News

The work has been commissioned by the UK government’s Department for Science, Innovation and Technology after a review by the UK Chief Medical Officer in 2019 found the evidence base around the links to children’s mental health were insufficient to provide strong conclusions suitable to inform policy.

The project – led by a team at the University of Cambridge, in collaboration with researchers at several leading UK universities – is aimed at improving policymakers’ understanding of the relationship between children’s wellbeing and smartphone use, including social media and messaging. It will help direct future government action in this area.

Project lead Dr Amy Orben from the Medical Research Council Cognition and Brain Sciences Unit (MRC CBU) at the University of Cambridge said: “There is huge concern about the impact of smartphone use on children's health, but the evidence base remains fairly limited. While the government is under substantial time pressure to make decisions, these will undoubtedly be better if based on improved evidence.

“This is a complex and rapidly evolving issue, with both potential harms and benefits associated with smartphone use. Technology is changing by the day, and scientific evidence creation needs to evolve and innovate to keep up.

“Our focus will be on deepening our causal understanding of the effects of new technologies, particularly over short timescales, to ensure that decisions are informed, timely and evidence-based.”

Dr Orben will lead a Project Delivery Team, with Consortium Members from the universities of Bath, Birmingham, Bristol, Glasgow, Manchester, Nottingham, Oxford and York and the London School of Economics. It will aim to identify which research methods and data sources will be most effective at identifying potential causal relationships between social media, smartphones, and the health and development of children and young people

Deputy project lead Dr Amrit Kaur Purba, also from the MRC CBU at Cambridge, said: “The impact of social media on young people is a pressing issue, and our project will ensure the research community is in a strong position to provide policymakers with the causal and high-quality insights they need. While we don’t expect this to be straightforward, our research will leverage diverse expertise from across the UK to deliver a comprehensive and informed response to make recommendations for how research in this area should be supported in future.”

The researchers will review and summarise existing research on the impact of smartphones and social media on children and young people’s mental health, wellbeing, physical health, lifestyle and health behaviours, and educational attainment. The review will recognise the diversity of perspectives that exist in this area and consider where further research could add valuable new insights to the evidence base. 

They will assess the various methods and data available to understand the causal impacts, including recognising that online habits and emerging technologies are changing at a rapid pace, and considering how the experiences of vulnerable children and young people – for example, LGBTQ+ young people and those with special needs or mental health issues – can be captured in future research projects.

This will allow the team to recommend and outline how future research studies could deliver robust and causal evidence on the impact of smartphones and social media on child development factors in the next two to three years.

Technology Secretary Peter Kyle, said: "The online world offers immense opportunities for young people to connect and learn. Ensuring they can do so in an environment which puts their safety first is my priority and will guide this government’s action on online safety.  

“That’s why we have launched new research, led by the University of Cambridge with support from other top UK universities, to better understand the complex relationship between technology and young people's wellbeing.

“This vital research will build a trusted evidence base for future action, helping us to protect and empower the next generation towards a safer and more positive digital future."

Cambridge researchers are leading the first phase of a new research project that will lay the groundwork for future studies into the impact on children of smartphone and social media use.

This is a complex and rapidly evolving issue, with both potential harms and benefits associated with smartphone use. Technology is changing by the day, and scientific evidence creation needs to evolve and innovate to keep upAmy OrbenOwen FrankenTeenager holding a smartphone

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Yes

While male brains tended to be greater in volume than female brains, when adjusted for total brain volume, female infants on average had significantly more grey matter, while male infants on average had significantly more white matter in their brains.

Grey matter is made up of neuron cell bodies and dendrites and is responsible for processing and interpreting information, such as sensation, perception, learning, speech, and cognition.  White matter is made up of axons, which are long nerve fibres that connect neurons together from different parts of the brain. 

Yumnah Khan, a PhD student at the Autism Research Centre, who led the study, said: “Our study settles an age-old question of whether male and female brains differ at birth. We know there are differences in the brains of older children and adults, but our findings show that they are already present in the earliest days of life.

“Because these sex differences are evident so soon after birth, they might in part reflect biological sex differences during prenatal brain development, which then interact with environmental experiences over time to shape further sex differences in the brain.”

One problem that has plagued past research in this area is sample size. The Cambridge team tackled this by analysing data from the Developing Human Connectome Project, where infants receive an MRI brain scan soon after birth. Having over 500 newborn babies in the study means that, statistically, the sample is ideal for detecting sex differences if they are present.

A second problem is whether any observed sex differences could be due to other factors, such as differences in body size.  The Cambridge team found that, on average, male infants had significantly larger brain volumes than did females, and this was true even after sex differences in birth weight were taken into account.

After taking this difference in total brain volume into account, at a regional level, females on average showed larger volumes in grey matter areas related to memory and emotional regulation, while males on average had larger volumes in grey matter areas involved in sensory processing and motor control.

The findings of the study, the largest to date to investigate this question, are published in the journal Biology of Sex Differences.

Dr Alex Tsompanidis who supervised the study, said: “This is the largest such study to date, and we took additional factors into account, such as birth weight, to ensure that these differences are specific to the brain and not due to general size differences between the sexes.

“To understand why males and females show differences in their relative grey and white matter volume, we are now studying the conditions of the prenatal environment, using population birth records, as well as in vitro cellular models of the developing brain. This will help us compare the progression of male and female pregnancies and determine if specific biological factors, such as hormones or the placenta, contribute to the differences we see in the brain.”

The researchers stress that the differences between males and females are average differences.

Dr Carrie Allison, Deputy Director of the Autism Research Centre, said: “The differences we see do not apply to all males or all females, but are only seen when you compare groups of males and females together. There is a lot a variation within, and a lot of overlap between, each group.”  

Professor Simon Baron-Cohen, Director of the Autism Research Centre, added: “These differences do not imply the brains of males and females are better or worse. It’s just one example of neurodiversity. This research may be helpful in understanding other kinds of neurodiversity, such as the brain in children who are later diagnosed as autistic, since this is diagnosed more often in males.”

The research was funded by Cambridge University Development and Research, Trinity College, Cambridge, the Cambridge Trust, and the Simons Foundation Autism Research Initiative.

Reference
Khan, Y.T., Tsompanidis, A., Radecki, M.A. et al. Sex differences in human brain structure at birth. Biol Sex Differ; 17 Oct 2024; DOI: 10.1186/s13293-024-00657-5

Sex differences in brain structure are present from birth, research from the Autism Research Centre at the University of Cambridge has shown.

We know there are differences in the brains of older children and adults, but our findings show that they are already present in the earliest days of lifeYumnah KhanChayene RafaelaPhotograph of a young girl hugging a baby boy

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YesLicence type: Public Domain

Researchers from the UK and China drew this conclusion after studying proteins from blood samples taken from over 42,000 adults recruited to the UK Biobank. Their findings are published today in the journal Nature Human Behaviour.

Social relationships play an important role in our wellbeing. Evidence increasingly demonstrates that both social isolation and loneliness are linked to poorer health and an early death. Despite this evidence, however, the underlying mechanisms through which social relationships impact health remain elusive.

One way to explore biological mechanisms is to look at proteins circulating in the blood. Proteins are molecules produced by our genes and are essential for helping our bodies function properly. They can also serve as useful drug targets, allowing researchers to develop new treatments to tackle diseases.

A team led by scientists at the University of Cambridge, UK, and Fudan University, China, examined the ‘proteomes’ – the suite of proteins – in blood samples donated by over 42,000 adults aged 40-69 years who are taking part in the UK Biobank. This allowed them to see which proteins were present in higher levels among people who were socially isolated or lonely, and how these proteins were connected to poorer health.

The team calculated social isolation and loneliness scores for individuals. Social isolation is an objective measure based on, for example, whether someone lives alone, how frequently they have contact with others socially, and whether they take part in social activities. Loneliness, on the other hand, is a subjective measure based on whether an individual feels lonely.

When they analysed the proteomes and adjusted for factors such as age, sex and socioeconomic background, the team found 175 proteins associated with social isolation and 26 proteins associated with loneliness (though there was substantial overlap, with approximately 85% of the proteins associated with loneliness being shared with social isolation). Many of these proteins are produced in response to inflammation, viral infection and as part of our immune responses, as well as having been linked to cardiovascular disease, type 2 diabetes, stroke, and early death.

The team then used a statistical technique known as Mendelian randomization to explore the causal relationship between social isolation and loneliness on the one hand, and proteins on the other. Using this approach, they identified five proteins whose abundance was caused by loneliness.

Dr Chun Shen from the Department of Clinical Neurosciences at the University of Cambridge and the Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, said: “We know that social isolation and loneliness are linked to poorer health, but we’ve never understood why. Our work has highlighted a number of proteins that appear to play a key role in this relationship, with levels of some proteins in particular increasing as a direct consequence of loneliness.

Professor Jianfeng Feng from the University of Warwick said: "There are more than 100,000 proteins and many of their variants in the human body. AI and high throughput proteomics can help us pinpoint some key proteins in prevention, diagnosis, treatment and prognosis in many human diseases and revolutionise the traditional view of human health.

"The proteins we’ve identified give us clues to the biology underpinning poor health among people who are socially isolated or lonely, highlighting why social relationships play such an important part in keeping us healthy.”

One of the proteins produced in higher levels as a result of loneliness was ADM. Previous studies have shown that this protein plays a role in responding to stress and in regulating stress hormones and social hormones such as oxytocin – the so-called ‘love hormone’ – which can reduce stress and improve mood.

The team found a strong association between ADM and the volume of the insula, a brain hub for interoception, our ability to sense what's happening inside our body – the greater the ADM levels, the smaller the volume of this region. Higher ADM levels were also linked to lower volume of the left caudate, a region involved in emotional, reward, and social processes. In addition, higher levels of ADM were linked to increased risk of early death.

Another of the proteins, ASGR1, is associated with higher cholesterol and an increased risk of cardiovascular disease, while other identified proteins play roles in the development of insulin resistance, atherosclerosis (‘furring’ of the arteries) and cancer progression, for example.

Professor Barbara Sahakian from the Department of Psychiatry at the University of Cambridge said: “These findings drive home the importance of social contact in keeping us well. More and more people of all ages are reporting feeling lonely. That’s why the World Health Organization has described social isolation and loneliness as a ‘global public health concern’. We need to find ways to tackle this growing problem and keep people connected to help them stay healthy.”

The research was supported by the National Natural Sciences Foundation of China, China Postdoctoral Science Foundation, Shanghai Rising-Star Program, National Key R&D Program of China, Shanghai Municipal Science and Technology Major Project, 111 Project, Shanghai Center for Brain Science and Brain-Inspired Technology, and Zhangjiang Lab.

Reference
Shen, C et al. Plasma proteomic signatures of social isolation and loneliness associated with morbidity and mortality. Nat Hum Behav; 3 Jan 2025; DOI: 10.1038/s41562-024-02078-1

Interactions with friends and family may keep us healthy because they boost our immune system and reduce our risk of diseases such as heart disease, stroke and type 2 diabetes, new research suggests.

More and more people of all ages are reporting feeling lonely. We need to find ways to tackle this growing problem and keep people connected to help them stay healthyBarbara SahakianNoah SillimanPerson looking out through window

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YesLicence type: Public Domain

Five Cambridge experts share their top tips on ways to boost your body and mind, backed up by their own research

Professor Richards joins Cambridge from the University of Oxford, where he has been since 2019. His particular research interest is the demonstration of clinical proof of concept of novel therapeutics through the application of experimental medicine techniques, especially human challenge studies.

As Climax Professor of Clinical Therapeutics, director of the Oxford Clinical Trial Research Unit (OCTRU), and the NIHR Oxford Clinical Research Facility, he led a broad portfolio focused on new medicines for multiple conditions. His focus has been the acceleration of promising new drug treatments through better decision-making in early phase clinical trials.

Professor Richards also brings with him a wealth of experience in a number of Pharmaceutical R&D clinical development roles. In 2003 he joined GSK and held a number of roles of increasing responsibility, latterly as Head of Clinical Pharmacology and Experimental Medicine, including directorship of GSK’s phase 1 and experimental medicine unit in Cambridge (CUC).

Commenting on his appointment, Professor Richards said: “As a clinical pharmacologist, I have been fortunate to work across a broad range of therapeutic areas over the years. I am excited by the breadth and depth of expertise within the Department of Medicine and look forward to working with the first-class scientific team. My goal is to work with the Department team, the Clinical School, and hospitals to maximise the impact of the important work taking place in Cambridge.”

Members of the department’s leadership team are looking forward to the continued development of the department under Professor Richards, building on its legacy of collaboration and groundbreaking translational research to drive our future success.

Professor Mark Wills, Interim Head of Department of Medicine, said: “Duncan brings to his new role a fantastic breadth of experience, which encompasses his clinical speciality in pharmacology, extensive experience of working within the pharmaceutical industry R&D at senior levels and most recently establishing academic clinical trials units and human challenge research facilities.

“I am very excited to welcome Duncan to the Department and looking forward to working with him, as he takes on the role of delivering of the Department of Medicine’s vision to increase the efficacy of translation of its world class fundamental research, and its impact upon clinical practice and patient wellbeing.”

Menna Clatworthy, Professor of Translational Immunology and Director of the Cambridge Institute for Therapeutic Immunology and Infectious Disease (CITIID), said: "Duncan has a wealth of leadership experience in biomedicine, in both academia and pharma. That skillset will be invaluable in ensuring the Department of Medicine continues to deliver world-leading research to transform patient outcomes."

Charlotte Summers, Professor of Intensive Care Medicine and Director of the Victor Phillip Dahdaleh Heart & Lung Research Institute, said: “Duncan’s exemplary track record of translating fundamental scientific discoveries into therapies that benefit patients will help us further increase the impact of our research as we continue our mission to improve human health.”

The appointment underpins the recently announced five-year collaboration between GSK and the University of Cambridge, the Cambridge-GSK Translational Immunology Collaboration (CG-TIC). The £50 million investment will accelerate research and development in kidney and respiratory diseases to improve patient outcomes.

Professor Richards will assume the role in February 2025, replacing Interim Head of Department Dr Mark Wills who was appointed after the departure of Professor Ken Smith in January 2024.  Dr Wills will continue as Director of Research and Deputy Head of the Department of Medicine as well as leading his research group. 

Professor Richards trained in medicine at Oxford University and after junior doctor roles in London, he returned to Oxford as Clinical Lecturer in Clinical Pharmacology. His DM thesis research was on a translational model using platelet ion flux to interrogate angiotensin biology and he is author of the Oxford Handbook of Practical Drug Therapy and the 3rd edition of Drug Discovery and Development.

Professor Richards has been a core member of the UK COVID-19 Therapeutics Advisory Panel. He is a member of the Oxford Bioescalator Management Board, UK Prix Galien Prize Committee, and the therapeutic advisory committee of several national platform clinical trials.

Professor Duncan Richards has today been announced as the new Head of the Department of Medicine at the University of Cambridge.

I am excited by the breadth and depth of expertise within the Department of Medicine and look forward to working with the first-class scientific teamDuncan Richards

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Yes

Researchers hope that early detection, through the simple urine test, could enable earlier treatment interventions, significantly improving patient outcomes and prognosis. Around 36,600 lives are saved from lung cancer in the UK every year, according to new analysis from Cancer Research UK.

Professor Ljiljana Fruk and Dr Daniel Munoz Espin and their teams at the University of Cambridge are leading on the research, funded by Cancer Research UK.

The work, at Cambridge’s Department of Chemical Engineering and Biotechnology, and the Early Cancer Institute, will provide a cheap, affordable sensor that uses urine samples to help doctors detect lung cancer before the disease develops.

Lung cancer has a poor prognosis for many patients because often there are no noticeable symptoms until it has spread through the lungs or into other parts of the body. The new urine test will allow doctors to spot the disease before it develops.

To create the test, scientists looked at proteins excreted by senescent cells: “zombie” cells which are alive but unable to grow and divide. It’s these cells that cause tissue damage by reprogramming their immediate environment to help promote the emergence of cancer cells.

Now, researchers have developed an injectable sensor that interacts with zombie cell proteins and releases easily detectable compound into urine, signalling their presence.

“Early detection of cancer requires cost-effective tools and strategies that enable detection to happen quickly and accurately,” said Fruk. “We designed a test based on peptide-cleaving proteins, which are found at higher levels in the presence of zombie cells, and in turn appear in the early stages of cancer.

“Ultimately, we want to develop a urine test that could help doctors identify signs of the early stages of cancer – potentially months or even years before noticeable symptoms appear.”

As well as targeting lung cancer, Fruk hopes her research, along with joint efforts across other university departments, will result in the development of probes capable of detecting other cancers.

“We have almost completed a functional urine test to detect ‘zombie' cells in lung cancer, which will spot cancer earlier and avoid the need for invasive procedures, but this test does have potential for other cancers,” she said. “Developing more efficient cancer treatments requires earlier detection and better therapies, but also work with other disciplines for a more holistic view of the disease, which is an essential part of my research.”

From uncovering the causes of lung cancer to pioneering drugs to treat it, Cancer Research UK has helped power progress for people affected by lung cancer. Over the last 10 years, the charity has invested over £231 million in lung cancer research.

“Cancer Research UK has played a key role in advancing lung cancer research and improving survival,” said Dr Iain Foulkes, Cancer Research UK’s executive director of research and innovation. “This project being led by Professor Fruk is another example of our commitment to driving progress so that more people can live longer, better lives, free from the fear of cancer.”

Adapted from a Cancer Research UK media release. 

Cambridge scientists have developed a urine test for early detection of lung cancer. The test, the first of its kind, detects ‘zombie’ cells that could indicate the first signs of the disease.

koto_feja via Getty ImagesClose-up of cancer cells

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Yes

A pivotal clinical trial of a 'pill-on-a-thread' test, which will decide if it becomes a new screening programme for oesophageal cancer, has welcomed its first participants.

The Human Cell Atlas is an ambitious project to map every cell in the human body. Its co-lead, Professor Sarah Teichmann, explains how the initiative is already changing our understanding of our bodies.

Researchers have developed a mindfulness therapy tailored specifically to appeal to teenagers to help them cope with increasing levels of depression and mental health problems.

Researchers in the UK Dementia Research Institute at the University of Cambridge screened more than 1,400 clinically-approved drug compounds using zebrafish genetically engineered to make them mimic so-called tauopathies. They discovered that drugs known as carbonic anhydrase inhibitors – of which the glaucoma drug methazolamide is one – clear tau build-up and reduce signs of the disease in zebrafish and mice carrying the mutant forms of tau that cause human dementias.

Tauopathies are neurodegenerative diseases characterised by the build-up in the brain of tau protein ‘aggregates’ within nerve cells. These include forms of dementia, Pick's disease and progressive supranuclear palsy, where tau is believed to be the primary disease driver, and Alzheimer’s disease and chronic traumatic encephalopathy (neurodegeneration caused by repeated head trauma, as has been reported in football and rugby players), where tau build-up is one consequence of disease but results in degeneration of brain tissue.

There has been little progress in finding effective drugs to treat these conditions. One option is to repurpose existing drugs. However, drug screening – where compounds are tested against disease models – usually takes place in cell cultures, but these do not capture many of the characteristics of tau build-up in a living organism.

To work around this, the Cambridge team turned to zebrafish models they had previously developed. Zebrafish grow to maturity and are able to breed within two to three months and produce large numbers of offspring. Using genetic manipulation, it is possible to mimic human diseases as many genes responsible for human diseases often have equivalents in the zebrafish.

In a study published today in Nature Chemical Biology, Professor David Rubinsztein, Dr Angeleen Fleming and colleagues modelled tauopathy in zebrafish and screened 1,437 drug compounds. Each of these compounds has been clinically approved for other diseases.

Dr Ana Lopez Ramirez from the Cambridge Institute for Medical Research, Department of Physiology, Development and Neuroscience and the UK Dementia Research Institute at the University of Cambridge, joint first author, said: “Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms. They also enable us to do so at scale, something that it not feasible or ethical in larger animals such as mice.”  

Using this approach, the team showed that inhibiting an enzyme known as carbonic anhydrase – which is important for regulating acidity levels in cells – helped the cell rid itself of the tau protein build-up. It did this by causing the lysosomes – the ‘cell’s incinerators’ – to move to the surface of the cell, where they fused with the cell membrane and ‘spat out’ the tau.

When the team tested methazolamide on mice that had been genetically engineered to carry the P301S human disease-causing mutation in tau, which leads to the progressive accumulation of tau aggregates in the brain, they found that those treated with the drug performed better at memory tasks and showed improved cognitive performance compared with untreated mice.

Analysis of the mouse brains showed that they indeed had fewer tau aggregates, and consequently a lesser reduction in brain cells, compared with the untreated mice.

Fellow joint author Dr Farah Siddiqi, also from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, said: “We were excited to see in our mouse studies that methazolamide reduces levels of tau in the brain and protects against its further build-up. This confirms what we had shown when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”

Professor Rubinsztein from the UK Dementia Research Institute and Cambridge Institute for Medical Research at the University of Cambridge, said: “Methazolamide shows promise as a much-needed drug to help prevent the build-up of dangerous tau proteins in the brain. Although we’ve only looked at its effects in zebrafish and mice, so it is still early days, we at least know about this drug’s safety profile in patients. This will enable us to move to clinical trials much faster than we might normally expect if we were starting from scratch with an unknown drug compound.

“This shows how we can use zebrafish to test whether existing drugs might be repurposed to tackle different diseases, potentially speeding up significantly the drug discovery process.”

The team hopes to test methazolamide on different disease models, including more common diseases characterised by the build-up of aggregate-prone proteins, such as Huntington’s and Parkinson’s diseases.

The research was supported by the UK Dementia Research Institute (through UK DRI Ltd, principally funded through the Medical Research Council), Tau Consortium and Wellcome.

Reference
Lopez, A & Siddiqi, FH et al. Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion. Nat Chem Bio; 31 Oct 2024; DOI: 10.1038/s41589-024-01762-7
 

A drug commonly used to treat glaucoma has been shown in zebrafish and mice to protect against the build-up in the brain of the protein tau, which causes various forms of dementia and is implicated in Alzheimer’s disease.

Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organismsAna Lopez RamirezKuznetsov_PeterZebrafish

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YesLicence type: Public Domain

The treatment – known as repetitive transcranial magnetic stimulation (TMS) – involves placing an electromagnetic coil against the scalp to relay a high-frequency magnetic field to the brain.

Around one in 20 adults is estimated to suffer from depression. Although treatments exist, such as anti-depressant medication and cognitive behavioural therapy (‘talking therapy’), they are ineffective for just under one in three patients.

One of the key characteristics of depression is under-activity of some regions (such as the dorsolateral prefrontal cortex) and over-activity of others (such as the orbitofrontal cortex (OFC)).

Repetitive transcranial magnetic stimulation applied to the left side of the dorsolateral prefrontal cortex (an area at the upper front area of the brain) is approved for treatment of depression in the UK by NICE and in the US by the FDA. It has previously been shown to lead to considerable improvements among patients after a course of 20 sessions, but because the sessions usually take place over 20-30 days, the treatment is not ideal for everyone, particularly in acute cases or where a person is suicidal.

In research published in Psychological Medicine, scientists from Cambridge, UK, and Guiyang, China, tested how effective an accelerated form of TMS is. In this approach, the treatment is given over 20 sessions, but with four sessions per day over a period of five consecutive days.

The researchers also tested a ‘dual’ approach, whereby a magnetic field was additionally applied to the right-hand side of the OFC (which sits below the dorsolateral prefrontal cortex).

Seventy-five patients were recruited to the trial from the Second People’s Hospital of Guizhou Province in China. The severity of their depression was measured on a scale known as the Hamilton Rating Scale of Depression.

Participants were split randomly into three groups: a ‘dual’ group receiving TMS applied first to the right- and then to the left-hand sides of the brain; a ‘single’ group receiving sham TMS to the right-side followed by active TMS applied to the left-side; and a control group receiving a sham treatment to both sides. Each session lasted in total 22 minutes.

There was a significant improvement in scores assessed immediately after the final treatment in the dual treatment group compared to the other two groups. When the researchers looked for clinically-relevant responses – that is, where an individual’s score fell by at least 50% – they found that almost half (48%) of the patients in the dual treatment group saw such a reduction, compared to just under one in five (18%) in the single treatment group and fewer than one in 20 (4%) in the control group.

Four weeks later, around six in 10 participants in both the dual and single treatment groups (61% and 59% respectively) showed clinically relevant responses, compared to just over one in five (22%) in the control group.

Professor Valerie Voon from the Department of Psychiatry at the University of Cambridge, who led the UK side of the study, said: “Our accelerated approach means we can do all of the sessions in just five days, rapidly reducing an individual’s symptoms of depression. This means it could be particularly useful in severe cases of depression, including when someone is experiencing suicidal thoughts. It may also help people be discharged from hospital more rapidly or even avoid admission in the first place.

“The treatment works faster because, by targeting two areas of the brain implicated in depression, we’re effectively correcting imbalances in two import processes, getting brain regions ‘talking’ to each other correctly.”

The treatment was most effective in those patients who at the start of the trial showed greater connectivity between the OFC and the thalamus (an area in the middle of the brain responsible for, among other things, regulation of consciousness, sleep, and alertness). The OFC is important for helping us make decisions, particularly in choosing rewards and avoiding punishment. Its over-activity in depression, particularly in relation to its role in anti-reward or punishment, might help explain why people with depression show a bias towards negative expectations and ruminations.

Dr Yanping Shu from the Guizhou Mental Health Centre, Guiyang, China, said: “This new treatment has demonstrated a more pronounced – and faster – improvement in response rates for patients with major depressive disorder. It represents a significant step forward in improving outcomes, enabling rapid discharge from hospitals for individuals with treatment-resistant depression, and we are hopeful it will lead to new possibilities in mental health care.”

Dr Hailun Cui from Fudan University, a PhD student in Professor Voon’s lab at the time of the study, added: “The management of treatment-resistant depression remains one of the most challenging areas in mental health care. These patients often fail to respond to standard treatments, including medication and psychotherapy, leaving them in a prolonged state of severe distress, functional impairment, and increased risk of suicide.

“This new TMS approach offers a beacon of hope in this difficult landscape. Patients frequently reported experiencing ‘lighter and brighter’ feelings as early as the second day of treatment. The rapid improvements, coupled with a higher response rate that could benefit a broader depressed population, mark a significant breakthrough in the field.”

Just under a half (48%) of participants in the dual treatment group reported local pain where the dual treatment was applied, compared to just under one in 10 (9%) of participants in the single treatment group. However, despite this, there were no dropouts.

For some individuals, this treatment may be sufficient, but for others ‘maintenance therapy’ may be necessary, with an additional day session if their symptoms appear to be worsening over time. It may also be possible to re-administer standard therapy as patients can then become more able to engage in psychotherapy. Other options include using transcranial direct current stimulation, a non-invasive form of stimulation using weak electrical impulses that can be delivered at home.

The researchers are now exploring exactly which part of the orbitofrontal cortex is most effective to target and for which types of depression.

The research was supported by in the UK by the Medical Research Council and by the National Institute for Health and Care Research Cambridge Biomedical Research Centre.*

Reference
Cui, H, Ding, H & Hu, L et al. A novel dual-site OFC-dlPFC accelerated repetitive transcranial magnetic stimulation for depression: a pilot randomized controlled study. Psychological Medicine; 23 Oct 2024; DOI: 10.1017/S0033291724002289

*A full list of funders is available in the journal paper.

A type of therapy that involves applying a magnetic field to both sides of the brain has been shown to be effective at rapidly treating depression in patients for whom standard treatments have been ineffective.

Our accelerated approach means we can do all of the sessions in just five days, rapidly reducing an individual’s symptoms of depressionValerie VoonTheDigitalArtistDigital image of a brain

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YesLicence type: Public Domain

Election to the Academy is considered one of the highest honours in the fields of health and medicine and recognises individuals who have demonstrated outstanding professional achievement and commitment to service.

“It is a great honour to have been elected to the National Academy of Medicine,”  said Professor Rowitch.

Professor Rowitch obtained his PhD from the University of Cambridge. His research in the field of developmental neurobiology has focused on glial cells that comprise the ‘white matter’ of the human brain. It has furthered understanding human neonatal brain development as well as white matter injury in premature infants, multiple sclerosis and leukodystrophy. Amongst numerous awards, he was elected a Fellow of the Academy of Medical Sciences in 2018 and Fellow of the Royal Society in 2021.

Professor Rowitch’s current interest focuses on functional genomic technologies to better diagnose and treat rare neurogenetic disorders in children. He is academic lead for the new Cambridge Children’s Hospital, developing integrated paediatric physical-mental healthcare and research within the NHS and University of Cambridge.

NAM President Victor J. Dzau said: “This class of new members represents the most exceptional researchers and leaders in health and medicine, who have made significant breakthroughs, led the response to major public health challenges, and advanced health equity.

“Their expertise will be necessary to supporting NAM’s work to address the pressing health and scientific challenges we face today. It is my privilege to welcome these esteemed individuals to the National Academy of Medicine.”

Professor Rowitch is one of 90 regular members and 10 international members announced during the Academy’s annual meeting. New members are elected by current members through a process that recognises individuals who have made major contributions to the advancement of the medical sciences, health care, and public health. 

Professor David Rowitch, Head of the Department of Paediatrics at the University of Cambridge, has been elected to the prestigious National Academy of Medicine in the USA.

Professor David Rowitch

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Yes

• The Cambridge-GSK Translational Immunology Collaboration (CG-TIC) combines University and GSK expertise in the science of the immune system, AI and clinical development with access to patients and their data provided by Cambridge University Hospitals.
• GSK is investing more than £50 million in CG-TIC, further strengthening Cambridge’s position as Europe’s leading life sciences cluster.

GSK plc is making this investment to establish the Cambridge-GSK Translational Immunology Collaboration (CG-TIC), a five-year collaboration with the University of Cambridge and Cambridge University Hospitals. The collaboration is focused on understanding the onset of a disease, its progression, how patients respond to therapies and on developing biomarkers for rapid diagnosis. Ultimately, the goal is to trial more effective, personalised medicines.

The collaboration will focus on kidney and respiratory diseases, both of which affect large numbers of people worldwide. Kidney disease is estimated to affect 850 million people (roughly 10% of the world’s population) (International Society of Nephrology) and chronic respiratory diseases around 545 million (The Lancet).

Many types of kidney disease remain poorly understood and treatments, where they exist, tend to have limited efficacy. Chronic kidney disease is particularly unpleasant and debilitating for patients, often leading to end-stage disease. Treatments such as transplant and dialysis involve complex medical regimes and frequent hospital visits, making effective prevention and treatment the aim.

To make progress in treating these challenging disease areas, CG-TIC will apply an array of new techniques, including the use of cutting-edge single cell technologies to characterise how genes are expressed in individual cells. AI and machine learning have a critical role to play in transforming how data is combined and interrogated.

Using these techniques, the ambition is to be able to initiate new studies and early phase trials of new therapies for a number of hard-to-treat diseases which affect the kidneys. The same techniques will be applied to respiratory diseases and findings will be shared across the disease areas potentially to help identify and share better treatments across these different targets.

Peter Kyle, Secretary of State for Science, Innovation and Technology, welcomed the collaboration: "The UK's life sciences industry is thriving, driving innovation and improving lives. This collaboration between GSK and the University of Cambridge demonstrates our country's leading research and development capabilities.

“By focusing on cutting-edge research and harnessing the power of AI, this partnership has the potential to advance the treatment of immune-related diseases, which could benefit patients both here in the UK and internationally. It's a clear example of how collaboration between industry, academia, and healthcare can deliver tangible results and strengthen the UK's position in healthcare innovation."

Tony Wood, Chief Scientific Officer, GSK, added: “Collaboration is at the heart of scientific progress and is fundamental to how we do R&D at GSK. We’re excited to build on our existing work with the University of Cambridge to further this world-leading scientific and technological capability in the UK. By bringing together Cambridge’s expertise and our own internal capabilities, including understanding of the immune system and the use of AI to accelerate drug development, we have an opportunity to help patients struggling with complex disease.”

The aim of CG-TIC is to improve outcomes for patients and Cambridge provides a unique environment in which to involve them, with Cambridge University Hospitals playing a pivotal role in the collaboration and Royal Papworth Hospital NHS Foundation Trust, the UK’s leading heart and lung hospital, a likely future partner.

Home to the hospitals and to much of the collaboration’s research activity, the Cambridge Biomedical Campus provides a unique environment where academia, industry and healthcare can come together and where human translational research is supported by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre.

Professor Deborah Prentice, Vice-Chancellor of the University of Cambridge, said: “The University sits at the heart of Europe’s leading life sciences cluster, where excellent research and the NHS’s clinical resources combine with the talent generated by the many innovative bioscience companies that call Cambridge home. Through this very important collaboration with GSK, Cambridge will be able to drive economic growth for the UK while improving the health of people in this country and around the world.”

Roland Sinker, CEO of Cambridge University Hospitals NHS Foundation Trust, also welcomed the collaboration, saying: “We are very excited to be part of this important partnership, which is another example of Cambridge experts working together to develop transformational new therapies, and use existing ones more precisely, to improve outcomes for patients with chronic and debilitating conditions.”

The Cambridge-GSK Translational Immunology Collaboration will be co-led by Nicolas Wisniacki, VP, Clinical Research Head, GSK (above left) and David Thomas, Professor of Renal Medicine, University of Cambridge and principal investigator at the Cambridge Institute for Therapeutic Immunology and Infectious Diseases.

 

 

The ambition of the partnership is to treat immune-related diseases more precisely with existing therapies and to rapidly develop new ones.

The UK's life sciences industry is thriving, driving innovation and improving lives. This collaboration between GSK and the University of Cambridge demonstrates our country's leading research and development capabilities. Peter Kyle, Secretary of State for Science, Innovation and TechnologyStillVisionDavid Thomas, Professor of Renal Medicine, University of Cambridge and Dr Nicolas Wisniacki, VP, Clinical Research Head, GSK

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YesLicence type: Public Domain

10 Cambridge spinouts on putting their research into practice to improve outcomes for cancer patients - and why Cambridge is a great place to do this.    

The significant funding commitment will enable world-class discovery science, unlocking new insights into how cancers develop, grow and spread, as well as examining how the immune system can be harnessed to combat the disease.  

Research at the CRUK Cambridge Institute focuses on understanding every stage of the cancer life cycle – how tumours grow and spread and how this is impacted by the characteristics of each individual patient.  By studying how tumours develop, adapt, and interact with their surroundings, scientists aim to uncover crucial insights into their behaviour. 

Vice-Chancellor of the University of Cambridge, Professor Deborah Prentice, said: “From understanding and detecting cancer at its very earliest stages, to developing kinder treatments to building Cambridge Cancer Research Hospital, a transformative new cancer research hospital for the region, Cambridge is changing the story of cancer. For many years now, Cancer Research UK has played a vital role in enabling this world-leading work. Today’s announcement will ensure our researchers continue to find new ways to transform the lives of patients locally, nationally and internationally.”

Today’s £173 million announcement further boosts CRUK’s unwavering commitment towards its mission to beat cancer. The charity is investing in exciting new research programmes, forging new partnerships and is on track to invest more than £1.5bn on research over the five-year period 2021/22 to 2025/26.   

Director of the CRUK Cambridge Institute, Professor Greg Hannon, said: “In a golden era for life sciences, this funding bolsters Cambridge as a major global hub for cancer research on an increasingly competitive worldwide stage and will greatly aid the recruitment of top-tier international talent.   

“Research from the Institute has already made a positive impact for patients and their families, from the development of innovative technologies, diagnostic tests, and advanced imaging methods to the roll out of personalised medicine programmes for those with brain, breast, pancreatic, and ovarian cancers. We believe that only by embracing the complexity of cancer and how the disease interacts with the normal cells of patients can we move the needle on the hardest to treat cancers.” 

The Institute is dedicated to improving cancer patients’ lives through discovery science and clinical translational research and has over 300 scientists working on groundbreaking discoveries taking research from laboratory bench to bedside.  

Established in 2007, it was the first major new cancer research centre in the UK for over 50 years. In 2013, it became a department of the University of Cambridge School of Clinical Medicine, strengthening links with researchers across the University and at Addenbrooke's Hospital,  and further enhancing its position as a world leader with research transitioning into clinical trials, and ultimately new and better cancer treatments. 

Professor Hannon added: "The Institute serves as a foundation for the entire Cambridge cancer research community through access to cutting-edge equipment and technical expertise. Only through understanding all aspects of the disease can we prevent, detect and treat cancer so that everybody can lead longer, better lives, free from fear of cancer.

“With this new funding, the Institute aims to accelerate its impact for patients, with new schemes to integrate clinicians into every aspect of our research and to embrace new technologies, including the promise of machine learning and artificial intelligence to enhance our discovery portfolio.”  

The award, which will support the Institute over the next seven years, follows a comprehensive review of the facility led by an independent panel of international cancer experts who recognised research innovation.  

CRUK Chief Executive, Michelle Mitchell, said: “We are delighted to confirm this incredible investment which is a reflection of  the world-leading research community at the CRUK Cambridge Institute. The funding will underpin long-term cutting-edge discovery research, as well as supporting researchers to find new ways to improve cancer prevention and treatment, while creating innovative solutions to diagnose the disease earlier. 

“This kind of funding would not be possible without the generosity of Cancer Research UK supporters and philanthropists."

Work undertaken at the Institute includes: 

• Understanding cancer: By gaining a deeper understanding of how tumours grow, adapt, and interact with their surroundings, scientists hope to uncover why some cells become cancerous and learn how each tumour's lifecycle can affect a patient’s response to treatment and prognosis.  Professor Greg Hannon's team developed a diagnostic tool using virtual reality to explore every cell and aspect of breast tumours in unprecedented detail.
• Unravelling tumour interactions: Researchers are investigating a tumours’ ‘microenvironment' – which includes the surrounding cells, blood vessels, and immune cells and how they interact. This is helping scientists to predict how well immunotherapy treatments will work.
• Cancer detection: Scientists are finding new ways to detect cancer earlier, predict the best course of treatments and tailor therapies to individual needs, to improve survival.  Using tumour DNA, scientists can monitor the effectiveness of treatments and catch signs of cancer returning.  Cambridge scientists are also working on a simple at-home test for future patients to regularly monitor their progress. 
• Personalised medicine: Looking at the unique genetic mutations of a person’s tumour, including how it behaves and responds to treatment, allows treatments to be developed and matched to the specific genetic change.  For example, Professor James Brenton's team discovered a specific mutation in the most common form of ovarian cancer which is now used across the NHS as a cancer marker to measure treatment response for the disease. 

Thanks to research, cancer death rates have fallen by 10% percent in the UK over the past decade. But in the East of England, around 37,400 people are still diagnosed, and around 15,700 lose their lives to the disease every year - underlining the vital need for new and better treatments. 

Major studies seeking more accurate treatments for the deadliest cancers like ovarian and oesophageal cancer will also be supported at the Institute.  Research undertaken by Professor Florian Markowetz and his team includes predicting cancer weaknesses to treatment, and spotting cancers as early as possible using AI technology. 

There are 17 research groups based at the Institute – based on the largest biomedical campus in Europe - studying a range of cancer and technologies to support improved cancer treatments. 

Find out how Cambridge is changing the story of cancer

Adapted from a press release from Cancer Research UK

Cancer Research UK (CRUK) has today announced a £173 million investment in its institute at the University of Cambridge - the largest single grant ever awarded by the charity outside of London.  

Today’s announcement will ensure our researchers continue to find new ways to transform the lives of patients locally, nationally and internationallyDeborah Prentice, Vice-ChancellorCancer Research UKCancer Research UK Cambridge Institute

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Yes

The collaboration, which includes researchers from the University of Cambridge, aims to accelerate progress on new neuro-technologies, including miniaturised brain implants designed to treat depression, dementia, chronic pain, epilepsy and injuries to the nervous system.

Neurological and mental health disorders will affect four in every five people in their lifetimes, and present a greater overall health burden than cancer and cardiovascular disease combined. For example, 28 million people in the UK are living with chronic pain and 1.3 million people with traumatic brain injury.

Neuro-technology – where technology is used to control the nervous system - has the potential to deliver new treatments for these disorders, in much the same way that heart pacemakers, cochlear implants and spinal implants have transformed medicine in recent decades.

The technology can be in the form of electronic brain implants that reset abnormal brain activity or help deliver targeted drugs more effectively, brain-computer interfaces that control prosthetic limbs, or technologies that train the patient’s own cells to fight disease. ARIA’s Scalable Neural Interfaces opportunity space is exploring ways to make the technology more precise, less invasive, and applicable to a broader range of diseases.

Currently, an implant can only interact with large groups of neurons, the cells that transmit information around the brain. Building devices that interact with single neurons will mean a more accurate treatment. Neuro-technologies also have the potential to treat autoimmune disorders, including rheumatoid arthritis, Crohn’s disease and type-1 diabetes.

The science of building technology small enough, precise enough and cheap enough to make a global impact requires an environment where the best minds from across the UK can collaborate, dream up radical, risky ideas and test them without fear of failure.

Professor George Malliarias from the University of Cambridge’s Department of Engineering is one of the project leaders. “Miniaturised devices have the potential to change the lives of millions of people currently suffering from neurological conditions and diseases where drugs have no effect,” he said. “But we are working at the very edge of what is possible in medicine, and it is hard to find the support and funding to try radical, new things. That is why the partnership with ARIA is so exhilarating, because it is giving brilliant people the tools to turn their original ideas into commercially viable devices that are cheap enough to have a global impact.”

Cambridge’s partnership with ARIA will create a home for original thinkers who are struggling to find the funding, space and mentoring needed to stress-test their radical ideas. The three-year partnership is made up of two programmes:

The Fellowship Programme (up to 18 fellowships)

Blue Sky Fellows – a UK-wide offer - we will search the UK for people from any background, with a radical idea in this field and the plan and personal skills to develop it. The best people will be offered a fellowship with the funding to test their ideas in Cambridge rapidly. These Blue Sky Fellows will receive mentorship from our best medical, scientific and business experts and potentially be offered accommodation at a Cambridge college. We will be looking for a specific type of person to be a Blue Sky Fellow. They must be the kind of character who thinks at the very edge of the possible, who doesn’t fear failure, and whose ideas have the potential to change billions of lives, yet would struggle to find funding from existing sources. Not people who think outside the box, more people who don’t see a box at all.

Activator Fellows - a UK-wide offer - those who have already proved that their idea can work, yet need support to turn it into a business, will be invited to become Activator Fellows. They will be offered training in entrepreneurial skills including grant writing, IP management and clinical validation, so their innovation can be ready for investment.

The Ecosystem Programme

The Ecosystem Programme is about creating a vibrant, UK-wide neurotechnology community where leaders from business, science, engineering, academia and the NHS can meet, spark ideas and form collaborations. This will involve quarterly events in Cambridge, road trip events across the UK and access to the thriving online Cambridge network, Connect: Health Tech.

“This unique partnership is all about turning radical ideas into practical, low-cost solutions that change lives,” said Kristin-Anne Rutter, Executive Director of Cambridge University Health Partners. “Cambridge is fielding its best team to make this work and using its networks to bring in the best people from all over the UK. From brilliant scientists to world-leading institutes, hospitals and business experts, everyone in this collaboration is committed to the ARIA partnership because, by working together, we all see an unprecedented opportunity to make a real difference in the world.”

“Physical and mental illnesses and diseases that affect the brain such as dementia are some of the biggest challenges we face both as individuals and as a society,” said Dr Ben Underwood, Associate Professor of Psychiatry at the University of Cambridge and Honorary Consultant Psychiatrist at Cambridgeshire and Peterborough NHS Foundation Trust. “This funding will bring together different experts doing things at the very limits of science and developing new technology to improve healthcare. We hope this new partnership with the NHS will lead to better care and treatment for people experiencing health conditions.”

Cambridge partners in the project include the Departments of Engineering and Psychiatry, Cambridge Neuroscience, the Milner Therapeutics Institute, the Maxwell Centre, Cambridge University Health Partners (CUHP), Cambridge Network, the Babraham Research Campus, Cambridgeshire and Peterborough NHS Foundation Trust, and Vellos. 

A team from across the Cambridge life sciences, technology and business worlds has announced a multi-million-pound, three-year collaboration with the Advanced Research and Invention Agency (ARIA), the UK government’s new research funding agency.

Science Photo Library via Getty ImagesIllustration of human brain

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Yes

Using ultra-high-resolution scanners that can see the living brain in fine detail, researchers from the Universities of Cambridge and Oxford were able to observe the damaging effects Covid-19 can have on the brain.

The study team scanned the brains of 30 people who had been admitted to hospital with severe Covid-19 early in the pandemic, before vaccines were available. The researchers found that Covid-19 infection damages the region of the brainstem associated with breathlessness, fatigue and anxiety.

The powerful MRI scanners used for the study, known as 7-Tesla or 7T scanners, can measure inflammation in the brain. Their results, published in the journal Brain, will help scientists and clinicians understand the long-term effects of Covid-19 on the brain and the rest of the body. Although the study was started before the long-term effects of Covid were recognised, it will help to better understand this condition.

The brainstem, which connects the brain to the spinal cord, is the control centre for many basic life functions and reflexes. Clusters of nerve cells in the brainstem, known as nuclei, regulate and process essential bodily functions such as breathing, heart rate, pain and blood pressure.

“Things happening in and around the brainstem are vital for quality of life, but it had been impossible to scan the inflammation of the brainstem nuclei in living people, because of their tiny size and difficult position.” said first author Dr Catarina Rua, from the Department of Clinical Neurosciences. “Usually, scientists only get a good look at the brainstem during post-mortem examinations.”

“The brainstem is the critical junction box between our conscious selves and what is happening in our bodies,” said Professor James Rowe, also from the Department of Clinical Neurosciences, who co-led the research. “The ability to see and understand how the brainstem changes in response to Covid-19 will help explain and treat the long-term effects more effectively.”

In the early days of the Covid-19 pandemic, before effective vaccines were available, post-mortem studies of patients who had died from severe Covid-19 infections showed changes in their brainstems, including inflammation. Many of these changes were thought to result from a post-infection immune response, rather than direct virus invasion of the brain.  

“People who were very sick early in the pandemic showed long-lasting brain changes, likely caused by an immune response to the virus. But measuring that immune response is difficult in living people,” said Rowe. “Normal hospital-type MRI scanners can’t see inside the brain with the kind of chemical and physical detail we need.”

“But with 7T scanners, we can now measure these details. The active immune cells interfere with the ultra-high magnetic field, so that we’re able to detect how they are behaving,” said Rua. “Cambridge was special because we were able to scan even the sickest and infectious patients, early in the pandemic.”

Many of the patients admitted to hospital early in the pandemic reported fatigue, breathlessness and chest pain as troubling long-lasting symptoms. The researchers hypothesised these symptoms were in part the result of damage to key brainstem nuclei, damage which persists long after Covid-19 infection has passed.

The researchers saw that multiple regions of the brainstem, in particular the medulla oblongata, pons and midbrain, showed abnormalities consistent with a neuroinflammatory response. The abnormalities appeared several weeks after hospital admission, and in regions of the brain responsible for controlling breathing.

“The fact that we see abnormalities in the parts of the brain associated with breathing strongly suggests that long-lasting symptoms are an effect of inflammation in the brainstem following Covid-19 infection,” said Rua. “These effects are over and above the effects of age and gender, and are more pronounced in those who had had severe Covid-19.”

In addition to the physical effects of Covid-19, the 7T scanners provided evidence of some of the psychiatric effects of the disease. The brainstem monitors breathlessness, as well as fatigue and anxiety. “Mental health is intimately connected to brain health, and patients with the most marked immune response also showed higher levels of depression and anxiety,” said Rowe. “Changes in the brainstem caused by Covid-19 infection could also lead to poor mental health outcomes, because of the tight connection between physical and mental health.”

The researchers say the results could aid in the understanding of other conditions associated with inflammation of the brainstem, like MS and dementia. The 7T scanners could also be used to monitor the effectiveness of different treatments for brain diseases.

“This was an incredible collaboration, right at the peak of the pandemic, when testing was very difficult, and I was amazed how well the 7T scanners worked,” said Rua. “I was really impressed with how, in the heat of the moment, the collaboration between lots of different researchers came together so effectively.”

The research was supported in part by the NIHR Cambridge Biomedical Research Centre, the NIHR Oxford Biomedical Research Centre, and the University of Oxford COVID Medical Sciences Division Rapid Response Fund.

 

Reference:
Catarina Rua et al. ‘7-Tesla quantitative susceptibility mapping in COVID-19: brainstem effects and outcome associations.’ Brain (2024). DOI: 10.1093/brain/awae215

Damage to the brainstem – the brain’s ‘control centre’ – is behind long-lasting physical and psychiatric effects of severe Covid-19 infection, a study suggests.

University of Cambridge3D projections of QSM maps on the rendered brainstem

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Yes

In 1994, a landmark paper identified a gene – BRCA1 – that significantly increases the risk of breast and ovarian cancers when faulty. Thirty years on, we look at the major impact it has had on how we understand and treat cancer – and why there is still much to learn.