Category Archives: Director’s Choice – From the Journals

Gluten Sensitivity but no Antibodies?

Consider the case of my good friend who developed gluten sensitivity in midlife. Subsequently he went on a gluten-free diet – his wife found this a terrible nuisance. So she surreptitiously re-introduced wheat to his diet. Within no time my friend complained and that he had been wrong, his symptoms had reoccurred despite no apparent exposure to wheat. He was disappointed with his wife when she had to confess to her clandestine challenge to his physiology. But I think she behaved like a true scientist!

The single case represented by my friend has been repeated on a larger-scale many times. The results have been the same; many people with gluten sensitivity manifest symptoms when challenged in blind studies.[1] Furthermore, unlike many types of putative psychosomatic illness, people with gluten sensitivity do not manifest different responses on psychological testing for depression or anxiety compared with those of the general population.

So what is the cause of this somatopsychic condition? It turns out that there are two main theories each with some evidence in their favour.[2] The theory that I prefer is called FODMAPs, based on the idea that wheat is a potent source of fermentable, short chain carbohydrates. These carbohydrates are poorly absorbed and thus ferment in the gut causing the typical symptoms of bloating, distention and discomfort. The alternative theory is that wheat, perhaps in the presence of certain alterations in the microbiome, causes an inflammatory reaction in the liver that is associated with symptoms.

It will be important to discern the cause, since treatment of excessive fermentation would consist of a more general reduction of foods containing large proportions of fermentable carbohydrates.

— Richard Lilford, CLAHRC WM Director

References:

  1. Skodje GI, Sarna VK, Minelle IH, Rolfsen KL, Muir JG, Gibson PR, Veierød MB, Henriksen C, Lundin KEA. Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten Sensitivity. Gastroenterol. 2018; 154: 529-39.
  2. Servick K. The war on gluten. Science. 2018; 360: 848-51.
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Vaccinating Against Mosquitoes

Getting bit by a mosquito could potentially lead to a wide variety of infections – dengue, yellow fever, Zika, malaria, etc. The usual method to try to prevent the spread of these diseases is vaccination, but this is hindered in most of these diseases due to the various sub-types and strain variations. But what if there was another way? That is what Jessica Manning and colleagues are looking into – developing a vaccine against mosquito saliva.[1] When a mosquito bites a person, it first injects its saliva into the blood stream before drinking blood, which triggers the person’s innate immune response. This immune response can then inadvertently help spread any pathogens through the lymphatic system. However, the authors hypothesise that by vaccinating a person against the saliva itself then the body will have a different, targeted immune response, which can hopefully destroy the pathogens before they spread and cause infection. A proof of principle has already been shown in animals that have been vaccinated against sand fly saliva, which prevents infection by Leishmania.

Although there is still a long way to go, it is an interesting approach that should be closely monitored.

— Peter Chilton, Research Fellow

Reference:

  1. Manning JE, Morens DM, Kamhawi S, Valenzuela JG, Memoli M. Mosquito Saliva: The Hope for a Universal Arbovirus Vaccine? J Infect Dis. 2018; 218 (1): 7-15.

A Randomised Trial of the Effect of Theological Training on Health and Welfare Outcomes: Whatever Next

The CLAHRC WM Director’s heroes, Adam Smith and Max Weber, argued that religiosity promotes diligence and wealth.[1] [2] But how to separate the effect of religion from the effect of being the kind of person who is religious? Only a randomised trial could do this. And, yes, it has been done.[3]

One hundred and sixty pastors were recruited for this study, which was based in the Philippines. The pastors each provided 15 weekly meetings to a total of 6,276 poor Filipino households that were randomised to either receive the programme or not. The intervention group had increased religiosity and income, but they were no more satisfied with life. The study suggested that intervention households had improved their levels of hygiene but discord within the family also seemed to increase. What does the CLAHRC WM Director make of this? Firstly, human beings are primed to be receptive to religious messages – they affect us and it was ever thus. However, the effects are not all necessarily beneficial. And, of course, religious instruction introduced later in life is not the same as growing up in a religious family.

— Richard Lilford, CLAHRC WM Director

References:

  1. Smith A. An Inquiry into the Nature and Cause of the Wealth of Nations. London, UK: W Strahan & T Cadell; 1776.
  2. Weber M. The Protestant Ethic and the Spirit of Capitalism. London, UK: Unwin Hyman; 1930.
  3. Bryan GT, Choi JJ, Karlan D. Randomizing Religion: The Impact of Protestant Evangelism on Economic Outcomes. NBER Working Paper Series. Working Paper No. 24278. 2018.

A JAMA Article that Spectacularly Misses the Point

A recent article in JAMA Surgery examined complication rates from bariatric surgery across a large number of hospitals in the US.[1] They found implausibly large differences ranging from 0.6% to 10.3%; a 17-fold difference. There was no real effect of surgical volume on these outcome rates. The authors go on at some length about risk adjustment and sampling variation, thereby spectacularly missing the point. Different observers determined the adverse events in different centres. In general, observers have a very low reliability. Such high Inter-observer variation has been demonstrated for wound infections and anastomotic leak in numerous studies. If you want to compare hospitals, then unless you have a very firm outcome such as death, you must have lots of observers and all the observers must examine different institutions. Those who try to drive up quality and safety need a much more sophisticated understanding of measurement theory.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Ibrahaim AM, Ghaferi AA, Thumma JR, Dimick JB. Variation in Outcomes at Bariatric Surgery Centers of Excellence. JAMA Surg. 2017; 152(7): 629-36.

Intravenous Fluids – Use with Care

So many of the things that were taken for granted when I was training in medicine have been overturned during my subsequent career. In my student days, academic doctors thought they could largely work things out from patho-physiological principles – this was before the rise of clinical epidemiology and ‘evidence-based medicine’. So we gave steroids for head injury, shaving before surgery, enemas before childbirth – the list goes on. Fluid management has changed as much as anything. I remember my (outstanding) professor of surgery, Prof DuPlessis, saying that blood transfusion pre-surgery should be given until blood pressure is fully restored. Wrong – just give enough to give enough to keep vital organs perfused, otherwise you will provoke more bleeding. We were told to replace colloid to maintain intra-vascular volume in shocked patients. Wrong – albumin and starch substitutes leak across damaged capillary membranes and impede organ (brain, kidney, lung) function. The main treatment protocol for children with diabetic ketoacidosis has been slow rehydration with isotonic fluids, as rapid administration was feared to lead to brain injury. Potentially wrong – a recent RCT in the New England Journal of Medicine found no significant differences between various rates of administration.[1] Current guidelines for patients following major abdominal surgery is to administer a restrictive intravenous-fluid strategy. Seems wrong – a recent trial found there were no differences in disability-free survival between patients who underwent a restrictive or liberal fluid regimen, and that the restrictive fluid regimen was associated with a higher rate of acute kidney injury.[2] Use balanced crystalloids rather than saline to avoid salt overload? Probably wrong.[3] Rapidly restore blood volume in shocked children with septicaemia – spectacularly wrong, as discussed in a recent News Blog.[4] So what should you do? How much of what should be used for which patient? I am honoured to chair the steering committee for a large factorial trial of treatment of severe pneumonia in East Africa where two fluid ‘replacement’ regimes will be compared (nasogastric feeds of breast milk / formula milk / cow’s milk vs. intravenous fluid infusion). In the meantime the lesson for doctors may be the same as that for actors – ‘less is more.’

— Richard Lilford, CLAHRC WM Director

References:

  1. Kuppermann N, Ghetti S, Schunk JE, et al. Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis. New Engl J Med. 2018; 378: 2275-87.
  2. Myles PS, Bellomo R, Corcoran T, et al. Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery. New Engl J Med. 2018; 378: 2263-74.
  3. Myburgh J. Patient-Centered Outcomes and Resuscitation Fluids. New Engl J Med. 2018: 378: 862-3.
  4. Lilford RJ. Raising Blood Pressure in Sepsis Patients. NIHR CLAHRC West Midlands News Blog. 13 October 2017.

More on why AI Cannot Displace Your Doctor Anytime Soon

News blog readers will be familiar with my profound scepticism about the role of artificial intelligence (AI) in medicine.[1] I have consistently made the point that there is no clear outcome to much medical process. This is quite different to a game of Go where, in the end, you either win or lose. Moreover, AI can simply replicate human error by replicating faulty parts of human processes. I previously used the example of racial bias in police work as an example.[2] Also, when you take a history, then the questions you ask are informed by medical logic or intuition. And eliciting the correct answer is partly a matter of good empathetic approach, as pointed out beautifully in a recent article by Alastair Denniston and colleagues.[3] So comparing AI with a physician is really comparing a physician with physician plus AI.

A further important article on the limitations of AI that has recently come out in the journal Science.[4] The article explains how AI can outperform human operators on a game of Space Invaders; but if the game is suddenly altered until all but one alien is removed, the AI performance deteriorates. A human player can immediately spot the problem, whereas the AI system is flummoxed for many iterations. The article explains how AI is coming full circle. First, computer scientists tried to mimic expert performance at a task. Then, AI completely bypassed the expert by means of a self-learning neural network. They declared victory when ‘AlphaGo’ beat Go champion Ke Jie. That was the high water mark for AI, and although a few enthusiasts declared victory,[5] serious AI scientists have turned back to human intelligence to inform their algorithms. They are even starting to study how children learn and using this knowledge in AI systems.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Update on AI. NIHR CLAHRC West Midlands News Blog. 1 June 2018.
  2. Lilford RJ. How Accurate Are Computer Algorithms Really? NIHR CLAHRC West Midlands News Blog. 26 January 2018.
  3. Liu X, Keane PA, Denniston AK. Time to regenerate: the doctor in the age of artificial intelligence. J Roy Soc Med. 2018; 111(4): 113-6.
  4. Hutson M. How researchers are teaching AI to learn like a child. Science. 24 May 2018.
  5. Lilford RJ. Computer Beats Champion Player at Go – What Does This Mean for Medical Diagnosis? NIHR CLAHRC West Midlands News Blog. 8 April 2016.

Update on AI

A recent article in Science [1] pointed out that scientists have to tweak their AI systems to get them to give the correct answer. But I have a different problem with AI – how do you know that the supposed right answer is actually right? In a game of Go this issue does not arise. You either win or you lose. But medicine is not like that. The machine may diagnose thyroid cancer. You take a biopsy and find thyroid cancer. But is this not the same thing as cases of thyroid cancer found in clinical practice – the machine may be unmasking cases that would never have come to light.[2] In a previous blog we pointed out that machine learning can replicate human bias – for instance, if police are more likely to charge black male youths than equally offending elderly white women, then the machine will learn precisely the wrong lesson, as pointed out in a previous News Blog.[3]

— Richard Lilford, CLAHRC WM Director

References:

  1. Hutson M. Has artificial intelligence become alchemy? Science. 2018; 360: 478.
  2. Lilford RJ. Thyroid Cancer: Another Indolent Tumour Prone to Massive Over Diagnosis. NIHR CLAHRC West Midlands News Blog. 24 March 2017.
  3. Lilford RJ. How Accurate are Computer Algorithms Really? NIHR CLAHRC West Midlands News Blog. 26 January 2018.

Are You Getting Enough?

Most people are aware of the importance of getting a good night’s sleep, but for many actually achieving this amidst work, household chores, children and needing to binge the latest television series, it is difficult. How dangerous is a lack of sleep though? A recent study [1] looked at data from over 43,000 Swedish people, followed up over 13 years, and found that adults (under the age of 65) who slept for fewer than five hours a night all week have a higher mortality risk compared to those who sleep for six or seven hours (hazard ratio 1.65, 95% confidence intervals 1.22-2.23). However, this could be counteracted by getting longer sleep on the weekend – people who had no more than five hours in the week, but were able to get at least eight hours on the weekend had no increased mortality. On the other end of the scale, the research also found that those people who regularly slept for more than eight hours also had a higher rate of mortality compared to those with six or seven hours (hazard ratio 1.25, 95% CI 1-05-1.50). After the age of 65 there doesn’t appear to be any differences. Of course, it is unknown what the causal relationship is between sleep and mortality, and the authors suggest that underlying health problems could be the cause of both extreme sleep patterns and increased mortality.

— Peter Chilton, Research Fellow

References:

  1. Åkerstedt T, Ghilotti F, Grotta A, Zhao H, Adami HO, Trolle-Lagerros Y, Bellocco R. Sleep duration and mortality – does weekend sleep matter? J Sleep Res. 2018.

Widespread Use of Antibiotics to Reduce Child Mortality

As discussed in our previous News Blog,[1] the rise in antibiotic resistance is a worrying situation, and it is widely recommended to limit the prescription of antibiotics to patients who are confirmed to have a treatable bacterial infection. However, a recent trial in three sub-Saharan African countries did the exact opposite with a mass distribution of azithromycin, a broad-spectrum antibiotic, to children under five with the aim of reducing child mortality.[2] This was a cluster-randomised trial of around 190,000 children in 1,533 communities of Malawi, Niger and Tanzania who were assigned to receive four biannual doses of antibiotic or a placebo. Overall, the mortality rate was 14.6 deaths per 1,000 person-years in areas that received the antibiotic, compared to 16.5 deaths in communities that received the placebo, while mortality was also 13.5% lower (95% confidence interval, 6.7-19.8) (p<0.001). The effect was greatest in the youngest sub-group of children, those aged between one and five months, with the authors estimating that one in four expected deaths were prevented due to administration of the antibiotic. There were no differences in serious adverse events within a week of administration. If this strategy was to be more widely rolled out, one approach to combat resistance developing would be to limit it to the populations most in need and only for a short time.[3]

— Peter Chilton, Research Fellow

References:

  1. Chilton PJ. Non-Antibiotic Medicines May Increase Antibiotic Resistance. NIHR CLAHRC West Midlands News Blog. 18 May 2018.
  2. Keenan JD, Bailey RL, West SK, Arzika AM, for the MORDOR Study Group. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. New Engl J Med. 2018; 378: 1583-92.
  3. Maxmen A. Giving at-risk children pre-emptive antibiotics reduces deaths. Nature. 25 April 2018.

What are the Effects of Body-Worn Cameras on Police and Citizen Behaviour?

There is evidence that people’s behaviour is altered by being watched.[1] After all this is the basis of the original Hawthorne effect. Likewise, people’s propensity to give to charity is increased if they know they are being observed.[2] So, what about body-worn cameras on police officers? Do they result in more temperate behaviour on the part of the police themselves, and/or the citizens with whom they come into contact?

To find out, a randomised trial was conducted in the US.[3] Most police people randomised to wear the body camera did so, while those in the control group did not. Intention to treat principles were followed. Four types of endpoint were used: use of force, civilian complaints, policing activity, and judicial outcomes.

Before reading on, do you want to guess the result?

102 DCiii - Police Body-Worn Cameras

Well, the results were null. In fact, the direction of effect is (non-significantly) towards more complaints, more instances of use of force, and more people prosecuted. The proportion of people arrested who were then found guilty was almost identical across groups.

This was a large study and could have detected moderate effects. The study was carried out in one particular district, so the results might be context-specific. It could be argued that the control group changed its behaviour as a result of contamination, but this is unlikely as no change was found over time. Use of force was self-reported, and so this might have affected the results. Quite a few locations have community cameras for surveillance and this might have reduced the marginal effect of a body-worn camera. If so, this is yet another example of the rising tide phenomenon described by CLAHRC WM.[4]

— Richard Lilford, CLAHRC WM Director

References:

  1. King D, Vlaev I, Everett-Thomas R, Fitzpatrick M, Darzi A, Birnbach DJ. “Priming” Hand Hygiene Compliance in Clinical Environments. Health Psychol. 2016; 35(1): 96-101.
  2. Ekström M. Do Watching Eyes Affect Charitable Giving? Evidence from a field experiment. Exp Econ. 2012; 15(3): 530-46.
  3. Yokum D, Ravishankar A, Coppock A. Evaluating the Effects of Police Body-Worn Cameras: A Randomized Controlled Trial. Washington, D.C.: The Lac @ DC; 2017.
  4. Chen YF, Hemming K, Stevens AJ, Lilford RJ. Secular trends and evaluation of complex interventions: the rising tide phenomenon. BMJ Qual Saf. 2016; 25: 303-10.