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A recovered Nils with his family

Oxford University researchers work with partners around the globe to develop new treatments to benefit people worldwide. Sometimes, those relationships enable our scientists, many of whom are also practising doctors, to benefit individuals too, as Kimberley Bryon-Dodd explains.

July 28 is World Hepatitis Day.  More than 300,000 people in the United Kingdom are known to be infected with Hepatitis C virus.  Although in some cases it can be a relatively mild infection and patients eventually eradicate the virus after a couple of weeks, it can also be a lifelong condition causing severe liver damage that requires a transplant and that can ultimately result in death.

Nils Nordal while ill with hepatitis C

Knowing that you're dying if nothing happens is very different to knowing that you will die soon.

Nils Nordal

In 2014 Nils Nordal was on the brink of death due to liver failure. After contracting the disease during dental treatment in Egypt 20 years ago he desperately needed a liver transplant to survive.  However, the hepatitis virus would attack any new liver so he urgently needed treatment before surgery to clear the virus from his bloodstream.

In an impossible situation, his body was so weak that the standard treatment to clear the virus (interferon) would likely kill him. Each week ten litres of excess fluid needed to be drained from his abdomen in an excruciatingly painful procedure, and he was bent over, unable to pick up his young children or walk without a cane.

'Everything that could go wrong with the liver had gone wrong with my liver. It was massively sclerotic. I had varices, I had ascites. It wasn't in good shape and it was pretty clear that I needed a liver transplant. '

There was one option. Sofosbuvir, a uridine nucleotide analogue that inhibits hepatitis C virus polymerase to prevent the virus replicating, had been shown to be incredibly effective in the USA and had just been approved in Europe for treatment of Hepatitis C.  NHS England were in the process of setting up the Early Access scheme scheme where patients, such as Nils, with advanced liver disease would receive these new drugs but it was in the early stages so the medication was not available to Nils.

'My baseline viral load was 494,000 copies of the virus per ml of blood'

As part of the Oxford Hepatology Research Team led by Dr Jane Collier and Professor Barnes we had experience of working with Gilead Sciences in the Phase III clinical trials with these new Direct Acting Anti-Virals, Sofosbuvir and Ledipasvir (now licensed as Harvoni) and we had treated patients with this drug in a clinical trial setting. I believe all of this had led to us having a good working relationship with Gilead which I think helped in pushing for Nils to receive Harvoni.

Denise O’Donnell, Senior Hepatology Research Nurse

Professor Ellie Barnes, Nils' consultant, was convinced that Sofosbuvir would eradicate the Hepatitis C virus from Nils' body and with his condition quickly deteriorating, she went directly to the maker, Gilead Sciences, to get it. Nils became one of the first people in the UK to receive Sofosbuvir outside a clinical trial.

'I started the course in May 2014. My baseline viral load was 494,000 copies of the virus per ml of blood. After I had been on Sofosbuvir for one week it was down to 64 copies per ml of blood. By week 2 it was down to 16 and by weeks 3 and 4 the virus was almost undetectable at between 0-15 copies per ml of blood. By week 5 amazingly the virus was no longer present.'

After eradicating the virus Nils was finally able to go on the transplant list for a new liver.  In August 2014 he saw his consultant in London and was told to spend as much time as he could with his children as he had at the best 6 months to live without a new liver. Nils was diagnosed with advanced liver disease and was starving to death due to an inability to process food to get any nourishment.

'Vampire in a casino'

'Knowing that you're dying if nothing happens is very different to knowing that you will die soon.

'When you get a transplant your new liver has to match your blood type and body size. It is a weird situation where you are like a vampire in a casino. You are waiting for your number to come up so that you can feed. Which means that somebody else is dead. It is an awful thing but you are praying for the right person to die.

 'I was the back-up person for a liver as they thought the person in front of me would not survive the operation. There is nothing worse than sitting in a hospital waiting to find out if you will live or die that day.'

Thankfully, Nils was able to receive a transplant in time and has now mostly recovered.

'In the ICU I was afloat in a sea of tubes. I had tubes in and out of my neck and my arms. I had drains in both sides of my abdomen to get rid of excess liquid. I had oxygen going down my nose and throat. It was me, excruciating pain, a solitary nurse, and a bunch of machines; but I was alive.

'I had an amazing recovery. The first step is just getting out of the bed and moving to a chair. I was out of ICU after 2 days and walking after a week. I woke up every morning with the sunrise because it was so amazing to be alive. 3 weeks after surgery I was able to be in the park with my kids. I was driven there but I could pick my daughter up for the first time in 6 months.

'I am alive because of the liver transplant but I have survived because of the treatment, Sofosbuvir. It is the most amazing drug and I completely credit it with my being alive. The joy of being alive and take care of my family is the best job I have ever had.

'I am tremendously grateful to everybody who contributed keeping me alive.'

Today, the hepatitis treatment service run by Dr Jane Collier is available in regions across the UK and has enabled relatively equitable access to drugs across England.

One challenge now faced by University researchers is to identify patients who are unaware that they are infected with Hepatitis C and to develop and provide a vaccine to prevent new cases.

Femurs

When it comes to your bone health, the benefits of alendronate outweigh the risks, Associate Professor Daniel Prieto-Alhambra from the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences tells Jo Silva

As an Associate Specialist in Metabolic Bone, I welcome strong evidence-based guidance on the safety of medication I'm likely to prescribe to my patients. As a clinical researcher, sometimes I get to answer my own questions.

Facts about osteoporosis

Worldwide, osteoporosis affects more than 200 million people and causes more than 8.9 million fractures annually, resulting in an osteoporotic fracture every 3 seconds.

In the UK, 1 in 2 women and 1 in 5 men over 50 will suffer a fracture related to osteoporosis, making it a much more common condition than other diseases which usually catch public attention, like breast or prostate cancer.

Currently, alendronate – a bisphosphonate drug – is one of the most common medications for osteoporosis, but prescription rates have declined by 50% in both the US and the EU amid fears of its potential risks of it leading to more (the so-called atypical) fractures.

This was bad news for osteoporosis patients. With it being the first line therapy, it was crucial to investigate the effects of taking alendronate for a long time. This can inform doctors and support patients to understand their treatment and options.

By using the Danish prescription registry, we are closer to an answer on the benefit/risk cost of alendronate. Holding almost 20 years of drug exposure data for all residents in the country, the registry can also be linked to all fractures treated in hospital in the same period.

The results of our study into alendronate using the Danish registry were recently published in the BMJ and suggest that taking this medication for over 10 years is associated with a reduced risk of hip fracture by 30% whilst not increasing other femoral fractures overall – both are excellent news to patients worldwide, as well as doctors tasked with prescribing suitable medication for their patients, like me.

How we did our study

We used anonymised records on hospital contacts and drug dispensations in the whole of Denmark.

From there, we identified all users of alendronate, and we followed them for as long as available (more than 10 years for some) until they fractured their hip or other parts of their femur. We then matched these fracture cases to non-fractured alendronate users to then study the association between drug use - long versus short-term use, and high versus low compliance -  and fracture risk.

What's next?

The main limitation of our study is its observational nature, meaning that patients were not randomly allocated to treatment but prescribed treatments based on clinical recommendations.

In addition, there are other potential side effects like osteonecrosis of the jaw (ONJ) that need quantification within the same cohort. We are now therefore working on an analysis of the risk of ONJ in this same population, which we hope to report upon in the coming few months.

Neptune

There's a funny atmosphere on Neptune…

Stuart Gillespie | 21 Jul 2016

It has been the farthest planet from the Sun since Pluto's 'relegation', but despite Neptune's remoteness in our solar system, it still holds plenty of interest for physicists – not least because of the unusual things going on in its atmosphere.

A new paper published in the journal Nature Communications by Dr Karen Aplin of Oxford University's Department of Physics attempts to get to the bottom of the 'wobbles' observed in Neptune's atmosphere over the past 40 years.

The study, written with Professor Giles Harrison of the University of Reading, evaluates two competing hypotheses for why we can see changes in the planet's brightness – a phenomenon essentially connected to its cloud cover. The results solve a long-standing conundrum in planetary science.

Dr Aplin says: 'Neptune's great distance from the Sun means that its atmosphere is very cold, but despite this it has some interesting weather, including clouds, winds, storms and perhaps lightning. It provides an entirely different environment to help us test our knowledge of atmospheres.

'Unlike Earth's atmosphere, which is mostly nitrogen, Neptune's atmosphere is mainly hydrogen and helium, with some methane. The methane absorbs much of the red light in the atmosphere, making the planet seem blue to us.

'Neptune’s atmosphere contains clouds made of a range of substances, such as ammonia and methane, whereas clouds on Earth are almost always made of water. Neptune's atmosphere is also a lot colder than ours – around -170C – because it receives 900 times less sunlight. Despite this, the Sun can still affect its clouds in subtle ways.'

Since the early 1970s, Neptune's brightness has been measured with great care by Dr Wes Lockwood of Lowell Observatory in Arizona. Because Neptune rotates around the Sun once every 165 years, each of its seasons is about 40 Earth years. Most of the ups and downs seen in Neptune's brightness since the 1970s are therefore due to its slowly changing seasons. However, even when the seasonal changes are accounted for, there are still some other small 'wobbles' in Neptune's clouds – and these are the subject of Dr Aplin's study.

Dr Aplin says: 'The "wobbles" in Neptune's cloudiness appeared to follow the Sun’s 11-year activity cycle, which could mean that they were influenced by small changes in sunlight. Another suggestion was that particles from outer space, called cosmic rays, which are also affected by the solar cycle, were changing the clouds. Using the different physics of the two mechanisms, we showed that the combined effect of the two "rival" hypotheses explained the changes in cloudiness more successfully than each would do individually.

'We also looked for a known marker of cosmic ray effects, a kind of fingerprint, in Neptune's cloud data. During the 1980s, when the Voyager 2 mission was nearing Neptune, we were able to compare both cosmic rays and clouds at Neptune and show that they had the same fingerprint. We were therefore able to confirm the effects of cosmic rays in planetary atmospheres.'

Another mission to Neptune would allow for even more scientific insight into this distant planet. But, with nothing currently planned, scientists will continue to rely on telescopic observations combined with simulation experiments of the type carried out in Dr Aplin's laboratory.

L'Oréal-UNESCO

Two of Oxford's most promising female scientists have been named among five new Fellows of the L'Oréal-UNESCO UK and Ireland For Women in Science programme.

Dr Maria Bruna, of Oxford Mathematics (and a member of the Computational Biology Group in the Department of Computer Science), and Dr Sam Giles, a palaeobiologist in Oxford's Department of Earth Sciences, were selected from 400 applicants for the Fellowships, which were announced at a ceremony hosted by the Royal Society.

The programme aims to support and help increase the number of women working in science and is designed to provide flexible financial help to outstanding female postdoctoral scientists to continue research in their chosen fields. The fellowships, worth £15,000 each, can be spent on whatever the winners may need to continue their research.

Dr Bruna and Dr Giles spoke to Science Blog about their work, their plans for the Fellowships, and the subject of women in science.

Dr Maria Bruna, Oxford Mathematics

'I work on developing mathematical methods to describe systems of interacting particles. These could be used to represent small-scale systems, such as a group of cancer cells in a tumour, or larger-scale systems such as animal flocks. The goal of my research is to understand how collective behaviour emerges from simple interactions between individuals. For example, how do the properties and behaviour of the individual cancer cells determine how the tumour will evolve?

'I can't remember how I first became interested in science, but I've always been a very curious person. I liked all sciences but in particular numbers and building things. That is why I started my studies with an engineering degree, followed by a maths one. Since then, I've found my place in applied mathematics, which allows me to combine my passion for maths with my engineering side.

'I'm very happy and excited to have been awarded this Fellowship. It comes at an ideal time for me, as I'm on maternity leave for the birth of my first son, and I will use the Fellowship to kickstart my research on my return from that.

'Awards like this one are very important to raise awareness of women in science and to help redress the gender imbalance in most sciences. While we have a lot more women in the University now than 50 years ago, I feel that in some sense the culture in academia (with long hours, more administration, scarcity of jobs) is becoming harsher, especially for women and people with young families. Initiatives like the L'Oréal-UNESCO awards, which offer practical support such as paying for childcare costs, are an excellent way to make things a bit easier for us.'

Dr Sam Giles, Department of Earth Sciences

'My research focuses on animals with backbones (vertebrates), a group that today includes over 60,000 species. Vertebrates have an evolutionary history stretching back over half a billion years, so it's really important to look at the fossil record to understand how the group became so hugely successful. Many major innovations, as well as important anatomical features, are found within the braincase, a kind of bony box that sits within the head and houses the brain and sensory organs.

'By using x-ray tomography, it is possible to "virtually" cut through the specimens and produce 3D reconstructions of the brain and braincase anatomy. Comparing these structures between key living and extinct animals allows for major evolutionary events to be put into context.

'I've been interested in science since I was very young, and I used to love reading science books and looking for different kinds of rocks and fossils. When I was at school, my favourite subject was geography – especially physical geography and the study of glaciers and volcanoes. I studied geology at university in Bristol and managed to get a (fairly boring) summer job in the palaeontology lab. As I got more involved in the work (basically picking microscopic fossil fragments out of a very big box), I read around the subject more and got more interested. I also got the chance to work on a beamline at the Swiss Light Source, a large particle accelerator that allows you to use X-rays to look at really tiny structures. This made me want to keep working in the field, and I applied for a DPhil at the University of Oxford. After finishing that, I started a Junior Research Fellowship at Christ Church, Oxford.

'I'm really happy and grateful to have been awarded this Fellowship, especially as it's so flexible, meaning I can use it in multiple ways to help my research: I can pay for my daughter's childcare for the next year, as well as buy expensive computer equipment and travel to international conferences. My plan is to stay in academia and hopefully get a lectureship somewhere.'

Illustration of HIV virus

Nowhere to hide

Tom Calver | 12 Jul 2016

While HIV is no longer the death sentence it once was, we are yet to defeat it entirely. However, a new study from Oxford University offers hope that HIV will eventually have nowhere to hide. Tom Calver spoke to Professor Lucy Dorrell about her work on clearing HIV from the body.

 

Completely curing HIV is difficult. The virus is able to hide in various places around the body, known as HIV reservoirs. 

Once we confirmed that the HIV was active again, we added ImmTAV. In four out of five cases, the process of reinfection was stopped completely.

Professor Lucy Dorrell, Nuffield Department of Medicine

Anti-Retroviral Therapy (ART) stops viral replication but is not able to eliminate cells that harbour dormant HIV.  So people can be treated successfully and become apparently free from the disease, but HIV bounces back if treatment is stopped and is able to keep re-seeding the reservoirs.

The final stage in defeating HIV is therefore to locate and destroy the lurking virus. If we can do that successfully, we may be able to cure HIV infections entirely.

Professor Lucy Dorrell and her team look at how we can do that. She explained: 'We are working with a leading UK biotechnology company based in Oxfordshire - Immunocore Ltd - to investigate the potency of novel engineered immune-mobilising T cell receptors-based drugs (ImmTAVs) – these are two-headed proteins that are designed to clear HIV-infected cells.'

In a recent paper published in the journal Molecular Therapy, Professor Dorrell and her team reported their findings on ImmTAVs.

HIV targets CD4+ T-cells, part of the immune system. If untreated, it is active HIV's destruction of these cells that leads to AIDS. But the virus can also enter some of the cells and remain dormant, so-called latent infection. If the dormant HIV is reactivated, the process of active infection begins again.

ImmTAVs are two-headed proteins. One end consists of a genetically engineered T cell receptor that is fine-tuned to detect HIV proteins in an infected cell, even when they are present at very low levels. The other end is an antibody that binds to CD3, which is present on the CD8+ T-cells that kill virus-infected cells. The ImmTAV can therefore recruit a large number of CD8+ T cells and re-direct them to purge the HIV-infected cells.

Professor Dorrell said: 'We used cells from HIV patients who had had successful ART. When we added ImmTAV we saw that their CD8+ T-cells killed the latently infected CD4+ T-cells more efficiently than the patients’ natural immune response.  Furthermore, if we took CD8+ T-cells from healthy donors and added these alongside the ImmTAV, we saw an even stronger response (up to 85% of the infected cells were removed). This may be because, despite long-term ART, there is some degree of generalised malfunction in CD8+ T cells that has not been fully repaired.  A test using only the donated CD8+ cells had no effect, confirming the essential role of the ImmTAV.'

Currently, researchers working on eradication of HIV are developing 'kick and kill' methods, where dormant HIV is reactivated and then a drug or vaccine is added in to eliminate the cells containing reactivated HIV. Having confirmed that ImmTAVs could be effective, the team combined them with the kick and kill approach in the lab.

Professor Dorrell said: 'We used latency-reversing agents, which wake up the HIV. Once we confirmed that the HIV was active again, we added ImmTAV. In four out of five cases, the process of reinfection was stopped completely.'

So are we close to a complete cure for HIV?

ImmTAVs are likely to be one part of an HIV eradication strategy, rather than a complete cure.

Professor Lucy Dorrell, Nuffield Department of Medicine

Professor Dorrell concluded: 'There is still work to do. This research was carried out in the lab but an effective cure has to take place in the patient. We need to prove that the effects we have seen can be replicated in people.

'ImmTAVs are likely to be one part of an HIV eradication strategy, rather than a complete cure. That strategy could comprise existing anti-retrovirals, ImmTAV and agents that address the weaknesses in HIV patients’ CD8+ T-cells. However, these positive results are cause for optimism.'

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