On 2016 Oct 18, Konstantinos Farsalinos commented:

I am surprised that a completely irrelevant to the study (or to my post) comment is published here. I am satisfied to see that Hong Yin had no comment whatsoever on the content of my analysis on the problems of the paper by Ji et al. (1). I invite Hong Yin to comment on anything inappropriate or inaccurate, and of course i will respond accordingly and even correct any inaccuracies in my analysis. Instead of doing that, Hong Yin characterized the critical approach to studies with major methodological problems, which is a fundamental purpose of science and the duty of a scientist, as an "attack". There is no need to further comment on that, especially since i am in the process of finalizing the comprehensive and detailed replication of the New England Journal of Medicine research letter, which will provide further justification for the well constructed analysis on the need for retraction (2).

The disclosure of any COI was not only transparent from my side but also included declaration of funding of the institute which took place more than 3 years ago. According to ICMJE guidelines, it was not necessary to declare this, but i did it for the shake of full transparency. Thus, the initial sentence in the comment by Hong Yin is unjustifiable.

Additionally, Hong Yin omitted to mention that a very detailed response to the alleged "problems" of my paper has been published in response to the Shihadeh et al. commentary, both by the authors of the original study (3) and by the editor of Addiction journal (4). In my response, i clearly presented the case that our study (5) evaluated the widely-known organoleptic parameter of dry puff detection in e-cigarettes. This phenomenon can easily result (and unfortunately is frequently resulting) in abuse of e-cigarettes in the laboratory and misleading reports on e-cigarette emissions which are irrelevant to human exposure. The authors of the letter characterized dry puffs as a term with "tenuous ontological status", despite the fact that this phenomenon has been described in the literature since 2013 (6) and is well-known and explained by e-cigarette users long before that.

The act of writing a comment is irrelevant when the content of the criticism is not examined. I will be happy to accept and respond to any criticism about the content of my research or my comments.

References:

1. Ji EH, Sun B, Zhao T, Shu S, Chang CH, Messadi D, Xia T, Zhu Y, Hu S. Characterization of Electronic Cigarette Aerosol and Its Induction of Oxidative Stress Response in Oral Keratinocytes. PLoS One. 2016 May 25;11(5):e0154447.

2. Bates CD, Farsalinos KE. Research letter on e-cigarette cancer risk was so misleading it should be retracted. Addiction. 2015 Oct;110(10):1686-7. doi: 10.1111/add.13018.

3. Farsalinos K, Voudris V, Poulas K. Response to Shihadeh et al. (2015): E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Nov;110(11):1862-4. doi: 10.1111/add.13078.

4. West R. Conflicts of conscience in Addiction. Addiction. 2015 Nov;110(11):1864. doi: 10.1111/add.13069.

5. Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Aug;110(8):1352-6.

6. Farsalinos KE, Romagna G, Tsiapras D, Kyrzopoulos S, Voudris V. Evaluation of electronic cigarette use (vaping) topography and estimation of liquid consumption: implications for research protocol standards definition and for public health authorities' regulation. Int J Environ Res Public Health. 2013 Jun 18;10(6):2500-14. doi: 10.3390/ijerph10062500.

On 2016 Oct 18, Clive Bates commented:

Dr. Farsalinos has provided a full disclosure statement. It would be better if the authors or their supporters responded to substantive criticisms of their work than complaining about who is making them.

This comment suggests that criticising other papers is somehow an 'attack'. Normally we refer to evidence-based criticism as 'science'.

With all due respect, the criticism of Jensen RP, 2015 by Farsalinos and I in a letter published in Addiction is well-founded. No adequate response to these criticisms has been made or will be. The reason is that the letter points to fundamental flaws in the study design: operating the device at excessively high temperature, and thereby running in 'dry puff' conditions that no human user ever experiences for more than an instant. Though completely unrealistic for humans, laboratory machines will reliably, but misleadingly, measure emissions under these conditions for hours.

The tendency among researchers and journals unfamiliar with actual vaping and vapers, but keen to publish laboratory results, is to overlook these real-world phenomena. That is why responsible researchers in the field need to know what methodology was used so they can decide whether the results are possibly interesting or whether they should be discarded as another failure of scientific comprehension, unchecked by peer review.

On 2016 Sep 14, Hong Yin commented:

Since Konstantinos Farsalinos had unrestricted funds from electronic cigarette companies, a full disclosure of the relationship to electronic cigarette industry is needed before making this kind of judgmental comment.

Similar attack was made on another published paper in The New England Journal of Medicine entitled “Hidden formaldehyde in e-cigarette aerosols” (1, 2).

In his comment, Farsalinos cited his recent publication “E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions” (3). This paper received comments such as “Insufficient Method Description”, “Incomplete Result Reporting”, and “Unjustified Conclusions" (4) (quoted from the commentary).

References:

1. Jensen RP, Luo W, Pankow JF, Strongin RM, Peyton DH. Hidden formaldehyde in e-cigarette aerosols. N Engl J Med. 2015 Jan 22;372(4):392-4.

2. Bates CD, Farsalinos KE. Research letter on e-cigarette cancer risk was so misleading it should be retracted. Addiction. 2015 Oct;110(10):1686-7.

3. Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Aug;110(8):1352-6.

4. Shihadeh A, Talih S, Eissenberg T. Commentary on Farsalinos et al. (2015): E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Nov;110(11):1861-2.

Disclosure: I have nothing to disclose with any cigarette industry.

On 2016 Jul 14, Clive Bates commented:

It is disappointing that the only reaction to Farsalinos' comment so far (anonymously via PubPeer) has been in relation to a disclosure statement, which in any event he has now added. There has been no substantive criticism of his work or response to his critique. Perhaps now the discussion should return to addressing the multiple methodological weaknesses he has identified in the Ji et al study.

Farsalinos and colleagues' study at ref #2 above shows clearly how machine measurements of e-cigarettes can become a misleading proxy for human exposure as power increases. Laboratory machines lack a critical control feedback - the reaction to a harsh taste by rapidly stopping vaping - that human subjects have. The acrid taste arises in situations where the liquid is undergoing thermal decomposition and its chemistry changes. If this is the case in the present experiment, the measurements are made under conditions that create exposures no human will experience. If Ji et al did not control to prevent this 'dry puff' condition arising during their experiment, the paper does not offer a basis for making any human risk assessments and is easily open to misinterpretation.

The uncertainty over the magnitude of the implied exposure, the lack of comparative context (the obvious comparator being tobacco smoke) and an uncertain operating regime capable of creating completely unrealistic exposures are major deficiencies. No conclusions about e-cigarette use and human health should be drawn from this study and the authors should discourage any over-interpretation of their findings.

Disclosure: I am a longstanding advocate for evidence-based 'harm reduction' approaches to public health. I was director of Action on Smoking and Health UK from 1997-2003. I have no competing interests with respect to any of the relevant industries.

On 2016 Jul 06, Konstantinos Farsalinos commented:

Paracelsus, the herald of modern toxicology, mentioned in the 16th century that: nothing is a poison and everything is poisonous; solely the dose determines that a thing is not a poison (Sola dosis facit venenum) (1). This principle, which still stands today and forms the basis of the dose-response concept, has been largely ignored by many scientists including the authors of this study. This study represents an unfortunate case of complete failure of the peer-review and editorial process of the journal.

One of the basic prerequisites for accepting a manuscript for publication is to provide a clear and detailed presentation of the methodology used in the experimental setup. In this case, the authors provide no information about:

1. The electronic cigarette device used in the experiment

2. The power settings on the electronic cigarette device that were used in the experiment

3. The puffing patterns (puff duration and interpuff interval). A range of 2 to 5s puff duration was mentioned only for the assessment of particle number concentration but not for cell exposure

4. The number of puffs performed during the aerosol generation procedure

5. The amount of liquid consumed during the aerosol generation procedure

6. The amount of aerosol dilution into the cell medium. There is no mention of the amount of cell medium used in the impingers and the amount of aerosol that was diluted into the cell medium.

7. The authors cite a study which has not been published or even accepted for publication but is marked as "submitted" for further details on the methodology (reference 11 of the manuscript)

Omissions 1-3 are extremely important because it is well-known that electronic cigarettes can be easily abused in a laboratory setting, which may result in the evaluation of unrealistic, dry puff, conditions. Such conditions are irrelevant to human exposure (2).

Omissions 4-6 are extremely important because they violate the basic principle of toxicology which dictates that the dose determines the toxicity. In fact, it is very easy in a cell culture to create an adverse cell response, just by manipulating the dose of exposure. Therefore, it is crucial to present the level (dose) of exposure and ensure that this is relevant to human exposure. Otherwise, the findings cannot be extrapolated to human effects and can only be used for comparing two different exposures. For the latter, it is surprising that the authors did not attempt to perform the same experiment with the same conditions and the same level of exposure with tobacco cigarette smoke. Thus, the study findings cannot even be used for comparative purposes.

Omission 7 is really unprecedented. It is the first time that i see a reference to a non-existing publication (marked as "submitted", so, not reviewed and not accepted) being accepted by the reviewers and the editor.

These omissions raise some important issues about the peer-review process and the editorial assessment of that study. In my opinion, this is a typical example of failure of the peer-review process and the study should be retracted or revised.

Disclosure. No funding or other support was provided for this comment. The author has no financial or other interest on e-cigarette companies. Two studies (unpublished) were performed with unrestricted funds provided to the institution (Onassis Cardiac Surgery Center) by 2 electronic cigarette companies in 2013, for which no researcher (including the author of this comment) received any financial compensation. Funding was provided more than 3 years ago, so the declaration is not necessary based on the ICMJE guidelines. Two published studies were performed using funds provided by the non-profit association AEMSA in 2013 (less than 3 years ago) and one published study was funded by the non-profit association Tennessee Smoke-Free Association in 2015.

References

1. Borzelleca JF. Paracelsus: herald of modern toxicology. Toxicol Sci. 2000 Jan;53(1):2-4.

2. Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Aug;110(8):1352-6.

On 2016 Jul 06, Konstantinos Farsalinos commented:

Paracelsus, the herald of modern toxicology, mentioned in the 16th century that: nothing is a poison and everything is poisonous; solely the dose determines that a thing is not a poison (Sola dosis facit venenum) (1). This principle, which still stands today and forms the basis of the dose-response concept, has been largely ignored by many scientists including the authors of this study. This study represents an unfortunate case of complete failure of the peer-review and editorial process of the journal.

One of the basic prerequisites for accepting a manuscript for publication is to provide a clear and detailed presentation of the methodology used in the experimental setup. In this case, the authors provide no information about:

1. The electronic cigarette device used in the experiment

2. The power settings on the electronic cigarette device that were used in the experiment

3. The puffing patterns (puff duration and interpuff interval). A range of 2 to 5s puff duration was mentioned only for the assessment of particle number concentration but not for cell exposure

4. The number of puffs performed during the aerosol generation procedure

5. The amount of liquid consumed during the aerosol generation procedure

6. The amount of aerosol dilution into the cell medium. There is no mention of the amount of cell medium used in the impingers and the amount of aerosol that was diluted into the cell medium.

7. The authors cite a study which has not been published or even accepted for publication but is marked as "submitted" for further details on the methodology (reference 11 of the manuscript)

Omissions 1-3 are extremely important because it is well-known that electronic cigarettes can be easily abused in a laboratory setting, which may result in the evaluation of unrealistic, dry puff, conditions. Such conditions are irrelevant to human exposure (2).

Omissions 4-6 are extremely important because they violate the basic principle of toxicology which dictates that the dose determines the toxicity. In fact, it is very easy in a cell culture to create an adverse cell response, just by manipulating the dose of exposure. Therefore, it is crucial to present the level (dose) of exposure and ensure that this is relevant to human exposure. Otherwise, the findings cannot be extrapolated to human effects and can only be used for comparing two different exposures. For the latter, it is surprising that the authors did not attempt to perform the same experiment with the same conditions and the same level of exposure with tobacco cigarette smoke. Thus, the study findings cannot even be used for comparative purposes.

Omission 7 is really unprecedented. It is the first time that i see a reference to a non-existing publication (marked as "submitted", so, not reviewed and not accepted) being accepted by the reviewers and the editor.

These omissions raise some important issues about the peer-review process and the editorial assessment of that study. In my opinion, this is a typical example of failure of the peer-review process and the study should be retracted or revised.

Disclosure. No funding or other support was provided for this comment. The author has no financial or other interest on e-cigarette companies. Two studies (unpublished) were performed with unrestricted funds provided to the institution (Onassis Cardiac Surgery Center) by 2 electronic cigarette companies in 2013, for which no researcher (including the author of this comment) received any financial compensation. Funding was provided more than 3 years ago, so the declaration is not necessary based on the ICMJE guidelines. Two published studies were performed using funds provided by the non-profit association AEMSA in 2013 (less than 3 years ago) and one published study was funded by the non-profit association Tennessee Smoke-Free Association in 2015.

References

1. Borzelleca JF. Paracelsus: herald of modern toxicology. Toxicol Sci. 2000 Jan;53(1):2-4.

2. Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Aug;110(8):1352-6.

On 2016 Sep 14, Hong Yin commented:

Since Konstantinos Farsalinos had unrestricted funds from electronic cigarette companies, a full disclosure of the relationship to electronic cigarette industry is needed before making this kind of judgmental comment.

Similar attack was made on another published paper in The New England Journal of Medicine entitled “Hidden formaldehyde in e-cigarette aerosols” (1, 2).

In his comment, Farsalinos cited his recent publication “E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions” (3). This paper received comments such as “Insufficient Method Description”, “Incomplete Result Reporting”, and “Unjustified Conclusions" (4) (quoted from the commentary).

References:

1. Jensen RP, Luo W, Pankow JF, Strongin RM, Peyton DH. Hidden formaldehyde in e-cigarette aerosols. N Engl J Med. 2015 Jan 22;372(4):392-4.

2. Bates CD, Farsalinos KE. Research letter on e-cigarette cancer risk was so misleading it should be retracted. Addiction. 2015 Oct;110(10):1686-7.

3. Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Aug;110(8):1352-6.

4. Shihadeh A, Talih S, Eissenberg T. Commentary on Farsalinos et al. (2015): E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Nov;110(11):1861-2.

Disclosure: I have nothing to disclose with any cigarette industry.

On 2016 Oct 18, Konstantinos Farsalinos commented:

I am surprised that a completely irrelevant to the study (or to my post) comment is published here. I am satisfied to see that Hong Yin had no comment whatsoever on the content of my analysis on the problems of the paper by Ji et al. (1). I invite Hong Yin to comment on anything inappropriate or inaccurate, and of course i will respond accordingly and even correct any inaccuracies in my analysis. Instead of doing that, Hong Yin characterized the critical approach to studies with major methodological problems, which is a fundamental purpose of science and the duty of a scientist, as an "attack". There is no need to further comment on that, especially since i am in the process of finalizing the comprehensive and detailed replication of the New England Journal of Medicine research letter, which will provide further justification for the well constructed analysis on the need for retraction (2).

The disclosure of any COI was not only transparent from my side but also included declaration of funding of the institute which took place more than 3 years ago. According to ICMJE guidelines, it was not necessary to declare this, but i did it for the shake of full transparency. Thus, the initial sentence in the comment by Hong Yin is unjustifiable.

Additionally, Hong Yin omitted to mention that a very detailed response to the alleged "problems" of my paper has been published in response to the Shihadeh et al. commentary, both by the authors of the original study (3) and by the editor of Addiction journal (4). In my response, i clearly presented the case that our study (5) evaluated the widely-known organoleptic parameter of dry puff detection in e-cigarettes. This phenomenon can easily result (and unfortunately is frequently resulting) in abuse of e-cigarettes in the laboratory and misleading reports on e-cigarette emissions which are irrelevant to human exposure. The authors of the letter characterized dry puffs as a term with "tenuous ontological status", despite the fact that this phenomenon has been described in the literature since 2013 (6) and is well-known and explained by e-cigarette users long before that.

The act of writing a comment is irrelevant when the content of the criticism is not examined. I will be happy to accept and respond to any criticism about the content of my research or my comments.

References:

1. Ji EH, Sun B, Zhao T, Shu S, Chang CH, Messadi D, Xia T, Zhu Y, Hu S. Characterization of Electronic Cigarette Aerosol and Its Induction of Oxidative Stress Response in Oral Keratinocytes. PLoS One. 2016 May 25;11(5):e0154447.

2. Bates CD, Farsalinos KE. Research letter on e-cigarette cancer risk was so misleading it should be retracted. Addiction. 2015 Oct;110(10):1686-7. doi: 10.1111/add.13018.

3. Farsalinos K, Voudris V, Poulas K. Response to Shihadeh et al. (2015): E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Nov;110(11):1862-4. doi: 10.1111/add.13078.

4. West R. Conflicts of conscience in Addiction. Addiction. 2015 Nov;110(11):1864. doi: 10.1111/add.13069.

5. Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Aug;110(8):1352-6.

6. Farsalinos KE, Romagna G, Tsiapras D, Kyrzopoulos S, Voudris V. Evaluation of electronic cigarette use (vaping) topography and estimation of liquid consumption: implications for research protocol standards definition and for public health authorities' regulation. Int J Environ Res Public Health. 2013 Jun 18;10(6):2500-14. doi: 10.3390/ijerph10062500.