Category Archives: Director’s Choice – From the Journals

Oh Dear – Evidence Against Alcohol Accumulates

Yes, more research [1] [2] on alcohol – increases in cancers of mouth, throat and oesophagus. Not good places to have cancer. Direct contact of C2-H5-OH with the membrane is the likely causal mechanism. So here is an hypothesis – the more dilute a given amount of alcohol, the better. So I think beer > wine > spirits, ceteris paribus. I guess this has been tested? But next week I may have some more reassuring news for us oenophiles.

— Richard Lilford, CLAHRC WM Director

References:

  1. LoConte NK, Brewster AM, Kaur JS, Merrill JK, Alberg AJ. Alcohol and Cancer: A Statement of the American Society of Clinical Oncology. J Clin Oncol. 2017; 35: 1-11.
  2. The Lancet. Alcohol and cancer. Lancet. 2017. 390: 2215.
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Intensive Care Harmful in Elderly Patients

An intervention to promote use of intensive care in elderly patients (over age 75) was evaluated in a cluster RCT of 20 French hospitals.[1] The intervention worked in the narrow sense that it did increase the rate of admission to the intensive care unit (ICU) (by nearly 70%). But did this result in improved survival? Not at all – in fact there was a statistically significant increase in death rates in the hospitals randomised to have lower thresholds for ICU care; both in hospital (18% increase) and at 6 months (16% increase). So a conservative policy dominates – it is both less expensive and more effective in old people. But this paper should make one think – how effective is ICU for other groups of patients? Apart from looking after people who need a breathing machine, is ICU really an effective treatment at all? It is highly invasive and intrusive. I am not a therapeutic nihilist, but one does have to wonder. Perhaps we should design a less intensive form of intensive care? Such an approach could be evaluated in RCTs before advocating global use of the current standard ICU model in high-income countries. Let me annoy my colleagues by proposing a hypothesis. ICU types think that it is the monitoring and fiddling with vital signs that saves lives. I think the main effect is better diagnosis – because patients are scrutinised carefully by highly trained people, conditions are spotted that would otherwise be missed. Just a thought!

I would like to thank News Blog reader Gus Hamilton for drawing my attention to this article.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Guidet B, Leblanc G, Simon T, et al. Effect of Systematic Intensive Care Unit Triage on Long-term Mortality Among Critically Ill Elderly Patients in France: A Randomized Clinical Trial. JAMA. 2017; 318(15): 1450-9.

Sudden Death in Sport is Rare

People with established health issues have an increased risk of sudden death during vigorous exercise. But the general population has a very low risk of death with strenuous exercise (any activity that increases metabolic rate by at least 6 times [i.e. >6 METs]) [1] – less than one death per 100,000 athlete years according to a recent study of deaths in people between the ages of 25 and 45, ascertained through an ambulance service.[2] But what about people older than 45, among whom I am numbered?!

— Richard Lilford, CLAHRC WM Director

Reference:

  1. World Health Organization. What is Moderate-Intensity and Vigorous-Intensity Physical Activity? [Online].
  2. Landry CH, Allan KS, Connelly KA, Cunningham K, Morrison LJ, Dorian P; for the Rescu Investigators. Sudden Cardiac Arrest during Participation in Competitive Sports. New Engl J Med. 2017; 377(20): 1943-53.

More on Mendelian Randomisation

News Blog readers know that the CLAHRC WM Director loves Mendelian randomisation studies, originally proposed by his erstwhile colleagues, Gray and Whitley.[1] The method has been used to crack open the story regarding lipids and coronary artery disease.[2] Everyone knows that low density lipoproteins are bad news – these fats clog up arteries. The association is confirmed by Mendelian studies. But what about those two old chestnuts, high density lipoproteins (HDLs) and triglycerides? In observational studies HDLs are consistently associated with reduced risk of coronary disease.[3] While triglyceride levels are associated with increased coronary risk, this effect disappears once confounders have been controlled in multi-variable analysis.[3] However, Mendelian randomisation tells a completely different story – HDLs are not associated with coronary risk, while triglycerides are.[4] [5] What is going on here? That is to say, why do the observational studies and the Mendelian studies give such different answers with respect to HDLs and triglycerides? More curious still, why does the association between triglyceride and coronary artery disease confirmed by Mendelian randomisation disappear after controlling for confounders? This is not entirely clear, but as HDL levels drop, so triglycerides tend to rise. Hence controlling for triglyceride levels when examining HDLs, and vice-versa, will give the wrong result. This may be yet another example of ‘over controlling’ but including in a multi-variable analysis / logistic regression variables that have a causal interaction with the explanatory variable of interest.[6]

— Richard Lilford, CLAHRC WM Director

References:

  1. Gray R & Wheatley K. How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant. 1991;7(s3):9-12.
  2. Emdin CA, Khera AV, Kathiresan S. Mendelian Randomization. JAMA. 2017; 318(19): 1925-6.
  3. Di Angelantonio E, Sarwar N, Perry P, et al.; Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009; 302(18): 1993-2000.
  4. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013; 45(11): 1345-52.
  5. Frikke-Schmidt R, Nordestgaard BG, Stene MCA, et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischaemic heart disease. JAMA. 2008; 299(21): 2524-32.
  6. Lilford RJ. A Very Interesting Paper Using Mendelian Randomisation to Determine the Effect of Extra Years of Education on Heart Disease. NIHR CLAHRC West Midlands News Blog. 10 November 2017.

Reducing Radiation Risk from Hospital Scans

Even though it is something carried out in hospitals hundreds of times a day, X-rays and CT (computed topography) scans are procedures that expose the patient to radiation. Yes, the radiation dosage for the majority of scans carried out is very little when compared to every day exposure; for example an X-ray of the arm is 0.001 mSv (millisievert), a dental X-ray is 0.005 mSv, a chest X-ray is 0.020 mSv – in comparison the average background radiation received over one day is 0.010 mSV, while someone flying across the continental USA would receive 0.040 mSV. However, other scans are higher, a mammogram is 0.400 mSv (equivalent of 40 days worth of exposure in one dose), while a head CT scan gives a dose of 2 mSv (equivalent to ~7 months) and a chest CT scan 7 mSv (equivalent to ~20 months) (see the below image from Randall Munroe for more examples).

Although the cells in our body are able to repair and restore DNA damage resulting from radiation, the greater the dose received in one go, and the greater received in the long-term, the more likely it is that damage won’t be repaired correctly. Thus, we should aim to reduce patients’ exposure to radiation where possible. A recent paper by Kitchen and colleagues may have an answer by using phase-contrast x-ray imaging.[1] Because soft tissue has similar X-ray absorption properties to bone, which results in poor image contrast the radiation dosage has to be increased in standard scans. This new technique combines CT scans with phase retrieval and an algorithm to define edges, densities, etc. and results in a reduction in dosage by a factor of 300 fold (with the potential for a reduction factor in the tens of thousands), while still retaining equivalent image quality. Although the study only tested this in an animal model it is an important first step.

092 DCvi - radiation

— Peter Chilton, Research Fellow

Reference:

  1. Kitchen MJ, Buckley GA, Gureyev TE, et al. CT dose reduction factors in the thousands using X-ray phase contrast. Sci Rep. 2017; 7: 15953.

Antioxidants and Age-Related Macular Degeneration

It is estimated that around 5% of the general population suffer from age-related macular degeneration (AMD),[1] where extracellular material known as drusen accumulate under the retina at the back of the eye and which can eventually lead to blurred or a loss of vision. It has been suggested that antioxidants may help prevent or delay development of AMD in people who do not suffer the condition by protecting the retina against oxidative stress, but it is unclear as to whether this is the case.

A systematic review in the Cochrane Database by Evans and Lawrenson looked at the effectiveness of antioxidant supplements as treatment in people who already had AMD,[2] and found that taking a multivitamin antioxidant vitamin may delay the progression of AMD when compared to a placebo or no treatment (odds ratio 0.72, 95% CI 0.58-0.90). The authors also conducted a systematic review looking at whether there was an association between taking antioxidant vitamins (carotenoids, vitamin C, vitamin E) or minerals (selenium, zinc) and the development of AMD in people without AMD.[3] Five RCTs were included, with a total of 76,756 individuals without AMD. These studies all looked at the use of various supplements against placebo. Generally, the various studies found that there was no effect of supplements on development of AMD, while in some cases there was evidence of an increased risk (see table below).

Comparison No. of studies Disease Risk Ratio (95% Confidence Interval)
Vitamin E vs. placebo 4 AMD 0.97 (0.90-1.06)
Late-stage AMD 1.22 (0.89-1.67)
Beta-carotene vs. placebo 2 AMD 1.00 (0.88-1.14)
Late-stage AMD 0.90 (0.65-1.24)
Vitamin C vs. placebo 1 AMD 0.96 (0.79-1.18)
Late-stage AMD 0.94 (0.61-1.46)
Multivitamin vs. placebo 1 AMD 1.21 (1.02-1.43)
Late-stage AMD 1.22 (0.88-1.69)

— Peter Chilton, Research Fellow

References:

  1. Owen CG, Jarrar Z, Wormald R, Cook DG, Fletcher AE, Rudnicka AR. The estimated prevalence and incidence of late stage age related macular degeneration in the UK. Br J Ophthalmol. 2012; 96(5): 752-6.
  2. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Sys Rev. 2017; 7: CD000254.
  3. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Sys Rev. 2017; 7: CD000253.

A Thoughtful Article on Unprofessional Behaviours

A recent article in BMJ Quality and Safety cites evidence that unprofessional behaviour is associated with (and likely causal of) unsafe practice.[1] This is an intriguing finding from a number of studies and has verisimilitude. These are not experimental studies and so cause and effect remains unproven. Nevertheless, there are good theoretical reasons for accepting a cause and effect explanation. In any case, it is good to exhibit professional behaviour, net of any technical association.

As to how to improve ‘professionalism’, that is a more complex matter. I think it would be very hard to select for this attribute, but I also suspect that cognitive ability and great role models are important in generating this, and other types of, desired behaviour.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Wong BM & Ginsburg S. Speaking up against unsafe unprofessional behaviours: the difficulty in knowing when and how. BMJ Qual Saf. 2017; 26: 859-62.

Diagnosing CTE in Living Patients

Earlier this year our News Blog included a study looking at the brains of former American footballers, which found chronic traumatic encephalopathy (CTE) was present in 110 of 111 footballers who had played in the National Football League (NFL).[1] [2] However, this can only be seen during autopsy, and, at present, we are only able to make a presumptive diagnosis of CTE while the patient is alive. Now a study published in Neurosurgery [3] has found that it may be possible to diagnose CTE in living patients. PET imaging was conducted on the brain of a footballer 52 months prior to this death, and after autopsy, it was found that data from the PET scan (showing the level of binding of a molecular imaging probe) correlated significantly with deposition of tau proteins in the brain (P=0.02). Although this is only a single patient, further investigation is warranted, which could confirm whether PET scanning is a useful diagnostic tool in patients at high-risk of CTE – not only American footballers, but also military personnel.

— Peter Chilton, Research Fellow

References:

  1. Lilford RJ. Two Hundred and Two Ex-(American) Footballers’ Brains Analysed After Death – This You Must Read. NIHR CLAHRC West Midlands News Blog. 15 September 2017.
  2. Mez J, Daneshvar DH, Kiernan PT, et al. Clinopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA. 2017; 318(4): 360-70.
  3. Omalu B, Small GW, Bailes J, et al. Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy. 2017.

The Scent of a Woman – Not as Important as Once Thought

It is a good story – given sweaty t-shirts, women sniff out those men whose HLA (human leucocyte antigen) type is convivial to reproduction.[1] However, it does not appear to be true for men sniffing the odours of women – at least according to a careful study of HLA-linked olfactory preferences for odours gathered just before ovulation.[2] Men readily differentiated between odours they preferred or disliked, but these preferences did not correlate with HLA types.

— Richard Lilford, CLAHRC WM Director

References:

  1. Wedekind C, Seebeck T, Bettens F, Paepke AJ. MHC-dependent preferences in humans. Proc Biol Sci. 1995; 260 (1359): 245–49.
  2. Probst F, Fischbacher U, Lobmaier JS, Wirthmüller U, Knoch D. Men’s preferences for women’s body odours are not associated with human leucocyte antigen. Prof R Soc B. 2017; 384: 20171830.

Snake Bites, a Much More Serious Problem Than you Thought

I hate snakes. It turns out that I hate them with due cause! Snake bites are responsible for 50,000 deaths per year in India alone and that is thought to be a considerable underestimate.[1] Most snakes bite in the day or early evening and most cause considerable pain at the location of the bite. Not so the common krait (Bungarus caeruleus).[2] The krait hunts by night and most of its bites occur after midnight. The poison is ten times more potent than that of the cobra. Fully one-third of krait bites are fatal. People are often bitten while sleeping on the ground. The krait’s teeth are like small needles, so the victim often does not know that they have been bitten. The victim will soon present with abdominal pain and descending paralysis, and may even become ‘locked in’.

Access to care is a big problem following snake bites, since every hour counts. However, mis-diagnosis, lack of anti-venom, and lack of ventilators all contribute to the high mortality rate from snake bites. The biggest problem is probably access, and thousands of people die through neglect. This is just one of many diseases that could be more successfully tackled if access to places of care was improved, a topic I am pursuing as part of Dion Morton’s NIHR Unit on Global Surgery.

— Richard Lilford, CLAHRC WM Director

References:

  1. Mohapatra B, Warrell DA, Suraweera W, et al. Snakebite mortality in India: a nationally representative mortality survey. PLoS Negl Trop Dis. 2011; 5: e1018.
  2. Bawaskar HS, Bawaskar PH, Bawaskar PH. Snake bite in India: a neglected disease of poverty. Lancet. 2017; 390: 1947-8.