Normally if I’m working on an outbreak response I won’t be in Cambridge. My research often requires me to travel many thousands of miles in order to observe or participate in a response. Watching one unfold from my own apartment, here in Cambridge, is a novel experience for me. 

I’m currently participating in several COVID-19-related projects. The one I’m most involved with is a COVID-19 surveillance platform, which I’m developing with Emma Glennon and Dr Olivier Restif in the Vet School, in collaboration with a number of researchers across Europe, North America and Africa. The platform is aimed at helping public health officials working in resource-limited settings to rapidly detect potential COVID-19 outbreaks. 

My research usually involves ethnographic observation, which means directly watching and documenting an outbreak response as it unfolds. This helps us to understand the factors that informed its trajectory and thus its overall effectiveness. With our larger surveillance platform project, I’m now doing more coordination and administrative work. In some ways this is nice, as I get to work closely with our research partners and funders. The drawback is that I’m not taking full advantage of the opportunity to directly observe a pandemic response unfolding.

Mounting an effective response to this pandemic will be extremely difficult because of variable information about how the disease is affecting different populations. Surveillance data informs response efforts by telling us where the disease is, who is being affected, and how well our interventions are going. Populations already well served by health systems - often groups of higher socio-economic status - tend to be captured by surveillance. Other groups, for instance rural sub-Saharan populations or minorities living in large North American cities, are just not visible in the same way. It is often only after the fact that we can estimate the damage in these populations.

As part of the Disease Dynamics Unit I have always enjoyed a supportive University research community. What’s caught me by surprise during the COVID-19 pandemic has been the extent of my colleagues’ commitment to helping me and my collaborators see our COVID-19 surveillance platform realised. For instance, with the unprecedented amount of email traffic I’ve inevitably overlooked important funding opportunities. But whenever this has occurred a colleague has stepped in, or taken the time to draw my attention to it. Knowing that people have your back in that way is hugely sustaining. 

Medical anthropology can help us be better prepared for ‘the next time’. The trajectory of a particular outbreak response is determined by a mix of political, social and ecological factors. Often these larger forces are the sum of seemingly innocuous personal undertakings by the population affected by the outbreak, and the public health professionals and other decision-makers charged with containing it. Medical anthropology enables us to locate and understand these influential, easily overlooked, moments of discretion. It can help us understand the gap between how we had imagined our outbreak surveillance and response systems would manage the COVID-19 pandemic, and what actually happened. 

I hope that interdisciplinary research like mine will be better funded in the future. Since the late 1980s there has been an emphasis on reactive responses, and technological solutions to emerging infectious disease threats. Research and development into novel vaccines, surveillance technologies and targeted treatments are often prioritised. These all have a place in disease control, but their power is limited in the absence of basic public health infrastructure, or in societies with significant social inequality. 

When the pandemic is over I’m looking forward to a proper weekend off, and to seeing my boyfriend and family again who are all locked down overseas.

Freya Jephcott is a Research Fellow at the University’s Disease Dynamics Unit, in the Department of Veterinary Medicine.

How you can support Cambridge’s COVID-19 research
 

Since the emergence of the SARS-CoV-2 virus in late 2019, more than 3.5 million people are known to have been infected, leading to over 240,000 deaths worldwide from COVID-19, the disease caused by the novel coronavirus. The race is on to find new drugs to treat COVID-19 patients and to develop a vaccine to prevent infection in the first place.

A team of researchers representing the International Union of Basic and Clinical Pharmacology today say there will be no ‘magic bullet’ to treat the disease and argue that a multi-pronged approach is needed to find new drugs. They caution that an effective and scalable vaccine is likely to take over a year before it can used to tackle the global pandemic.

When a virus enters our body, unless we have already developed immunity from previous infection or vaccination, it will break into our cells, hijacking their machinery and using it to replicate and spread throughout the body. Often, the symptoms we see are a result of our immune system fighting back in an attempt to clear the infection. In severe cases, this immune response can become overactive, potentially leading to a so-called cytokine storm, causing collateral damage to organs along the way.

“Any drug to treat COVID-19 will need to focus on the three key stages of infection: preventing the virus entering our cells in the first place, stopping it replicating if it gets inside the cells, and reducing the damage that occurs to our tissues, in this case, the lungs and heart,” said Professor Anthony Davenport from the University of Cambridge, one of the authors of the review.

The review looks at potential therapeutic drug targets – the chinks in the virus’s own armour or weak spots in the body’s defences. Two key targets appear to be proteins on the surface of our cells, to which SARS-CoV-2 binds allowing it entry – ACE2 and TMPRSS2. TMPRSS2 appears to be very common on cells, whereas ACE2 is usually present at low levels that increase depending on sex, age, and smoking history.

“As we know these two proteins play a role in this coronavirus infection, we can focus on repurposing drugs that already have regulatory approval or are in the late stages of clinical trials,” said Professor Davenport. “These treatments will have already been shown to be safe and so, if they can now be shown to be effective in COVID-19, they could be brought to clinical use relatively quickly.”

One promising candidate is remdesivir, a drug originally developed for Ebola. Although clinical trials found it to be insufficiently effective at treating Ebola, clinical trials in the USA have suggested the drug may be beneficial for treating patients hospitalised with COVID-19, and the FDA has now approved it for emergency use. There have also been promising findings from studies of monoclonal antibodies, but this type of drug is expensive to produce and therefore less likely to be scalable.

“While we're waiting for a vaccine, drugs currently being used to treat other illnesses can be investigated as treatments for COVID-19 – in other words repurposed,” said Dr Steve Alexander from the University of Nottingham.

“There’s unlikely to be a single magic bullet – we will probably need several drugs in our armoury, some that will need be used in combination with others. The important thing is that these drugs are cheap to produce and easy to manufacture. That way, we can ensure access to affordable drugs across the globe, not just for wealthier nations.”

The team say that we need to move quickly to identify existing drugs that are effective in clinical trials so that we can begin treating patients as rapidly as possible, but also because cases are likely to fall during the summer meaning there will be fewer people who can be recruited to clinical trials ahead of an anticipated second wave of the disease in autumn. They estimate there are currently more than 300 clinical trials taking place worldwide, though many of these investigational drugs are unlikely to be effective for widespread use because either it is not clear which part of the disease pathway they are targeting or they cause unpleasant side-effects.

They also advise patience for the promise of developing an effective vaccine against the virus anytime soon. Even after a new vaccine candidate has been shown to offer immunity against the coronavirus in humans, it needs to be tested in larger numbers of people to ensure it is safe to use. Manufacturing and distributing a vaccine at the scale needed to tackle this pandemic will also present significant challenges.

“Although there are a lot of vaccines being developed around the world, which we hope will be successful, it's still going to take a long time before those vaccines are shown to be effective and can be manufactured at the scale needed to make an impact,” said Dr Steve Alexander.

“Some of the vaccines may not work, so the more drugs that can be tested and the more we know about the targets, the more likely we are to get something which is effective. The very specificity of vaccines means they are limited in which viruses they can neutralise. The lessons we learn and the drugs we generate will hopefully provide a greater degree of protection, not just against the COVID-19 virus, but also against the next viral threat.”

Professor Davenport is a member of the Department of Medicine, University of Cambridge, and a Fellow at St Catharine’s College.

Reference
Alexander, SPH, et al. A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development. British Journal of Pharmacology; 1 May 2020; DOI: 10.1111/bph.15094 

Inactive participants in the study spent just over four days more in hospital over the next ten years than those who did at least some physical activity, whether for work or leisure. And similar results were observed ten years later when the same participants were 50–90 years old.

The study, by researchers at the University of Cambridge’s Department of Public Health and Primary Care and MRC Epidemiology Unit, calculates that for every inactive person who started to take at least some exercise, the NHS could save around £247 per year. This would equate to around 7% of the UK’s per capita health expenditure.

The findings, published in BMC Geriatrics, are based on a general British population cohort study of 25,639 men and women aged 40–79 living in Norfolk and recruited from general practices between 1993 and 1997 (The European Prospective Investigation into Cancer in Norfolk).

The researchers found that in the first ten years active participants were 25–27% less likely than inactive participants to have more than twenty hospital days or more than seven admissions per year with similar results over the subsequent ten years. They also reported that in 9,827 study participants with repeated measurements, those who remained physically active or increased their activity were 34% less likely to spend twenty days in hospital.

Lead author Robert Luben from the Institute of Public Health says: 

“Our study provides some of the clearest evidence yet that small, feasible increases in usual physical activity substantially reduce the future hospital usage of middle-aged and older people, and would significantly ease pressure on the NHS.”

The study is one of relatively few to examine the physical activity (both occupational and leisure-time) of middle-aged and older men and women – validated against heart rate monitoring with individual calibration – and their subsequent healthcare use. As well as studying a large cohort over a long follow-up period, the researchers used record linkage to hospital data and took a range of demographic and lifestyle factors into account. 

When recruited, participants completed a lifestyle questionnaire where they were asked about their physical activity. Occupational activity was assessed using a four category question (“sedentary”, “standing”, “moderate physical work” and “heavy manual work”) with examples such as office worker, shop assistant, plumber and construction worker respectively. 

Leisure activity in both summer and winter was assessed from the number of hours per week spent cycling, attending keep fit classes or aerobics and swimming or jogging. Estimated average hours of leisure activity was calculated as the mean of summer and winter activities. Based on a score (validated using heart rate monitoring with individual calibration) combining leisure and occupational elements, individuals were categorised as “inactive”, “moderately inactive”, “moderately active” and “active”.

The study found that those with a physical activity score of at least “moderately inactive” had fewer hospital admissions and fewer days in hospital, than those who were “inactive”.

While previous studies have suggested that pre-admission physical activity programmes may lower duration of hospital stay, these are short term, require funding and are targeted at a limited number of individuals. But these new findings indicate that usual physical activity patterns in the general population predict hospital usage over the next two decades.

The researchers acknowledge that participants may be physically inactive because of known or preclinical illness which may also predispose them to increased later hospitalisation. But sensitivity analyses excluding those with a self-reported chronic disease at baseline (heart attack, stroke or cancer), and excluding hospital admissions occurring in the first five years of follow-up, did not differ materially from the main findings.

Reference 

R. Luben, S. Hayat, N. Wareham, P. Pharoah, K-T. Khaw, ‘Usual physical activity and subsequent hospital usage over 20 years in a general population: the EPIC-Norfolk cohort’. BMC Geriatrics, 6 May 2020). DOI: 10.1186/s12877-020-01573-0.10.1186/s12877-020-01573-0.

The UK was first placed on lockdown in response to the coronavirus pandemic on 23 March. Only essential businesses were allowed to remain open and everyone was told to stay at home, only to venture out for exercise and shopping.

Almost overnight, people’s lives were up-ended, with some people working from home while others have lost their jobs or been furloughed. People who live by themselves have suddenly found themselves with no social contact other than virtual.

To find out what impact this has had on people’s behaviour, Dr Valerie Voon from the University of Cambridge and Prof Henrietta Bowden-Jones, Director of the National Problem Gambling Clinic, London, have launched an online survey, HabiT– Habit Tracker – asking about changes in habits during lockdown, specifically quantifying alcohol, smoking, and online use of gambling, gaming and pornography.  The habit tracker survey is available online. All responses will be anonymous.

The survey is short, only taking 10 minutes to complete. The researchers are keen to hear from both those people who do not consider themselves to be vulnerable or exhibit problem behaviours and those who have struggled in the past or are struggling now.

“We expect to see an increase in these behaviours across the UK in response to the unprecedented circumstances we find ourselves in,” says Dr Voon. “In many cases, these changes will be people’s strategies for coping with the anxiety and stress caused by the pandemic and lockdown and, we hope, won’t have a long term impact if the behaviour can be controlled.

“For some people who might already have been struggling with or have a history of addiction these increased habits could prove problematic. The same goes for those people who find themselves in difficult circumstances, for example having lost their job or facing financial difficulties, or are struggling to cope with the lockdown. These more vulnerable individuals may find their behaviour has a more marked longer lasting effect, triggering an alcohol relapse, for instance, or reigniting a gambling addiction.”

Survey respondents may also take part in CrusH, an alcohol avoidance online training game for smartphones being developed which can be accessed as part of the survey.

Five tips for coping during the lockdown

1. Keep active: exercise outdoors and take part in online exercise workouts
2. Keep in touch with people socially online – try FaceTime, Skype or Zoom so that you see people
3. Maintain some regular structure: sleep, wake, work
4. Don't spend too much time looking at news
5. Use this as an opportunity to try something new – try baking, learning a new language, writing that novel you always dreamed of writing

“For many people, adolescence - between the ages of 10 and 24 - is when you want to be making more social connections, not losing them. It’s also a time of increased risk-taking and sensitivity to peer influence,” said Jack Andrews at the UCL Institute of Cognitive Neuroscience, and first author of the paper. “For some adolescents it’s a challenge to stick to social distancing rules, particularly if their friends aren’t following the rules.” 

Breaking social distancing rules is a risk-taking behaviour, putting at risk the health of the rule-breaker and of others - in many places with legal or financial consequences. But adolescents are particularly sensitive to the negative effects of social exclusion, and may prefer to risk breaking the rules rather than lose their friends, say the researchers of the paper published in the journal Trends in Cognitive Sciences. 

Campaigns led by adults that try to influence adolescent behaviour often have mixed success. The COVID-19 pandemic has resulted in the widespread implementation of social distancing measures, led by governments, which are likely to be in place in some form for the foreseeable future. But media reports of large student gatherings in the US in March demonstrated the challenge of stopping young people from meeting their friends face-to-face. 

Social distancing guidance could be more effective if adolescents are allowed to develop and deliver their own campaigns, focused on changing peer attitudes around the importance of social distancing. With the current restrictions on face-to-face interventions, social media is expected to be particularly effective in promoting social distancing behaviours amongst adolescents. 

“Adolescents look to their peers to understand social norms, and align their behaviour with the group they want to belong to. The speed and extent of peer influence online is likely to amplified, because social media has such a wide and immediate reach,” said Professor Sarah-Jayne Blakemore at the University of Cambridge’s Department of Psychology, who led the report. 

Previous studies have shown that adolescents are more likely to take certain risks, such as experimenting with drugs or posting sexual content online, when peers are present or doing the same things. Adolescents are also more likely to get involved in beneficial activities, such as volunteering in the community, if they know others who are doing them.

Young people’s capacity to encourage each other in a positive way has been demonstrated in previous studies, for example in a peer-led approach to reducing bullying in schools. This study identified highly-connected, well-liked students, and asked them to develop their own anti-bullying campaigns to share with their peers. Bullying dropped by 25% as a result, compared with other schools.

“The advantage of social media influencers is that the motivation for social distancing comes naturally from the young people themselves. Influencers could post videos or photos online, for example, showing how they are following social distancing rules by staying at home, and add tags to increase their visibility through sharing and Likes. Many YouTubers are already doing this. It’s really just presenting public health advice in a more accessible way that adolescents are more likely to listen to,” said Blakemore. 

If social distancing can be established as a group norm amongst friends, it is more likely to be copied by others. Another advantage of targeting social media influencers is that they exist across many spheres of interest so have the potential to reach diverse groups of young people.

The researchers say that to create positive change, adolescents must be given the capacity to lead their own ideas. They hope that their proposals will be taken up by charities and public health bodies who can work with influencers to make sure the correct type of information is being shared.

Reference
Andrews, J.L. et al: ‘Peer influence in adolescence: Public-health implications for COVID-19.’ May 2020, Trends in Cognitive Sciences.DOI: 10.1016/j.tics.2020.05.001

How you can support Cambridge’s COVID-19 research

A team of researchers, led by the University of Cambridge and Simon Fraser University, designed a series of tests for medical image reconstruction algorithms based on AI and deep learning, and found that these techniques result in myriad artefacts, or unwanted alterations in the data, among other major errors in the final images. The effects were typically not present in non-AI based imaging techniques.

The phenomenon was widespread across different types of artificial neural networks, suggesting that the problem will not be easily remedied. The researchers caution that relying on AI-based image reconstruction techniques to make diagnoses and determine treatment could ultimately do harm to patients. Their results are reported in the Proceedings of the National Academy of Sciences.

"There’s been a lot of enthusiasm about AI in medical imaging, and it may well have the potential to revolutionise modern medicine: however, there are potential pitfalls that must not be ignored," said Dr Anders Hansen from Cambridge’s Department of Applied Mathematics and Theoretical Physics, who led the research with Dr Ben Adcock from Simon Fraser University. "We’ve found that AI techniques are highly unstable in medical imaging, so that small changes in the input may result in big changes in the output."

A typical MRI scan can take anywhere between 15 minutes and two hours, depending on the size of the area being scanned and the number of images being taken. The longer the patient spends inside the machine, the higher resolution the final image will be. However, limiting the amount of time patients spend inside the machine is desired, both to reduce the risk to individual patients and to increase the overall number of scans that can be performed.

Using AI techniques to improve the quality of images from MRI scans or other types of medical imaging is an attractive possibility for solving the problem of getting the highest quality image in the smallest amount of time: in theory, AI could take a low-resolution image and make it into a high-resolution version. AI algorithms ‘learn’ to reconstruct images based on training from previous data, and through this training procedure aim to optimise the quality of the reconstruction. This represents a radical change compared to classical reconstruction techniques that are solely based on mathematical theory without dependency on previous data. In particular, classical techniques do not learn.

Any AI algorithm needs two things to be reliable: accuracy and stability. An AI will usually classify an image of a cat as a cat, but tiny, almost invisible changes in the image might cause the algorithm to instead classify the cat as a truck or a table, for instance. In this example of image classification, the one thing that can go wrong is that the image is incorrectly classified. However, when it comes to image reconstruction, such as that used in medical imaging, there are several things that can go wrong. For example, details like a tumour may get lost or may falsely be added. Details can be obscured and unwanted artefacts may occur in the image.

"When it comes to critical decisions around human health, we can’t afford to have algorithms making mistakes," said Hansen. "We found that the tiniest corruption, such as may be caused by a patient moving, can give a very different result if you’re using AI and deep learning to reconstruct medical images – meaning that these algorithms lack the stability they need."

Hansen and his colleagues from Norway, Portugal, Canada and the UK designed a series of tests to find the flaws in AI-based medical imaging systems, including MRI, CT and NMR. They considered three crucial issues: instabilities associated with tiny perturbations, or movements; instabilities with respect to small structural changes, such as a brain image with or without a small tumour; and instabilities with respect to changes in the number of samples.

They found that certain tiny movements led to myriad artefacts in the final images, details were blurred or completely removed, and that the quality of image reconstruction would deteriorate with repeated subsampling. These errors were widespread across the different types of neural networks.

According to the researchers, the most worrying errors are the ones that radiologists might interpret as medical issues, as opposed to those that can easily be dismissed due to a technical error.

"We developed the test to verify our thesis that deep learning techniques would be universally unstable in medical imaging," said Hansen. "The reasoning for our prediction was that there is a limit to how good a reconstruction can be given restricted scan time. In some sense, modern AI techniques break this barrier, and as a result become unstable. We’ve shown mathematically that there is a price to pay for these instabilities, or to put it simply: there is still no such thing as a free lunch."

The researchers are now focusing on providing the fundamental limits to what can be done with AI techniques. Only when these limits are known will we be able to understand which problems can be solved. "Trial and error-based research would never discover that the alchemists could not make gold: we are in a similar situation with modern AI," said Hansen. "These techniques will never discover their own limitations. Such limitations can only be shown mathematically."

Reference:
Vegard Antun et al. ‘On instabilities of deep learning in image reconstruction and the potential costs of AI.’ Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.1907377117

Patients admitted to NHS hospitals are now routinely screened for the SARS-CoV-2 virus, and isolated if necessary. But NHS workers, including patient-facing staff on the front line, such as doctors, nurses and physiotherapists, are tested and excluded from work only if they develop symptoms of the illness. Many of them, however, may show no symptoms at all even if infected, as a new study published in the journal eLife demonstrates.

The Cambridge team pro-actively swabbed and tested over 1,200 NHS staff at Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, throughout April. The samples were analysed using a technique called PCR to copy and read the genetic information of material present on the swab, producing a colour change whenever the coronavirus was present in a specimen. At the same time, staff members were asked about relevant coronavirus symptoms.

Of the more than 1,000 staff members reporting fit for duty during the study period, 3% nevertheless tested positive for the coronavirus. On closer questioning, around one in five reported no symptoms, two in five had very mild symptoms that they had dismissed as inconsequential, and a further two in five reported COVID-19 symptoms that had stopped more than a week previously.

To probe routes of possible transmission of the virus through the hospital and among staff, the researchers also looked at whether rates of infection were greater among staff working in “red” areas of the hospital, those areas caring for COVID-19 patients. Despite wearing appropriate personal protective equipment (PPE), “red” area staff were three times more likely to tested positive than staff working in COVID-19 free “green” areas. It’s not clear whether this genuinely reflects greater rates of transmission from patients to staff in red areas. Staff may have instead transmitted the virus to each other or acquired it at home. Staff working in the “red” areas were also swabbed earlier in the study, closer to when the lockdown was first initiated, so the higher rates of infection in this group might just be a symptom of higher rates of virus circulating in the community at the time.

Nevertheless, extrapolating these results to the more than half a million patient-facing staff working across the NHS UK-wide suggests that as many as 15,000 workers may have been on duty and infected, with the potential to transmit the virus to co-workers, family members and patients, during the month of April. In fact, this figure could be even higher in settings where the supply of PPE has been very problematic.

The implications of the new study, say senior authors Dr Mike Weekes and Professor Stephen Baker from the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), are that hospitals need to be vigilant and introduce screening programmes across their workforces. 

“Test! Test! Test! And then test some more,” Dr Weekes explains. “All staff need to get tested regularly for COVID-19, regardless of whether they have any sort of symptoms – this will be vital to stop infection spreading within the hospital setting.”

The research was mainly funded by Wellcome and the Addenbrooke’s Charitable Trust.

Reference
Rivett, L, et al. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission. eLife; 11 May 2020; DOI: 10.7554/eLife.58728

The new Fellows have been chosen for their exceptional contributions to advancing biomedical science via world-leading research discoveries, running national science communication and engagement programmes and translating scientific advances into benefits for patients and the public.

The value of medical science has never been more apparent than during the current coronavirus global health crisis. From testing and vaccine development, to public health and behavioural science, to addressing the impacts of lockdown measures on mental health, biomedical and health scientists are helping to guide the UK through unprecedented challenges.

Several new Fellows have redirected their research efforts to tackle the effects of the pandemic, such as Professor Ludovic Vallier FMedSci, a stem cell expert from the University of Cambridge, who has refocussed part of his team to study the effects of coronavirus on the liver. Professor Tamsin Ford CBE FMedSci, a Professor of Psychiatry at Cambridge, has channelled her expertise into looking at mental health impacts of the pandemic on children and young people.

Professor Sir Robert Lechler PMedSci, President of the Academy of Medical Sciences said: “This year our new Fellows announcement happens amidst a global health crisis. Never has there been a more important time to recognise and celebrate the people behind ground-breaking biomedical and health research, working harder than ever to further knowledge and protect patients and the public.

“It brings me great pleasure to congratulate the new Fellows, and see our Fellowship grow to even greater heights of evidence-based advice, leadership and expertise.”

The University of Cambridge Fellows elected in 2020 are:

Professor Menna Clatworthy FLSW, NIHR Research Professor and Professor of Translational Immunology, University of Cambridge and Associate Faculty, Wellcome Sanger Institute, Fellow, Pembroke College

Dr Helen Firth, Consultant Clinical Geneticist, Cambridge University Hospitals, Honorary Faculty Member, Wellcome Sanger Institute, Bye-Fellow, Newnham College

Professor Tamsin Ford CBE, Professor of Child and Adolescent Psychiatry, University of Cambridge, Fellow, Hughes Hall

Professor Ziad Mallat, Professor of Cardiovascular Medicine, University of Cambridge

Dr Nitzan Rosenfeld, Senior Group Leader, Cancer Research UK Cambridge Institute, University of Cambridge

Professor Ludovic Vallier, Professor of Regenerative Medicine, Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Fellow, St Edmund’s College

The new Fellows will be formally admitted to the Academy on 25 June 2020.

Millions of UK lives have been changed significantly in the last few weeks, even those who have not been infected by the virus. Three of the most widespread changes for many working age adults have been:

1. The loss of a job or a large reduction in working hours
2. A shift in the place of work from the employer’s premises to homeworking
3. Living in social isolation alone or with other members of one’s household (adults and children) who are also spending more time at home. 

We know from past research that any one of these can have negative mental health consequences, but the combined effects of these changes is unprecedented and unexplored. There are already media reports of the strain that this is putting on individuals and families. It is likely that many of these problems will be exacerbated over the coming months. 

Deteriorating levels of mental health in the population will not just cause individual misery - for instance through increased symptoms of anxiety and depression - but the research to date on unemployment suggests that this will likely lead to knock on effects on the family, particularly a spouse. It may also lead to increased breaches of social distancing rules or civil unrest.

The Chancellor’s plans to save jobs through the furlough scheme are largely aimed at the financial fallout of the pandemic: the desire to avoid widespread hunger, destitution and financial insecurity, while also recognising the importance to society’s overall wellbeing of the ability for businesses to recover quickly.

Why employment matters beyond income

As social scientists have found repeatedly, in different countries and different demographic groups, the loss of the wage only explains a small fraction of the very large mental health deficit associated with unemployment and economic inactivity.  

We now know that the ‘incidental’ aspects of having a job – e.g. time structure, social contact, shared goals, sense of achievement, enforced activity – are hugely important for our wellbeing. In our new short video, Lil Woods, a freelance arts charity worker, discusses how the lockdown has left her missing a sense of purpose: “When my work disappeared, I felt like part of my identity, my place in the world, went with it.”

It has proven almost impossible to find substitutes for jobs that fulfil the same functions: leisure activities, voluntary work or workfare just don’t provide us with the same levels of wellbeing through feeling valued. While some post-work utopians dream of a world where work is largely eliminated, there is little evidence that it could exist as a reality. In fact, recent ONS data shows work has become a coping mechanism in this crisis.

So, it seems, we have an impossible situation – for most people good mental health requires a job, but there simply aren’t enough jobs in the right sectors or with the right skill sets to go around, and this situation is likely to last for many more months of the current pandemic.

A possible solution: short-time working

Fortunately there’s a solution to this paradox, and one that’s being taken seriously in other countries: short-time working. The hastily-introduced measures to protect jobs in the UK encourage employers to retain some or all staff where:

• there is essential work to be done, for example health and emergency workers
• the work can be done at home, as with many office workers
• the work can be done while maintaining safe distancing, such as some agricultural jobs.

Other employees and self-employed workers will be stopped from working, and either be paid to stay at home or lose their wage too. How does it work? Other European countries, such as Germany and Austria, have traditionally used short-time work programmes to deal with economic crises. Employers can reduce the hours of employees, typically with some compensation from public funds to mitigate some of the loss of hours. This has several benefits over the all-or-nothing job shedding being used in the UK. 

• Employees retain their attachment to an employer and have more certainty over their future.  
• It is easier for employers to vary their volume and type of labour power as the pandemic peaks and then we start an exit strategy.  
• Employees can be redeployed depending on their skills, adaptability of the job to homeworking or safe-distancing, or the pre-existing health conditions of the employee.

Recent research by economists from the universities of Cambridge, Oxford and Zurich suggest that, by early April 2020, 15% of people in the UK had lost their jobs due to the coronavirus outbreak compared to only 5% in Germany. 

Turning back to the psychological functions of paid work, just how much employment is needed each week to preserve the mental health of employees, and at what point does their wellbeing drop to be closer to those who are unemployed? 

Could it work in the UK?

The surprising finding from our research using UK and EU datasets is that increasing individuals’ hours of work from zero to just eight hours a week provides a large boost to their mental health, and there is little or no further psychological benefit as weekly hours are increased from eight to 40. The lesson for government strategy is clear: where possible (and with population health being the priority) keep everyone in paid work; even one day a week will keep more of us sane in these volatile times.

The Employment Dosage research team is led by Dr Brendan Burchell from the Department of Sociology, with co-investigators Dr Daiga Kamerade, Dr Adam Coutts, Dr Ursula Balderson and Dr Senhu Wang.  
 

How you can support Cambridge's COVID-19 research effort

Donate to support COVID-19 research at Cambridge

I normally work in the Old Cavendish Laboratory, where I run the Cambridge Social Decision-Making lab. It’s a historic landmark where Watson and Crick discovered the structure of DNA. I never thought I’d say this, but I miss the tour groups pausing below my window every morning. I work from my home in Cambridge now, around the corner from Midsummer Common. The cows are out this time of year, so we often exchange theories about the pandemic when I go for a walk. They seem mostly skeptical, uninterested, and refuse to wear masks, but we get along well otherwise.

In my view, the pandemic is as much a behavioural as a biological problem. We need a vaccine, but we also need people around the world to coordinate their behaviours to help slow the spread of the virus. The required behavioural changes range from the relatively mundane, such as frequent hand washing, to making costly personal sacrifices by self-isolating at home. This necessitates knowledge about human cooperation as well as economic and social inequalities. Models that attempt to forecast the benefits of widespread social distancing and self-isolation also depend on accurate estimates of human behaviour under various conditions. 

Behavioural science is also relevant in terms of how to communicate the science to the wider public, how to communicate uncertainty and risk, and how to protect people from the onslaught of fake news and misinformation about COVID-19. I am honoured to have been part of an effort to synthesize what behavioural science has to contribute to the pandemic, as part of a team of 40 international experts around the world. I hope that the article Using social and behavioural science to support COVID-19 pandemic response, published in the journal Nature Human Behaviour, will be useful to policy-makers. 
 
My research looks at how humans make judgments and decisions. This could be about information, risk, societal issues, or other people. In collaboration with our partners we developed Bad News, an award-winning interactive online game. It helps inoculate players against fake news and misinformation, including fake news about COVID-19. We rely on the biomedical analogy: just as administering a weakened dose of a virus triggers the production of antibodies to confer immunity against future infection, the same can be achieved with information. By actively exposing people to severely weakened doses of the tactics used to produce fake news, people gain psychological immunity (or mental ‘antibodies’) against misinformation. 

We use a large variety of methods to study human decision-making. We frequently test our interventions ‘in the wild’, for example, our study on the BBC news site tested how people react to uncertainty about scientific facts, and when ‘reality’ is not an option, we use virtual reality! So in a sense, our ability to do research has not been massively affected by the pandemic. A large chunk of it happens online using experimental and computational methods, online surveys, and ‘big data’. 

Human behaviour is notoriously variable, and difficult to change and predict. I think it’s one of the biggest challenges of this pandemic. If we don’t get it right, there’s a chance the spread of the virus will pick up again as restrictions are relaxed. The constant stream of misinformation is also a major challenge. For example, concerted disinformation campaigns have the potential to undermine public willingness to vaccinate if people do not believe the vaccine is safe. In addition, several leading nations in the world have not adopted evidence-based strategies, which is a major hurdle. 

I’ve been really impressed by the way the research community has come together so quickly. I’m on the management board of the Winton Centre for Risk and Evidence Communication, which has been able to track public opinion on COVID-19 around the world almost immediately. The Centre has pivoted many of their resources to help provide empirical data on how to best communicate evidence during the pandemic. The Cambridge press office has also been fantastic in helping researchers communicate their findings and expertise. 

My own research programme has taught me the power of a proactive approach. Prevention is better than cure. People forget that this applies to psychology and communication too. For example, inoculation is all about pre-emptively protecting people from future harm, both in a biological as well as in a psychological sense. The same goes for communication of risk. Much of the response to COVID-19 was reactive, too late, and not well-prepared. One of the wonders of the human brain is our ability to simulate the future. We can start now.

When the pandemic is over, I’m looking forward to a cold beer with friends who are less than six feet away. I can’t wait to sit outside in the sun with colleagues, family, and friends, and have a good laugh again. It’s the little things in life. In the words of Sir Arthur Conan Doyle, “It has long been an axiom of mine that the little things are infinitely the most important.”

Sander van der Linden is Director of the Cambridge Social Decision-Making Lab in the Department of Psychology and a Fellow of Churchill College.

How you can support Cambridge’s COVID-19 research

Announcing her appointment, Business Secretary Alok Sharma from the Department for Business, Energy and Industrial Strategy, said: “Professor Leyser’s appointment comes at a critical time for the UK. The coronavirus pandemic has shown the importance of science for our future and UKRI has a vital role to play in this.

“As the new Chief Executive, Professor Leyser will drive forward UKRI’s mission to create the great British companies of the future and help keep the UK at the cutting edge of global research and development.

“I would like to thank Sir Mark Walport for his dedication to UKRI, leading its transformation programme and championing science, engineering and technology across the UK.”

Science Minister Amanda Solloway said: “I am thrilled with the appointment of Professor Leyser and I look forward to working closely with her to drive forward our shared ambition to boost our world-leading research and development.

“Since its launch in 2018, UKRI has gone from strength to strength. Professor Leyser has already led a highly collaborative lab in her previous role which will be a great skill to bring to UKRI as it embarks on a new stage of exciting evolution.”

Dame Ottoline has a long-term interest in inclusiveness and engagement in science and has driven many initiatives to support an open and collaborative research culture that delivers high quality research that is both valuable and valued. This includes ongoing work to improve research culture. She has for a long time been actively engaged in science policy, currently chairing the Royal Society’s Science Policy Expert Advisory Committee and serving on the Prime Minister’s Council for Science and Technology. 

In 2017 Professor Leyser was appointed Dame Commander of the Order of the British Empire for services to plant science, science in society and equality and diversity in science. Her own research has resulted in major advances in our knowledge of plant development and includes pioneering work in studying hormonal control of shoot branching through interdisciplinary approaches.

Dame Ottoline, who is also a Fellow of Clare College, said: “UKRI has a unique opportunity to make a profound contribution to tackling the many challenges facing the world.

“In my career, I have seen the power of genuinely collaborative cultures to catalyse the transformative thinking needed to create effective solutions.

“I look forward to working with the UKRI team to ensure that the UK’s superb research and innovation system continues to work for everyone, by pioneering new partnerships, developing innovative funding models and strengthening international collaboration.”  

Professor Stephen Toope, Vice-Chancellor at the University of Cambridge, said: “I warmly congratulate Ottoline on her appointment. She is an extremely well respected colleague and will make a very worthy successor to Sir Mark Walport.

“The unprecedented challenges facing our society at present, in particular the coronavirus pandemic and climate crisis, demonstrate why investment in research and innovation has never been more important. With her passion for research, understanding of the sector and willingness to engage with government, Ottoline will be in a strong position to steer UKRI at this crucial time.”

Lord Grabiner QC, Master of Clare College, added: “On behalf of the Fellows, staff and students of Clare College, Cambridge I am delighted to congratulate Professor Dame Ottoline Leyser on her appointment as CEO at UKRI. Ottoline is one of our most distinguished Fellows and is well equipped to meet the significant challenges she will be presented with.”

Dame Ottoline will take up her position on 29 June 2020, replacing Sir Mark Walport, who is standing down. Professor Henrik Jönsson will take over as Acting Director of the Sainsbury Laboratory.

The researchers, from the University of Cambridge and Imperial College London, have clinically validated and tested the AI on large sets of CT scans and found that it was successfully able to detect, segment, quantify and differentiate different types of brain lesions.

Their results, reported in The Lancet Digital Health, could be useful in large-scale research studies, for developing more personalised treatments for head injuries and, with further validation, could be useful in certain clinical scenarios, such as those where radiological expertise is at a premium.

Head injury is a huge public health burden around the world and affects up to 60 million people each year. It is the leading cause of mortality in young adults. When a patient has had a head injury, they are usually sent for a CT scan to check for blood in or around the brain, and to help determine whether surgery is required.

“CT is an incredibly important diagnostic tool, but it’s rarely used quantitatively,” said co-senior author Professor David Menon, from Cambridge’s Department of Medicine. “Often, much of the rich information available in a CT scan is missed, and as researchers, we know that the type, volume and location of a lesion on the brain are important to patient outcomes.”

Different types of blood in or around the brain can lead to different patient outcomes, and radiologists will often make estimates in order to determine the best course of treatment.

“Detailed assessment of a CT scan with annotations can take hours, especially in patients with more severe injuries,” said co-first author Dr Virginia Newcombe, also from Cambridge’s Department of Medicine. “We wanted to design and develop a tool that could automatically identify and quantify the different types of brain lesions so that we could use it in research and explore its possible use in a hospital setting.”

The researchers developed a machine learning tool based on an artificial neural network. They trained the tool on more than 600 different CT scans, showing brain lesions of different sizes and types. They then validated the tool on an existing large dataset of CT scans.

The AI was able to classify individual parts of each image and tell whether it was normal or not. This could be useful for future studies in how head injuries progress, since the AI may be more consistent than a human at detecting subtle changes over time.

“This tool will allow us to answer research questions we couldn’t answer before,” said Newcombe. “We want to use it on large datasets to understand how much imaging can tell us about the prognosis of patients.”

“We hope it will help us identify which lesions get larger and progress, and understand why they progress so that we can develop more personalised treatment for patients in future,” said Menon.

While the researchers are currently planning to use the AI for research only, they say with proper validation, it could also be used in certain clinical scenarios, such as in resource-limited areas where there are few radiologists.

In addition, the researchers say that it could have a potential use in emergency rooms, helping get patients home sooner. Of all the patients who have a head injury, only between 10 and 15% have a lesion that can be seen on a CT scan. The AI could help identify these patients who need further treatment, so those without a brain lesion can be sent home, although any clinical use of the tool would need to be thoroughly validated.

The ability to analyse large datasets automatically will also enable the researchers to solve important clinical research questions that have previously been difficult to answer, including the determination of relevant features for prognosis which in turn may help target therapies.

The research was supported in part by the European Union, the European Research Council, the Engineering and Physical Sciences Research Council, Academy of Medical Sciences/The Health Foundation, and the National Institute for Health Research.

Reference:
Miguel Monteiro et al. ‘Multi-class semantic segmentation and quantification of traumatic brain injury lesions on head CT using deep learning: an algorithm development and multicentre validation study.’ The Lancet Digital Health (2020). DOI: 10.1016/S2589-7500(20)30085-6

The interim report for the Inquiry, led by Professor Martin Millett, outlines a plan of action from Lent Term 2020 that includes research conducted by two new Research Fellows to be based in the Centre for African Studies working in an interdisciplinary context across the University, and information gathered from related work across the Collegiate University. 

In support of this research, the report said the Inquiry will use its website and an email list to provide current information about the project and related activities across the Collegiate University and to serve as a hub for research and engagement around the theme.

A priority over the next two years will be presenting the Inquiry and seeking input on it from a broad audience, both within the University and beyond. In addition to an ongoing series of public forums and seminars, the Inquiry will seek to support research and public-facing engagement on enslavement and its legacies by students, staff, and organisations and institutions throughout the University.

Discussions are also progressing with the University of Cambridge Museums about an exhibition in 2022 that will explore aspects of the subject and a plan for the work to culminate in a major international conference in 2022. Other ideas include involvement in University outreach events and programmes.

In all this, the Inquiry welcomes proposals and ideas for collaboration from across the Collegiate University.

An external advisory panel comprised of academics from King's College, Warwick University, Bristol and the University of Edinburgh has also been added to provide help and advice to the Inquiry. 

The Inquiry was convened in April 2019 by Vice-Chancellor Professor Stephen J Toope to advise him ​on the University of Cambridge’s historical links with enslavement and on the legacies of those links in light of the growing public interest in the issue of British universities’ historical links to enslavement and the slave trade. 

The two-year inquiry will explore University archives and a wide range of records elsewhere to uncover how the institution may have gained from slavery and the exploitation of coerced labour, through financial and other bequests to departments, libraries and museums.

It will also investigate the extent to which scholarship at the University of Cambridge, an established and flourishing seat of learning before and during the period of Empire, might have reinforced and validated race-based thinking between the 18th and early 20th Century.

Professor Millett said: “This will be an evidence-led and thorough piece of research into the University of Cambridge’s historical relationship with the slave trade and other forms of coerced labour. We cannot know at this stage what exactly it will find but it is reasonable to assume that, like many large British institutions during the colonial era, the University will have benefited directly or indirectly from, and contributed to, the practices of the time.”

The Advisory Group is expected to deliver its final report to the Vice-Chancellor in 2022. Alongside its findings on historical links to the slave trade, the report will recommend appropriate ways for the University to publicly acknowledge such links and their modern impact.

Full initial report

The coronavirus pandemic has imposed an unprecedented challenge on global healthcare systems, societies and governments. The virus SARS-CoV-2, which causes COVID-19 disease, has been detected in every country, with more than 4.6 million confirmed cases and a death toll of 312,000 worldwide to date.

There are currently no effective treatments for the disease and a widely-available vaccine is likely to be at least a year away. The principal strategy to control the disease globally has focused on measures that minimise person-to-person transmission of SARS-CoV-2 through social distancing; including isolating suspected infected individuals, shielding vulnerable groups, school closures, and lockdowns.

While such measures are effective at slowing disease spread and preventing health systems becoming overwhelmed, these measures can also lead to significant job losses, financial insecurity and social disruption. As such, there is a growing concern that these interventions may be unsustainable over the long term. An alternative approach may be to alternate stricter measures with intervals of relaxed social distancing (with measures of effective “test-contact trace-isolate” and shielding of the vulnerable kept in place).

However, it is unclear what the frequency and duration of such dynamic interventions should be and which strategy could be adapted globally across countries with diverse health and economic infrastructures.

To address these uncertainties, an international team of researchers from the Global Dynamic Interventions Strategies for COVID-19 Collaborative Group modelled three scenarios across sixteen countries, from Belgium to India, that vary in setting and income. Their results are published today in the European Journal of Epidemiology.

In particular, the researchers were interested in the difference in impact between strategies aimed at mitigation and those aimed at suppression. Mitigation measures reduce the number of new infections, but at a relatively slow rate. These might include a combination of measures, such as general social distancing, hygiene rules, case-based isolation, shielding of vulnerable groups, school closures or restricting of large public events. On the other hand, suppression measures lead to a faster reduction in the number of new infections by applying additional interventions such as strict physical distancing, including lockdown.

The first scenario modelled the impact of imposing no measures. As might be expected, the number of patients requiring treatment in intensive care units (ICUs) would quickly exceed the available capacity significantly for every single country, resulting in a total of 7.8 million deaths across the 16 countries. Under this scenario, the duration of the epidemic would last nearly 200 days in the majority of the countries included.

The second scenario modelled a rolling cycle of 50-day mitigation measures followed by a 30-day relaxing. Such a strategy would be likely to reduce the R number (the number of people each infected individual goes on to infect) to 0.8 in all countries. However, it would still be insufficient to keep the number of patients requiring ICU care below the available critical care capacity. While proving effective for the first three months for all the countries, after the first relaxation, the number of patients requiring ICU care would exceed the hospital capacity and would result in 3.5 million deaths across the 16 countries. In this scenario, the pandemic would last approximately 12 months in high-income countries, and about 18 months or longer in the other settings.

The final scenario involved a rolling cycle of stricter, 50-day suppression measures followed by a 30-day relaxing. Such intermittent cycles would reduce the R number to 0.5 and keep ICU demand within national capacity in all countries. Since more individuals remain susceptible at the end of each cycle of suppression and relaxation, such an approach would result in a longer pandemic, lasting beyond 18 months in all countries. However, a significantly smaller number of people – just over 130,000 across the 16 countries modelled – would die during that period.

In comparison, the team found that after a continuous, three-month strategy of strict suppression measures, most countries would reduce new cases to near zero. Looser, mitigation strategies would require approximately 6.5 months to reach the same point. However, such prolonged lockdowns would be unsustainable in most countries due to potential knock-on impacts on economy and livelihood.

Dr Rajiv Chowdhury, a global health epidemiologist the University of Cambridge, UK, and lead author on the paper, said: “Our models predict that dynamic cycles of 50-day suppression followed by a 30-day relaxation are effective at lowering the number of deaths significantly for all countries throughout the 18-month period.

“This intermittent combination of strict social distancing, and a relatively relaxed period, with efficient testing, case isolation, contact tracing and shielding the vulnerable, may allow populations and their national economies to ‘breathe’ at intervals – a potential that might make this solution more sustainable, especially in resource-poor regions.”

The researchers say that the specific durations of these interventions would need to be defined by specific countries according to their needs and local facilities. The key is to identify a pattern that allows countries to protect the health of the population not only from COVID-19 but also from economic hardship and mental health issues.

Professor Oscar Franco from the University of Bern, Switzerland, said: “Our study provides a strategic option that countries can use to help control COVID-19 and delay the peak rate of infections. This should allow them to buy valuable time to shore up their health systems and increase efforts to develop new treatments or vaccines.

“There’s no simple answer to the question of which strategy to choose. Countries – particularly low-income countries – will have to weigh up the dilemma of preventing COVID-19 related deaths and public health system failure with the long-term economic collapse and hardship.”

The research was supported by the European Union’s Horizon 2020 programme.

Reference
Chowdhury, R, et al. Dynamic interventions to control COVID-19 pandemic: a multivariate prediction modelling study comparing 16 worldwide countries. European Journal of Epidemiology; 20 May 2020; DOI: 10.1007/s10654-020-00649-w

How you can support Cambridge’s COVID-19 research

The vast majority of young people who self-harm or experience suicidal thoughts appear to have only mild or moderate mental distress, instead of more obvious symptoms associated with a diagnosable disorder, according to a new study.

As such, measures to reduce suicide risk in young people should focus on the whole population, not just those who are most distressed, depressed or anxious, said Cambridge University researchers during Mental Health Awareness week.

They argue that the small increases in stress across the entire population due to the coronavirus lockdown could cause far more young people to be at risk of suicide than can be detected through evidence of psychiatric disorders. 

“It appears that self-harm and suicidal thinking among young people dramatically increases well within the normal or non-clinical range of mental distress,” said Professor Peter Jones, senior author of the study from Cambridge’s Department of Psychiatry.

“These findings show that public policy strategies to reduce suicide should support better mental health for all young people, not only those who are most unwell,” said Jones, who is also a consultant psychiatrist at Cambridgeshire and Peterborough NHS Foundation Trust and director of the NIHR Applied Research Collaboration East of England.

“Even modest improvements in mental health and wellbeing across the entire population may prevent more suicides than targeting only those who are severely depressed or anxious.”

The Cambridge researchers conducted the study with colleagues from University College London. It was supported by the Wellcome Trust and the National Institute for Health Research, and is recently published in the journal BMJ Open.  

Recent studies suggest a broad range of mental health problems – e.g. depression, anxiety, impulsive behaviour, low self-esteem, and so on – can be taken as a whole to measure levels of “common mental distress” (CMD).

Researchers analysed levels of CMD in two large groups of young people through a series of questionnaires.

They also separately collected self-reported data on suicidal thinking and non-suicidal self-injury: predictive markers for increased risk of suicide – the second most common cause of death among 10-24 year-olds worldwide.

Both groups consisted of young people aged 14-24 from London and Cambridgeshire. The first contained 2,403 participants. The study’s methods – and findings – were then reproduced with a separate group of 1,074 participants. 

“Our findings are noteworthy for being replicated in the two independent samples,” said Jones.

CMD scores increase in three significant increments above the population average: mild mental distress, followed by moderate, and finally severe distress and beyond – which often manifests as a diagnosable mental health disorder.

Those with severe mental distress came out highest for risk of suicide. However, the majority of all participants experiencing suicidal thoughts or self-harming – 78% and 76% respectively in the first sample, 66% and 71% in the second – ranked as having either mild or moderate levels of mental distress.

“Our findings help explain why research focusing on high-risk subjects has yet to translate into useful clinical tools for predicting suicide risk,” said Jones. “Self-harm and suicidal thoughts merit a swift response even if they occur without further evidence of a psychiatric disorder.”

The findings point to a seemingly contradictory situation, in which most of the young people who take their own life may, in fact, be from the considerably larger pool of those deemed as low- or no-risk for suicide.

“It is well known that for many physical conditions, such as diabetes and heart disease, small improvements in the risks of the overall population translate into more lives saved, rather than focusing only on those at extremely high risk,” said Jones.

“This is called the ‘prevention paradox’, and we believe our study is the first evidence that mental health could be viewed in the same way. We need both a public health and a clinical approach to suicide risk.”

“We are surrounded by technology designed to engage the attention of children and young people, and its effect on wellbeing should be seen by industry as a priority beyond profit.”

“At a government level, policies affecting the economy, employment, education and housing, to health, culture and sport must all take account of young people; supporting their wellbeing is an investment, not a cost. This is particularly important as the widespread effects of the Covid-19 pandemic unfold.”

Reference:
Polek E, Neufeld SAS, Wilkinson P, Goodyer I, St Clair M, Prabhu G, Dolan RJ, Bullmore ET, Fonagy P, Stochl J, Jones PB. How do the prevalence and relative risk of non-suicidal self-injury and suicidal thoughts vary across the population distribution of common mental distress (the p factor)? Observational analyses replicated in two independent UK cohorts of young people. BMJ Open 2020;10:e032494. doi: 10.1136/bmjopen-2019-032494  

A new trial to prevent organ failure and death in COVID-19 patients has been launched, led by clinicians and scientists in Cambridge and London.

TACTIC, as the trial is known, will test whether re-purposing existing drugs, which target the body’s own immune response, can prevent people suffering severe organ failure or death. The trial is part of the coordinated national approach by the UK Government to support the early phase development of potential new treatments for COVID-19.

For the majority of people with COVID-19, the infection causes only mild symptoms, including a fever and cough.  However, around 15% of patients develop severe disease, including serious damage to the lungs and multiple organ failure, and about two percent die.

The serious symptoms appear to be mostly caused by the body’s own immune system responding to the presence of infected cells and ‘over-reacting’, destroying healthy cells as well as virus-infected ones.

Two drugs will initially be tested through TACTIC on patients at a network of hospitals across the UK, including Cambridge University Hospitals NHS Foundation Trust (CUH), Guy’s and St Thomas’ NHS Foundation Trust, and King’s College Hospital.

The first patient was recruited onto the study at Addenbrooke’s Hospital in Cambridge on Friday 8 May.

The two drugs, Ravulizumab and Baricitinib, have been carefully selected by a consortium of doctors and scientists with expertise in treating immune-response diseases. They are both thought to have a high chance of reducing the sometimes fatal over-reaction of the immune system seen in very sick patients with COVID-19.

This study is one of a number of COVID-19 studies that have been given urgent public health research status by the Department of Health and Social Care. It is supported by the National Institute for Health Research (NIHR) Biomedical Research Centres at Cambridge and Guy’s and St Thomas’ and UK Research and Innovation; the drug manufacturers , Lilly and Alexion, have each supplied the drug for up to 469 subjects as well as contributing up to £200,000 in running costs for the project.

If the trial demonstrates that a drug is effective, it will be quickly moved into NHS care pathways, to treat the patients with severe COVID-19 related disease.  Similarly, if the trial reveals that a drug is not effective, it can be quickly removed so that other options can be tested.

UK Research and Innovation Chief Executive, Professor Sir Mark Walport, said: “By supporting the rapid progress of these re-purposed drugs into early clinical trials we will test whether they can prevent the development of severe COVID-19 symptoms. Trialling drugs that have the potential to suppress the severe inflammation caused by an over-reaction of the immune system is an important part of tackling the COVID pandemic.”

Dr Frances Hall, Consultant Rheumatologist, CUH, and TACTIC Chief Investigator, said: “It is striking that the severe COVID-19-related disease is associated with the person’s own immune system causing most of the damage. It seems that, while most people’s immune system attacks the virus appropriately, in those who become really sick, the immune response appears to overreact.

“We have selected the first two drugs for the TACTIC study based on their ability to ‘dial-down’, or block, two distinct types of response, each of which appear important in the immune response which causes damage to lungs and other organs in COVID-19-related disease. Baricitinib acts through the network of cytokines (soluble immune system signals running between cells); it reduces the upscaling of the cytokine response which leads to the “cytokine storm” evident in severe COVID-19-related disease.  On the other hand Ravulizumab inhibits the activation of a trigger in a “tag-team” of molecules, called the complement cascade, which serves to rapidly ramp up inflammation and cell killing.”

The two drugs are used routinely as treatments – Baricitinib in severe rheumatoid arthritis and Ravulizumab in blood diseases where complement activation destroys red blood cells. Dr Hall says there is good reason to believe that either or both of these strategies could help prevent severe organ failure and even death in patients with COVID-19.

Professor Ian Wilkinson, Director of the Cambridge Clinical Trials Unit, and Professor of Therapeutics at the University of Cambridge, said: "This is a time of huge national effort in the fight against COVID-19 and I am delighted that Cambridge is playing a key role in this. TACTIC will test the effectiveness of a number of existing and new drugs in patients admitted to hospital, in a similar way to the RECOVERY trial, but with a strong focus on modulating the immune response and collecting high quality data that can be used by our partner pharmaceutical companies to seek the necessary approvals for widespread international use.”

Dr James Galloway, Senior Lecturer in Rheumatology at King’s College London, and a Co-Investigator on the TACTIC trial, said: “By testing existing drugs that we think have the best chance of working against COVID-19, we hope that we can find proven ways to treat the disease. Identifying the high risk patients taking part in this research will be key, and we’re incredibly grateful to the patients who have been so willing to take part, and their families.”

Dr Hall is a Fellow in Medical and Veterinary Scienceat Sidney Sussex College. Professor Wilkinson is a Fellow in Clinical Medicine at Trinity Hall.

Adapted from a press release from Cambridge University Hospitals NHS Foundation Trust

On Friday 20 March, Karl Wilson, received a phone call which would turn his life upside-down for the next six weeks.

“After a hectic week of closing down labs across the University, I was adjusting to my first day of working from home,” remembers Wilson. “I’d managed a couple of hours work in my spare room (having just set up my new desk with the ‘help’ of my four year old daughter), when I received a call to say that the University would be partnering with pharmaceutical giants AstraZeneca and GSK to set up a testing centre for Covid-19, in the newly built Anne McLaren Building.

“I knew it would be a huge undertaking but there was no question in my mind about it. It was just a case of ‘yes, let’s do this.’”

An hour later Wilson found himself at the lab discussing floor plans, safety cabinets and sample-prepping-robots. “It’s been a whirlwind ever since,” he says. 

A project of this scale would ordinarily take around six months to complete but incredibly the lab was ready to begin trialling tests in just three weeks. Wilson explained that this phenomenal feat was testament to the positive approach of everyone involved in the project. “There’s never been any hesitation, never a question of ‘what’s in it for me?’ It’s always just been a case of ‘how can I help?’”

It’s the small snippets of personal stories which demonstrate the dedication to the project of every individual involved. Wilson shares about a Programme Manager who left his family to move temporarily to Cambridge, to set up the IT infrastructure key to running the robotics. In another instance of generosity, two building firms, Mace and Mick George worked together to create a vital walkway to the test centre at short notice, and then waived fees of approximately £20,000. And from the very moment the project began, manufacturers have developed and supplied complex scientific equipment in a fraction of the time it would usually have taken them to do so.

Wilson says that the timely completion of the test centre was only possible through teamwork, collaboration, flexibility and the sheer number of hours put in by employees. It’s been estimated that 2292 hours have been worked overall to get us to this stage.

Wilson describes the feeling on site as being “very much a ‘camp vibe.’” He says, “You're thrusting a lot of people who don't know each other into a new situation, under very unusual circumstances. We were typically on site 13 hours a day – working together, talking together, eating together and taking time-out together. We all really bonded – you’d never have known we’d met for the first time just a few weeks before – it now feels like we’ve been friends for years.”

When days were tough it was the ‘why’ that kept the teams going. “We were just thinking ‘the quicker we get the centre open, the sooner we can help the country move forward, get out of lockdown, and hopefully return to some semblance of normality,” says Wilson. 

With the project nearing completion Wilson is finally able to catch his breath and begin to reflect on what has been both the greatest challenge and most rewarding venture of his career to date. He credits the success of the project to every individual involved who “just wanted to do a great job.”

“Everyone took real ownership of their roles and such pride in their work,” he says. “I think everyone is really pleased with what we’ve accomplished.

“We’re excited to see the lab in action and, in a sense, see the fruits of our labour. And one day, hopefully in the not too distant future, we’re all looking forward to going out together, to raise a toast to the success of a job well done.”

Research by academics at the Faculty of Education, University of Cambridge, Addis Ababa University and the Ethiopian Policy Studies Institute, examined the progress of thousands of students in Ethiopia, including a large number of ‘first-generation learners’: children whose parents never went to school.

The numbers of such pupils have soared in many low and middle-income countries in recent decades, as access to education has widened. Primary school enrolment in Ethiopia, for example, has more than doubled since 2000, thanks to a wave of government education investment and reforms.

But the new study found that first-generation learners are much more likely to underperform in Maths and English, and that many struggle to progress through the school system.

The findings, published in the Oxford Review of Education, suggest that systems like Ethiopia’s – which a generation ago catered mainly to the children of an elite minority – urgently need to adapt to prioritise the needs of first-generation learners, who often face greater disadvantages than their contemporaries.

Professor Pauline Rose, Director of the Research for Equitable Access and Learning (REAL) Centre in the Faculty of Education, and one of the paper’s authors, said: “The experience of first-generation learners has largely gone under the radar. We know that high levels of parental education often benefit children, but we have considered far less how its absence is a disadvantage.”

“Children from these backgrounds may, for example, have grown up without reading materials at home. Our research indicates that being a first-generation learner puts you at a disadvantage over and above being poor. New strategies are needed to prioritise these students if we really want to promote quality education for all.”

The study used data from Young Lives, an international project studying childhood poverty, to assess whether there was a measurable relationship between being a first-generation learner and children’s learning outcomes.

In particular, they drew on two data sets: One, from 2012/13, covered the progress of more than 13,700 Grade 4 and 5 students in various Ethiopian regions; the other, from 2016/17, covered roughly the same number and mix at Grades 7 and 8. They also drew on a sub-set of those who participated in both surveys, comprising around 3,000 students in total.

Around 12% of the entire dataset that includes those in school were first-generation learners. The researchers found that first-generation learners often come from more disadvantaged backgrounds than other pupils: for example, they are more likely to live further from school, come from poorer families, or lack access to a home computer. Regardless of their wider circumstances, however, first-generation learners were also consistently more likely to underperform at school.

For example: the research compiled the start-of-year test scores of students in Grades 7 and 8. These were standardised (or ‘scaled’) so that 500 represented a mean test score. Using this measure, the average test score of first-generation learners in Maths was 470, compared with 504 for non-first-generation pupils. In English, first-generation learners averaged 451, compared with 507 for their non-first-generation peers.

The attainment gap between first-generation learners and their peers was also shown to widen over time: first-generation learners from the Grade 4/5 cohort in the study, for example, were further behind their peers by the end of Grade 4 than when they began.

The authors argue that a widespread failure to consider the disadvantages faced by first-generation learners may, in part, explain why many low and middle-income countries are experiencing a so-called ‘learning crisis’ in which attainment in literacy and numeracy remains poor, despite widening access to education.

While this is often blamed on issues such as large class sizes or poor-quality teaching, the researchers say that it may have more to do with a surge of disadvantaged children into systems that, until recently, did not have to teach as many pupils from these backgrounds.

They suggest that many teachers may need extra training to help these pupils, who are often less well-prepared for school than those from more educated (and often wealthier) families. Curricula, assessment systems and attainment strategies may also need to be adapted to account for the fact that, in many parts of the world, the mix of students at primary school is now far more diverse than a generation ago.

Professor Tassew Woldehanna, President of Addis Ababa University and one of the paper’s authors, said: “It is already widely acknowledged that when children around the world start to go back to school after the COVID-19 lockdowns, many of those from less-advantaged backgrounds will almost certainly have fallen further behind in their education compared with their peers. This data suggests that in low and middle-income countries, first-generation learners should be the target of urgent attention, given the disadvantages they already face.”

“It is likely that, at the very least, a similar situation to the one we have seen in Ethiopia exists in other sub-Saharan African countries, where many of today’s parents and caregivers similarly never went to school,” Rose added.

“These findings show that schooling in its current form is not helping these children to catch up: if anything, it’s making things slightly worse. There are ways to structure education differently, so that all children learn at an appropriate pace. But we start by accepting that as access to education widens, it is inevitable that some children will need more attention than others. That may not be due to a lack of quality in the system, but because their parents never had the same opportunities.”

While the initial coronavirus peak is starting to pass – in Europe, at least – without the ventilator shortages many feared, the spectre of a second wave or future outbreak means questions of medical rationing still hold sway.

New research suggests that current ICU protocols and ethical guidelines lack detail, and leave doctors exposed to legal liability if another contagion surge forces them to make painful snap decisions due to insufficient resources.

While the latest analysis focuses on ventilators, University of Cambridge researchers say that many of their arguments apply to other potential medical shortages e.g. a lack of properly staffed ICU beds, dialysis machines or related supplies or equipment.

If shortages lead to denial of treatment based on disability – including ‘chronic illness’ – or age, or treatment withdrawal during sedation, it could violate patient rights and cause unlawful death, argue the Cambridge lawyers.   

They say that legal liability could extend to the UK Government if it is required to defend failures to purchase more medical supplies or publish ICU rationing guidance, despite knowledge of risks to life posed by the pandemic.

The study, published in the Journal of Medical Ethics, is based on UK law, but researchers say it is relevant to other European nations.

“We’re definitely not out of the woods,” said Dr Kathy Liddell, Director of the Cambridge Centre for Law, Medicine and Life Sciences. “With lockdown easing, we might well see a second Covid-19 spike in intensive care units, and health services should be prepared legally as well as medically.”

“The law requires more of hospitals, doctors and clinical commissioning groups than is currently set out in the guidelines provided by the British Medical Association, the Intensive Care Society and medical ethicists.”

“The legal rights of patients matter, and they are not being given the attention they deserve,” she said.

Around 2.5% of Covid-19 patients require mechanical ventilation to live while they fight the virus, and a patient can need assisted breathing for up to three weeks.

Early concerns that the virus would see patient demand overwhelm ventilator supply prompted researchers to investigate the legal limits of ventilator allocation.

They found “little concrete guidance” centrally in the UK, and argue that a shortage could see “postcode lotteries” of patient rights to life saving treatment – as decisions are taken at a local level by hospitals and doctors.

“The guidelines we reviewed differed in many ways,” said co-author Dr Jeff Skopek, from Cambridge’s Faculty of Law. “But they generally had the same goal: save as many lives as possible. While this is of course a worthy goal, it can lead to the violation of patients’ rights – rights are not suspended merely because we are in a crisis.”

The researchers argue that a ventilator cannot be denied on the grounds that a patient has a disability. “Denying treatment because of a disability, which includes chronic illness, violates the Equalities Act 2010. Denying treatment based on age may also do so,” said Liddell.

“In fact, the Equalities Act requires efforts be taken not to disadvantage disabled people. This may mean giving people with disabilities longer assessment periods on ventilation, or actually not de-prioritising them,” she said.

The analysis points out that if an initial trial of treatment is proposed, it must not be too short. No one should be taken off a ventilator for reallocation purposes until the trial has been long enough to generate reliable evidence for predicting the patient’s outcome.

Any decision to withhold or remove ventilation must involve consultation with the patient or their family. Moreover, withdrawing a ventilator without bringing the patient out of sedation risks unlawful killing.

“Even though returning to consciousness would be deeply distressing, all patients must be given a chance to breathe independently if they have a meaningful chance of surviving until another ventilator is available,” said Liddell.

If some of these scenarios occur during another virus spike, the researchers say doctors could be directly liable under criminal law for charges such as gross negligence manslaughter, criminal battery or willful neglect.

Even the UK Government could be held responsible. As Skopek highlights, the decision taken by government in April 2020 not to provide a national policy on handling ICU shortages – despite recommendations from its Moral and Ethical Advisory group – could result in a violation of its obligations under Article 8 of the European Convention on Human Rights.

“Without a national policy, the task of drawing up ICU rationing guidelines was left to individual CCGs and hospitals, and many lacked support to ensure their guidelines were legal and ethically sound,” he said.  

Added Skopek: “If we end up with another surge in patients that overwhelms our critical care infrastructure, hospitals and doctors may end up acting unlawfully – and worse, patients may end up dying unlawfully.”

Their method is able to recognise these toxic particles, known as amyloid-beta oligomers, which are the hallmark of the disease, leading to hope that new diagnostic methods can be developed for Alzheimer’s disease and other forms of dementia.

The team, from the University of Cambridge, University College London and Lund University, designed an antibody which is highly accurate at detecting toxic oligomers and quantifying their numbers. Their results are reported in the Proceedings of the National Academy of Sciences (PNAS).

“There is an urgent unmet need for quantitative methods to recognise oligomers – which play a major role in Alzheimer’s disease, but are too elusive for standard antibody discovery strategies,” said Professor Michele Vendruscolo from Cambridge’s Centre for Misfolding Diseases, who led the research. “Through our innovative design strategy, we have now discovered antibodies to recognise these toxic particles.”

Dementia is one of the leading causes of death in the UK and costs more than £26 billion each year, a figure which is expected to more than double in the next 25 years. Estimates put the current cost to the global economy at nearly £1 trillion per year.

Alzheimer’s disease, the most prevalent form of dementia, leads to the death of nerve cells and tissue loss throughout the brain, resulting in memory failure, personality changes and problems carrying out daily activities.

Abnormal clumps of proteins called oligomers have been identified by scientists as the most likely cause of dementia. Although proteins are normally responsible for important cell processes, according to the amyloid hypothesis, when people have Alzheimer’s disease these proteins –including specifically amyloid-beta proteins – become rogue and kill healthy nerve cells.

Proteins need to be closely regulated to function properly. When this quality control process fails, the proteins misfold, starting a chain reaction that leads to the death of brain cells. Misfolded proteins form abnormal clusters called plaques which build up between brain cells, stopping them from signalling properly. Dying brain cells also contain tangles, twisted strands of proteins that destroy a vital cell transport system, meaning nutrients and other essential supplies can no longer move through the cells.

There have been over 400 clinical trials for Alzheimer’s disease, but no drug that can modify the course of the disease has been approved. In the UK, dementia is the only condition in the top 10 causes of death without a treatment to prevent, stop, or slow its progression.

“While the amyloid hypothesis is a prevalent view, it has not been fully validated in part because amyloid-beta oligomers are so difficult to detect, so there are differing opinions on what causes Alzheimer’s disease,” said Vendruscolo. “The discovery of an antibody to accurately target oligomers is, therefore, an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control.”

The lack of methods to detect oligomers has been a major obstacle in the progress of Alzheimer’s research. This has hampered the development of effective diagnostic and therapeutic interventions and led to uncertainty about the amyloid hypothesis.

“Oligomers are difficult to detect, isolate, and study,” said Dr Francesco Aprile, the study’s first author. “Our method allows the generation of antibody molecules able to target oligomers despite their heterogeneity, and we hope it could be a significant step towards new diagnostic approaches.”

The method is based on an approach for antibody discovery developed over the last ten years at the Centre for Misfolding Diseases. Based on the computational assembly of antibody-antigen assemblies, the method enables the design of antibodies for antigens that are highly challenging, such as those that live only for a very short time.

By using a rational design strategy that enables to target specific regions, or epitopes, of the oligomers, and a wide range of in vitro and in vivo experiments, the researchers have designed an antibody with at least three orders of magnitude greater affinity for the oligomers over other forms of amyloid-beta. This difference is the key feature that enables the antibody to specifically quantify oligomers in both in vitro and in vivo samples.

The team hopes that this tool will enable the discovery of better drug candidates and the design of better clinical trials for people affected by the debilitating disease. They also co-founded Wren Therapeutics, a spin-out biotechnology company based at the Chemistry of Health Incubator, in the recently opened Chemistry of Health building, whose mission it is to take the ideas developed at the University of Cambridge and translate them into finding new drugs to treat Alzheimer’s disease and other protein misfolding disorders.

The antibody has been patented by Cambridge Enterprise, the University’s commercialisation arm.

Reference:
Francesco A. Aprile et al. ‘Rational design of a conformation-specific antibody for the quantification of Aβ oligomers.’ Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.1919464117