Displaying 11-20 letters out of 509 published
A missing important factor: vitamin D deficiency
I read with interest the published study. For a long time, no study has convincingly shown very strong predictability of symptomatic atherosclerotic cardiovascular disease (ASCVD) with conventional risk factors at population level. In fact, at the population level more patients presenting with ASCVD have either no major risk factors or has single/minor risk factors, particularly in low socioeconomic countries. For last 15 years vitamin D is shown to have important implications in cardiovascular health and diseases like atherosclerosis. [1,2,3,4]
It is timely that researchers focus on vitamin D deficiency as an important, preventable, highly cost-effective and easily treatable disorder with far-reaching implications in the prevention and control of ASCVD.
1. Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr, 2005;94:483-492.
2. Holick MF. Vitamin D deficiency. N Engl J Med, 2007;357:266-281.
3. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2011;96:1911-1930.
4. Danik JS, Manson JE. Vitamin D and cardiovascular disease. Curr Treat Options Cardiovasc Med, 2012;14:414-424.
Conflict of Interest:
Second thought on the study design
I read with interest the design of this timely study. This topic is of immense public health importance due to the burgeoning epidemic of diabetes mellitus in many parts of the world. I have 2 suggestions to offer:
1. When bisphosphonates are used, vitamin D level is commonly checked (as they work with sufficient vitamin D level in the blood), therefore more patients in the control group will receive vitamin D supplementation. This may vitiate the trial.
2. Why use fibrates in patients with serum triglycerides above 220 mg%. Why not prefer statins? The statins work well with hypertriglyceridemia as well (when used in sufficient doses), particularly as the trials with fibrates are not so encouraging and well-accepted in the routine clinical practice.
Conflict of Interest:
The improvement in outcomes should be the goal.
The study is topical. However, it could have been more meaningful, if a control group would have been included. The patients were assessed on day 3 of admission; usually depression takes more time to evolve and develop into the full-blown picture. It may have been better to follow-up the patients for at least 3 months to see the correct magnitude of the problem (most studies revealed rates of depression in such patients around 30% or higher).
Most interesting would have been to document the improvement/lack of improvement in cardiovascular outcomes with the treatment of depression, as earlier studies in this regard showed conflicting results.[1,2,3]
1. Ibrahim MA, Feldman JG, Sultz HA, et al. Management after myocardial infarction: a controlled trial of the effect of group psychotherapy. Int J Psychiatry Med, 1974;5:253-268.
2. Rahe RM, Ward HW, Hayes V. Brief group therapy in myocardial infarction rehabilitation: three-to-four year follow-up of a controlled trial. Psychosom Med, 1979;41:229-242.
3. The ENRICHD Investigators. Effects of treating depression and low perceived social support on clinical events after myocardial infarction. The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA, 2003;289:3106-3116.
Conflict of Interest:
Re:Consultants as victims of bullying and undermining
Thank you for the comments and support for our work.
Firstly you raise the issue of access to the survey and response rate. The RCOG is aware that IT systems within NHS organisations can sometimes prohibit access to our surveys and we are unable to resolve this at the college as it is often related to NHS firewalls. In terms of response rate the RCOG reports that its usual response rate to a national survey is around 30% and thus our response rate of 28% was consistent with that figure. Yet it is unfortunate that a small number of consultants, such as you, could not participate.
We would agree with your observations regarding bullies as victims and indeed other work we have undertaken and hope to publish would corroborate this. We would also agree that interventions targeted at promoting self-awareness and helping to break this cycle are key, although with the caveat that since few such interventions publish any effective evaluation of what worked, for whom and why, it is difficult to be certain.
Conflict of Interest:
authors of original article
Change to Inclusion and Exclusion Criteria
To more align with previous work and clinical practice based on current evidence 1,2,3,4,5, we have adjusted the inclusion criteria as follows:
Update Inclusion criteria 3
"Chronic hypercapnia (daytime arterial partial pressure of carbon dioxide (PaCO2) > 6.5kPa)" "Chronic hypercapnia (daytime arterial partial pressure of carbon dioxide (PaCO2) > 6.0kPa)".
Obese patients (BMI>35 kg/m2) with chronic respiratory failure (PaCO2>6.5 kPa) and evidence of sleep-disordered breathing on a single night self-ventilation oximetry study (4% oxygen desaturation index (ODI) >10 events/h and/or >30% of the total analysis time with an oxygen saturation (SpO2) <90%) will be recruited and randomised. Obese patients (BMI>35 kg/m2) with chronic respiratory failure (PaCO2>6.0 kPa) and evidence of sleep-disordered breathing on a single night self- ventilation oximetry study (4% oxygen desaturation index (ODI) >10 events/h and/or >30% of the total analysis time with an oxygen saturation (SpO2) <90%) will be recruited and randomised.
Exclusion criteria 4
"Prior acute hypercapnic respiratory failure requiring intubation" "Hypercapnic respiratory failure requiring intubation within the last 28 days".
Finally, the protocol shows an end date of May 2017 with a planned publication date of Jan 2018. Ethics has been updated with an end date of April 2018, therefore planned publications will be Dec 2019.
1. Murphy PB, Davidson C, Hind MD, et al . Volume targeted versus pressure support non-invasive ventilation in patients with super obesity and chronic respiratory failure: a randomised controlled trial. Thorax 2012;67:727-34. doi:10.1136/thoraxjnl-2011-201081
2. Masa JF et al . The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest 2001;119:1102-7. doi:10.1378/chest.119.4.1102
3. Mandal S, Suh ES, Boleat E, et al . A cohort study to identify simple clinical tests for chronic respiratory failure in obese patients with sleep-disordered breathing. BMJ Open Respir Res 2014;1:e000022. doi:10.1136/bmjresp-2014-000022
4. Juan F. Masa et al. Efficacy of Different Treatment Alternatives for Obesity Hypoventilation Syndrome. Pickwick Study. American Journal of Respiratory and Critical Care Medicine, Vol. 192, No. 1 (2015), pp. 86-95. doi: 10.1164/rccm.201410-1900OC 4. S Mandal, G Arbane, P Murphy, et al Medium-term cost-effectiveness of an automated non-invasive ventilation outpatient set-up versus a standard fixed level non-invasive ventilation inpatient set-up in obese patients with chronic respiratory failure: a protocol description. BMJ Open 2015 5:e007082; doi:10.1136/bmjopen-2014- 007082
Conflict of Interest:
Consultants as victims of bullying and undermining
This type of work has been long coming and I applaud you for carrying this out. I have a few comments. The low response rate needs to be investigated. If I recall correctly, my email link to the survey did not work and I have therefore not contributed to the survey. I contacted the website manager and did not get a helpful response. I think it would be in your interest to enquire why there was such a low response rate. From the sample of responses published, it appears that bullying for some, persisted after a period of quiet, once the victim had complained. Bullying is sociopathic behaviour and this is a characteristic of sociopaths. They get frightened for a while and then start to re-emerge in their actions once the coast is clear or they get bored. A lot of bullies have themselves been victims and some have been victims of child abuse in different forms. There is little we can do to correct that in them as the damage has already been done. However what we can do is educate people about recognising the signs in themselves and to curb the urge to hurt others as others have hurt them. I think this is one way of breaking the vicious cycle of bullying and sociopathic behaviour that exists in human beings. We are privileged in that we have access to a platform for discussion but also that we belong to a knowledge society wherein we can use education to better ourselves and others.
Conflict of Interest:
Do Statins only postpone death by three or four days?
Kristensen et al. report results from a meta-analysis of statin trials on years of life gained published in BMJ Open in 2015 (1). The authors conclude that death was postponed between -5 and 19 days in primary and between -10 and 27 days in secondary prevention trials. The paper has been widely quoted in newspapers under headlines such as "Statins are NOT a magic bullet for longer life" and "Statins may only postpone death by three or four days", potentially contributing to the growing skepticism against lipid-lowering treatment. But is the conclusion correct? And what are the assumptions underlying the article's conclusion? The authors use the well-known demographic fact that life extension is equal to the area between the survival curves, and refer to the paper by Wright & Weinstein (2). However they apparently overlook that this article states "A model must be constructed to extrapolate the survival curves beyond the end of the study, and the estimate of the gain in life expectancy may be very sensitive to the choice of model". Kristensen et al. implicitly use a model for extrapolation that assumes that the difference in survival between the treatment groups is 0 immediately after the close of the trial. This is not a very likely scenario, and the authors have in the limitations stated that they have only looked at lifetime gain in the studies' running time. Which makes their claims formally correct, but unfortunately also largely irrelevant. The meta-analysis in the paper calculates the overall mortality reduction in the included study populations and produces rate-ratios (RR) of 0.89, respectively 0.91 for included and excluded studies associated with statin use. In guidelines for treatment of diabetes, statins are recommended for almost all diabetes patients, so diabetes patients constitute a substantial fraction of statin treated patients. Therefore, to elucidate the effect of statin use in a more realistic way, we have calculated life expectancy for people with diabetes with or without statin treatment. We included persons registered in the Danish National Diabetes Register (3) defined as those with a diabetes diagnosis, treated with glucose lowering drugs or receiving foot care as part of their diabetes management. We modeled the mortality of persons with diabetes with age-period-cohort models for ages 0-99 for the period between 1 January 1995-31 December 2012, and used the predicted mortality rates for 2012 to calculate the remaining life expectancy with and without statin therapy at different ages, and various levels of assumed risk reduction by statin therapy.
The figure attached (http://bendixcarstensen.com/DMreg/statinYLL.pdf) shows that the gained life expectancy with statins is e.g. 1.1 years for a man aged 50 assuming a relative mortality rate of 90% which is close to the risk reduction calculated in the meta-analysis. At age 30 the years of life gained is 1.3, while at age 70 closer to 0.7 years, varying according to the risk reduction associated with statin treatment.
The simple message from the meta-analysis by Kristensen et al., that statin treatment contributes only a few days life extension, is in our view thus highly misleading since the most basic demographic assumptions have not been included in the data interpretation. For most diabetes patients the likely life extension is between 6 and 12 months, and patients currently prescribed statins for other reasons are likely to see similar average gain in life time.
A full overview of data and analysis is available at http://bendixcarstensen.com/DMreg/demoYLL.pdf
References 1 Kristensen ML, Christensen PM, Hallas J. The effect of statins on average survival in randomised trials, and analysis of end point postponement. BMJ Open 2015;5:e007118
2 Wright JC, Weinstein MC. Gains in life expectancy from medical interventions-standardizing data on outcomes. N Engl J Med 1998;339:380
3 Carstensen B, Kristensen JK, Ottosen P, Borch-Johnsen K; Steering Group of the National Diabetes Register. The Danish National Diabetes Register: trends in incidence, prevalence and mortality. Diabetologia. 2008 Dec;51(12):2187-96
Conflict of Interest:
Cholesterol on Sunset Boulevard: the decline of a myth
Cholesterol on Sunset Boulevard: the decline of a myth 1,2Massimo Cocchi, 1Lucio Tonello, 1Fabio Gabrielli 1"Paolo Sotgiu" Institute for Research in Quantitative & Quantum Psychiatry & Cardiology, L.U.de.S. HEI, Via dei Faggi 4, Quartiere La Sguancia, 6912 Lugano-Pazzallo, Switzerland. 2Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra, 50, 40064 Ozzano Emilia (Bologna).
Dear Editor The aim of this letter is to highlight some new aspects of the "cholesterol" risk pointing out some experimental evidences, which seem to reduce its importance in Cardiovascular Disease. According to Popper "Thus science starts from problems, and not from observations" (K.R. Popper, Conjectures and Refutations: The Growth of Scientific Knowledge, London: Routledge, 1963, 10, VI: 222). In the last decades, cholesterol has been the subject of many investigations because of its alleged role in ischemic heart disease, but we need to remember that it is primarily involved in the maturation of the brain, in regulating the mobility of cell membranes, in the production of basic substances for the organism such as vitamin D and sex hormones. Guidelines have been created that have increasingly reduced the safety levels of circulating cholesterol to prevent cardiovascular diseases. Now, most of the scientific community considers as safe a total cholesterol of 180 mg/dl. The research conducted in Framingham, started in 1948 and lasted for some generations of people. The Framingham Heart Study has bequeathed to us those cardiovascular risk factors that are universally recognized: age, smoking, total cholesterol, HDL cholesterol, high blood pressure. Among these, age is certainly an unchangeable risk that increases from 20 years up to 80 years (1). Hypertension, among the five risk factors, is certainly a true pathology and considered, in most of the cases, as "essential". Smoking, cholesterol and HDL cholesterol have reached a universal media notoriety. People consider the cholesterol, despite being indispensable to life, a real bugbear for life itself. Over the past 10 years, research conducted by our working group made it possible to classify subjects with ischemic heart disease by combining: 1. Platelet fatty acid composition as a concise and complete source of information 2. A mathematical analysis through a non-linear self-organizing system The complexity of membrane dynamics required the use of advanced non- linear analytical tools, namely an Artificial Neural Network: the SOM [Self Organizing Map-Kohonen Network] (2, 3, 4). The results obtained with the Self Organizing Map (SOM) show the evidence of three fatty acids, Arachidonic Acid (AA), Linoleic Acid (LA) and Oleic Acid (OA) in a peculiar position with respect to the biochemical characterization of the ischemic subjects (5, 6, 7, 8). We tried to identify an index that could express the saturation level of the platelet membrane according to the SOM logic. For this purpose, we used the Stearic/Oleic ratio (SI-Saturation Index). The SI trend was coherent with the SOM built to characterize the ischemic subjects, and, with respect to the data of normal subjects, was perfectly overlapping the Framingham risk for age. This means that the risk for age did not reach the pathologic area of the SOM. Because the age is a physiological risk, we can compare our result to the huge number of cases studied by Framingham Heart Study. The Framingham score, constructed on a statistical basis, offers as a result a pure number that quantifies a risk but it does not correspond to the diagnosis of ischemia. On the contrary, we have investigated subjects undergoing coronary angiography; our SOM provided the certainty of the diagnosis. Our database of 83 cases included 66 subjects with hypercholesterolemia, 61 with HDL < 50, 75 with hypertension, 9 smokers, 28 no smokers and 46 past smokers. Ultimately, those who possessed one or all of the risk factors or who did not have none of them did not influence the position within the SOM for the diagnosis of ischemia according to the platelet fatty acids above mentioned. No one disputes that the Framingham risk factors are such, however, the ischemic heart disease will also recognize another risk factor: the composition of the platelet fatty acids. The biochemical role exerted by each of the fatty acids identified by the SOM, on platelets, it is well known, e.g. oleic acid and linoleic acid on the ion channels [sodium, potassium, calcium etc.] (9, 10). We can conclude that cholesterol and the other Framingham risk factors are not such a resounding risk factors but that, perhaps, it is also dangerous reduce, e.g., the cholesterol beyond certain limits. Its forced and excessive removal could compromise the structure of cell membranes in the regulatory expression of their functions. We are in agreement with Ravnskov et al. (11) in stating that it is need to re-evaluate the guidelines of the risk factors of ischemic heart disease and of the cholesterol-lowering therapy.
References 1. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 years of follow-up from the Framingham study. JAMA 1987; 24; 257(16):2176-80. 2. Kohonen T. Self-Organized formation of topologically correct feature maps. Biol. Cybern 1982; 43: 59-69. 3. Kohonen T. Self-Organizing Maps, 3rd ed.; Springer: Berlin, 2001. 4. Kohonen T, Kaski S, Somervuo P, Lagus K, Oja M, Paatero V. Self- organizing map. Neurocomputing 1998; 21: 113-122. 5. Cocchi M, Tonello L, Bosi S, Cremonesi A, Castriota F, Puri B, Tsaluchidu S. Platelet oleic acid as Ischemic Cardiovascular disease marker. BMJ 2004; 329:1447. 6. Cocchi M, Tonello L. "Bio molecular considerations in Major Depression and Ischemic Cardiovascular Disease". Central Nervous System Agents in Medicinal Chemistry 2010; 9: 2-11. 7. Cocchi M, Tonello L, Gabrielli F. "Platelet, Fatty Acids, Membrane Viscosity, Depression and Ischemic Heart Disease: Biological-Molecular- Path with Medical-Anthropology Insights" in "Coronary Angiography-Advances in Noninvasive Imaging Approach for Evaluation of Coronary Artery Disease", InTech, September 2011, ISBN 978-953-307-675-1. 8. Cocchi M, Gabrielli F, Tonello L. Platelet's Fatty Acids Secrets in Coronary Artery Disease (CAD), Lett to Ed BMJ. 2013; Oct 28. 9. Yasser AM, Christensen SB. Oleic and linoleic acids are active principles in Nigella sativa and stabilize an E2P conformation of the Na,K -ATPase. Fatty acids differentially regulate cardiac glycoside interaction with the pump. Biochimica et Biophysica Acta 2011; 1808: 2413-2420 10. Ruf T, Arnold W. Effects of polyunsaturated fatty acids on hibernation and torpor: a review and hypothesis. Am J Physiol Regul Integr Comp Physiol 2008; 294: 1044-52. 11. Ravnskov U, Diamond DM, Hama R et al. Lack of an association or an inverse association between low-density lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 2016; 6: e010401.
Conflict of Interest:
No competing interests
The need to attend to outcome reporting bias
I am the author of the NEJM article cited as reference #17, in which we showed stark differences in antidepressant efficacy according to two data sources-published journal articles and FDA reviews. The authors of this BMJ Open protocol list a number of sources they plan to search. What is not clear is how what they plan to do when faced with results of the same clinical trial from two (or more) sources. In our NEJM article, we found 11 trials which were positive according to journal articles but negative according to the FDA. When one considers that those journal articles were authored by those with a conflict of interest, and that the discrepancies were due to post hoc outcome switching, it seems clear that FDA reviews should be prioritized as the more credible data source.
Conflict of Interest:
Re:Statins do prevent heart attacks and strokes in the elderly
One of Daniel Kellers arguments is right; association is not the same as causation. However, an inverse association is one of the strongest arguments against causation. Furthermore, we have not written that statin treatment is useless, but that its effect is minuscule. Keller has used a meta-analysis of statin trials in old people as an argument, but to claim that the risk of myocardial infarction was lowered by 39.4% and stroke by 23% is seriously misleading, because the absolute risk reduction was only 1.2% and 0.7%, respectively, and in accordance with our findings neither total or cardiovascular mortality was lowered.
Conflict of Interest: