We commend El Dib and colleagues(1) on their extensive review effort and offer the following critiques:
a. In their analysis regarding ENDS vs. ENNDS for smoking cessation (Figure 5)(1), the authors have chosen to compare the 6-month cessation rate for the ASCEND(2) study with the 12-month cessation rate in the ECLAT(3) study. Using equal time frames seem like it would allow a more homogenous comparison, particularly because this is available from the ECLAT publication. This does raise the bigger issue that an important conclusion in review related to e-cigarette and smoking cessation should be advocating for uniformity in outcome reporting, as has been proposed in prior publications (e.g. the Russel Standard)(4).
b. We disagree with the author's main analysis where subjects lost to follow-up (LFU) excluded. It is incorrect to assume that the cessation rate in the LFU group is the same as the subject who actually completed the study. Regardless of this, the authors have indeed performed a "worse case" analysis but here we find discrepancy between the published cessation data from the studies and the numbers used in the analysis. Using an intention-to-treat (ITT) analysis, for instance, the ASCEND trial reported a cessation rate for ENDS of 21/289 (30/289 including non-verified) while in ECLAT this was 22/200. This is in contrast to 25/289 and 34/200, respectively, as used in the author's analysis. In the ENNDS subg...
b. We disagree with the author's main analysis where subjects lost to follow-up (LFU) excluded. It is incorrect to assume that the cessation rate in the LFU group is the same as the subject who actually completed the study. Regardless of this, the authors have indeed performed a "worse case" analysis but here we find discrepancy between the published cessation data from the studies and the numbers used in the analysis. Using an intention-to-treat (ITT) analysis, for instance, the ASCEND trial reported a cessation rate for ENDS of 21/289 (30/289 including non-verified) while in ECLAT this was 22/200. This is in contrast to 25/289 and 34/200, respectively, as used in the author's analysis. In the ENNDS subgroup, we found discrepancy as the ASCEND trial reported a rate of 3/73 (4/73 including non-verified), in contrast to the 6/73 used in the meta-analysis. The ECLAT ENNDS cessation rate was published as 5/100 (6-months) and 4/100 (12-month), versus the utilized 14/100 rate.
c. Using the aforementioned published verified cessation rates for both ASCEND (2 e-cig arms) and ECLAT, our calculations of pooled Mantel-Haenszel risk ratio (random effects model) provide an RR= 2.02 (95% CI 0.97-4.21), p=0.06, which can lead to a very different discussion than that presented by the authors.
d. It is important to emphasize that the analysis of ENDS vs. ENNDS really only provides insight into the role of nicotine, not e-cigarettes, in smoking cessation. Adequate trials comparing ENDS vs. other methods are needed to address the important clinical question: Are e-cigarettes useful to help patients quit regular cigarette use? To our knowledge, only the ASCEND trial and the non-randomized trial by Hajek et al.(5) have been published in this regard. Analysis of these two sets of data is difficult as only 1-month data is available for the latter.
As clinicians, we should strive for patients to be abstinent from both regular cigarettes and e-cigarettes. However, the potential role of limited e-cigarette dosing for smoking cessation is unclear and inappropriate analysis of data can further confuse the clinician looking for answers.
Very truly yours,
Orellana -Barrios MA, MD
Payne D, DO
Nugent K, MD
1. El Dib, Regina, et al. "Electronic nicotine delivery systems and/or electronic non-nicotine delivery systems for tobacco smoking cessation or reduction: A systematic review and meta-analysis." BMJ Open 7.2 (2017): e012680.
2. Bullen, Christopher, et al. "Electronic cigarettes for smoking cessation: a randomised controlled trial." The Lancet 382.9905 (2013): 1629-1637.
3. Caponnetto, Pasquale, et al. "EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized control design study." PloS one 8.6 (2013): e66317.
4. West, Robert, et al. "Outcome criteria in smoking cessation trials: proposal for a common standard." Addiction 100.3 (2005): 299-303.
5. Hajek, P., et al. "Adding e-cigarettes to specialist stop-smoking treatment: City of London pilot project." J Addict Res Ther 6 (2015): 2.
We can further clarify T. Tuuminen's suspicions of a conflict of interest.
Considering researcher AV, his role in the Social Insurance Institute of Finland does not cause any conflict of interest regarding this study. Social Insurance Institute of Finland is an organization where the research unit is administratively separate from the section where AV works as a part-time medical consult for a team which handles social security benefits. Thus, his part-time work (including the cases he handles) and our study do not have any interface. We have now declared all author affiliations with insurance companies, which however have no role in funding or initiating the study.
We would also like to correct some misunderstandings. First, mindfulness is not a method in our study. The scope of our study is precisely presented in Figure 1 of the article. We study factors which influence the recovery from non-specific symptoms. We do not study immunological mechanisms, nor question or oppose an immuno-toxicological mechanism explanation.
At the moment in Finland, indoor air related issues raise discussion and emotions. Our study hypothesis is based on a biopsychosocial model for non-specific, persistent symptoms associated with indoor air, which does not exclude the effect of environmental factors (Fig 1). We study whether there is a treatment effect on chronic, nonspecific symptoms. Registered RCT-studies with published protocols are scarce...
At the moment in Finland, indoor air related issues raise discussion and emotions. Our study hypothesis is based on a biopsychosocial model for non-specific, persistent symptoms associated with indoor air, which does not exclude the effect of environmental factors (Fig 1). We study whether there is a treatment effect on chronic, nonspecific symptoms. Registered RCT-studies with published protocols are scarce in this difficult research field. It is obvious that more high quality studies both on mechanisms and treatment are needed.
On behalf of the research group,
If it is true, as I read in the media, that France is a country that has achieved gender equality in the use of surnames, this would be a great strength of this current study. Studies of female author publication profiles in many countries suffer from bias due to surname changes, despite the fact that academia is about personal brand power, which would one would think lead female academics to be more inclined to retain their surnames - even if for practical not ideological reasons. However, this does not really seem to be my experience in the UK. So, the cultural context of this paper seems a great strength, yet also it may be difficult to generalise the results about female academics to other cultural contexts.
Online resources predicting the chances of a live birth will educate women and help them avoid unnecessary or even harmful IVF cycles. IVFs are cost effective up to age 43, according to NICE.  Ovarian and uterine cancers are increased 4-fold and 5-fold respectively, after IVF treatment, as this excellent long term follow up study of tens of thousands of women clearly demonstrated.  Serious and debilitating health consequences later on should be remembered when calculating additional benefits of continuing IVF cycles.
Irresponsible IVF Clinics abroad offer luring fertility tourism packages to UK patients rejected at home, even to women older than 50.  Very few women will proceed in such costly practices, especially after they are correctly and ethically informed about long term health consequences.
Access to the AXIS tool in full is available at this website www.epinet.net
Given the increased use of antidepressants during pregnancy over the last two decades, there is understandable concern about possible adverse effects on antenatally exposed offspring. Using data from the Quebec Pregnancy Cohort, Bérard et al claim that exposure to antidepressants during pregnancy elevates the risk of major congenital malformations (MCM) in exposed offspring (1). The study compares depressed/anxious women who took medication to depressed/anxious women who did not. The results presented are dramatic: 11.1% MCM in the unmedicated cohort and 12-13.4% in SSRI, SNRI, and TCA exposed cohorts, with paroxetine, citalopram, tricyclic antidepressants and venlafaxine associated with organ-specific defects.
But the authors’ conclusion that antidepressants cause major congenital malformations is not supported by their data. First, the study’s numbers for the unmedicated groups are far above the baseline risk of 3-5% generally cited in the literature. The authors state that this high percentage is due to “genetic risk factors stemming from the ‘founding’ French ancestors.” But the paper cited to support this claim—written by the same authors—says nothing of the kind. In fact, that study reports a rate of 3.6%, consistent with North American background risks (2).
Second, since no data are presented for healthy, unmedicated pregnancies, it is impossible to know how the two studied groups compare to general population risk. To us, it appears that whatever is...
Second, since no data are presented for healthy, unmedicated pregnancies, it is impossible to know how the two studied groups compare to general population risk. To us, it appears that whatever is raising the risk for major congenital malformations in the unmedicated group is raising the risk only slightly more in the exposed group. This suggests that antidepressant use may be a marker for more severe psychiatric illness. The authors’ results may well be confounded by indication – that is, depression and/or anxiety (rather than antidepressant exposure) may be associated with adverse outcomes in the offspring.
The authors conclude that “Antidepressants with effects on serotonin reuptake during embryogenesis increased the risk of some organ-specific malformations in a cohort of pregnant women with depression.” We believe that the data support another conclusion: “Depression and/or anxiety may be associated with genetic, environmental, and behavioral variables that increase the risk of major congenital malformations.”
1. Berard, A, Zhao J-P, Sheehy O: Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort. BMJ Open 2017;7:e013372. Doi;10.1136/bmjopen-2016-013372.
2. Zhao J-P, Sheehy O, Berard A: Regional variations in the prevalence of major congenital malformations in Quebec: The importance of fetal growth environment. J Popul Ther Clin Pharmacol 2015;22(3);e198-e210;November 11, 2015.
Please note that the published version of the article was a resubmission of an earlier manuscript that was rejected by BMJ Open. The prepublication history has now been updated and includes the peer review of both submissions along with all versions of the manuscript.
Initially the prepublication history of only the second submission was included. We apologise for this error and any confusion caused.
Several concerns/comments came up while I was reading this interesting study. The association between outcomes of interest (preference and knowledge) and different interventions (two formats of guideline presentation) might not be as strong or might be even weaker for the following reasons. 1. Preference: Noticeably, there were some differences in preferred knowledge source between the two groups at baseline- 5% more participants in the standard format group preferred that from colleagues. This might reflect somewhat varied levels of acceptance for practice guidelines or other evidence sources of high quality and more reliable in the two groups. This would partially explain the difference in proportions of participants who preferred the formats they respectively saw in the interventions. 2. Knowledge: The authors did not test the level of medical knowledge or practice experience in the two groups at baseline. It is possible that participants in the multilayered format group had a better knowledge fund or more experienced in the issues addressed in the guideline before the interventions. Thus, they scored slightly better in the MCQs (not statistically significant in the study) than the standard format group. Additionally, the MCQs might not cover all the contents or information delivered through the interventions. Therefore, the small difference in MCQs performance may not accurately reflect the difference of knowledge levels in the two groups after the interventions.
Nonetheless, there are multiple steps from establishment of guidelines to improving patient outcomes; improved knowledge fund and preference to some guideline format are only the very early steps/stages. Clinical inertia has been discussed in the context of evidence-based medicine, which refers to the phenomena physicians still follow their own practice, rather than the latest guidelines with new changes. This possibly contributes to unsatisfactory management of some chronic conditions. Whether the multilayered and digitally structured format or others could really promote/facilitate physicians implement the guidelines in daily practice and whether they could be implemented appropriately might also be worth exploring, given the evaluation on patient outcomes is usually not immediate.
Having reviewed this publication by Hashem et al, the International Sweeteners Association (ISA) would like to highlight that a range of low calorie sweeteners, either used alone or in combination, are already successfully used to reduce or totally replace sugars in beverage products and provide a variety of reduced or zero calorie options.
Importantly, a number of randomised control trials (RCTs), as well as systematic reviews and meta-analyses, have consistently shown that low calorie sweetened drinks lead to reduced energy intake and can help in weight loss and maintenance, when used in place of sugar-sweetened beverages. On the basis of the above strong body of evidence, the ISA strongly refutes the claims that they could be associated with increasing risk of the same chronic diseases linked to the consumption of sugars. On the contrary, the available scientific data confirm the exact opposite, that low calorie sweeteners use facilitates, rather than impairs, weight loss, in both children and adults, as they provide sweetness with low or no calories.
At a time when obesity (a major risk factor for non-communicable diseases) is increasing, low calorie sweeteners such as acesulfame-K, aspartame, cyclamate, saccharin, steviol glycosides and sucralose are useful tools in food and drink reformulation strategy to reduce free sugars content in certain products.
References (non-exhaustive list):
1. Rogers PJ, et al. Int J Obes 2016; 40(3): 381-94...
References (non-exhaustive list):
1. Rogers PJ, et al. Int J Obes 2016; 40(3): 381-94
2. Peters JC, et al. Obesity (Silver Spring) 2016; 24(2): 297-304
3. Romo-Romo A, et al. Plos One 2016; 11(8): e0161264
4. Bellisle F. Curr Obes Rep 2015; 4(1): 106-110
5. De Ruyter J, et al. N Engl J Med 2012;367:1397-1406
Finnish fraud to be finished
Reply to S. Selinheimio
Thank you for your response in regards to the publication of Selinheimo S. et al. There remain several important issues of concern which I feel obliged despite a short format to explain explicitly.
In Finland, in 1995 and later in 2015 the §121 paragraph in the Finnish Employment Accident and Occupational Disease Law 459/2015 was added to the legislation. This paragraph grants insurance institute doctors an exceptional right to write out patient statements without complying with Act on Health Care Professionals 23 § adopted for certified medical statements. Putting it simply that means that a medical doctor from an insurance company does not need to sign patient statements through his/her honor and conscience, like any other health care professional. Due to the adoption of this shameful paragraph the social security of those patients who had accidents or got professional diseases has weakened dramatically. This paragraph has now got nearly 12 000 protests (1). In view of the exceptional rights of doctors working in insurance companies it is therefore difficult to assess their honesty and to know when he/she makes any kind of statements that complies with the accepted norms for medical professionals and when not.
The constitutional rights of Finnish patients suffering from poor indoor air are violated. FIOH exercises a great deal of psycologization and claims that...
The constitutional rights of Finnish patients suffering from poor indoor air are violated. FIOH exercises a great deal of psycologization and claims that patients’ somatic problems are in fact due to misconceptions, fear and exaggeration of environmental threats or due to psychological conditioning like in the Palvov’s dog model (2). Now morbidity caused by poor indoor air is explained as functional (3). The mindfulness therapy has almost no effect on patients’ health as the authors found in their studies. It was clear a priori that this kind of intervention has nothing to do with cure from environmental mycotoxicosis, immune system activation or deprivation, imbalance of homeostasis due to oxidative stress reaction, mitochondriopathy, etc (4). In this particular case the mindfulness therapy is not able to alleviate disability and improve the quality of life. This is simply because the best treatment when the patient gets sensitized to indoor air pollutants is avoidance of re-exposure. The mindfulness therapy proposed by the authors, on the contrary, is based on re-exposure. Many patients do understand this fundamental issue, and therefore the authors experienced a significant drop out of the volunteers after the start of the study.
FIOH and some other medical officials refuse to consider mechanisms of morbidly. They remain deaf to patients’ aspirations and needs and blind to the findings of modern toxicology and immunology. They continue perusing medical practices that are not based on evidence based medicine. For example, they urge the patients return back to work in spite of experiencing severe breathing symptoms that might lead even to anaphylaxis. They call immuno-toxicological re-exposure as a desensibilisation process (2).
As the authors mentioned, Social Insurance Institute of Finland (KELA) funded the study. One of the authors (AV), as was finally disclosed by Seniheimo S., is partly employed by KELA. Isn’t it a conflict of interests? The possible conflicts of interests of other co-authors, except of KK continue to be nondisclosed. In my opinion any affiliation with insurance companies or any other affiliations should be clearly stated. It is up to the readers to estimate whether or not the conclusions drawn by the authors might have a potential benefit for any commercial source.
Finally, I would like to remind about the publication of a position paper by Bush et al (5). These authors did not disclose their conflicts of interest. The topic of their publication was also related to morbidity caused by poor indoor air. Their publication caused a stormy response by scientists and medical doctors (see the multitude of replies, some of those pointed here) emphasizing that the conflict of interest might have influenced the message of their communication. Some responders even demanded withdrawal of the original publication. In my opinion the ICMJE questionnaire is obligatory to all authors, and as stated, nondisclosure of conflicts of interest is perilous to the advancement of science.
Specialist in Clinical Microbiology
Adj Professor in Medical Microbiology
Bacteriology & Immunology
University of Helsinki
1. Vakuutuslääkärit on asetettava totuusvelvoitteen piiriin (Web petition; Fin (Insurance Physicians must be set within the scope of the obligation to the truth). https://www.adressit.com/vakuutuslaakarit_on_asetettava_totuusvelvoittee... Assessed 2.2.2017
2. Homeongelmien toisinajattelija: Täyskäännös tulossa – sisäilmaongelmista kärsiviä aletaankin siedättää? Mold Problems dissident: Full Translation coming - patients affected by indoor air problems are to start tolerate? http://yle.fi/uutiset/3-7788328. Assessed 2.2.2017
3. http://laakaripaivat.fi/2017/kurssit/nuppi-ja-kroppa-tunnista-ja-puutu-t... Seminar to the medical doctors in 2017. Assessed 2.2.2017
4. Salin JT1, Salkinoja-Salonen M2, Salin PJ3, Nelo K4, Holma T5, Ohtonen P6, Syrjälä H7. Building-related symptoms are linked to the in vitro toxicity of indoor dust and airborne microbial propagules in schools: A cross-sectional study. Environ Res. 017 Jan 17;154:234-239. doi: 10.1016/j.envres.2017.01.015. [Epub ahead of print]
5. Bush RK, Portnoy JM, Saxon A, Terr AI, Wood RA. The medical effects of mold exposure. J Allergy Clin Immunnol 2006 Feb;117(2):326-33.
The role of airborne mold in chronic rhinosinusitis. [J Allergy Clin Immunol. 2006]
How solid is the Academy position paper on mold exposure? [J Allergy Clin Immunol. 2006]
Adverse health effects of indoor mold exposure. [J Allergy Clin Immunol. 2006]
Rigor, transparency, and disclosure needed in mold position paper. [J Allergy Clin Immunol. 2006]
Nondisclosure of conflicts of interest is perilous to the advancement of science. [J Allergy Clin Immunol. 2006]
Hypersensitivity pneumonitis may be home-induced by common domestic mold spores. [J Allergy Clin Immunol. 2008]
Respirable trichothecene mycotoxins can be demonstrated in the air of Stachybotrys chartarum-contaminated buildings. [J Allergy Clin Immunol. 2006]
Adverse reactions to fungal metabolic products in mold-contaminated areas. [J Allergy Clin Immunol. 2006]
Position paper on molds is seriously flawed. [J Allergy Clin Immunol. 2006]