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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: Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline Florence Anam, Teresia Otieno, Gordon H Guyatt, Graham P Taylor, et al. 358:doi 10.1136/bmj.j3961

Dear Editor:

We thank Dr. Fowler and colleagues for taking the time to consider and comment on our BMJ Rapid Recommendation (1). They speculate on reasons why tenofovir and emtricitabine increased the risk of neonatal mortality and early preterm delivery in their trial (2) and then say that the current evidence does not support a recommendation for alternative NRTIs over a tenofovir-based antiretroviral therapy (ART) regimen. We do agree that most, but not all, of the evidence comes from a single study, which may have overestimated harm. Our systematic review attempted to generate the current best evidence, and is not definitive: it is moderate-to-low quality for key outcomes (3). However, we disagree with the implication that based on this evidence, most women would choose a tenofovir-based ART regimen.

The PROMISE authors suggest that results of the comparison between tenofovir-ART and AZT-ART are untrustworthy because the risk of neonatal death was lower in the AZT-ART arm in the earlier period 1 before the tenofovir-ART arm was introduced (2). However, the difference between the two time-periods in the AZT-ART arm could easily be explained by chance (neonatal mortality 1.4% in period 1 vs. 0.6% in period 2, p=0.39; very preterm delivery 3.4% in period 1 vs. 2.6% in period 2, p=0.60). Regardless, the only reliable comparison between tenofovir-ART and AZT-ART is during period 2 when randomisation to both AZT and tenofovir-based ART occurred. Despite these reservations, we performed sensitivity analyses that included data from the AZT-arm in period 1 before the tenofovir-ART arm was introduced (3). The increased risk of early preterm delivery and stillbirth with tenofovir/emtricitabine remained statistically significant and interpretation does not change when data from period 1 is included. Dr. Fowler and colleagues have also suggested that there may have been “some unknown confounder” wherein tenofovir-ART caused harm during period 2, but would not have been harmful to the participants in period 1 (2, 4). We consider this unlikely. Even if true, no such confounder has been identified and women faced with choosing an ART regimen will not know whether or not tenofovir-ART has the potential for harm in their case.

We agree that when tenofovir and emtricitabine are used in combination with lopinavir/ritonavir, it is possible that the risk is higher than with efavirenz; although it is unlikely that if tenofovir is indeed the ‘culprit’ medication, that there would be no risk at all when combined with efavirenz. Put another way, even if the risk of premature delivery and neonatal death is low with tenofovir/emtricitabine plus efavirenz, based on the available evidence, the risk with AZT/lamivudine plus efavirenz may be even lower.

We did not state that the pathophysiology of stillbirth and early neonatal death are the same. Perinatal mortality has long been a global standard outcome measure of maternal and perinatal healthcare (5) and is likely to be similarly important to women, thus our panel pre-specified that it was appropriate to combine them in our evidence summary.

We agree with their concern regarding the possibility that all combination ART regimens may increase the risk of prematurity (versus no ART or monotherapy), albeit this is uncertain and not the focus of this guidance. Given the unique physiology (and pathophysiologies) of pregnancy, the lack of an understood biological rationale at this stage should neither lead to a definitive conclusion nor reassurance. It remains possible that potential pharmacokinetic interactions, and failing or restoring immune systems are different in pregnancy. These are all good reasons to recognise that work from non-pregnant male and female adults cannot always be applied directly to pregnant women. Instead, these are strong justifications for further pregnancy-specific research. We believe that pregnant women (and their babies) should have an equitable standard of research evidence, and thus disagree that it is unlikely that there will be other randomised trials. It is imperative that further randomised trials are conducted. Regulatory authorities, and perhaps the WHO, have a responsibility to ensure that the appropriate studies are performed by the pharmaceutical industry to ensure that pregnant women are not disadvantaged.

Fowler et al. assert that the available observational evidence should provide reassurance to pregnant women. In this, we believe they are misguided. We reviewed the entirety of the observational evidence, including the single observational study that they cite (6); it cannot provide such assurance. First, even the highest quality observational studies are at high risk of residual confounding (7). Second, none of the studies controlled for all of the most important known confounders, including HIV disease status (CD4 count and viral load), socioeconomic status, and availability and quality of healthcare. Third, the studies were inconsistent with some showing harm with tenofovir and others benefit. Fourth, the results were imprecise with the confidence intervals including a magnitude of harm that almost all women would find important.

We strongly disagree with any implication that most women would be willing to risk the health of their child when other options exist. The decision about which vertical transmission strategy or combination ART regimen to use should rest squarely with each informed woman, based on her own values and preferences. This message was consistent from the linked systematic review on the values and preferences of women living with HIV (8), from the three women living with HIV on the guideline panel, as well as an associated opinion piece written by a woman living with HIV (9). Avoiding death in a newborn child is tremendously important to all or almost all women and even if the increased risk of stillbirth or neonatal mortality is extremely low with tenofovir/emtricitabine, almost all women would choose to use a different regimen. Unless future randomised trials show that tenofovir/emtricitabine is safe, we believe that most fully informed women would choose an alternative. Efforts should be made to share the best available evidence and empower women who are pregnant or might consider pregnancy to choose their medications for themselves rather than a ” one size fits all” approach to HIV treatment.

Sincerely,
Reed A.C. Siemieniuk, Graham P. Taylor, Gordon H. Guyatt, Lyubov Lytvyn, Yaping Chang, Paul E. Alexander, Yung Lee, Thomas Agoritsas, Arnaud Merglen, Haresh Kirpalani, Susan Bewley

References
1. Siemieniuk RA, Lytuyn L, Ming JM et al. Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline. BMJ 2017;358:j3961.

2. Fowler MG, Qin M, Fiscus SA, et al. Benefits and risks of antiretroviral therapy for perinatal prevention. N Engl J Med 2016;375:1726-37.

3. Siemieniuk RA, Foroutan F, Mirza R et al. Antiretroviral therapy for pregnant women living with HIV or hepatitis B: a systematic review and meta-analysis. BMJ Open 207;7:e019022.

4. Peer review of Siemieniuk RA, Foroutan F, Mirza R et al. Antiretroviral therapy for pregnant women living with HIV or hepatitis B: a systematic review and meta-analysis. BMJ Open 207;7:e019022. Available at: http://bmjopen.bmj.com/content/bmjopen/7/9/e019022.reviewer-comments.pdf Accessed October 9, 2017.

5. World Health Organization. “Maternal and perinatal health.” http://www.who.int/maternal_child_adolescent/topics/maternal/maternal_pe... Accessed October 9, 2017.

6. Zash R, Jacobson DL, Diseko M, et al. Comparative Safety of Antiretroviral Treatment Regimens in Pregnancy. JAMA Pediatr. 2017 Oct 2;171(10):e172222.

7. Agoritsas T, Merglen A, Shah ND, O'Donnell M, Guyatt GH. Adjusted Analyses in Studies Addressing Therapy and Harm: Users' Guides to the Medical Literature. JAMA. 2017 Feb 21;317(7):748-759.

8. Lytvyn L, Siemieniuk RA, Dilmitis S, et al. Values and preferences of women living with HIV who are pregnant, postpartum or considering pregnancy on choice of antiretroviral therapy during pregnancy. BMJ Open. 2017 Sep 11;7(9):e019023.

9. Welbourn, A. WHO and the rights of women living with HIV. BMJ Opinion. Available at: http://blogs.bmj.com/bmj/2017/09/11/alice-welbourn-who-and-the-rights-of... Accessed October 9, 2017.

Competing interests: No competing interests

10 October 2017
Reed A.C. Siemieniuk
Physician
Graham P. Taylor, Gordon H. Guyatt, Lyubov Lytvyn, Yaping Chang, Paul E. Alexander, Yung Lee, Thomas Agoritsas, Arnaud Merglen, Haresh Kirpalani, Susan Bewley
McMaster University
1280 Main St West, Hamilton, ON, Canada
Re: Corticosteroids for treatment of sore throat: systematic review and meta-analysis of randomised trials Lyubov Lytvyn, Per Olav Vandvik, Arnaud Merglen, Gordon H Guyatt, et al. 358:doi 10.1136/bmj.j3887

I agree with the previous correspondents in thinking that dexamethasone 10 milligrams is not low dose. It has the potential to raise blood sugar, and cause insomnia, mood disturbance, and oral thrush. The evidence presented is of low benefit from this prescription and incomplete data about harms. The administration of dexamethasone requires a consultation, prescription and dispensing at a time when we are trying to reduce demand on NHS services. My normal practice for uncomplicated sore throat is to provide telephone advice regarding fluids and analgesia, and reserve face to face consultations for those patients who are significantly unwell. The studies used for this review appear to have been related to face to face consultations, and thus do not take into account all the patients who self managed their sore throats. This may increase the impression of benefit with steroids.

GPs are under pressure to reduce the amount of antibiotics they prescribe. I am perturbed by the idea that I should prescribe dexamethasone instead for a mostly self limiting illness. I already feel under pressure to prescribe dexamethasone for mild croup in children (hoarseness and painful cough but no respiratory difficulty), when formerly I would have treated this also with oral fluids and analgesia.

At a time when the NHS is creaking under the strain of the mismatch of demand and resources I don't think we can or should take on the workload of prescribing dexamethasone for sore throat.

Competing interests: No competing interests

09 October 2017
Janet P Watters
General Practitioner, salaried, Out of Hours
Belfast Health and Social Care Trust
64 Crumlin Road, Belfast BT14 6AG
Re: Threat to human health from environmental plastics Sephanie L Wright, Frank J Kelly. 358:doi 10.1136/bmj.j4334

Whilst I welcome Stephanie Wright's article on health implications of environmental plastics, I have a slight issue with the conclusion that we need to establish safe threshold for exposure. I believe the urgent need is to stem the tide of plastic entering the environment in the first place. We must all challenge ourselves, our communities and our leaders to transition from a linear chuck it away economy to a circular one. Here every item is manufactured with its ultimate disposal in mind be it recycling or reusing.

Let's start by ending single use plastics - the classic example of convenience over common sense. As well as being a GP I work with Surfers against Sewage. We have just launched our Plastic Free Coastline campaign working with local communities to reduce usage of plastics. The response has been overwhelming positive with a real desire to be part of the solution. As doctors, I believe we have a responsibility to reduce our own plastic footprint and work with our employers to look at usage on a larger scale. As doctors we have a powerful voice - should we not use it to support initiatives such as the proposed deposit return scheme for plastic bottles? Should we not lobby government to make manufacturers responsible for the final destination of their products?

What you decide to do after reading this letter will determine whether you become part of the solution or part of the problem. Your choice!!

James Szymankiewicz
GP North Devon
Regional Representative Surfers Against Sewage

Competing interests: No competing interests

09 October 2017
James D Szymankiewicz
GP North Devon and regional representative for Surfers Against Sewage
Nil
Barnstaple, North Devon
Re: Do patients at risk of infective endocarditis need antibiotics before dental procedures? Thomas J Cahill, Mark Dayer, Bernard Prendergast, Martin Thornhill. 358:doi 10.1136/bmj.j3942

We are grateful for Buchan and colleagues’ positive comments. We agree that the lack of microbiology information associated with an infective endocarditis diagnosis is a significant weakness of the ICD-10-CM coding system used for the NHS Hospital Episode Statistics (HES) Admitted Patient Care episodes. We are hopeful that ongoing prospective registry studies in the UK and Europe will provide insights into the microbiological aetiology of excess cases, but these cohorts may not have such broad coverage as HES.

Buchan et al request details of the two deceased patients whose spouses gave input to our article, a commendable requirement from the BMJ for this series. In these two cases, one had a prosthetic valve and one a bicuspid valve. Both had received antibiotic prophylaxis before invasive dental procedures prior to the 2008 NICE guideline change, but were advised by their dentists that it was no longer needed following the change. It is notable, however, that only one would be considered high-risk under current ESC guidelines. Alongside clarifying the role of antibiotic prophylaxis, both relatives emphasised that more must be done to educate those at moderate- and high-risk of endocarditis, as well as clinicians (especially GPs and dentists), about the symptoms of infective endocarditis in order to reduce delays in diagnosis and improve outcomes (see Infographic at http://www.bmj.com/content/358/bmj.j3942).

Parrish suggests that dental infection could be a confounder for dental procedures. A challenge for future studies will be to gain insights into patient-level risk factors such as oral hygiene status, while being adequately sized for statistical power. Parrish also estimates that the number needed to prevent (NNP) a case of infective endocarditis may be as high as 2000. Estimates of the NNP for antibiotic prophylaxis are highly variable, and in comparison, UK data (based on excess cases since antibiotic prophylaxis was withdrawn) suggests a NNP of 277 (95% CI 156-1217).1 In the context of the current uncertainty, we would reiterate our approach: to educate all at-risk patients about infective endocarditis, to outline the evidence available, and to offer antibiotic prophylaxis to those in high-risk groups.

References
1. Dayer MJ, Jones S, Prendergast B, et al. Incidence of infective endocarditis in England, 2000–13: a secular trend, interrupted time-series analysis. Lancet;385(9974):1219-28. doi: 10.1016/S0140-6736(14)62007-9

Competing interests: See original article

09 October 2017
Thomas J Cahill
Cardiology Specialist Registrar
Dr Mark Dayer, Professor Bernard Prendergast, Professor Martin Thornhill
Oxford Heart Centre, Oxford University Hospitals NHS Foundation Trust
Oxford
Re: WHO advises blanket anti-worming treatment for children despite lack of benefit Nigel Hawkes. 359:doi 10.1136/bmj.j4589

This is a response to the five scientists from the INDIAN COUNCIL OF MEDICAL RESEARCH

They have welcomed mass drug administration. Could they please comfirm that they have practised what they preach? If so, it would be interesting to know the names of the drugs they themselves ingested, the quantities ingested and the duration of the needless medication.

Thank you

Competing interests: No competing interests

09 October 2017
JK Anand
Retired doctor
Free spirit
Peterborough
Re: Diagnosis and management of postpartum haemorrhage Edwin Chandraharan, Archana Krishna. 358:doi 10.1136/bmj.j3875

Dear Sir,

I was disappointed by the lack of reference to Interventional Radiology (IR) in the above clinical update by Edwin Chandraharan and Archana Krishna BMJ 2017; 358: j3875 Published 27 Sep 2017. IR plays a major role in the prevention and treatment of post partum haemorrhage (PPH) and the need for early involvement of interventional radiology in the management of patients with PPH is stressed in the Royal college of obstetricians and gynaecologists good practice guidelines (1-19). Uterine artery embolisation should be mentioned in the “What you need to know” panel and the need for early involvement of IR described explicitly in the text. This review fails to recognise that IR is a specialty in its own right.

I would draw your attention to multiple publications (1-13) describing the benefit of IR techniques in PPH and a health care commission report (14) which highlights the potential of IR to save lives.
Arterial balloon occlusion and embolisation performed by an interventional radiologist in an IR suite can prevent major blood loss acutely reducing the need for blood transfusion and hysterectomy. The technique involves percutaneous femoral artery access with incisions of 1-2mm and using X-ray guidance to access either the anterior division of the internal iliac artery or more selectively the uterine artery to prevent or arrest acute haemorrhage. A variety of different embolic agents can be used including gelfoam, glue, coils and particles. A similar technique is also commonly used as part of a prophylactic strategy in abnormal placentation.

It is crucial that your readers are made aware of the potential benefit of early involvement of interventional radiology in the management of a patient with PPH and not denied potentially life saving treatments.

Dr R Uberoi
President of the British Society of Interventional Radiologists
Royal College of Radiologists
Lincoln Inn Fields
London.
Raman.uberoi@ouh.nhs.uk

1. Heaston DK, Mineau DE, Brown BJ et al (1979) Transcatheter arterial embolization for control of persistent massive puerperal hemorrhage after bilateral surgical hypogastric artery ligation AJR Am J Roentgenol 133:152–154
2. Pelage JP, Le Dref O, Mateo J et al (1998) Life-threatening primary postpartum hemorrhage: treatment with emergency selective arterial embolization. Radiology 208:359–362
3. Deux JF, Bazot M, Le Blanche AF et al (2001) Is selective embolization of uterine arteries a safe alternative to hysterectomy in patients with postpartum hemorrhage? AJR Am J Roentgenol 177:145–149
4. Ratnam LA, Gibson M, Sandhu C et al (2008) Transcatheter pelvic arterial embolisation for control of obstetric and gynaecological haemorrhage. J Obstet Gynaecol 28:573–579
5. Boulleret C, Chahid D, Gallot D et al (2004) Hypogastric arterial selective and superselective embolization for severe postpartum hemorrhage: a retrospective review of 36 cases. Cardiovasc Intervent Radiol 27:334–348
6. Ojala K, Perala J, Kariniemi J et al (2005) Arterial embolization and prophylactic catheterization for the treatment of severe obstetric hemorrhage. Acta Obstet Gynecol Scand 84:1075–1080
7. Tsang ML, Wong WC, Kun KY et al (2004) Arterial embolisation in intractable primary post-partum haemorrhage: case series. Hong Kong Med J 10:301–306
8. Tourne G, Colleta F, Seffert P et al (2003) Place of embolization of the uterine arteries in the managementof post-partum haemorrhage:a study of 12 cases. Eur J Obstet Gynecol Reprod Biol110:29–34
9. Tixier H, Loffroy R, Guiu B et al (2009) Complications and failure of uterine artery embolisation for intractable postpartum haemorrhage. BJOG 116:55–61
10. Deux JF, Bazot M, Le Blanche AF, Tassart M, Khalil A, Berkane N, Uzan S, Boudghe`ne F (2001) Is selective embolization of uterine arteries a safe alternative to hysterectomy in patients with postpartum hemorrhage ? AJR Am J Roentgenol 177:145–149
11. Soyer P etal, Transcatheter Arterial Embolization for Postpartum Hemorrhage: Indications, Technique, Results, and Complications CVIR Feb 2015 Oct;38(5):1068-81
12. Multidisciplinary approach to manage antenatally suspected placenta percreta: updated algorithm and patient outcomes.Lee PS, Kempner S, Miller M, Dominguez J, Grotegut C, Ehrisman J, Previs R, Havrilesky LJ, Broadwater G, Ellestad SC, Secord AA. Gynecol Oncol Res Pract. 2017 Aug 22;4:11.
13. Endovascular management of massive post-partum haemorrhage in abnormal placental implantation deliveries. Rebonato A, Mosca S, Fischer M, Gerli S, Orgera G, Graziosi L, Maiettini D, Di Renzo GC, Epicoco G, Krokidis M, Rossi M, Scialpi M. Eur Radiol. 2016 Jun;26(6):1620-30.
14. Investigation into 10 maternal deaths at, or following delivery at, Northwick Park Hospital, North West London Hospitals NHS Trust, between April 2002 and April 2005. Health care Commission
15. Royal College of Obstetricians and Gynaecologists (2007) The role of emergency and elective interventional radiology in postpartum hemorrhage. Royal College of Obstetricians and Gynaecologists Good Practice Guideline No. 6. Royal College of Obstetricians and Gynaecologists, London. Available at: http://www.rcog.org.uk/ womens-health/clinical-guidance/role-emergency-and-electiveinterventional- radiology-postpartum-haem.
16. Royal College of Obstetricians and Gynaecologists 2011; Placenta Praevia, Placenta Praevia Accreta and Vasa Praevia - .Royal College of Obstetricians and Gynaecologists Good Practice Guideline No. 27. Royal College of Obstetricians and Gynaecologists https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_27.pdf
17. Royal College of Obstetricians and Gynaecologists (2016)Prevention and management of post partum haemorrhage .Royal College of Obstetricians and Gynaecologists Good Practice Guideline No. 52. Royal College of Obstetricians and Gynaecologists, London. Available at: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg52/

Competing interests: No competing interests

09 October 2017
Raman Uberoi
Doctor
President of the Bristish Society of Radiologists
Royal College of Radiologists, Lincoln Inn fields, London
Re: Faltering growth in children: summary of NICE guidance Eva Gonzalez-Viana, Katharina Dworzynski, M Stephen Murphy, Russell Peek. 358:doi 10.1136/bmj.j4219

We acknowledge that this paper is not intended to focus on specific medical or surgical problems that cause faltering growth but rather on a general approach of assessment and management in these children.

Several online resources have been recognised by the guideline committee and we believe one further guideline may be beneficial to your audience. Ineffective suckling, clicking sounds or nasal regurgitation whilst feeding may indicate a cleft palate or submucous cleft palate undetected at newborn assessment. This recent best practice guide produced by the RCPCH promotes the following six recommendations to ensure early detection of a cleft palate:

1. Healthcare professionals should examine a baby’s hard and soft palate as part of the full newborn physical examination and record this in the child health record.

2. Examination of the baby’s palate should be carried out by visual inspection.

3. A torch and method of depressing the tongue should be used to visualise the whole palate.

4. Parents should be informed if the whole palate (including the full length of the soft palate) has not been visualised during the newborn examination.

5. If the whole palate is not able to be visually inspected at first attempt then a further attempt at visual examination should be made within 24 hours.

6. Trusts should provide training on the correct method of visual inspection of the palate to all healthcare professionals required to carry out the newborn examination. 1

According to the CRANE annual report, in 2015, 28.3% of children born with a cleft palate had a late diagnosis (more than 24 hrs after birth). 4.3% were diagnosed after one month of age and some patients may not yet have had their cleft identified.2 Analysis performed by CRANE over the last five years has shown that diagnosis times for detection of cleft palate have not improved in recent years. This delays referral to specialist cleft centres and more importantly delays valuable input from specialist cleft nurses. We hope that you find this resource as useful as we have.

1. RCPCH. (2014). Palate examination: Identification of cleft palate in the newborn. Lindsey Hunter and Alex Habel
http://www.rcpch.ac.uk/improving-child-health/clinical-guidelines-and-st...
2. CRANE Database. Annual Report 2016. London, Clinical Effectiveness Unit, The Royal College of Surgeons of England. www.crane-database.org.uk

Competing interests: No competing interests

09 October 2017
Sophie Butterworth
Junior Cleft Fellow
David Sainsbury, Peter Hodgkinson
Royal Victoria Infirmary, Newcastle upon Tyne
Northern and Yorkshire Cleft Lip and Palate Service
Re: Limits on working hours may be relaxed after Brexit, warns employment expert Anne Gulland. 359:doi 10.1136/bmj.j4547

I welcome Anne Gulland’s article highlighting the issue of safe working hours for doctors. Many doctors are sleep deprived because of working long hours [1] and as many as 44% of doctors in some medical specialties report disrupted sleep [2]. As well as long hours, other job stressors can contribute to sleep deprivation for doctors and interact with the number of hours worked to make the outcomes quite serious. For example, sleep deprived doctors are more likely to make riskier or impaired medical decisions and errors [1], [3], [4]. The outcomes of sleep deprivation are also quite serious for doctors’ health e.g. it has cardiovascular and immune effects [5] and sleep deprivation also reduces safety e.g. 41% of doctors have fallen asleep while driving home after a night shift [6].

Policymakers considering whether to abolish the concept of safe working hours should therefore consider the impact on disrupted sleep for doctors. Sleep deprivation makes doctors feel more stressed and that, in turn, worsens their clinical performance such as by reducing surgical dexterity [7], mood and confidence – especially for junior doctors [8]. As well as increasing stress, sleep deprivation can increase the risk of doctors having relationship difficulties, depression and committing suicide [1]. There are initiatives into improving sleep for hospital staff working night shifts [9] and research into the effects of sleep deprivation on clinical performance [1], [3], [4], [7], [8] but more research is needed to clarify the long-term effects of sleep deprivation on doctors’ health.

A limit on working hours per week is therefore important because it will protect doctors from sleep deprivation and its consequences.

References

[1] Eddy R. (2005). Sleep deprivation among physicians. BCMJ 2005; 47(4): 176-180.

[2] Medisauskaite, A. and Kamau, C. (2017). Prevalence of oncologists in distress: systematic review and meta-analysis. Psycho-Oncol 2017; Early view: Retrieved from http://doi.org/10.1002/pon.4382

[3] Weinger MB, Ancoli-Israel S. Sleep deprivation and clinical performance. JAMA 2002; 287(8):955-7.

[4] Aran A, Wasserteil N, Gross I, Mendlovic J, Pollak Y. Medical decisions of pediatric residents turn riskier after a 24-hour call with no sleep. Med Decis Making 2017; 37(1):127-33.

[5] Tobaldini E, Cogliati C, Fiorelli EM, Nunziata V, Wu MA, Prado M, Bevilacqua M, Trabattoni D, Porta A, Montano N. One night on-call: sleep deprivation affects cardiac autonomic control and inflammation in physicians. ‎Eur J Intern Med 2013; 24(7):664-70.

[6] British Medical Assocation. More than a third of doctors fall asleep while driving. BMA News 2017; 26 January. Retrieved from https://www.bma.org.uk/news/2017/january/more-than-a-third-of-doctors-fa...

[7] Taffinder NJ, McManus IC, Gul Y, Russell RC, Darzi A. Effect of sleep deprivation on surgeons' dexterity on laparoscopy simulator. Lancet 1998; 352(9135):1191.

[8] Lewis KE, Blagrove M, Ebden P. Sleep deprivation and junior doctors’ performance and confidence. ‎Postgrad Med J 2002;78(916):85-7.

[9] Farquhar, M. We must recognise the health effects associated with shift working. BMJ Opinion 2017; October 6. Retrieved from http://blogs.bmj.com/bmj/2017/10/06/michael-farquhar-we-must-recognise-t...

Competing interests: No competing interests.

Competing interests: No competing interests

09 October 2017
Caroline Kamau
Lecturer
Birkbeck, University of London
Malet Street, London, WC1E 7HX
Re: Gun injuries cost US nearly $3bn a year in hospital charges Gareth Iacobucci. 359:doi 10.1136/bmj.j4641

Trying to prove a point exclusively using numerical data for economic cost can be counterproductive.
Advocates for gun possession might respond that cumulative costs for sophisticated electronic security systems, defensive fences, police patrols, arrests of criminals, detention of jailed offenders, are increased when citizens are prohibited from keeping guns at home.

Competing interests: No competing interests

09 October 2017
Stavros Saripanidis
Consultant in Obstetrics and Gynaecology
Hellas
Re: Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13 Ashlyn Pinto, Ajay Aggarwal, et al. 359:doi 10.1136/bmj.j4530

“We demand rigidly defined areas of doubt and uncertainty!” This quote was lifted from Douglas Adams’ Hitchhiker’s Guide to the Galaxy and is perceived by most to be absurd (those who thought it was extracted from NICE’s Guide to the methods of technology appraisal, go to the bottom of the class).

But you might be forgiven for expressing exactly that sentiment after reading this article. The researchers found that most oncology drugs entering the market between 2009 and 2013 did so without clear evidence of a marked improvement in the quality or quantity of patients’ lives.

However, in order to approve a treatment for use, the European Medicines Agency must conclude that the benefits of introducing a new treatment outweigh the risks. So, how can we be sure that only cancer treatments that are clinically and cost effective become available in the NHS? How do we balance the demand for early access to innovative treatments with the concern that public funds could be wasted? It’s a tough job but one that NICE relishes.

In 2016, there were some important changes to the way we appraised cancer medicines, and NICE and NHS England starting working together much more closely. The Cancer Drugs Fund was reformed to become a managed access fund for promising treatments with significant clinical uncertainty. This means that before a medicine is made available via the Cancer Drugs Fund, a managed access agreement is drawn up. It specifies the data that will be collected to address the uncertainty. The price the NHS pays during the managed access period reflects the level of uncertainty in the evidence. Afterwards, NICE reviews its guidance in light of the new evidence to decide if the treatment can be made routinely available in the NHS.

Perhaps in the context of managed access, ‘rigidly defined areas of doubt and uncertainty’ isn’t such an absurd concept after all!

Competing interests: No competing interests

09 October 2017
Linda J Landells
Associate director - Technology Appraisals (Cancer Drugs Fund) - National Institute for Health and Care Excellence
National Institute for Health and Care Excellence, Level 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT

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