Thursday, 22 March 2018

The PACE Trial continues to unravel …

A major study has been released today (22nd March) which again looks at the PACE Trial, and this in turn has led to a lot of coverage in the media.

“The message is clear – CBT and GET are not effective ways of treating a serious neuroimmune disease. The sooner this message gets across to health professionals the better.” (Dr Charles Shepherd, The ME Association).

The study –

Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT


PDF download: 

Some of the media coverage –

BBC

Chronic fatigue trial results 'not robust', new study says


Belfast Telegraph

Findings of chronic fatigue study ‘not reliable’
The study faced intense criticism from patients and charities


Daily Mail

Findings of chronic fatigue study `not reliable´


The Canary

The mainstream medical community just declared war on people living with ME


The Times

Findings of £5m ME chronic fatigue study ‘worthless’



The ME Association’s response

Reanalysis of the PACE trial finds impressive claims for recovery following CBT and GET are ‘not statistically reliable’


ME Association Press Release, 21st March 2018

Benefits reported in a controversial medical trial part-funded by the Department of Work of Pensions were “not reliable,” a major study has found.

A large-scale, government-funded trial, known as PACE, claimed psychotherapy and exercise helped the estimated 250,000 sufferers of the devastating illness, M.E. (myalgic encephalomyelitis).

Manifesting as unrelenting fatigue and profound pain, the condition, also known as chronic fatigue syndrome, has no known cure and is made worse by exertion.

Sufferers are often confined to their beds, unable to walk, and need help even to shower – an action that could then lay them low for hours, days, weeks or longer.

When the results of the five-year PACE trial were published in 2011, researchers claimed that graded exercise therapy (GET) and cognitive behaviour therapy (CBT) were “moderately effective” forms of treatment.

The trial concluded that both treatments led to recovery in over a fifth of patients.

But PACE has since faced intense criticism from patients and charities, such as the ME Association, over how the results were obtained, analysed and presented.

Parliament has previously heard claims that the data was deliberately flawed to “remove people from long-term benefits and reduce the welfare bill”.

After a long legal battle, unpublished data from the trial was released and has now been independently reanalysed. The paper, published in the journal BMC Psychology, has found that the benefits reported for psychotherapy and exercise therapy are modest and not statistically reliable.

Lead author Carolyn Wilshire, said:

“Our reanalysis was designed to explore how the PACE trial outcomes would have looked if the investigators had adhered to the primary outcome they described in their original published protocol.

“We also looked into the published data on long-term outcomes to examine whether they had been influenced by the treatments patients had received after the trial had ended.

“We found that the groups receiving CBT or GET did not significantly outperform the control group after correcting for the number of comparisons specified in the trial protocol. Rates of recovery were consistently low and not significantly different across treatment groups.”

In surveys carried out by the ME Association, more than half of patients who had followed the recommended graded exercise programme saw a worsening in their symptoms.

Dr Charles Shepherd, Honorary Medical Adviser to the ME Association, today said:

“The ME Association has always been very critical of the way in which the PACE trial was designed, especially the lack of any objective outcome measures.

“And we have not been impressed by the way in which the results have been reported in medical journals, especially claims relating to recovery following CBT and GET.

“So, it comes as no surprise to find that a very careful re-analysis of some of the PACE trial data by Carolyn Wilshire and colleagues has concluded that impressive claims for recovery following CBT and GET are not statistically reliable.

“It is also very concerning to note that this data was only released through use of the Freedom of Information Act and a very costly Tribunal – which ordered the release of data.

“This sends a powerful message to the research community that they must be willing to share data where there are serious concerns about protocols or the reliability of results from a clinical trial.

“The ME Association believes that it is very important to encourage research data sharing and, where appropriate, independent reanalysis – which is why we made a significant financial contribution towards the processing fee for publication of this paper.

“The message is clear – CBT and GET are not effective ways of treating a serious neuroimmune disease. The sooner this message gets across to health professionals the better.”

The PACE trial data was used justify NHS recommendations of exercise and cognitive behaviour therapy and no changes were made as a result.

But a patient revolt has forced the government and NICE (the National Institute of Clinical Excellence) to review the guidelines used by UK doctors. That review may not be completed before 2020.


Forward ME Letter to The Times: Patients with ME/CFS ‘are not simply “deconditioned” as claimed by many psychiatrists’ | 23 March 2018

http://www.meassociation.org.uk/2018/03/forward-me-letter-to-the-times-patients-with-me-cfs-are-not-simply-deconditioned-as-claimed-by-many-psychiatrists-23-march-2018/

Letter to The Times, 23rd March, 2018.

Treatment for patients with M.E.

Sir,

The article by Tom Whipple, (“Findings of £5m ME chronic fatigue study ‘worthless’,” Mar 22) highlights a long-standing problem.

The National Institute for Health and Care Excellence (Nice) is in the process of replacing its guideline for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but this will take time.

Patients with ME/CFS in this country continue to receive damaging treatment in the form of graded exercise therapy (GET). Despite evidence of disabling metabolic abnormalities in their muscles, patients are advised to “exercise back to fitness”.

They are not simply “deconditioned” as claimed by many psychiatrists. Forced exercise above very low levels characteristically incapacitates most patients.

The “exercise will make you better doctrine” applied to ME/CFS is profoundly incorrect and has no scientific evidence base.

The human cost is enormous, with many sufferers from ME/CFS rendered worse by inappropriate medical management.

Even worse, such management is inflicted compulsorily on some patients, both adults and children, with their informed consent being bypassed via the use of mental health and child protection legislation.

Signatures

Countess of Mar, Forward-ME; Dr William Weir, infectious disease consultant; Dr Nigel Speight, paediatrician; Dr Charles Shepherd, ME association; Dr Vance Spence, ME research UK; Jonathan Davies, ME research UK; Dr Gareth Tuckwell, ME trust; Dr Paul Worthley, ME trust; Jane Colby, Tymes trust; Helen Brownlie, 25 per cent ME group; Tanya and Christine Harrison, Brame; William and Janice Kent, Remember; Hannah Clifton, ME trust; Clare Ogden, Action for ME

Wednesday, 14 March 2018

OMF-funded research: a metabolic ‘trap’ hypothesis for ME/CFS



March 14, 2018

On this #OMFScienceWednesday we highlight a new project that OMF is funding, which proposes a new metabolic ‘trap’ hypothesis for ME/CFS. This project is just getting started under the direction of Dr. Robert Phair, Chief Science Officer of Integrative Bioinformatics, Inc., an expert in computational modelling of biological processes. Dr. Phair has been collaborating with Dr. Ron Davis’ team at Stanford for nearly 2 years on investigating mechanisms behind ME/CFS. In this project, they will test a new hypothesis that could help to explain some of the genetic and metabolic characteristics of ME/CFS patients.

The big data study of severely ill ME/CFS patients that we funded identified several genes that carry damaging mutations. Dr. Phair’s hypothesis, based on computational predictions, suggests that some of these mutations may slow down enzymes that process important metabolites required for our energy, brain function, and immune system. If this is true, it could explain some of the symptoms of ME/CFS. Identifying interesting mutations is the (relatively) easy part, though – experimental evidence is needed to confirm their impact. During this project, the team will test how cells with these mutations carry out the relevant metabolic reactions, using special ‘tracer’ metabolites that can be easily followed as they are processed by the cells. These experiments will determine whether the mutations are indeed creating a metabolic ‘trap’ that could lead to the neurological and/or immunological symptoms of ME/CFS. We’ll be happy to share more details as the results provide more evidence. Stay tuned!

Read more about Dr. Phair and his research:

Wednesday, 7 March 2018

Trial By Error: News About My Plans by Dr David Tuller



5th March 2018

By David Tuller, DrPH

So I’ve been asked about my plans after June 30th, which is the end of the period covered by last year’s crowdfunding campaign. There’s been significant progress since I launched that effort. Among other developments, the CDC dropped its recommendations for CBT and GET, NICE decided to withdraw its preliminary reaffirmation of its disastrous 2007 guidance and pursue a full overhaul, and Scottish National Party MP Carol Monaghan recently held a groundbreaking parliamentary hearing about PACE.

In regards to the latter, it is awesome that a smart politician in a position to make noise [*This sentence has been changed for clarification; details at end of post] has noted publicly that PACE “will become known as one of the biggest medical scandals of the 21st century.” (Personally, I’d say PACE is on track to become one of the biggest scandals of the current millennium, even though the current millennium is less than 20 years old.) In reporting on MP Monaghan’s efforts, The National, a Scottish daily newspaper, noted the following: “After campaigners went to court to force researchers to release the raw data, that study, known as the PACE trial, has been discredited.”

What a delight to read such a statement in a mainstream U.K. news article. The sentence makes the point that the debunking of PACE is a fact—not just a hopeful assertion made by advocates.

All these changes unequivocally demonstrate that there has been significant erosion in support for the fake claims promoted by the CBT/GET ideological brigades. Besides the flaws in PACE, it has become apparent that many of the other studies from the biopsychosocial crowd are rife with ethical and methodological missteps. That’s on top of the fact that they are all open-label trials with subjective outcomes, which would present an insurmountable obstacle to obtaining reliable and valid results even without all the other violations of scientific principles.

I have recently documented such problems with two studies from the BMJ group of journals—last fall’s Lightning Process study, and the 2011 school absence study, both conducted by investigators from the University of Bristol. In both cases, the evidence shows that the investigators abused the ethical review process. Perhaps they presumed no one would read supporting documents, such as trial protocols or ethics committee opinions that have been wrongly cited to support problematic methodological choices.

So far, the journals have not taken the necessary steps to address these egregious problems. This sort of stonewalling will ultimately harm the reputations of all involved, and it indicates that this is not the time for me to stop examining the issues or to call it quits on this project. When I published my big PACE investigation in October, 2015, I assumed no study could survive the exposure of the nonsense perpetrated by the investigators. I didn’t recognize the degree to which the highest levels of the U.K. academic and medical establishment were ensnared in the delusion that PACE represented quality science and that the researchers involved were actually honorable and honest researchers.

I also had no idea how recalcitrant journals would be to acknowledge their self-evident mistakes, once these were authoritatively documented. And while I thought I might end up being sued, it didn’t occur to me that any self-respecting academic institution would try to squelch my accurate and necessary efforts to expose wrongdoing, the way Bristol University has in formally complaining about my work to Berkeley. I’m glad my own university retains some understanding, unlike Bristol, of the value of academic freedom and the importance of doing the right thing.

So I plan to conduct another crowdfunding campaign to support the project for another year—from July 1st, 2018, to June 30th, 2019. This time, I am working with Berkeley’s own crowdfunding platform, which is made available two or three times a year for university projects. Last year, that wasn’t an option; I was lucky that the foundation running Retraction Watch agreed to act as my fiscal sponsor and donate the money to Berkeley without taking any fees. This time, the funds will go directly to my home base at the university, the Center for Global Public Health, to support my half-time position.

Berkeley’s crowdfunding platform is open for the month of April. I’ll be providing more details about the campaign before or on the April 1st launch. My hope is that, with so much happening on multiple fronts, progress will actually accelerate in the next year and the CBT/GET paradigm will continue its downward spiral to oblivion–the fate it deserves.

*Clarification: The sentence originally referred to “a government official in a position of authority.” In the U.S., members of Congress are considered part of the government and they are considered to have authority, even if they are not in the executive branch. However, it was pointed out to me that the words mean something different in the U.K. The original sentence appeared to indicate that MP Monaghan is part of the government in power, which she clearly is not.

Saturday, 3 March 2018

I have chosen thee in the furnace of affliction



C H Spurgeon's Morning Devotional for 3rd March

"I have chosen thee in the furnace of affliction."

Isaiah 48:10

Comfort thyself, tried believer, with this thought: God saith, "I have chosen thee in the furnace of affliction." Does not the word come like a soft shower, assuaging the fury of the flame? Yea, is it not an asbestos armour, against which the heat hath no power? Let affliction come-God has chosen me. Poverty, thou mayst stride in at my door, but God is in the house already, and He has chosen me. Sickness, thou mayst intrude, but I have a balsam ready-God has chosen me. Whatever befalls me in this vale of tears, I know that He has "chosen" me. If, believer, thou requirest still greater comfort, remember that you have the Son of Man with you in the furnace. In that silent chamber of yours, there sitteth by your side One whom thou hast not seen, but whom thou lovest; and ofttimes when thou knowest it not, He makes all thy bed in thy affliction, and smooths thy pillow for thee. Thou art in poverty; but in that lovely house of thine the Lord of life and glory is a frequent visitor. He loves to come into these desolate places, that He may visit thee. Thy friend sticks closely to thee. Thou canst not see Him, but thou mayst feel the pressure of His hands. Dost thou not hear His voice? Even in the valley of the shadow of death He says, "Fear not, I am with thee; be not dismayed, for I am thy God." Remember that noble speech of Caesar: "Fear not, thou carriest Caesar and all his fortune." Fear not, Christian; Jesus is with thee. In all thy fiery trials, His presence is both thy comfort and safety. He will never leave one whom He has chosen for His own. "Fear not, for I am with thee," is His sure word of promise to His chosen ones in the "furnace of affliction." Wilt thou not, then, take fast hold of Christ, and say-

"Through floods and flames, if Jesus lead,
I'll follow where He goes."

Thursday, 1 March 2018

DNA gets away: Scientists catch the rogue molecule that can trigger autoimmunity and 'Low T3 Syndrome'


DNA gets away: Scientists catch the rogue molecule that can trigger autoimmunity

(This is not specifically about ME, but may be of interest as many believe that ME may well be an autoimmune condition.)


A research team has discovered the process -- and filmed the actual moment -- that can change the body's response to a dying cell

Date: February 22, 2018

Source: Monash University

Summary: A research team has discovered the process -- and filmed the actual moment -- that can change the body's response to a dying cell. Importantly, what they call the 'Great Escape' moment may one day prove to be the crucial trigger for autoimmune diseases like arthritis.

Full Story

A research team has discovered the process - and filmed the actual moment - that can change the body's response to a dying cell. Importantly, what they call the 'Great Escape' moment may one day prove to be the crucial trigger for autoimmune diseases like arthritis.

The research team, led by Professor Benjamin Kile from Monash University's Biomedicine Discovery Institute (BDI), has discovered - and filmed - the exact moment when DNA escapes out of the mitochondria (the organelles inside cells that produce energy) during cell death. The study, published today in the journal Science, involved major collaborators from the Walter and Eliza Hall Institute and the Howard Hughes Medical Institute's Janelia Research Campus in the US.

Mitochondria are the ultimate double agent; they are essential to keep cells alive, but when damaged, they can trigger the body's own immune system with potentially devastating consequences. Because the DNA inside mitochondria (mtDNA) has many similarities with bacterial DNA (they share common ancestry), the body reacts to its presence outside the mitochondria, or indeed, outside the cell, as if under attack from invading pathogens. It is a similar failure to distinguish 'self' from 'non-self' that underlies inflammatory and autoimmune diseases.

While the release of mtDNA is thought to contribute to autoimmune diseases such as lupus, how it escapes from the mitochondria has never been explained. Monash BDI researcher Dr Kate McArthur, while completing her PhD at the Walter and Eliza Hall Institute, used a revolutionary new microscope at the Janelia Research Campus in the US to capture the moment when mitochondria form a 'hernia' that balloons out of the mitochondria expelling the DNA into the rest of the cell.

The live-cell lattice light-sheet microscopy (LLSM) system developed by Nobel Prize winner Eric Betzig is a new technique that allows scientists to observe living cells at groundbreaking resolution. Dr McArthur travelled to the Janelia Research Campus in Virginia multiple times between 2015-2017, and remembers the moment when she witnessed, for the first time, the mitochondria actively expelling its DNA.

"As scientists, we are taught to be quite sceptical when we see something unexpected, so I think my initial reaction was 'no way...'

"It was only after I had carefully repeated the experiment many times that I began to realise what we had found," Dr McArthur said.

According to Professor Kile, when a cell commits suicide (a normal part of the human body's balancing act to control blood cell numbers), two proteins called BAK and BAX are triggered.

"What we witnessed - in real time - was these professional killer proteins opening up huge 'macropores' in the outer membrane of the mitochondria, leading the inner contents to herniate out, bringing the mtDNA with it," Professor Kile said.

"BAK and BAX deliver the 'kill shot' designed to permanently disable the cell. But in doing that, mtDNA is lost from the mitochondria. In essence, this is collateral damage, which, if it isn't controlled properly, triggers the immune system to drive pathological inflammation," he said.

The discovery was cemented by images captured by Monash University's Titan Krios cryo-electron microscope, currently the most advanced microscope for biological electron microscopy, and the Walter and Eliza Hall Institute's new lattice light-sheet microscope, custom built by collaborators in the Institute's Centre for Dynamic Imaging.

Professor Kile stressed that, in research, "fundamental discoveries such as this are rare, and this one has profound implications for the understanding of a wide range of autoimmune diseases and infections.

"This has been a brilliant collaboration - between Monash's Biomedicine Discovery Institute, the Walter and Eliza Hall Institute of Medical Research here in Melbourne and the Janelia Research Campus in the US - which has brought together cutting-edge technologies and first-class expertise to address questions that before now, had never been asked, and would have been impossible to answer," he said.


Higher prevalence of ‘low T3 syndrome’ in patients with chronic fatigue syndrome: A case-control study

(This very much fits in with the research showing that ME is a hypometabolic disease e.g, the research at Stanford University, California.)


Begoña Ruiz-Núñez 1, 2*, Rabab Tarasse 1, Emar Vogelaar 3, Janneke Dijck-Brouwer 1 and Frits Muskiet 1

1 Laboratory Medicine, University Medical Center Groningen, Netherlands
2 Healthy Institute, Spain
3 European Laboratory of Nutriënts (ELN), Netherlands

Chronic fatigue syndrome (CFS) is a heterogeneous disease with unknown cause(s). CFS symptoms resemble a hypothyroid state, possibly secondary to chronic (low-grade) (metabolic) inflammation. We studied 98 CFS patients (21-69 years, 21 males) and 99 age- and sex-matched controls (19-65 years, 23 males). We measured parameters of thyroid function, (metabolic) inflammation, gut wall integrity and nutrients influencing thyroid function and/or inflammation. Most remarkably, CFS patients exhibited similar TSH, but lower FT3 (difference of medians 0.1%), TT4 (11.9%), TT3 (12.5%), %TT3 (4.7%), SPINA-GD (14.4%), SPINA-GT (14.9%), 24-hour urinary iodine (27.6%) and higher %rT3 (13.3%). FT3 below the reference range, consistent with the 'low T3 syndrome', was found in 16/98 CFS patients vs. 7/99 controls (OR 2.56; 95% CI=1.00 - 6.54). Most observations persisted in two sensitivity analyses with more stringent cut-off values for BMI, hsCRP and WBC. We found possible evidence of (chronic) low-grade metabolic inflammation (ferritin and HDL-C). FT3, TT3, TT4 and rT3 correlated positively with hsCRP in CFS patients and all subjects. TT3 and TT4 were positively related to hsCRP in controls. Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels. The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. They resemble a mild form of 'non thyroidal illness syndrome' and 'low T3 syndrome' experienced by a subgroup of hypothyroid patients receiving T4 monotherapy. Our study needs confirmation and extension by others. If confirmed, trials with e.g. T3 and iodide supplements might be indicated.