Displaying 1-10 letters out of 35 published
Authors' Response: Postpartum bleeding is reduced with sublingual powdered misoprostol when compared with oxytocin injection, but a new formulation of misoprostol is unlikely to revolutionise postpartum haemorrhage care
We thank Beverly Winikoff and Jill Durocher for their thoughtful commentary.(1) Winikoff and Durocher note that the incidence of PPH in our study's (2) oxytocin group was higher than expected. This deviance can occur, particularly in studies with relatively small samples such as ours. Regardless, the randomization produced study groups with similar characteristics to each other,(2) although this particular sample of women had higher risk of postpartum hemorrhage than the general population, something that might be expected in the study hospital, a referral center.
Our results were also consistent with a previously published study comparing sublingual administration of 400 mg tablet misoprostol with oxytocin, one among various criteria upon which causal associations are judged to exist that our study met.(3) We agree and question the pragmatism of a powdered formulation in the article.(2) The potential to reduce drug costs by 33% remains substantial for a medication that is widely recommended for PPH prevention.(4)
We think there is little basis to question the drug potency in our study. The drug manufacturer, Astra-Zeneca provided us with the study medication directly, and we assume the potency was acceptable to the manufacturer upon distribution. Unlike the oxytocin stored under variable field conditions, potentially exposed to sunlight and high temperatures (potentially without refrigeration prior to their purchase in the cited Ghana study),(5) the packaged study medications were stored in a refrigerator maintained at 2 to 8 degrees Celsius within the clinical pharmacy department at our hospital until their use as stated in the manuscript.(2) What is not well known is whether intramuscular administration of oxytocin is less efficacious than oxytocin administered in intravenous solution; the Cochrane Review of uterotonics for PPH prevention typically analyzed IM and IV administration jointly(6) and whether the strong observed effect is attributable to the powdered formulation.
We agree that further investigation of these issues will clarify the questions our article raises about sublingual administration of lower dose misoprostol for PPH prevention.
1. Winikoff B, Durocher J. Postpartum bleeding is reduced with sublingual powdered misoprostol when compared with oxytocin injection, but a new formulation of misoprostol is unlikely to revolutionise postpartum haemorrhage care. Evid Based Med. 2012 Nov 2. 10.1136/eb-2012-100966.
2. Bellad M, Tara D, Ganachari M, et al. Prevention of postpartum haemorrhage with sublingual misoprostol or oxytocin: a double-blind randomised controlled trial. BJOG 2012;119:975-86.
3. Rothman KJ. What is Causation?" in Epidemiology: An Introduction. Oxford University Press, New York. 2012;pp 33
4. WHO recommendations for the prevention and treatment of postpartum haemorrhage 2012 http://apps.who.int/iris/bitstream/10665/75411/1/9789241548502_eng.pdf
5. Stanton C, Koski A, Cofie P, et al. Uterotonic drug quality: an assessment of the potency of injectable uterotonic drugs purchased by simulated clients in three districts in Ghana. BMJ Open 2012;2:e000431.
6. Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD000494. DOI: 10.1002/14651858.CD000494.pub3.
Conflict of Interest:
It is unethical to give placebo
Dear Editor, The trial has two arms: magsulf and placebo. In my opinion the subjects should give informed consent and instead of blinding the treatment, the subjects should be able to opt for which arm they would like to participate. And lastly, instead of placebo some other treatment like diazepam or phenytoin should have been given as denying treatment is unethical. Moreover, the magsulf has severe side effects e.g. respiratory rate goes down. Because of low therapeutic index, it has to be given cautiously.
Conflict of Interest:
How should we measure psychological consequences of false-positive screening mammograms adequately?
In this week's EBM, Bond and colleagues report a systematic review entitled: 'Psychological consequences of false-positive screening mammograms in the UK'.(1) Their two main outcomes are self-reported questionnaires, and attendance at the next screening round.
Together with two colleagues, I conducted a systematic review in 2004 on the adequacy of measurement of short and long-term consequences of false-positive screening mammography.(2) We concluded that the generic measures (GHQ, HADS and STAI) "should not be used to measure psychological consequences of any kind of cancer screening" and that a condition- specific measure (PCQ) was preferable.(2) We also concluded, "Given the inadequacy of the measurement instruments used, any current conclusions about the long-term consequences of false-positive results of screening mammography must remain tentative."(2) Therefore, we conducted six focus group interviews to test the content validity of the PCQ in a time frame of 1-12 months after a false-positive screening mammography.3 Because we had to make major changes to the PCQ, we developed a new questionnaire: Consequences Of Screening in Breast Cancer (COS-BC).(3) We have validated the COS-BC using the Rasch Item Response Theory model and found that the measure is a reliable multi-dimensional instrument for short- and long- term psychosocial consequences of false-positive screening mammography.(4;5) Therefore, it is unfortunate that Bond and colleagues do not discuss the inadequacy of the psychological measures included in their systematic review, and that a valid and reliable self-reported outcome measure with high content validity does exist. The inadequacy of the generic measures included in Bond et al's review could also be a plausible explanation as to why they found that: "Heterogeneity was such that meta- analysis was not possible".
It is also difficult to understand why Bond and colleagues have limited their review only to include trials conducted in the UK. Why should we expect different psychological reactions to a false-positive screening mammography in different countries? The COS-BC has been translated, adapted, and tested for relevance in a Swedish context, and we found essentially no differences in psychosocial consequences of false- positive screening mammography in Denmark and Sweden.(6) Together with other colleagues, I have conducted the same translation, adaptation, and test of relevance of the COS-BC in Norway, the Netherlands, and Germany, with the same result as in Sweden (these projects are in progress).
The second outcome of Bond and colleagues is attendance to the next screening round after a false-positive mammography. In some countries, researchers have found that these women have a higher attendance to the next screening round than those with a normal screening result. In other countries, researchers have found the opposite, or similar attendance rates. In my qualitative single- and focus group-interviews, some women said that they did not dare to go to next screening after all they had experienced after a false-positive result.(4) Others said they did not dare to stay away.(4) If the psychological impact of a false-positive screening mammography can be ambivalent feelings about attendance to the next screening round, re-attendance is a poor surrogate outcome for the psychological impact of a false-positive screening mammography.
(1) Bond M, Pavey T, Welch K, et al. Psychological consequences of false-positive screening mammograms in the UK. Evid Based Med 2012.
(2) Brodersen J, Thorsen H, Cockburn J. The adequacy of measurement of short and long-term consequences of false-positive screening mammography. J Med Screen 2004;11(1):39-44.
(3) Brodersen J, Thorsen H. Consequences Of Screening in Breast Cancer (COS-BC): development of a questionnaire. Scand J Prim Health Care 2008; 26(4):251-256.
(4) Brodersen J. Measuring psychosocial consequences of false- positive screening results - breast cancer as an example. Department of General Practice, Institute of Public Health, Faculty of Health Sciences, University of Copenhagen: M?nedsskrift for Praktisk L?gegerning, Copenhagen. ISBN: 87-88638-36-7; 2006.
(5) Brodersen J, Thorsen H, Kreiner S. Validation of a condition- specific measure for women having an abnormal screening mammography. Value in Health 2007;10(4):294-304.
(6) Bolejko A, Wann-Hansson C, Zackrisson S, et al. Adaptation to Swedish and further development of the 'Consequences of Screening - Breast Cancer' questionnaire: a multimethod study. Scand J Caring Sci 2012.
Conflict of Interest:
Antiemetics and arrhythmias.
One third of patients who undergo surgery will experience postoperative nausea and vomiting (PONV) which can be very distressing (wound dehiscences and pulmonary complications). Rawlinson and colleagues  have made an excellent systematic review of randomised controlled trials, whose conclusions included the confirmation of intravenous dexamethasone and ondansetron (5-HT3 antagonist) as effective drugs for prophylaxis of PONV when compared to controls. However, a recent FDA safety alert refers that a single 32 mg intravenous dose of ondansetron may affect the electrical activity of the heart (QT interval prolongation), which could predispose patients to develop an abnormal and potentially fatal heart rhythm known as "torsades de pointes". Additionally, ondansetron is a very expensive drug, which in the present financial crisis is very relevant. So, it may be useful to remember the old and low-priced antiemetic metoclopramide as a cheaper and safer alternative to ondansetron. Metoclopramide has not yet been associated with "torsades de pointes". As it blocks dopaminergic (D2) receptors, it is contraindicated in Parkinson's disease, and with chronic use may induce extrapyramidal reactions. But, for a single or short therapeutic course this problem seems not frightening, and furthermore, it has the advantage to increase GI motility, which may be useful to reduce the opioid gastric side effects, and if used before anaesthesia induction, it may also mitigate the danger of gastric content aspiration.
1- Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350:2441-51.
2- Evid Based Med. 2012;17(3):75-80.
3- FDA at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm272041.htm
Conflict of Interest:
Re:Conflicts of interest
Disclosure of conflicts of interest in Japanese randomized controlled trials
Disclosure of potential conflicts of interest (COI) is essential in interpreting randomized controlled trials with less risk of bias. In 2008, the Japanese Ministry of Health, Labour and Welfare issued an ethical guideline for clinical research that endorsed disclosure of potential COI 1. To assess impact of the guideline, we investigated the proportion of Japanese randomized controlled trial articles which disclosed COI published during 2009-2010.
We used ICHUSHI Web 2, the largest database of medical literature in Japan run by the Japan Medical Abstracts Society, to identify articles with the following characteristics; post-marketing, double-blind, randomized controlled trial of prescription drugs; published by official journals of medical associations belonging to the Japanese Association of Medical Science; conducted in Japan and by public research institute (i.e., not by pharmaceutical company).
We identified 18 articles which met the above criteria. Funding source(s) was disclosed in 56% (10/18). Pre-registration was indicated in 17% (3/18). Study endpoint was clearly specified in 50%. Most trials (88%) reported results favoring trial drugs over comparator drugs or placebo.
The 18 articles were published in 14 journals. In submission requirements of these journals during 6-12 months prior to the publication, disclosure of potential COI was requested in 43% (6/14). It was requested in 55% (6/11) of journals written in English and 0% (0/3) in Japanese.
These findings suggest that Health Ministry's guideline has not taken full effects, and that caution should be practiced in interpreting Japanese randomized controlled trials for their financial and scientific integrity.
1. Ministry of Health, Labour and Welfare. ethical guideline for clinical research,2008(http://www.mhlw.go.jp/general/seido/kousei/i-kenkyu/#4)
2. Japan Medical Abstracts SocietyVer.4(http://www.jamas.or.jp/)
As a practicing clinician, who reads Evidence Based Medicine to keep up to date with significant progress in medicine, I cannot help feeling perplexed about the review of Ambrosy and Gheorghiade on the article by Zannad et al (Eplerenone in patients withsystolic heart failure and mild symptoms, NEJM 2011; 364 : 11-21). Throughout their commentary, the reviewers fail to mention that the main conclusion of the study,namely that a potassium sparing diuretic is beneficial in systolic heart failure while increasing the risk of hyperkalaemia, is hardly innovative, since aldosterone-receptor blockade has been part of recommended therapy for a number of years (1,2). This being the case, it is also perplexing why Ambrosy and Gheorghiade fail to mention that the choice of a placebo in the control group, and the excess mortality hence recorded,is particularly difficult to justify under the Helsinki Declaration of Human Rights, according to which a new method should be tested against the best available alternative. Ethical considerations aside, such an unbalanced comparison artificially expands any measure of relative risk reduction in mortality achieved by Eplerenone. It also deprives the prescriber, perphaps not unintentionally in an industry-funded trial, of an answer to the question of whether the significant extra cost of this drug buys any substantial benefit over that achieved by Spironolactone. If the journal really prides itself in providing a fair and comprehensive review of recent medical developments, these omissions should be urgently rectified.
1) Hunt SA, Abraham WT, Chin MH et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the diagnosis and management of heart failure in adults : A report from the American College of cardiology Foundation/American Heart Association Task Force on Practice Guidelines; developed in collaboration with the International Sociaty for Heart and Lung Transplantation. Circulation 2010;121 (12):e258.
2) Dickstein K, Cohen-Solal A, Filippatos G et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008 - The Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of teh European Society of Cardiology; developed in collaboration with the Heart Failure Association ot the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Failure 2008;10:933-989.
Comment on "A qualitative approach to Bayes' theorem" by Medow and Lucey
We welcome the publication of Medow and Lucey in the December issue, describing a qualitative approach to Bayes' theorem . Especially because the authors provide a new impulse to the development of clinician-friendly strategies for teaching clinical decision making skills.
However, the approach proposed by the authors is not new. We reported a didactic model based on a visual representation of Bayesian logic on a logarithmic scale eight years ago in peer-reviewed journals [ 2-4]. Our logical frame is also categorical and similar to the one proposed here, but it is more elaborate: it allows for the extremes of the probability scale, it provides more test power categories, and it covers asymmetry of test results.
The authors report a major limitation of their model: it applies to the intermediate range of probabilities (10-90), leaving the very high post test probabilities often at stake in specialist care and the very low concerned in general practice to the discretion of the clinician. In our model, using a log odds scale, findings with a "weak" power allow to advance or regress half step towards or away from diagnosis, "good" arguments one step, "strong" arguments one and a half and "very strong" two steps. In the author's model only two categories of test values are considered, good and very good. In case of weaker tests, the authors propose to change the probability category scale. Our model offers four categories of power of tests, reportedly also used by Alan Turing 50 years ago, corresponding to the log10 of the likelihood ratio rounded to half the unit .
Finally, their model somehow suggests symmetry of test results, a major misconception of junior clinicians. This symmetry applies to their example of a nuclear stress test, but not e.g., to D-dimers which are useful to exclude a pulmonary embolism, but add almost nothing for confirmation of the diagnosis.
We apply this approach for more than a decade in under and post graduate teaching and in clinical decision making workshops in different countries of Europe, Asia, Africa and South America with enthusiastic acceptance by trainees, but the effect of training with this approach still needs thorough assessment .
 Medow MA, Lucey CR. A qualitative approach to Bayes' theorem. Evid Based Med 2011;16(6):163-167.
 Van Puymbroeck H, Remmen R, Denekens J, et al. Teaching problem solving and decision making in undergraduate medical education: an instructional strategy. Med Teach 2003;25(5):547-550.
 Van Den Ende J, Bisoffi Z, Van Puymbroek H, et al. Bridging the gap between clinical practice and diagnostic clinical epidemiology: pilot experiences with a didactic model based on a logarithmic scale. J Eval Clin Pract 2007;13(3):374-380.
 Van Den Ende J, Moreira J, Basinga P, et al. The trouble with likelihood ratios. Lancet 2005;366(9485):548.
 Good I. AM Turing's statistical work in world war II. (Studies in the history of probability and statistics XXXVII). Biometrika 1979;66(2):393-396.
 Moreira J, Bisoffi Z, Narvaez A, et al. Bayesian clinical reasoning: does intuitive estimation of likelihood ratios on an ordinal scale outperform estimation of sensitivities and specificities? J Eval Clin Pract 2008;14(5):934-940.
Gate control pain modulation theory invalidates the control groups used in these RCTs
The dorsal horns are not merely passive transmission stations but sites at which dynamic activities (inhibition, excitation and modulation) occur. 
Via a series of filters and amplifiers, the nociceptive message is integrated and analysed in the cerebral cortex, with interconnections with various areas. 
The processing of pain takes place in an integrated matrix throughout the neuroaxis and occurs on at least three levels, at peripheral, spinal, and supraspinal sites. 
Knowledge of the modalities of pain control is essential to correctly adapt treatment strategies (drugs, neurostimulation, psycho-behavioural therapy, etc.).
Dysfunction of pain control systems causes neuropathic pain. 
Spinal Cord Stimulation modalities evolved from the gate-control theory postulating a spinal modulation of noxious inflow.             
It has been demonstrated in multiple studies that dorsal horn neuronal activity caused by peripheral noxious stimuli could be inhibited by concomitant stimulation of the dorsal columns. 
Pain relief was more prominent at pain ascending through C fibers than pain ascending through Adelta fibers 
Many theories on the mechanism of action of Spinal Cord Stimulation have been suggested, including activation of gate control mechanisms, conductance blockade of the spinothalamic tracts, activation of supraspinal mechanisms, blockade of supraspinal sympathetic mechanisms, and activation or release of putative neuromodulators. 
At present, Spinal Cord Stimulation is a well established form of treatment for failed back surgery syndrome, complex regional pain syndromes (CRPS), low back pain with radiculopathy and refractory pain due to ischemia.    
Stimulation produced analgesia can provide a level of analgesia and efficacy that is unattainable by other treatment modalities. 
Spinal Cord Stimulation for the treatment of chronic pain is cost- effective when used in the context of a pain treatment continuum. 
Precise subcutaneous field stimulation is targeted to specific areas of neuropathic pain. 
We aim at attenuation or blockade of pain through intervention at the periphery, by activation of inhibitory processes that gate pain at the spinal cord and brain. 
Segmental noxious stimulation produces a stronger analgesic effect than segmental innocuous stimulation. 
That is exactly what intradermal sterile water or subcutaneous saline injections do!
Chloride, used in subcutaneous "sham" injections, independently regulates the pain pathway. 
In these studies there was no valid control group receiving sham injections.
In the past, other researchers, in similar studies, have also had difficulties in blinding and comparing with control groups. 
These RCTs simply compared an established therapeutic intervention to another established therapeutic intervention.
 Labat JJ, Robert R, Delavierre D, et al. Anatomy and physiology of chronic pelvic and perineal pain. Prog Urol 2010;20(12):843-52. Epub 2010 Oct 20.
 Moharic M, Burger H. Effect of transcutaneous electrical nerve stimulation on sensation thresholds in patients with painful diabetic neuropathy: an observational study. Int J Rehabil Res 2010;33(3):211-7.
 Shrivastav M, Musley S. Spinal cord stimulation for complex regional pain syndrome. Conf Proc IEEE Eng Med Biol Soc 2009;2009:2033-6.
 Kunnumpurath S, Srinivasagopalan R, Vadivelu N. Spinal cord stimulation: principles of past, present and future practice: a review. J Clin Monit Comput 2009;23(5):333-9.
 Price TJ, Cervero F, Gold MS, et al. Chloride regulation in the pain pathway. Brain Res Rev 2009;60(1):149-70. Epub 2008 Dec 31.
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Accurate, but is it patient-centred?
Although the accuracy of a mercury sphygmomanometer can be debated, automatic and semi-automatic devices which inflate the cuff often do so to well above the systolic pressure and can cause patients considerable discomfort even when an appropriate cuff size has been used. These devices frequently re-inflate for a variety of reasons, but out of control of the operator who is waiting for a reading.
Anecdotally, I have had several patients request I use what they call the "old fashioned" mercury sphygmomanometer at future consultations.
Conflict of Interest:
Do not discard your mercury sphygmomanometers, yet.
It would not be surprising to find that the "error" rate in blood pressure determinations with the "old fashioned" sphygmomanometer was due, in part, to a faulty technique by the individuals taking the blood pressures. Remarkably, little or no time is spent in teaching medical students the proper technique for blood pressure determination including the appropriate cuff size to use, the various audible phases, etc. One cannot determine if there is an exaggerated second phase of Karotkoff sounds, which is an indicator of the presence of atherosclerotic disease, with an electronic blood pressure apparatus. Neither can one determine the presence of a pulsus paradoxicus with an electronic device. The relegation of the stethoscope to the rubbish bin or museum was predicted decades ago and has not yet taken place. I, for one, will continue to use my stethoscope and take my patients' blood pressures with a manual sphygmomanometer, thank you.
Conflict of Interest:
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