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.
Advertisements

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.

50 Year Anniversary of the First Human Heart Transplant: Lessons for Today

On 3 December we commemorated the 50 year anniversary of the world’s first heart transplant. The operation took place in the early hours of a Saturday morning at the Groote Schuur hospital in Cape Town, South Africa. Christiaan Barnard sutured Denise Darvall’s donated heart into the chest of the recipient, Louis Washkansky. Barnard restarted the new heart with an electric shock and then tried to wean the recipient off the heart and lung machine. But the new heart could not take the strain and Washkansky had to go back on the machine. The second attempt also failed, but when the heart and lung machine was turned off for the third time the recipient’s blood pressure started to climb. It kept on climbing, and soon Denise Darvall’s small heart had taken over the perfusion of Louis Washkansky’s large frame. Later that morning the world woke to the news of the world’s first heart transplant. Looking back over fifty years what should we make of Barnard’s achievement?

The transplant in an historical perspective

The two decades preceding the heart transplant have sometimes been referred to as the golden age of medical discovery.[1] The transplant can be ‘fitted’ retrospectively as the culmination of this golden age just as Neil Armstrong’s moon walk, two years later, can be seen as the crowning achievement of the space race. They belong to a number of technical achievements, including the first “test tube” baby and the first man in space, which are emblematic of human progress. They generate great public interest and media attention, but differ from more fundamental intellectual discoveries, such as the double helix in DNA or Higgs boson, that are rewarded with Nobel prizes.

The heart transplant in the ‘heroic’ medical age

In his book ‘One Life’ Barnard provides an interesting cameo of the power and autonomy of the medical profession in his time.[2] He recalls writing up the routine operation note that must follow any surgical procedure. The anaesthetist, ‘Oz’, suggested that Dr Jacobus Burger, the hospital superintendent, should be informed. Barnard asked whether he should wake him so early in the morning, but Oz replied that the night’s events warranted such an intrusion. At first the befuddled Dr Burger, aware if work in the animal lab, thought that he was being informed about another heart transplant in dogs. However, even when he learned that the transplant involved a human heart, he cryptically thanked the surgeon and replaced the receiver. Nowadays, the idea of carrying out a procedure of such novelty, cost and risk without formal sanction would be unfathomable. The vignette from the doctor’s tearoom vividly illustrates how the relationship between the medical profession and the broader society has changed over one generation. Rene Amalberti argues [3] that many professions progressed through a heroic age in the twentieth century before gradually becoming more formalised and regulated – aviation followed a similar trajectory following Charles Lindbergh’s dramatic flight across the Atlantic in 1927.

Gradually changing ethical norms

The ethics of heart transplants relate mainly to organ donation. In ‘One Life’ Barnard describes the tense atmosphere in the operating room as the team waited for the donor heart to stop after turning off Darvall’s ventilator. In fact, they did not wait, and Barnard’s brother Marius has stated he persuaded Christiaan to stop the donor heart by injecting a concentrated dose of potassium in order to give Washkansky the best chance of survival. Today two different doctors need to independently carry out tests to confirm the donor is brain stem dead before the heart can be removed, as opposed to waiting for death by the whole-body standard, i.e. when there is brain death and the heart has stopped beating.

Public views of heart transplants, then and now

Following the operation the exhausted Barnard went home for a sleep. In the afternoon he returned to the hospital where he was surprised to find his route obstructed by a large crowd of reporters. He had unleashed a tide of publicity and acclaim that resonated for many decades, but dissenting voices were also heard. Some, notably Malcolm Muggeridge, the editor of Punch magazine, attacked the operation on the basis of a near mystical reverence for the human heart and to this Barnard had a succinct response: “it’s merely a pump.” Others worried about the allocation of scarce resources to such a high-tech solution when people were dying from malnutrition and malaria. Defence of the procedure came, albeit years later, from the economics profession when it was shown that the operation has a highly favourable cost-to-benefit ratio (at least in a high-income country).[4] The procedure not only extends life by many years on average, but greatly improves the quality of that life. In fact, patients feel much better from the moment they regain consciousness after the operation despite pain from the sternotomy. The operation is now uncontroversial and is performed routinely in high-income countries. It was long predicted that a mechanical pump would supplant the need for transplantation. Mechanical hearts have improved,[5] but they are largely seen as a bridge to transplantation, rather than a better alternative.

If Christiaan Barnard had not performed his operation, heart transplants would have developed anyway (the second transplant was carried out independently by Adrian Kantrowitz in the USA on 6 December). I was a school boy with hopes of getting into medical school when Washkansky received his new heart. I was among the many millions who were swept up in the wonder of the event and it still stirs my imagination half a century later. And my family knows that I wish to donate my own heart if the circumstances arise.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Future Trends in NHS. NIHR CLAHRC West Midlands. 25 November 2016.
  2. Barnard C & Pepper CB. One Life. Toronto, Canada: Macmillan; 1969.
  3. Amalberti R. The paradoxes of almost totally safe transportation systems. Saf Sci. 2001; 37(2-3): 109-26.
  4. O’Brien BJ, Buxton MJ, Ferguson BA. Measuring the effectiveness of heart transplant programmes: Quality of life data and their relationship to survival analysis. J Chron Dis. 1987; 40(s1): s137-53.
  5. Girling AJ, Freeman G, Gordon JP, Poole-Wilson P, Scott DA, Lilford RJ. Modeling payback from research into the efficacy of left-ventricular assist devices as destination therapyInt J Technol Assess Health Care. 2007; 23(2): 269-77.

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.

Is Research Productivity on the Decline Internationally?

I have written previously on the so-called ‘golden age of medical research,’ [1] which coincides roughly with the first two decades of my life – 1950-1970. The premise of a golden age entails the conclusion that it is followed by a less spectacular age where marginal returns are lower per unit of input – say per researcher. So, where does the truth lie – is research becoming ever more efficient, or is the productivity of research declining? This subject has been carefully examined by a number of scholars, most recently by Bloom and others.[2] First they looked at aggregate supply of researchers and economic output across the US economy, and they found a relationship that looks like this:

091 DCB Figure 1

So, productivity per researcher appears to decline with time and does so quite rapidly – the graph uses log scales. The drop in unit productivity has been fully compensated by growth in the number of researchers.

Given the obvious problems of studying this phenomenon at the aggregate level, the researchers turn to individual topics, such as number of transistors packed onto a single chip. It turns out that keeping Moore’s law going takes a rapidly increasing number of researchers. However, diminishing returns are not just observed in electronics, the authors found the same phenomenon in agriculture and medicine. Research productivity in the pharmaceutical industry is one-tenth of what it was in 1970, and mortality gains have peaked in cancer and in heart disease. To some extent one can see this effect in the number of authors of medical papers, such as those in genetic epidemiology – they often run literally into hundreds. It would appear that ideas really are getting harder to find and/or when found they portend smaller gains.

I have previously made the obvious point that improved care reduces the headroom for future improvements.[3] Of course, economic growth and further improvement in health still turn on new knowledge and technology without which the supply-side of the economy must stagnate. The phenomenal growth of some emerging economies has been possible because of the non-rivalrous nature of previous discoveries made elsewhere. But we need to continue to advance for all that advances are hard to make. One of these advances concerns making optimal use of existing knowledge, and that is where CLAHRCs come into their own – we trade in knowledge about knowledge.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Future Trends in NHS. NIHR CLAHRC West Midlands. 25 November 2016.
  2. Bloom N, Jones CI, Van Reenen J, Webb M. Are Ideas Getting Harder to Find? Centre for Economic Performance Discussion Paper No. 1496. 2017.
  3. Lilford RJ. Patient Involvement in Patient Safety: Null Result from a High Quality Study. NIHR CLAHRC West Midlands. 18 August 2017.

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.