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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Engaging with Engagement

Engagement is easy. We are in a fortunate position in CLAHRC West Midlands that there is seemingly a long queue of people keen to talk to us about interesting and exciting health and social care projects. However, there is little point in engagement for engagement’s sake: our resources are too scarce to invest in projects or relationships with little or no return, and so meaningful engagement is much harder.

In putting together our application for hosting an Applied Research Collaboration we were faced with our perennial challenge of who to engage with and how. To do so we began to map our networks (see figure) and quickly realised even the number of NHS organisations (71) was too broad for us to work across in depth, never mind the wide range of academic, social care, voluntary sector and industry partners in the wider landscape beyond.

Our approach has been to work with partners who are keen to work with us; we make no apology for being a coalition of the willing. However, we have worked purposefully to ensure reach across all sectors, actively seeking out collaborators with whom we have had more limited interactions with, but who we know can help deliver the reach we require for research and implementation. For instance, we have one of the best performing and most forward thinking ambulance services in the country, with paramedics working at the very interface between physical and mental health, social care and emergency medicine. Given that we know some of these problems are best addressed upstream, the ambulance service gives us the opportunity to head closer to where the river rises than ever before.

[1] Based in 2013/14 figures from RAWM
[2] Department of Business Enterprise Innovation and Skills, Business Population Estimates

In addition to this, we seek to use overarching bodies to help reach across spaces which are too diffuse and fragmented to allow us to access (such as the voluntary, charitable and third sectors). Even using these we will have to be selective from the 21 which exist when we seek to engage with voluntary groups (for example around priority setting, Public and Community Involvement Engagement and Participation, or co-production). Elsewhere, we utilise networks of networks, for example collaborating with the Membership Innovation Councils of the West Midlands Academic Health Science Network which draw in representatives from a wide cross section of organisations and professions who can then transmit our message to their respective organisations and local networks. Our experience tells us these vicarious contacts can often deliver some of the most useful engagement opportunities.

Finally, we have always been committed within CLAHRC to cross-site working and having our researchers and staff embedded as much as possible within healthcare organisations. This is in part to ensure our research remains grounded within the ‘real world’ of service delivery, rather than the dreaming spires (or concrete and glass tower blocks) of academia. However, we know that regardless of how well you plan and construct your network, some of the best ideas come about through chance encounters and corridor conversations. Nobel prize-winning economist Elinor Ostrom, much beloved by the CLAHRC WM team, elegantly described the value of ‘cheap talk’ in relation to collectively owned resources.[3] The visibility of our team can often prompt a brief exchange to rule in or out an idea for CLAHRC where a formal contact or approach might not have been made, making our ‘cheap talk’ meaningful through its context. Perhaps this is how we should see ourselves in CLAHRC West Midlands; as a finite but shared resource to the health and social care organisations within our region.

— Paul Bird, Head of Programmes (engagement)

References:

1. RAWM. The West Midlands Voluntary and Community Sector. 2015.
2. Rhodes C. Business Statistics. Briefing Paper No. 06152. 2018.
3. Ostrom E. Beyond Markets and States: Polycentric Governance of Complex Economic Systems. Am Econ Rev. 2010; 100(3): 641-72.

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.

Demand-Led Research: A Taxonomy

We have previously discussed research where a service manager decides that an intervention should be studied prospectively. We have made the point that applied research centres, such as CLAHRCs/ARCs, should be responsive to requests for such prospective evaluation. Indeed, the request or suggestion from a service manager to evaluate their intervention provides a rich opportunity for scientific discovery since the intervention is a charge to the service not to the research funder. In some cases many of the outcomes of interest may be collected from routine data systems. In such circumstances the research can be carried out at a fraction of the usual cost for prospective evaluations. Nor should it be assumed that research quality must suffer. We give two examples below where randomised designs were possible, one where individual staff members were randomised to different methods to encourage uptake of seasonal influenza vaccine and the other where a step wedge cluster design was used to evaluate roll out of a community health worker programme across a heath facility catchment area in Malawi. Data from these studies has been collected and is being analysed.

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(1) Improvement Project Around Staffs’ Influenza Vaccine Uptake [1]
At the time of this study staff at University Hospitals Birmingham NHS Foundation Trust were invited to take up the Influenza vaccination every September, and then reminded regularly. This study involved staff being sent one of four randomised letters to see if it would directly influence vaccination uptake. One factor of the letters emphasised being invited by an authority figure; the other factor emphasised vaccination rates in peer hospitals.

(2) Evaluating the impact of a CHW programme… in Malawi [2]
This study estimated the effect a CHW programme had on a number of health outcomes, including retention in care for patients with chronic non-communicable diseases, and uptake of women’s health services. Eleven health centres / hospitals were arranged into six clusters, which were then randomised to receive the intervention programme at various, staggered points. Each cluster crossed over from being a control group to an intervention group until all received the intervention.

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In previous articles [3][4] we have examined the practical problems that can be encountered in obtaining ethical approvals and registering demand-led studies. These problems arise because of the implicit assumption that researchers, not service managers, are responsible for the interventions that are the subject of study. In particular we have criticised the Ottawa declaration on the ethics of cluster studies for making this assumption. We have pointed out the harm that rigid adherence to the tenets of this declaration could do by limiting the value that society could reap from evaluations of the large number of natural experiments that are all around us.

However, demand-led research is not homogeneous and so the demands on service manager and researcher vary from case to case. The purpose of this news blog article is to attempt a taxonomy of demand-led research. Since we are unlikely to get this right on our first attempt, we invite readers to comment further.

We discern two dimensions along which demand-led research may vary. First, the urgency dimension and second a dimension to describe the extent, if any, to which the researcher may have participated in the design of the intervention.

As a general rule, demand-led research is done under pressure of time. If there was no time pressure, then the research could be commissioned in the usual way through organisations such as the NIHR Service Delivery and Organisation Programme and the US Agency for Health Quality Research. Demand-led research is done under shorter lead times that are incompatible with the lengthy research cycle. However, permissible lead times for demand-led research vary from virtually no time to many months. In both of the studies above the possibility of the research was mooted only four or five months before roll-out of the index intervention was scheduled. We had to ‘scramble’ to develop protocols, obtain ethics approvals, and register the studies, as required for an experimental design, before roll-out ensued.

The second manner in which demand-led research may vary is in the extent of researcher involvement in design of the intervention itself. If the intervention is designed solely by the researcher or is co-produced, but under the researcher initiative, then this cannot be classified as demand-led. However, the intervention may be designed entirely by the service provider or it may be initiated by the service provider but with some input from the researcher. The vaccination intervention described in the box was initiated by the service who wished to include an incentive as part of a package of measures but they sought advice over the nature of the incentive from behavioural economists in our CLAHRC. On the other hand the intervention to train and deploy community health workers in Malawi was designed entirely by the service team with no input from the evaluation team whatsoever.

Contribution to research dominates because if the researcher makes no contribution to the intervention, then the researcher has little or no responsibility – full argument provided elsewhere.[4]

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford R, Schmidtke KA, Vlaev I, et al. Improvement Project Around Staffs’ Influenza Vaccine Uptake. Clinicaltrials.gov. NCT03637036. 2018.
2. Dunbar EL, Wroe EB, Nhlema B, et al. Evaluating the impact of a community health worker programme on non-communicable disease, malnutrition, tuberculosis, family planning and antenatal care in Neno, Malawi: protocol for a stepped-wedge, cluster randomised controlled trial. BMJ Open. 2018; 8(7): e019473.
3. Lilford RJ. Demand-Led Research. NIHR CLAHRC West Midlands News Blog. 18 January 2019.
4. Watson S, Dixon-Woods M, Taylor CA, Wore EB, Dunbar EL, Chilton PJ, Lilford RJ. Revising ethical guidance for the evaluation of programmes and interventions not initiated by researchers. J Med Ethics. [In Press].