Wednesday, October 15, 2014

Untested Treatments for the Current Ebola Outbreak

Using Untested Treatments

Given that we have no specific treatment for Ebola virus disease (EVD), and given that the doubling rate for incidence in West Africa is about 4 weeks, it is clear that urgent action is required. Much effort is rightly being put into health education and the community response, and the British Government’s input in supplying money has been exemplary.

This paper relates specifically to the medical response. It is very clear that we need to step outside of normal treatment development protocols and test any treatment that offers a reasonable, if at first theoretical, possibility of assisting recovery from the disease. Normal protocols for drug development are rightly detailed, precautionary and protracted, taking months or years before a treatment can be offered to patients. This approach is not appropriate to the current Ebola crisis. The medical profession must be enabled to step outside of the normal system of treatment assessment and deploy untested treatments, “off-license”, but in an orderly way so that the benefit or disbenefit of any treatment can be discovered. Specifically, doctors need to know that they are not at risk of being sued if a patient who has been given an untested treatment dies.

This approach can legitimately be used in the UK on a “Named Patient Basis”, and in the USA under the “Expanded Access Programme”.

Ideally, experimental treatments should be assessed in Randomised Controlled Trials (RCTs), but in the situation on the ground in Africa, this may not be possible. In this case, simple audits of treatments may be used instead.

Prioritising health care staff
If medications are in short supply, they should be reserved for health care staff who may become infected with EVD.

There are three reasons for this:

First, the staff will be able to give informed consent to the treatment, understanding that it has not been fully tested.

Second, healthcare staff need to feel that they have an improved chance of recovery in case they become infected. Without this job-related bonus, there is a possibility that morale may fall to a point where they simply stop coming to work. If supplies permit, their family may also be offered vaccination, in order to help overcome the fear of contamination from the worker that some families show.

Third, the staff will be able to be followed up and monitored for side effects and for blood tests.

Treatments available

There are two broad categories of treatment: Vaccines (active and passive) directed at the virus itself, and those directed at the cytokine storm that is the cause of the high morbidity and mortality of Ebola.

Vaccines exist for Ebola which have been shown to be effective in animal studies. Some take 6 months to produce immunity, but others produce antibodies within 28 days. Health care staff (and if possible, their families) should be offered vaccination on a voluntary basis as and when they become available.

ZMapp is a monoclonal antibody that provides passive immunity by attacking the Ebola virus. It has been effective in rhesus macaque monkey trials, but has not been in human trials. It is produced by a genetically modified tobacco plant, and supplies ran out in August 2014, after 7 patients had been treated. Of those seven, 5 recovered, 2 died. This compares favourably with 2 recoveries and 5 deaths that would be expected from the untreated population, although of course the number of cases treated is far too small to be of any statistical significance.

The use of ZMapp in these cases sets an important precedent for using untested treatments in this present crisis.

Treating the Cytokine Storm

Cytokine storm can be seen as an over-reaction on the part of the immune system. A positive feedback loop forms between cytokines released at the site of infection which attract more defence cells, which produce more cytokines. It is this that causes Ebola infection (and, incidentally, other viral infections such as SARS and high-morbidity influenza such as type H5N1) to have such high mortality.

Several approaches have been put forward for reducing cytokine storm:

1. OX40 is a protein secreted by T-cells that keeps them from dying, and therefore perpetuates the feedback loop. OX40 IG is a synthetic immunoglobulin that neutralises this protein. It has been shown to be effective in mice. It was tested in 2003, but its present availability is uncertain, and its cost is likely to be high.

2. Simvastatin and Gemfibrozil, both lipid-lowering drugs in common use, have been shown to have an effect in reducing the cytokine response. In the case of Simvastatin, an effect has been shown in humans, albeit not in acute infection.

3. ACE Inhibitors and Angiotensin II receptor blockers are medications in common use against hypertension. They have been shown to reduce the cytokine feedback loop especially in lung conditions.

4. TNF Blockers are medications routinely used in arthritis and other inflammatory conditions. They may have a role to play, but are relatively costly.

5. Naltrexone, an established opioid receptor antagonist, may inhibit cytokine storm. There is evidence from animal studies that it may be clinically effective. It is inexpensive.

6. Antioxidants such as Ascorbic acid may have a role to play in reducing the adverse effects of cytokine storm.

Note that the latter five groups of medicines are already in use, and therefore have been tested for human acceptability. They are also low-cost. Their side effects are known. It is true that we do not know what happens when they are used in patients infected with the Ebola virus, but the only way to find out is to test them. They may have adverse effects in the given situation, they may have no benefit, but equally, one or more of them may prove helpful, and the exercise will be worthwhile – even, possibly, game changing.

In conclusion, there are several modalities of treatment for Ebola that must be tried in the present outbreak. Their deployment will be “off-licence” and their effectiveness must be monitored, but to forbid or delay their use because they have no official license to be used in this condition would be unethical and irrational.

A fully referenced version of this paper will be available shortly

Tuesday, October 14, 2014

20 locations where health problems are associated with low level radiation around nuclear power stations

This is a list I compiled years ago, back in the days of pen and paper, when I began green activity with the anti-nuclear movement. I have not kept up with it, but have been refreshing my knowledge because I have been invited to speak to some Italian journalists who are coming to meet the Stop Hinkley campaign.
Here is a list of places where man-made radioactivity is associated with cancers. In every case, the nuclear industry will dispute the connection. Taken together, it is hard for them to deny that a pattern has emerged.

1. Leiston - 14 leukaemia cases near Sizewell A. Workers - 8 times the expected level.
2. Lydney - 6 cases near Oldbury & Berkeley
3. Dorset - cases near Winfrith
4. Southport near Springfields
5. Menai straits
6. Burnham - excess breast cancer cases &c
7. Hunterston in West Scotland, leukaemia 1975-81 double the expected rate
8. Chapel Cross
9. Chernobyl
10. Sellafield - four times more childhood leukaemias than expected.
11. Dounreay : leukaemia 1979-84 among under-25s within a 7 mile radius of the plant 10 x the national average
12. Aldermaston
13. Winfrith
14. Holy Loch
15. Rocky Flats
16. Nuclear workers prostate cancer (BMJ)
17. Downwinders : Nevada, Hanford,
18. Marshall Islands - after nuclear bomb tests.
19. Cap La Hague
20. Mainz study - double risk Leukaemia for children 5km from Nuclear Power Stations.

Communicating with the Nuclear Power Industry

I am having a lovely afternoon on the phone.

I am researching health problems around Hinkley point nuclear power station.

There is an increased  incidence of cancer of blood breast, prostate, and lung cancer, along with increases in perinatal mortality, greater in proximity to the mud flats where the Hinkley radioactive discharges are deposited. The infant mortality problems spike in 1996, suggesting an event in the previous years.

Hinkley was fined £22,000 for a discharge in October 1994 from a unit designed to hold back radioactive Iodine. 2 tonnes of radioactive CO2 were released to air, and I want to know if there were leaks to water also.

So I pick up the phone:

  1. Hinkley EDF refer me to their Press Office
  2. EFD Press office takes a recorded message, and refers me to their customer "care" line.
  3. EDF Press refers me to the Nuclear Decommissioning Authority (NDA)
  4. NDA will call back.
  5. NDA call back, suggests Public Health England
  6. Public Health England suggest the Office of Nuclear Regulation or Magnox
  7. Magnox is in Out Of Hours mode (it is 12:34 hrs on a Tuesday)
  8. ONR number gives me another number within ONR. I reach a grumpy-sounding  man who puts me back to switchboard and the line goes dead.
  9. Phone back in to ONR who put me through to a nice lady who asks me to put it in an email.
  10. Which I have done
  11. Magnox have phoned to confirm what it is I want (15:42)
  12. 15:50 Email from ONR: Try the Environment Agency
  13. 17:32 Nice lady from Magnox says will get back to me tomorrow.

Wednesday, October 08, 2014

Climate Science & Falsifiability

This piece is copied with permission from Philosophy Now, a non-peer reviewed magazine of philosophical ideas. I am hoping that it will help to shift the debate on climate change to a focused, critical examination of the hypothetical stance of those who believe that man-made Carbon Dioxide will not seriously affect the global climate.

Richard Lawson shows how Karl Popper can help settle the climate debate.
Policymakers worldwide face a major headache relating to energy strategy. On the one hand, most climate scientists are warning that we must make a radical change away from reliance on carbon-based fossil fuels in order to avoid a catastrophic long-term change in global climate. On the other hand, the politicians are intensively lobbied by, and sometimes financed by, immensely wealthy and powerful fossil fuel corporations. Moreover, many popular newspapers and influential commentators are sceptical of prevailing climate science, and there is an active and noisy campaign against climate theory by contrarians in the social media. The electorate is of two minds; they do not like the apparently abnormal kinds of weather they are experiencing, but neither do they like the idea of the higher fuel bills or taxes that may be forced by decarbonisation. Small wonder that politicians have gone quiet on climate change.

Philosophers may not find this a particularly attractive arena to step into, but we have a moral duty to help unlock the truth about climate change if we can. And we do possess a key, in the form of the principle of falsifiability set out by Karl Popper in his book The Logic of Scientific Discovery (1934).
black swan
A black swan
Photo © Grant Bartley 2014
Earlier, logical positivists such as A.J. Ayer had argued that for a proposition to be meaningful, it must in principle be capable of proof (‘verification’). But Popper argued that the hallmark of a genuinely scientific proposition is not that it can be verified (because no number of observations can conclusively prove a hypothesis), but that the proposition can in principle be disproved (‘falsified’). For example, the proposition ‘All swans are white’ cannot be proved no matter how many swans you see; but it can be disproved by seeing just one black swan.

Popper & Kuhn

Is Popper still popular? W.V.O. Quine was happy to endorse falsification, although he modified the principle to make allowances for the quality of data purporting to overthrow a hypothesis, and to allow that new findings might simply force a modification of a hypothesis rather than its absolute refutation – with which idea Imre Lakatos agreed. But Thomas Kuhn in The Structure of Scientific Revolutions (1962) instead described the historic processes science follows: a consensus position or paradigm prevails in some area of science, but will eventually be overthrown by some radically new paradigm.

Both sides of the climate debate have availed themselves of Kuhn’s ideas. Climate contrarians have tried to present themselves as overthrowers of the prevailing climate science paradigm. However, there is more to being a Galileo than merely objecting to the prevailing consensus. It is necessary to possess a convincing and powerful alternative theory, and with the contrarians this is not the case, as we will see.

Indeed, the prevailing climate science might itself be characterised as having overthrown an old way of thinking. Soon after Svante Arrhenius first raised the possibility of an anthropogenically-enhanced greenhouse effect in 1896, Anders Angstrom argued on the basis of a simple laboratory experiment that the effect of carbon dioxide in absorbing infra red energy was very limited. Angstrom’s view prevailed until the 1960s, when it became understood that convection processes within the atmosphere means that his argument does not hold up. So it can be said that the contrarians represent the old paradigm; and indeed, Angstrom’s argument is still a core talking point in the contrarian community.

Not that this has much to do with the validity or otherwise of either side’s argument. In essence, Kuhn’s theory has more to do with the sociology of science than with its content. However, Kuhn did emphasise criteria for choosing one scientific theory over another: accuracy, consistency, broad scope, simplicity, and fruitfulness. Popperian falsifiability is implied by Kuhn’s first criterion – accuracy.

It is of course only too true that social and psychological factors influence what scientists accept and believe, but this is peripheral to the core of science. It’s what scientists might call ‘noise’. The central matter, the ‘signal’, is our changing understanding of objective reality, which scientists encounter as data, and data is still what they have to deal with. We can conclude that the refutation of theories through contrary data remains at the heart of the scientific method.

The Paradox of Science

Karl Popper (1902-1994)
Popper’s falsifiability principle implies that, contrary to popular misunderstanding, there is no such thing as scientific ‘proof’. The best status that even the best scientific theory can attain is ‘not-yet-disproven’. Even the most durable and revered laws, such as Newton’s laws of motion, may find extreme conditions where they no longer apply. (This does not necessarily mean that the old law is completely overthrown, but rather that its area of application becomes circumscribed.)

This absence of final, definitive proof creates a paradox: science, which we rightly regard as the most certain form of knowledge of the world, exists in a continuous state of uncertainty. In their daily lives scientists are perfectly happy with this uncertainty, not least because each new research paper can truthfully be concluded “More research is needed” – hopefully ensuring a continued supply of funding, and certainly ensuring a continued arena in which they can exercise their curiosity.

The paradox of science can be exploited in the media by opponents of any scientific case, who are able to challenge unwelcome scientific knowledge by saying, “Prove it to me! There you are, you see, you cannot!” The scientist can put forward his evidence; but unfortunately most scientists are trained to be meticulous, and meticulous exposition does not sit easily with the standard two minute popular media discussion.

This then is the predicament in which climate scientists find themselves. They can put forward the evidence, but they cannot force their audience to agree with them. They can point to the fact that carbon dioxide is a greenhouse gas, that its levels in the atmosphere have risen by 40% since the Industrial Revolution, and that we can only account for the recent rise in global temperatures by including the enhanced greenhouse effect alongside known natural factors such as solar variability and ocean currents. They can point to the observed patterns of warming as consistent with warming due to greenhouse gases in contrast to other possible causes of warming. But in the end, the reasoning is inductive, not deductive. It is not proof. To be persuaded, the listener has to recognise a pattern that satisfies a number of questions and agrees with a large number of different lines of evidence. But in the end, no person can be compelled to make an inductive judgement that he or she does not wish to make. A creationist cannot be compelled to believe the evidence of evolution, for example.

This leaves climatologists with a problem. They can make a coherent and reasonable case, presenting the facts to decision-makers. But the decision-makers can also imagine the angry cries of the climate contrarians, and the sound of strife frightens them. They ask the scientists for proof, and all the scientists can say is that further research will narrow down the uncertainties. The only way for the politician to stay in his comfort zone is by deferring the decision to act against carbon-based energy – thus allowing the situation to get worse, forcing the next set of decision-makers to face even more difficult decisions. So the controversy rolls on, with the machinery of climate contrarianism every week putting forward another question to create doubt in the minds of the public, journalists and politicians. A few climatologists and activists devote their free time to answering them, but it is like fighting a Hydra: answer one question, and two more spring up to take its place.

Disproving the Doubters

Is this how it has to be? Can a handful of dissidents, using the megaphone of mass media, sustain inaction on a process of global warming that might well end in disaster for the human species?

Philosophy has revealed the means to resolve this problem. Science may not do proof, but it certainly does do disproof. So although it may not be possible for climatologists to prove their case conclusively, itis possible to look at the contrary hypothesis and refute it. And the contrarians do have a hypothesis: it is that man-made carbon dioxide will not have a severe effect on global climate. This angle transforms the debate into a question about the degree to which the global climate will change given the known increase in greenhouse gases.

There is no reasonable doubt that, ignoring feedback mechanisms, a doubling of carbon dioxide will raise the planet’s surface temperature by about 1.2°C, because this fact is derived from calculations based on universally accepted textbook physics, and is accepted by climatologists and reasonable contrarians alike. The real debate is about climate sensitivity – or what will result from this 1.2°C rise. The Earth’s climate is a complex system of interrelated energy flows, and any warming will result in an array of changes in the system. Most of these changes provide positive feedbacks – that is, they will further increase the initial warming. A number of different lines of evidence drawing from known or deduced changes in global temperature, recent and palaeological, all converge on an eventual temperature rise of between 1.5-4.5°C, with the most likely value being 3°C. Against this, classical climate contrarians put forward a value of 0.5-1°C as their figure for the final temperature increase resulting from a doubling of atmospheric carbon dioxide concentrations. This is their hypothesis; and it is refutable through measuring and calculating the known positive feedbacks – increase in atmospheric water vapour, changes in ice and snow albedo (reflectivity), changes in vegetation, and from secondary releases of carbon dioxide and methane from soil and ocean. The main negative feedbacks (temperature reducers) are a change in heat distribution in the atmosphere, which can be calculated as slightly reducing the positive water vapour feedback, and an increase in total energy radiation from the warming Earth (a feedback which probably sets a limit to extreme planetary overheating). Several attempts have been made by sceptical climate scientists to substantiate their 0.5-1°C warming hypothesis, but each of these has ended in failure. Contrarian scientists placed their faith in clouds to provide a strong negative feedback, for instance, but recently, measurements by Andrew Dessler have shown that the net effect of clouds is more positive than negative (see Science, Vol.330, 10 December 2010).

Perhaps as a result of realising the unsustainability of the idea of ultra-low climate sensitivity, a small sub-set of climate sceptics has emerged recently, the ‘lukewarmers’, who argue for a figure somewhere below that of the consensus view but above that of the classical contrarians. However, given that their evidence base is much smaller than the evidence for higher climate sensitivity, this group is in a very weak position to claim that there is no need decarbonise the global energy supply.

In conclusion, despite the complexity and ongoing uncertainty in understanding the future effects of greenhouse gases on the climate system, one thing is certain: the hypothesis that the effect of carbon dioxide and other greenhouse gases is trivial and warrants no action simply does not hold up. It does not match the facts. It has been refuted. Journalists may not be able to understand science or the philosophy of science to any great depth, but they can understand the concept of ‘disproven’, and climate scientists can indeed disprove the contrarian hypothesis that greenhouse gases will have no significant effect on the global climate.

© Dr Richard Lawson 2014