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Biomedical research: the gender dimension

1 Aug

Dr Elizabeth Pollitzer, Director of Portia, recently wrote to the Financial Times.

Portia was established by a group of female scientists working at Imperial College, to respond to government concerns about under-representation of women in Science, Engineering and Technology.

Portia’s mission is to help women and men have the same opportunities for engagement and advancement in science, across all science disciplines, and to further the understanding and appreciation of the gender dimension in science knowledge making.

Dr Pollitzer responded to Anjana Ahuja’s article: “Britain must stop inflating the biomedical bubble” (July 17, probable paywall) which highlighted the issue of the failure of biomedical industry to translate the huge investment in research into improvements in the quality of medicine.

She pointed out that in 2014, following problems in replicating early pre-clinical studies and differences in efficacy and adverse effects of drugs in women and men, the US National Institutes of Health called for gender to be taken into account in study design and data analysis.

Between 1997 and 2000, ten prescription drugs were withdrawn from the market in the US; eight were judged to be more dangerous for women than for men.

Dr Pollitzer continued:

“Gene expression, immune response and how drugs are metabolised have been shown to differ between women and men. Taking into account these basic biological differences would improve the rigour, transparency and generalisability of pre-clinical research findings.

“Biomedical research has historically relied on experiments that used significantly more males than females as subjects (cells, tissues, animals, people) creating bias in fundamental knowledge of disease processes”.

She ends by saying that this research bias has an impact on how disease outcomes and responses to treatment are determined, resulting potentially in poorer quality of results for women.

Elizabeth Pollitzer has 20 years’ experience teaching and researching in the Department of Computing at Imperial College, University of London. Her original training was in Biophysics. She now applies this scientific background to promoting effective strategies for gender equality in Science, Engineering and Technology.

 

 

 

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Weigh the value of new ‘tools’; apply the precautionary principle

3 Jun

There is mounting evidence of unintended harmful consequences in many sectors – including medicine, pharmacology, agriculture, energy generation, finance, engineering and transport. The most widely read post on this site in May reported the Lancet’s publication of the World Health Organisation’s finding that glyphosate, a widely used ingredient in weedkiller, is probably carcinogenic.

Michael J. Coren‘s article in Quartz magazine summarised the findings of Jameson Wetmore, an engineer turned social researcher at the Arizona State University’s School for the Future of Innovation in Society. Wetmore opened:

“The motto of the 1933 World Fair in Chicago was “Science Finds, Industry Applies, Man Conforms. Governments and companies were saying that technology can lead us out of this. It may not always be comfortable, but we have to ride it out. Household technologies were all the rage. When you hit the 1960s and 1970s, there is this shift.

“I think the hallmarks of that shift are the dropping of the atomic bomb, and then of course you have Ralph Nader’s Unsafe at Any Speed, and you also have Rachel Carson’s Silent Spring”.

“Whereas much of the contemporary world sees technological progress as inevitable, even a moral imperative, Wetmore finds that the Amish watch their neighbours and carefully consider how each one will change their culture before embracing it: They . . . watch what happens when we adopt new technology, and then they decide whether that’s something they want to adopt themselves.”

We don’t think about the impact technology might have on our lives beyond the initial big idea.

“The automobile was sold to us with this idea of a freedom we never had before. With that freedom came a heavy toll of injury and death. So can we anticipate unintended consequences way the Amish do, or are these systems just too complex to go much beyond first-order effects?

A more rigorous application of the EU’s Article 191 (left) would help to do this.

“Less than a mile from where I’m standing [in Phoenix, Arizona], Elaine Herzberg was killed by an autonomous Uber vehicle. I fully recognize the only way we’re going to automated vehicles is running in this world is to test them on city streets. Now, if we were to sit back and think about the values of the society here, we might say that testing those vehicles at 10 PM at night outside of a concert hall where a huge amount of alcohol had been served was not the best place to be testing. Perhaps testing in a school zone when children are present is not the best place to test an autonomous vehicle. But those are decisions that local people did not have the chance to make.”

The idea that technology is an unmitigated good is beginning to be questioned

Wetmore thinks that today Americans have a much more nuanced view of things. The number of people who think technology is an unmitigated good is continuing to shrink, but most haven’t abandoned the idea that there are a lot of problems and technology will play a role in solving them.

The precautionary principle detailed in Article 191 of the Treaty on the Functioning of the European Union aims at ensuring a higher level of environmental protection through preventative decision-taking in the case of risk. It also covers consumer policy, European Union (EU) legislation concerning food, human, animal and plant health. It has been recognised by various international agreements, notably in the Sanitary and Phytosanitary Agreement (SPS) concluded in the framework of the World Trade Organisation (WTO).  

Jeremy Corbyn led the proposal (right) to retain Article 191’s environmental principles after exit day, narrowly defeated by 16 votes.

 

Time for change?

 

 

 

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Probe launched into dengue fever vaccine

29 Dec

Dengue Fever Swept Southeast Asia in 2013 and in February 2016 Sanofi Pasteur, the vaccines division of France’s Sanofi SA, made Dengvaxia, its vaccine for dengue fever, widely available in the Philippines. Sanofi said the vaccine had later been launched in ten other countries: Brazil, Mexico, Costa Rica, Indonesia, Guatemala, Salvador, Peru, Singapore, Paraguay and Thailand.

Dengvaxia was said to have been recommended for use by the World Health Organization in April 2016 – but WHO denies this.

In a July report, the World Health Organization noted that the vaccination “may be ineffective or may theoretically increase the future risk of hospitalized or severe dengue illness” in those who have not had dengue at the time of vaccination.

After a fast-track approval process more than 730,000 people, mostly children older than nine, were given the vaccine, manufactured by the vaccinations division of French pharma giant Sanofi SA.

However, Jake Maxwell Watts, writing in the Wall Street Journal on December 4th, reports that the Philippines has suspended the Dengvaxia dengue fever vaccine. An investigation has been launched, after evidence showed it could worsen symptoms in some cases.

Representative of Paris based pharmaceutical company Sanofi-Pasteur, Thomas Triumphe Head for Asia Pacific, answers questions during the senate inquiry on the Dengvaxia vaccine

Sanofi said new data found the vaccine was effective for people who had already had dengue, but not for those who hadn’t. Regulators have now been asked to change the vaccine label to recommend that people don’t take the vaccine if they haven’t been infected previously to avoid developing a more severe form of the disease.

The government has suspended its vaccination program. Though no deaths or cases of severe dengue have been definitely linked to the vaccine, some politicians have pointed to cases of children who have died since receiving it.

Philippine Health Secretary Francisco Duque III told local media that the government would assess responsibility for the vaccine, which was approved under the previous administration, and consider charges against its manufacturer.

 

 

 

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Valproate: rely on self-regulation?

29 Sep

The advisory European Medicines Agency – which has no legal power – is examining the effectiveness of Valproate warnings

Valproate is an anti-epilepsy drug first licensed in the UK in 1975. Taking the drug during pregnancy had – for some years – been suspected by epilepsy experts to have a strong link with the development of ‘dysmorphic features’ – such as eyes set wider apart and a thinned upper lip – in children born subsequently. They also suspected that valproate use in pregnant mothers might lead to longer term developmental problems – but the evidence for this was anecdotal at the time. More evidence emerged throughout the 1990s. In 2005, UK patient information leaflets included concerns about delayed development in children.

In 2004 the New Scientist reported that a study (BMJ reference: Journal of Neurology, Neurosurgery and Psychiatry (vol 75, p 1575), led by Dr Naghme Adab from the Walton Centre for Neurology and Neurosurgery, Liverpool, UK, showed that children born to mothers who were on valproate when pregnant were eleven times more likely to have a verbal IQ score of 69 or below, compared with children born in the general population. To read the statistics and percentages click on the link above.

The researchers added that their results could have been partly skewed because only 40% of the mothers contacted for the study actually responded – mothers who cooperated might be more likely to believe their children were harmed by anti-epilepsy drugs. They added, however, that even if it is assumed the other 60% of children all had normal IQs, the children of valproate users would still be twice as likely to have a low IQ (below 79) than the general population.

“Epilepsy is the second most common cause of maternal deaths,” Tim Betts, a neuropsychiatrist at the University of Birmingham UK, told New Scientist. He warns that women should not stop taking prescribed anti-epilepsy drugs during pregnancy without consultation, and adds that safe alternatives are available. “When we see women before pregnancy we invariably try to get them off valproate,” he says.

Instructions for doctors – and, more recently, patient leaflets – say valproate should not be used during pregnancy unless there is no safer alternative and only after a careful discussion of the risks. The medicines regulator said warnings had been updated as more information had become available. Many women whose babies were affected say nobody warned them of the extent of the dangers. Warnings were only added to the outside of valproate pill packets in Britain last year.

Humane French politicians put Britain’s business friendly government to shame

In France, 1,200 families are preparing to sue the drug manufacturer, accusing it of failing to sufficiently inform women of the risks. The French government is supporting the legal action and has put aside about £9m (€10m) to compensate the families.

By contrast in 2010, families in England and Wales had to abandon a court case when their legal aid was withdrawn three weeks before the case was due to begin. They signed letters promising never to sue again, and in return were not billed for Sanofi’s multi-million pound legal costs. They are now calling for a judge-led public enquiry. An article on a BBC website this month adds that about 20,000 babies in the UK alone have been left with disabilities since valproate was introduced in the 1970s.

It also reports that women whose children have been harmed by the epilepsy drug sodium valproate are giving evidence to a European-wide safety review in London. The European Medicines Agency will examine whether warnings about risks to unborn babies are strong enough. Reuters reports that a  final recommendation is expected in December.

 

 

 

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Science, precaution, innovation: learn tragically ‘late lessons from early warnings’

30 Jul

 

Glyphosate herbicides, harmful pharmaceuticals, infected blood transfusions, mercury preservative in infant vaccines, organophosphate insecticides, GM technology and fluoridation of the water supply . . . the damage to human and environmental health has been incalculable.

pprof mcgladeAs Professor Jacqueline McGlade, Chief Scientist and Director of the Division of Early Warning and Assessment of the United Nations Environment Programme, said in her preface to Late lessons from early warnings: science, precaution, innovation:

“There is something profoundly wrong with the way we are living today. There are corrosive pathologies of inequality all around us — be they access to a safe environment, healthcare, education or clean water. These are reinforced by short-term political actions and a socially divisive language based on the adulation of wealth . . .

“One thing that has become clearer over the past decade is that certain chemical substances are highly stable in nature and can have long-lasting and wide ranging effects before being broken down into a harmless form. The risk of a stable compound is that it can be bio-accumulated in fatty tissues at concentrations many times higher than in the surrounding environment . . . So exposure to toxic chemicals and certain foodstuffs are at risk of causing harm, especially to vulnerable groups such as foetuses in the womb or during childhood when the endocrine system is being actively built. Even with small dose exposures, the consequences can in some instances be devastating with problems ranging from cancer, serious impacts on human development, chronic diseases and learning disabilities”.

chemical exposures coverProfessor McGlade points out that well-informed individuals and communities would ‘more properly’ set ‘the power to act’, than current political systems which have become ‘silted up by vested interests and a determination to protect assets’ – and, we would add, to accumulate profits. She calls for “a more ethical form of public decision-making based on a language in which our moral instincts and concerns can be better expressed . . .”

Above, a book by Claudia Miller, M.D., M.S., a tenured Professor in Environmental and Occupational Medicine and Vice Chair of the Department of Family and Community Medicine of the University of Texas Health Science Center at San Antonio (UTHSCSA), who has written extensively on the health effects of low-level chemical exposures.

One simple measure could be adopted. Every scientific report or review should be prefaced by a declaration of the researcher’s competing financial interests

From the Nature/ British Dental Journal’s declaration of the authors’ competing financial interests Critique of the review of ‘Water fluoridation for the prevention of dental caries’ published by the Cochrane Collaboration in 2015, we learn that – out of 17 – these authors had such an interest – see footnote, with names added to the initials in the list.

The Cochrane review noted- amongst many other findings – that only two studies since 1975 have looked at the effectiveness of reducing cavities in baby teeth, and found fluoridation to have no statistically significant impact – and within the ‘before and after’ studies none showed the benefits of fluoridated water for adults.

In view of the authors’ competing interests it is not surprising that they cast doubt on the validity of the unfavourable findings of the Cochrane Review, which is ’unconstrained by commercial and financial interests’.

Footnote:

  1. A. J. Rugg-Gunn: AJRG was a member of the MRC (UK) working group on water fluoridation and health and is a trustee of The Borrow Foundation (long associated with milk fluoridation).
  2. A.J. Spencer: AJS is a member of the Australian Government Department of Health, Nutritional Reference Values Fluoride Expert Working Group and the National Health and Medical Research Council Fluoride Reference Group.
  3. H.P. Whelton: HPW is Principal Investigator of the FACCT study funded by the Irish Health Research Board and is an evaluation of the impact of changes in the policy on children’s oral health in Ireland. She is an independent advisor to the British Fluoridation Society.
  4. C.Jones: CJ is a member of the British Fluoridation Society, the Cochrane Oral Health Group and commented on the Cochrane review protocol.
  5. J. F. Beal: JFB is vice-chairman, British Fluoridation Society.
  6. P.Castle: PC is a communications adviser to the National Alliance for Equity in Dental Health and the British Fluoridation Society. 
  7. P.V. Cooney: PVC was Chief Dental Officer for Canada.
  8. J. Johnson: JJ is President, American Fluoridation Society. 
  9. M.P. Kelly: MPK is co-investigator on the CATFISH study of a water fluoridation scheme in Cumbria.
  10. M.A. Lennon: MAL was a member of the Advisory Panel for the York Review, a member of the MRC Expert Group and formerly Chair of the British Fluoridation Society.
  11. J. McGinley: JMcG is manager, Fluoridation Activities, American Dental Association.
  12. D. O’Mullane: DO’M is a member of the Irish Expert Body on Fluorides and Health.
  13. P.P. Sharma: PPS is the President, Ontario Association of Public Health Dentistry. 
  14. W.M. Thomson: WMT was a member of the panel which produced the Royal Society of New Zealand report on community water fluoridation.
  15. S. M. Woodward: SMW works for The Borrow Foundation.
  16. S.P. Zusman: SPZ is Chief Dental Officer with Israeli Ministry of Health.

 

 

 

Questions arising from PHE’s ‘community water fluoridation toolkit for local authorities’

24 Mar

Is it authoritative? Hardly:

“This toolkit has no legal status and does not represent legal advice. A local authority involved with or considering water fluoridation should familiarise itself with the relevant legislation and secure its own legal advice on the interpretation and implementation of that legislation.

Who profits? American manufacturers?

In this report, published by Public Health England, local authorities were said to be the driving force behind the introduction of water fluoridation schemes in England in the 1960s. Were they? Or was it the manufacturers of sodium fluoride, used to fluoridate watersee 25 American companies.

A well accepted process? No only 10% of British people have artificially fluoridated drinking water (see blurred but readable map at the foot of the article)

Fluoridation has been banned by Germany, Finland, Japan, Netherlands, Sweden, Switzerland and Denmark.

“At 1 January 2016, 26 local authorities had Community Water Fluoridation (CWF) schemes covering the whole or parts of their area with some six million people in England receiving a fluoridated water supply, principally in the North-East and in the West and East Midlands”.

But there are 433 principal authorities in the UK: 27 county councils, 55 unitary authorities, 32 London boroughs, 36 Metropolitan boroughs, 201 districts, 32 Scottish unitary authorities, 22 Welsh unitary authorities, and 26 Northern Ireland districts (the City of London and the Isles of Scilly are non-party based).

There is no credible scientific evidence of harm to the health of people supplied with fluoridated water was found: accurate?

Here are a few of the examples recorded in our database:

  • The Irish Examiner ( 09 Jan 2002) reported that research carried out at Boston University of School of Public Health, using data from the Irish National Cancer Registry and its northern equivalent, found 40% more people suffer from the rare bone cancer osteosarcoma in the Republic than the North, where water is not fluoridated. The Washington Post reported in 2005 that federal investigators and Harvard University officials were exploring an allegation that Professor Chester Douglass had tried to suppress research suggesting a link between fluoridated tap water and bone cancer in adolescent American boys.
  • In the Journal of American Physicians and Surgeons, Volume 10 Number 2 Summer 2005, Page 42: “After 20 years, the ten fluoridated cities had 10% more cancer deaths than the non-fluoridated cities. The cancers were found in the tongue, mouth, pharynx, oesophagus, stomach, colon, rectum, pancreas, larynx, bronchi, and lungs”.
  • In 2006 a 500-page review of fluoride’s toxicology was undertaken by a distinguished panel appointed by the National Research Council of the National Academies (NRC, 2006). It concluded that the US Environmental Protection Agency’s (EPA) safe drinking water standard for fluoride (i.e. maximum contaminant level goal or MCLG) of 4 parts per million (ppm) is unsafe and should be lowered. The report listed many basic research questions that have not been addressed over 60 years of fluoridation. The panel reviewed a large body of literature in which fluoride has a statistically significant association with a wide range of adverse effects. These include an increased risk of bone fractures, decreased thyroid function, lowered IQ, arthritic-like conditions, dental fluorosis and, possibly, osteosarcoma.
  • Lead author of a report published in the British Medical Journal, Professor Stephen Peckham, from the Centre for Health Service Studies, said: “I think it is concerning for people living in those areas. The difference between the West Midlands, which fluoridates, and Manchester, which doesn’t was particularly striking. There were nearly double the number of (thyroid) cases in Manchester. Underactive thyroid is a particularly nasty thing to have and it can lead to other long-term health problems. I do think councils need to think again about putting fluoride in the water. There are far safer ways to improve dental health.”

A blank cheque? PHE will keep this arrangement under continuous review. One factor will be changes in unit cost of materials, particularly the fluoridation chemicals

“The secretary of state is required to meet the reasonable capital and operating costs incurred by water undertakers operating water fluoridation schemes in England. The secretary of state has the power to require local authorities whose populations are serves by those schemes to make payments to the secretary of state to meet these costs. At present PHE meets the capital cost of schemes and recovers the operating costs from local authorities. Local authorities also pay for the cost of feasibility studies . . . At present PHE meets the capital costs of schemes and recovers only the operating costs from local authorities . . .

A reversible decision? Only at a cost

A Page 35 link describes how requirements are imposed on how local authorities must exercise their powers to propose, vary or terminate fluoridation schemes: they must (c) consider—

(i) the capital and operating costs which are likely to be incurred in giving effect to such variation of the arrangements as is specified in a variation proposal, or

(ii) the decommissioning and associated costs which are likely to be incurred in giving effect to the termination of the arrangements specified in a termination proposal; and

(d) consider any other available scientific evidence in relation to the variation or termination proposal, including any evidence of benefit to the health and well-being of individuals who would be affected by the proposal.

Can a determined, well–informed public can stop the process? See Hampshire’s example:

  • Despite consultation showing the majority of people who responded did not want it to be implemented, plans to put fluoride into water in parts of Hampshire were approved in 2009 by the South Central Strategic Health Authority.
  • The Parliamentary and Health Service Ombudsman then ‘threw out’ a judicial challenge by New Forest East MP Julian Lewis and Hampshire county councillor David Harrison to stop fluoridation.

But a year later the plans to add fluoride to the public water supply in Southampton and parts of Hampshire were scrapped. Public Health England said it still endorsed water fluoridisation but would not proceed without backing from Southampton City Council.

fluoridation map

The government ‘toolkit’ may be read in full here.

 

Reviews into antibiotics and anti-microbial resistance proliferate

21 Dec

tracy and pigTracy Worcester has drawn our attention to the subject of antibiotic resistance, which is growing – developing not in humans, but in bacteria that can then infect humans. Surgical and cancer chemotherapy patients rely on antibiotics to protect them from potentially life-threatening illnesses and declining efficacy could turn routine procedures into life-threatening ones.

Calls for funding aka ‘adequate market incentives’

antibiotics report coverAmerica’s Center for Disease Dynamics, Economics & Policy (CDDEP) produces independent, multidisciplinary research to advance the health and wellbeing of human populations in the United States and around the world.

Its October publication (right) estimates that between 38·7% and 50·9% of pathogens causing surgical site infections and 26·8% of pathogens causing infections after chemotherapy are resistant to standard prophylactic antibiotics in the USA.

RAND Europe and KPMG have both assessed the future impact of antimicrobial resistance [AMR] and a recent Chatham House report on new business models for antibiotics highlighted the problem of inadequate market incentives.

The use of antibiotics in agriculture

Haroon Siddique writes in the Guardian about another study, commissioned by David Cameron. The Review on Antimicrobial Resistance has been produced by a team of economists and administrators with one scientific adviser, supported by the Wellcome Trust fund.

It finds that the unpredictable nature of the development of resistance to such drugs, and the limits put on the sale of antibiotics to ensure they are used appropriately, are two factors which many pharmaceutical companies mention to explain why they have cut back or stopped altogether their investment in R&D on new antimicrobials.

antibiotics 2approvals to 2010

It warns that the use of antibiotics in agriculture is fuelling drug resistance and must be cut back or even banned where they are important for humans – see CDDEP risk assessment below, deemed over-cautious by some.

antibiotics 2graph by 2050

The review found that global use of antimicrobials in food production at least matched that by humans, extending even to the widespread application in some areas of “last resort” antibiotics for humans – which cannot be replaced when ineffective – to animals.

Acknowledging that the proper use of antibiotics is essential for treating infections in animals, as in humans, and offers considerable benefits for food production, the authors stress that “excessive and inappropriate” deployment, including to stop development of infections within a flock or herd, or simply to increase the pace at which animals gain weight, is a problem.

The team proposes that there should be a limit for each country to reduce antibiotic use in food production to an agreed level per kilogram of livestock and fish.

This should be determined by experts, but they suggest that a good starting point would be reducing levels to that of Denmark – an average of less than 50mg of antibiotics per year per kilogram of livestock in the country. Denmark has combined low use with being one of the world’s largest exporters of pork.

Tracy Worcester has a different proposal: use the power of the purse

Instead of buying meat from animal factories that cram so many pigs into vast sheds which need routine doses of antibiotics to keep the animals alive, we can buy meat from real farms. Pigs on outdoor farms, or indoors with adequate space and bedding, are healthy and hardly ever need antibiotics.

One of her fellow-campaigners, actor Dominic West, opposed a recent factory farming application. He hopes that when we buy British we know we are not supporting this type of cruel and dangerous farming: ‘The costs are much too high, from the superficial horrors of stench and stressed, unhealthy animals to antibiotic resistance that brings us closer to the end of antibiotics as a cure for human diseases. He says, ‘The world must move on, and we can all help by only buying pork from high welfare UK farms.’

Tracy points out that we have the choice to buy meat with the high welfare labels RSPCA Assured, Outdoor Bred, Free Range or Organic – eat less meat as Anna advocates – or go meat-free. See the World Health Organisation on the health issues here.