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Rapid responses are electronic letters to the editor. They enable our users to debate issues raised in articles published on thebmj.com. Although a selection of rapid responses will be included online and in print as readers' letters, 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. Letters are indexed in PubMed.

Re: Lack of evidence for interventions offered in UK fertility centres D Nunan, A Plüddemann, OA Gbinigie, I Onakpoya, et al. 355:doi 10.1136/bmj.i6295

To The Editor, BMJ

Dear Dr Godlee

Balen et al have responded to our papers. [1,2] In our BMJ open paper we systematically identified 276 claims of benefit relating to 41 different fertility interventions and 16 published references were cited 21 times on 13 of the 74 websites we searched.[1] In our BMJ analysis paper, we systematically examined the evidence for ‘38 additional fertility interventions’ and found evidence of improvements in live birth rates for only five interventions. We used standard critical appraisal techniques (as detailed in our paper) to explore the quality of these studies. We identified that for all five of these interventions the studies had methodological problems, raising uncertainty about the significance of the results. This is a serious issue for patients, public health, public trust, and regulators.

Balen et al suggest that our evidence review included - and found evidence lacking for - things which are not “add-ons”. We classified ‘add-ons’ in the BMJ analysis article in response to peer review where the issue was discussed (see online peer review comments).

Peer review comment: ‘The methodology has led them to five interventions for which there may be some evidence of improvement in live birth rates. One of these is intrauterine insemination in a natural cycle. This is an alternative treatment, rather than an “add-on”, and usually not one applied to the population who require IVF, and certainly not one intended to increase live birth rate.’

Our response: ‘We have also added a further table 1: Classifications of IVF Interventions: This is the only reference in the HFEA we could find on the words ‘add-on’ which was only discussed at the Feb 2016 meeting: 'The committee discussed which techniques are more common or established and may be incorporated into other sections of the website. The committee agreed that the remaining techniques for discussion could be placed onto a page about ‘Treatment add-ons’. And we note there is no current definition of what is an ‘Add-on’ treatment as it very much depends on what [the] clinic offers.'

We, therefore, classified 27 of these as ‘Add-on’ interventions: six as alternative treatments to IVF and five treatments for the preservation of fertility (see Table 1 in the paper). We, therefore, followed the advice of peer review. By ‘we’ we mean two general practitioners adjudicated and all authors confirmed the classifcation. Of note, there were concerns that we are not fit to do this. However, the HFEA’s advice is that when it comes to IVF “you should talk to your GP to go through the options available”.

Also in response to peer review, we added to our conclusion the following: ‘Clinics vary significantly in what they offer and there is a lack of clarity on what actually constitutes an ‘Add-on’ intervention. Clear classification systems could aid understanding and reduce variation in what is offered to couples.’

I also draw your attention to the HFEA Press statement at the time that did not question our classification. HFEA statement on fertility treatment 'add-ons' 28 November 2016 (http://www.hfea.gov.uk/10541.html)

HFEA official response to BBC Panorama regarding fertility treatment 'add-ons'.

‘UK fertility clinics generally provide excellent patient care. However, an increasing number of patients tell us they feel unsure about IVF treatment add-ons – whether they work and are worth the extra cost. This puts pressure on patients to make difficult decisions at what is already a stressful time for them.

'We are concerned about the recent step change in the use of treatment add-ons. Unfortunately, we have limited powers to stop clinics offering them, nor to control pricing. Instead, we publish information directly for patients, so that they can have the facts at their fingertips before they go to a clinic and are able to make informed decisions and properly consent to treatment.

'With expert advice from our scientific committee, we have for some years been publishing information about add-ons such as reproductive immunology and PGS, making it clear whether or not they are proven to be effective. We are also working on producing information for our new website about a wider range of add-ons, introducing a simple labeling system to highlight their levels of effectiveness and potential harm.’

Balen et al, therefore, appear to disagree with our categorisation of the 27 interventions as add-ons (see Box 2 of the paper). [2] This is a matter for reasonable debate, but more importantly suggests a lack of outward clarity to many users of this information, notably patients. We stand by our methods (we searched systematically for a classification system at the outset), and to the best of our knowledge, The BMJ is the only journal to have a published classification system.

Regardless, of whether Balen et al prefer to categorise interventions as “add-ons” or part of core treatment, this does not affect our conclusion: there is little or no evidence supporting interventions available from UK fertility clinics to improve live birth rate. We note that this is not a conclusion that is directly challenged by Balen et al.

Balen et al criticise our research team on the grounds that we are evidence based medicine researchers, clinicians, and epidemiologists, not “specialists in reproductive medicine”. This would seemingly seem an unusual line of argument. Given the known concerns over potential conflicts of interests in the IVF industry, and the extensive list of conflicts highlighted at the end of Balen et al’s letter, it was paramount that this work was conducted by an independent group with no ties to the IVF industry. [3] That said, should the opportunity arise for further work assessing the quality of evidence for fertility interventions we would be happy to consider collaborating with co-signatories to improve the evidence-base.

Balen et al appear to object to our use of “live birth” as the core metric of success. Once again, this appears to be an unusual line of argument to take. We refer Balen et al to our recent paper in Trials Journal entitled “Why clinical trial outcomes fail to translate into benefits for patients”. [4] In this paper we highlight some of the issues with substantial amounts of clinical research utilising surrogate, composite and subjective endpoints and failing to take account of patients’ perspectives when designing research outcomes. We agree with Barnhart, who highlights the need for the reproductive industry to make live births as the correct, patient focused, outcome for trials evaluating therapies for infertility. [5] We were therefore pleased to see that live birth rates are being used as a key outcome by RCTs currently recruiting patients in the UK.

Balen et al say that the sector has been well regulated by the HFEA. We question the strength of their argument to support this. Following the publication of our paper, we were pleased to note that the HFEA themselves have committed to updating their evidence to ‘provide free, clear and impartial information to all affected by assisted reproduction,’ and to provide clear evidence-based information to patients and the public as stated in their 2017 innovation and regulation plan. [6] We also noted that the Director of Strategy at the HFEA, Juliet Tizzard, publicly stated, in reference to our work, that the HFEA “don't regulate this but do care deeply.” [7]

Balen et al also comment that we highlight the intervention “Intralipid”, which they suggest is not widely used. This suggestion is not in keeping with our systematic findings. Our analysis stemmed from identification of claims of benefit on fertility centre websites, and we found three such instances claiming benefits for Intralipid; however, Intralipid is offered more widely (four offer Intralipid without stating a claim benefit on the website), meaning approximately 1 in 10 of the clinics we searched offer this intervention. We highlighted our concern for the widespread advocacy of Intralipid, especially given the lack of evidence for this intervention, as noted by both the BFS and Royal College of Obstetricians and Gynaecologists. [2]

Balen et al state that ‘many of the items have a clearly defined role in specific situations; e.g. for a man with a physical blockage sperm has to be extracted surgically, frozen and used in an IVF cycle combined with intra-cytoplasmic sperm injection (ICSI).’ We agree and ICSI was not categorised as an ‘add-on’ treatment in our analysis; we show to whom these interventions apply according to NICE guidance in our data supplement. [8] Balen et al say that looking for improved outcomes is irrelevant for this group of patients because ‘without those interventions (which are clearly not “add-ons”) IVF cannot happen.’ NICE, however, in their research recommendations (45 guideline CG156) state the need to ‘determine the long term effects of IVF with or without ICSI in children in the UK.’ [9]

We were pleased to note that Balen et al recognise that the evidence for some interventions is poor. We note that since the publication of our paper the evidence continues to evolve: a new systematic review on time-lapse imaging reported that there is insufficient evidence to support time-lapse imaging compared to conventional methods and there is a need for ‘more well-designed RCTs’ [10] ; a further systematic review, published in May 2017, on strategies to improve fertilisation rates with assisted conception, further stated that ‘adequately powered multicentre randomised trials are required to evaluate these techniques before considering clinical application.’ [11]

We note that Balen et al have said there are shortcomings in our assessments of the quality of evidence for these interventions improving patients’ chances. If the authors can now provide these, we will happily review these and engage in constructive discussion on the emerging findings.

Finally, the use of ad hominem comments provides little benefit to anyone in this debate. Although we recognise the sensitivities and emotions that our work may have evoked amongst the IVF community, and despite widespread concerns over conflicts of interests in the IVF field, we would urge Balen et al to refocus their concerns at the IVF industry itself, and take a lead in utilising their extensive resources to reassure end users, the HFEA and the wider scientific community that their industry’s work is genuinely patient focused and evidence based. We would further suggest that the first step towards this would be to engage with the media, patient groups, policymakers and regulators to address the systemic findings that many interventions that lack good evidence to back them up are being offered to patients.

Carl Heneghan, Ben Goldacre, Elizabeth A Spencer, Jack O’Sullivan, Kamal R Mahtani,

References
[1] Spencer EA, Mahtani KR, Goldacre B, et al Claims for fertility interventions: a systematic assessment of statements on UK fertility centre websites. BMJ Open 2016;6:e013940. doi: 10.1136/bmjopen-2016-013940.
[2] Heneghan Carl, Spencer E A, Bobrovitz N, Collins D R J, Nunan D, Plüddemann A et al. Lack of evidence for interventions offered in UK fertility centres BMJ 2016; 355 :i6295
[3] Don’t dismiss conflict-of-interest concerns in IVF, they have a basis
https://theconversation.com/dont-dismiss-conflict-of-interest-concerns-i...
[4] Carl Heneghan, Ben Goldacre, Kamal R. Mahtani. Why clinical trial outcomes fail to translate into benefits for patients. Trials, 2017, Volume 18, Number 1, Page 1
[5] Kurt T. Barnhart. Live Birth is the Correct Outcome for Clinical Trials Evaluating Therapy for the Infertile Couple Fertil Steril. 2014 May; 101(5): 1205–1208.
[6] HFEA: Innovation in regulation Feb 2017. http://ifqtesting.blob.core.windows.net/umbraco-website/1796/innovation-...
[7] https://twitter.com/Juliet_Tizzard/status/803511618806104064
[8] http://www.bmj.com/content/bmj/suppl/2016/11/25/bmj.i6295.DC1/henc36462....
[9] Fertility problems: assessment and treatment. Clinical guideline [CG156] Published date: February 2013 Last updated: August 2016 https://www.nice.org.uk/guidance/cg156
[10] Does time-lapse imaging have favorable results for embryo incubation and selection compared with conventional methods in clinical in vitro fertilization? A meta-analysis and systematic review of randomized controlled trials. Chen M, Wei S, Hu J, Yuan J, Liu F.PLoS One. 2017 Jun 1;12(6):e0178720.
[11] Strategies to improve fertilisation rates with assisted conception: a systematic review. Jeve YB, Potdar N, Blower JA, Gelbaya T. Hum Fertil (Camb). 2017 May 26:1-19. doi: 10.1080/14647273.2017.1324182.

Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following: CH has received grant funding from WHO, the National Institute for Health Research (NIHR), and the NIHR School of Primary Care and occasionally receives expenses for teaching evidence based medicine. He jointly runs the EvidenceLive Conference with BMJ, is editor in chief of the BMJ Evidence-Based Medicine Journal and receives payment as an NHS GP in urgent care. BG has received research funding from the Laura and John Arnold Foundation, the Wellcome Trust, the NIHR, the Health Foundation, and WHO; he also receives personal income from speaking and writing for lay audiences on the misuse of science. KM has received funding from the NIHR and the RCGP for independent research projects. The views expressed here are those of the authors and not necessarily those of any of the affiliated institutions mentioned in the manuscript.
14 June 2017

Carl Heneghan
Professor of EBM

Ben Goldacre, Elizabeth A Spencer, Jack O'Sullivan, Kamal R Mahtani
Centre For Evidence-Based Medicine, Nuffield Department of Primary Care Health Scienes, University of Oxford
Radcliffe Observatory Quarter, Woodstock Road, Oxford. OX2 6GG
@carlheneghan

Competing interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following: CH has received grant funding from WHO, the National Institute for Health Research (NIHR), and the NIHR School of Primary Care and occasionally receives expenses for teaching evidence based medicine. He jointly runs the EvidenceLive Conference with BMJ, is Editor in Chief of the BMJ Evidence-Based Medicine Journal and receives payment as an NHS GP in urgent care. BG has received research funding from the Laura and John Arnold Foundation, the Wellcome Trust, the NIHR, the Health Foundation, and WHO; he also receives personal income from speaking and writing for lay audiences on the misuse of science. KM has received funding from the NIHR and the RCGP for independent research projects. The views expressed here are those of the authors and not necessarily those of any of the affiliated institutions mentioned in the manuscript.

16 June 2017
Carl Heneghan
Professor of Evidence-Based Medicine
Ben Goldacre, Elizabeth A Spencer, Jack O'Sullivan, Kamal R Mahtani
Centre For Evidence-Based Medicine, Nuffield Department of Primary Care Health Scienes, University of Oxford
Radcliffe Observatory Quarter, Woodstock Road, Oxford. OX2 6GG
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56
Re: Pathological gambling Henrietta Bowden-Jones. 357:doi 10.1136/bmj.j1593

Sports gambling industry has become huge, transacting $4 trillion annually. [1]
Total underground illegal gambling cannot be precisely calculated.
Brief contracts trading currencies is a form of legalized financial gambling, transacting $5 trillion daily. [2]
The total notional derivatives value, futures betting, is about $1.5 quadrillion. [3]
Governments earn considerable sums by taxing gambling activities.
References
[1] http://www.stuff.co.nz/sport/other-sports/67786452/illegal-gambling-push...
[2] http://www.businessinsider.com/heres-how-much-currency-is-traded-every-d...
[3] http://www.globalresearch.ca/global-derivatives-1-5-quadrillion-time-bom...

Competing interests: No competing interests

16 June 2017
Stavros Saripanidis
Consultant in Obstetrics and Gynaecology
Kalamaria, Thessaloniki, Greece
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71
Re: Interpreting iron studies Alison U Kelly, Stephen T McSorley, Prinesh Patel, Dinesh Talwar. 357:doi 10.1136/bmj.j2513

Dear Editors,
Iron deficiency in infancy, with or without anaemia, is associated with impaired mental and psychomotor development [4][5][8][10][11][12][13][15][18][19][20][21][22][23][24][25][26][28][30], which persist despite long-term iron therapy [12][17][19][20][21][22][24][25][26][30][31], even up to 19 years of age [15][21][25].
Ferritin and circulating RBC volume measure hematologic effects in infants better than blood Hct. [1][6]
Low ferritin in infancy is associated with altered auditory recognition memory [3], diminished performance in mental and psychomotor tests at 5 years of age [2], alterations in visual attention and concept acquisition [7].
Iron deficiency in infancy has been associated to asthma [9], long term sleep alterations [14][19][26], slower eye-blinking rates [16], impaired upper-extremity motor functions [17], schizophrenia in adulthood [21], impaired social-emotional behaviour [23], long term altered prolactin responses [27], impaired auditory and visual responses [31].
Iron deficiency is very common, even in children from developed Countries. [4][5][8].
Delayed umbilical cord-clamping can reduce iron deficiency anaemia in term infants, even in industrialized Countries, and prevent all these long-term irreversible consequences [29].
We can expect many more benefits from prenatal iron use.

References

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Circulating RBC volume, measured with biotinylated RBCs, is superior to the Hct to document the hematologic effects of delayed versus immediate umbilical cord clamping in preterm neonates.
Strauss RG, Mock DM, Johnson K, Mock NI, Cress G, Knosp L, Lobas L, Schmidt RL.
Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.

http://www.ncbi.nlm.nih.gov/pubmed/12869126

[2] J Pediatr. 2002 Feb;140(2):165-70.
Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age.
Tamura T, Goldenberg RL, Hou J, Johnston KE, Cliver SP, Ramey SL, Nelson KG.
Department of Nutrition Sciences, Civitan International Research Center, University of Alabama at Birmingham 35294-3360, USA.

http://www.ncbi.nlm.nih.gov/pubmed/11865266

[3] Pediatr Res. 2004 Jun;55(6):1034-41.
Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers.
Siddappa AM, Georgieff MK, Wewerka S, Worwa C, Nelson CA, Deregnier RA.
Division of Neonatology, Department of Pediatrics, University of Minnesota, MN 55455, USA.

http://www.ncbi.nlm.nih.gov/pubmed/15155871

[4] J Paediatr Child Health. 1998 Jun;34(3):250-3.
Iron status and dietary iron intake of 6-24-month-old children in Adelaide.
Oti-Boateng P, Seshadri R, Petrick S, Gibson RA, Simmer K.
Department of Paediatrics and Child Health, Flinders Medical Centre, South Australia, Australia.

http://www.ncbi.nlm.nih.gov/pubmed/9633972

[5] Arch Pediatr Adolesc Med. 1997 Oct;151(10):986-8.
Iron deficiency in 1- to 3-year-old children. A pediatric failure?
Eden AN, Mir MA.
Department of Pediatrics, Wyckoff Heights Medical Center, Brooklyn, NY, USA.

http://www.ncbi.nlm.nih.gov/pubmed/9343007

[6] J Fam Pract. 1996 Mar;42(3):237-40.
Failure of hematocrit to detect iron deficiency in infants.
Kazal LA Jr.
Navajo Nation Health Foundation, Sage Memorial Hospital, Ganado, Arizona 86505, USA.

http://www.ncbi.nlm.nih.gov/pubmed/8636674

[7] Kobe J Med Sci. 1995 Apr;41(1-2):1-17.
The effect of iron deficiency and mental stimulation on Indonesian children's cognitive performance and development.
Soewondo S.
Faculty of Psychology, University of Indonesia, Jakarta, Indonesia.

http://www.ncbi.nlm.nih.gov/pubmed/7490909

[8] Arch Fr Pediatr. 1989 Aug-Sep;46(7):487-90.
Iron deficiency and psychomotor development tests. Longitudinal study between 10 months and 4 years of age.
Dommergues JP, Archambeaud MP, Ducot B, Gerval Y, Hiard C, Rossignol C, Tchernia G.
Departement de Pediatrie, Hopital de Bicetre, Le Kremlin-Bicetre.

http://www.ncbi.nlm.nih.gov/pubmed/2596947

[9] Lung India. 2010 Apr;27(2):51-3.
Anemia as a risk factor for childhood asthma.
Ramakrishnan K, Borade A.
Department of Pediatrics, Amrita School of Medicine, Kochi, India.

http://www.ncbi.nlm.nih.gov/pubmed/20616934

[10] J Child Neurol. 2011 Aug 29. [Epub ahead of print]
Effect of Chronic Iron Deficiency on Neuropsychological Domains in Infants.
Beltrán-Navarro B, Matute E, Vásquez-Garibay E, Zarabozo D.
Instituto de Neurociencias, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico.

http://www.ncbi.nlm.nih.gov/pubmed/21876067

[11] J Nutr. 2011 Apr 1;141(4):740S-746S. Epub 2011 Feb 23.
Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction.
Lozoff B.
Center for Human Growth and Development and Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.

http://www.ncbi.nlm.nih.gov/pubmed/21346104

[12] Indian J Pediatr. 2011 Jan;78(1):58-64. Epub 2010 Oct 15.
Developmental and neurophysiologic deficits in iron deficiency in children.
Madan N, Rusia U, Sikka M, Sharma S, Shankar N.
Department of Pathology, University College of Medical Sciences & Guru Tegh Bahadur Hospital, New Delhi, 110092, India.

http://www.ncbi.nlm.nih.gov/pubmed/20953851

[13] Pediatrics. 2010 Aug;126(2):e427-34. Epub 2010 Jul 26.
Iron deficiency anemia and cognitive function in infancy.
Carter RC, Jacobson JL, Burden MJ, Armony-Sivan R, Dodge NC, Angelilli ML, Lozoff B, Jacobson SW.
Division of Emergency Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.

http://www.ncbi.nlm.nih.gov/pubmed/20660551

[14] Sleep Med. 2010 Aug;11(7):637-42.
Sleep alterations and iron deficiency anemia in infancy.
Peirano PD, Algarín CR, Chamorro RA, Reyes SC, Durán SA, Garrido MI, Lozoff B.
Sleep and Functional Neurobiology Laboratory, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile.

http://www.ncbi.nlm.nih.gov/pubmed/20620103

[15] Nutr Neurosci. 2010 Apr;13(2):54-70.
Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory.
Lukowski AF, Koss M, Burden MJ, Jonides J, Nelson CA, Kaciroti N, Jimenez E, Lozoff B.
Department of Psychology and Social Behavior, University of California, Irvine, California 92697, USA.

http://www.ncbi.nlm.nih.gov/pubmed/20406573

[16] J Nutr. 2010 May;140(5):1057-61. Epub 2010 Mar 24.
Eye-blinking rates are slower in infants with iron-deficiency anemia than in nonanemic iron-deficient or iron-sufficientinfants.
Lozoff B, Armony-Sivan R, Kaciroti N, Jing Y, Golub M, Jacobson SW.
Center for Human Growth and Development and; 4Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.

http://www.ncbi.nlm.nih.gov/pubmed/20335633

[17] Infant Behav Dev. 2009 Dec;32(4):366-75. Epub 2009 Jul 9.
Iron deficiency anemia in infancy and reach and grasp development.
Shafir T, Angulo-Barroso R, Su J, Jacobson SW, Lozoff B.
The Molecular & Behavioral Neuroscience Institute (MBNI), University of Michigan, 205 Zina Pitcher Pl, Rm 1066, Ann Arbor, MI 48109-0720, USA.

http://www.ncbi.nlm.nih.gov/pubmed/19592115

[18] Brain Dev. 2010 Mar;32(3):213-6. Epub 2009 Mar 26.
Effect of iron deficiency anemia on visual evoked potential of growing children.
Monga M, Walia V, Gandhi A, Chandra J, Sharma S.
Department of Physiology, All India Institute of Medical Sciences, New Delhi, India.

http://www.ncbi.nlm.nih.gov/pubmed/19327925

[19] J Pediatr Gastroenterol Nutr. 2009 Mar;48 Suppl 1:S8-15.
Sleep and neurofunctions throughout child development: lasting effects of early iron deficiency.
Peirano PD, Algarín CR, Chamorro R, Reyes S, Garrido MI, Duran S, Lozoff B.
Sleep and Functional Neurobiology Laboratory, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile.

http://www.ncbi.nlm.nih.gov/pubmed/19214058

[20] Biochem Soc Trans. 2008 Dec;36(Pt 6):1267-71.
The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus.
Georgieff MK.
Department of Pediatrics, Division of Neonatology, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.

http://www.ncbi.nlm.nih.gov/pubmed/19021538

[21] Arch Gen Psychiatry. 2008 Oct;65(10):1136-44.
Maternal iron deficiency and the risk of schizophrenia in offspring.
Insel BJ, Schaefer CA, McKeague IW, Susser ES, Brown AS.
New York State Psychiatric Institute, 1051 Riverside Dr, Unit 23, New York, NY 10032, USA.

http://www.ncbi.nlm.nih.gov/pubmed/18838630

[22] Neurotox Res. 2008 Aug;14(1):45-56.
Brain iron deficiency and excess; cognitive impairment and neurodegeneration with involvement of striatum and hippocampus.
Youdim MB.
Eve Topf and USA National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel.

http://www.ncbi.nlm.nih.gov/pubmed/18790724

[23] J Pediatr. 2008 May;152(5):696-702, 702.31-3. Epub 2007 Nov 19.
Dose-response relationships between iron deficiency with or without anemia and infant social-emotional behavior.
Lozoff B, Clark KM, Jing Y, Armony-Sivan R, Angelilli ML, Jacobson SW.
Center for Human Growth and Development, University of Michigan, Ann Arbor, MI 48109-5406, USA.

http://www.ncbi.nlm.nih.gov/pubmed/18410777

[24] Food Nutr Bull. 2007 Dec;28(4 Suppl):S560-71.
Iron deficiency and child development.
Lozoff B.
Center for Human Growth and Development, Department of Pediatrics and Communicable Diseases, University of Michigan, 300 N. Ingalls, Ann Arbor, MI 48109-5406, USA.

http://www.ncbi.nlm.nih.gov/pubmed/18297894

[25] Arch Pediatr Adolesc Med. 2006 Nov;160(11):1108-13.
Double burden of iron deficiency in infancy and low socioeconomic status: a longitudinal analysis of cognitive test scores to age 19 years.
Lozoff B, Jimenez E, Smith JB.
Center for Human Growth and Development, and Department of Pediatrics and Communicable Diseases, University of Michigan, 300 N. Ingalls, Ann Arbor, MI 48109, USA.

http://www.ncbi.nlm.nih.gov/pubmed/17088512

[26] Food Nutr Bull. 2003 Dec;24(4 Suppl):S104-10.
Effect of iron-deficiency anemia on cognitive skills and neuromaturation in infancy and childhood.
Walter T.
Institute of Nutrition and Food Technology, University of Chile, Santiago.

http://www.ncbi.nlm.nih.gov/pubmed/17016952

[27] Pediatr Res. 2006 Nov;60(5):513-7. Epub 2006 Sep 11.
Iron deficiency in infancy predicts altered serum prolactin response 10 years later.
Felt B, Jimenez E, Smith J, Calatroni A, Kaciroti N, Wheatcroft G, Lozoff B.
Center for Human Growth and Development, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109-0406, USA.

http://www.ncbi.nlm.nih.gov/pubmed/16966351

[28] Asia Pac J Public Health. 2005;17(1):19-21.
Iron deficiency anaemia and child development.
Hokama T, Gushi Ken M, Nosoko N.
Maternal & Child and Global Health, School of Health Science, Faculty of Medicine, University of the Ryukyus, Japan.

http://www.ncbi.nlm.nih.gov/pubmed/16044827

[29] Ann Trop Paediatr. 2004 Mar;24(1):3-16.
Late umbilical cord-clamping as an intervention for reducing iron deficiency anaemia in term infants in developing and industrialised countries: a systematic review.
van Rheenen P, Brabin BJ.
Emma Kinderziekenhuis, Academic Medical Centre, Amsterdam, The Netherlands.

http://www.ncbi.nlm.nih.gov/pubmed/15005961

[30] J Nutr. 2003 May;133(5 Suppl 1):1468S-72S.
Iron deficiency alters brain development and functioning.
Beard J.
Graduate Program in Nutrition, The Pennsylvania State University, University Park, PA 16802, USA.

http://www.ncbi.nlm.nih.gov/pubmed/12730445

[31] Pediatr Res. 2003 Feb;53(2):217-23.
Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning.
Algarín C, Peirano P, Garrido M, Pizarro F, Lozoff B.
Laboratory of Sleep and Functional Neurobiology, INTA, University of Chile, Chile.

http://www.ncbi.nlm.nih.gov/pubmed/12538778

Competing interests: No competing interests

16 June 2017
Stavros Saripanidis
Consultant in Obstetrics and Gynaecology
Kalamaria, Thessaloniki, Greece
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64
Re: Stress at work Thomas Despréaux, Olivier Saint-Lary, Florence Danzin, Alexis Descatha. 357:doi 10.1136/bmj.j2489

Stress is a part of life and unavoidable. It is the attitude towards stress that counts for a lot. A positive attitude changes the stress into eustress, which is helpful and promotes health.
Meditation, yoga & exercise are very helpful and healthy measures to handle stress.
Regards,
Dr Rajiv Kumar

Competing interests: No competing interests

16 June 2017
Dr. Rajiv Kumar
Faculty
Dept. Of Pharmacology, Government Medical College & Hospital, Chandigarh- India.
DRrajiv.08@gmail.com
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58
Re: Vaccination alone will not halt the next global pandemic Allen G Ross. 357:doi 10.1136/bmj.j2864

Why are we not able to prevent the future pandemic of certain infectious diseases?

It is individuals' responsibility to prevent the spread of vaccine preventable diseases. Vaccines are definitely useful to prevent many viral diseases such as polio and smallpox to the maximum extent

The change in viral genome by mutations and an individual's as well as parent's immune resistant status can also determine the spread of vaccine preventable diseases.

And infection also travels in a prodromal state, and the full blown state of a viral and bacterial infection passing from one country to another that is not using vaccine for prevention of these infections is a big problem nowadays.

And also the appearance of older infections with newer mutations of viral and bacterial infections are also the cause of epidemics in recent years.

These are the some of the reasons for not preventing the future pandemic of certain viral and bacterial infections.

Competing interests: No competing interests

16 June 2017
M.A. Aleem
Neurologist
A.M.Hakkim
ABC Hospital
Annamalainagar Trichy 620018 Tamilnadu India
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Re: Every breath we take Rebecca Coombes. 357:doi 10.1136/bmj.j2892

It is good to read the Editor's Choice (Every breath we take).
We are responsible for the quality of air that we breathe. The present technological advancement that has become our part of life has adverse consequences similar to ADRs. Timely measures need to be taken to handle this serious global problem.
We must not forget that the "Nature is above all".
On a spiritual note, it is said that the number of breaths in one's life is already decided.
Regards,
Dr Rajiv Kumar

Competing interests: No competing interests

15 June 2017
Dr. Rajiv Kumar
Faculty
Dept. Of Pharmacology, Government Medical College & Hospital, Chandigarh- India.
DRrajiv.08@gmail.com
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Re: Orthopaedic surgeons: as strong as an ox and almost twice as clever? Multicentre prospective comparative study C A Willis-Owen, et al. 343:doi 10.1136/bmj.d7506

If I am not mistaken, in 1988 the BMJ published a paper comparing the glove sizes of orthopaedic surgeons and general surgeons. The comments were wonderful: "Are orthoaedic surgeons really gorillas?" "An orthopaedic surgeon has the power of an ox but difficulties in spelling it". I cited these humorous quotations often and accepted them as examples of good British humour. It seems that a study without medical scientfic relevance should be repeated every 29 years.

Competing interests: No competing interests

15 June 2017
Chanan Tauber
Retired orthopedic surgeon
Bathia Israel 7680400
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Re: Suicides among junior doctors in the NHS Rachel Clarke, Martin McKee. 357:doi 10.1136/bmj.j2527

Following surgery prompt provision of adequate analgesia, if required, is of utmost importance to both patient and recovery ward staff. Unfortunately although pain is sometimes very visible, often those affected suffer in silence - or at least quietly and unnoticed. We regard acute pain as a vital sign - just as important as blood pressure & pulse rate - and specifically measure it by asking patients to quantify it on a scale from 0 (no pain) to 10 (worst imaginable). Knowing a 'pain score' allows us to respond appropriately, and repeat scoring allows us to monitor the effectiveness of our interventions.

Anguish amongst our colleagues can be equally difficult to see: more so as our focus is naturally on our patients. However, it is apparent that its detection and proper management is also of utmost importance to all of us. Perhaps we should routinely monitor self-assessed 'anguish scores'. Even if this was anonymous but allowed weekly public display of minimum, mean and maximum reported scores, it would allow greater awareness & reflection and hopefully promote a more supportive, caring and compassionate working environment.

Just as safety is everyone's business, so is safeguarding friends & colleagues.

Competing interests: No competing interests

15 June 2017
Hayleigh E Morris
CT1 anaesthetist
Mark W Davies, consultant in anaesthesia & perioperative medicine
Royal Liverpool & Broadgreen University Hospitals NHS Trust
Liverpool L7 8XP
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Re: Suicides among junior doctors in the NHS Rachel Clarke, Martin McKee. 357:doi 10.1136/bmj.j2527

Dear Editor

In their editorial in the issue of the 10th of June (BMJ 201;357:2527) Clarke and McKee discuss whether suicide by junior doctors can be attributed to work related stress. I agree that meaningful concerted action by the profession to support junior doctors to recognise any mental health issues they may experience and to seek appropriate help is needed.

In the 30 years of clinical practise as an Anaesthetist (1981 to 2011) I can call to mind 10 suicides of colleagues, some junior doctors some senior. In about half of these tragic deaths, the person took their life whilst at work, but in all cases there were multiple factors that finally came together to bring the person to the point where life was not worth continuing. Two of the senior colleagues took their lives by hanging, and in both cases a recent clinical catastrophe had bought them to the point of suicide. One senior colleague took her life entirely due to personal circumstances. This experience leads me to counsel against making all doctor suicides automatically a work related death. In every case that I have had involvement in and knowledge of, the remaining colleagues have been devastated by the loss of their friend, and departments have taken a long time to grieve and move forward.

There are indeed many reasons why someone should take his or her life, and Anaesthetists have easy access to the wherewithal to take their life. The reason a person reaches the point where they believe the world would be better without them in it may be personal, distressing to family and friends, and quite unrelated to work. The coroner's inquest is quite sufficient a nightmare for the relatives without further inspection by the authorities. Coroners are at liberty, if they think it appropriate to comment on any contribution by workplace based events, and certainly the GMC could usefully collect statistics on the incidence, but let us stop short of creating another level of bureaucracy and enquiry to trouble those who remain forever anxious that they could somehow have prevented the death.

Yours sincerely

Dr Lesley Bromley
Retired Consultant Anaesthetist

Competing interests: No competing interests

15 June 2017
Lesley M Bromley
Retired Consultant Anaesthetist
Selsey
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Re: Every breath we take Rebecca Coombes. 357:doi 10.1136/bmj.j2892

We should never forget that before 'breath becomes air' [1] - air becomes breath.

When Breath Becomes Air. Paul Kalanithi. Random House

Competing interests: No competing interests

15 June 2017
Mark W Davies
consultant in anaesthesia & perioperative medicine
Royal Liverpool & Broadgreen University Hospitals NHS Trust
Liverpool L7 8XP
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