Category Archives: Director’s Choice – From the Journals

Making Mosquitoes Feel Full

Mosquitoes are responsible for transmitting a number of highly dangerous diseases when they feed on human blood, but it has been noticed that once they have fed they no longer bite until their eggs are laid a few days later. A neurobiologist at the Rockefeller University wondered if this fact could be exploited in some way, and set out to see if it was possible to suppress a mosquito’s appetite.[1] In humans, appetite-suppressant drugs target neuropeptide Y (NPY) receptors, and these are also involved in the food-seeking behaviour of many other animals. When the researchers fed mosquitoes with a solution containing NPY-activating drugs they found that they were less likely to approach a ‘lure’ than the control group, an effect that lasted for two days. Using CRISPR gene-editing they created mosquitoes with a mutation in the gene encoding the NPY-like receptor 7 protein and found that the drug no longer had any effect, suggesting that this gene was the key. Following this they worked on screening for compounds that could suppress the appetites of mosquitoes, but not humans, and identified six such potential compounds. Although there is still a large amount of work to be done (very high concentrations are needed; lures that mimic humans are costly and complicated; other insects may feed on the compounds in the wild; etc.) it certainly shows promise that transmission can be decreased.

— Peter Chilton, Research Fellow

Reference:

  1. Duvall LB, et al. Small-Molecule Agonists of Ae. aegypti Neuropeptide Y Receptor Block Mosquito Biting. Cell. 2019; 176: 687-701.
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Statins, Yes More on Statins

An interesting paper in the BMJ examines the effects of statins specifically in people over the age of 75.[1] It finds that while they reduce cardiovascular mortality in people with diabetes, they have no such protective effect in people over the age of 75 who do not have diabetes. The study was based on a retrospective cohort of nearly 50,000 people over 65 years old from a routine database in Spain.

This result seems at variance with the limited evidence beyond the age of 75 in randomised trials. The interesting question relates to possible bias in non-randomised evidence. Database studies, in addition to possible confounders not included in the model, can suffer from survival bias. This subtle, but important, bias results from a control group that misses out people who would have survived to take the intervention in the intervention group.  This study mentions this form of bias, in one sentence, but does not say much more about it, though they did apply something called prescription time-distribution matching.  I did not fully understand this but take it to be a method to mitigate survival bias.

Taken in the round, I think this study leaves the jury out as far as statins in older people are concerned. One thing it does confirm is that statins have a bigger net benefit in people with diabetes than in age-controlled, non-diabetic people.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Ramos R, Comas-Cufí M, Martí-Lluch R, et al. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study. BMJ. 2018; 362: k3359.

Gene-Editing Bananas

Bananas are a staple food in many low- and middle-income countries; however, many have a virus within – the Banana Streak Virus (BSV). This virus is integrated inside the DNA of the banana’s genome and becomes active when the banana plant is stressed by heat or drought, which can result in the destruction of the entire plantation. It can also be triggered through propagation methods, meaning BSV is a major constraint in banana breeding programmes. Researchers from the International of Tropical Agriculture in Kenya recently used CRISPR gene editing to inactive the virus, resulting in 75% of edited bananas remaining asymptomatic when placed in stressful conditions (compared to non-edited controls).[1] It is hoped that not only we can use these edited plants to breed virus-free plants for farmers, but we can also utilise the technique to safeguard the future of the Cavendish variant of bananas. Cavendish bananas account for the vast majority of bananas in international trade, but they are threatened by Tropical Race 4 a fungal disease. As the Cavendish is sterile, it is not possible to breed resistant varieties, so CRISPR editing offers an opportunity to introduce resistance.

— Peter Chilton, Research Fellow

Reference:

  1. Tripathi JN, Ntui VO, Ron M, et al. CRISPR/Cas9 editing of endogenous banana streak virus in the B genome of Musa spp. overcomes a major challenge in banana breeding. Comm Biol. 2019.

Is It All About Good Management? Not According to Data About Football Managers

News blog readers know that the CLAHRC WM Director is interested in the variance in performance due to training and the environment versus in the innate features of individuals. The word from the herd suggests that good management can get extraordinary performance from ordinary people. However, the evidence does not bear that out.

Analysis of league football confirms the above finding.[1] And analysis of five top leagues from 2004 to 2018 showed players, even at an individual level, had more influence on the performance of their team than the managers. When a star manager moves to a new job they are no more likely to be in the top then in the bottom half of distribution by results.

Of course this does not mean we should be nihilistic about good managers. But nor should we reify them. Good frontline workers and luck are probably more important.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. The Economist. Managers in Football Matter Much Less Than Most Fans Think. The Economist. 19 Jan 2019.

Case Study of Physician Associates

Health care is becoming increasingly complex as a result of the developments in therapy and changing demography. Health care is a massive service industry and one of the largest parts of the economy in high-income countries. Like most service industries, health care relies heavily on human resources, and costs can be controlled by skill substitution from more expensive people making judgements under uncertainty to less expensive people operating in a more algorithmic way. So it is interesting to read an account of physician associates recently published in the BMJ Open.[1] The UK will soon graduate over 3,000 physician associates per year – about a third as many as the number of doctors. So it is good to learn from this paper that they are well accepted in hospital practice by staff and patients alike, and appear to function effectively. In other countries they may prescribe medicines and x-rays with prohibition. The UK should follow suit with respect to medicines that are widely used and have high therapeutic indices. I also think physician associates may have a larger role in primary care in the future.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Drennan VM, Halter M, Wheeler C, et al. What is the contribution of physician associates in hospital care in England? A mixed methods, multiple case study. BMJ Open. 2019; 9: e027012.

Big Science: the Global Virome Project

Most pandemics have a viral aetiology of animal origin. Each is followed by a scramble to produce a vaccine. How much better then, to prepare all these vaccines in advance. The problem is that it is estimated that there are going on 1 million potential viruses that could spread from animals to humans. Identifying this number of viruses would be a gargantuan task, never mind producing vaccines for each one.

Enter the massive global virome project.[1] However, by focusing on the most high risk sources of viral zoonoses, the GVP team predict that they could do the task for a mere $1.2 billion.

The project is now underway, funded largely by USAID. The, now completed, pilot project cost $170 million, and seems to have found only about 1,000 new risky viruses.

This is a massive project but it has a long way to go before we can feel safe about the next pandemic.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Carroll D, Daszak P, Wolfe ND, et al. The Global Virome Project. Science. 2018; 359: 872-4.

Sleep for a Healthy Heart

We have talked before in this blog about the effect a lack of sleep has on health,[1-2] and now there is evidence of another potential risk.[3] Research published in the Journal of the American College of Cardiology looked at almost 4,000 participants, separated into four groups based on sleep duration, as measured by actigraph. The authors found that, after adjusting for risk factors, sleeping for fewer than six hours was independently associated with an increased risk of subclinical atherosclerosis (build up of plaque in the arteries), when compared to people who slept between seven and eight hours (p=0.008, odds ratio 1.27, 95%CI 1.06-1.52). There was also an association seen in people with the highest proportion of fragmented sleep (p=0.006, OR 1.34, 95%CI 1.09-1.64). Interestingly there was also an association between sleeping more than eight hours and an increased risk, but only in women, and the number of participants who fell into this category was small.

Although previous studies have shown a link between sleep duration and risk of cardiovascular disease, this study used a healthy population and measured atherosclerosis levels throughout the body, not just around the heart.

— Peter Chilton, Research Fellow

References:

  1. Lilford RJ. The CLAHRC WM Director Should Get More Sleep. NIHR CLAHRC West Midlands News Blog. 14 December 2018.
  2. Chilton P. Are You Getting Enough? NIHR CLAHRC West Midlands News Blog. 1 June 2018.
  3. Domínguez F, Fuster V, Fernández-Alvira JM, et al. Association of Sleep Duration and Quality with Subclinical Atherosclerosis. J Am Coll Cardiol. 2019; 73(2).

Do Physicians From Higher Ranking Medical Schools Get Better Patient Outcomes?

Here is another fascinating paper deriving its data from Medicare services.[1] The authors took a random sample of nearly 1,000,000 patients age 65 or over who had been admitted to hospital as an emergency. They looked to see whether physicians from higher ranking medical schools achieved better mortalities, lower spending or lower rates of readmission. There were no differences whatsoever in mortality, despite the very high precision afforded by a study of nearly 1,000,000 patients. Spending per patient was slightly lower among the physicians from high ranking medical schools than among their colleagues from lower ranking schools. Two different rankings were used – for one of these the alumni of higher ranking schools had lower readmission rates, whereas there was no difference when the other ranking system was used.

It is known that there is quite a large variation in practice between doctors, but the variation between doctors would seem to be much greater than the variation between the graduates of different medical schools. Of course, the outcome as measured here might not be highly sensitive to a physician quality. It is likely that process measures would be a more sensitive reflection of performance than summary measures such as mortality and readmission rates. In fact, this is born out when propensity to write opioid prescriptions are compared, showing that graduates from lower ranking schools are more likely to overprescribe.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Tsugawa Y, Blumenthal DM, Jha AK, Li KT, Orav EJ, Jena AB, Newhouse RL. Association between physician US News & World Report medical school ranking and patient outcomes and costs of care: observational study. BMJ. 2018; 362: k3640.

Mental Health Disorders: Discrete Entities or the Extreme in a Population Distribution of Attributes?

A few years ago I wrote a News Blog post about the prevention of non-psychotic and non-severe mental illness.[1] My argument was, simply put, that there is too much mild mental illness going around for treatment to be the sensible approach to the problem. I read that ‘up to 30% of people are depressed.’ That does not ring true. To me that sounds like saying that 30% of people are short – in other words if you put the cut-off at x%, then defining the ‘affected’ population size by that cut off is tautologous. So my argument is that the milder forms of mental illness are simply the lower reaches of a population distribution. In that case, said I, let’s not exhaust ourselves providing hot and cold running therapists of various hews, let’s rather shift the distribution. Hence my argument for psychoprophylaxis – reduce bullying in schools, improve workplace culture, reduce loneliness, and so on.

This non-psychiatrist, having weight in on a psychiatric topic, what do I find but another much more prominent non-psychiatrist, England’s Chief Medical Officer no less, weighs in on the opposite side of the argument![2] The argument in this beautifully written Lancet paper is that ‘being a mental health ‘case’ may not simply reflect the lower end of a distribution where lots of factors (many gene / social interactions) determine phenotype in a way that cannot be unravelled, rather it is argued, non-psychotic mental health conditions have a specific aetology and correspondingly a specific treatment.’ Divesting resources to shifting the distribution may not improve outcomes for the ‘disease’ group. So they are arguing, as far as non-psychotic, non-severe diseases, that they are more like cystic fibrosis or rheumatoid arthritis than being short or not terribly good at maths.

This is difficult territory because, while there are some conditions that really are very specific, most are multi-factorial. So at the extreme we have conditions that stand alone, like cystic fibrosis (and most single gene diseases), and/or that have a specific aetiology, like brain trauma. A population distribution would look like this:

118dcii-fig1

Some times the feature is superimposed on a distribution, such as this for height or cognitive ability.

118dcii-fig2

Severe mental illness would have a distribution similar to the first pattern:

118dcii-fig3

But depression and anxiety – what pattern do they follow?

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. The New and Growing Interest in Mental Health: Where Should it be Directed? NIHR CLAHRC West Midlands News Blog. 9 June 2017.
  2. Pearson-Stuttard J, Murphy O, Davies SC. A new Health Index for England: the Chief Medical Officer’s 2018 annual reportLancet. 2019; 393:10-11.

Fish oil supplementation in pregnancy and the size and body composition of the progeny

Almost 25 years ago I carried out a randomised trial of fish oil in pregnancy, finding no improvement in pre-eclampsia or fatal condition at birth.[1] This finding was subsequently corroborated by meta-analyses of subsequent trials, as well as my own.[2]

Well, birth outcome is one thing, but what about the growth of the children resulting from pregnancies with or without supplementation?

Vinding and colleagues report a randomised trial that specifically aimed to determine the effects of fish oil supplementation in pregnancy on the body composition and growth of children over the first six years of life.[3]

They randomised 523 pregnant women and provided either fish oil or olive oil supplements from 24 weeks of pregnancy to the child was six years old. They found significantly higher body lean mass and bone mineral content, but not fat mass in the fish oil supplemented children.

I guess the real question, however, is the effect of these apparently beneficial changes on long-term health. Sadly, this trial will be woefully underpowered to detect an effect on these long-term outcomes.

— Richard Lilford, CLAHRC WM Director

References:

  1. Onwude JL, Lilford RJ, Hjartardottir H, Staines A, Tuffnell D. A randomised double blind placebo controlled trial of fish oil in high risk pregnancy. Br J Obstet Gynaecol. 1995; 102(2): 95-100.
  2. Middleton P, Gomersall JC, Gould JF, Shepherd E, Olsen SF, Makrides M. Omega-3 fatty acid addition during pregnancyCochrane Database Syst Rev. 2018; 11: CD003402.
  3. Vinding RK, Stokholm J, Sevelsted A, et al. Effect of fish oil supplementation in pregnancy on bone, lean, and fat mass at six years: randomised clinical trial. BMJ. 2018; 362:k3312.