Friday, July 13, 2007

Women warned against late start on HRT

The study reported below would seem to be a very close replication of another much-criticized study that was prematurely terminated some years ago. Media report below followed by journal abstract. The basic point to note is again that only a tiny proportion of women (a fifth of one percent) in the study suffered any heart disease. Such low numbers are a very poor indicator of a causal relationship. As a sufferer from a REAL iatrogenic illness, I can assure everyone that a real iatrogenic illness is much more relentless than anything reported below. The time factor is however the big unknown. Many adverse outcomes of medication take years to emerge. But the study below simply has no information on that. I do understand why they had to stop the study after 12 months. Having ANY women dying on you would be too big a risk legally and heart attacks do take you perilously close to death. So the result basically is an unknown. But even if the adverse relationship is causal, most medications and most things we do every day do carry risks -- often much greater risks than described below. It should also be noted that even the authors below are not critical of women who go straight on to HRT after menopause. Apparently the few deaths they observed were among women who were in their 60s before they started taking HRT. That group would of course have a higher mortality anyhow. Note also that there is some very direct evidence that estrogen therapy is beneficial to the heart

WOMEN have again been advised not to start hormone replacement therapy many years beyond menopause, after a second major study showed it could increase the risk of heart attacks and blood clots. The study, which involved nearly 5700 women in Britain, Australia and New Zealand, found the risk of clots increased more than seven-fold. The risk of heart attack, stroke and other heart-related events was significantly higher among older women who were randomly assigned to take it an average of 15 years after menopause.

The reports' authors stress HRT is a safe, short-term treatment when initiated in younger women shortly after menopause, when it is used to reduce symptoms such as hot flushes. The latest findings, published today online by the British Medical Journal, echo the shock results of a 2002 US study that found women aged 50 to 79 who took a combined oestrogen and progestogen pill were at greater risk of stroke, breast cancer and clots in the lungs, compared with women given a dummy pill. That result overturned hopes that HRT could be used to reduce heart risk, and millions of women stopped taking HRT as a result.

Today's study was stopped in 2002 when the US results became known, by which point only one-quarter of the planned 22,300 subjects had been enrolled. The 5692 women who had joined the study, including 319 in Australia, had been followed up for barely one year, instead of the planned 10 years. Even with the limited data to analyse, the results showed that the increased risk from HRT translated to an extra 27 heart attacks or blood clots in a year per 10,000 women treated. Although there were only 11 heart attacks, clots or other cardiovascular events, all were recorded in women taking hormones.

On the other hand, bone fractures dropped by a third among women taking HRT compared with those who were not, although this finding was statistically doubtful due to the low numbers. Study co-author Alastair MacLennan, head of obstetrics and gynaecology at the University of Adelaide, said that as the trial was stopped before many younger women were recruited, it remained unclear what age cut-off should apply - in other words, when the benefits of starting a woman on HRT no longer outweighed the risks. "That's the $64,000 question," Professor MacLennan said. "People starting HRT under the age of 60 need not be at all concerned."

If women started HRT before this age and if "they need to take HRT for 15 years because of symptoms which may still be persisting, they are not putting themselves at risk". In a BMJ editorial published online today, senior lecturer in women's health at Auckland University Helen Roberts said HRT had "come full circle". Current advice was that women needing relief from menopausal symptoms should take the lowest dose to relieve them. "Healthy women in early menopause are at low absolute risk whether they take hormones or not, and they are unlikely to face substantially increased risks when using hormones for a few years," she says.


Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women

By Madge R Vickers et al.


Objective: To assess the long term risks and benefits of hormone replacement therapy (combined hormone therapy versus placebo, and oestrogen alone versus combined hormone therapy).

Design: Multicentre, randomised, placebo controlled, double blind trial.

Setting: General practices in UK (384), Australia (91), and New Zealand (24).

Participants: Postmenopausal women aged 50-69 years at randomisation. At early closure of the trial, 56 583 had been screened, 8980 entered run-in, and 5692 (26% of target of 22 300) started treatment.

Interventions: Oestrogen only therapy (conjugated equine oestrogens 0.625 mg orally daily) or combined hormone therapy (conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily). Ten years of treatment planned.

Main outcome measures: Primary outcomes: major cardiovascular disease, osteoporotic fractures, and breast cancer. Secondary outcomes: other cancers, death from all causes, venous thromboembolism, cerebrovascular disease, dementia, and quality of life.

Results: The trial was prematurely closed during recruitment, after a median follow-up of 11.9 months (interquartile range 7.1-19.6, total 6498 women years) in those enrolled, after the publication of early results from the women's health initiative study. The mean age of randomised women was 62.8 (SD 4.8) years. When combined hormone therapy (n=2196) was compared with placebo (n=2189), there was a significant increase in the number of major cardiovascular events (7 v 0, P=0.016) and venous thromboembolisms (22 v 3, hazard ratio 7.36 (95% CI 2.20 to 24.60)). There were no statistically significant differences in numbers of breast or other cancers (22 v 25, hazard ratio 0.88 (0.49 to 1.56)), cerebrovascular events (14 v 19, 0.73 (0.37 to 1.46)), fractures (40 v 58, 0.69 (0.46 to 1.03)), and overall deaths (8 v 5, 1.60 (0.52 to 4.89)). Comparison of combined hormone therapy (n=815) versus oestrogen therapy (n=826) outcomes revealed no significant differences.

Conclusions: Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause. The results are consistent with the findings of the women's health initiative study and secondary prevention studies. Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause, when the effect may be different.


Autism: the truth

As the leaked and incomplete results of a study on autism again raise fears among parents, the scientist leading the research tells our correspondent that the new reports are alarmist and wrong

If you want to stoke parental anxiety, there are few better ways than announcing a dramatic rise in the incidence of autism. That is exactly what happened at the weekend with a story that the incidence of autism was far higher than previously thought - as many as one in 58 children - with the MMR vaccine back in the dock as a possible culprit.

The story was the result of the leak of an unpublished report put together by a team of British scientists including Professor Simon Baron-Cohen, head of the Autism Research Centre at Cambridge University and one of the most authoritative figures in the field.

One of the two team members reported as resurrecting the discredited theory that MMR causes autism is Dr Carol Stott, a developmental psychologist who once worked at ARC. Baron-Cohen says she left ARC some time ago. She is now listed as a member of staff at Thoughtful House, a research centre in developmental disorders in Texas. Thoughtful House is run by Dr Andrew Wakefield, the gastroenterologist who first raised the possibility of a MMR-autism link in 1998. The other figure named as having revived the MMR-autism link was Dr Fiona Scott, who still works at ARC as an honorary research associate and runs training courses on how to diagnose autism. Scott has issued a statement denying that she privately believes in any link between MMR and autism.

Baron-Cohen says the news story is alarmist and wrong. He does not believe that MMR has anything to do with autism. "We are gobsmacked, really, at how this draft report has got out," Baron-Cohen says. "It was only in the hands of the authors - about half a dozen people. There are three professors listed, including me, and none of us was contacted. It was also seen by two PhD students for whom I have the utmost respect because they are very careful scientists. "I don't believe that the MMR vaccine causes autism and I don't believe that there are hidden environmental reasons for any rise in cases. For the moment, we should assume [any rise] is more to do with diagnostic practice." Baron-Cohen says that health services are more geared towards early diagnosis, and there has been a broadening of the autism spectrum. Children that would have been thought eccentric or withdrawn a decade ago are now being given diagnoses such as Asperger's syndrome, a high-functioning form of autism in which intellect is unimpaired but social interaction is compromised.

It transpires that Wakefield is up before the General Medical Council's Fitness to Practise panel next week, on charges of serious professional misconduct. Two other doctors - Professor John Walker-Smith and Professor Simon Murch - who co-authored the original controversial 1998 Lancet paper with Wakefield, face similar charges, all relating to that single, disputed paper, which was later retracted. If found guilty, all face being struck off.

The draft report was leaked a week ahead of their GMC appearance. Baron-Cohen puts it like this: "We think it [the report] has been used. They've picked out the one figure that looks most alarmist." Cambridge University is now trying to hunt down the source of the leak.

So, what are the facts on autism? Does the one-in-58 figure hold up? Baron-Cohen says their study of Cambridgeshire children, which has been running for five years, comes out with a range of figures from one in 58, to one in 200, depending on various factors. The draft report, he says, "is as accurate as jottings in a notebook". He adds that the data is with public health officials, who are crunching the numbers.

A definitive number from the study, the professor hopes, will be published this year. It is possible that the one-in-58 figure comes from ARC's use of the Childhood Asperger's Syndrome Test (CAST), a questionnaire that parents can use to assess whether their child may have autism. The ARC team has used it on Cambridgeshire children in mainstream schools. However, it does not provide a diagnosis and is known to result in a high number of false positives. Around half the children flagged up by CAST as possibly having autism turn out not to.

In the meantime, he says that the best, most carefully conducted studies all show around 1 per cent of children lie on the autism spectrum and there is no reason to suspect that this has suddenly changed. There has been a gradual rise over decades, he says, but this reflects the fact that children are more routinely assessed, greater public awareness, and a wider diagnostic net. The National Autistic Society also quotes a figure of 1 per cent for the incidence of autistic spectrum disorders. Benet Middleton, the NAS's director of communications, says that, having spoken to Baron-Cohen, the charity had no plans to revise its figures. Middleton says: "This is an unpublished study that has not been peer-reviewed, and there are lots of reasons why studies don't get published. The research that's been published and peer-reviewed suggests a rate of 1 per cent. "The news story made a connection between two unrelated issues [the incidence of autism and the MMR vaccine]. I don't think that was a valid connection." Middleton adds that the charity does not advise parents whether or not to have the MMR jab, but instead directs them to their GP.

Baron-Cohen says that the results will be published eventually: "We've been sitting on this data since 2005 because we wanted to get the best advice. There's a number of different estimates for this population [the Cambridgeshire schoolchildren] depending on how you count. We need to work out which figures are the most reliable. "Research is sometimes slow but it is better to go slowly and get it right. Now things have been taken out of our hands and it's very dismaying."



`If the MMR vaccine was not the cause of my son's autism, then why has he got traces of measles virus in his bowels?' This was the question put to me five years ago by one of the parents involved in the litigation against the measles, mumps and rubella vaccine (MMR), who was a passionate supporter of the campaign led by the former Royal Free Hospital researcher Andrew Wakefield who first claimed a link between MMR and autism. The claim, made in 2002 by a team led by Dublin pathologist John O'Leary, that the measles virus RNA had been detected in gut biopsies of children with autism and gastro-intestinal disturbances, appeared to provide powerful vindication for Wakefield's hypothesis that a distinctive inflammatory bowel condition - dubbed `autistic enterocolitis' - was the mediating link between MMR and autism.

Testimony in a US court last week by London-based molecular biologist Stephen Bustin comprehensively exposed the unreliability of O'Leary's findings, based on an investigation of his laboratory carried out in early 2004. `It has been incredibly frustrating', Professor Bustin told me on his return from the USA. `For three years we have been unable [for legal reasons] to reveal our findings. Now, based on the publicly available information, I want to get the message out about the O'Leary/Wakefield research: there's nothing in it.'

Bustin's revelations follow a series of studies, using the most rigorous analysis techniques, which have failed to replicate O'Leary's results, while other researchers have disputed the existence of `autistic enterocolitis' as a distinctive disease entity (see footnotes 1-3). All these results are reassuring to parents of autistic children, whose anxieties have been needlessly provoked by the Wakefield campaign. Parents facing decisions about immunisation can also be reassured that the MMR-autism scare has been shown to have no basis in science.

Though it is good news for parents, the testimony of Bustin and other expert witnesses was yet another blow for the anti-vaccine campaigners as Andrew Wakefield returns to London next week from his new base in a private clinic in Texas to face charges of professional misconduct at the General Medical Council.

The hearings in the USA mark the culmination of two parallel anti-vaccine campaigns. In the UK, following Wakefield's now notorious 1998 paper in the Lancet, which first advanced the MMR-autism thesis, parents of more than 1,400 children were drawn into litigation against vaccine manufacturers. This collapsed in 2004 when the Legal Services Commission realised that, in the absence of scientific evidence for the thesis, the claim had no chance of succeeding. Meanwhile in the USA, campaigners blame the mercury-based preservative thimerosal in some vaccines for the apparent increase in the prevalence of autism. The facts that the prevalence of autism has continued to rise after the removal of thimerosal from vaccines and that MMR has never contained thimerosal have not deterred campaigners from trying to link mercury and MMR in the causation of autism, through a series of speculative and improbable pathways.

In the `omnibus autism proceedings' in the US Court of Federal Claims in Washington DC, the families of more than 4, 800 children are claiming damages from the $2.5billion government fund set aside to compensate people harmed by vaccination. Over 12 days last month the court heard the first test case put forward by the petitioners - that of 12-year-old Michelle Cedillo, whose parents believe that the combination of early childhood immunisations containing thimerosal with MMR at 16 months resulted in the development of autism, inflammatory bowel disease and a range of additional disabilities.

Unfortunately for the petitioners, and to the embarrassment of some of their supporters, there was no real contest - in terms of personal expertise or scientific substance - between the expert witnesses put forward in support of the vaccine-autism theory and those challenging this hypothesis. For example, Marcel Kinsbourne, a long-retired paediatric neurologist who admitted that he had not treated children for 17 years and who has become a professional expert witness, appearing in hundreds of vaccine litigation cases, appeared on questioning to lack any relevant specialist knowledge. Vera Byers, an immunologist, also long-retired, claimed a series of qualifications and academic attachments - including one to Nottingham University - that turned out to be bogus. On questioning, her faculty status at the University of California at San Francisco boiled down to attending courses, using the library, and, bizarrely, `going to their parties'.

Another elderly witness, environmental toxicologist Vasken Aposhian from Tucson, Arizona, caused bemusement by apparently denying the significance of dose levels of mercury and conflating in vitro, laboratory studies, with in vivo studies in animals and humans. By contrast, the experts testifying against the vaccine-autism theories included a range of doctors and scientists actively engaged in relevant clinical activity and research, such as the autism specialist Eric Fombonne, now in Montreal, but well-known in the UK for his many years at the Maudsley in London, Cleveland paediatric neurologist Max Wiznitzer, and Baltimore virologist Diane Griffen.

Whereas the petitioners' experts were unable to produce convincing evidence that mercury and MMR had combined to make Michelle autistic, the respondents' experts produced powerful evidence against this thesis.

* Michelle's developmental record, including videos at 9, 12 and 15 months - before her MMR - revealed early abnormalities of social interaction, motor delays and other features consistent with a diagnosis of autism;

* Blood tests and other investigations revealed no evidence of `immune suppression' or of an abnormal reaction to MMR;

* Biopsy specimens taken at endoscopy did not show changes consistent with inflammatory bowel disease.

The respondents' expert witnesses all expressed their sympathy for Michelle and their respect for her parents; they were equally unanimous in dismissing the notion that any vaccine was the cause of her condition.

Then, in more than 100 pages of testimony, Stephen Bustin, introduced as the author of the `bible of PCR' (`polymerase chain reaction' - the basic investigative technique of molecular biology), produced what he describes as `just a summary' of his investigation of the O'Leary lab. One of the first things that he thought `peculiar' when he arrived was that the door of the adjoining lab was labelled `Plasmid Room'. As he explained to the court, plasmids are used to replicate DNA molecules in bacteria for experimental purposes; Bustin said he was alarmed because contamination is the bane of PCR studies. `You never want to have any plasmid DNA anywhere near your lab when doing PCR', he says. And yet, he said in the Washington court, there was plasmid DNA, in thousands of millions of copies, just next door to O'Leary's lab.

Parents who received the results of their children's biopsy specimens from the O'Leary lab tended to think of the tests in terms of familiar bench tests: you stick litmus paper in acid and it turns red, in alkali and it turns blue. Straightforward, black and white (at least red and blue) easily done, easily confirmed. Nothing could be further from the reality of PCR testing, as Bustin's exhaustive explanation of the complexities of this technology to the Washington court confirms. His investigation revealed problems in O'Leary's lab at every step of the process, from the quality of the preparations used to the conduct of the testing, the use of controls, the analysis and interpretation of data. His conclusions were categorical: `The assay used was not specific for measles and it was not properly carried out.' The positive results were positive for DNA - confirming contamination, because `if it's DNA it can't be measles' (measles is an RNA virus).

For Bustin it was `a scientific certainty' that the O'Leary lab had failed reliably to identify measles virus RNA in Michelle or any other child (and this includes claims, reported in other studies, that the O'Leary lab had identified measles RNA in blood and cerebrospinal fluid). Bustin's devastating testimony effectively destroyed the only piece of positive evidence that has been produced in support of the MMR-autism thesis since it was launched nearly a decade ago. It raises further questions for Professor O'Leary, for the lawyers who led the UK litigation, and for Dr Wakefield.

In May Professor O'Leary delivered his inaugural lecture (on the unrelated subject of cancer genetics) as head of the department of pathology at Trinity College Dublin (4). It seems that his status in Ireland has been unaffected by the damaging disclosures in Washington, which have received little publicity on this side of the Atlantic. Though it is not clear how O'Leary, a pathologist rather than a virologist, became involved in his collaboration with Wakefield, it is known that he set up a commercial company - Unigenetics - which received around 800,000 pounds in legal aid funding from the UK litigation. Though he supervised the lab, it has emerged that much of the work was carried out by graduate - or even undergraduate - students. Though O'Leary has disassociated himself from Wakefield's campaign against MMR, he has never admitted that the notion - firmly believed by many parents - that his lab had at least confirmed the presence of measles virus in their guts, was entirely false.

Bustin's report on the O'Leary lab was key to the collapse of the anti-MMR litigation in the UK. When the lawyers at the Legal Services Commission discovered this authoritative investigation concluding that O'Leary's findings were unreliable they realised that, putting this together with the wider evidence against the MMR-autism thesis, the litigation had no chance of succeeding. Yet the lawyers leading the campaign refused to acknowledge openly that the scientific case against the MMR-autism link was overwhelming and advise their clients to conclude the action. Instead, they continued to pursue the case, allowing it to drag on for a small number of families, acting without legal aid funding, for a further three years.

This not only prolonged the ordeal for these families, it prevented the Bustin study from being made public. Indeed, lawyers for the UK families continued to resist the disclosure of this important investigation until the bitter end - until the eve of the US hearings when the High Court ruled in favour of allowing this testimony, prepared for the UK litigation, to be heard in Washington. (Of the 15million in legal aid funding spent on the MMR litigation, around 8million went to the solicitors, 1.7million to barristers, 4.3million was shared among expert witnesses; the children, of course, were left with nothing.)

When Andrew Wakefield made a rare public appearance in the UK at a (largely sympathetic) conference of parents of autistic children in Bournemouth in February, I asked him why it was that, after 10 years of promoting his MMR-autism theory, he had failed to win the support of a single autism specialist, paediatrician or paediatric gastroenterologist in the UK (who is not exclusively in private practice or a beneficiary of the litigation)? He refused to answer. The Washington hearings have raised further questions. Nicholas Chadwick, now a biochemist in Manchester, told the court how he, as a postgraduate student in Wakefield's team at the Royal Free, conducted PCR studies for measles virus on biopsy specimens of the 12 children included in the Lancet study. His studies showed that all specimens were negative (and that earlier results had shown `false positives' resulting from contamination). Wakefield suppressed these results and Chadwick insisted on his name being removed from the published paper, which declared that `virological studies were underway' to investigate what Chadwick had already investigated and found negative results. This information, first disclosed in Brian Deer's 2004 television documentary, has now been presented in a court of law and still demands a full explanation (5).

As Wakefield staggers towards his date with the GMC, his supporters claim that he has been the victim of a conspiracy by the medical establishment and big pharma. The revelations in Washington seem to suggest that something approximating to the opposite is true: Wakefield appears to have been the beneficiary of a conspiracy of silence that has prevented the truth about his research from being revealed. As a junior member of the Royal Free team, Chadwick was apparently deterred from blowing the whistle by familiar concerns about his own position. Others in a position to reveal the falsity of his claims - and those emerging from the O'Leary lab - were deterred from doing so for a range of motives, from personal and professional loyalty to the inclination to give a colleague the benefit of the doubt. Still others were restricted by considerations of confidentiality and legality.

What now for Stephen Bustin? He says that, after three years of enforced silence on this subject, he is keen to get wider publicity for the message that science shows no link between MMR and autism. He has written to the Lancet summarising his findings. After years of anxiety and confusion, parents of children with autism will welcome the triumph of quality science over junk science even if we have had to wait a long time for it.



Just some problems with the "Obesity" war:

1). It tries to impose behavior change on everybody -- when most of those targeted are not obese and hence have no reason to change their behaviour. It is a form of punishing the innocent and the guilty alike. (It is also typical of Leftist thinking: Scorning the individual and capable of dealing with large groups only).

2). The longevity research all leads to the conclusion that it is people of MIDDLING weight who live longest -- not slim people. So the "epidemic" of obesity is in fact largely an "epidemic" of living longer.

3). It is total calorie intake that makes you fat -- not where you get your calories. Policies that attack only the source of the calories (e.g. "junk food") without addressing total calorie intake are hence pissing into the wind. People involuntarily deprived of their preferred calorie intake from one source are highly likely to seek and find their calories elsewhere.

4). So-called junk food is perfectly nutritious. A big Mac meal comprises meat, bread, salad and potatoes -- which is a mainstream Western diet. If that is bad then we are all in big trouble.

5). Food warriors demonize salt and fat. But we need a daily salt intake to counter salt-loss through perspiration and the research shows that people on salt-restricted diets die SOONER. And Eskimos eat huge amounts of fat with no apparent ill-effects. And the average home-cooked roast dinner has LOTS of fat. Will we ban roast dinners?

6). The foods restricted are often no more calorific than those permitted -- such as milk and fruit-juice drinks.

7). Tendency to weight is mostly genetic and is therefore not readily susceptible to voluntary behaviour change.

8). And when are we going to ban cheese? Cheese is a concentrated calorie bomb and has lots of that wicked animal fat in it too. Wouldn't we all be better off without it? And what about butter and margarine? They are just about pure fat. Surely they should be treated as contraband in kids' lunchboxes! [/sarcasm].

Trans fats:

For one summary of the weak science behind the "trans-fat" hysteria, see here. Trans fats have only a temporary effect on blood chemistry and the evidence of lasting harm from them is dubious. By taking extreme groups in trans fats intake, some weak association with coronary heart disease has at times been shown in some sub-populations but extreme group studies are inherently at risk of confounding with other factors and are intrinsically of little interest to the average person.


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