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Recent rapid responses

Rapid responses are electronic letters to the editor. They enable our users to debate issues raised in articles published on bmj.com. Although a selection of rapid responses will be included as edited readers' letters in the weekly print issue of the BMJ, their first appearance online means that they are published articles. If you need the url (web address) of an individual response, perhaps for citation purposes, simply click on the response headline and copy the url from the browser window.

All rapid responses

Displaying 1-10 out of 95218 published

Re: Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. Rajiv Chowdhury, Setor Kunutsor, Anna Vitezova, Clare Oliver-Williams, Susmita Chowdhury, et al. 348:doi:10.1136/bmj.g1903

We cordially thank Dr Grant for his comments. We agree that while prior ecological studies are supportive of our current findings based on meta-analysis of observational studies; further work, especially those involving well-powered randomized intervention studies, is required. We would, however, like to add that the respective pooled risk ratios (RRs) that we reported by combining the primary and secondary prevention cohorts, are based on indirect comparison (ie, only a subset of studies provided mortality risk data on people with pre-existing disease).

We also thank Dr Bolland and colleagues for their observations and thoughts. The overall estimate from the vitamin D3 randomized controlled trials were indeed presented as a combination of both active and inactive vitamin D3 supplements, given a lack of power in each component in isolation. Additionally, we included the Campbell et al trial (1) as a study evaluating the effects of vitamin D3 alone without any concurrent administration of other pharmacological interventions (and was similarly kept as a vitamin D alone study in the earlier Cochrane report). Nonetheless, when this study and the other 3 calcitriol trials (2-4) were removed from the analyses, there was no significant effect of “any vitamin D supplementation” on mortality (which remains consistent with our original results). The pooled effect estimate for the 10 vitamin D3 trials became slightly attenuated (0.91 (95% CI 0.82-1.00) in our calculation), however, this apparent inverse effect differed significantly with the corresponding pooled estimate of vitamin D2 (P from meta-regression analysis=0.03, for a comparison between vitamin D3 and vitamin D2 trials). That said, we agree with Dr Bolland and colleagues that the selection criteria (eg, randomised vs. non-randomised, with vs. without calcium supplementation, etc.) and decisions on subgroup analyses vary across reviews on this topic, and may explain the differences of findings across these reports. However, as was discussed in our paper (and the accompanying editorial), all these reviews (including ours) are based on largely overlapping trials that principally included high risk, elderly populations (with an average age >75 years in all trials combined). Therefore, before any policy formulation, further large-scale and sufficiently prolonged trials involving sufficient samples derived from the general population will be required.

(1) Campbell AJ, Robertson MC, La Grow SJ, Kerse NM, Sanderson GF, Jacobs RJ, et al. Randomised controlled trial of prevention of falls in people aged > or =75 with severe visual impairment: the VIP trial. BMJ 2005;331:817.
(2) Grady D, Halloran B, Cummings S, Leveille S, Wells L, Black D, et al. 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: a randomized controlled trial. J Clin Endocrinol Metab 1991;73:1111-7.
(3) Gallagher JC. The effects of calcitriol on falls and fractures and physical performance tests. J Steroid Biochem Mol Biol 2004;89-90:497-501.
(4) Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 2007;25:669-74.

Rajiv Chowdhury[1]
cardiovascular epidemiologist
Oscar H Franco[2]
On behalf of Setor Kunutsor, Anna Vitezova, Clare Oliver-Williams, Susmita Chowdhury, Jessica C Kiefte-de-Jong, Hassan Khan, Cristina P Baena, Dorairaj Prabhakaran, Moshe B Hoshen, Becca S Feldman, An Pan, Laura Johnson, Francesca Crowe, and Frank B Hu
[1] Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK
[2] Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands

Competing interests: None declared

Oscar Franco, Professor

Rajiv Chowdhury

ErasmusMC, Department of Epidemiology Erasmus MC, University Medical Center Rotterdam Office Na 29-16 PO Box 2040, 3000 CA Rotterdam, The Netherlands

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Re: Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. Evropi Theodoratou, Ioanna Tzoulaki, Lina Zgaga, John P A Ioannidis. 348:doi:10.1136/bmj.g2035

Boucher [1] presents a number of arguments in favour of the opinion that vitamin D supplementation has substantial benefits, but this is not clearly shown in our review [2]. Given the study selection protocol, the risk of overlap of original studies is minimal for any given outcome, as we only selected one review per outcome for our analysis. The importance of the supplementation dose and of pre-supplementation 25-hydroxyvitamin D (25-OHD) levels is valid. In our discussion we highlighted that inappropriately low dose or short duration of vitamin D supplementation in the randomised controlled trials might be inadequate to raise the body’s vitamin D concentrations enough to show a difference between the arms of a trial. However, there is no certainty that high doses and long duration would necessarily be effective and it is widely used practice to use such arguments to avoid accepting that an intervention is simply ineffective, as documented in vitamin E, hormone treatment, or invasive cardiac interventions in stable patients cases [3,4]. We also mentioned that large differences in baseline plasma concentrations of 25-OHD in different populations could interfere with the effect of the supplementation, but similarly, this could have an impact in either direction.

Calcium supplementation was discussed in our review mainly because vitamin D and calcium were co-administered in the majority of vitamin D trials. On the other hand, we believe that interactions between multiple vitamins are very difficult to be reliably investigated, unless one specifically designs trials that study the supplementation of multiple vitamins. Finally, to account for the specific problems of observational nutrient intake studies (as the ones described by Ioannidis [5]) we decided to exclude observational meta-analyses of dietary or supplementary vitamin D intake. Overall, we conclude that trends for survival benefits in subgroups of trials should be seen as exploratory and need further validation.

1. Letter by Boucher [based on her rapid response http://www.bmj.com/content/348/bmj.g2035/rr/693593 ]
2. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.
3. Siontis GC, Tatsioni A, Katritsis DG, Ioannidis JP. Persistent reservations against contradicted percutaneous coronary intervention indications: citation content analysis. Am Heart J. 2009;157(4):695-701.
4. Tatsioni A, Bonitsis NG, Ioannidis JP. Persistence of contradicted claims in the literature. JAMA. 2007;298(21):2517-26.
5. Ioannidis JP. Implausible results in human nutrition research. BMJ. 2013;347:f6698.

Competing interests: None declared

Evropi Theodoratou, Research Fellow

John PA Ioannidis

Centre for Population Health Sciences, Teviot Place Edinburgh EH8 9AG

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Re: Oseltamivir: the real world data. Nick Freemantle, L J Shallcross, D Kyte, T Rader, M J Calvert. 348:doi:10.1136/bmj.g2371

The list of pros and cons concerning non-interventional (=observational) studies vs. controlled clinical trials misses one important point.

At least since the mid-1990s all pharma-sponsored interventional trials must have been conducted adhering to ICH E6 (also called the GCP guidelines). These regulatory guidelines require, among other things, monitoring, source data verification, and drug accounting. All these measures are to verify to the extent possible that the data are based on true facts, i.e. the patients existed, had the indication in question, and were actually treated with study medication and assessed and reported according to the protocol. In the USA for a long time, and in Europe at least since about 2004, sponsors have had to envisage regulatory inspections verifying that the study has been conducted in this way.

None of these rules are compulsory for NIS. These studies are explicitly excluded from any GCP regulation, although some sponsors sometimes might deliberately announce or even implement some of the GCP rules. Nevertheless, NIS have hardly ever been inspected by authorities in the past. So: Little to no control, no risk of inspection.

Then readers should understand how physicians (I hesitate writing investigators in case of NIS) normally get paid for participating in NIS: by completed CRF. Nothing else.

The consequence of all these aspects is that there is the risk that some data from NIS might have been completely invented. You may speculate that this rate would be as low as 1%, but can anybody really exclude a rate of 50% for every trial? And could 1% from the set of important data not also be relevant?

So, beside the design, there is one other important aspect why NIS should usually be considered as hypothesis-generating (at best), and people should be very careful with writing “prove” when relying on NIS.

Competing interests: None declared

Hans-Joachim Kremer, Medical Writer

Medical Writing Service, Alemannenstraße 101, 79117 Freiburg, Germany

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Re: Doctor is struck off for failing to prevent hallucinating patient from discharging herself. Clare Dyer. 348:doi:10.1136/bmj.g2606

Re the comment by Dr Blewett, presumably the Approved Mental Health Professional was not immediatly available. According to the article, the patient was referred to the mental health team but refused to wait, and discharged herself.
I find it hard to understand how the emergency specialist could have prevented the patient from leaving if she was not yet detained under the Mental Health Act, especially since the article states that "he had no power to do so".

Competing interests: None declared

Paul E BAILEY, Psychiatrist

Centre Hospitalier, Rouffach, France

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Re: The “Saatchi bill” will allow responsible innovation in treatment. Michael D Rawlins. 348:doi:10.1136/bmj.g2771

In his discussion of the Medical Innovation Bill, Michael Rawlins [1] refers to Judge Butler-Sloss’s forceful criticism of the Bolam principle while she was president of the High Court’s Family Division because it leaves doctors open to legal action for negligence if they depart from what is regarded as “the standard of care”. We have direct experience of the adverse consequence of an important omission from Judge Butler-Sloss’s judgement.

We co-chaired the MRC Prion-1 trial steering committee at the time (17 Dec 2002) that the father of a young man with variant Creutzfeld-Jakob Disease (vCJD) appealed to the High Court for permission to seek treatment for his son using pentosan polysulphate injected into the brain. The father believed that the drug might slow his son’s decline because it appeared to have done this in an animal model of the disease studied in Japan. Judge Butler-Sloss granted permission for the father to seek treatment for his son [2], and similar judgements were made subsequently in respect of other sufferers of vCJD.

In making her ruling Judge Butler-Sloss suggested that treatment with penicillin might never have been attempted if the Bolam principle had been applied. What she failed to do was to require organised, prospective documentation and publication of the characteristics and progress of patients receiving pentosan polysulphate for vCJD, as had happened with the first series of cases treated with the penicillin [3]. The consequence of this important omission from her judgement has been that patients, their parents, and the people involved in the PRION 1 trial and other related research remained and remain unnecessarily ignorant about the possible benefits and harms of this proposed treatment.

This unsatisfactory state of affairs cannot be allowed to be a feature of any treatments that may become available under the provisions of the Medical Innovation Bill. Rawlins [1] notes that, ‘just because a particular intervention seems to have been effective in an individual patient it cannot be assumed that the results are generalisable’. We regret that he did not go on to call for proper, publicly available documentation to inform decisions made by other patients and those caring for them. Failure to make such evidence accessible was one of the factors that led to the TGN 1412 disaster [4].

Lester Firkins
Iain Chalmers
Co-chairs, MRC Prion 1 trial steering committee

[1] Rawlins MD. “Saatchi Bill” will encourage innovation in treatment. BMJ 2014;348:13.

[2] CJD case: the judgement. BBC News. http://news.bbc.co.uk/1/hi/health/2585049.stm

[3] Abraham EP, Chain E, Fletcher CM, Gardner AD, Heatley NG, Jennings AM, Florey HW. Further observations on penicillin. Lancet 1941;2:177-189.

[4] Chalmers I. TGN1412 and The Lancet’s solicitation of reports of phase 1 trials. Lancet 2006;368:2206-2207.

Competing interests: None declared

Iain Chalmers, Coordinator

Lester Firkins

James Lind Initiative, Summertown Pavilion, Middle Way, Oxford OX2 7LG

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Re: The role of NHS gatekeeping in delayed diagnosis. Nigel Hawkes. 348:doi:10.1136/bmj.g2633

It is hard to get actual facts about whether the gate keeper role of GP in the UK is responsible for some of the poor cancer statistics (though also we do very well in others). The BMJ has already published an article highlighting that cancer UK figures for GP delays are wrong.

To move on though we as GP face huge obstacles in investigating patients. A request for an urgent CT by me will result in weeks to get the scan and weeks more for a report. If I advise them just to go to A and E they will get their scan and report and on the same day. It will though cost the CCG and the NHS money they don't have and will hugely increase the radiation dose to the population.

Employing GPs in emergency departments is already happening. But these are the same people who are needed to care for the population in primary care with multiple chronic illnesses, terminal care and the whole spectrum of what GP probably do well. If they are in A and E there will be even fewer appointments available in General Practice. The anecdotes of poor outcome and GP bashing don't change the fact that most people with headaches don't have tumours, many more would if all were repeatedly scanned. Symptoms evolve over time. Primary care needs to do better, especially in terms of follow up and ease of appointments.

Advising people to go straight to A and E for everything will collapse the NHS. Perhaps Nigel Hawkes has not heard of on- line appointments but certainly our reception staff do a fantastic job sorting out about 1 million appointments every day. Vastly more than are seen and diagnosed in the private sector and accident departments.

Competing interests: None declared

Nicholas J Sharvill, GP

Balmoral Surgery, Deal, Kent

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Re: Medical education’s authenticity problem. Brian W Powers, Amol S Navathe, Sachin H Jain. 348:doi:10.1136/bmj.g2651

I agree with Powers et al (1) in their assertion that authenticity is an important goal for doctors to aspire to and currently absent from the goal-orientated learning which typifies much medical education. Physicians who know how to do things, but not why to do them are at risk of becoming “implementers” rather than innovators; lacking the skills in critical thinking, self-awareness and creativity to provide confident leadership. However, while undergraduate selection and assessment processes are important opportunities for enhancing future physicians’ self-awareness, it may be that many students personal values are not yet fully formed at this stage of life.

Powers et al (1) suggest reflective practice can be a route to authenticity. For some this may mean reflective writing, but many physicians lack the time, opportunity or indeed motivation to write in the depth that is likely to enhance authenticity. “Enforced” reflection, such as in the assessment portfolio of trainee GPs in the UK, is unlikely to result in genuine opportunities for authenticity as the writing falls under a summative (as well as formative) gaze, thus not truly belonging to the writer. Correspondingly, those involved in undergraduate learning should also resist the temptation to formalise authenticity in their curricula, for this may result in the unhappy paradox of reducing students’ agency through superficial learning led by assessment.

So how might doctors’ search for authenticity be assisted? Interviews with GP trainers about their experiences of education found that clinical teaching provides an opportunity for physicians to examine their own values and thus a means for re-examining their professional identities - an alternative route to authenticity (2). Finally, doctors cannot truly become authentic individuals unless they are treated as adults, and allowed to learn and develop accordingly.

1. Powers BW, Navathe AS, Jain SH (2014) ‘Medical education’s authenticity problem’. BMJ 348:g2651
2. Lake J (2013 'Teaching Doctors: The Relationship Between Physicians’ Clinical and Educational Practice.' EdD Thesis University of Exeter.

Competing interests: None declared

Jonathan Lake, GP

University of Winchester, Department of Education, Health and Social Care, University of Winchester, Hants, UK.

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Re: Care.data doesn’t care enough about consent. Margaret McCartney. 348:doi:10.1136/bmj.g2831

This article uplifted me: A GP speaking with authority and clarity as to the naked reality of the care.data project and how it represents an evasion of clinicians' moral duties and a threat to the therapeutic relationship. Confidentiality & consent form the keystones of ethical clinical practice and are both essential for trust. Furthermore care.data processing does not adhere to the NHS Constitution regarding privacy and confidentiality, or possibly to the 1998 Data Protection Act.

As a GP and clinical ethicist I have difficulty believing that new legislation and NHS bodies are set to ride a cart & horses through the profession's centuries-old ethical principles as well as central tenets of English common law and article 8 of the Human Right Convention - the right to privacy and family life. Indeed this article was invoked by the European Court of Human Rights in relation to medical data in Z v Finland (1997) 25 EHRR 371 where the importance of patients' sense of privacy and their trust in the medical profession was viewed as vital. Aside the damage to relationships, it is worth remembering that if trust is lost, patients will not disclose valuable medical information and may put themselves and others at risk. At a meeting regarding care.data I was a lone voice arguing that we cannot accept 'opt out' as valid consent. Many patients will not have had the opportunity to understand the risks and benefits of data upload and to what purposes it is to be used - if they even know about it at all. Even if it is a minority - say 20% - we are still talking millions. Why the unseemly haste and the compulsory obligation for GPs to upload? For example, The Nuffield Council on Bioethics (of which I am a member) is exploring the ethical issues regarding biological and health data, but will not report till the late autumn. Why is patient consent so much resisted (i.e. patients given a real choice to opt in or out) when 'choice' is trumpeted as key to the NHS reforms? We are told that there this would lead to far less data being made available and that it could be biased. So paternalistic utilitarian reasons trump important ethical and legal principles. We were also told that there had been no serious breaches with the hospital data for 25 years - we recently found out that there have been.[1] The risks that patient identifiable information may fall into the wrong hands, despite safeguards, cannot simply be airbrushed away.

Data comes from the Latin dare 'to give'. Some patients are willing to offer their personal medical information for the common good, but they do so in the belief that they are in a gift relationship underpinned by solidarity and community. The selling of this gift to pharmaceutical and for-profit healthcare corporations (which can be defined under the vague heading of 'promotion of health), we are witnessing the exploitation of altruistic donation in a commodified market-system.

It is time that GPs become subversive and refuse to comply until their patients are given the real opportunity to consent. We owe it to our patients and to the profession's integrity.

1. http://www.pulsetoday.co.uk/your-practice/practice-topics/it/identifiabl...

Competing interests: None declared

Paquita C de Zulueta, GP

Imperial College, London W11 2NS

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Re: Introducing a new group B meningococcus vaccine. David Isaacs, Jodie McVernon. 348:doi:10.1136/bmj.g2415

The process around the decision to recommend routine vaccination with the 4CMenB vaccine has been a controversial one. Isaacs and McVernon summarise some of the issues and raise some controversial points in turn. As they point out, the introduction of a new vaccine is highly complex, particularly a new category of vaccine with no biological precedent. Of course while true, this concept has fortunately not stopped us introducing novel vaccines, such as the highly successful HPV vaccines which were, at that time, a completely new class of vaccine whose introduction was indeed “with no biological precedent” (1). In fact, millions of doses of other OMV-based meningococcal vaccines have already been given in other countries (2,3).

It is also certainly true that the considerations around this vaccine have been the subject of unprecedented attention from healthcare workers, charities and the general public. Such involvement and enthusiasm in contemplating a new vaccine is welcome and should be harnessed further as we move toward potential vaccine introduction. Meningitis is uniformly the top fear that parents have for their children, preventing it is their highest priority. If there is a "cost" in terms of more reactogenicity and fevers, we need to share and discuss this with parents so that they can anticipate and manage it as well as recognise the risks and benefits involved. The response from the public thus far suggests that this is a "cost" that they will accept (4). At its introduction there was no alternative to the highly reactogenic whole cell pertussis vaccine - would the same argument have been sustained i.e. this is a vaccine that is too reactogenic to introduce? Fortunately history has shown us the wisdom of this decision. History has also shown us that flexibility in decision making is required as new vaccines are developed and introduced.

(1) Schiller JT, Lowy DR. Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol. 2012 Oct;10(10):681-92.
(2) Holst J, Oster P, Arnold R, Tatley MV, Næss LM, Aaberge IS, Galloway Y, McNicholas A, O'Hallahan J, Rosenqvist E, Black S. Vaccines against meningococcal serogroup B disease containing outer membrane vesicles (OMV): lessons from past programs and implications for the future. Hum Vaccin Immunother. 2013 Jun;9(6):1241-53.
(3) McNicholas A, Galloway Y, Stehr-Green P, Reid S, Radke S, Sexton K, Kieft C, Macdonald C, Neutze J, Drake R, Isaac D, O'Donnell M, Tatley M, Oster P, O'Hallahan J. Post-marketing safety monitoring of a new group B meningococcal vaccine in New Zealand, 2004-2006. Hum Vaccin. 2007 Sep-Oct;3(5):196-204.
(4) Joint Committee on Vaccination and Immunisation Meningococcal subcommittee. Minute of the meeting held on Friday 13th July 2012. London: Department of Health, 2012. https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-...

Competing interests: PTH has conducted clinical trials of capsular group B meningococcal vaccines on behalf of St Georges, University of London funded by Novartis Vaccines and Pfizer, but has no personal pecuniary or other interests with any vaccine manufacturer.

Paul T. Heath, Professor of Paediatric Infectious Diseases

St Georges, University of London, Paediatric Infectious Diseases Research Group & Vaccine Institute

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Re: GSK is facing accusations of bribery in Poland. Shelley Jofre. 348:doi:10.1136/bmj.g2759

Dear Sir/Madam,

I would argue that this shocking news is just the tip of the iceberg in terms of world practice. Bribery direct or indirect is a very common and widespread practice in India where medical practitioners take cut money to refer patients for blood tests, scans and drug prescriptions. The Oncology world is one of the most corrupt as the drugs are so expensive that most leading Oncology companies routinely take Oncologists on foreign trips, etc, based around ASCO, World Lung meetings, etc. This widespread nexus needs to be investigated by the Indian Medical Council seriously rather than letting it be buried under the carpet.


Dr.Sankha Mitra & Dr.Susmita Ghosh
Consultants NHS UK

Competing interests: None declared

Sankha Suvra Mitra, Consultant Clinical Oncologist

Dr.Susmita Ghosh

BSUH, RSCH,Eastern road, Brighton BN2 5BE

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