Journal of Negative Results in BioMedicine - Latest Comments

To the Editor of Journal of Negative Results in Biomedicine

Kamal Chaouachi — 2007-11-07T00:00:00Z

In response to the points raised by Drs Eissenberg, Maziak, Shihadeh and Ward, I offer the following comments:

POINT 1- Because of the granted space for publication, I could not provide all details concerning Hoffmann et al's historical experiment on a Syrian shisha. All details -from puff volume and frequency, product used [tumbâk], to quality [including humidity] and quantity - were published in the Tetralogy on Hookah and Health [Ref 5-6, CWR (Critique of WHO Report)][1]. Hoffmann was certainly aware that the parameters he used were not so realistic.

As for Rakower and Fatal [Ref 10, CWR], they used a puff volume of 200 ml based on a correct observation of narghile smokers at that time and that place (Jews from Yemen). I can confirm this because I have led field anthropological work in this very country as early as 1997 [Ref 17, CWR]. What is not understood here is the very simple idea that the smoke chemistry varies according to the smoking product (tumbak, tobamel, jurâk, etc.), hence involving striking contrasts in puffing volumes. This is mainly due to an arbitrary use of a functionalist and nominalist neologism: "waterpipe"[2].

Unfortunately, the conditions in which Shihadeh et al. [Ref 7-8, CWR] observed "real" narghile smokers were biased [1][2]. Yields of toxicants obtained with an FTC-based smoking machine (Hoffmann's) or any other (Rakower's) do not reflect a less realistic view of human hookah smoking than that of others (Shihadeh's). In any case, Rakower and Fatal's parameters (though with tumbâk), are certainly closer to the reality of today's hookah smoking (with tobamel/mu'essel; the tobacco-molasses based mixture) than Shihadeh's artificial smoking. Dismissing the results of Rakower and Hoffmann's teams is all the more unacceptable that they were the first to work on key elements of hookah smoke. Anyway, the use of smoking machines should be discontinued, particularly when their set-up causes the actual charring of the product. This is also in agreement with expert recommendations [Ref 12, CWR][3].

As for the Hadidi et al' study [Ref 11, CWR], not only are the puffs number and the duration different from Shihadeh's but also, strikingly, the quantity of the smoking product (tobamel). Two other high-quality studies (in Lebanon & Jordan) confirm the use of 20 g of tobamel and not the arbitrary 10 g [4][5].

POINT 2- The narghile smokers in Shihadeh's topography were far from behaving (and smoking) "naturally" so, together with other flaws, there cannot be any "validated instrument" based on such a smoking machine. The "detail" about the charcoal left during one full hour in the same position over the bowl containing the tobamel and subject to intense and periodical puffing- is certainly not an "anecdote". Charring a product and then measuring tar and other toxicants in such conditions is definitely not the right method [2].

POINT 3- The "scenario" on the narghile epidemic by Rastam et al [Ref 30, CWR] is wrong. The critique of the WHO report is clear and does not refer to « some satellite channels (i.e., Egyptian films) ». The Egyptian films here are those of the 70s and 80s, i.e. long before the spread of satellite TV in that region [1].

POINT 4- The WHO report certainly insists on an Indian origin just as the main study it is based on does [6]. The resulting confusion led to crediting Chattopadhyah [Ref 2, CWR] with what he never said (about "the indigenous peoples of Africa and Asia"). In most of their studies, the authors have usually not distinguished between tobacco burning and heating. The WHO report uses t the word "burn" two times; e.g.: "Commonly used heat sources that are applied to burn tobacco [.]"(p.5). Paradoxically, most recent studies in this field have been focussing exclusively on tobamel. Therefore, the WHO report is absolutely not "demonstrably precise and accurate" but very confusing.

POINT 5- Independent research on addiction continues to generate new negative biomedical results. The "nicotine addiction" dogma has hampered sound research on cigarette smoking. Cohen et al. have established that, in rats, nicotine may be necessary for the initiation of dependence but not for its maintenance [7]. Frenk and Dar's book [Ref 33, CWR] is now a world reference in this field and their last review is even more promising: "the wide endorsement of the nicotine delivery kinetics hypothesis is unjustified. Critical research is required to resolve the anomalies within the nicotine addiction theory of smoking."[8]

PEER-REVIEW

I have already addressed this question in my reply to Drs HENNINGFIELD and DYBING and, most recently, in The Lancet online where Dr BETTCHER, Dir WHO/TFI, raised the issue in similar terms [9]. I stated that all my publications have been peer-reviewed by academic teams mainly at French universities and centres of research excellence (CNRS, INSERM, etc.). Amazingly, not only the first WHO report, supposed to have been intensively peer-reviewed, contains serious errors but also the second one [9][10]. Also, both reports contain direct or indirect references to absolutely non-peer-reviewed materials (e.g. popular press). In a recent Cochrane review, strangely similar in its form and substance (incl. errors) to the WHO report [11], the authors avoid citing appropriate references, including the WHO 84 page second report on shisha smoking [10].

PURPORTED "CONFLICT OF INTEREST"

My manuscript was submitted to JNRBM in July 2006, therefore more than 1 year after I completely left the no-carbon monoxide harm reduction hookah project (see relevant section). I have put into practice my early CO-related research findings within the wide harm reduction framework that includes cutting-edge tobacco research on such promising products as the Eclipse cigarette (based on the narghile principle) or smokeless tobacco (a real alternative to cigarette smoking)[12].

I wished Dr EISSENBERG, who participated in the design of a smoking topography product (Plowshare Technologies, Inc.) had also declared his competing interests since he has made use of it in several studies. The device is "critical in the assessment of nicotine dependence in smokers [.] Moreover, there is a similar need for a smoking topography measurement device capable of measuring any substance, which can be inhaled through the mouth [.]"[13]. In the relevant section of the Cochrane review, the authors literally evaded the question [11]. Finally, it would have been certainly more ethical if Dr MAZIAK's actual co-authorship of the WHO report had been clearly declared in the document itself and not in a corner of the comment on my critique, more than 2 years later.

CONCLUSION

I am a lifelong non-smoker now convinced that being "anti-tobacco" is not a guarantee of scientific soundness [14][15].

Dr Kamal T. Chaouachi

http://publicationslist.org/kamal.chaouachi

____________

References:

[1] Chaouachi K. A Critique of the WHO's TobReg "Advisory Note" entitled: "Waterpipe Tobacco Smoking: Health Effects, Research Needs and Recommended Actions by Regulators". Journal of Negative Results in Biomedicine 2006 (17 Nov); 5:17.

http://www.jnrbm.com/content/5/1/17

[2] Chaouachi K. The narghile (hookah, shisha, goza) epidemic and the need for clearing up confusion and solving problems related with model building of social situations. TheScientificWorldJOURNAL: TSW Holistic Health &Medicine 207 (7): 1691-6. DOI 10.1100/tsw.2007.255.

[3] Hammond D, Wiebel F, Kozlowski LT, Borland R, Cummings KM, O'Connor RJ, McNeill A, Connolly GN, Arnott D, Fong GT. Revising the machine smoking regime for cigarette emissions: implications for tobacco control policy. Tobacco Control 2007;16:8-14; doi:10.1136/tc.2005.015297

[4] Bacha ZA, Salameh P, Waked M. Saliva cotinine and exhaled carbon monoxide levels in natural environment waterpipe smokers. Inhal Toxicol. 2007 Jul;19(9):771-7.

[5] Shafagoj YA, Mohammed FI, Hadidi KA. Hubble-Bubble (Water Pipe) Smoking: Levels of Nicotine and Cotinine in Plasma, Saliva and Urine. Int J Clin Pharmacol Ther 2002; 40(6):249-55.

[6] Maziak W, Ward KD, Afifi Soweid RA, Eissenberg T. Tobacco smoking using a waterpipe: a re-emerging strain in a global epidemic. Tobacco Control 2004; 13: 327-333.

[7] Cohen C, Perrault G, Griebel G, Soubrié P. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: Reversal by the cannabinoid (CB1) receptor antagonist, Rimonabant (SR141716). Neuropsychopharmacology. 2005, 30(1): 145-55.

[8] Dar R, Frenk H. Reevaluating the nicotine delivery kinetics hypothesis. Psychopharmacology (Berl). 2007 May;192(1):1-7.

[9] Chaouachi K. WHO and Peer-Review Standards in Studies on Hookah Smoking. The Lancet Early Online Publication 2007 (29 Oct). In reply to Dr Douglas Bettcher, Dir. WHO/TFI a.i.'s comment: Bettcher D. WHO Response to Use of evidence in WHO recommendations. The Lancet Early Online Publication 2007 (10 Sept).

http://www.thelancet.com/journals/lancet/article/PIIS0140673607606758/comments?totalcomments=1#1305

[10] WHO-EMRO (World Health Organisation - Eastern Mediterranean Regional Office) and ESPRI (Egyptian Smoking Prevention Research Institute). Shisha Hazards Profile "Tobacco Use in Shisha - Studies on Waterpipe Smoking in Egypt". Cairo, 14 March 2007. ISBN: 978-92-9021-569-1. 84 pages. Prepared by Senior editors: Mostafa K. MOHAMED, Christopher A. LOFFREDO, Ebenezer ISRAEL et al.

[11] Maziak W, Ward K, Eissenberg T. Interventions for waterpipe smoking cessation. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005549.

[12] Phillips CV, Wang C, Guenzel B. You might as well smoke; the misleading and harmful public message about smokeless tobacco. BMC Public Health. 2005 Apr 5;5(1):31.

[13] Likness MA, Wessel RM. Apparatus for Measuring Smoking Topography. US Patent, 6,814,083 B2; 2004 (9 Nov).

[14] Phillips CV. Warning: Anti-tobacco activism may be hazardous to epidemiologic science. Epidemiologic Perspectives & Innovations 2007 (22 Oct);4:13.

[15] Chaouachi K. Rapid Response: Re: Combating Lysenko Pseudoscience. BMJ 2007 (27 Oct). Comment on: Enstrom JE. (Rapid Response) Combating Lysenko Pseudoscience. BMJ 2007 (16 Oct).

http://www.bmj.com/cgi/eletters/326/7398/1057#178649

In Reply to Dr Henningfield and Dr Dybing's Comment

Kamal Chaouachi — 2007-08-25T00:00:00Z

Dear Editor,

I would like to clarify that my thesis was not a “graduate” but a postgraduate doctoral one and that it was actually published (ANRT). The authors of the comment also doubt that the personal publications I had cited in the critique of the WHO report were peer-reviewed.

Instead of drafting below a long detailed list of documents, let me inform Dr Henningfield and Dr Dybing that I will be happy to provide them with the full names of the academic teams (French research centres and universities among others) who have thoroughly peer-reviewed the corresponding manuscripts.

-Concerning dose and compensatory smoking regarding nicotine, my own publications show that I have analysed and described in detail the corresponding process and findings as early as 1998 (see my comments on Macaron’s work for instance). With other researchers (particularly Dar and Frenk), I contend that nicotine does not play the main central role in the addiction phenomenon in general (cigarettes). I am confident that research on hookah smoking will help reconsider many granted ideas in this field (see for instance Al-Mutairi et al.’s).

-Concerning the heating of the smoking product, my thesis showed that what is chemically taking place inside the bowl of a shisha filled with tobamel (the tobacco [or no-tobacco]-molasses based smoking mixture), and topped with a pierced aluminium foil and some charcoal, is something different from “combustion”. I showed it was a chemical process more akin to the Maillard Reaction (with a “distillation” dimension) than a “combustion”.

-As for tar, quantity is definitely less important than quality. In the case of cigarettes, it is obvious (let us just consider nitrosamines and the consequences on public warnings). In the case of hookah smoking, the very different temperatures imply a different carcinogenicity. References to relevant studies are given in my publications.

-Smoking machines, particularly one set with parameters that cause the actual charring of the smoking product, are certainly not an adequate method to analyse hookah smoke. In the critique of the WHO report, I have quoted recommendations from Kozlowski and I could cite a recent study by Hammond et al. What is true for cigarette smoking is obviously true for hookah (shisha, narghile) smoking simply because the length of a session (just to take one isolated parameter) is sometimes then times longer.

-Unfortunately, not a single study has been carried on so far on the other substances that the burning charcoal emits. A comparative analysis between the diverse kinds of charcoal in use today (natural, semi-natural, self-lighting) will also be useful for the advancement of research. In my opinion, this is the most pressing issue as far as public health is concerned.

-Finally, Dr Henningfield and Dr Dybing contend that I would “characterize[s] inaccurately the Advisory Note’s summary of the history of waterpipes […].” Let me draw again their attention to the very first sentence of the WHO report which credits a researcher (Chattopadhyay) with what he did not state in his study: “waterpipes have been used to smoke tobacco and other substances by the indigenous peoples of Africa and Asia for at least four centuries”.

Dr Kamal T. Chaouachi

Researcher and Consultant in Tobacco Control (Paris)

Contact: kamchaAgmail.com

Misrepresentations and conflict of interest in JNRBM

Thomas Eissenberg — 2007-08-25T00:00:00Z

To the Editor of the Journal of Negative Results in Biomedicine:

We are writing to address a commentary (Chaouachi, 2006) regarding the WHO TobReg Advisory Note on waterpipe tobacco smoking (WHO, 2005). This letter demonstrates two facts: 1) the commentary misrepresents data-based, peer-reviewed literature, and 2) the author does not disclose a competing interest.

First, the commentary misrepresents the scientific literature and/or the TobReg Advisory Note. We will not list each such misrepresentation, but present five examples below:

1) The commentary omits key features of the scientific literature to which it refers. For instance, the commentary highlights apparent “discrepancies” between “tar” yields in Hoffman et al (1963) and information described in the TobReg Advisory. However, the commentary does not note that Hoffman et al. (1963) used U.S. Federal Trade Commission testing parameters intended for cigarettes, and that these parameters involve puff volumes an order of magnitude smaller (i.e., 35 ml) than those reported for waterpipe users (200 ml, but no supporting data are presented; Rakower and Fatal, 1962) or observed in waterpipe users (mean = 530 ml, N = 52; Shihadeh et al., 2004). Hoffman et al. (1963) note of their own data: “Data for cigarettes and cigars are reproducible within the accepted analytical deviations. Data for the smoke of pipe and water pipe do not meet the requirements for this analytical standard because the amount of burned tobacco could not be completely standardized and the tobacco in the oriental water pipe had to be repeatedly ignited” (see Hoffman et al., 1963, page 630). In another instance, the commentary cites as contradictory to the TobReg Advisory the puff number and duration described by Hadidi & Mohammed (2004), but does not mention that this reference provides no data justifying the puff number and duration it describes. The commentary’s omissions misrepresent the published research record.

2) The commentary rejects the large “tar” yields reported in the TobReg Advisory by speculating that “the laboratory model completely differed from actual human hookah smoking” or that the TobReg advisory relied on data produced using “a distorted model of actual human smoking behaviour”. In fact, as the commentary does not explain, the TobReg Advisory relies on state-of-the-art smoke toxicant research (Shihadeh and Saleh, 2005) that is based on observation of 52 waterpipe users who smoked naturally while numerous smoking parameters were measured with a custom-designed, validated instrument (see Shihadeh et al., 2004). The commentary justifies its criticism of this rigorous and detailed observational work with reference to another study that reports what waterpipe smokers “usually” do (see Hadidi and Mohammed, 2004, p. 913). Thus, the commentary uses anecdote to challenge rigorous science.

3) The commentary misrepresents a multi-factor hypothesis regarding the spread of waterpipe use (i.e., introduction of flavored waterpipe tobacco and depictions of waterpipe use on satellite TV and e-media; Rastam et al., 2004). The commentary isolates one factor (satellite TV) and then attempts to contradict that factor’s influence by referring to the content shown on some satellite channels (i.e., Egyptian films). While the Rastam et al (2004) hypothesis is misrepresented, no data are brought forward to refute it.

4) Contrary to the commentary’s text, the TobReg Advisory note neither insists on an Indian origin of the waterpipe, nor states that waterpipe tobacco is burnt (see commentary’s sections entitled “Origins” and “Heating and burning”). In fact, the TobReg Advisory Note uses a published article from India as a reference for the fact that waterpipes have been used for at least four centuries (Chattopadhyay, 2000), and notes that this article provides “one” account of the origin of the waterpipe (i.e., indicating that there are other accounts). Also, the TobReg Advisory Note states that waterpipe tobacco “. . . does not burn in a self-sustaining manner” (p. 2, emphasis added). To clarify further the waterpipe tobacco smoking process, the TobReg Advisory Note continues “. . .heated air, which now also contains charcoal combustion products, passes through the tobacco, and the mainstream smoke aerosol is produced” (p. 2). In these and other examples, the commentary misrepresents the TobReg Advisory Note as imprecise or inaccurate in cases where the TobReg Advisory Note is demonstrably precise and accurate.

5) The commentary states that “there is a serious debate over the central role of nicotine in the dependence process”. No such debate exists (e.g., Unites States Department of Health and Human Services, 1988).

The value of any scientific publication is challenged when, as with this commentary, the publication’s foundation rests on omission of key facts or methods, misrepresentation of the existing literature, and allusion to nonexistent imprecision, inaccuracy, and debate.

Second, the commentary’s author declares no competing interests when a competing interest exists. The “Instructions for Journal of Negative Results in Biomedicine Authors” includes in a list of potential competing interests “hold[ing] or . . . currently applying for any patents relating to the content of the manuscript” and notes that “Authors should disclose any financial competing interests but also any non-financial competing interests that may cause them embarrassment were they to become public after the publication of the manuscript”. The author of this commentary is co-inventor on a patent application for a “Hookah with simplified lighting” (Billard et al., 2005). This patent application clearly represents a competing interest as defined by the journal and readers of Dr. Chaouachi’s work should be informed of it.

We also note that, over the last several years, this author has taken many opportunities to speculate on rigorous, data-based, peer-reviewed publications regarding waterpipe use. These speculations, which are not peer-reviewed, are referenced in the commentary, as are other documents by this author that have not been subjected to a formal peer-review process. We believe that using non-peer-reviewed speculation as the basis for a commentary on the data-based WHO TobReg Advisory Note is inconsistent with the standards and goals of modern scientific discourse. Indeed, when frequent reference to non-peer-reviewed speculation is combined with misrepresentations of rigorous, peer-reviewed literature and undisclosed competing interests, we believe our obligation is to identify the resulting work as the antithesis of science.

Sincerely,

Thomas Eissenberg

Virginia Commonwealth University and Syrian Center for Tobacco Studies

Wasim Maziak

University of Memphis and Syrian Center for Tobacco Studies

Alan Shihadeh

American University of Beirut

Ken Ward

University of Memphis and Syrian Center for Tobacco Studies

References

Billard, G., Chaouachi, K., De La Giraudiere, A-P. (2005). Hookah with simplified lighting. United States Patent Application Publication. Publication No.:2005/0279371 A1. Application number 11/148,194.

Chattopadhyay, A. (2000). Emporer Akbar as healer and his eminent physicians. Bulletin of the Indian Institute of the History of Medicine, 30, 151-158.

Chaouachi, K. (2006). A critique of the WHO TobReg's "Advisory Note" report entitled: "Waterpipe tobacco smoking: health effects, research needs and recommended actions by regulators". Journal of Negative Results in BioMedicine, 5:17.

Hadidi, K.A., Mohammed, F.I. (2004). Nicotine content in tobacco used in hubble-bubble smoking. Saudi Med J, 25, 912-917.

Hoffman, D., Rathkamp, G., Wynder, E. (1963). Comparison of the yields of several selected components in the smoke from different tobacco products. Journal of the National Cancer Institute, 31, 627-635.

Rakower, J., Fatal, B. (1962). Study of Narghile Smoking in Relation to Cancer of the Lung.

Br J Cancer, 16, 1-6.

Rastam, S., Ward, K.D., Eissenberg, T., Maziak, W. (2004). Estimating the beginning of the waterpipe epidemic in Syria. BMC Public Health, 4, 32.

Shihadeh, A. & Eissenberg, T. (2006). Tobacco smoking using a waterpipe: product, prevalence, chemistry/toxicology, pharmacological effects, and health hazards. Waterpipe tobacco smoking – Building the Evidence Base. Part 1: The smoke Chemistry. RITC Monograph Series No. 2. International Development Research Center, Ottawa, Canada.

Shihadeh, A., Saleh, R. (2005). Polycyclic aromatic hydrocarbons, carbon monoxide, “tar”, and nicotine in the mainstream smoke aerosol of the narghile water pipe. Food and Chemical Toxicology, 43, 655-661.

Shihadeh, A., Azar, S., Antonius, C., Haddad, A. (2004). Towards a topographical model of narghile water-pipe café smoking. Biochemistry, Pharmacology, and Behavior, 79, 75-82.

World Health Organization. (2005). TobReg Advisory Note. Waterpipe tobacco smoking: health effects, research needs and recommended actions by regulators. World Health Organization, Geneva, Switzerland.

United States Department of Health and Human Services (1988). The Health Consequences of Smoking: Nicotine Dependence. Government Printing Office, Washington, DC.

Response from the Study Group on Tobacco Product Regulation of the World Health Organization

Gemma Vestal — 2007-08-15T00:00:00Z

Dr Erik Dybing

Division of Environmental Medicine

Norwegian Institute of Public Health

P.O. Box 4404 Nydalen

NO-0403 Oslo

Norway

erik.dybing@fhi.no

Dr Jack Henningfield

Pinney Associates

3 Bethesda Metro Center, Suite 1400

Bethesda, Maryland 20814

United States of America

jhenning@pinneyassociates.com

To the Editor of the Journal of Negative Results in Biomedicine:

In response to the World Health Organization (WHO) Study Group on Tobacco Product Regulation (TobReg) Advisory Note entitled Waterpipe Tobacco Smoking: Health Effects, Research Needs and Recommended Actions by Regulators (WHO, 2005), Dr. Kamal Chaouachi published a commentary that purports to examine critically the Advisory Note. We are writing on our own behalf and in response to a request from the Tobacco Free Initiative Department of WHO to address a few of the many statements in the commentary that are either wrong or misrepresentations of fact and process.

The process for developing an Advisory Note is much more extensive than the process for developing a journal article, and an Advisory Note is subject to multiple layers of review and verification. The Advisory Note on waterpipe tobacco smoking was initiated in response to the growing body of literature demonstrating that there may be a misperception among the public that waterpipes provide a safe form of tobacco use. Also, the practice of waterpipe tobacco smoking appears to be spreading globally, which provided another impetus for the Advisory Note. In brief, the process for developing the Advisory Note was initiated in discussions with tobacco experts including the TobReg, the WHO Tobacco Free Initiative staff, and other tobacco experts throughout the world. Subsequently, a background paper was commissioned by the WHO Secretariat to be written by a team of internationally recognized experts in tobacco use, pharmacology and toxicology, who had been focusing their efforts in recent years on waterpipe toxicology and epidemiology. The background paper was presented and discussed at the June 2005 TobReg meeting in Rio, Brazil, and its implications considered in light of other knowledge and from the perspective of global tobacco regulation challenges. Major conclusions were reached by TobReg, and a draft Advisory Note was prepared. Several additional months of review, revision, and evaluation through the WHO approval process led to the final Advisory Note.

As implied by its title and length, a WHO Advisory Note is not intended to be a comprehensive review article, but rather a practically disseminable and generally understandable report advising the public, health professionals, and policy makers on public health issues. For the Advisory Note on waterpipe tobacco smoking, it was considered essential to communicate that waterpipe tobacco smoking exposes users to many of the same toxicants and the same addicting agent, nicotine, as other forms of tobacco use. Key research questions for which there are presently only preliminary or no published scientific data were also identified.

Several potential health concerns raised in the Advisory Note were addressed by Dr. Chaouachi. Whereas he presumes that questions about health concerns have been satisfactorily answered and/or that the Advisory Note is wrong (e.g., concerning quantitative and qualitative aspects of waterpipe toxicant emissions), the Advisory Note calls for further empirical research. It is noteworthy that few, if any, of his 14 citations are peer-reviewed, an important criterium of scientific studies.

Elements of Dr. Chaouachi’s critique rely on his apparent misunderstanding of the pharmacology of tobacco use and of toxicology in general. For example, concerning nicotine, the critique reveals a lack of understanding of the importance of dose, compensatory smoking, and the fact that nicotine has been established unequivocally as the key addictive drug in tobacco (even though, as is the case with all addictive drugs, not all of their users are addicted).

Furthermore, Dr. Chaouachi states, “What renders tar dangerous is not its quantity but its quality and above all its temperature.” This statement is both misleading and confusing. First, exposure level (“quantity”) is a critical determinant of harm posed by carcinogens and other toxicants, which are constituents of tar. Second, even preliminary studies have identified key toxicants, including known carcinogens, as constituents of waterpipe smoke. The reference to the “temperature” of tar is vague and presented without explanation. It is possible that Dr. Chaouachi was referring to the tobacco combustion temperature at which the tar is produced. In general, it has been found that mutagenicity increases with tobacco pyrolysis temperature. While it is true that waterpipe tobacco is smoked at a lower temperature than cigarette tobacco, the same is not necessarily true of the charcoal used in waterpipe smoking, which is consumed at a greater rate than the tobacco mixture during a typical use session (Shihadeh, 2003; Shihadeh and Saleh, 2005). Burning charcoal has been shown to emit a variety of carcinogenic compounds (WHO, 2006), and it is misleading to emphasize the lower temperatures of waterpipe tobacco in assessing waterpipe smoke toxicity.

Dr. Chaouachi characterizes inaccurately the Advisory Note’s summary of the history of waterpipes, their physical nature, and patterns of use. Additionally, his account of patterns of use in various societies, including at least some use by children, is at odds with published surveys and accounts referenced by the Advisory Note. In several discussions (e.g., tar yield) the commentary counters the conclusions and peer-reviewed scientific citations of the Advisory Note with references to unpublished work, including Dr. Chaouachi’s own graduate thesis.

There are many additional deficiencies in Dr. Chaouachi's commentary, but it is beyond the scope of this letter to address all of them. Rather, we urge those interested in the topic to read the Waterpipe Advisory Note, which is readily available on the internet. We stand behind the conclusions of the Advisory Note. Again we advise health professionals, policy makers, and the public that smoking tobacco through waterpipes is not safe, and we urge that waterpipe tobacco use be included among all other forms of tobacco use for the purpose of policies related to environmental smoke exposure, use prevention and cessation, and research.

On behalf of WHO TobReg,

Erik Dybing

Chair, WHO TobReg

Jack Henningfield

Member, WHO TobReg

CC: World Health Organization Tobacco Free Initiative

Corrigenda to this article

Daniel A. Wagenaar — 2007-02-27T00:00:00Z

Corrigenda to this article have been published [1]. Please visit http://www.jnrbm.com/content/6/1/3 or http://www.biology.ucsd.edu/~dwagenaa/jnrbm to view them.

[1] Wagenaar DA, Pine J, Potter SM: Correction: Searching for plasticity in dissociated cortical cultures on multi-electrode arrays. J. Negat. Results BioMed. 2007, 6:3.

This Article has a Published Correction

Steve Potter — 2007-02-27T00:00:00Z

Please see our correction to this article on

http://www.jnrbm.com/content/6/1/3

After publication of this article we became aware that the numerical codes for two of the datasets, protocols III.3 and III.4, were inadvertently confused during the writing of the paper. The main conclusions of the paper are unchanged, but a number of important corrigenda have been noted on the page linked above.

Alternative explanation for decline in statin studies

An-Wen Chan — 2005-08-17T00:00:00Z

Shafiq and colleagues present an interesting review of the many postulated indications for statins in healthcare. We would like to comment briefly on their hypothesis and conclusion that statin research may be on the decline. This assertion was based on an apparent decline in the number of annual citations identified on PubMed, from over 1600 citations in 2003 to fewer than 1200 citations in 2004.

We have an alternative explanation for the presumed decline in citations identified from 2004. The indexing date of citations on PubMed falls well behind the actual publication dates in journals. For example, we conducted repeated PubMed searches for clinical trials published in December 2000, and found that citations identified from identical search strategies continued to be added to the database up until our last search date in July 2002 (ie. sixteen months after publication). The PubMed search by Shafiq et al would have been conducted prior to February 7, 2005, as this corresponds to the submission date of their manuscript for publication. This search date would allow only 1–13 months for studies to be indexed on PubMed.

We also performed a quick PubMed search (“statins OR *statin”) for entries indexed from February 7 to August 2005, and identified 101 citations published in 2004. These would have been missed in their paper.

Therefore, the relatively low number of citations observed by Shafiq et al for the year 2004 is likely an underestimate, as citations will continue to be added to PubMed. Repeated literature searches over the next year would likely identify additional studies and provide a more accurate estimate of the true prevalence of statin research published in 2004.

An-Wen Chan & Douglas G Altman (Centre for Statistics in Medicine, Oxford)

The interpretation of negative results demands more caution than exhibited here

A Lynch — 2005-06-09T00:00:00Z

The concept of a journal for publishing ‘negative’ results arising from rigorous studies is sound, and as a tool to counter publication bias it has clear merit (although whether it is uniformly of benefit in this matter is open to debate). However there are a number of possible explanations for a negative result and care must be taken not to over-interpret such a finding. The oft-used motto ‘absence of evidence is not evidence of absence’ [1] has perhaps never been more at home than it would be if adopted by the JNRBM.

This article by Stenberg et al. [2] causes me concern with regard to two issues. One is how the authors interpret their results, and the other is the level of information provided to allow others to interpret the results.

The authors state that they “do not find any major immunological deficiency … that could explain the increased incidence of otitis media”, which is true, but is not the same as saying there is no major immunological deficiency. They also state that “Normal levels of most lymphocyte- and immunoglobulin subpopulations were registered”. One can see what the authors perhaps mean; for each individual the readings tend to be within the reference 95% confidence intervals, however taken as a group it would be hard to argue that there was not evidence of a difference in the mean levels for girls with TS verses controls. In particular I am thinking of IgG in figure 2 of their paper.

To conclude that “Therefore, treatment with immunotherapy is not an option…” seems rash based upon these results. The comparison of five otitis-prone girls with 6 otitis-free girls using the Mann-Whitney U test does not suggest that the test is adequately powered for any but the most extreme magnitudes of difference. Even if the rankings split as drastically as (1,2,3,4,9) and (5,6,7,8,10,11) then the authors would not find the results to be ‘significant’. Only one rogue result, perhaps one child who’s otitis has a different provenance, will prevent any ‘positive’ findings.

The strength of the authors’ interpretation would be less concerning if enough data were presented to allow us to make up our own minds. The very first paper published in this journal [3] ran with the title “Prominent medical journals often provide insufficient information to assess the validity of studies with negative results” wherein was stressed the importance of reporting confidence intervals for results and power calculations.

In fact power calculations are often unhelpful for interpreting negative results, being based on values that prove to be inaccurate, and tending to be superseded by the information provided by a confidence intervals. However it would be good practice to routinely report sample-size calculations for a variety of reasons. Indeed this is item 7 of the Revised CONSORT statement (www.consort-statement.org) and item 10 of the current version (version 2) of the STROBE Statement (www.strobe-statement.org), respectively guidelines for the reporting of randomized trials and observational studies.

Confidence intervals are certainly of great value for the interpretation of ‘negative’ results [4]. Unfortunately the paper in discussion is one where calculating confidence intervals is not straight-forward for the main results, since non-parametric methods are (possibly quite rightly) employed. The authors interpret the Mann-Whitney U test as a test for a difference in medians, and an approximate confidence interval for the difference in medians could be produced, however with so few observations this might not be an illuminating exercise.

Thus we are left with no way of adequately interpreting these ‘negative’ results. So what could have been done?

A) Examination of this article along with those referenced within it ([5-8]) suggests that it would not be unreasonable to model the difference in means on the log scale (equivalently the log-ratio of means) as being normally distributed. As a pragmatic second step, the confidence interval based on this model could have been presented to aid interpretation of the results of the Mann-Whitney.

B) For the comparison of girls with TS to controls, it is possible to estimate confidence intervals from the previous papers [5-8] (only approximately in some cases because information has to be extrapolated) and these could potentially be used to perform a ‘mini-meta analysis’. The authors of this article comment on the small size of some previous studies, but the combined numbers in these referenced studies far exceed those in the current one, so showing what the new findings add to previous studies would be of value.

C) Also given the relatively small size of the data-set and the electronic nature of the medium, it would seem trivial to present the raw data that have led to these conclusions.

Caution should always be shown when interpreting ‘negative’ results, and whilst it is sometimes unavoidable that sample sizes are small, and sometimes tricky to calculate confidence intervals, in these circumstances the tone of conclusions should see even greater moderation. Additionally I would suggest that as much effort should go into providing the reader with the tools to interpret a result as go into obtaining it.

1. Altman DG, Bland JM: Statistics Notes - Absence of Evidence Is Not Evidence of Absence. Br Med J 1995, 311(7003):485-485.

2. Stenberg A, Sylven L, Magnusson C, Hultcrantz M: Immunological parameters in girls with Turner syndrome. Journal of Negative Results in BioMedicine 2004, 3(1):6.

3. Hebert R, Wright S, Dittus R, Elasy T: Prominent medical journals often provide insufficient information to assess the validity of studies with negative results. Journal of Negative Results in BioMedicine 2002, 1(1):1.

4. Altman D, Bland JM: Confidence intervals illuminate absence of evidence. Br Med J 2004, 328(7446):1016-1017.

5. Cacciari E, Masi M, Fantini MP, Licastro F, Cicognani A, Pirazzoli P, Villa MP, Specchia F, Forabosco A, Franceschi C et al: Serum Immunoglobulins and Lymphocyte Sub-Populations Derangement in Turners Syndrome. Journal of Immunogenetics 1981, 8(5):337-344.

6. Jensen K, Petersen PH, Nielsen EL, Dahl G, Nielsen J: Serum Immunoglobulin-M, Immunoglobulin-G, and Immunoglobulin-a Concentration Levels in Turners Syndrome Compared with Normal Women and Men. Hum Genet 1976, 31(3):329-334.

7. Lorini R, Ugazio AG, Cammareri V, Larizza D, Castellazzi AM, Brugo MA, Severi F: Immunoglobulin Levels, T-Cell Markers, Mitogen Responsiveness and Thymic Hormone-Activity in Turners Syndrome. Thymus 1983, 5(2):61-66.

8. Rongenwesterlaken C, Rijkers GT, Scholtens EJ, Vanes A, Wit JM, Vandenbrande JL, Zegers BJM: Immunological Studies in Turner Syndrome before and During Treatment with Growth-Hormone. J Pediatr 1991, 119(2):268-272.

Full supporter of your initiative

Gaël Hédou — 2003-07-01T00:00:00Z

Dear editors of JNRBM,

I wanted to tell you how your initiative in founding this journal really rings a bell in my mind. I think it represents exactly what was crutially missing in the field. To my point of view there is however no real negative results but so far only so-called positive ones received attention and I always wondered why. The thing is that minds have to drastically change in order for scientists to consider those so-called negative results being critical in potentially explaining the diffulties one ever encounters while trying to design and test new experiments, drugs or chemicals and to challenge widely accepted theories. These results are as important as the ones from "succeeding" experiments. While proceeding with this email I'm feeling the semantic difficulty of only writing about these results. And this is maybe the first criticism I wanted to address. The name of this journal comprises and maybe gather the negative image of these kind of results. The first time I saw it I thought I will take a little time to read those articles to relax and laugh a little as I thought it might be something related to the IgNobel prize (http://www.improb.com/ig/ig-top.html) which is obviously not. Thus if possible in order to make it less negative title suggestions would be "the alternative journal of unexpected results in biomedicine" or "the journal of controversy in biomedical research" or "the progressive journal of realistic results in biomedicine" or a mix of that.

The second criticism I wanted to address is that only scientits or medical doctors working in the US have been elected in the editorial board. Broadening this board by including scientists world wide would greately improve the impact of this publication.

In any case, I wish more people will massively submit manuscripts to the journal (and I know people for whom this might be helpful to allow them to express opinions that are litteraly censored by results, miraculous in nature, that were previously published in high impact journals). Also I whish this journal might help publishing comparative results showing the different outcomes emanating from different experimental contexts and procedures, using specific animal strain and provider, chemical enanthiomers, concentrations, administration routes, etc etc.

Thanks for your attention and your initiative

Gael Hedou.