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Tackling COVID-19: Dr Sharath Srinivasan

source: www.cam.ac.uk

“Without trust, we don’t flatten the curve,” says Sharath Srinivasan, whose work in developing countries has given him an acute insight into how people’s worldviews and perspectives affect who and what they choose to trust. Through a new communications tool he’s helping to engage communities in Somalia so that COVID-19 risks are communicated effectively and rumours are quashed.

I’ve spent most of the last few years in Kenya and eastern Africa. When I wasn’t there, I was usually scampering back and forth between the Alison Richard Building on Cambridge’s Sidgwick site and King’s College, somehow covering my daily steps quota. Now I’m working at the kitchen table, my son’s desk in his room, or the bedroom. I’m missing the study we never had!

I work on the ‘Risk Communications and Community Engagement’ part of the global pandemic response. This is about understanding the experience of the virus from a community perspective, then delivering trusted and effective messaging to support healthy behaviours as well as communicating feedback to public health actors and authorities.

My own expertise lies in understanding citizen-authority relations in developing countries, and how citizens engage with and hold to account decision-makers in policy-making and service delivery. Over the years I’ve also worked on innovations using media and communication technology to engage with and hear from hard-to-reach populations, and derive rapid social insights from large volumes of local language textual data. My work led to the spin-off Africa’s Voices Foundation, a non-profit I cofounded, based in Kenya. The team deploys our novel method combining local language radio and a free SMS channel to deliver governance and social change programmes.

As soon as COVID-19 hit, we were engaging populations in Kenya and Somalia. Two years ago, I was supported by the Wellcome Trust and UK DFID to evaluate the use of our interactive radio method for rapid social insights in health crises, as part of a global rethink following the West African Ebola outbreak. We’re now using this method and delivering insights to the wider national and international COVID-19 response.

I also work on improving socio-technical solutions for effective risk communication and community engagement, in collaboration with Luke Church in the Computer Laboratory. COVID-19 motivated us to rapidly build a communications tool for handling large volumes of one-to-one SMS conversations. If people raise urgent concerns, convey rumours, misinformation or stigma, or ask questions about COVID-19, the Africa’s Voices team needs to respond to each person quickly and empathetically but using an approved response protocol. A bot simply won’t do. We developed a tool called katikati that’s being used in Somalia right now, handling many thousands of interactions each week.

Trust is the biggest challenge of this pandemic. Who and what is trusted by people determines how they respond. How much do we trust in ourselves and our communities, in our social/religious leaders, in scientific expertise, and in people, nations, governments and international agencies globally? Without trust playing a very large role, we don’t flatten the curve through distancing and hygiene, achieve track and trace, protect the vulnerable, adopt new vaccines, reopen our businesses, institutions, even our borders, and ready ourselves to tackle a possible second wave.

Our research is about unearthing the worldviews and perspectives of communities, then thinking about the communications that will make sense for them. Imagine you’re a Somali forcibly displaced from your home due to drought and conflict, now in a crowded informal camp with no running water and limited sanitation, in the midst of a locust plague that is wreaking havoc on food production and livelihoods. Your life is precarious already, and you face a range of risks and anxieties. You are told by a government announcement that this new virus is sweeping the world, and to protect your community you must change the way you live in ways that are hard to achieve and put your livelihood in greater peril. You turn to your local Sheikh for guidance, as you always do – it’s what they say that matters, not what the government, or WHO, or UNICEF is saying.

Somehow this pandemic arrived when our communication technologies and data transmission capabilities were ready for global remote networked collaboration. We might all be a bit ‘Zoomed out’, but I’m amazed every day by how I can collaborate on a response in Somalia with multiple organisations and far flung individuals. Ten years ago cloud computing was in its infancy, and we could not have managed this.

I am more motivated and passionate than ever about the importance and value of applied interdisciplinary research that really harnesses expertise across social, biomedical and technological sciences. In Cambridge there’s a strong spirit of collaboration across departments and disciplines that’s very inspiring. I’ve seen this through the support given to me by initiatives such as Cambridge-Africa and Cambridge Global Challenges.

When the pandemic is over I’m looking forward to traveling back to Kenya and eastern Africa and meeting up again with the amazing Africa’s Voices team.

Sharath Srinivasan is David and Elaine Potter Lecturer in Governance & Human Rights and Co-Director of the Centre of Governance and Human Rights (CGHR), and Fellow of King’s College, Cambridge. Read more about the Africa’s Voices project on Somali views in the early days of COVID-19.

How you can support Cambridge’s COVID-19 research


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Human interactions with wild and farmed animals must change dramatically to reduce risk of another deadly pandemic

Pig farming
source: www.cam.ac.uk

Compiled by a team of international wildlife and veterinary experts, a new study has identified seven routes by which pandemics could occur and 161 options for reducing the risk. It concludes that widespread changes to the way we interact with animals are needed; solutions that only address one issue – such as the trade in wild animals – are not enough.

We can’t completely prevent further pandemics, but there are a range of options that can substantially reduce the risk.

Silviu Petrovan

The authors of the new report argue that well-meaning but simplistic actions such as complete bans on hunting and wildlife trade, ‘wet markets’ or consumption of wild animals may be unachievable and are not enough to prevent another pandemic. Measures like these can be difficult to implement so must be carefully planned to prevent proliferation of illegal trade, or alienation and increasing hardship for local communities across the world who depend on wild animals as food.

Zoonotic diseases of epidemic potential can also transmit from farmed wildlife (such as civets) and domesticated animals (as exemplified by swine flu and avian flu), with greater risks occurring where humans, livestock and wildlife closely interact.

Compiled by a team of 25 international experts, the study considered all major ways that diseases with high potential for human to human transmission can jump from animals to humans (termed zoonotic diseases). The authors say that dealing with such a complicated mix of potential sources of infection requires widespread changes to the ways humans and animals interact.

“A lot of recent campaigns have focused on banning the trade of wild animals, and dealing with wild animal trade is really important yet it’s only one of many potential routes of infection. We should not assume the next pandemic will arise in the same way as COVID-19; we need to be acting on a wider scale to reduce the risk,” said Professor William Sutherland in the University of Cambridge’s Department of Zoology and the BioRISC Research Initiative at St Catharine’s College, Cambridge, who headed the research.

Potential ways another human pandemic could arise include: wildlife farming, transport, trade and consumption; international or long distance trade of livestock; international trade of exotic animals for pets; increased human encroachment into wildlife habitats; antimicrobial resistance – especially in relation to intensive farming and pollution; and bioterrorism.

Some of the ways to reduce the risk of another pandemic are relatively simple, such as encouraging smallholder farmers to keep chickens or ducks away from people. Others, like improving biosecurity and introducing adequate veterinary and hygiene standards for farmed animals across the world, would require significant financial investment on a global scale.

The 161 options include:
• Laws to prevent the mixing of different wild animals or the mixing of wild and domestic animals during transport and at markets;
• Increase switching to plant-based foods to reduce consumption of, and demand for, animal products;
• Safety protocols for caving in areas with high bat density, such as use of waterproof coveralls and masks;
• Improve animal health on farms by limiting stocking densities and ensuring high standards of veterinary care.

“We can’t completely prevent further pandemics, but there are a range of options that can substantially reduce the risk. Most zoonotic pathogens are not capable of sustained human-to-human transmission, but some can cause major epidemics. Preventing their transfer to humans is a major challenge for society and also a priority for protecting public health,” said Dr Silviu Petrovan, a veterinarian and wildlife expert from the University of Cambridge and lead author of the study.

“Wild animals aren’t the problem – they don’t cause disease emergence. People do. At the root of the problem is human behaviour, so changing this provides the solution,” said Professor Andrew Cunningham, Deputy Director of Science at the Zoological Society of London and co-author of the study.

Solutions were focused on measures that can be put in place in society at local, regional and international scales. The study did not consider the development of vaccines and other medical and veterinary medicine options. It does not offer recommendations, but a set of options to help policy-makers and practitioners think carefully about possible courses of action.

All categories of animal – wildlife, captive, feral, and domestic – were included in the study. The focus was on diseases, particularly viruses, which could rapidly become epidemics through high rates of human-to-human transmission once they have jumped from an animal. This excludes some well-known zoonotic diseases such as rabies and Lyme disease that require continuous transmission from animals.

The report is currently being peer reviewed. The findings were generated by a method called Solution Scanning, which uses a wide range of sources to identify a range of options for a given problem. Sources included the scientific literature, position papers by Non-Governmental Organisations, industry guidelines, experts in different fields, and the expertise of the study team itself.

This work was funded by The David and Claudia Harding Foundation, Arcadia, and MAVA.

Reference (unpublished report available as preprint)
Petrovan, S. et al: Post COVID-19: a solution scan of options for preventing future zoonotic epidemics. DOI: 10.17605/OSF.IO/5JX3G. 

How you can support Cambridge’s COVID-19 research

 


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Opinion: Why Too Much Focus On COVID-19 Could Be Harming Our Children

Child with hands over face - children may be at risk by too much focus on COVID-19
source: www.cam.ac.uk

COVID-19 hurts even those who escape infection – particularly children, writes paediatrician Dr Kai Hensel from the University of Cambridge in the journal Archives of Disease in Childhood.

There seems to be almost only one relevant diagnosis these days: the new virus

Kai Hensel

In preparation for the COVID-19 pandemic and the anticipated overwhelming demand on hospitals, the NHS moved towards of a policy of providing only essential treatments. Doctors were asked to postpone all non-urgent clinical activities including face-to-face outpatient visits, diagnostic procedures and hospital-based therapies.

As nations declared themselves ‘at war’ against the virus, they may have become blinded to the impact on other conditions. “There seems to be almost only one relevant diagnosis these days: the new virus,” writes Hensel.

This has meant that, thanks to the preparations, a major hospital could have more than 450 empty beds and less than 50% surgical theatre activity.

“The message is unmistakable: we are prepared. But this comes at a price… Antenatal care is widely reduced, cancer surgeries are limited and emergency room attendance has decreased to far less than 50% as compared with pre-coronavirus times. Where are all the sick patients that usually keep us busy?”

In fact, the level of busyness may depend entirely on the medical specialty in question. Healthcare workers in adult intensive care units face facing long hard shifts treating severely unwell patients, while most paediatric specialties are seeing a drastically decreased workload.

“Healthcare allocation, in times of COVID-19 more than ever, is a risk management game. But the ‘flatten-the-curve imperative’ inevitably comes at a price, and the bill is yet to come. As one curve is plateauing, others may even rise.”

Hensel argues that children may be getting “a bad deal” as a result of healthcare policies. They tend to have milder disease if infected, yet are missing out on other important services.

He presents the example of a two-year-old boy who was referred to his team for suspected very-early-onset inflammatory bowel disease (IBD). This is usually confirmed by endoscopy or MRI. It was only by the team successfully pressing for the boy to be considered an exception that endoscopy revealed that his symptoms were caused by a single juvenile rectal polyp (abnormal tissue growth), which was then removed. The remainder of the procedure was normal, and the boy was discharged without further medical treatment. If the team had not urged for the boy to be placed on one of the few emergency lists, he would have been mistakenly diagnosed with IBD and given immunosuppressant drugs with potential side effects while he continued to suffer symptoms.

Policies to manage resources during COVID-19 risks having a disproportionate impact on children, writes Hensel. Three months since the UK first went into lockdown, more and more negative public health consequences are beginning to unfold. Lockdown regulations and school closures are making vulnerable children even harder to reach, prompting the World Health Organization to issue a joint leaders’ statement entitled “Violence against children: a hidden crisis of the COVID-19 pandemic”.

“Tragically, detrimental social and health effects will hit the socioeconomically disadvantaged communities disproportionally harder,” writes Dr Hensel. “Food insecurity and loss of academic achievement are expected to significantly contribute to the exacerbation of the already existing inequalities.” He argues that a public health approach is urgently needed to improve child health in these challenging times, to manage domestic violence and to fight under-the-radar child neglect.

With the performance of policy-makers being judged according to internationally comparable coronavirus numbers, Dr Hensel says it is the job of physicians to speak up on behalf of underrepresented patient groups.

“We need to advocate, to give our patients a voice and to spread the message: in COVID-19 times, there is not just one diagnosis that matters.”

Reference
Hensel, KO. Double-edged sword of limiting healthcare provision for children in times of COVID-19: the hidden price we pay. BMJ; 23 June 2020; DOI: 10.1136/archdischild-2020-319575


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The text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified.  All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

New Artificial Heart Valve Could Transform Open-Heart Surgery

An advanced prototype of the PoliValve
source: www.cam.ac.uk

A new type of artificial heart valve, made of long-lived polymers, could mean that millions of patients with diseased heart valves will no longer require lifelong blood-thinning medication after valve replacement surgery.

These impressive results show the PoliValve is a promising alternative for valve replacement surgery

Geoff Moggridge

The valve, called PoliValve, has been developed by scientists at the Universities of Cambridge and Bristol. The team’s latest in vitro results, published in the journal Biomaterials Science, suggest that the PoliValve can last for up to 25 years in patients, far longer than other types of replacement heart valves. In addition, a small pilot study in sheep showed that the valve is highly compatible with biological tissue. The researchers anticipate that the PoliValve can be tested in humans within five years.

More than 1.3 million patients with diseased heart valves need valve replacement globally each year. There are two types of artificial valves currently available, however both have limitations either in durability or in biocompatibility.

Biological valves are made from pig or cow tissue and have good biocompatibility, meaning patients do not need lifelong blood-thinning medication; however, they only last 10-12 years before failing. And mechanical valves, while they have good durability, have poor biocompatibility and patients must take daily blood-thinning drugs to prevent blood clots.

Professor Geoff Moggridge from the University of Cambridge and Professor Raimondo Ascione from the University of Bristol have spent three years conducting developmental work and testing on the PoliValve, supported by funding from the British Heart Foundation.

The device is made from a special co-polymer and is designed to resemble a natural heart valve. It was created by Professor Moggridge, Dr Marta Serrani and Dr Joanna Stasiak at Cambridge and Professor Ascione in Bristol, and builds on earlier work by Professor Maria Laura Costantino’s group at the University of Milan.

The PoliValve combines excellent durability with biocompatibility, addressing the limitations of current biological and mechanical artificial valves. It is made through a simple moulding process, which also sharply reduces manufacturing and quality control costs.

“These impressive results show the PoliValve is a promising alternative for valve replacement surgery,” said Moggridge, who leads the Structural Materials Group at Cambridge’s Department of Chemical Engineering and Biotechnology. “While further testing is needed, we think it could make a major difference to the hundreds of thousands of patients who get valve replacement surgery every year.”

According to ISO standards, a new artificial heart valve must withstand a minimum of 200 million repetitions of opening and closing during laboratory testing, equivalent to five years of life span, before it can be tested in humans. The new Cambridge-Bristol polymeric valve has comfortably surpassed this.

Initial testing in sheep has been undertaken at Bristol’s Translational Biomedical Research Centre (TBRC) facility as a first step to ensure safety. Long-term testing in sheep, also funded by the British Heart Foundation, will be carried out before bringing this new treatment to human patients.

“Patients requiring an artificial heart valve are often faced with the dilemma of choosing between a metallic or tissue valve replacement,” said Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation. “A metallic valve is long-lasting but requires the patient to take lifelong blood-thinning drugs. Although this medication prevents clots forming on the valve, it also increases the risk of serious bleeding. Patients who have a tissue valve replacement usually don’t need to take this medication. However, the valve is less durable and means the patient may face further surgery.

“The polymer valve combines the benefits of both – it is durable and would not require the need for blood-thinning drugs. While further testing is needed before this valve can be used in patients, this is a promising development, and the BHF is pleased to have supported this research.”

The PoliValve has also exceeded the requirements of ISO standards for hydrodynamic testing, showing a functional performance comparable to the best-in-class biological valve currently available on the market. The small pilot study in sheep demonstrated the device is easy to stitch in, and showed no mechanical failure, no trans-valvular regurgitation, low trans-valvular gradients, and good biocompatibility with tissue.

“The transformational PoliValve results from an advanced Bristol/Cambridge-based biomedical cross-fertilisation between experts in biomaterials, computational modelling, advanced preclinical development/testing and clinical academics understanding the patient needs. The new valve could help millions of people worldwide and we aim to test in patients within the next five years,” said Ascione.

The British Heart Foundation-funded study also included Dr James Taylor from Cambridge’s Whittle Laboratory, a team at Newcastle University headed by Professor Zaman, Professor Saadeh Sulaiman at University of Bristol and Professor Costantino’s group at Politecnico di Milano.

Reference:
Joanna R. Stasiak et al. “Design, Development, Testing at ISO standards and in-vivo feasibility study of a novel Polymeric Heart Valve Prosthesis.” Biomaterials Science (2020). DOI: 10.1039/D0BM00412J

Adapted from a University of Bristol press release.


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New Programme To Accelerate AI Research Capability at Cambridge

source: www.cam.ac.uk

A new initiative at Cambridge will equip young researchers outside computer science with the skills they need to use machine learning and artificial intelligence techniques to power their research.

This programme will help ensure that Cambridge continues to be a beacon for the very best young global researchers, and that we’re giving them the tools they need to thrive

Vice-Chancellor Professor Stephen Toope

Supported by a donation from Schmidt Futures, a philanthropic initiative founded by Eric and Wendy Schmidt, the Accelerate Programme for Scientific Discovery will level the playing field for young researchers, providing them with specialised training in these powerful techniques, which have the potential to speed up the pace of discovery across a range of disciplines.

The programme will initially be aimed at researchers in STEMM (science, technology, engineering, mathematics and medicine), but will grow to include arts, humanities and social science researchers who want to use machine learning skills to accelerate their research.

The Accelerate Programme will be led by Professor Neil Lawrence, DeepMind Professor of Machine Learning.

“Machine learning and AI are increasingly part of our day-to-day lives, but they aren’t being used as effectively as they could be, due in part to major gaps of understanding between different research disciplines,” said Lawrence. “This programme will help us to close these gaps by training physicists, biologists, chemists and other scientists in the latest machine learning techniques, giving them the skills they need while accelerating the excellent research already taking place at the University.”

“As the intellectual home of Alan Turing, the father of artificial intelligence and modern computer science, Cambridge has long fostered technological innovation and invention,” said Vice-Chancellor Professor Stephen Toope. “This programme will help ensure that Cambridge continues to be a beacon for the very best young global researchers, and that we’re giving them the tools they need to thrive.”

The five-year programme will be designed and delivered by four new early-career specialists, who will work with researchers from the Department of Computer Science and Technology as well as collaborators from industry. In the first year, the specialists will provide structured training in machine learning techniques to 32 PhD students and postdoctoral researchers, with training provided to a total of 160 PhD students and postdocs over the first five years of the programme. The specialists will also have the opportunity to pursue their own research interests as part of their fellowships.

The programme will also benefit from in-kind support from DeepMind. The world-leading British AI company, founded by Queens’ College alumnus Demis Hassabis, has assisted in the development of the programme, and will offer programme participants guest lectures from DeepMind’s research team and the opportunity to apply for internship positions.

“Machine learning and AI have the potential to revolutionise any number of fields, but there simply aren’t enough scientists with machine learning skills in those fields at the moment,” said Professor Ann Copestake, Head of the Department of Computer Science and Technology. “This programme will combine Cambridge’s research depth and breadth with the unparalleled expertise in machine learning research we have here in the Department, to build a new type of research culture equipped to face the challenges and opportunities of the 21st century.”

“We are delighted to support this far-reaching program at Cambridge,” said Stuart Feldman, Chief Scientist at Schmidt Futures. “We expect it to accelerate the use of new techniques across the broad range of research as well as enhance the AI knowledge of a large number of early-stage researchers at this superb university.”

One of the goals of the Accelerate Programme is to build a network of machine learning experts across the University. The PhD students and postdoctoral researchers who are trained through the Programme will share their knowledge with colleagues, building up capacity throughout Cambridge at scale.

Cambridge’s AI expertise has recently been expanded with the appointment of Dr Ferenc Huszár, who joins the University from Twitter, Dr Carl Henrik Ek, who is joining from the University of Bristol, and Dr Nicholas Lane who is joining from the University of Oxford.


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Faulty Brain Processing of New Information Underlies Psychotic Delusions, Finds New Research

Problems in how the brain recognizes and processes novel information lie at the root of psychosis, researchers from the University of Cambridge and King’s College London have found. Their discovery that defective brain signals in patients with psychosis could be altered with medication paves the way for new treatments for the disease.

Novelty and uncertainty signals in the brain are very important for learning and forming beliefs. When these signals are faulty, they can lead people to form mistaken beliefs, which in time can become delusions.

Graham Murray

The results, published today in the journal Molecular Psychiatry, describe how a chemical messenger in the brain called dopamine ‘tunes’ the brain to the level of novelty in a situation, and helps us to respond appropriately – by either updating our model of reality or discarding the information as unimportant.

The researchers found that a brain region called the superior frontal cortex is important for signaling the correct degree of learning required, depending on the novelty of a situation. Patients with psychosis have faulty brain activation in this region during learning, which could lead them to believe things that are not real.

“Novelty and uncertainty signals in the brain are very important for learning and forming beliefs. When these signals are faulty, they can lead people to form mistaken beliefs, which in time can become delusions,” said Dr Graham Murray from the University of Cambridge’s Department of Psychiatry, who jointly led the research.

In novel situations, our brain compares what we know with the new information it receives, and the difference between these is called the ‘prediction error’. The brain updates beliefs according to the size of this prediction error: large errors signal that the brain’s model of the world is inaccurate, thereby increasing the amount that is learned from new information.

Psychosis is a condition where people have difficulty distinguishing between what is real and what is not. It involves abnormalities in a brain chemical messenger called dopamine, but how this relates to patient experiences of delusions and hallucinations has until now remained a mystery.

The new study involved 20 patients who were already unwell with psychosis, 24 patients with milder symptoms that put them at risk of the condition, and 89 healthy volunteers.

Participants were put into a brain scanning machine called a functional MRI and asked to play a computer game. This allowed the researchers to record activity in the participants’ brains as they engaged in situations with a potential variety of outcomes.

In a second part of the study, 59 of the healthy volunteers had their brains scanned after taking medications that act on the signaling of dopamine in the brain. These medications changed the way that the superior frontal cortex prediction error responses were tuned to the degree of uncertainty.

“Normally, the activity of the superior frontal cortex is finely tuned to signal the level of uncertainty during learning. But by altering dopamine signaling with medication, we can change the reactivity of this region. When we integrate this finding with the results from patients with psychosis, it points to new treatment development pathways,” said Dr Kelly Diederen from the Institute of Psychiatry, Psychology & Neuroscience at King’s College London, who jointly led the study with Dr Murray.

In addition to studying brain activation, the researchers developed mathematical models of the choices made by participants in the computer game, to better understand the strategies of how people learn. They found that patients with psychosis did not take into account the level of uncertainty during learning, which may be a good strategy in some circumstances but could lead to problems in others.  Learning problems were related to alterations in brain activation in the superior frontal cortex, with patients with severe symptoms of psychosis showing more significant alterations.

“While these kind of abnormal brain responses were predicted several years ago, this is the first time the changes have actually been shown to be present. The results give us confidence that our theoretical models of psychosis are correct,” said Dr Joost Haarsma from University College London, first author of the study.

This research was funded by the Wellcome Trust.

Reference
Haarsma, J. et al: ‘Precision-weighting of cortical unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis.’ Molecular Psychiatry, June 2020. DOI: 10.1038/s41380-020-0803-8


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Genomes Front and Centre of Rare Disease Diagnosis

DNA Double Helix
source: www.cam.ac.uk

Cambridge-led study discovers new genetic causes of rare diseases, potentially leading to improved diagnosis and better patient care.

This research shows that quicker and better genetic diagnosis will be possible for more NHS patients

Willem Ouwehand

A research programme pioneering the use of whole genome sequencing in the NHS has diagnosed hundreds of patients and discovered new genetic causes of disease. Whole genome sequencing is the technology used by the 100,000 Genomes Project, a service set up by the government to introduce routine genetic diagnostic testing in the NHS.

The results of the study, published in the journal Nature, demonstrate that sequencing the whole genomes of large numbers of individuals in a standardised way can improve the diagnosis and treatment of patients with rare diseases. It was led by researchers at the University of Cambridge together with Genomics England.

The researchers studied the genomes of groups of patients with similar symptoms, affecting different tissues, such as the brain, eyes, blood or the immune system. They identified a genetic diagnosis for 60% of individuals in one group of patients with early loss of vision.

The programme offered whole-genome sequencing as a diagnostic test to patients with rare diseases across an integrated health system, a world first in clinical genomics. The integration of genetic research with NHS diagnostic systems increases the likelihood that a patient will receive a diagnosis and the chance that a diagnosis will be provided within weeks rather than months.

“Around 40,000 children are born each year with a rare inherited disease in the UK alone. Sadly, it takes more than two years, on average, for them to be diagnosed,” said Willem Ouwehand, Professor of Experimental Haematology at Cambridge, the National Institute for Health Research BioResource and NHS Blood and Transplant Principal Investigator. “We felt it was vital to shorten this odyssey for patients and parents.

“This research shows that quicker and better genetic diagnosis will be possible for more NHS patients.”

In the study, funded principally by the National Institute for Health Research, the entire genomes of almost 10,000 NHS patients with rare diseases were sequenced and searched for genetic causes of their conditions. Previously unobserved genetic differences causing known rare diseases were identified, in addition to genetic differences causing completely new genetic diseases.

The team identified more than 172 million genetic differences in the genomes of the patients, many of which were previously unknown. Most of these genetic differences have no effect on human health, so the researchers used new statistical methods and powerful supercomputers to search for the differences which cause disease – a few hundred ‘needles in the haystack’.

“Our study demonstrates the value of whole-genome sequencing in this context and provides a suite of new diagnostic tools, some of which have already led to improved patient care,” said Professor Adrian Thrasher of the UCL Great Ormond Street Institute of Child Health (ICH) in London.

Using a new analysis method developed specifically for the project, the team identified 95 genes in which rare genetic differences are statistically very likely to be the cause of rare diseases. Genetic differences in at least 79 of these genes have been shown definitively to cause disease.

The team searched for rare genetic differences in almost all of the 3.2 billion DNA letters that make up the genome of each patient. This contrasts with current clinical genomics tests, which usually examine a small fraction of the letters, where genetic differences are thought most likely to cause disease. By searching the entire genome researchers were able to explore the ‘switches and dimmers’ of the genome – the regulatory elements in DNA that control the activity of the thousands of genes.

The team showed that rare differences in these switches and dimmers, rather than disrupting the gene itself, affect whether or not the gene can be switched on at the correct intensity. Identifying genetic changes in regulatory elements that cause rare disease is not possible with the clinical genomics tests currently used by health services worldwide. It is only possible if the whole of the genetic code is analysed for each patient.

“We have shown that sequencing the whole genomes of patients with rare diseases routinely within a health system provides a more rapid and sensitive diagnostic service to patients than the previous fragmentary approach, and, simultaneously, it enhances genetics research for the future benefit of patients still waiting for a diagnosis,” said Dr Ernest Turro from the University of Cambridge and the NIHR BioResource.

“Thanks to the contributions of hundreds of physicians and researchers across the UK and abroad, we were able to study patients in sufficient numbers to identify the causes of even very rare diseases.”

Although individual rare diseases affect a very small proportion of the population, there exist thousands of rare diseases and, together, they affect more than three million people in the UK. To tackle this challenge, the NIHR BioResource created a network of 57 NHS hospitals which focus on the care of patients with rare diseases. Nearly 1000 doctors and nurses working at these hospitals made the project possible by asking their patients and, in some cases, the parents of affected children to join the NIHR BioResource.

“In setting up the NIHR BioResource Project, we were taking uncharted steps in a determined effort to improve diagnosis and treatment for patients in the NHS and further afield” said Dr Louise Wood, Director of Science, Research and Evidence at the Department of Health and Social Care.“This research has demonstrated that patients, their families and the health service can all benefit from placing genomic sequencing at the forefront of clinical care in appropriate settings.

Based on the emerging data from the present NIHR BioResource study and other studies by Genomics England, the UK government announced in October 2018 that the NHS will offer whole-genome sequencing analysis for all seriously ill children with a suspected genetic disorder, including those with cancer. The sequencing of whole genomes will expand to one million genomes per year by 2024.

Whole-genome sequencing will be phased in nationally for the diagnosis of rare diseases as the ‘standard of care’, ensuring equivalent care across the country.

The benefits include a faster diagnosis for patients, reduced costs for health services, improved understanding of the reasons they suffer from disease for patients and their carers and improved provision of treatment.

Reference:
Turro E et al. ‘Whole-genome sequencing of patients with rare diseases in a national health system.’ Nature (2020). DOI: 10.1038/s41586-020-2434-2

Adapted from an NIHR press release.

 


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Tackling COVID-19: Professor Ravi Gupta

Professor Ravi Gupta (third from left) with colleagues in CITIID
source: www.cam.ac.uk

“This virus is probably going to be circulating for years – it will take a long time to sort out.” In a building that has been largely empty for the past three months, Ravi Gupta has been working non-stop alongside other virus experts. Their trial of a rapid diagnostic test using the ‘SAMBA II’ machine made headlines in April: results are returned in 90 minutes, helping healthcare workers ensure that those infected can be quickly directed to specialised wards. But there remains much work to do.

I work at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) in the Department of Medicine. We have stayed operational throughout the COVID-19 pandemic. I was impressed by the way CITIID came together, speeding up completion of our containment level 3 labs (designed to safely handle infectious diseases) by four to six months. This institute came alive at the time it was needed most, and our work spans basic science to diagnostics. Few places in the world have been able to do this.

I’m used to working with another killer disease that creates a lot of fear. I’m a virologist, and I’ve spent the last decade studying HIV. The work I’ve done has been useful preparation for the COVID-19 pandemic, so it felt like the team was in the right place at the right time. Both HIV and COVID-19 are multi-system diseases, and HIV is still enigmatic after 30 years. As we discover the effects of COVID-19 on the human body, such as patients developing heart problems and lung damage, it looks like it will have far-reaching implications that will take a long time to sort out.

We wanted to use our expertise as virologists to help tackle COVID-19. We made ‘pseudo-viruses’ that are part coronavirus and part HIV, but are very safe and don’t cause disease, to try and understand how antibodies were working in people infected with the virus. By taking blood samples from COVID-19 patients and mixing them with our pseudo-virus, we could see that these patients had immunity that would prevent our virus infecting their cells.

One of the big problems with COVID-19 has been making a diagnosis quickly. Tests are being sent off to a lab and taking two to four days to come back, and that’s not quick enough. We’ve been trialling a new rapid point-of-care test to look for antibodies in patients – and we needed the corresponding lab-based study to understand how well this was working. We’re now about to implement a point-of-care antibody test to help diagnosis.

We’ve also recently introduced a new rapid diagnostic test called SAMBA II at Addenbrooke’s Hospital. This followed a four week clinical study we did in April that showed using this test was quick and effective, and that it had a very significant impact on preserving hospital capacity and patient safety. The SAMBA II machines were developed by a University of Cambridge spinout company called Diagnostics for the Real World. You take the nose or throat swab for people who you think have COVID-19, and get a result back in 90-minutes.

The lab has also started a programme to understand the basis of the second, inflammation-mediated part of the disease. This is likely to involve macrophages – the white blood cells that locate disease particles in the body and engulf them. We’re trying to understand the effects of low oxygen levels on the way macrophages behave, and find out why some patients get so much inflammation in their lungs that it becomes fatal. We’re also looking at whether drugs such as azithromyin and chloroquine can stop the inflammation – so not working directly on the virus, but trying to stop the body reacting against itself.

I think there are three big challenges posed by the pandemic: developing wide-scale rapid tests to keep track of the virus and control outbreaks, designing a vaccine that works throughout time and over long periods, and finding effective treatments. The virus is probably going to be circulating for some years, but it may mutate. So even if we have a vaccine we need to make sure it carries on working. We also need really good treatments in order to test vaccines. For a lot of diseases we can give someone a vaccine, and then infect them with the disease to see whether the vaccine works. But while we don’t have any good treatments for COVID-19, we can’t do that.

This has been a big team effort involving lots of people. We’re collaborating with the MRC Laboratory for Molecular Biology, and with colleagues in the Department of Pathology. There are also many people who switched the focus of their research to join us – some were interested in viruses, some were immunologists, but most were not coronavirus experts. Before COVID-19 there were very few of those.

The pandemic has shown us that we can make huge strides in understanding things very quickly and then deal with them appropriately, when we try. We need to communicate well, prepare early, and work together for a common goal. I hope we can all learn from this experience. The experience of the interaction between scientists and government is also something we can learn from.

In the future I want to keep doing COVID-19 research alongside the HIV research. This is partly because there’ll be plenty to do, and partly because I think there’s lots to learn that could translate to other viruses. The next pandemic may be a related virus, so we really do need to keep plugging away.

When the pandemic is over I’m looking forward to travelling again, for work and pleasure. I have projects in South Africa and I want to be back there to get them restarted. That’s where I see the need for our work on both HIV and COVID-19.

Ravi Gupta has been Professor of Clinical Microbiology at the Cambridge Institute for Therapeutic Immunology and Infectious Diseases since 2019. Deployment of the SAMBA II rapid diagnostic testing machines in Addenbrooke’s Hospital was reported here, and in a BBC interview, in April 2020.

 

How you can support Cambridge’s COVID-19 research


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Stigma of Broken Family Relationships Compounded By Lockdown

Woman at home alone
source: www.ac.uk

Lockdown restrictions have not brought estranged family members closer together, and recent focus on the importance of family support has made dealing with the pandemic even more difficult for those with challenging family situations, a new study published today has found.

The report, by researchers at the University of Cambridge, Edge Hill University and the UK-based charity Stand Alone, brings together over 800 responses to a survey sent out to the charity’s UK community. The survey asked individuals about the experience of being estranged from family during the current crisis, and how it has impacted them and their family relationships. Over half of the respondents said they felt more isolated now than they had before lockdown.

During the pandemic many estranged people have become more conscious of not having family to support them, for example to help with grocery shopping while they can’t go to the supermarket themselves. For some it has brought the realisation that their well-being is not important to other family members, and compounded the feeling of being unloved and uncared for.

78% of respondents had maintained the same level of non-contact with their estranged family member during lockdown, and 6% had experienced even less contact. One respondent said they hadn’t spoken to another person for over two months.

“There’s a lot of stigma around estrangement, and people in this situation have experienced it in a heightened way during lockdown. Many have become more aware that they have smaller support networks than others,” said Dr Susan Imrie at the University of Cambridge’s Centre for Family Research, who was involved in the study.

The researchers say the importance of family relationships has been highlighted repeatedly throughout lockdown in television advertising, news headlines and social media. But for those who were already estranged from family, the pandemic and the messages surrounding it have compounded feelings of stigma and social isolation.

“Since lockdown began there has been a lot of talk about what family members should be doing to support each other at this time of crisis. We’ve all been encouraged to keep in touch with relatives through Skype and FaceTime. But this has really compounded feelings of isolation for those who don’t have close family relationships,” said Dr Sarah Foley at the University of Cambridge’s Centre for Family Research, who was also involved in the study.

It is estimated that over five million people in the UK are estranged from a family member, but despite being so common it is not something that is widely known about or discussed.

“Despite the assumption that family members will be a source of support during the COVID-19 crisis, this is not always the case. One in five families across the UK have no contact with an estranged family member, and this new report finds that very little has changed for them during the pandemic,” said Dr Becca Bland, CEO of Stand Alone.

Stand Alone supports people who have more challenging experiences of family, and who are estranged from their entire family or a key family member. The reasons behind estrangement in the community are varied: some are surviving abuse and neglect, others have been distanced for coming out as LGBT+ or for rejecting cultural, religious and political values. It is the only charity in the UK that works to support people who are estranged from family members.

The results of this study will help Stand Alone understand how best to target support during the pandemic. The researchers also hope it will raise awareness of family estrangement so that it can be handled more sensitively as lockdown continues.

The researchers say it is difficult to know the extent to which the survey respondents reflect the level of estrangement from family across the UK population as a whole.

A minority of the survey respondents who were estranged from family said they actually felt more connected during lockdown because everyone else was suddenly unable to see their family too. They hoped this might help others understand their situation better.

“Different people are being affected differently by the lockdown. Advice about coping shouldn’t assume that everyone has family relationships that are close and loving. Even subtle changes in the language used could have a really positive effect on people’s experiences,” said Dr Lucy Blake, Senior Lecturer in Children, Young People and Families at Edge Hill University, who was also involved in the study.

Reference
Family Estrangement and the COVID-19 Crisis: A closer look at how broken family relationships have been impacted by the COVID-19 crisis. Report by Dr Lucy Blake (Edge Hill University), Dr Becca Bland (Stand Alone), Dr Sarah Foley and Dr Susan Imrie (Centre for Family Research, University of Cambridge).


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Blood Test To Monitor Cancer Up To Ten Times More Sensitive Than Current Methods

Human Colon Cancer Cells
source: www.cam.ac.uk

A new method of analysing cancer patients’ blood for evidence of the disease could be up to ten times more sensitive than previous methods according to new research led by the University of Cambridge.

While this may be several years away from clinical use, our research shows what is possible when we push such approaches to an extreme

Nitzan Rosenfeld

In the coming years, this method and others based on this approach could lead to tests that more accurately determine if a patient is likely to relapse after treatment and could pave the way for the development of pinprick home blood tests to monitor patients. The research, funded by Cancer Research UK, is published in the journal Science Translational Medicine

The technique uses personalised genetic testing of a patient’s tumour to search blood samples for hundreds of different genetic mutations in circulating tumour DNA (ctDNA); DNA released by cancer cells into the bloodstream.

Combined with new methods to analyse this data to remove background noise and enhance the signal, the team was able to reach a level of sensitivity that in some cases could find one mutant DNA molecule among a million pieces of DNA – approximately ten times more sensitive than previous methods.

Dr Nitzan Rosenfeld, senior group leader at the Cancer Research UK Cambridge Institute who led the team that conducted this research, said: “Personalised tests that can detect if cancer is still present, or find it early if it is returning, are now being tested in clinical trials.

While this may be several years away from clinical use, our research shows what is possible when we push such approaches to an extreme. It demonstrates that the levels of sensitivity we’ve come to accept in recent years in relation to testing for ctDNA can be dramatically improved. At present this is still experimental, but technology is advancing rapidly, and in the near future tests with such sensitivity could make a real difference to patients.”

Detecting ctDNA in blood samples is what is known as a ‘liquid biopsy’. It allows doctors to find out more about a patient’s cancer without the need for invasive surgery. The technique is important for monitoring cancer patients, particularly after they’ve received treatment, as it can be an indicator of whether the treatment was successful and if the patient might relapse. In some situations, other types of tests can be used to detect some cancers before they display any symptoms or show up on a scan.

Currently, the sensitivity of the methods depends on having a high enough number of mutant pieces of DNA, either relative to background DNA or in absolute numbers. When the amount of ctDNA is low, a test can produce a negative result even if a patient has residual cancer in their body that could lead to relapse.

A single tumour will contain many different mutations that caused the cancer to form. While some of them are commonly known across certain cancer types, such as EGFR in lung cancer, the overall set of mutations for a tumour varies from person to person. By analysing the genetic makeup of an individual’s tumour and targeting a set of mutations in a personalised way, liquid biopsies to monitor cancer can become much more sensitive.

Until recently, these personalised liquid biopsies have searched for around 10-20 mutations in the blood and up to around 100 at most. In the material from a tube of blood, these would be able to detect ctDNA to levels on the range of one mutant molecule among 30,000 pieces of DNA.

This new technique looks for hundreds and sometimes thousands of mutations in each blood sample, routinely achieving a sensitivity of one mutant molecule per 100,000, and under optimal conditions can reach a level measured in parts per million.

The researchers describe traditional liquid biopsies as like looking for a needle in a haystack. This new approach of using personalised genetic profiles to search for many different mutations rather than just one, increases the number of ‘needles’ that can be found, making chances of success more likely.

They also say the ‘haystack’ itself could be made smaller; as the methods developed for this research could mean that smaller and smaller amounts of blood could be required for the test to still work. Eventually, this could lead to tests that would require only a pinprick of blood – a procedure that patients could perform at home – that would then be sent to a lab for analysis. This would not only mean fewer visits to the hospital, but would also allow the patient to be more frequently monitored.

The researchers and their collaborators studied samples from 105 cancer patients, testing the method on small sets of patients with five different cancer types, with both early and late stage disease.

The method showed promising results and was able to detect ctDNA at high sensitivity in patients with advanced breast and melanoma cancer, and in patients with glioblastoma, which is notoriously difficult to detect in blood. The test was also able to detect ctDNA in patients with earlier-stage disease, where the level of ctDNA in the blood is much lower and difficult to find. This included patients with lung or breast cancer, as well as patients with early-stage melanoma who had already had surgery, which makes detection even more difficult.

In ongoing studies funded by Cancer Research UK, the team and their collaborators plan to use this method to measure ctDNA levels in individuals who are at high risk of developing cancer to help refine future tests for cancer early detection.

Michelle Mitchell, chief executive of Cancer Research UK, said: “Liquid biopsies have the potential to revolutionise all aspects of cancer care, from early detection to personalised treatment and monitoring. As a field that relies heavily on technology, this kind of proof-of-concept research is incredibly important for us to invest in as a charity, as it’s what makes potential future leaps in the use of liquid biopsies possible, and ultimately save more lives.”

Reference:
Jonathan C. M. Wan et al. ‘ctDNA monitoring using patient-specific sequencing and integration of variant reads.’ Science Translational Medicine (2020). DOI: 10.1126/scitranslmed.aaz8084

Adapted from a Cancer Research UK press release.


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People in England’s Poorest Towns ‘Lose Over a Decade of Good Health’, Research Finds

source: www.cam.ac.uk
researchers find major health inequalities – as well as a geographic divide – between the most and least deprived English towns. They say that life expectancy in cities is now overtaking towns for the first time.

The previous pattern of rising life expectancy has stalled or gone into reverse in many English towns

Mike Kenny

Populations in England’s poorest towns have on average 12 fewer years of good health than those in the country’s richest towns, according to new research from the University of Cambridge’s Bennett Institute.

The study shows that the number of hospital admissions for self-harm in the most deprived towns is – on average – almost double that of the most affluent, with alcohol-related admissions over 75% higher than in the least deprived towns.

Lung cancer is twice as prevalent in the most deprived towns, and child obesity in the poorest towns stands at an average of 23% by the end of primary school, compared to around 12% in the wealthiest.

In fact, researchers say the overall life expectancy of town-based populations is “moving in a worse direction” compared to cities – with female life expectancy now higher in English cities than towns for the first time this century.

“The previous pattern of rising life expectancy has stalled or gone into reverse in many English towns,” said Prof Mike Kenny, report coauthor and Director of the Bennett Institute for Public Policy. “Declining fortunes and debates over Brexit have highlighted the chasm that divides many town inhabitants from those in cities.

“However, on some key health measures, inequalities between towns are much greater than the average difference between towns and cities. People in England’s most deprived towns lose over a decade of good health compared to the populations of wealthy towns.”

“There is an overriding need for policies to address the large and widening gaps in the health and opportunities of many towns. These policies should be integral to post-pandemic economic recovery agendas,” Kenny said.

The team found a “strong geographical context”: most of the healthiest towns are in the South East, while most of the unhealthiest towns are situated in former industrial areas of Northern England.

Towns with the longest life expectancy include Frimley in Surrey and Filton, near Bristol. Populations with the shortest lives, on average, were found in Thurnscoe, near Barnsley, and Oldham.

Two seaside towns at either end of the country, Blackpool in the Northwest and Jaywick in East Anglia, had the highest levels of self-harm. Another coastal town, Newbiggin-by-the-sea, near the former collieries north of Newcastle, had the highest child obesity rates. Eccles and Salford on the outskirts of Manchester are the towns with most alcohol-related hospital admissions.

Hertforshire contains a number of England’s healthiest and wealthiest towns, such as Radlett and Harpenden, while many of the country’s unhealthiest towns – scattered across the north – are also those with the largest populations.

The provision of public green spaces – so important for physical and mental health, and never more so than during the recent coronavirus lockdown – was another dividing line between wealthy and unhealthy towns.

The most affluent towns are on average twice as likely as the most deprived towns to have a common or municipal park within their “built-up area boundary”, according to researchers.

They also found that the most deprived towns had – on average, per capita – 50% more fast food shops than the most affluent towns.

“More deprived towns are much less likely to have a green town centre and much more likely to have high numbers of fast food outlets than their wealthier counterparts,” said Ben Goodair, the report’s lead researcher. “Both these factors contribute significantly to the widening of geographic health inequalities in England.”

“There is every chance that the coronavirus pandemic will make the inequalities we see in our research even worse,” said Goodair. “Many deprived towns have an older age profile, and are more susceptible to the worst effects of the virus, as well as low employment prospects that will be reduced even further by the economic consequences of lockdown.”

The report only looked at COVID-19 data up to mid-April, but found a slightly higher death rate was already visible in the more deprived towns during the early phase of the pandemic.

Added Kenny: “The current government has said it is committed to ‘levelling up’ England’s regions. Tackling the factors damaging the health of the poorest towns will have to go much further than the hospital walls, including boosting skill levels, promoting local employment and building community resilience.”


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UK Modelling Study Finds Case Isolation and Contact Tracing vital To COVID-19 Epidemic Control

Coronavirus (COVID-19) Sheffield, UK
source: www.cam.ac.uk

In the absence of a vaccine or highly effective treatments for COVID-19, combining isolation and intensive contact tracing with physical distancing measures—such as limits on daily social or workplace contacts—might be the most effective and efficient way to achieve and maintain epidemic control, according to new modelling research published in The Lancet Infectious Diseases journal.

The BBC data gives a uniquely detailed picture of how people in the UK mix and the extent of contact tracing that will be necessary if we return to social mixing patterns as they were before the pandemic

Julia Gog

Using social-contact data on more than 40,000 individuals from the BBC Pandemic database to simulate SARS-CoV-2 transmission in different settings and under different combinations of control measures, the researchers estimate that a high incidence of COVID-19 would require a considerable number of individuals to be quarantined to control infection. For example, a scenario in which 5,000 new symptomatic cases were diagnosed each day would likely require 150,000–200,000 contacts to be quarantined every day if no physical distancing was in place.

The study is the first time researchers have used social contact data to quantify the potential impact of control measures on reducing individual-level transmission of SARS-CoV-2 in specific settings. They aimed to identify not only what would theoretically control transmission, but what the practical implications of these measures would be in terms of numbers quarantined.

However, the authors note that the model is based on a series of assumptions about the effectiveness of testing, tracing, isolation, and quarantine—for example about the amount of time it takes to isolate cases with symptoms (average 2.6 days) and the likelihood that their contacts adhere to quarantine (90%)—which, although plausible, are optimistic.

“Our findings reinforce the growing body of evidence which suggests that we can’t rely on one single public health measure to achieve epidemic control,” said Dr Adam Kucharski from the London School of Hygiene & Tropical Medicine. “Successful strategies will likely include intensive testing and contact tracing supplemented with moderate forms of physical distancing, such as limiting the size of social gatherings and remote working, which can both reduce transmission and the number of contacts that need to be traced.”

He adds: “The huge scale of testing and contact tracing that is needed to reduce COVID-19 from spreading is resource intensive, and new app-based tracing, if adopted widely alongside traditional contact tracing, could enhance the effectiveness of identifying contacts, particularly those that would otherwise be missed.”

In the study, researchers analysed data on how 40,162 people moved about the UK and interacted with others prior to COVID-19 to simulate how combinations of different testing, isolation, tracing, and physical distancing scenarios—such as app-based tracing, remote working, limits on different sized gatherings, and mass population-based testing—might contribute to reducing secondary cases [3]. They also modelled the rate at which the virus is transmitted—known as the reproductive number (R), or the average number of people each individual with the virus is likely to infect at a given moment—under different strategies. To keep the COVID-19 epidemic declining, R needs to be less than 1.

In the model, the secondary attack rate (the probability that a close contact of a confirmed case will be infected) was assumed to be 20% among household contacts and 6% among other contacts. The researchers calculated that, had no control measures been implemented, R would be 2.6—meaning that one infected person would infect, on average, 2–3 more people.

The model suggested that mass testing alone, with 5% of the population undergoing random testing each week (i.e. 460,000 tests per day in UK), would lower R to just 2.5, because so many infections would either be missed or detected too late (table 3 and infographic).

Compared with no control measures, self-isolation of symptomatic cases (at home) alone reduced transmission by an estimated 29% (lowering R to 1.8); whilst combining self-isolation, household quarantine, and tracing strategies could potentially lower transmission by as much as 47% (R 1.4) when using app-based contact tracing (assuming the app is adopted by 53% of the population), and by 64% with manual tracing of all contacts (R 0.94).

Achieving such a thorough level of contact tracing may be impractical, but the new study suggests that a large reduction in transmission could also be achieved by supplementing with moderate physical distancing measures. For example, they estimate that, limiting daily contacts outside home, school, and work to four people (e.g. by restricting mass gatherings) along with manual tracing of acquaintances only (i.e. people they have met before) and app-based tracing, would have the greatest impact, reducing disease spread by 66%, and lowering R to 0.87. However, they note that the effectiveness of manual contact tracing strategies is highly dependent on how many contacts are successfully traced, with a high level of tracing required to ensure R is lower than 1, especially if it takes time to isolate symptomatic cases.

The researchers also modelled the number of contacts that might need to be quarantined under different contact tracing strategies. They estimate that a scenario in which 1,000 new symptomatic cases were reported daily would likely require a minimum of 15,000 contacts quarantined every day (isolation plus app-based testing) and a maximum of 41,000 (isolation plus manual tracing all contacts). This could increase to an average of 150,000–200,000 contacts quarantined daily in a scenario where 5,000 new symptomatic cases were diagnosed each day (table 4).

“Our results highlight several characteristics of SARS-CoV-2 which make effective isolation and contact tracing challenging. The high rate of transmission, the short time between one person becoming infected and infecting another, and transmission that occurs without symptoms all make things difficult,” said co-author Dr Hannah Fry from University College London. “If there are a lot of symptomatic COVID-19 cases, then tracing, testing, and trying to quarantine a huge number of contacts will be a big challenge. How well we manage it will affect how and when it is possible to reduce transmission predominantly through targeted isolation and tracing measures or whether ongoing physical distancing measures will be required to control the epidemic.”

According to co-author Professor Julia Gog from Cambridge’s Department of Applied Mathematics and Theoretical Physics, “Planning for control based on isolation and contact tracing should consider the likely need for large numbers of cases to be tested and also a large number of contacts rapidly quarantined. Crucially, this work is able to quantify the scales of what is needed for a successful control strategy involving tracing and isolation by making use of the dataset from the BBC pandemic project. The BBC data gives a uniquely detailed picture of how people in the UK mix and the extent of contact tracing that will be necessary if we return to social mixing patterns as they were before the pandemic.”

The authors highlight several limitations to their study, including that it did not consider more detailed settings beyond home, school, work, or ‘other’ categories, or explicitly include imported infections, which may be detected at a different rate to local infections.

Writing in a linked Comment, Professor Raina MacIntyre (who was not involved in the study) from The University of New South Wales, Australia, says, “Whilst the study is specific to the UK, the findings are relevant to all countries. For countries which are opening up for business and resuming social activities, as social contacts increase, non-pharmaceutical interventions become even more critical. It may even be worthwhile for countries to invest in strategies to vastly improve the uptake of contact tracing apps to enable rapid response to resurgence of COVID-19. If you don’t trace, you leave a chain of transmission free to grow undetected and exponentially. With 80% of cases being mild, it may take several generations of silent epidemic growth before it is even recognised.”

Reference:
Adam J Kucharski et al. ‘Effectiveness of isolation, testing, contact tracing, and physical distancing on reducing transmission of SARS-CoV-2 in different settings: a mathematical modelling study.’ The Lancet Infectious Diseases (2020). DOI: 10.1016/ S1473-3099(20)30457-6

Adapted from a press release by The Lancet.

 

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

Donate to support COVID-19 research at Cambridge

 


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Professor David Abulafia Awarded Wolfson History Prize 2020

source: www.cam.ac.uk

Abulafia wins for his epic history of humanity’s relationship with the world’s oceans, The Boundless Sea.

A remarkable book which through immense and impeccable research helps us to understand humanity’s relationship with the waters on which our future depends.

Wolfson History Prize judges

This year’s Wolfson History Prize has been awarded to David Abulafia, Emeritus Professor of Mediterranean History and Fellow of Gonville and Caius College, for his book The Boundless Sea: A Human History of the Oceans, published last autumn.

The book traces the history of human movement, trade and communication around and across the world’s greatest bodies of water, charting our relationship with the oceans from the time of the earliest seafaring societies to the maritime networks of today’s container ships.

The award was announced on Monday night at the Wolfson Prize’s first virtual ceremony, which featured guest appearances from previous winners, including Professor Mary Beard from the University’s Faculty of Classics. The virtual winner announcement can be viewed below.

The Chair of the Wolfson Prize judging panel, Professor David Cannadine, described the book as one of “deep scholarship” and said it was brilliantly written.

“The Boundless Sea tackles a world encompassing subject: humanity’s constantly changing relationship with the seas that cover most of our planet and on which our very lives depend,” Cannadine said.

In The Boundless Sea, Abulafia follows merchants, explorers, pirates, cartographers and travellers in their quests for spices, gold, ivory, slaves, lands for settlement and knowledge of what lay beyond. It builds on Abulafia’s previous book The Great Sea, a human history of the Mediterranean.

The Boundless Sea aims to go beyond “Eurocentric” approaches, examining the Atlantic waters before Columbus, and showing how lucrative trade routes were created that carried goods and ideas along the “Silk Route of the Sea” well before Europeans burst into the Indian Ocean around 1500.

“Winning the Wolfson History Prize I see as a tribute to all of us who have been trying to communicate history to the public, writing in an accessible way without jargon, and making sure that people see the past as an essential part of our human experience,” said Abulafia, a former Chair of Cambridge’s Faculty of History.

The Wolfson History Prize is run and awarded by the Wolfson Foundation, an independent charity that awards grants in the fields of science, health, heritage, humanities, and the arts.

Paul Ramsbottom, chief executive at the Wolfson Foundation, said that the Prize celebrates “the importance to society of outstanding and accessible history writing”.

“David Abulafia’s book is magnificently ambitious, brilliantly examining the changing, extraordinary connections between the vast oceans and humanity,” said Ramsbottom. “While broad in chronological sweep, this clearly has a strong contemporary resonance – as our relationship with the natural world (including the oceans) is under scrutiny as never before.”

Professor David Abulafia is a maritime historian who has spent his career teaching and researching in the History Faculty at Cambridge University. He is the Papathomas Professorial Fellow of Gonville and Caius College, and a Fellow of the British Academy.


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AI Reduces ‘Communication Gap’ For Nonverbal People By As Much As Half

source: www.cam.ac.uk

Researchers have used artificial intelligence to reduce the ‘communication gap’ for nonverbal people with motor disabilities who rely on computers to converse with others.

This method gives us hope for more innovative AI-infused systems to help people with motor disabilities to communicate in the future

Per Ola Kristensson

The team, from the University of Cambridge and the University of Dundee, developed a new context-aware method that reduces this communication gap by eliminating between 50% and 96% of the keystrokes the person has to type to communicate.

The system is specifically tailed for nonverbal people and uses a range of context ‘clues’ – such as the user’s location, the time of day or the identity of the user’s speaking partner – to assist in suggesting sentences that are the most relevant for the user.

Nonverbal people with motor disabilities often use a computer with speech output to communicate with others. However, even without a physical disability that affects the typing process, these communication aids are too slow and error-prone for meaningful conversation: typical typing rates are between five and 20 words per minute, while a typical speaking rate is in the range of 100 to 140 words per minute.

“This difference in communication rates is referred to as the communication gap,” said Professor Per Ola Kristensson from Cambridge’s Department of Engineering, the study’s lead author. “The gap is typically between 80 and 135 words per minute and affects the quality of everyday interactions for people who rely on computers to communicate.”

The method developed by Kristensson and his colleagues uses artificial intelligence to allow a user to quickly retrieve sentences they have typed in the past. Prior research has shown that people who rely on speech synthesis, just like everyone else, tend to reuse many of the same phrases and sentences in everyday conversation. However, retrieving these phrases and sentences is a time-consuming process for users of existing speech synthesis technologies, further slowing down the flow of conversation.

In the new system, as the person is typing, the system uses information retrieval algorithms to automatically retrieve the most relevant previous sentences based on the text typed and the context the conversation the person is involved in. Context includes information about the conversation such as the location, time of day, and automatic identification of the speaking partner’s face. The other speaker is identified using a computer vision algorithm trained to recognise human faces from a front-mounted camera.

The system was developed using design engineering methods typically used for jet engines or medical devices. The researchers first identified the critical functions of the system, such as the word auto-complete function and the sentence retrieval function. After these functions had been identified, the researchers simulated a nonverbal person typing a large set of sentences from a sentence set representative of the type of text a nonverbal person would like to communicate.

This analysis allowed the researchers to understand the best method for retrieving sentences and the impact of a range of parameters on performance, such as the accuracy of word-auto complete and the impact of using many context tags. For example, this analysis revealed that only two reasonably accurate context tags are required to provide the majority of the gain. Word-auto complete provides a positive contribution but is not essential for realising the majority of the gain. The sentences are retrieved using information retrieval algorithms, similar to web search. Context tags are added to the words the user types to form a query.

The study is the first to integrate context-aware information retrieval with speech-generating devices for people with motor disabilities, demonstrating how context-sensitive artificial intelligence can improve the lives of people with motor disabilities.

“This method gives us hope for more innovative AI-infused systems to help people with motor disabilities to communicate in the future,” said Kristensson. “We’ve shown it’s possible to reduce the opportunity cost of not doing innovative research with AI-infused user interfaces that challenge traditional user interface design mantra and processes.”

The research paper was published at CHI 2020.

The research was funded by the Engineering and Physical Sciences Research Council.

Reference:
Kristensson, P.O., Lilley, J., Black, R. and Waller, A. ‘A design engineering approach for quantitatively exploring context-aware sentence retrieval for nonspeaking individuals with motor disabilities.’ In Proceedings of the 38th ACM Conference on Human Factors in Computing Systems (CHI 2020). DOI: 10.1145/3313831.3376525


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Striking Differences Revealed in COVID-19 Mortality Between NHS Trusts

Coronavirus
source: www.cam.ac.uk

A University of Cambridge team led by Professor Mihaela van der Schaar and intensive care consultant Dr Ari Ercole of the Cambridge Centre for AI in Medicine (CCAIM) is calling for urgent research into the striking differences in COVID-19 deaths they have discovered between the intensive care units of NHS trusts across England.

It is crucial to understand the reasons for these between-centre differences as we plan our response to similar situations in the future

Ari Ercole

Using data science techniques, the team revealed that the NHS trust in which a COVID-19 patient ended up in intensive care is as important, in terms of the risk of death, as the strongest patient-specific risk factors such as older age, immunosuppression or chronic heart/kidney disease. In the worst case, COVID-19 patients in the intensive care unit (ICU) of a particular NHS trust were over four times as likely to die in a given time period than COVID-19 patients in an average trust’s ICU.

From the earliest days of the coronavirus pandemic, clinicians and scientists have been deciphering the risk factors that make someone with COVID-19 more likely to die. The uncovering of determinants of risk has allowed doctors to focus resources on the most vulnerable patients and has proved important in planning for the surge in demand for intensive care units created by the pandemic. It has also informed the public of which groups should take greater measures to shield or socially distance themselves. The new study is the first to reveal the extent to which ICU-patient location is a factor.

“COVID-19 has stretched most ICUs well beyond their normal capacity and necessitated them finding additional space, equipment and skilled staff – in an already stretched NHS – to deal with demand for highly specialist life-supporting therapies,” says Dr Ercole. “It is possible that some hospitals found this harder either because they didn’t have time to react or the necessary resources. It is crucial to understand the reasons for these between-centre differences as we plan our response to similar situations in the future: how and where to build capacity, and how to use what we have most effectively.”

The peer-reviewed paper – “Between-centre differences for COVID-19 ICU mortality from early data in England” – has been accepted for publication in Intensive Care Medicine. A preprint of the study, posted prior to the completion of peer-review, is available online.

The analysis was carried out on anonymised data from the COVID-19 Hospitalisation in England Surveillance System (CHESS) dataset, supplied by Public Health England. The data were anonymised not only in terms of the patients but also in terms of the NHS trusts. The data covered 8 February to 22 May, during which there were 5062 ICU cases in 94 NHS trusts across England, with 1547 patient deaths and 1618 discharges from ICU.

The researchers call for urgent “comparative effectiveness research” to get to the bottom of these marked differences between NHS trusts. Knowledge gained in this direction could inform how ICUs are optimised and improve best practice in dealing with surges in COVID-19 cases in England, and perhaps beyond.


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High Doses of Ketamine Can Temporarily Switch Off The Brain, Say Researchers

Neon brain by Dierk Schaefer on Flickr (modified)
source: www.cam.ac.uk

Researchers have identified two brain phenomena that may explain some of the side-effects of ketamine. Their measurements of the brain waves of sheep sedated by the drug may explain the out-of-body experience and state of complete oblivion it can cause.

We think of anaesthetic drugs as just slowing everything down. That’s what it looks like from the outside…but when we looked at the brain activity, it seems to be a much more dynamic process.

Jenny Morton

In a study aimed at understanding the effect of therapeutic drugs on the brains of people living with Huntington’s disease, researchers used electroencephalography (EEG) to measure immediate changes in the animals’ brain waves once ketamine – an anaesthetic and pain relief drug – was administered. Low frequency activity dominated while the sheep were asleep. When the drug wore off and the sheep regained consciousness, the researchers were surprised to see the brain activity start switching between high and low frequency oscillations. The bursts of different frequency were irregular at first, but became regular within a few minutes.

“As the sheep came round from the ketamine, their brain activity was really unusual,” said Professor Jenny Morton at the University of Cambridge’s Department of Physiology, Development and Neuroscience, who led the research. “The timing of the unusual patterns of sheep brain activity corresponded to the time when human users report feeling their brain has disconnected from their body.”

She added:  “It’s likely that the brain oscillations caused by the drug may prevent information from the outside world being processed normally,”

The findings arose as part of a larger research project into Huntington’s disease, a condition that stops the brain working properly. The team want to understand why human patients respond differently to various drugs if they carry the gene for this disease. Sheep were used because they are recognised as a suitable pre-clinical model of disorders of the human nervous system, including Huntington’s disease.

Six of the sheep were given a single higher dose of ketamine, 24mg/kg. This is at the high end of the anaesthetic range. Initially, the same response was seen as with a lower dose. But within two minutes of administering the drug, the brain activity of five of these six sheep stopped completely, one of them for several minutes – a phenomenon that has never been seen before.

“This wasn’t just reduced brain activity. After the high dose of ketamine the brains of these sheep completely stopped. We’ve never seen that before,” said Morton. Although the anaesthetised sheep looked as though they were asleep, their brains had switched off. “A few minutes later their brains were functioning normally again – it was as though they had just been switched off and on.”

The researchers think that this pause in brain activity may correspond to what ketamine abusers describe as the ‘K-hole’ – a state of oblivion likened to a near-death experience, which is followed by a feeling of great serenity. The study is published today in the journal Scientific Reports.

Ketamine abusers are known to take doses many times higher than those given to the sheep in this research. It is also likely that progressively higher doses have to be taken to get the same effect. The researchers say that such high doses can cause liver damage, may stop the heart, and be fatal.

To conduct the experiment sheep were put into veterinary slings, which are commonly used to keep animals safe during veterinary procedures. Different doses of ketamine were given to 12 sheep and their brain activity recorded with EEG.

Ketamine was chosen for the study because it is widely used as a safe anaesthetic and pain-relief drug for treating large animals including dogs, horses and sheep. It is also used medically, and is known as a ‘dissociative anaesthetic’ because patients can appear awake and move around, but they don’t feel pain or process information normally – many report feeling as though their mind has separated from their body.

At lower doses ketamine has a pain-relieving effect, and its use in adult humans is mainly restricted to field situations such as frontline pain-relief for injured soldiers or victims of road traffic accidents.

“Our purpose wasn’t really to look at the effects of ketamine, but to use it as a tool to probe the brain activity in sheep with and without the Huntington’s disease gene,” said Morton. “But our surprising findings could help explain how ketamine works. If it disrupts the networks between different regions of the brain, this could make it a useful tool to study how brain networks function – both in the healthy brain and in neurological diseases like Huntington’s disease and schizophrenia.”

Ketamine has recently been proposed as a new treatment for depression and post-traumatic stress disorder. Beyond its anaesthetic actions, however, very little is known about its effects on brain function.

“We think of anaesthetic drugs as just slowing everything down. That’s what it looks like from the outside: the animals basically go to sleep and are unresponsive, and then they wake up very quickly. But when we looked at the brain activity, it seems to be a much more dynamic process,” said Morton.

This research was funded by CHDI Inc. It was reviewed and approved by the Ethics Committee of the University of Cambridge.

Reference
Nicol, A.U. & Morton, A.J. ‘Characteristic patterns of EEG oscillations in sheep (Ovis aries) induced by ketamine may explain the psychotropic effects seen in humans.’ Scientific Reports, June 2020. DOI: 1038/s41598-020-66023-8

 


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Recruitment underway as Cambridgeshire NHS trusts join COVID-19 vaccine trial

Coronavirus

Recruitment has begun at three leading Cambridgeshire NHS Trusts for volunteers to take part in the nationwide COVID-19 vaccine trial.

Developing an effective vaccine is key to controlling the COVID-19 pandemic

Estee Torok

The COV002 trial, developed by the University of Oxford, aims to assess how well people across a broad range of ages could be protected from COVID-19 using a new vaccine called ChAdOx1 nCoV-19. It will also provide valuable information on safety of the vaccine and its ability to generate good immune responses against the virus.

Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge University Hospitals NHS Foundation Trust and Royal Papworth Hospital NHS Foundation Trust are recruiting healthy staff aged between 18-55 years old who have not been infected with coronavirus but have regular face-to-face contact with COVID-19 patients, to take part in the trial.

Eligible participants will be randomised to receive one dose of either the trial vaccine (ChAdOx1 nCoV-19) or a licensed meningitis vaccine (MenACWY) that will be used as a ‘control’ for comparison. Following vaccination, participants will be followed up over 12 months.

Dr Estée Török from the Department of Medicine at the University of Cambridge and Principal Investigator at Cambridge University Hospitals NHS Foundation Trust, said: “Developing an effective vaccine is key to controlling the COVID-19 pandemic. We are delighted to be working with CPFT and Royal Papworth on this UK national priority vaccine trial. We are looking for healthy volunteers at high risk of COVID-19 infection at CUH to participate in this study and are most grateful to them for doing so.”

Dr Ben Underwood, Deputy Medical Director and Principal Investigator (study lead) at CPFT said: “We are grateful to all our staff for their brilliant response to the coronavirus pandemic.  Our research teams are playing a vital role in international efforts to secure a vaccine, which we hope will protect those most at risk, save more lives and minimise the disruption caused by the virus. Thank you to all volunteers who take part and make clinical trials possible.”

Dr Robert Rintoul, Director, Papworth Trials Unit Collaboration, and Reader in Thoracic Oncology at the Department of Oncology, University of Cambridge, said: “We at Royal Papworth Hospital are proud to be supporting research into possible vaccines and treatments for COVID-19. I would like to thank our staff members who have chosen to participate in this important public health project.”

Adapted from a press release by Cambridge University Health Partners.


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Widespread facemask use could shrink the ‘R’ number and prevent a second COVID-19 wave – study

Be kind, wear a mask sticker
source: www.cam.ac.uk

Even basic homemade masks can significantly reduce transmission if enough people wear them when in public, according to latest modelling. Researchers call for information campaigns that encourage the making and wearing of facemasks.

We have little to lose from the widespread adoption of facemasks, but the gains could be significant

Renata Retkute

Population-wide use of facemasks keeps the coronavirus ‘reproduction number’ under 1.0, and prevents further waves of the virus when combined with lockdowns, a modelling study led by the University of Cambridge suggests.

The research suggests that lockdowns alone will not stop the resurgence of SARS-CoV-2, and that even homemade masks with limited effectiveness can dramatically reduce transmission rates if worn by enough people, regardless of whether they show symptoms.

The researchers call for information campaigns across wealthy and developing nations alike that appeal to our altruistic side: ‘my facemask protects you, your facemask protects me’. The findings are published in the Proceedings of the Royal Society A.

“Our analyses support the immediate and universal adoption of facemasks by the public,” said lead author Dr Richard Stutt, part of a team that usually models the spread of crop diseases at Cambridge’s Department of Plant Sciences.

“If widespread facemask use by the public is combined with physical distancing and some lockdown, it may offer an acceptable way of managing the pandemic and reopening economic activity long before there is a working vaccine.”

Dr Renata Retkute, coauthor and Cambridge team member, said: “The UK government can help by issuing clear instructions on how to make and safely use homemade masks.”

“We have little to lose from the widespread adoption of facemasks, but the gains could be significant.”

The new coronavirus is transmitted through airborne droplets loaded with SARS-CoV-2 particles that get exhaled by infectious people, particularly when talking, coughing or sneezing.

For the latest study, Cambridge researchers worked to link the dynamics of spread between individuals with population-level models, assessing varying degrees of facemask adoption combined with periods of lockdown.

The modelling included the different stages of infection, and transmission via surfaces as well as air. Researchers also considered negative aspects of mask use, such as increased face touching.

The reproduction or ‘R’ number – the number of people an infected individual passes the virus onto – needs to stay below 1.0 for the pandemic to slow.

The study found that if people wear masks whenever they are in public it is twice as effective at reducing ‘R’ than if masks are only worn after symptoms appear.

In all modelling scenarios, routine facemask use by 50% or more of the population reduced COVID-19 spread to an R less than 1.0, flattening future disease waves and allowing less-stringent lockdowns.

Viral spread reduced further as more people adopted masks when in public. 100% mask adoption combined with on/off lockdowns prevented any further disease resurgence for the 18 months required for a possible vaccine.

The models suggest that – while the sooner the better – a policy of total facemask adoption can still prevent a second wave even if it isn’t instigated until 120 days after an epidemic begins (defined as the first 100 cases).

The team investigated the varying effectiveness of facemasks. Previous research shows that even homemade masks made from cotton t-shirts or dishcloths can prove 90% effective at preventing transmission.

The study suggests that an entire population wearing masks of just 75% effectiveness can bring a very high ‘R’ number of 4.0 (the UK was close to this before lockdown) all the way down to under 1.0, even without aid of lockdowns.

In fact, masks that only capture a mere 50% of exhaled droplets would still provide a ‘population-level benefit’, even if they quadrupled the wearer’s own contamination risk through frequent face touching and mask adjustment – a highly unlikely scenario.

The researchers point out that crude homemade masks primarily reduce disease spread by catching the wearer’s own virus particles, breathed directly into fabric, whereas inhaled air is often sucked in around the exposed sides of the mask.

“There is a common perception that wearing a facemask means you consider others a danger,” said Professor John Colvin, coauthor from the University of Greenwich. “In fact, by wearing a mask you are primarily protecting others from yourself.”

“Cultural and even political issues may stop people wearing facemasks, so the message needs to be clear: my mask protects you, your mask protects me.”

“In the UK, the approach to facemasks should go further than just public transport. The most effective way to restart daily life is to encourage everyone to wear some kind of mask whenever they are in public,” Colvin said.

Professor Chris Gilligan, coauthor from Cambridge’s Epidemiology and Modelling Group in the Department of Plant Sciences, added: “These messages will be vital if the disease takes hold in the developing world, where large numbers of people are resource poor, but homemade masks are a cheap and effective technology.”

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

Donate to support COVID-19 research at Cambridge


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Improved MRI Scans Could Aid In Development of Arthritis Treatments

3D model of a knee with osteoarthritis
source: www.cam.ac.uk

An algorithm that analyses MRI images and automatically detects small changes in knee joints over time could be used in the development of new treatments for arthritis.

Thanks to the engineering expertise of our team, we now have a better way of looking at the joint

James MacKay

A team of engineers, radiologists and physicians, led by the University of Cambridge, developed the algorithm, which builds a three-dimensional model of an individual’s knee joint in order to map where arthritis is affecting the knee. It then automatically creates ‘change maps’ which not only tell researchers whether there have been significant changes during the study but allow them to locate exactly where these are.

There are few effective treatments for arthritis, and the technique could be a considerable boost to efforts to develop and monitor new therapies for the condition. The results are reported in the Journal of Magnetic Resonance Imaging.

Osteoarthritis is the most common form of arthritis in the UK. It develops when the articular cartilage that coats the ends of bones and allows them to glide smoothly over each other at joints, is worn down, resulting in painful, immobile joints. Currently, there is no recognised cure and the only definitive treatment is surgery for artificial joint replacement.

Osteoarthritis is normally identified on an X-ray by a narrowing of the space between the bones of the joint due to a loss of cartilage. However, X-rays do not have enough sensitivity to detect subtle changes in the joint over time.

“We don’t have a good way of detecting these tiny changes in the joint over time in order to see if treatments are having any effect,” said Dr James MacKay from Cambridge’s Department of Radiology, and the study’s lead author. “In addition, if we’re able to detect the early signs of cartilage breakdown in joints, it will help us understand the disease better, which could lead to new treatments for this painful condition.”

The current study builds on earlier work from the same team, who developed an algorithm to monitor subtle changes in arthritic joints in CT scans. Now, they are using similar techniques for MRI, which provides more complete information about the composition of tissue – not just information about the thickness of cartilage or bone.

MRI is already widely used to diagnose joint problems, including arthritis, but manually labelling each image is time-consuming, and may be less accurate than automated or semi-automated techniques when detecting small changes over a period of months or years.

“Thanks to the engineering expertise of our team, we now have a better way of looking at the joint,” said MacKay.

The technique MacKay and his colleagues from Cambridge’s Department of Engineering developed, called 3D cartilage surface mapping (3D-CaSM), was able to pick up changes over a period of six months that weren’t detected using standard X-ray or MRI techniques.

The researchers tested their algorithm on knee joints from bodies that had been donated for medical research, and a further study with human participants between 40 and 60 years old. All of the participants suffered from knee pain, but were considered too young for a knee replacement. Their joints were then compared with people of a similar age with no joint pain.

“There’s a certain degree of deterioration of the joint that happens as a normal part of aging, but we wanted to make sure that the changes we were detecting were caused by arthritis,” said MacKay. “The increased sensitivity that 3D-CaSM provides allows us to make this distinction, which we hope will make it a valuable tool for testing the effectiveness of new therapies.”

The software is freely available to download and can be added to existing systems. MacKay says that the algorithm can easily be added to existing workflows and that the training process for radiologists is short and straightforward.

As part of a separate study funded by the European Union, the researchers will also be using the algorithm to test whether it can predict which patients will need a knee replacement, by detecting early signs of arthritis.

Reference:
James W. MacKay et al. ‘Three-dimensional Surface-based Analysis of Cartilage MRI data in Knee Osteoarthritis: Validation and Initial Clinical Application.’ Journal of Magnetic Resonance Imaging (2020). DOI: 10.1002/jmri.27193


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Codecheck Confirms Reproducibility of COVID-19 Model Results

source: www.cam.ac.uk

Cambridge researcher confirms reproducibility of high-profile Imperial College coronavirus computational model.

The code, script and documentation of the 16 March report, which is available on Github, was subject to an independent review led by Dr Stephen Eglen, from Cambridge’s Department of Applied Mathematics and Theoretical Physics.

Eglen co-founded Codecheck last year to help evaluate the computer programs behind scientific studies. Researchers provide their code and data to Codecheck, who run the code independently to ensure the work can be reproduced.

Last week, Codecheck certified the reproducibility of arguably the most talked-about computational model of the COVID-19 pandemic, that of the Imperial College group led by Professor Neil Ferguson. The model suggested that there could be up to half a million deaths in the UK if no measures were taken to slow the spread of the virus, and has been cited as one of the main reasons that lockdown went into effect soon after. However, the Imperial group did not immediately make their code publicly available.

Codecheck.org.uk provided an independent review of the replication of key findings from Report 9 using CovidSim reimplementation. The process matches domain expertise and technical skills, taking place as an open peer review. The reviewer conducts the codecheck and submits the resulting certificate as part of their review.

The results confirm that the key finding of Report 9 – on the impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand – are reproducible. Eglen did not review the epidemiology that went into the Imperial model, however.

In his analysis, Dr Eglen said: “Each run generated a tab-delimited file in the output folder. Two R scripts provided by Prof Ferguson were used to summarise these runs into two summary files… These files were compared against the values generated by Prof Ferguson…The results were found to be identical. Inserting my results into his Excel spreadsheet generated the same pivot tables.”

The codecheck found that: “Small variations (mostly under 5%) in the numbers were observed between Report 9 and our runs.” The codecheck confirmed the trends and findings of the original report.

Building in part on code originally developed, published and peer-reviewed in 2005 and 2006, the code used for Report 9 continues to be actively developed to allow examination of the wider range of control policies now being deployed as countries relax lockdown. The Imperial team is sharing the code to enhance transparency and to allow others to contribute and make use of the simulation.

Refactoring the code has allowed changes to be made more quickly and reliably, including incorporating new data that has become available as the pandemic has progressed.

In addition to the features presented in Imperial Report 9, further strategies can now be examined such as testing and contact tracing, which was not a UK policy option in March.

Users also now have the ability to vary intensity of interventions over time and to calibrate the model to country-specific epidemic data.

Adapted from a piece originally published on the Imperial College London website

 

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

Donate to support COVID-19 research at Cambridge

 


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COVID-19: ‘R’ Number Increasing Across England and Highest In North West

Women wearing face masks against coronavirus
source: www.cam.ac.uk

The R number for COVID-19 – the number of people an infected individual passes the virus onto – has risen to above 1 in the North West of England and to 1 in the South West, according to the latest findings published by the Medical Research Council Biostatistics Unit at the University of Cambridge. When R is greater than or equal to 1, it means transmission will be sustained.

Real-time tracking of a pandemic, as data accumulate over time, is an essential component of a public health response to a new outbreak. A team of statistical modellers at the Unit are working with Public Health England (PHE) to regularly ‘nowcast’ and forecast COVID-19 infections and deaths. This information feeds directly to SAGE sub-group, Scientific Pandemic Influenza sub-group on Modelling (SPI-M) and to regional PHE teams.

The work uses a transmission model, data on daily COVID-19 confirmed deaths from PHE, and published information on the risk of dying and the time from infection to death, to reconstruct the number of new COVID-19 infections over time, estimate a measure of ongoing transmission, and predict the number of new COVID-19 deaths in different regions and age groups.

In the latest findings, published today, the researchers say:

  • There are an estimated 17,000 new infections arising each day across England
  • The number of deaths each day is likely to fall to between 100–250 by mid-June
  • The R number is below 1 in all regions of England with the exception of the North West and the South West
  • In the South West, although R is around 1, the numbers of new infections occurring in the region on a daily basis is relatively low
  • There is some evidence that R has risen in all regions, probably due to increasing mobility and mixing between households and in public and workplace settings
  • This increase in R will lead to a slowdown in the decrease in new infections and deaths
  • The increases in the regional R numbers may result in the decline in the national death rate being arrested by mid-June

For further details, see Nowcasting and Forecasting of COVID-19.


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Opinion: The Learning of Scientific Advisers Is The Other Curve To Consider

source: www.cam.ac.uk

Policymakers around the world are relying on the expertise of scientists to help make decisions around the COVID-19 pandemic. But how do scientists learn to advise policymakers? Noam Obermeister from Cambridge’s Department of Geography argues that this has been overlooked in the past, and suggests how studying their learning might help us prepare for future emergencies.

Despite years of experience advising the government, Professor Neil Ferguson couldn’t have anticipated that his private life would become a matter of public scrutiny last month, essentially ending his formal relationship with government. No less surprising is the move from a former Government Chief Scientific Adviser, Professor Sir David King, to set up a so-called ‘Independent SAGE’ – laying bare the kinds of deliberations that would have taken place behind closed doors during his appointment.

The bottom line for high-profile scientists and scientific advisers is that the rules of the game have changed. They may have learned that discretion is highly valued by policymakers, and yet, calls for transparency continue to resound louder than ever. How are scientists dealing with these new circumstances? What are they learning?

In a recent paper, I argue that too little attention has been given to how experts learn to advise policymakers. Although there is no shortage of guidelines and fragments of wisdom for researchers who want to see their work (or the work of colleagues) inform policymaking, scientific advice to governments is largely a case of learning on the job.

In their role as scientific advisers, experts learn what is and isn’t appropriate behaviour, what is and isn’t politically acceptable, and to draw the line where the science ‘ends’ and the politics ‘begin’. Scientific advice is a tricky balancing act between making expert judgments on the best available evidence and calibrating those judgments to the politics of the issues at hand. Like a tightrope walker, the scientific adviser has to learn to get the balance just right.

The journey from full-time academic to part-time scientific adviser can be a transformative one. Researchers might initially set out with expectations of how scientists and policymakers interact and have had to revisit those expectations in view of their various encounters and experiences. While their learning may not always be transformative, I suggest that it is always necessarily situated: different organisations and environments will influence and shape their learning in different ways. This includes discussions with peers on scientific advisory committees, for example. How and what advisers learn, then, is never quite divorced from where they learn.

So why should we care? Taking the long view, I see three reasons why we might want to put advisers’ learning under the microscope:

  1. Compiling the know-how of experienced advisers can be helpful for less experienced or early-career researchers who wish to engage with policymakers. Because there is no universal roadmap for success, I think we should focus on coming up with some ‘warning signs’ – as opposed to ‘direction signs’ – by identifying and communicating common pitfalls, for instance.
  2. Given the situated nature of their own learning, advisers can directly contribute to the institutional learning and memory of the science-policy organisations they are part of. Involving committee members in decision-making can help prevent needless reinvention of the wheel and improve organisational reforms, leading to more sustainable change.
  3. As both academics and policy advisers, scientific advisers are particularly well-placed to understand how academic research informs (or fails to inform) policymaking, as well as how the scientific community works and is governed. Therefore, they are knowledgeable not only about science for policy, but also about policy for science. For those reasons, I think that research funding organisations – such as UKRI research councils – should more systematically consult experienced science advisers in the formulation of their policies, especially in relation to research impact. For instance, improved impact evaluation frameworks would have positive trickle-down effects on the wider academic community, especially for early-career researchers who tend to base their understanding of impact in large part on the existing guidelines for grant applications or job descriptions.

The core message is that as the nature of both science and policymaking continues to change, the learning experiences of expert advisers is an abundant resource that has yet to be tapped into. This has become all the more evident with COVID-19, as scientific advisers’ learning curves are likely to be steep. In the aftermath of the pandemic, we’ll need an evaluation of ‘what happened’ and ‘what went wrong’.

For the whole picture, we can’t just rely on the loudest or the most visible voices. We’ll need to turn to those scientific advisers whose stories go largely untold. Importantly, we’ll need to understand why the acquired skillset of scientific advisers may not be suited for crisis situations. Only then can we ensure that lessons are learned and that our networks of science advice are prepared for future emergencies.


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Tackling COVID-19: Dr Sarah Caddy

Dr Sarah Caddy
source: www.cam.ac.uk

Before the COVID-19 outbreak, Sarah Caddy was conducting research on a number of different viruses. “I was looking at how antibodies can neutralise rotavirus and influenza, to help develop better vaccine candidates,” she says, “so it wasn’t a huge leap to extend my research to include coronavirus.”

I’m a clinical research fellow and veterinary surgeon in the new Cambridge Institute for Therapeutic Immunology and Infectious Diseases (CITIID) on the Biomedical Campus. Over the past few months I have divided my time between CITIID, and volunteering in the Department of Virology as part of the COVID-19 Genomics Consortium.

My initial role in the COVID-19 pandemic was related to diagnostics. I gained experience of testing patient samples for viruses during the Ebola outbreak in 2015 in Sierra Leone, so when COVID-19 cases started rising in the UK I volunteered to help the Public Health England lab in Addenbrookes. From there I joined Professor Ian Goodfellow’s team working to sequence full genomes of the virus from patients across East Anglia. As case numbers are being brought under control I’ve been able to transition back to virus research, which aims to improve our understanding of coronavirus immunity.

My research usually focuses on the antibody response to viruses. This means it hasn’t been too large a leap to extend my research to include coronaviruses. We need to determine how coronavirus-specific antibodies are working, in order to find out what the ‘ideal’ antibody response to SARS-CoV-2 is. This will be valuable for development of effective vaccines and for identification of people that may be susceptible to repeat infections.

As a veterinarian, I have also been closely following the news about COVID-19 in animals. There are many myths and misconceptions in this area, so I‘ve been actively engaged in reassuring veterinary professionals and the public about risks to pets. I’ve written a number of articles for The Conversation and the Naked Scientists on this in recent weeks (there’s still zero evidence of pets transmitting the virus to humans). With support from colleagues in CITIID, I have also established a new project for COVID-19 testing in animals.

Development of safe, effective, and widely available vaccines is an incredible challenge facing scientists right now. Many different vaccine approaches are being studied, but we don’t yet know which is going to be successful. The number of trials currently underway for SARS-CoV-2 vaccines is beyond anything the vaccine field has previously seen.

I have always been keen to seen molecular biology translated for use in medical settings. There is now cross-talk between research institutes and the hospitals like never before, and the scientists and clinicians are collaborating at an impressive rate!

Many lessons have been learnt about our ability and capacity to test for viruses in the UK. The number of scientists wanting to volunteer to help with testing has been immense, so in future I hope logistics and organisation will be able to match this enthusiasm much quicker.

When the pandemic is over, I’m looking forward to travelling anywhere outside of Cambridge! Much as I love this city, I really miss venturing further afield to see family, friends, and explore new places. I’d also really like to sit in a busy café with a good coffee!

Sarah Caddy is a Wellcome Trust Clinical Research Fellow in Viral Immunology at the Cambridge Institute for Therapeutic Immunology and Infectious Disease.

 

How you can support Cambridge’s COVID-19 research


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Harnessing AI In The Fight Against COVID-19

source: www.cam.ac.uk

AI assisted COVID-19 diagnostic and prognostic tool could improve resource allocation and patient outcomes.

AI offers huge potential to support agile clinical decision making, ensuring patients receive the most appropriate support and leading to better patient outcomes

Evis Sala

An open-source artificial intelligence (AI) tool, combining chest imaging data with laboratory and clinical data, is being developed by Cambridge researchers to support the rapid diagnosis and triaging of patients with COVID-19 in the UK.

The team, led by Professors Carola-Bibiane Schönlieb and Evis Sala, brings together expertise in AI for imaging with expertise in radiology and clinical applications from Addenbrooke’s and Papworth Hospitals, as well as collaborators from the UK, China, Austria and Italy, to develop a prediction model that can rapidly and reliably diagnose and suggest a prognosis to doctors.

Reverse-transcription polymerase chain reaction (RT-PCR) tests are currently the most common tool used to diagnose COVID-19, but they are only up to 70% sensitive, meaning there are up to 30% false negatives.

While chest X-rays and CT scans provide valuable diagnostic and monitoring information that can complement laboratory and clinical data, it is a complex task typically done by radiologists, whose expertise is often in high demand. Fast and accurate diagnosis of patients in order to limit disease spread, together with the rapid determination of whether a patient is likely to recover, require intensive care unit (ICU) admission, or intensive ventilation, is key to allocating resources and to improving patient outcomes.

“AI offers huge potential to support agile clinical decision making, ensuring patients receive the most appropriate support and leading to better patient outcomes,” said Sala, who is based at the Department of Radiology.

Recent studies have suggested that using AI could have a meaningful impact on the management of patients with COVID-19. AI tools such as deep learning can offer automated image analysis and integration with clinical data to help clinicians make more informed decisions for treatment.

However, good quality data and computing power are required to train and optimise predictive AI models and data availability is a major bottleneck when developing new systems. Coupled with this, the lack of standardisation of datasets makes it challenging to reuse existing AI tools in a different country than the one that it was trained for. Most current AI tools have been developed on small, locally collected datasets. Data that is being collected in hospitals all over the world varies in what is being collected and how the data is processed. Therefore, an effort for developing a widely applicable tool for COVID-19 hospital support must be open source so it can be adapted to different environments; be based on a serious data sharing and data curation, data cleaning and standardisation effort; and be developed with mathematical, statistical and engineering expertise to develop robust and translatable tools.

To address these challenges, the team from the Cambridge Centre for Mathematical Imaging in Healthcare (CMIH) is developing a flexible, open-source AI tool that could be used by hospitals worldwide. Drawing on their history of global research collaboration and expertise in data governance, the team is gathering datasets from Austria, China, Italy and the UK for their work. Data scientists and clinicians are working in close collaboration, following standard protocols to identify bias during development. “Rigorous mathematical models play a key role in mitigating bias and improving the efficacy of the prediction model as they follow universal rules with mathematical guarantees,” said Schönlieb.

Using deep learning approaches along with mathematical and statistical analysis methods, the new tool will be accompanied by a comprehensive algorithmic strategy that will allow fine-tuning for datasets with different characteristics and implementation in different countries. The team are hoping to launch the AIX-COV-NET tool within the next 12 to 18 months. The project has recently received funding from the EU-funded Innovative Medicines Initiative and Intel.

“Our team’s strength is the close dialogue we have between clinicians and data scientists, and the passion we all bring for advancing AI solutions for COVID-19,” said Schönlieb, from Cambridge’s Department of Applied Mathematics and Theoretical Physics.

“AI offers huge potential to support agile clinical decision making, ensuring patients receive the most appropriate support and leading to better patient outcomes,” said Sala.

The core project team is comprised of data scientists and clinicians from across Cambridge and is led by Professor Carola-Bibiane Schönlieb, Director of the Centre for Mathematical Imaging in Healthcare, and Professor Evis Sala, Professor of Oncological Imaging, University of Cambridge & Honorary Consultant Radiologist, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust. The team is supported by an AI and image analysis team, drawn from subject experts across Cambridge and around the world, a clinical team comprised of colleagues from hospitals in Cambridge, London and Vienna, and a support team based in the Faculty of Mathematics. Partner institutions include hospitals in Wuhan, China; Milan, Italy; and Madrid, Spain, and universities in Manchester, Vienna and London.

The University of Cambridge has an impressive record of achievement in multidisciplinary research and innovation. The CMIH is a collaboration between mathematics, engineering, physics and biomedical scientists and clinicians and is one of five centres to receive investment from the Engineering and Physical Sciences Research Council (EPSRC). A key aim of this partnership is the delivery of high quality, multidisciplinary research that will help overcome some of the major challenges facing the NHS.

 

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

Donate to support COVID-19 research at Cambridge

 


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Rapid Coronavirus Test Speeds Up Access To Urgent Care and Will Free Up Beds Ahead of Winter

source: www.cam.ac.uk

Researchers say faster tests helped expedite access to life-saving treatments such as organ transplants – and might make all the difference later this year.

Rapidly testing admissions for SARS-CoV-2 at the point of care is essential for reducing COVID-19 transmission in hospitals, speeding up access to urgent care and allowing safe discharge to care homes

Ravi Gupta

The first analysis of a new point-of-care ‘nucleic acid test’ for SARS-CoV-2 in a UK hospital setting shows these machines dramatically reduce time spent on COVID-19 ‘holding’ wards – allowing patients to be treated or discharged far quicker than with current lab testing set-ups.

The rapid diagnostic capability of SAMBA II devices – an average of 2.6 hours compared with 26.4 hours for standard lab tests – led to an increased availability of ‘isolation rooms’ needed for infected patients, as well as fewer hospital bay closures.

University of Cambridge researchers behind the new study, currently a pre-print and awaiting peer-review, say that the time and hospital capacity spared by these devices will be “critical as we move towards autumn and winter”.

The SAMBA II machine was developed by a University spinout company, Diagnostics in the Real World, and deployed for trials in Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust (CUH).

“The backlog of routine operations and screenings as a result of the pandemic is a huge issue, and must be resolved ahead of winter, when the NHS will face even more pressure from other infections like norovirus and influenza,” said study lead author Professor Ravi Gupta.

“Rapidly testing admissions for SARS-CoV-2 at the point of care is essential for reducing COVID-19 transmission in hospitals, speeding up access to urgent care and allowing safe discharge to care homes. It could make all the difference in a few months’ time.”

“Use of point-of-care testing would speed up the identification of patients for COVID-19 clinical trials, and receiving an experimental treatment a day earlier could make a clinical difference.”

“Hospitals across the UK, as well as care homes and prisons, could benefit from SAMBA II devices,” said Gupta, from the Cambridge Institute of Therapeutic Immunology & Infectious Diseases (CITIID). “Given the technological capital of the UK we should not be falling so short on rapid point-of-care testing.”

Standard tests are sent for analysis in central laboratories, where backlogs can see delays of two days or more. SAMBA machines can produce a diagnosis in as little as 90 minutes.

Dr Helen Lee, CEO of Diagnostics in the Real World, developed the SAMBA II technology while at Cambridge’s Department of Haematology. The chemistry behind the machines has been used for on-the-spot HIV diagnostics across Africa.

The devices search for tiny traces of virus genetic code, and are extremely sensitive in the detection of active infections. Once nose and throat swabs have been loaded into a SAMBA machine, the process is fully automated, making them easy to use.

The initial ‘COVIDx’ clinical study led by Gupta at Addenbrooke’s with 149 participants found SAMBA II had 96.9% sensitivity (accurate identification of positive cases) and 99.1% specificity (accurate identification of negative cases) compared to the standard lab test. It was also around 24 hours faster.

The success of the COVIDx study saw the hospital switch nearly all of its SARS-CoV-2 testing from the standard lab ‘RT-PCR’ tests over to the use of SAMBA II during May: an opportunity for a “real-world” comparison and its effect on hospital functioning.

Gupta and colleagues compared data from the electronic patient records of all those who had in-hospital tests done in the ten days before and then after the switch to SAMBA devices at CUH.

The researchers found that the average length of time patients had to spend on a COVID019 ‘holding’ ward before they could be discharged or progress with treatment almost halved: dropping from 58.5 hours to just 30 hours.

They also saw a fall in use of the single-occupancy ‘isolation’ rooms in which COVID-19 patients are ideally treated – from 30.8% to 21.2% after SAMBA’s introduction, as patients with symptoms were shown to be COVID-19 negative.

In fact, the researchers say the testing devices prevented 11 ward closures in the ten days after implementation. “Keeping surgical bays open means fewer cancelled operations, speeding up access to life-saving clinical intervention,” said Gupta.

The majority of those tested using SAMBA II during the first ten days of hospital-wide use were admissions to the Emergency Department (ED). The remainder included pre-op screenings and discharges to nursing homes.

The SAMBA II tests were “beneficial” for 76% of ED patients: expediting treatment or discharge, and allowing the release of examination rooms. The 24% without benefit was mainly due to triage or discharge before results were returned.

Some 96% of the SAMBA testing on pre-operative patients increased speed of “surgical intervention”, including kidney and liver transplants. The tests also allowed earlier discharge to nursing homes or into supported living in 79% of those cases, with the remainder delayed by “systematic issues” not tests themselves.

Dr Dami Collier, who coordinated and analysed COVIDx, said: “Our research demonstrates that point-of-care testing with SAMBA II machines is not only reliable, accurate and much faster, but that the diagnostic speed leads to significant real-world improvements for patient care and safety.”

CUH Medical Director, Dr Ashley Shaw, said: “Point of care testing has been hugely beneficial in enabling our clinical teams to make well-informed and timely decisions, keeping patients and staff as safe as possible throughout this difficult period.”

This work was supported by Wellcome, the Addenbrooke’s Charitable Trust, and the National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre.

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

Donate to support COVID-19 research at Cambridge

 


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The text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified.  All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.