Open letter to the editor of The Lancet, Dr. Richard Horton by 6 professors about the PACEtrial's fatal flaws

@ www.virology.ws:

Dr. Richard Horton
The Lancet125 London Wall
London, EC2Y 5AS, UK

Dear Dr. Horton:

In February, 2011, The Lancet published an article called “Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomized trial.” The article reported that two “rehabilitative” approaches, cognitive behavior therapy and graded exercise therapy, were effective in treating chronic fatigue syndrome, also known as myalgic encephalomyelitis, ME/CFS and CFS/ME. The study received international attention and has had widespread influence on research, treatment options and public attitudes.

The PACE study was an unblinded clinical trial with subjective primary outcomes, a design that requires strict vigilance in order to prevent the possibility of bias. Yet the study suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings. The patient and advocacy communities have known this for years, but a recent in-depth report on this site, which included statements from five of us, has brought the extent of the problems to the attention of a broader public. The PACE investigators have replied to many of the criticisms, but their responses have not addressed or answered key concerns.

The major flaws documented at length in the recent report include, but are not limited to, the following:

*The Lancet paper included an analysis in which the outcome thresholds for being “within the normal range” on the two primary measures of fatigue and physical function demonstrated worse health than the criteria for entry, which already indicated serious disability. In fact, 13 percent of the study participants were already “within the normal range” on one or both outcome measures at baseline, but the investigators did not disclose this salient fact in the Lancet paper. In an accompanying Lancet commentary, colleagues of the PACE team defined participants who met these expansive “normal ranges” as having achieved a “strict criterion for recovery.” The PACE authors reviewed this commentary before publication.

*During the trial, the authors published a newsletter for participants that included positive testimonials from earlier participants about the benefits of the “therapy” and “treatment.” The same newsletter included an article that cited the two rehabilitative interventions pioneered by the researchers and being tested in the PACE trial as having been recommended by a U.K. clinical guidelines committee “based on the best available evidence.” The newsletter did not mention that a key PACE investigator also served on the clinical guidelines committee. At the time of the newsletter, two hundred or more participants—about a third of the total sample–were still undergoing assessments.

*Mid-trial, the PACE investigators changed their protocol methods of assessing their primary outcome measures of fatigue and physical function. This is of particular concern in an unblinded trial like PACE, in which outcome trends are often apparent long before outcome data are seen. The investigators provided no sensitivity analyses to assess the impact of the changes and have refused requests to provide the results per the methods outlined in their protocol.

*The PACE investigators based their claims of treatment success solely on their subjective outcomes. In the Lancet paper, the results of a six-minute walking test—described in the protocol as “an objective measure of physical capacity”–did not support such claims, notwithstanding the minimal gains in one arm. In subsequent comments in another journal, the investigators dismissed the walking-test results as irrelevant, non-objective and fraught with limitations. All the other objective measures in PACE, presented in other journals, also failed. The results of one objective measure, the fitness step-test, were provided in a 2015 paper in The Lancet Psychiatry, but only in the form of a tiny graph. A request for the step-test data used to create the graph was rejected as “vexatious.”

*The investigators violated their promise in the PACE protocol to adhere to the Declaration of Helsinki, which mandates that prospective participants be “adequately informed” about researchers’ “possible conflicts of interest.” The main investigators have had financial and consulting relationships with disability insurance companies, advising them that rehabilitative therapies like those tested in PACE could help ME/CFS claimants get off benefits and back to work. They disclosed these insurance industry links in The Lancet but did not inform trial participants, contrary to their protocol commitment. This serious ethical breach raises concerns about whether the consent obtained from the 641 trial participants is legitimate.

Such flaws have no place in published research. This is of particular concern in the case of the PACE trial because of its significant impact on government policy, public health practice, clinical care, and decisions about disability insurance and other social benefits. Under the circumstances, it is incumbent upon The Lancet to address this matter as soon as possible.

We therefore urge The Lancet to seek an independent re-analysis of the individual-level PACE trial data, with appropriate sensitivity analyses, from highly respected reviewers with extensive expertise in statistics and study design. The reviewers should be from outside the U.K. and outside the domains of psychiatry and psychological medicine. They should also be completely independent of, and have no conflicts of interests involving, the PACE investigators and the funders of the trial.

Thank you very much for your quick attention to this matter.

Sincerely,

Ronald W. Davis, PhD
Professor of Biochemistry and Genetics
Stanford University

Jonathan C.W. Edwards, MD
Emeritus Professor of Medicine
University College London

Leonard A. Jason, PhD
Professor of Psychology
DePaul University

Bruce Levin, PhD
Professor of Biostatistics
Columbia University

Vincent R. Racaniello, PhD
Professor of Microbiology and Immunology
Columbia University

Arthur L. Reingold, MD
Professor of Epidemiology
University of California, Berkeley

Puzzling statement from Professor Michael Sharpe on sense about science ...

In this statement on the 28th of October 2015 Lead author of the study, Michael Sharpe, Professor of Psychological Medicine, University of Oxford says:

"The study did not contradict the view that ME/CFS is a chronic illness. These treatments, which we have found previously to be moderately helpful, are not a cure, and they do not benefit everyone. But the good news is, the benefit of these treatments is still apparent two years later, and they do not lead to a relapse of the illness. This new finding should reassure patients who want to try these treatments."

 So he confirms that "These treatments," ie CBT and GET ... "are not a cure" yet in the PACEtrial recovery article they claim that they cure 22% with these treatments. (The percentages (number/total) meeting trial criteria for recovery were 22% (32/143) after CBT, 22% (32/143) after GET, (31 January 2013, Psychological Medicine (2013), 43, 2227–2235) This sounds like a case of serious back peddling ...

 - See more at: http://www.senseaboutscience.org/for_the_record.php/214/response-to-headlines-suggesting-me-is-all-in-the-mind

The Independent: British psychiatrist Professor Simon Wessely should be stripped of an award, fellow scientists said last night

SANCHEZ MANNING, SUNDAY 25 NOVEMBER 2012, The Independent:

A British psychiatrist should be stripped of an award, fellow scientists said last night, as one of the most heated debates in medical science continued.

Professor Simon Wessely, one of Britain's foremost experts on ME, won the John Maddox Standing up for Science honour earlier this month. The prize was created by the journal Nature and the charitable trust Sense about Science. It was given to Professor Wessely for "courage" in speaking out about his studies into ME in the face a prolonged hate campaign and death threats. The Chinese science writer Fang Shi-min shared the award.

But critics protested against the decision last night. They said the professor's work perpetuates the idea that myalgic encephalomyelitis, also known as chronic fatigue syndrome (CFS), is a mental health problem, trivialising what they claim is a largely physical illness. Malcolm Hooper, emeritus professor of medicinal chemistry at Sunderland University, said: "He's responsible for trying to make ME into a psychiatric condition when it's not. He has done very poor science."

Another opponent, the Countess of Mar, said: "I was absolutely horrified when I read he'd won the award and I would like to see it retracted."

Dr William Weir, a retired consultant physician who says ME is caused by a chronic viral infection, called the decision "almost satirical". "If the scientific data is properly examined it will be seen that Professor Wessely's doctrine is wrong and it will be proved to be wrong in about five years' time," he said.

Professor Erich D. Ryll: Infectious venulitis, ME and CFS are all Communicable Diseases

Erich D. Ryll, M.D., Assistant Clinical Professor of Medicine:

INFECTIOUS VENULITIS CHRONIC FATIGUE SYNDROME MYALGIC ENCEPHALOMYELITIS Erich D. Ryll, M.D. Assistant Clinical Professor of Medicine Division of Infectious & Immunologic Diseases University of California, Davis

HISTORY
In the spring and summer of 1975 there occurred a major, severe epidemic of a communicable, apparent viral disease at the Mercy San Juan Hospital in Carmichael, a suburb of Sacramento, California.

The first two cases became ill in February; the bulk of the cases fell ill between July and November of 1975. Several cases tailed out to 1978. The epidemic spread to all departments of the Hospital. It was equally severe in all departments. I was appointed chairman of a committee to investigate the outbreak. Fearing that some people might die, I asked that the CDC (Communicable Disease Center of Atlanta, Georgia) to become involved.

An epidemic intelligence officer of the CDC spent one week in residence, and an epidemiologist from the California State Department of Health, Berkeley, came for a day. Cultures were obtained for all known viruses, bacteria, mycoplasma, and rickettsiae, and all were found to be negative.

The disease was apparently due to an unknown agent, presumably a virus.

At the time we did a literature search and found three reports of outbreaks that were called EPIDEMIC PHLEBODYNIA (EP), meaning painful veins. While the disease at the Mercy San Juan Hospital (MSJ) was somewhat similar, it included many more features than were described in EP and so at the time I did not believe it was the same disease.

Additional literature search showed that the disease was very similar to EPIDEMIC NEUROMYASTHENIA/MYALGIC ENCEPHALOMYELITIS (ENM/ME). But troublingly, very few vascular features were mentioned. I have followed these patients on a daily basis since 1975. This is the longest continual study of this type of disease that has ever been made. Because of this, I have learned all the nuances, all the signs and symptoms of the disease.

Because the complaints of patients are so many and often seemingly bizarre, I often attempted to disclaim them as being real. But I learned that you patients were always right and I was always wrong. In studying this disease, one must always have an open mind. This disease teaches the physician to be humble.

One must remember what a famous French physician, Jean Martin Charcot, said many years ago; "DISEASE IS VERY OLD AND NOTHING ABOUT IT HAS CHANGED. IT IS WE WHO CHANGE AS WE LEARN TO RECOGNIZE WHAT FORMERLY HAS BEEN IMPERCEPTIBLE." Read more>>

What cell line 22Rv1 tells us about XMRV

By Gerwyn Morris, (13 January 2011) PA institute:

The XMRV from 22RV1 cells cannot be the source of wild type XMRV. The 22RV1 cell line originated from a prostate cancer patient in 1993 (4).

XMRV was isolated from a patient whose blood sample was taken in 1984! (3, 17) Read more>>

New Suspect In Gulf War Syndrome

By Dr. Douglas Fields, Posted: March 3, 2010 02:25 PM

Washington, D.C.-- On February 26, 2010, the Veterans Affairs Department announced that it will re-examine the disability claims of thousands of Persian Gulf War veterans still suffering from the mysterious Gulf War illnesses two decades after the war ended. At a meeting of the Federal Advisory Committee on Gulf War Veteran's Illnesses held yesterday in Washington, D.C., scientists from around the country presented their latest research to committee members searching for clues to this mysterious illness. Early in the meeting a new culprit emerged -- "the other brain" -- the non-electric portion of the brain composed of brain cells called glia.

"This is one of the best explanations I've heard," commented distinguished neuroscientist Floyd Bloom, after a presentation by Dr. Linda Watkins of the University of Colorado speaking about her latest research showing that glial cells, called microglia, are the unsuspected agents in chronic pain and drug addiction. Previously neurons were thought to be the sole cause of chronic pain and morphine tolerance. However, the new insight into how these "immune cells" of the brain aggravate neurons after an injury by releasing substances that produce excruciating pain, a parallel with Gulf War Syndrome became apparent.

Gulf War syndrome is characterized by a collection of unexplained symptoms, many of them neurological, including chronic pain, chronic fatigue, depression, sleep disturbances, memory loss, as well as gastrointestinal and lung problems. A number of causes have been suspected, including exposure to low-level neurotoxins, including sarin gas, drugs taken to protect soldiers from biological and chemical warfare agents, pesticides used to treat tents and soldier's uniforms stationed in the desert, depleted uranium from munitions, and the toxic mixture of fumes released for a year after the war ended from oil fields set ablaze by the retreating Iraq soldiers. The toxic fumes blotted out the sun at midday for miles.

Many people suffer chronic pain after an injury. Unlike normal pain, chronic pain does not end after the injury heals; in fact it often gets worse. The latest research shows that chronic pain results from an interaction between the immune system and the brain. When we are sick, substances are released by the body that tell the brain to initiate the familiar "sickness response," which we have all experienced, for example when we catch the flu. Profound fatigue, headache, sensitivity to light and sound, and painful joints and muscles, drive us to bed. This sickness response forces us to rest and give the body the opportunity to fight the invading germ. This sounds a lot like the symptoms of many Gulf War veterans.

What Dr. Watkins suspects, based on her research on microglia in chronic pain, is that an initial exposure to some toxin "primes" the microglia in the brain to make them hyper alert. Then when a second infection, injury, or toxin is experienced, the brain's immune cells over-react, releasing too much of the chemical signals that cause the "sickness response", and they do not stop releasing the substances after the body heals. In the case of Gulf War veterans, the "initial trigger" could have been a reaction to an immunization, stress, or exposure to low-level toxins. Later a second insult to the body unleashes a run-away illness. Research from several labs on microglia in chronic pain has identified many steps in this neuro-immune signaling process that become disrupted and researchers have found specific drugs to restore the normal function of these pain circuits, thus ending the chronic pain. Most of this work is in laboratory animals but clinical studies are now under way.

In my overview to the committee on the four major kinds of glial cells in "the other brain", several other ways in which glia could be involved in Gulf War illnesses were recognized. This includes the involvement of glial cells, called astrocytes, in processing toxins in the brain. Parkinson's disease, for example can be caused by astrocytes acting on a foreign substance (a recreational drug), and converting it into a toxin that kills the neurons that die in Parkinson's Disease. Astrocytes also release factors that protect neurons from damage caused by inflammation or oxidation, and they release growth factor proteins that stimulate the growth and repair of neurons.

The latest research on the myelin insulation on nerve fibers in the brain, which is essential for sending electrical signals, is revealing a previously unsuspected role of myelin in cognition and psychiatric illness. Myelin insulation is especially vulnerable to blast injuries and to autoimmune diseases in which the body's immune system attacks the myelin sheath. The myelin sheath is made by a type of glial cell, called an oligodendrocyte. Prevously this insulation was of interest in diseases such as multiple sclerosis, but because the insulation speeds the rate of electrical transmission through nerve fibers (axons), myelin is now understood to have an important role in cognitive function, psychological illness, and learning.

One of the reasons the Gulf War Syndrome may have been so difficult to understand is that glia--the other brain--has itself been such a mystery until recently.

The only thing that GET does in ME ...

The conference of delusionism at the College of Physicians...

If you are curious about the upcoming CFS Conference at the College of whatever, and you want all the details which famous know it alls about ME will be there, let me help you out a bit. Here’s the line-up of speakers:

Professor CBT talking about I don't know what CFS and ME are.

Professor CBT the 2nd, on what causes malingering and so in psychiatrists....

Professor CBT the 3rd on why collusional delusionism affects psychiatrists when they talk about neurological disorders at a conference at the College of Physicians.

Then there is the approach of denying it all, another one will talk about the highlights in the hair of NICE people, recently acquired to enlighten their friends at the College, then there is the psychiatric approach on how to deny illnesses, there is another professor talking about using CBT and GET to GET someone at the conference the next time who actually knows what ME is, maybe Dr Carruthers or so, yes you are right, that doctor from the Canadian Guidelines who is obviously not there this year as he knows too much about ME and that would be counterproductive.

And then another doctor will talk about what medication is best, to cure delusional psychiatrists....

Oh, and what did Dr Enlander say in his email to the College, no he is not one of the speakers, again, he seems to know a thing or two about ME and that means they don't want him at the conference of delusionism.

"Sir

I think it is absurd for the Royal Society of Medicine to promote a meeting on Myalgic Encephalomyelitis where the predominant thrust is the psychiatric aspect of this physical disease.

There is enough physical evidence over the past fifty years, dating from Melvin Ramsay’s work in 1955, to show that this is a primary physical problem with secondary psychological depression.

I would presume that the august body, R.S.M., would not hold a cancer forum staffed predominately with psychiatrists. The notion that psychiatrists could treat cancer on the thesis that secondary depression in cancer is the cause and therefore the prime treatment modality. Perhaps you see the absurdity.

Please invite clinicians and physicians to speak at your meeting on the medical aspects and medical treatment of M.E., there happens to be a medical conference on this very subject in Cambridge a few days later, some of the clinicians speaking at this meeting may be interested in participating in the R.S.M.

After all, you are a medical and not a psychiatric society."

Dr Derek Enlander, M.D.,M.R.C.S., L.R.C.P. (Lon)
New York.

And you can mail him and thank him, by clicking on his name: Dr Derek Enlander

Oh, and if you want to read more about this fabtastic event of the year, then just click here for a new ME site about ME Events in the UK. Just found it, so have a look....

Emergency treatment ...

ME Diner ...