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Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The JJ竞技 reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.

From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.

The word limit for letters selected from posted responses remains 300 words.

Re: Artificial sweeteners and risk of cardiovascular diseases: results from the prospective NutriNet-Santé cohort Nathalie Druesne-Pecollo, Younes Esseddik, Fabien Szabo de Edelenyi, Cédric Agaësse, et al. 378:doi 10.1136/bmj-2022-071204

Dear Editor

The observational NutriNet-Santé study of Debras et al. on artificial sweetener (AS) intake and cardiovascular disease (CVD) [1] raises logical and methodological issues.

1/ Diabetes is a strong risk factor for CVD, and subjects with abnormal glucose metabolism are generally advised to replace sugar with AS. If subjects with diabetes at the start of follow-up were excluded from analyses, subjects with incident diabetes during follow-up were part of the cohort, and there was no adjustment for incident diabetes or new use of anti-diabetic drugs during the 9-year follow-up.

2/ A soda can (250 mL) contains around 200 mg of aspartame. A daily intake of AS of about 318 mg for a European adult of 80 kg is common [2]. In the article, mean daily intakes of AS in lower and higher consumer groups were 7.5 and 77.6 mg/day, respectively. Hence compared to general populations, daily intakes of AS of subjects included in the NutriNet-Santé cohort are trivial. If risk estimates between AS or aspartame and CVD reported by Debras et al. were true, a marked epidemic of CVD should have been noticed since long among regular soda drinkers.

3/ There is a tenfold difference in mean daily AS consumption AS consumption between the lower and higher consumers. However, hazard rations (HR) for CVD are nearly equal (HR=1.19 and 1.20 in Supplement Table 1). Results for CHD suggest a higher risk for the lower than for the higher consumer group. These results are hardly believable.

4/ Debras et al report that “Competing risks were accounted for in all analyses”. But methods used for competing risk analyses are not clear. Authors have used the Fine-Gray (FG) method. But the FG method is not appropriate in the context of this study. This study is about aetiology (is AS intake associated with raised risk of CVD?), and not about prediction (what is the probability of being diagnosed with CVD according to AS intake?). When a study is about aetiology, the cause-specific HR is to be used for causal inference thinking, not subdistribution HR obtained using the FG method [3, 4]. Moreover, if the FG method is used, articles need to report all cause-specific hazards and cumulative incidence functions [5].

Methodological and logical concerns should be addressed before going further in the interpretation of study results.

Philippe Autier, MD, PhD, and Patrick Mulie, PhD
International Prevention Research Institute (iPRI)
Chemin des Cuers 18
69570 Dardilly (France)
ORCID : 0000-0003-1538-5321

Ph Autier and P Mullie have no conflict of interest related to their comments.


1. Debras, C., et al., Artificial sweeteners and risk of cardiovascular diseases: results from the prospective NutriNet-Santé cohort. Bmj, 2022.
2. Huvaere, K., et al., Dietary Intake of Artificial Sweeteners by the Belgian Population. Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment, 2011. 29: p. 54-65.
3. Lau, B., S.R. Cole, and S.J. Gange, Competing risk regression models for epidemiologic data. Am J Epidemiol, 2009. 170(2): p. 244-56.
4. Austin, P.C. and J.P. Fine, Practical recommendations for reporting Fine-Gray model analyses for competing risk data. Stat Med, 2017. 36(27): p. 4391-4400.
5. Latouche, A., et al., A competing risks analysis should report results on all cause-specific hazards and cumulative incidence functions. J Clin Epidemiol, 2013. 66(6): p. 648-53.

Competing interests: No competing interests

12 September 2022
Philippe AUTIER
VP, Population Research
Patrick Mullie
International Prevention Research Institute
Chemin des Cuers 18 69570 Dardilly (France)
Re: Artificial sweeteners and risk of cardiovascular diseases: results from the prospective NutriNet-Santé cohort Nathalie Druesne-Pecollo, Younes Esseddik, Fabien Szabo de Edelenyi, Cédric Agaësse, et al. 378:doi 10.1136/bmj-2022-071204

Dear Editor,

Whereas in the text of the article, the authors correctly mention that causation may not be derived from the results of the study, their abstract and main tune of the text leads readers to the understanding of sweeteners as a cause of the disease. The wording 'risk factors' may help, but for a long time it has been misused as a synonym for causative factor.

This is a cohort study, and it is not well suited for the cause and effect interpretation. It is well known that the use of sweeteners is a personal choice of people. It was shown, that overweight people, who use sweeteners, increase their weight faster. Such results are many.

Small increase in the relative risk is additional advice not to go for a causal interpretation.

While the study is great and informative, there is a danger that the almost explicit invitation to the causal interpretation may lead to public misunderstanding.

Competing interests: No competing interests

12 September 2022
Vasiliy Vlassov
HSE University
Miasnitskaia 20 Moscow 101000 Russia
Re: Artificial sweeteners and risk of cardiovascular diseases: results from the prospective NutriNet-Santé cohort Nathalie Druesne-Pecollo, Younes Esseddik, Fabien Szabo de Edelenyi, Cédric Agaësse, et al. 378:doi 10.1136/bmj-2022-071204

Dear Editor,
An important article with a treasure of references and good suggestions for additional reading.
I gather from the article, the references and suggested additional reading that:
* The sweeteners are added to tempt the buyer,
* Artificially sweetened food change intestinal microbiom,
* Artificially sweetened food and so called jink food causes problems including
- adverse effects on fertility,
- metabolic syndrome including obesity, diabetes mellitus, hypertension, coronary artery disease,
- such type of food may also increase generalized atherosclerosis,
- such food may increase incidence of cerebrovascular disease,
- such food may increase risk of malignancies.
There may be many other problems that I have not mentioned.
There are certain things that can be easily done, such as labeling of food and beverages which prominently list hazardous ingredients, enforcing advertising standards so that consumers are not lured(similar to what is done in case of tobacco products).
More difficult is the task of educating parents and future parents about harms of unhealthy foods and beverages. Sadly this needs to be undertaken with sincerity zeal and zest.
It is really sad to see parents and grandparents pampering children with packaged eatables and beverages of dubious health effects.


Competing interests: No competing interests

09 September 2022
Arvind Joshi
Social Work
Convener Our Own Discussion Group
Mumbai PIN 400028, Kharghar PIN 410210, Maharashtra India
Re: Artificial sweeteners and risk of cardiovascular diseases: results from the prospective NutriNet-Santé cohort Nathalie Druesne-Pecollo, Younes Esseddik, Fabien Szabo de Edelenyi, Cédric Agaësse, et al. 378:doi 10.1136/bmj-2022-071204

Dear Editor
Caffeine may lower the risk of stroke. Caffeine is a very common additive in sweetener containing beverages. Was caffeine analysed as a confounding or mitigating variable is this study, the financial consequence of which could be very large? It is possible that caffeine may interact differently with the eight different sweeteners listed.

Reference: Zhang Y, Yang H, Li S, Wang Y. Consumption of coffee and tea and risk of developing stroke, dementia or poststroke dementia: a cohort study in the UK Biobank. PLOS Medicine

Competing interests: No competing interests

09 September 2022
William P. Tormey
Medical doctor and Journal editor
Royal Academy of Medicine in Ireland
Royal academy of Medicine in Ireland. Kildare St, Dublin 2
Re: Energy, social care, pay: Truss’s first 100 days Rebecca Coombes. 378:doi 10.1136/bmj.o2173

Dear Editor

Wishes to the new prime minister of the UK.

Her Majesty Queen Elizabeth II

The death of Queen Elizabeth II [08.09.2022] is a moment of sadness to the world.

Her reign of 70 years and 214 days is the longest of any British monarch and the second-longest recorded of any monarch of a sovereign country.

Her Majesty Queen Elizabeth II will always be remembered in World history.

Competing interests: No competing interests

09 September 2022
M.A. Aleem
Professor of Neurology * Consultant Neurologist **
Dhanalakshmi Srinivasan Medical College Siruvathur Perambalur * ABC Hospital **
Annamalai nagar, Trichy 620018Tamilnadu India
Re: Risks of mental health outcomes in people with covid-19: cohort study Yan Xie, Evan Xu, Ziyad Al-Aly. 376:doi 10.1136/bmj-2021-068993

Dear Editor,

I read with interest the study by Xie et al. concerning the neuropsychiatric sequelae of COVID-19 survivors (1). In related publications (2), the authors reported an increased incidence of cardiovascular (3), metabolic (4), and renal (5) long-term conditions among COVID-19 survivors. While these reports are important, there are open questions regarding data analysis that cast serious doubts on the authors’ main conclusions.

It is of utmost importance to understand that EHR data do not only reflect the patients’ health, but their interactions with the health care system (6). For example, surveillance bias implies that patients who are followed-up with increased vigilance are more likely to receive EHR diagnoses (8,9). In other words, an EHR diagnosis must not only be interpreted as a proxy for sickness, because it might also be a proxy for diagnostic intensity. Closely related, informed presence bias implies that patients with higher frequency of healthcare encounters, receive more EHR diagnoses, due to repeated interactions with the healthcare system (10), which necessitates a code for these encounters. In fact, some researchers believe that the predictive value of underlying healthcare processes might even be more relevant than the predictive value of the pathophysiological processes (6).

I reassessed the data of this study and found evidence of different healthcare utilization between exposure and control group. The authors report that 50.95% of COVID-19 patients had three or more encounters with the healthcare system vs. 27.83% of the control group. Fortunately, the authors used “frequency of outpatient encounters” as a covariate and achieved balance after matching. Nonetheless, according to the raw data in Nature, COVID-19 patients received more significantly more EHR codes for “medical examinations”, “encounters for administrative purposes” and reception of “diagnostic agents”. The latter clearly implies larger diagnostic work-up of COVID-19 patients. Of course, this might indicate poorer health of COVID-19 patients in general, however to the absolute minimum, the possible role of these biases and their impact on the measured findings must be highlighted as a major limitation of all conclusions in this study.

The authors contradict themselves in their published reports. In the Nature study, substance use disorders are not associated with COVID-19, except a positive trend for alcohol-related disorders. In the JJ竞技 study, they do. Further baseline characteristics of COVID-19 patients differed dramatically. For example, after matching, the JJ竞技 study reports 23.95% of COVID 19 patients suffering from diabetes mellitus type 2, vs. 29.27% in Nature vs. 24.39% in the Nature Medicine or vs. 39.4% in the JASN report, respectively. To the authors defense, all studies differ in statistical adjustment and selection of covariates but the degree of model dependence is concerning.

Strangely enough, in the Nature study, the authors show that COVID-19 is inversely associated with tobacco- and cannabis-related disorders, which is evidently implausible and clearly indicates residual confounding. What is most concerning, however, is that in the JJ竞技 report the authors report substance use disorders – except tobacco-related disorders, which is the only outcome indicating uncontrolled confounding. The authors provide no rationale why they leave out the data on nicotine adherence.

Lastly, the authors used traumatic events and neoplasms as negative-outcome controls. The authors state that “if there were biases in the analytical approach, this would extend to the chosen negative-outcome controls”. However, the authors only chose outcomes, which align with their hypothesis. According to the raw data in Nature, COVID 19 is also associated with “refractive errors” and “acquired foot deformities”. It remains unclear, why those are not considered negative-outcome controls, as they are clearly not “plausibly associated to COVID-19 infections”.

The conclusions of this author group is hampered by severe uncontrolled confounding and needs careful reevaluation. To optimally assess the epidemiological burden of long-term sequelae of COVID-19, we must not rely on self-report or observational data, but on gold-standard prospective, double-blinded cohort studies (14).

I declare no competing interests.

The opinions expressed here do not necessarily represent the opinions of my affiliations.

1. Xie, Y., Xu, E. & Al-Aly, Z. Risks of mental health outcomes in people with covid-19: cohort
study. JJ竞技 e068993 (2022) doi:10.1136/bmj-2021-068993.
2. Al-Aly, Z., Xie, Y. & Bowe, B. High-dimensional characterization of post-acute sequelae of
COVID-19. Nature 594, 259–264 (2021).
3. Xie, Y., Xu, E., Bowe, B. & Al-Aly, Z. Long-term cardiovascular outcomes of COVID-19. Nature
Medicine 28, 583–590 (2022).
4. Xie, Y. & Al-Aly, Z. Risks and burdens of incident diabetes in long COVID: a cohort study. The
Lancet Diabetes & Endocrinology 10, 311–321 (2022).
5. Bowe, B., Xie, Y., Xu, E. & Al-Aly, Z. Kidney Outcomes in Long COVID. Journal of the American
Society of Nephrology 32, 2851–2862 (2021).
6. Agniel, D., Kohane, I. S. & Weber, G. M. Biases in electronic health record data due to
processes within the healthcare system: retrospective observational study. JJ竞技 k1479 (2018)
7. Hripcsak, G., Albers, D. J. & Perotte, A. Parameterizing time in electronic health record studies.
Journal of the American Medical Informatics Association 22, 794–804 (2015).
8. Haut, E. R. Surveillance Bias in Outcomes Reporting. JAMA 305, 2462 (2011).
9. Pierce, C. A. et al. Surveillance Bias and Deep Vein Thrombosis in the National Trauma Data
Bank: The More We Look, The More We Find. Journal of Trauma: Injury, Infection & Critical
Care 64, 932–937 (2008).
10. Goldstein, B. A., Bhavsar, N. A., Phelan, M. & Pencina, M. J. Controlling for Informed Presence
Bias Due to the Number of Health Encounters in an Electronic Health Record. American
Journal of Epidemiology 184, 847–855 (2016).
11. Vai, B. et al. Mental disorders and risk of COVID-19-related mortality, hospitalisation, and
intensive care unit admission: a systematic review and meta-analysis. The Lancet Psychiatry 8,
797–812 (2021).
12. Mena, G. E. et al. Socioeconomic status determines COVID-19 incidence and related mortality
in Santiago, Chile. Science (1979) 372, (2021).
13. Lipsitch, M., Tchetgen Tchetgen, E. & Cohen, T. Negative Controls. Epidemiology 21, 383–388
14. Sneller, M. C. et al. A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline
Findings. Annals of Internal Medicine 175, 969–979 (2022)

Competing interests: No competing interests

09 September 2022
Mohamed Mahde Saleh, MD, PhD
Neurology/Population Health Science
Re: David Oliver: A bittersweet farewell to my ward David Oliver. 378:doi 10.1136/bmj.o2150

Dear Editor,

Thanks to David for his personal view. Powerful.

The one thing that stood out was his comment about the “exponential” rise in complexity of patients. Advancing medical science achieved by very clever people focusing on one system has led to much greater longevity. However, for generalists, both GP and hospital, this results in patients whose multi system “complexity” is beyond executive management by even the most motivated and brilliant physician. When things go wrong, which they do because of the complexity, the same one system people make comments on why things went wrong and the “brilliant” failing general physician feels a lot less brilliant. The net result is very good doctors feel like bad doctors, which makes them even less able to deal with the unmanageable complexity.

Competing interests: No competing interests

09 September 2022
Graeme Mackenzie
Re: The illusion of evidence based medicine Jon Jureidini, Leemon B. McHenry. 376:doi 10.1136/bmj.o702

Dear Editor.

Throwing the baby out with the bathwater seems to me to be the wrong way to go in this case too.

First of all, Sackett et al. define evidence-based medicine as a way to provide the best available external evidence as a basis for concrete therapy decisions. How this evidence is formed and what formal, content-related and ethical preconditions it comes from is another topic. Sackett formulates nothing more than a seemingly self-evident counter-position to a practical medicine that lives on authority expertise and selective experience. The fact that this is still a significant paradigm today should not be devalued by pointing out inadequacies at meta-levels. Or should we be under the illusion that such authority-led medicine is less susceptible to negative influences than "evidence-based research" or even provides a "better medicine"?

No, it is not, because it lacks an important factor: the self-correction process of the scientific community. In this, too, as in all human-driven activities, there are shortcomings, weaknesses and also deliberate failures. For example, this includes the fading out of plausibility and consistence for a over-focus on medical statistics. But to let this affect the concept of Sackett et al. in such a way that the whole paradigm of EBM is to be regarded as a failure is completely wrong.

Winston Churchill's well-known bon mot that democracy is the best of all bad forms of government is therefore undoubtedly also applicable to evidence-based medicine, certainly to that defined by Sackett et al. We do not have a crisis of EBM per se, but a crisis of scientific research and its evaluation.

And this is often a crisis of framework conditions that, for example, put independent research under pressure to publish, hold evaluation work in low esteem and push more into hypes than promote careful research. This seems to me to have little or nothing to do with EBM as a concept.

Competing interests: No competing interests

08 September 2022
Udo W. Endruscheit
Scientific author, editor
Information Network Homeopathy, Germany
45307 Essen, Germany
Re: Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT) Natalia Perdek, Paul Pfeffer, Giulia Vivaldi, Sheena Maltby, et al. 378:doi 10.1136/bmj-2022-071230

Dear Editor

The title of this paper is somewhat misleading. It turned out to be a randomised UNCONTROLLED trial. The reason for this is that the subjects in the control group were not controlled. They were simply told that they were not going to receive vitamin D, and they were not given a placebo. Guess what? Many of them obtained their own supplies of vitamin D (the subject of the study) and the mean blood level of vitamin D in the "control" group at the end of the study was 66.2nmol/L, not far short of 79.4nmol/L in the low dose vitamin D group. The baseline blood levels of vitamin D in the vitamin D groups were 40.9 and 41.5nmol/L, and we must assume that it was similar in the control group although testing was not undertaken.

The other problem in respect of evaluating the efficacy of vitamin D is that the trail was underpowered, in that there were no Covid-19 or other respiratory infection deaths and just one ventilation necessary in each of the three groups. Infection rates and hospital admission rates were very similar in all groups. This made evaluation of the putative benefit of vitamin D impossible. It is obviously necessary to have a participation group far larger than 6,200 if normal healthy adults are to be studied, rather than specific high risk groups in whom endpoints would be more frequent.

It is stated in the text: "Ultimately however, this trial was designed to investigate the effectiveness of a pragmatic test-and-treat approach to boosting population vitamin D status, rather than biological efficacy of vitamin D to prevent acute respiratory tract infections, and our findings should be interpreted accordingly:"

The study demonstrated the effectiveness of a test-and-treat approach, but the results tell us nothing about the efficacy or lack of efficacy of vitamin D in the prevention of Covid-19 or other respiratory infections, fatal or otherwise.

Competing interests: No competing interests

08 September 2022
David S Grimes
Physician – retired
Langho, Lancs
Re: David Oliver: A bittersweet farewell to my ward David Oliver. 378:doi 10.1136/bmj.o2150

Dear Editor

Retirement needs to be taken more seriously, as a gradual process rather than a sudden "falling off a cliff" event.

There is plenty to be done, teaching, mentoring, examining and much else that does not require the physical stamina of intense clinical work. A system is needed that enables older doctors to keep up to date and provides a trusted mentor who will watch out for signs that it really is time to stop.

Ignoring this is not only bad for doctors' mental and physical health, it is a waste of valuable resources.

Competing interests: No competing interests

08 September 2022
Lesley Bacon
Retired SRH consultant


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