Oxford Science Blog

Tamiflu: an analysis of all the data

Jonathan Wood | 10 Apr 2014

These drugs were handed out via a phoneline during the swine flu pandemic of 2009 as part of a wider public health strategy.

Professor Carl Heneghan of Oxford University's Department of Primary Care Health Sciences and colleagues in the independent Cochrane Collaboration are clear that the money was wasted. They argue that the decision to stockpile the drugs might have been different had we had access to all the clinical data on their effectiveness.

Now we do have that evidence, and Carl says: 'There is no credible way these drugs could prevent a pandemic.' Speaking at a media briefing at the Science Media Centre in London, he said the money spent on stockpiling had been 'thrown down the drain'.

Since 2009, the Cochrane researchers have had a long running battle with the drug firms that manufacture Tamiflu and Relenza (Roche and GSK, respectively) to get unconditional access to their full data. They finally received everything last year, after first GSK then Roche said they would provide the materials – a significant development in the campaign to increase openness and accessibility of complete trial data.

The Cochrane group has been significant players, along with the AllTrials campaign, the BMJ medical journal, Ben Goldacre and others, in changing the whole approach to this issue among researchers, journals, drug firms and regulators. The simple argument is that if we are to make the right decision on what are the best drugs – considering their safety, effectiveness and the balance of benefits they offer in treating conditions over their side-effects – we need to have all the evidence available.

The researchers have now made that assessment for Tamiflu in the prevention and treatment of flu. They have reviewed a phenomenal amount of material, and with the BMJ and the Cochrane Collaboration, have published their conclusions today. They call on government and health policy decision makers to review guidance on the use of Tamiflu in light of their new evidence.

They found that Tamiflu is effective – but it shortens symptoms of flu by only around half a day on average. And importantly, they say, there is no good evidence to support claims that it reduces complications of influenza or admissions to hospital.

Then there are the side effects. Using Tamiflu to treat flu, the evidence confirms an increased risk of suffering from nausea and vomiting.

When Tamiflu is used to prevent flu, the drug can reduce the risk of people suffering symptomatic influenza. But there was an increased risk of headaches, psychiatric disturbances, and kidney events.

The review authors, Drs Tom Jefferson, Carl Heneghan and Peter Doshi, conclude that there are insufficient grounds to support the stockpiling of Tamiflu for mass use in a pandemic. From the best conducted randomised trials, there just isn’t enough evidence on the crucial elements of reducing serious complications of flu that can lead to hospitalisation and death, and the prevention of spread of flu. On the other hand we know there would be side-effects.

Not all scientists agree on the assessment of the balance of benefits of these antivirals versus their side-effects. Virologist Professor Wendy Barclay at Imperial College London believes the shorter time that symptoms last is important: 'Although one day does not sound like a lot, in a disease that lasts only 6 days, it is…We have only two drugs with which we can currently treat influenza patients and there is some data to suggest they can save lives. It would be awful if, in trying to make a point about the way clinical trials are conducted and reported, the review ended up discouraging doctors from using the only effective anti-influenza drugs we currently have.'

Roche, the manufacturers of Tamiflu, fundamentally disagree with the overall conclusions of the Cochrane review and criticised some of the report’s methodology. In media reports, UK Medical Director Dr Daniel Thurley has said: 'Roche stands behind the wealth of data for Tamiflu and the decisions of public health agencies worldwide, including the US and European Centres for Disease Control & Prevention and the World Health Organization.'

Indeed, Roche have pointed to a large observational trial in the Lancet Respiratory Medicine that they funded which recently reported a reduction in deaths among those hospitalised with swine flu H1N1, though there are some who disagree with that analysis too.

So what to make of all of this? An editorial in the Guardian concludes: 'The only way to resolve the argument is proper science. That means transforming clinical trials, harmonising the way they are carried out. It has happened with malaria drugs, and it is happening with HIV. The industry must allow access to their data. Confident that like is compared with like, trials can then be subjected to meta-analysis, allowing statisticians to drill down into sub-populations to establish when a drug performs most effectively.'

The editorial points to the need to be able to react swiftly and carry out good research actually during pandemics, as former Oxford University professor and now director of the Wellcome Trust, Jeremy Farrar, argued in the paper last month.

What has really changed is the ability to have these discussions based on all of the evidence. There is a real shift in the level of scrutiny and the analyses that are now possible with access to all clinical trial data (although dealing with all these reams of data also brings new challenges too). That is a phenomenal change and a real achievement by the Cochrane researchers.

David Spiegelhalter, Winton Professor of the Public Understanding of Risk at the University of Cambridge, comments: 'This is a ground-breaking review. Since important studies have never been published, the reviewers have had to go back to clinical trial reports comprising over 100,000 pages: the effort to obtain these is a saga in itself. The poor quality of these reports clearly made extracting relevant data a massive struggle, with many pragmatic assumptions having to be made, but the final statistical methods are standard and have been used in hundreds of Cochrane reviews. Let’s hope that in future high-quality data can be routinely obtained and this type of review becomes unnecessary.'

MeerKAT is shape of things to come

Pete Wilton | 1 Apr 2014

In a remote semi-desert region of South Africa, the Karoo veld, what looks like a huge satellite dish has risen up to dominate the landscape.

But instead of tuning into TV this dish is the first part of a giant radio telescope called MeerKAT that will play a key role in the creation of the world’s largest telescope, the Square Kilometre Array (SKA).

Last week saw the official launch of this first dish of many, I asked Matt Jarvis of Oxford University's Department of Physics, one of the Oxford scientists involved in MeerKAT, about plans for the new telescope and where it will lead…

OxSciBlog: What is MeerKAT and why is it important?
Matt Jarvis: MeerKAT is actually made up of 64 dishes, each 13.5m in diameter. All of these dishes are connected to make up a single telescope that operates at radio wavelengths (around medium-wave for the people who still have analogue radios), much like a satellite dish but rather than receiving information from satellites it detects radio waves from astrophysical phenomena such as jets emanating from around black holes and sites of star formation. It is the precursor to the Square Kilometre Array which will extend MeerKAT from 64 to 254 dishes in around 2020, making it much more powerful.

OSB: What questions will MeerKAT investigate?
MJ: MeerKAT will detect radio waves from the distant reaches of the cosmos. It allows us to trace a range of physical processes that occur in the Universe, such has high-speed jets (moving at close to the speed of light) which arise from accretion around black holes, both in our own galaxy and from supermassive black holes in the centres of distant galaxies. It will also be able to detect neutral hydrogen gas, the fundamental building block of all the things that we can see in the Universe, from stars to galaxies, enabling us to determine how this gas gets turned into stars over the history of the Universe. By using the radio emission from these distant galaxies we will also be able to investigate the impact of Dark Energy and Dark Matter in the Universe and how these may evolve, possibly leading us to reassess how gravity acts on very large scale.

OSB: How are Oxford scientists involved in the project?
MJ: Oxford has a large involvement in MeerKAT. Two of the Large Surveys to be undertaken on MeerKAT are co-led by Oxford staff. I’m the co-PI of the deep radio continuum survey (MIGHTEE) to study how galaxies evolve over the history of the Universe and Rob Fender is the co-PI of the THUNDERKAT survey which aims to detect all of the phenomena which go bang, such as stars colliding together, bursts of radiation when a star dies and accretion events on to a black hole. We have also been involved in some of the technical development for the receivers on the dishes.

OSB: How will work with MeerKAT feed into SKA?
MJ: MeerKAT is essentially a stepping stone to the SKA, in terms of both science and engineering. The work we will do will set the stage for the SKA to really move us forward into a whole different regime of radio astronomy. MeerKAT will be a fantastic facility in its own right, providing us with the most sensitive radio surveys in the southern hemisphere, however, the SKA will be able to take such surveys and expand them by an order of magnitude in sensitivity and ability to map large volumes of the Universe. From a more technical perspective, the lessons learned from constructing MeerKAT will feed into the design specifications of the SKA, and will also mean that we can test new algorithms to turn the raw data into scientifically useful maps and catalogues for use throughout the community.

OSB: What are the challenges of dealing with data from MeerKAT/SKA?
MJ: The main challenges are the sheer data volume that we need to handle. For example, we are unable to store the raw data coming from the telescope, and have to reduce it very quickly in order to keep up with the observations. This requires a large effort in data transport, supercomputers and having the necessary computer code to handle the data effectively.

OSB: What is the next big milestone in MeerKAT's progress?
MJ: The next big milestone will be when there are 16 dishes on the ground and all hooked up. This will then enable us to start carrying out the science, before the whole 64 dishes are in place. This is something quite unique to radio astronomy, in that we don't need the whole telescope to start doing some of the science.

Why males stray more than females

Pete Wilton | 24 Mar 2014

Do males have more to gain than females from mating with additional partners?

The theory that they do, and that this can help to explain different sex roles observed in the males and females of many species, is known as 'Bateman's principles', named after the work of English geneticist Angus John Bateman.

In a recent study reported in Proceedings of the Royal Society B a team, led by Oxford University researchers, investigated Bateman's principles in relation to populations of red junglefowl (Gallus gallus), the wild ancestor of the domestic chicken.

'Bateman's principles state that males are more variable than females in the number of offspring they produce and number of sexual partners,' explains Dr Tom Pizzari of Oxford University's Department of Zoology, one of the research team. 'This leads to a stronger relationship between number of offspring and number of partners in males than in females. In other words, males gain more reproductive success by mating with additional partners than females do.

'This difference is explained by the fact that males produce orders of magnitude more sperm than there are eggs available for fertilisation, so their reproductive success is strongly limited by female (egg) availability. Females on the other hand tend to produce a smaller number of larger eggs, and generally mating with additional males does not influence the number of eggs that a female can afford to produce.'

To test the principles the team studied groups of red junglefowl and carefully recorded all mating events and assigned parentage to every offspring produced. They then ran experiments to test the relationship between reproductive and mating success.

'Studying Bateman's principles properly presents many challenges,' Tom tells me. 'First, detailed information on mating success (who mates with whom) is required. Previous studies did not measure mating behaviours, but simply inferred who mates with whom based on parentage of the offspring. This approach however, misses out all those mating events which failed to result in fertilisation.

'Second, Bateman's principles are concerned with how males increase their reproductive success by mating with additional females. However, there are other pathways through which males can increase the number of offspring sired: mating with particularly fecund females, and defending their paternity in sperm competition. Again, most studies so far have explored Bateman's principles without controlling for these alternative pathways.

'Finally, one must be very careful about how to interpret a positive relationship between reproductive success and mating success in females. One possibility is that females genuinely increase the number of offspring produced by mating with additional males, another is that females that are inherently more fecund are more attractive to males and so end up with more partners.' 

The new study showed that in failing to address these challenges traditional approaches can lead to very drastic biases in estimating Bateman's principles and that future research in this area should combine independent data on mating behaviour, multivariate statistics, and experimental tests.

'Our results suggest that once these biases are controlled for, Bateman was essentially correct: males gain more reproductive success by mating with additional partners than females, however these sex differences are much smaller than estimated by traditional methods,' Tom comments.

'This means that males are more strongly selected to compete over access to mates than females, explaining why sexual selection is typically more intense in males, providing an answer to Darwin's original question of why it is males that often display more exaggerated traits in a species.'

How short is your time?

Jonathan Wood | 19 Mar 2014

Our perception of time can depend on a number of factors – what we’re doing, how much we’re focusing on it, how we’re feeling. But there's also quite a bit of variability between us in our individual sense of time passing.

Researchers at Oxford University have investigated what plays a part in our perception of short, fleeting times of under a second.

In a new paper published today in the Journal of Neuroscience, they show that levels of a chemical in the brain – a neurotransmitter called GABA – accounts for some of the difference in our perceptions of subsecond intervals in what we’re seeing.

Oxford Science Blog asked Dr Devin Terhune of the Department of Experimental Psychology about the study. So depending on who you are and your judgement of time, if you have somewhere between 2 and 5 minutes to spare, read on.

OxSciBlog: Why is perception of time important to understand?
Devin Terhune: Our ability to perceive duration is one of the most fundamental features of conscious experience and thus it is of great importance to our emerging understanding of how the brain generates consciousness. Second, time perception is necessary for a wide range of abilities, from playing sports and musical instruments to day-to-day decision-making. Studying time perception has considerable potential to greatly inform the broader domains of psychology and neuroscience.

OSB: What can influence time perception?
DT: A variety of factors can affect our perception of time. Two common factors are attention and emotion. If we focus on something, time seems to slow down somewhat (hence the common phrase 'a watched kettle never boils'), whereas it seems to go by faster if we're daydreaming or thinking about something else. In contrast, we tend to overestimate time when we’re frightened, or underestimate it when we’re experiencing joy.

OSB: Tell us about the sort of time perception you investigated in this study
DT: We studied people's perception of short durations of visual images lasting around half a second.

In the specific task we used, participants were first trained on a particular image that lasted around half a second. Subsequently, they saw the same image for a range of different intervals – some shorter, some longer. Participants were asked whether each image was shorter or longer in duration than the trained interval. This task allowed us to determine whether someone is underestimating or overestimating the duration of the images, as well as their precision in the task. 

OSB: And this judgement of time can be affected by the way neurons in the brain respond to what we are seeing?
DT: A number of studies have recently shown that when neurons in visual regions of the brain 'fire' more strongly, a person is more likely to overestimate the duration of a visual event, whereas when the neurons 'fire' less, they are more likely to underestimate the event. Accordingly, different ways of altering these firing responses may thus affect time perception.

OSB: What did you find?
DT: Our study showed that participants' tendency to under- or over-estimate how long the image lasted was associated with a particular neurotransmitter in the brain known as GABA.

Individuals who tended to underestimate the visual intervals were found to have higher GABA levels in the region of the brain responsible for visual processing.

Importantly, GABA levels in a second region of the brain that supports movement and motor functions were unrelated to time perception. Also, GABA levels in the visual area were unrelated to time perception in a non-visual task.

These results suggest that GABA levels in visual regions of the brain may account for variability in our perception of visual intervals.

OSB: What does this suggest is going on in the brain?
DT: We believe that higher GABA levels results in a greater reduction of the firing of neurons in response to a visual image, leading to underestimation.

OSB: Do we as individuals really differ in how we perceive time and events?
DT: It's intuitive to think that our perception of the world is similar to others, but just like many other conscious visual experiences, there is considerable variability in our ability to perceive time. This variability is more apparent for longer intervals – for instance, we all have friends who say they were only gone for two minutes when it was actually closer to ten. This variability is present for very short intervals too.

OSB: Could this tell us anything about our perception of time in everyday situations?
DT: This finding may account for why some people are better at judging very short durations than others. Since we used particular types of images in the lab, we have to be careful about how much we can generalize. However, these very short intervals are important to a range of tasks. For instance, running to catch a ball requires you to estimate when the ball will arrive in a particular location that you can reach. Similarly, when playing a musical instrument as part of an orchestra or band, it is important that you can accurately judge the specific time at which you need to play a particular note.

OSB: Is it wrong to feel slightly unsettled that what we experience and think to be an accurate representation of time passing may not be?
DT: At first glance, it could be somewhat unsettling. However, in the grand scheme of things, the vast majority of people have decent time perception. It's just that some of us are better than others, just like in a range of other cognitive, motor, and perceptual functions. Some of us have better attention or memory than others, some of us are better at riding bicycles, and so on.

Sex, skinks, and personality

Pete Wilton | 13 Mar 2014

When it comes to spatial learning males are better than females, and bold and shy individuals are better than average ones, at least if you're a lizard.

The findings, from a new study of the Easter Water Skink (Eulamprus quoyii) - a lizard that lives throughout Eastern Australia and can grow over 12cm long - are the first evidence of sexual learning differences in a reptile. A report of the research is published in this week's Proceedings of the Royal Society B.

A team led by Oxford University and Macquarie University, Sydney, scientists took 64 skinks, 32 males and 32 females, and released them into a series of strange environments to investigate how differences in personality influence how they learn. These environments included features they would like, a 'warm' refuge made of a box with three entrances heated by an incandescent bulb, and features they wouldn't, a 'cold' refuge made of a similar box chilled with ice packs.

By introducing the skinks to simulated predator events (being chased away into a refuge) the researchers determined which returned quickly to bask in a warm refuge ('bold' lizards) and which took longer than average to return ('shy' lizards). They then tested the lizards once a day for 20 days in a setting where they were again exposed to simulated predatory attacks and given a choice between a safe refuge (chasing stopped) and an unsafe refuge (the refuge was lifted and chasing continued) that were always located in the same place.

'We found that male lizards were better at this spatial learning task than females, with twice as many males as females learning the spatial task within 20 trials,' explains Pau Carazo of Oxford University's Department of Zoology, who led the research.

'While this is the first evidence ever of sexual learning differences in a reptile, we believe it reflects the fact that males are forced to spend more time moving through their environment in search for females or patrolling their territory to guard it against other rival males. We also show that, across the sexes, the boldest and shyest individuals were overall better learners than intermediate individuals.'

According to the team this is the first evidence that individuals at the extreme ends of a personality axis are better learners than individuals with intermediate personality traits. This does not fit well with current theories about how personality and learning may co-evolve: the team proposes the idea that spatial learning ability and personality are both linked with male reproductive strategies.

'In Eulamprus, as in many other lizard species, male lizards exhibit two alternative reproductive strategies. Some male lizards defend territories, which not only requires them to be bold but also to constantly patrol their territory and remember rival males at its boundaries (which would favour good spatial learners),' Pau tells me.

'In contrast, other males adopt an alternative sneaker strategy whereby they are forced to navigate over long distances (which would also favour good spatial learning abilities) to sneak into other males' territories and try to mate with resident females. Because these males do not defend territories and normally avoid fights, they are likely to be shy.

'We suggest that males that are particularly good at either of these two strategies are likely to be good spatial learners and are either extremely bold or extremely shy individuals. This new hypothesis may help to explain how personality and learning co-evolve, and to understand the evolutionary processes that may lead to the striking individual differences in learning than can be observed in most animal species studied to date.'

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