobaccocontrol-2015- 052822. [Epub ahead of print] 7. Detry MA, Lewis RJ. The Intention-to Treat principle. How to assess the true effect of choosing a medical treatment. JAMA 2014; 312:85-86. 8.Wilcox A, Wacholder S. Observational data and clinical trials. Narrowing the gap? Editorial. Epidemiology 2008;19: 765. 9. Herna?n MA, Alonso A, Logan R, et al. Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Epidemiology. 2008;19:766-779.

Conflict of Interest:

None declared

NOT PEER REVIEWED The American Indoor Hygiene Association (AIHA) i.e. Experts in in this particular field on passive exposure, have, previously, concluded conversely to Bauld et al (1). As they state:

"If the only individual affected by using e-cigarettes were the vaper, the discussion could end here. That is not, however, the case. Similar to secondhand smoke, the ingredients exhaled by the vaper include nicotine, metals, flavorings, and glycol that accumulate in the ambient air. Recipients of secondhand vapor have not chosen to - many, in fact, have explicitly chosen not to - use e-cigarettes. The exposure to secondhand vapor, just like secondhand smoke, raises issues of involuntary exposure and competing rights. This is even more critical for groups that may be, and probably are, more susceptible to adverse effects of secondhand vapor, including children, pregnant women, and people with already compromised health, some of whom may have limited ability to leave the spaces in which vaping occurs or has occurred."

This scientific postulation of second-hand inhalation of e-cigarette aerosol and subsequent adverse health effects has been further substantiated: via users of e-cigarettes, in their own personal, real- world experiences (2). They subsequently, and eloquently argue, that the devices should not be utilised in enclosed public spaces, due to these events occurring.

Linda Bauld has previously argued in an extended article that:

". . . there is no good evidence that [second hand] exposure is harmful to bystanders . . . To argue otherwise is just factually incorrect." (3)

However, the phrase "harmful to bystanders" provides a hyperlink to a review paper (4) of the potential for second hand exposures that, incongruently to Professor Bauld's claim, concludes that e-cigarettes:

". . . impart a LOWER potential disease burden than conventional TCs" (my emphasis)

I.E. therefore, NOT zero potential disease burden.

It is to be commended that Bauld et al wish to enhance the potential for adult smoking cessation maximally, however, in this case, there IS evidence that such a policy of non-restricted use potentially infringes the rights of non-users to avoid passive inhalation and subsequent adverse health effects, as the AIHA postulate, and as users of e-cigarettes have confirmed in real-world conditions.

1) American Industrial Hygiene Association: https://www.aiha.org/government- affairs/Documents/Electronc%20Cig%20Document_Final.pdf

2) "Vaping e-cigs in public" Available at: https://www.youtube.com/watch?v=6c5Ln69hWUc

3) Linda Bauld (2015). Available at: https://www.theguardian.com/science/sifting-the- evidence/2015/feb/23/theres-no-evidence-e-cigarettes-are-as-harmful-as- smoking

4) Oh, A. & Kacker, A. 2014 Do electronic cigarettes impart a lower potential disease burden than conventional tobacco cigarettes? Review on E-cigarette vapor versus tobacco smoke. Laryngoscope 124(12):2702-6. doi: 10.1002/lary.24750. Epub 2014 Oct 9.

David Bareham

"All views are my own and do not necessarily reflect those of my employer"

Conflict of Interest:

I have 3 presentations to local clinicians in Lincolnshire within the last 18 months entitled: "E-cigarettes: update on evidence", organised by GlaxoSmithKline. No payment was requested nor provided for this work.

NOT PEER REVIEWED David Bareham cites 'Rip Tripper' as evidence that e-cigarette users report experiences of allergies being exacerbated in non users by vapour and describes Mr Tripper's subsequent rather mangled argument that the devices should not be used in enclosed public spaces as "eloquent".

Perhaps Mr Bareham is unaware that Mr Tripper has also claimed that vaping causes limb cramps and dry knuckles which was a surprise to most vapers, until they spotted the affiliate link to where they could purchase electrolytes and a lotion to 'cure' them (1).

(1) 'Rip Trippers exposed as a sellout' Jh Reviews https://youtu.be/F1EJkbM0m7g (contains profanity)

Conflict of Interest:

I am a trustee of NNA(UK) which is a consumer driven charity which aims to improve health by increasing awareness and understanding of reduced risk alternatives to smoked tobacco.