I want to express my concern regarding “Curcumin and proton pump inhibitors for functional dyspepsia: a randomised, double blind controlled trial” by Kongkam et al(1). It was published against the journal’s editorial policy and has serious issues with reporting and interpretation of results.
The article shouldn’t have been published in the first place. It lacks prospective registration, which directly contradicts the BMJ Evidence-based medicine editorial policy stating that a prospective registration is mandatory for any clinical trials(2). The Thai Clinical Trials Registry(3) registration TCTR20221208003 is retrospective which is clearly stated in the registry. The registration was submitted on 07 December 2022, just before a preprint was posted on medRxiv on 09 December 2022, while the study was completed on 30 April 2020.
On top of that, there are serious issues with the reporting and interpretation of results.
According to the authors an equivalence design was used with the equivalence margin of 2 points in the SODA score. Nine comparisons of SODA scores in the curcumin plus omeprazole (C+O), curcumin only (C), and omeprazole only (O) groups were reported. For three of those confidence intervals include equivalence margin. The only available interpretation here is that the trial failed to demonstrate equivalence. To demonstrate equivalence the confidence intervals should be between the two equivalence margins rath...
I want to express my concern regarding “Curcumin and proton pump inhibitors for functional dyspepsia: a randomised, double blind controlled trial” by Kongkam et al(1). It was published against the journal’s editorial policy and has serious issues with reporting and interpretation of results.
The article shouldn’t have been published in the first place. It lacks prospective registration, which directly contradicts the BMJ Evidence-based medicine editorial policy stating that a prospective registration is mandatory for any clinical trials(2). The Thai Clinical Trials Registry(3) registration TCTR20221208003 is retrospective which is clearly stated in the registry. The registration was submitted on 07 December 2022, just before a preprint was posted on medRxiv on 09 December 2022, while the study was completed on 30 April 2020.
On top of that, there are serious issues with the reporting and interpretation of results.
According to the authors an equivalence design was used with the equivalence margin of 2 points in the SODA score. Nine comparisons of SODA scores in the curcumin plus omeprazole (C+O), curcumin only (C), and omeprazole only (O) groups were reported. For three of those confidence intervals include equivalence margin. The only available interpretation here is that the trial failed to demonstrate equivalence. To demonstrate equivalence the confidence intervals should be between the two equivalence margins rather than include them. The fact that “no significant differences were observed among the three groups” is also fully irrelevant, it does not demonstrate equivalence, as the latter cannot be claimed on the basis of nonsignificant tests(4).
Another striking deficiency in reporting is the unexplained loss to follow-up difference between the study arms. While 17 participants were lost to follow-up in the curcumin plus omeprazole and 17 in the curcumin only groups, only 1 was lost to follow-up in the omeprazole only arm. At the same time, the numbers of subjects who withdrew consent were also noticeably different – 2, 2 and 18 respectively. This difference is unlikely to have arisen by chance alone. There are two possible explanations: either the numbers of subjects who withdrew consent and those lost to follow-up were mistakenly swapped, or the loss to follow-up was systematically different in the omeprazole only arm compared to the two arms with curcumin. The former would question the peer review, the latter would question the blinding. Given the taste and smell of curcumin the blinding should have been questioned even if there were no differences in attrition.
It’s hard to believe that CONSORT requirements, explicitly stating that the interpretation must be consistent with the results and the primary and secondary outcome measures need to be completely defined and pre-specified, were sufficiently taken into consideration during the review process. I hope appropriate actions will be taken by the journal to correct for that.
(1) Kongkam P, Khongkha W, Lopimpisuth C, et alCurcumin and proton pump inhibitors for functional dyspepsia: a randomised, double blind controlled trialBMJ Evidence-Based Medicine 2023;28:399-406.
(4) Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG, CONSORT Group FT. Reporting of Noninferiority and Equivalence Randomized Trials: Extension of the CONSORT 2010 Statement. JAMA. 2012;308(24):2594–2604. doi:10.1001/jama.2012.87802
We were surprised that BMJ Evidence Based Medicine chose to publish the flawed article by Høeg and co-authors on methodological limitations of research on long COVID (1). This piece appears to be a ‘Trojan Horse’ article where a scientifically dubious proposition escapes proper scrutiny because it is cloaked in otherwise plausible research commentary.
As the authors state, we need well designed studies to provide a valid measure of the long-term effects of acute COVID-19 infection (Long COVID). Such studies require robust case definitions, adequate duration of follow-up, and suitable comparison groups.
But in a section titled “The most well-designed studies provide reassuring estimates”, the authors include just two studies to support that sweeping statement. This highly selective ‘mini meta-analysis’ subverts the very purpose of evidence-based medicine. The main message of the Høeg paper appears to be that there is a negligible risk of long COVID, based on the selection of papers they have cited. That message does not fit with the actual body of scientific evidence (2). There is now overwhelming research that SARS-CoV-2 infection carries a significant risk of long-term effects over and above the generic effects of post-ICU syndrome and pneumonia (3).
The evidence of long-term effects comes from multiple sources, including epidemiological studies and basic science research looking at the severe and lasting pathological changes that occur in some pati...
We were surprised that BMJ Evidence Based Medicine chose to publish the flawed article by Høeg and co-authors on methodological limitations of research on long COVID (1). This piece appears to be a ‘Trojan Horse’ article where a scientifically dubious proposition escapes proper scrutiny because it is cloaked in otherwise plausible research commentary.
As the authors state, we need well designed studies to provide a valid measure of the long-term effects of acute COVID-19 infection (Long COVID). Such studies require robust case definitions, adequate duration of follow-up, and suitable comparison groups.
But in a section titled “The most well-designed studies provide reassuring estimates”, the authors include just two studies to support that sweeping statement. This highly selective ‘mini meta-analysis’ subverts the very purpose of evidence-based medicine. The main message of the Høeg paper appears to be that there is a negligible risk of long COVID, based on the selection of papers they have cited. That message does not fit with the actual body of scientific evidence (2). There is now overwhelming research that SARS-CoV-2 infection carries a significant risk of long-term effects over and above the generic effects of post-ICU syndrome and pneumonia (3).
The evidence of long-term effects comes from multiple sources, including epidemiological studies and basic science research looking at the severe and lasting pathological changes that occur in some patients following SARS-CoV-2 infection. This research shows that COVID-19 is a multisystem disease that can cause microclots, changes to the immune system, viral persistence in tissues, and other effects even in mild cases (4). These effects provide a basis for well-described sequelae of COVID-19 such as impaired brain function, extreme fatigue, and stroke.
Furthermore, tissue-level effects can be clinically silent but they include known risk factors for heart disease and other conditions, raising concerns for future population health. Viral persistence suggests additional potential for long-term effects that may take years or decades to emerge, as we have seen with other infections (5).
Even the research selectively cited in the Hoeg article is not as reassuring as the authors imply. Antonelli et al. reported an overall lower risk of Long COVID for Omicron compared with Delta infection (6). But they noted that Omicron variants have caused far higher case numbers and the conclusion of their article is that "future numbers with long COVID will inevitably rise".
Full declaration of potential conflicts of interest is important in evidence-based medicine. Yet at least two of the authors here have made no secret of their unorthodox scientific views on the origins, transmission, severity and prevention of COVID-19 and appear to be associated with particular ideological positions and organisations (7, 8).
Rather than the robust science we might reasonably expect from the highly regarded BMJ Evidence-Based Medicine, the Høeg paper serves to illustrate the very biases and errors which evidence-based medicine was established to challenge. It appears to be a ‘Trojan Horse’ from a partisan group. Its publication significantly damages the reputation of the journal as a platform for rigorous, principled, and balanced scientific debate.
References
1. Hoeg TB, Ladhani S, Prasad V. How methodological pitfalls have created widespread misunderstanding about long COVID. BMJ Evid Based Med 2023 doi: 10.1136/bmjebm-2023-112338 [published Online First: 2023/09/26]
2. Altmann DM, Whettlock EM, Liu S, et al. The immunology of long COVID. Nature reviews Immunology 2023;23(10):618-34. doi: 10.1038/s41577-023-00904-7 [published Online First: 2023/07/12]
3. Bowe B, Xie Y, Al-Aly Z. Postacute sequelae of COVID-19 at 2 years. Nat Med 2023;29(9):2347-57. doi: 10.1038/s41591-023-02521-2 [published Online First: 2023/08/22]
4. Castanares-Zapatero D, Chalon P, Kohn L, et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Annals of medicine 2022;54(1):1473-87. doi: 10.1080/07853890.2022.2076901 [published Online First: 2022/05/21]
5. Chen B, Julg B, Mohandas S, et al. Viral persistence, reactivation, and mechanisms of long COVID. eLife 2023;12 doi: 10.7554/eLife.86015 [published Online First: 2023/05/04]
6. Antonelli M, Pujol JC, Spector TD, et al. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet 2022;399(10343):2263-64. doi: 10.1016/S0140-6736(22)00941-2 [published Online First: 2022/06/20]
7. Bragman W. New scientist group calling for pandemic answers is tied to rightwing Dark Money. OptOut, 2023; https://www.optout.news/newsletters/norfolk-group.
8. Prasad V. Do not report COVID cases to schools & do not test yourself if you feel ill. Vinay Prasad's Observations and Thoughts, 2023; https://vinayprasadmdmph.substack.com/p/do-not-report-covid-cases-to-sch....
Dr Juan Franco
Editor-In-Chief
BMJ Evidence Based Medicine
BMA House
Tavistock Square
London WC1H 9JP
UNITED KINGDOM
31 October 2023
Dear Editor-In-Chief,
We read with interest the recent article by Høeg and colleagues that describes how methodological limitations in long COVID research distort risk and overestimate prevalence.[1]
The authors propose criteria to improve epidemiological research of long COVID. We write in support of these criteria, and to suggest two additions. We recently compared outcomes three months after PCR-confirmed COVID-19 infection with PCR-confirmed influenza infection, and found no difference between these illnesses.[2] Our comparative observational study had limitations (which we acknowledged) but was noteworthy because it was conducted in an Australian population that was primarily exposed to the Omicron variant after achieving high vaccination rates (>90%).
As a result, our two proposed additions to Høeg et al’s criteria relate to the exposed population which, as they suggest, should have diagnostic evidence of infection.
The first addition is to document the COVID variant to which this population was exposed. Recent data from Sweden shows a progressive (and substantial) decrease in the risk of long COVID from the wild type to the Omicron variant.[3] In addition, the type and frequency of symptoms has changed as the virus evolves.[4] This inclusion would improv...
Dr Juan Franco
Editor-In-Chief
BMJ Evidence Based Medicine
BMA House
Tavistock Square
London WC1H 9JP
UNITED KINGDOM
31 October 2023
Dear Editor-In-Chief,
We read with interest the recent article by Høeg and colleagues that describes how methodological limitations in long COVID research distort risk and overestimate prevalence.[1]
The authors propose criteria to improve epidemiological research of long COVID. We write in support of these criteria, and to suggest two additions. We recently compared outcomes three months after PCR-confirmed COVID-19 infection with PCR-confirmed influenza infection, and found no difference between these illnesses.[2] Our comparative observational study had limitations (which we acknowledged) but was noteworthy because it was conducted in an Australian population that was primarily exposed to the Omicron variant after achieving high vaccination rates (>90%).
As a result, our two proposed additions to Høeg et al’s criteria relate to the exposed population which, as they suggest, should have diagnostic evidence of infection.
The first addition is to document the COVID variant to which this population was exposed. Recent data from Sweden shows a progressive (and substantial) decrease in the risk of long COVID from the wild type to the Omicron variant.[3] In addition, the type and frequency of symptoms has changed as the virus evolves.[4] This inclusion would improve our understanding of post-viral impacts by variant, and add important context to Høeg et al’s sensible suggestion of a symptom-based approach to support patients.
The second addition involves documenting the population’s vaccination status, including (if possible) the time since last dose. A systematic review found that COVID-19 vaccination could protect against long COVID, but also noted that study quality was generally low for the reasons argued by Høeg et al.[5] While ongoing reinfections and decreased diagnostic testing may cloud the benefits of vaccination, vaccination status offers important insights into the symptoms and impacts of each COVID variant.
Finally, we concur with the article’s observations about the ongoing impact of regular negative reports about long COVID. We have heard people say they are “more afraid of getting long COVID than they are of getting COVID”. Høeg and colleagues have provided a framework to challenge the many inflated claims that may contribute to this fear and anxiety. While we believe and support those who experience post-viral effects, we must remember the most likely outcome after COVID-19 infection is a full recovery.
Yours sincerely,
Matthew Brown (Program Manager, Queensland Long COVID Response)
John Gerrard (Chief Health Officer, Queensland)
Ross Andrews (Senior Consultant Epidemiologist)
References
1 Hoeg TB, Ladhani S, Prasad V. How methodological pitfalls have created widespread misunderstanding about long COVID. BMJ Evid Based Med 2023.
2 Brown M, Gerrard J, McKinlay L, et al. Ongoing symptoms and functional impairment 12 weeks after testing positive for SARS-CoV-2 or influenza in Australia: an observational cohort study. BMJ Public Health 2023; 1(1).
3 Hedberg P, Naucler P. Post COVID-19 condition after SARS-CoV-2 infections during the omicron surge compared with the delta, alpha, and wild-type periods in Stockholm, Sweden. J Infect Dis 2023.
4 Looi MK. How are covid-19 symptoms changing? BMJ 2023; 380: 3.
5 Byambasuren O, Stehlik P, Clark J, et al. Effect of covid-19 vaccination on long covid: systematic review. BMJ Medicine 2023; 2(1).
I would like to congratulate Dr. Abbott and her team in generating this piece of important and interesting article, which applied the methods of meta-science to the early systematic review articles and the infodemics related to COVID-19.
Indeed, the COVID-19 pandemic came quick and ferocious, starting early 2020 and lasted till recently and with new possible variants emerging, it still presents the medical community and indeed the scientific circles with challenging question. Thankfully to the selfless work of researchers, patients and frontline medical staffs, we now have some valuable means to deal with this Pandemic.
The research community was presented with a rather challenging task of designing and conducting researches to answer important questions relating to the new infectious diseases at the time of early 2020. The “new” corona virus was ravaging parts of our world without checks. So studies were conducted at pace, which unfortunately resulted in much duplicated and poor methodological studies conducted. But on the other hand, the sheer volume of studies itself may be useful as it generated evidence to inform us of what does and what does not work in terms combating the COVID-19. For example, dexamethasone (RECOVERY trial) was found to be essential for severe COVID-19 patients and the use of Hydroxychloroquine is ineffective for COVID-19.
Having said this, I must state that I am not in support of the generation of poor quality clinical studi...
I would like to congratulate Dr. Abbott and her team in generating this piece of important and interesting article, which applied the methods of meta-science to the early systematic review articles and the infodemics related to COVID-19.
Indeed, the COVID-19 pandemic came quick and ferocious, starting early 2020 and lasted till recently and with new possible variants emerging, it still presents the medical community and indeed the scientific circles with challenging question. Thankfully to the selfless work of researchers, patients and frontline medical staffs, we now have some valuable means to deal with this Pandemic.
The research community was presented with a rather challenging task of designing and conducting researches to answer important questions relating to the new infectious diseases at the time of early 2020. The “new” corona virus was ravaging parts of our world without checks. So studies were conducted at pace, which unfortunately resulted in much duplicated and poor methodological studies conducted. But on the other hand, the sheer volume of studies itself may be useful as it generated evidence to inform us of what does and what does not work in terms combating the COVID-19. For example, dexamethasone (RECOVERY trial) was found to be essential for severe COVID-19 patients and the use of Hydroxychloroquine is ineffective for COVID-19.
Having said this, I must state that I am not in support of the generation of poor quality clinical studies, but what I am saying is that different clinical / public health circumstances may call for different overall research strategies, sometimes we need quick answers to important clinical questions, then unfortunately, quality is often sacrificed/overlooked for the sake of the generation of "rapid" evidence, and the early phase of the COVID-19 pandemic may fall into this category. A relative lake of research capacity and resources may also contributed to this unfortunate phenomenon as we just do not have the means to generate massive amount of high quality researches in a short period of time.
It is my view that medical research can perhaps be broadly divided into four categories:
1). Very Important and urgent: such as the COVID-19 or any past or future public health emergencies
2). Important but not urgent: hypertension, diabetes etc.
3). Not as important but urgent: diagnosis or care of rare genetic diseases etc.
4). Least important and not urgent: patient flow, drug compliance issues etc.
I would concur with Dr. Abbott and her team and both the authors and the editors of the scientific community share the "duty" of ensuring and also improve the quality of systematic reviews. As an educator, we are equally responsible for providing future clinicians and scholars with the knowledge and skills to conduct high quality studies. Furthermore, meta-researches are as important to provide us with a scoping view of the evidences of review articles and to remind us of the need of research vigilance. Lastly it is perhaps also the responsibility of the policy makers and governments to ensure the persistent and appropriate resources are channeled into the research community, especially in times of future public health emergencies.
Dear Editor,
This response is in relation to the titled article above published in June 2019. Firstly, I would like to commend the outstanding work of research done. While reading the article, I understood the correlation between the nursing field, evidence-based research, and ways in which patients benefit from current health practices. Furthermore, the research conducted a wide range of research benefits in other nursing career paths globally. It showed experts views on teaching evidenced based prospectus, evidence-based deliberations, and stakeholders’ engagement which can impact patients involved. I agree with the study conducted and how research is essential for future advancements as well as improvements in care to patients. Unfortunately, there aren’t as much published research work in The Bahamas on evidence-based practices from an expert view. Through further research this thesis can become widespread to obtain more views on this pressing matter.
My name is Student Nurse Montel Stuart. from the University of the Bahamas. I have read your article and found the area of research to be very interesting and encourage to you to further your research on the effect of counselling on uninsured patients.
Regards,
Montel Stuart
Dr. Terry Campbell, a lecturer at the university's School of Nursing
This is a response to the article that was published on August 31, 2019, which can be seen above. The article was quite fascinating to read since it focuses on hypertension and how the therapy would effect medication usage in insured individuals; however, the study that was offered was based on a review of the healthcare system in China's population. After reading this study, I have come to the conclusion that it is essential to supply patients with information that is pertinent to their conditions and to take into account the patients' values in the process of making clinical decisions. Doing so can boost patient participation and contribute to the development of patient-centered, individualized care. The researcher provided individual counseling and found that the rate of willingness to pay completely out of pocket for antihypertensive drugs dropped significantly after evidence- based individualised counselling; however, it is uncertain whether that evidence- based, individualised counselling regarding hypertension and its treatment would actually impact medication use in insured patients with mild hypertension.
The findings of this research are restricted in a few important ways. To begin, it may be affected by reporting bias, which is a typical worry in data that is self-reported. This bias may occur when people lie about what they did. Prescription refills, patients'...
Dr. Terry Campbell, a lecturer at the university's School of Nursing
This is a response to the article that was published on August 31, 2019, which can be seen above. The article was quite fascinating to read since it focuses on hypertension and how the therapy would effect medication usage in insured individuals; however, the study that was offered was based on a review of the healthcare system in China's population. After reading this study, I have come to the conclusion that it is essential to supply patients with information that is pertinent to their conditions and to take into account the patients' values in the process of making clinical decisions. Doing so can boost patient participation and contribute to the development of patient-centered, individualized care. The researcher provided individual counseling and found that the rate of willingness to pay completely out of pocket for antihypertensive drugs dropped significantly after evidence- based individualised counselling; however, it is uncertain whether that evidence- based, individualised counselling regarding hypertension and its treatment would actually impact medication use in insured patients with mild hypertension.
The findings of this research are restricted in a few important ways. To begin, it may be affected by reporting bias, which is a typical worry in data that is self-reported. This bias may occur when people lie about what they did. Prescription refills, patients' scales, and self-reporting are only few of the measures that are regularly used to assess a patient's level of adherence to their medical regimen. Because the antihypertensive prescription could be refilled at any hospital, primary care centers, or even pharmacies in the city where the study was conducted. This was due to the fact that the network among the hospitals, centers, and pharmacies had not yet been established, which meant that we were unable to check all of the refills that were obtained from various locations for a single patient. As a consequence of this, the prescription history kept only at the community health centers where this research was carried out was available and would underestimate the real refills. The patients' scales was not used in this research was due to the fact that they had not been adequately validated for the purpose of researching patients' adherence to antihypertensive medication in Chinese communities. In addition, it is yet unknown whether or not patients' drug-taking behaviors will alter if the EBI counselling had been provided by the attentive doctors; for this reason, more study is still required.
Title: “Claims about the main claim”
Author: Suhail A, Doi, Polychronis, Kostoulas, Paul, Glasziou
In response to the published article "Likelihood ratio interpretation of the relative risk"
Rapid response :
September 16, 2022
The problem in evidence-based medicine arises when we port relative risks derived from one study to settings with different baseline risks. For example, a baseline risk of 0.2 and treated risk of 0.4 for an event in a trial gives a RR of 2 (0.4/0.2) and the complementary cRR of 0.75 (0.6/0.8). Thus the ratio of LRs (RR/cRR) is 2/0.75 = 2.67. If applied to a baseline risk of 0.5 the predicted risk under treatment with the RR “interpretation” is 1.0 but with the ratio of LRs “interpretation” is 0.73. Here, the interpretation of the risk ratio as a likelihood ratio, using Bayes’ theorem, clearly gives different results, and solves the problem of impossible risks as clearly depicted in the manuscript and the example.
If, in our effort to highlight the need of this correct interpretation, we have used strong wording that annoyed the commentator we feel the need to express regret. We hope that the commentator could also feel similarly for his scientifically unbecoming choice of wording that culminated with “Doi’s Conjecture”.
Conflict of Interest
None declared
I am writing to request further clarification on the paper “Likelihood ratio interpretation of the relative risk”. The “key messages” section of this paper states that the study adds the following to the literature:
⇒ It is demonstrated that the conventional interpretation of the relative risk is in conflict with Bayes’ theorem.
⇒ The interpretation of the relative risk as a likelihood ratio connecting prior (unconditional) intervention risk to outcome conditional intervention risk is required to avoid conflict with Bayes’ Theorem
I will refer to the first bullet point as “Doi’s Conjecture”. Doi’s Conjecture is also stated in the second section of the main text, where it is claimed that “the usual interpretation (33% increase in the +ve outcome under treatment) contravenes Bayes Theorem”.
No attempt is made within the text to prove Doi’s Conjecture. But perhaps more worryingly, no attempt is made to define the term “interpretation”, a term which is not defined in standard probability theory. The meaning of Doi’s Conjecture is therefore at best ambiguous. Moreover, the manuscript relies substantially on claims about how effect measures are “perceived”, another term which is defined neither in probability theory not in the manuscript.
The relative risk is defined as the risk of the outcome under treatment, divided by the risk of the outcome under the control condition; that is, as a ratio of two probabilities. Thi...
I am writing to request further clarification on the paper “Likelihood ratio interpretation of the relative risk”. The “key messages” section of this paper states that the study adds the following to the literature:
⇒ It is demonstrated that the conventional interpretation of the relative risk is in conflict with Bayes’ theorem.
⇒ The interpretation of the relative risk as a likelihood ratio connecting prior (unconditional) intervention risk to outcome conditional intervention risk is required to avoid conflict with Bayes’ Theorem
I will refer to the first bullet point as “Doi’s Conjecture”. Doi’s Conjecture is also stated in the second section of the main text, where it is claimed that “the usual interpretation (33% increase in the +ve outcome under treatment) contravenes Bayes Theorem”.
No attempt is made within the text to prove Doi’s Conjecture. But perhaps more worryingly, no attempt is made to define the term “interpretation”, a term which is not defined in standard probability theory. The meaning of Doi’s Conjecture is therefore at best ambiguous. Moreover, the manuscript relies substantially on claims about how effect measures are “perceived”, another term which is defined neither in probability theory not in the manuscript.
The relative risk is defined as the risk of the outcome under treatment, divided by the risk of the outcome under the control condition; that is, as a ratio of two probabilities. This manuscript appears to claim that “interpreting” the relative risk in the manner that it is defined, is inconsistent with Bayes’ Theorem, a fundamental result in probability theory. If this is true, probability theory is in deep conceptual trouble.
There are multiple correct (and mathematically equivalent) ways to represent effects within a study, to predict risk under treatment and to determine the posterior probability. This manuscript provides no coherent reason for one valid approach to take precedence over another valid approach.
Airborne transmission and inhalation, of SARS-CoV-2 is recognized by international public health agencies (Addleman et al. 2021) from both short- and long-range aerosol transmission (Tang et al. 2021).
When comparing filtering face piece (FFP) respirators, with a surgical (medical) masks, for protection against an inhalable (ISO 7708) airborne virus such as SARS-CoV-2, “EQUIPOISE” a central tenet for conducting a randomised control trial (RCT), does not exist. The futility of using a RCT is analogous to carrying out a study in a construction site for hard hats or seat belts in a passenger vehicle. FFP respirators used in Canada are selected and used in accordance with CAN/CSA-Z94.4-18 (Selection, use, and care of respirators). Specifications are provided in CSA Z94.4.1:21 (Performance of filtering respirators).
At least two international studies using RCT have been initiated since the start of the COVID-19 pandemic.
a) United Kingdom: The impact of different grades of respiratory protective equipment on sickness absence due to respiratory infections including SARS-CoV-2 for healthcare workers (The funding committee did not recommend funding).
b) Canada, multi-centre: where nurses are randomized to either use of a medical mask or to a fit-tested N95 respirator when providing care for patients with febrile respiratory illness.
The findings from a poorly designed RCT may also be used as improper and biased rationale to downgrade respirator (masks...
Airborne transmission and inhalation, of SARS-CoV-2 is recognized by international public health agencies (Addleman et al. 2021) from both short- and long-range aerosol transmission (Tang et al. 2021).
When comparing filtering face piece (FFP) respirators, with a surgical (medical) masks, for protection against an inhalable (ISO 7708) airborne virus such as SARS-CoV-2, “EQUIPOISE” a central tenet for conducting a randomised control trial (RCT), does not exist. The futility of using a RCT is analogous to carrying out a study in a construction site for hard hats or seat belts in a passenger vehicle. FFP respirators used in Canada are selected and used in accordance with CAN/CSA-Z94.4-18 (Selection, use, and care of respirators). Specifications are provided in CSA Z94.4.1:21 (Performance of filtering respirators).
At least two international studies using RCT have been initiated since the start of the COVID-19 pandemic.
a) United Kingdom: The impact of different grades of respiratory protective equipment on sickness absence due to respiratory infections including SARS-CoV-2 for healthcare workers (The funding committee did not recommend funding).
b) Canada, multi-centre: where nurses are randomized to either use of a medical mask or to a fit-tested N95 respirator when providing care for patients with febrile respiratory illness.
The findings from a poorly designed RCT may also be used as improper and biased rationale to downgrade respirator (masks) to surgical masks (Greenhalgh et al. 2022).
A subject should be enrolled in an RCT only if there is true uncertainty (equipoise) about which of the trial arms is likely to benefit the participants (Fries & Krishan 2004), otherwise the study may be unethical. Other study methodology should not be discounted and EBM+ provides a way forward.
An “observational” cohort study from Switzerland, covering 2919 HCWs spread over 7 health care networks, demonstrated 21% of infections occurred for HCWs using respirator masks compared with 35% for those using surgical/mixed masks (Dorr et al. 2022). Infections may have been greatly reduced if there was a solid respiratory protection program in place, which is not clear from the information provided.
An observational study by Ferris et al. 2021, demonstrated how important it is for HCWs caring for patients with COVID-19, whether aerosol generating procedures (AGPs) were undertaken or not to use respirators and not surgical masks.
A cross-sectional prospective study from Finland clearly demonstrated that respirators are superior (Oksanen et al. 2021). A systematic review where eight studies (9164 participants) were included after screening 153 articles followed by a meta-analysis (Collins et al. 2021).
Healthcare workers (at risk) need respiratory protection in accordance with international standards; plus, good ventilation, and administrative controls, to limit their risk of exposure to infected co-workers and patients. Reduced infection lowers the risk of work overload, moral injury and household and community transmission.
The Canada, Quebec’s court decision, ensures that all health-care professionals are provided an N95 respirator immediately when a resident or patient is suspected to be infected with COVID-19 (Hedges et al 2021, Justice Philippe Bouvier – court decision 2021).
“Thousands of lives were likely lost as a result of what was incorrectly claimed to be an evidence-based approach dismissing or downgrading mechanistic evidence, overvaluing the findings from poorly designed or irrelevant RCTs, and advocating for inaction where RCT evidence was lacking” (Greenhalgh 2022, p.1).
All relevant disciplines must be engaged (e.g., engineers, occupational hygienists, aerosol scientists, social and behavioural scientists, epidemiologists) in the research so that “up to date” and mechanistic evidence (Greenhalgh et al. 2022a, table 2) is incorporated in important policy decision making.
EBM+ provides a framework moving forward at this critical time.
References
Addleman S, Leung V, Asadi, L, Sharkawy, A, McDonald J 2021, “Mitigating airborne transmission of SARS-CoV-2”. Canadian Medical Association Journal (CMAJ), CMAJ July 05, 2021 193 (26) E1010-E1011; DOI: Retrieved 9 August 2022: https://doi.org/10.1503/cmaj.210830
Canadian Aerosol Transmission Coalition (CATC), January 4 2021, “There is still time to address aerosol transmission of COVID-19”, correspondence with Canadian and Provincial, Public Health Agency of Canada (PHAC), premiers and ministers. Retrieved 9 August 2022: https://www.aerosoltransmissioncoalition.ca/_files/ugd/cdecb4_0c05d1fea9...
Canadian CSA Group CAN/CSA-Z94.4-18 Selection, use, and care of respirators. Retrieved 9 August 2022: https://www.csagroup.org/store/product/CAN%25100CSA-Z94.4-18/
Canadian CSA Group CSA Z94.4.1, Performance of filtering respirators. Retrieved 9 August 2022: https://www.csagroup.org/store/product/2429470/
Collins AP, Service BS, Gupta S, Mubarak, N, Zeini, IM, Osbahr DC, Romeo AA 2021, N95 respirator and surgical mask effectiveness against respiratory viral illnesses in the healthcare setting: A systematic review and meta-analysis. J Am Coll Emerg Physicians Open .2021 Oct 28;2(5):e12582. doi: 10.1002/emp2.12582. eCollection 2021 Oct. Retrieved 9 August 2022: https://pubmed.ncbi.nlm.nih.gov/34746923/
Dörr, T Sabine, Haller TS, Müller MF, Friedel A, Vuichard D, Kahlert CR, Kohler P 2022, Risk of SARS-CoV-2 Acquisition in Health Care Workers According to Cumulative Patient Exposure and Preferred Mask Type, JAMA Network Open, Infectious Diseases, Open. 2022;5(8). August 15 2022.
Ferris M, Ferris R, Workman C, O’Connor E, Enoch DA, Goldesgeyme E, Quinnell N, et al. 2021, “ Efficacy of FFP3 respirators for prevention of SARS-CoV-2 infection in healthcare workers”, Epidemiology and Global Health | Microbiology and Infectious Disease, eLife 2021;10:e71131. DOI: Retrieved 9 August 2022: https://doi.org/10.7554/eLife.71131
Fries JF, Krishnan E 2004, Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development, Arthritis Res Ther. 2004;6(3):R250-5. doi: 10.1186/ar1170. Epub 2004 Mar 18. Retrieved 9 August 2022. https://pubmed.ncbi.nlm.nih.gov/15142271/
Greenhalgh T, Kane B, Reicher S 2022, “Downgrade your mask before entering”—a dangerous NHS policy at a critical public health juncture”. BMJ 2022;378:o1929. Retrieved 9 August 2022: https://www.bmj.com/content/378/bmj.o1929
Greenhalgh T, Fisman D, Cane DJ, et al. 2022a. “Adapt or die: how the pandemic made the shift from EBM to EBM+ more urgent” BMJ Evidence-Based Medicine Published Online First: 19 July 2022. doi: 10.1136/bmjebm-2022-111952. Retrieved 9 August 2022: https://ebm.bmj.com/content/early/2022/07/19/bmjebm-2022-111952
Hedges K, 2021, Correspondence with the Government of Canada, Responsible Conduct of Research, Tri-council Federal Office Panel on the responsible conduct of research, The Secretariat on Responsible Conduct of Research (SRCR) on behalf of Workplace Health Without Borders WHWB (International). Retrieved 9 August 2022: https://healthcareworkersaustralia.com/wp-content/uploads/2020/08/REBTri...
ISO 7708:1995, Air quality — Particle size fraction definitions for health-related sampling. Retrieved 9 August 2022: https://www.iso.org/standard/14534.html
Justice Philippe Bouvier (Quebec court decision) (2021):
(Paragraph 16 of Décision 735965 (N95) of the TRIBUNAL ADMINISTRATIF DU TRAVAIL
(Division de la santé et de la sécurité du travail) of March 23, 2021).([16] Par ailleurs, le Tribunal
retient que l’un des modes de transmission du virus duSRAS-CoV-2 est la voie aérienne ou par
inhalation. Dans cette perspective, les masquesmédicaux, qu’ils soient qualifiés de chirurgical ou
de procédure, ne représentent pas une protection efficace pour les travailleurs affectés aux
zones chaudes et tièdes. Le Tribunaljuge également que les Employeurs ne se sont pas acquittés
de leurs obligations en matière de santé et sécurité du travail dans la détermination des zones à
risque et de la création des équipes dédiées).
McMaster University (Canada), Office of Academic Integrity 2021, follow up correspondence to Hedges K, 2021. Retrieved 9 August 2022: https://www.aerosoltransmissioncoalition.ca/_files/ugd/cdecb4_f3401b5e36...
National Institute for Health and Care Research (Funding and Awards), “WIPPET: The impact of different grades of respiratory protective equipment on sickness absence due to respiratory infections including SARS-CoV-2 in healthcare workers”. Retrieved 9 August 2022: https://fundingawards.nihr.ac.uk/award/NIHR135521
Njoo H 2021, Deputy Chief Public Health Officer, Interim Vice-President, Infectious Disease Prevention and Control Branch, Public Health Agency of Canada (PHAC), March 2021, response to correspondence (CATC of January 4, 2021). Retrieved 9 August 2022: https://www.aerosoltransmissioncoalition.ca/_files/ugd/cdecb4_08749cfd02...
Oksanen, LM, Sanmark, E, Oksanen, E, SA, Antilla, VJ, Paterno, JJ, Lappalainen, M, Lehtonen, L, Geneid, A 2021, “Sources of healthcare workers’ COVID-19 infections and related safety guidelines”. International Journal of Occupational Medicine and Environmental Health (IJOMEH 2021; 34 (2)). Retrieved 9 August 2022: http://ijomeh.eu/Sources-of-healthcare-workers-COVID-19-infections-and-r...
Tang JW, Bahnfleth WP, Bluyssen PM, et al. (2021), Dismantling myths on the airborne transmission of severe acute respiratory syndrome coronavirus (SARS-CoV-2). J Hosp Infect. 2021;110:89–96. Retrieved 9 August 2022: https://www.journalofhospitalinfection.com/article/S0195-6701(21)00007-4/fulltext
Workplace Health Without Borders (WHWB) International, April 2020, correspondence with the Government of Canada, Minister of Health and Chief Public Health Officer Public Health Agency of Canada. Retrieved 9 August 2022: https://www.ioha.net/wp-content/uploads/2020/04/WHWB-to-Canada-Minister-...
World Health Organization WHO (2021)Coronavirus disease (COVID-19): How is it transmitted? [news release]. Geneva: World Health Organization; modified 2021 Apr. 30. Available: https://www.who.int/news-room/q-a-detail/coronavirus-disease-covid-19-ho...
US National Library of Medicine ClinicalTrials.gov, Medical Masks vs N95 Respirators for COVID-19 - ClinicalTrials.gov Identifier: NCT04296643, Retrieved 9 August 2022: https://clinicaltrials.gov/ct2/show/NCT04296643 see also: https://www.smartpatients.com/trials/NCT04296643
Dear Editorial Office,
I want to express my concern regarding “Curcumin and proton pump inhibitors for functional dyspepsia: a randomised, double blind controlled trial” by Kongkam et al(1). It was published against the journal’s editorial policy and has serious issues with reporting and interpretation of results.
The article shouldn’t have been published in the first place. It lacks prospective registration, which directly contradicts the BMJ Evidence-based medicine editorial policy stating that a prospective registration is mandatory for any clinical trials(2). The Thai Clinical Trials Registry(3) registration TCTR20221208003 is retrospective which is clearly stated in the registry. The registration was submitted on 07 December 2022, just before a preprint was posted on medRxiv on 09 December 2022, while the study was completed on 30 April 2020.
On top of that, there are serious issues with the reporting and interpretation of results.
According to the authors an equivalence design was used with the equivalence margin of 2 points in the SODA score. Nine comparisons of SODA scores in the curcumin plus omeprazole (C+O), curcumin only (C), and omeprazole only (O) groups were reported. For three of those confidence intervals include equivalence margin. The only available interpretation here is that the trial failed to demonstrate equivalence. To demonstrate equivalence the confidence intervals should be between the two equivalence margins rath...
Show MoreWe were surprised that BMJ Evidence Based Medicine chose to publish the flawed article by Høeg and co-authors on methodological limitations of research on long COVID (1). This piece appears to be a ‘Trojan Horse’ article where a scientifically dubious proposition escapes proper scrutiny because it is cloaked in otherwise plausible research commentary.
As the authors state, we need well designed studies to provide a valid measure of the long-term effects of acute COVID-19 infection (Long COVID). Such studies require robust case definitions, adequate duration of follow-up, and suitable comparison groups.
But in a section titled “The most well-designed studies provide reassuring estimates”, the authors include just two studies to support that sweeping statement. This highly selective ‘mini meta-analysis’ subverts the very purpose of evidence-based medicine. The main message of the Høeg paper appears to be that there is a negligible risk of long COVID, based on the selection of papers they have cited. That message does not fit with the actual body of scientific evidence (2). There is now overwhelming research that SARS-CoV-2 infection carries a significant risk of long-term effects over and above the generic effects of post-ICU syndrome and pneumonia (3).
The evidence of long-term effects comes from multiple sources, including epidemiological studies and basic science research looking at the severe and lasting pathological changes that occur in some pati...
Show MoreDr Juan Franco
Editor-In-Chief
BMJ Evidence Based Medicine
BMA House
Tavistock Square
London WC1H 9JP
UNITED KINGDOM
31 October 2023
Dear Editor-In-Chief,
We read with interest the recent article by Høeg and colleagues that describes how methodological limitations in long COVID research distort risk and overestimate prevalence.[1]
The authors propose criteria to improve epidemiological research of long COVID. We write in support of these criteria, and to suggest two additions. We recently compared outcomes three months after PCR-confirmed COVID-19 infection with PCR-confirmed influenza infection, and found no difference between these illnesses.[2] Our comparative observational study had limitations (which we acknowledged) but was noteworthy because it was conducted in an Australian population that was primarily exposed to the Omicron variant after achieving high vaccination rates (>90%).
As a result, our two proposed additions to Høeg et al’s criteria relate to the exposed population which, as they suggest, should have diagnostic evidence of infection.
The first addition is to document the COVID variant to which this population was exposed. Recent data from Sweden shows a progressive (and substantial) decrease in the risk of long COVID from the wild type to the Omicron variant.[3] In addition, the type and frequency of symptoms has changed as the virus evolves.[4] This inclusion would improv...
Show MoreI would like to congratulate Dr. Abbott and her team in generating this piece of important and interesting article, which applied the methods of meta-science to the early systematic review articles and the infodemics related to COVID-19.
Indeed, the COVID-19 pandemic came quick and ferocious, starting early 2020 and lasted till recently and with new possible variants emerging, it still presents the medical community and indeed the scientific circles with challenging question. Thankfully to the selfless work of researchers, patients and frontline medical staffs, we now have some valuable means to deal with this Pandemic.
The research community was presented with a rather challenging task of designing and conducting researches to answer important questions relating to the new infectious diseases at the time of early 2020. The “new” corona virus was ravaging parts of our world without checks. So studies were conducted at pace, which unfortunately resulted in much duplicated and poor methodological studies conducted. But on the other hand, the sheer volume of studies itself may be useful as it generated evidence to inform us of what does and what does not work in terms combating the COVID-19. For example, dexamethasone (RECOVERY trial) was found to be essential for severe COVID-19 patients and the use of Hydroxychloroquine is ineffective for COVID-19.
Show MoreHaving said this, I must state that I am not in support of the generation of poor quality clinical studi...
Dear Editor,
This response is in relation to the titled article above published in June 2019. Firstly, I would like to commend the outstanding work of research done. While reading the article, I understood the correlation between the nursing field, evidence-based research, and ways in which patients benefit from current health practices. Furthermore, the research conducted a wide range of research benefits in other nursing career paths globally. It showed experts views on teaching evidenced based prospectus, evidence-based deliberations, and stakeholders’ engagement which can impact patients involved. I agree with the study conducted and how research is essential for future advancements as well as improvements in care to patients. Unfortunately, there aren’t as much published research work in The Bahamas on evidence-based practices from an expert view. Through further research this thesis can become widespread to obtain more views on this pressing matter.
Dear Editor:
My name is Student Nurse Montel Stuart. from the University of the Bahamas. I have read your article and found the area of research to be very interesting and encourage to you to further your research on the effect of counselling on uninsured patients.
Regards,
Montel Stuart
Dr. Terry Campbell, a lecturer at the university's School of Nursing
This is a response to the article that was published on August 31, 2019, which can be seen above. The article was quite fascinating to read since it focuses on hypertension and how the therapy would effect medication usage in insured individuals; however, the study that was offered was based on a review of the healthcare system in China's population. After reading this study, I have come to the conclusion that it is essential to supply patients with information that is pertinent to their conditions and to take into account the patients' values in the process of making clinical decisions. Doing so can boost patient participation and contribute to the development of patient-centered, individualized care. The researcher provided individual counseling and found that the rate of willingness to pay completely out of pocket for antihypertensive drugs dropped significantly after evidence- based individualised counselling; however, it is uncertain whether that evidence- based, individualised counselling regarding hypertension and its treatment would actually impact medication use in insured patients with mild hypertension.
Show MoreThe findings of this research are restricted in a few important ways. To begin, it may be affected by reporting bias, which is a typical worry in data that is self-reported. This bias may occur when people lie about what they did. Prescription refills, patients'...
Title: “Claims about the main claim”
Author: Suhail A, Doi, Polychronis, Kostoulas, Paul, Glasziou
In response to the published article "Likelihood ratio interpretation of the relative risk"
Rapid response :
September 16, 2022
The problem in evidence-based medicine arises when we port relative risks derived from one study to settings with different baseline risks. For example, a baseline risk of 0.2 and treated risk of 0.4 for an event in a trial gives a RR of 2 (0.4/0.2) and the complementary cRR of 0.75 (0.6/0.8). Thus the ratio of LRs (RR/cRR) is 2/0.75 = 2.67. If applied to a baseline risk of 0.5 the predicted risk under treatment with the RR “interpretation” is 1.0 but with the ratio of LRs “interpretation” is 0.73. Here, the interpretation of the risk ratio as a likelihood ratio, using Bayes’ theorem, clearly gives different results, and solves the problem of impossible risks as clearly depicted in the manuscript and the example.
If, in our effort to highlight the need of this correct interpretation, we have used strong wording that annoyed the commentator we feel the need to express regret. We hope that the commentator could also feel similarly for his scientifically unbecoming choice of wording that culminated with “Doi’s Conjecture”.
Conflict of Interest
None declared
Dear Prof. Franco,
I am writing to request further clarification on the paper “Likelihood ratio interpretation of the relative risk”. The “key messages” section of this paper states that the study adds the following to the literature:
⇒ It is demonstrated that the conventional interpretation of the relative risk is in conflict with Bayes’ theorem.
⇒ The interpretation of the relative risk as a likelihood ratio connecting prior (unconditional) intervention risk to outcome conditional intervention risk is required to avoid conflict with Bayes’ Theorem
I will refer to the first bullet point as “Doi’s Conjecture”. Doi’s Conjecture is also stated in the second section of the main text, where it is claimed that “the usual interpretation (33% increase in the +ve outcome under treatment) contravenes Bayes Theorem”.
No attempt is made within the text to prove Doi’s Conjecture. But perhaps more worryingly, no attempt is made to define the term “interpretation”, a term which is not defined in standard probability theory. The meaning of Doi’s Conjecture is therefore at best ambiguous. Moreover, the manuscript relies substantially on claims about how effect measures are “perceived”, another term which is defined neither in probability theory not in the manuscript.
The relative risk is defined as the risk of the outcome under treatment, divided by the risk of the outcome under the control condition; that is, as a ratio of two probabilities. Thi...
Show MoreAirborne transmission and inhalation, of SARS-CoV-2 is recognized by international public health agencies (Addleman et al. 2021) from both short- and long-range aerosol transmission (Tang et al. 2021).
Show MoreWhen comparing filtering face piece (FFP) respirators, with a surgical (medical) masks, for protection against an inhalable (ISO 7708) airborne virus such as SARS-CoV-2, “EQUIPOISE” a central tenet for conducting a randomised control trial (RCT), does not exist. The futility of using a RCT is analogous to carrying out a study in a construction site for hard hats or seat belts in a passenger vehicle. FFP respirators used in Canada are selected and used in accordance with CAN/CSA-Z94.4-18 (Selection, use, and care of respirators). Specifications are provided in CSA Z94.4.1:21 (Performance of filtering respirators).
At least two international studies using RCT have been initiated since the start of the COVID-19 pandemic.
a) United Kingdom: The impact of different grades of respiratory protective equipment on sickness absence due to respiratory infections including SARS-CoV-2 for healthcare workers (The funding committee did not recommend funding).
b) Canada, multi-centre: where nurses are randomized to either use of a medical mask or to a fit-tested N95 respirator when providing care for patients with febrile respiratory illness.
The findings from a poorly designed RCT may also be used as improper and biased rationale to downgrade respirator (masks...
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