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Recent eLetters

Displaying 1-10 letters out of 305 published

  1. Risk factors for stroke

    Blomstrand et al's study on stroke incidence among women and associations with risk factors deserves comments.

    First, using arbitrary cut-points for risk factors is not appropriate when there is a continuous distribution of the values with no obvious modal values. Moreover, they risk factors were based on a single assessment at baseline and there are multiple dimensions including amount and duration as well as timing. Accordingly, the title is misleading, although the incidence study is prospective, the risk factors study is cross sectional. Breaches in such basic principles contrasts with the use of Cox proportional hazards regression models with complex adjustments and may explain why hazard ratios were low. The box "Strengths and limitations of this study" must be modified.

    Second hazard ratio is a relative measure, it tells us nothing about absolute risk and no gives us no information about how soon the stroke will occur.

    Third, Blomstrand et al should provide the population attributable fraction (PAF) which facilitates the true understanding of the contribution of a risk factor to disease burden: PAF is the proportional reduction in population disease or mortality that would occur if exposure to a risk factor were reduced to an alternative ideal exposure scenario.

    1 Blomstrand A, Blomstrand C, Ariai N, et al. Stroke incidence and association with risk factors in women: a 32-year followup of the Prospective Population Study of Women in Gothenburg. BMJ Open 2014;4:e005173.

    Conflict of Interest:

    None declared

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  2. Fundamental concepts for male circumcision

    Surgery should not be performed unless a medical condition has developed. This is a fundamental concept in surgery [1, 2]. Unless a disease or medical condition is present the risk of surgery cannot be balanced against a risk of disease. If no disease is present no risk can be accepted [1]. This would make male circumcision in infants unacceptable, especially given the risk of death due to blood loss [3,4].

    Hidden motivations for circumcision can result from the trauma associated with the amputation of an area of the genitals [5]. People who have been circumcised, had people close to them circumcised or performed circumcision could encourage others to embrace circumcision, without fully considering the dangers, in order to deal with the trauma. This may occur consciously or subconsciously.

    Research into amputation would require consenting adults who would be fully informed about what will be amputated and the associated dangers. An alternative to this would be people having tissue removed to help solve a medical problem that has developed. The person's health after the procedure can then be monitored and studied. For many occurrences of male circumcision it appears the surgery has been carried out on children and now attempts are being made to explain why it was done. An example of this is the argument about circumcision to prevent sexually transmitted diseases (STDs) and the human immunodeficiency virus (HIV). A person who is circumcised can still contract HIV.

    Circumcision cannot be compared to vaccination as unlike vaccination it deprives the child of healthy tissue.

    Care must be taken to watch out for any bias in research (conscious or subconscious). This is relatively easy to notice in male circumcision research. For example the basic surgical concept (mentioned above) will often not be addressed or mentioned. Alternative arguments will not be addressed or discussed. There are three examples of this for male circumcision. Firstly, alternative factors, such as personal hygiene and exposure to carcinogens will not be discussed or considered. Secondly, lack of education amongst adults and medics means they often retract the foreskin with force causing damage to the gland, foreskin and opening the urethra further increasing the risk of infection especially during bathing. This concept of lack of education is often ignored and forgotten when a bias exists. Thirdly, less extreme methods (such as education and testing before sexual intercourse for HIV prevention and less invasive surgery for foreskin tightness [6]) will be ignored.

    REFERENCES 1. J M Hutson, Circumcision: a surgeon's perspective, J Med Ethics, 2004;30:238.

    2. American Academy of Pediatrics, Committee on Fetus and Newborn. Standards and recommendations for hospital care of newborn infants. [5th ed]. Evanston, IL: American Academy of Pediatrics, 1979

    3. Baker RL. Newborn male circumcision: needless and dangerous. Sexual Medicine Today. 1979;3(11):35-36.

    4. Bollinger, Dan. Lost Boys: An Estimate of U.S. Circumcision- Related Infant Deaths. Thymos: Journal of Boyhood Studies. 2010;4(1):78- 90.

    5. R Goldman, Circumcision: The Hidden Trauma, Boston, Vanguard Publishing, 1997

    6. P. M. Cuckow, G Rix, and P. D.E. Mouriquand Preputial Plasty: A Good Alternative to Circumcision Journal of Pediatric Surgery, Vol 29 (4): (April), 1994: pp 561-563

    Conflict of Interest:

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  3. Erratum

    Figure 3 reports yearly lung cancer incidence per 100 000 inhabitants and not percentage as stated in the main text (page 5, end of results).

    Conflict of Interest:

    None declared

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  4. Correction of affiliation of some of the authors

    Please note: Anna Coleman,Julia Segar, and Imelda Mcdermott are in the Centre for Primary Care, University of Manchester and not in University of Kent.

    Conflict of Interest:

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  5. Erratum for BMJ 2014-006608

    Dear Editor in Chief-BMJ Open,

    Figures 3 and 4 in the above publication are misplaced and marked with the wrong captions What is Figure 3 should be Figure 4 and Figure 4 should be Figure 3.

    The right captions would then be: Figure 3: Summary of the PAMANECH Intervention (in blue)

    Figure 4: PAMANECH Project Data collection plan (table in black and white).

    Kind regards,

    Pauline Bakibinga-on behalf of the authors

    Conflict of Interest:

    None declared

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  6. Supervised Learning Events: is rebranding enough?

    Dear Editor

    I read with great interest the article by Rees et al (1) which represents the first assessment of trainee and trainer perceptions towards 'supervised learning events' (SLEs). The Foundation Programme in the UK has been pioneering in its transition from 'workplace based assessments' (WBAs) to SLEs, with the aim of emphasising the formative intent of the tools, to improve engagement of trainees with their learning potential.

    When reading the original recommendation from the GMC, to adopt this new nomenclature, I asked myself if this simple 'rebranding' would be sufficient to change the prevailing negativity that exists within the medical workplace towards, what many trainees, and some trainers, see as simply 'tick-box' exercises (2).

    It was interesting to read that, in general, trainees perceived SLEs in a more positive light than WBAs. However, what was clear is that some confusion persists - apparently more so in trainers. A recommendation from this study that is repeatedly highlighted in numerous other publications on this subject is the need for training - of both trainees and trainers, in the use of these tools. The lack of understanding that apparently exists in the workplace is no doubt at the root of much of the dissatisfaction and misuse of WBA and SLE tools.

    It was not clear from the study if the issue of training was examined by the authors. It would have been interesting to gain an insight into what (if any) training both trainees and trainers received in the use (and introduction) of these 'new' tools. I wonder if no specific training was provided to either group.

    This work appears to demonstrate that rebranding WBAs as SLEs has gone some way to improve trainee perceptions, but that there remains much potential for improvement. I would propose that until trainees and trainers have a more complete understanding of WBA tools, negative perceptions and misuse of WBA or SLE tools will remain prevalent in the workplace.

    References

    1. Rees CE, Cleland JA, Dennis A, Kelly N, Mattick K, Monrouxe LV. Supervised learning events in the Foundation Programme: a UK-wide narrative interview study. BMJ Open. 2014 16;4(10)

    2. Ali J. Workplace-based assessments: Lost in translation? Clinical Teacher 2014; 11(1): 68-9

    Conflict of Interest:

    None declared

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  7. Nalmefene: Extrapolation, Exaggeration or Evidence Based Medicine?

    How Lundbeck's conclusion "Nalmefene can be seen as a cost-effective treatment for alcohol dependence, with substantial public health benefits" can have been published?(1) Should "Open" in BMJ Open means open to aggressive marketing from the drug industry, open not to hope but to hype, open without proper discussion despite several gross limitations.

    First, the piece apply a mathematical model to three trials that were sponsored by Lundbeck with authors who were on its payrolls. The first two trials of six months' duration (ESENSE 1 and 2) are negative, however the EuropeanMedicines Agency granted a marketing authorization on a subgroup analysis comprising only a quarter of the patients, with half of the data missing in the nalmefene group.(2) The thrid study (SENSE) is also negative in intention to treat analysis.(3) The publication has little to do with science as it associated per protocol analysis, sub group analysis, post hoc analysis, and added to 16 end points of the genuine protocol (which failed to evidence a relevant effect), a 17 and 18th end points (heavy drinking days and reduction of total alcohol consumption) at 13 months.(3) Both editors of the journal failed to respond a proposal to comment these major flaws.(personal experience) Last, Laram?e failed to included results from previous trials.(1) In 1998 Contral Pharma Ltd tried to develop nalmefene for alcohol related problems but in 2003 nalmefene didn't succeed to meet phase III clinical end points statistically significant. Lundbeck must have the data, it paid for it when buying the patent to Contral Pharma. Other previous nalmefene unsuccessful development included interstitial cystitis, schizophrenic patients ...P values must be corrected for multiple testings.

    Second, the three studies are limited to surrogate endpoints: heavy drinking days and total alcohol consumption. Although the European Medicines Agency has accepted a reduction in drinking at 6 months as an end point, the US Food and Drug Administration (FDA) does not accept it yet. FDA is right, this surrogate endpoint has not been validated. Harm reduction strategy used to minimize the personal harm and adverse societal effects of alcohol dependence is not yet evidence based.(5,6). Moreover theses surrogate end points in the nalmefene trials were obtained from patient reports, a non reliable method.(6,7) Approving an alcohol misuse drug on the basis of an increase in non-drinking days is similar to approving a weight reduction intervention on the basis of reducing the number of cakes consumed daily rather than the weight loss achieved or ideally obesity related complications or obesity related death.(4) At best, daily alcohol consumption is 5 to 9 grams lower with nalmefene than with placebo and the impact of nalmefene on the complications of alcohol dependence is not known. The crucial first step in the management of alcohol-dependent patients is to establish a relationship built on trust and to provide psychological and social support. When medication is considered, it is better to choose acamprosate or naltrexone, drugs that are only moderately effective but better-assessed.(8)

    Third, regarding ethics, the lack of effective treatment in the controlled group is a serious concern. Three treatments are validated (acamprosate, naltrexone, disulfiram) to treat alcohol use disorders. Why patients were deemed effective treatments for six months or even a year? To avoid comparisons with an effective comparator? Indeed nalmefene do not perform better than naltrexone but exhibits greater side effects.(9) This is a breach in Helsinki declaration! Nalmefene should have been studied on relevant clinical end points vs one of the usual treaments.

    Last, despite Markov is a random process usually characterized as memoryless, we must not forget Lundbeck's records. On June 19, 2013, the European Commission imposed a fine of 93.8 million euros on Lundbeck and fined several producers of generic pharmaceuticals a total of 52.2 million euros after Lundbeck made agreements with the other companies to delay less expensive generics of Lundbeck's branded citalopram, it best-selling product at the time, from entering the market. In return for the ability to maintain a monopoly on the drug's manufacture, Lundbeck offered payments and other kickbacks. These violated EU antitrust rules that prohibit anticompetitive agreements (Article 101 of the Treaty on the Functioning of the European Union - TFEU). Commission Vice-President Joaqu?n Almunia: "Agreements of this type directly harm patients and national health systems, which are already under tight budgetary constraints".(10) In conclusion, Markov chain Monte Carlo, named after Andrey Markov, a Russian mathematician, now evokes me the exaggeration of a russian oligarch gambling in the small tax haven of the French Riviera, not an hypothesis to be tested on robust data for the patients' benefit.

    1 Laram?e P, Brodtkorb TH, Rahhali N, et al. The cost-effectiveness and public health benefit of nalmefene added to psychosocial support for the reduction of alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels: a Markov model. BMJ Open 2014;4:e005376.

    2 Braillon A.Nalmefene in alcohol misuse: junk evaluation by the European Medicines Agency. BMJ 2014;348:g2017.

    3 van den Brink W, S?rensen P, Torup L, Mann K, Gual A; for the SENSE Study Group. Long-term efficacy, tolerability and safety of nalmefene as- needed in patients with alcohol dependence: A 1-year, randomised controlled study. J Psychopharmacol 2014;28:733-744.

    4 McNulty SJ1, Williams P. Bad medicine: using surrogate markers. BMJ 2014;348:g2012.

    5 Pendery ML, Maltzman IM, West LJ. Controlled drinking by alcoholics? New findings and a reevaluation of a major affirmative study. Science 1982;217:169-75.

    6 Muckle W, Muckle J, Welch V, Tugwell P. Managed alcohol as a harm reduction intervention for alcohol addiction in populations at high risk for substance abuse. Cochrane Database Syst Rev 2012;12,CD006747

    7 Wetterling T, Dibbelt L, Wetterling G et al. Ethyl glucuronide (EtG): better than breathalyser or self-reports to detect covert short- term relapses into drinking. Alcohol Alcohol 2014;49:51-4.

    8 Editorial. Nalmefene. Alcohol dependence: no advance. Prescrie Int 2014;23:150-2.

    9 Drobes DJ, Anton RF, Thomas SE, Voronin K. A clinical laboratory paradigm for evaluating medication effects on alcohol consumption: naltrexone and nalmefene. Neuropsychopharmacology 2003;28:755-64.

    10 http://europa.eu/rapid/press-release_IP-13-563_en.htm

    Conflict of Interest:

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  8. Why exclude adverse events possibly due to medication or to some procedure?

    This protocol is enterprising, interesting and important, but it nowhere refers to adverse events that might be effects of medication, or of failure of a medicine to work.

    Research on 'patient safety' in hospital has developed quite separately from pharmacovigilance and the elucidation of harms possibly caused by medicines and their prevention, but they are related both conceptually and in practice. They need integration, or at least to take notice of one another. This study could take a big step in that direction.

    A further valuable dimension would be added by including all events ['incidents'] that might be attributable to a medication or a diagnostic or therapeutic procedure. I very much hope this will be put into the protocol. It would in any case be very useful also to collect all reports of suspected and reported adverse drug reactions in the study cohort, with their timelines, and to examine them as fully as the other events that will be collected.

    One other aspect is not clear from the protocol: who first noticed and mentioned the 'incident', and how did the conversations about it develop? (For example: patient> nurse> doctor; pharmacist> doctor>; nurse> doctor >patient) That could influence how to set about improving detection, reporting, analysis and communication.

    Conflict of Interest:

    None declared

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  9. Response to the comments published by Pruthu et al.

    Thank you for your comments on the published paper. C1) Recruitment: In Bissau the majority of TB patients are diagnosed at a laboratory at the local health centre, where the patient upon a positive smear is referred to the TB nurse at the same facility who will then start treatment immediately. Patients with smear negative TB are diagnosed at the national TB hospital upon x-ray and physician consultation, and are also from there given treatment on the same day. There is therefore no delay in this part of the process except in rare events of drug stock-outs etc, but in general day of diagnosis and day of treatment initiation will be the same.

    C2) Censoring: As it is described in the paper the patient inclusion stopped at 4th of June 2010. From then patients were followed through the treatment period. The mortality data follow up was censored at 27th of April 2011 when the final data-analysis was done. The details of this censoring could definitely have been described in more detail in the manuscript and we thank the eLetter authors for pointing this out.

    C3) Lost to follow up: In mortality studies the lost to follow up data are always important and can be essential to evaluate the data strength and weaknesses of the data collection. In our case the focus of the paper was on treatment delay, clinical severity at the diagnosis of TB and the risk factor analysis. The mortality data was included to confirm the effect of long-term anti-TB treatment for presumed smear negative TB patients. It is important to understand that the follow up data mentioned concerning effects of treatment assessed by change in clinical severity (e.g. TBscore) is taken from the six months trial clinical examinations - at the end of treatment. When it comes to treatment delay and mortality the results are inconclusive. The mortality analysis was done over the entire mortality follow up time at 24 months but because of the significant challenges with infrastructure and mobility of the population in a country like Guinea Bissau there was a substantial number of "lost to follow up" cases after 2 years. This would probably explain at least part of the missing association between treatment delay and mortality.

    C4) Beta coefficient vs. relative risk The risk factor analysis has been done on categorical independent variables and the treatment delay variable (dependent) is continuous (though logtransformed because of outliers). It is a simple linear regression as it is described in the paper. We did a search on a proper cutoff for delay and found differing information in the literature and therefore decided to use the continuous variable instead as to not "loose" too much data strength. The results are as you correctly point out given as a beta-coefficient and should have been described as such in the paper.

    C5) Observation time on smear-negative TB-cases: This is a helpful argument and we thank the authors of the E-letter. We could have pointed this out in more detail in the discussion session. It is widely accepted and well known that the diagnosis of TB-smear negative TB is a process where there is a natural and inevitable delay in the diagnosis and treatment of TB. The results of the paper only present the difference in time whether it being a delay or a natural cause of TB-smear negative diagnosis could always be discussed.

    Conflict of Interest:

    None declared

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  10. Reply to Rydahl and Clausen

    Rydahl and Clausen are right about problems with the validity of some official statistics published by central institutions or on the home page of the State Serum Institute (SSI). These processed data are, however, not the same as raw data from the Danish Birth Registry (DBR).

    Today, official statistics are typically made by data managers in severely understaffed units in our central administration, often without the possibility of knowledge sharing with clinical expertise. Please don't make us accountable for these flawed statistics and the changes made in them over time.

    Misinterpretation of DBR data is, however, not the same as unreliable DBR data. Making reliable statistics from raw diagnosis, procedural or surgical codes is indeed not simple, even with a hard end point such as stillbirth. For this reason, we have argued that such statistics should be made at least in collaboration with clinicians with research experience in handling registry data. Unfortunately, the central administrative units do not always (in contrast to good old days) have budget for this proposal to be effected.

    Some people, e.g. Rydahl and Clausen apparently do not discriminate between flawed analyses of valid registry data on the one hand, and the baseline validity of the analysed data on the other hand, leading to the rambling conclusion that all analyses based upon DBR data necessarily are flawed.

    For some years, the DBR has been provided with data from the National Health Registry, supplemented by chart data from home deliveries (which are not recorded in the National Health Registry) and by a separate feed from death certificates which are not always included in the National Health Registry. To achieve valid numbers of stillbirths demands all of these three sources of death data to be collected and analysed together. By doing so, provides in our opinion rather precise estimates of the real number of stillbirths. And our guess is that one or two of these sources of data may be missing in some of the official statistics. But that is nothing but a qualified guess.

    Considering all these challenges, it is a little hard to understand why Rydahl and Clausen get so incensed that someone now publishes carefully prepared analyses on stillbirths, since such qualified analyses according to Rydahl and Clausen have been missing.

    Conflict of Interest:

    See original paper.

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