Neurobiological & spinal fluid abnormalities in CFS are not influenced by psychiatric status

Research highlights:

  • Patients have higher brain ventricular lactate, more abnormal spinal fluids, lower brain GSH, and reduced cerebral blood flow than controls
  • Psychiatric comorbidity does not influence any of these potential biological markers of CFS
  • 50% of the patients had more than one of these abnormalities
  • The subgroup of patients with brain abnormalities may have an underlying encephalopathy producing their illness

Research abstract:

The purpose of this study was to investigate whether CFS patients without comorbid psychiatric diagnoses differ from CFS patients with comorbid psychiatric diagnoses and healthy control subjects in neuropsychological performance, the proportion with elevated spinal fluid protein or white cell counts, cerebral blood flow (CBF), brain ventricular lactate and cortical glutathione (GSH).

The results of the study did not show any differences in any of the outcome measures between CFS patients with and without psychiatric comorbidity, thus indicating that psychiatric status may not be an exacerbating factor in CFS. Importantly, significant differences were found between the pooled samples of CFS compared to controls. These included lower GSH and CBF and higher ventricular lactate and rates of spinal fluid abnormalities in CFS patients compared to healthy controls.

Thirteen of 26 patients had abnormal values on two or more of these 4 brain-related variables. These findings, which replicate the results of several of our prior studies, support the presence of a number of neurobiological and spinal fluid abnormalities in CFS.

These results will lead to further investigation into objective biomarkers of the disorder to advance the understanding of CFS.

Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity by BH Natelson, X Mao, AJ Stegner, G Lange, D Vu, M Blate, G Kang, E Soto, T Kapusuz, DC Shungu in J Neurol Sci. 2017 Apr 15;375:411-416 [Epub 2017 Feb 22]

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Video lecture on clinical case definitions by Prof Jason

Youtube video published 17 March 2017: Leonard Jason’s Presentation on Case Definitions to European Network

The issue of research and clinical case definitions were discussed in this 30 min March 2-017 talk, and then the European scientists asked questions for the remaining 30 min.

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How a study about CFS was doctored, adding to pain and stigma

The Conversation blog, by Steven Lubet, 23 March 2017: How a study about Chronic Fatigue Syndrome was doctored, adding to pain and stigma 

The public relies on scientists to report their findings accurately and completely, but that does not always happen. Too often, researchers announce only their most favorable outcomes, while keeping more disappointing results well out of sight.

This phenomenon, first identified by the psychologist Robert Rosenthal in 1979, is called the “file drawer problem.” Although it is widely recognized – affecting drug trials, psychology experiments and most other fields – it has seldom been documented, for obvious reasons. Suppressed results are, well, suppressed, and they are usually discovered only by chance.

It was therefore almost unprecedented when a group of patients, at the end of last year, successfully unmasked the skewed data behind an influential British study, first published in Lancet in 2011, of the devastating disease known as Chronic Fatigue Syndrome (sometimes called myalgic encephalomyelitis or ME/CFS).

My interest in this issue is both professional and personal. As a law professor, I have devoted much of my career to the study of judicial ethics, including the problem of implicit biases that can undermine the reliability of both court trials and clinical trials.

I have also been living with ME/CFS for over a decade, so I am acutely attuned to the need for responsible and transparent research on the illness. Unfortunately, the most extensive study of ME/CFS – called the PACE trial – was deeply flawed from its inception, in ways that the principal investigators have yet to acknowledge.

‘Dysfunctional’ beliefs all too real for those in pain
The story began in 2005, when a group of psychiatrists set out to test their theory that ME/CFS is primarily a psychosocial illness, characterized by patients’ “unhelpful cognitions” and their “dysfunctional” beliefs that their symptoms are caused by an organic disease.

Under this assumption, they recruited over 600 ME/CFS patients for the PACE trial and randomly divided them into four categories. One group was treated with cognitive behavior therapy (CBT), a form of psychotherapy that addresses patients’ “false perceptions” of their illness, and a second group received graded exercise therapy (GET), which consisted of supervised increases in their activity levels. The other two groups were essentially controls, receiving neither of the treatments under study.

In a 2013 article in Psychological Medicine, the PACE team announced its most striking results. This follow-up article claimed that the therapy arms of the study – CBT and GET – had achieved impressive 22 percent recovery rates – not just improvement rates – as opposed to only seven or eight percent in the control arms.

The result was enthusiastically promoted in the press, but many patients were suspicious, especially of the GET outcomes, which contradicted their experience of debilitating crashes following the simple movements of daily life.

ME/CFS patients have consistently explained that exertion exacerbates their worst symptoms. For many, even moderate exercise can result in a days-long crash, in which they are nearly immobilized by muscle weakness and joint pain. In the U.S., post-exertional relapse has been recognized as the defining characteristic of the illness by the Centers for Disease Control, the National Institutes of Health and the Institute of Medicine.

For the PACE investigators, however, the announced recovery results validated their conviction that psychotherapy and exercise provided the key to reversing ME/CFS.

There was just one problem. A subsequent investigation found that the PACE investigators had changed the standard for recovery midstream, weakening one of the key criteria to the point that a subject could actually have gotten worse in the course of the trial and yet still count as “recovered” following supervised GET.

Unraveling the mystery
Here is how it worked, as shown by the investigation: At the outset of the trial, patients were recruited who scored at 65 or lower on a measure called the physical function score, and recovery was defined as achieving a subsequent score of 85 or higher, which indicates a relatively healthy person.

Before the unblinded trial was completed, however, the definition of recovery was reduced to a score of 60, which was below the level that qualified research subjects in the first place.

It was the change in this outcome measure (and several others) that allowed the PACE researchers to declare their favorable outcome for GET. The unimpressive results under the original protocol went unpublished, as though they had been stuck in a figurative file drawer.

When the Psychological Medicine article was published in 2013, members of the patient community immediately pointed out the discrepancy. Because the study had been publicly funded, they sought the underlying data under the U.K.’s Freedom of Information law. The PACE investigators refused to release any of the raw results.

In October 2015, David Tuller of the University of California at Berkeley published a lengthy expose of the PACE trial, pointing out the jiggered outcome measure, as detailed above, and many other flaws. His report attracted the attention of numerous American scientists who joined an open letter seeking an independent review of the PACE data.

Finally, in summer 2016, a British Freedom of Information tribunal ordered the PACE team to unlock the file drawer and disclose their raw data. A revelation followed.

Exaggerated recovery claims
A group of patients and scholars reanalyzed the PACE data according to the original determinants and, as suspected, the “recoveries” under CBT and GET all but disappeared. As they reported last December in a peer-reviewed medical journal, the recovery rate for CBT fell to seven percent and the rate for GET fell to four percent, which were statistically indistinguishable from the three percent rate for the untreated controls.

Thus, the PACE investigators proved nothing more than a familiar adage among statisticians: If you torture the data, they will confess anything.

Researchers in the U.S. and Australia have recently made great progress toward identifying biomarkers for ME/CFS, which may lead to an effective medical intervention. Over 100 prominent researchers, clinicians and organizations have called on Psychological Medicine to retract the PACE article, although the journal has not yet publicly responded.

Thanks to the original PACE announcement, however, graded exercise is still routinely prescribed throughout the U.S. and the U.K. despite reports that the treatments can cause intolerable pain and relapse. Those who question GET are often told that they must simply exercise more, no matter how badly they crash afterward.

It is bad enough to torture the data, but it is indefensible to torture patients based on manipulated results

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An open letter re PACE trial to Psychological Medicine, again!

Virology blog post, by Prof Vincent Racaniello, 23 March 2017: An open letter to Psychological Medicine, again!

Last week, Virology Blog posted an open letter to the editors of Psychological Medicine. The letter called on them to retract the misleading findings that participants in the PACE trial for ME/CFS had “recovered” from cognitive behavior therapy and graded exercise therapy. More than 100 scientists, clinicians, other experts and patient organizations signed the letter.

Three days later, I received a response from Sir Robin Murray, the UK editor of Psychological Medicine. Here’s what he wrote:

Thank you for your letter and your continuing interest in the paper on the PACE Trial which Psychological Medicine published. I was interested to learn that Wilshire and colleagues have now published a reanalysis of the original data from the PACE Trial in the journal Fatigue: Biomedicine, Health & Behavior, a publication that I was not previously aware of. Presumably, interested parties will now be able to read this reanalysis and compare the scientific quality of the re-analysis with that of the original. My understanding is that this is the way that science advances.

This is an unacceptable response.  Sir Robin Murray is misguided if he believes that science advances by allowing misleading claims based on manipulated data to stand in the literature. When researchers include participants who were already “recovered” on key indicators at baseline, the findings are by definition so flawed and nonsensical they must be retracted.

That the editors of Psychological Medicine do not grasp that it is impossible to be “disabled” and “recovered” simultaneously on an outcome measure is astonishing and deeply troubling. It is equally astonishing that the PACE authors now defend themselves, as noted in a New York Times opinion piece on Sunday, by arguing that this overlap doesn’t matter because there were also other recovery criteria.

In response to the comments from Psychological Medicine, we are reposting the open letter with 17 added individuals and 23 more organizations, for a total of 141 signatories altogether. These include two lawyers from Queen Mary University of London, the academic home of lead PACE investigator Peter White, along with other experts and ME/CFS patient groups from around the world. [including WAMES]

Sir Robin Murray and Dr. Kenneth Kendler
Psychological Medicine
Cambridge University Press
University Printing House
Shaftesbury Road
Cambridge CB2 8BS UK

Dear Sir Murray and Dr. Kendler:

In 2013, Psychological Medicine published an article called “Recovery from chronic fatigue syndrome after treatments given in the PACE trial.”[1] In the paper, White et al. reported that graded exercise therapy (GET) and cognitive behavioural therapy (CBT) each led to recovery in 22% of patients, compared with only 7% in a comparison group. The two treatments, they concluded, offered patients “the best chance of recovery.”

PACE was the largest clinical trial ever conducted for chronic fatigue syndrome (also known as myalgic encephalomyelitis, or ME/CFS), with the first results published in The Lancet in 2011.[2] It was an open-label study with subjective primary outcomes, a design that requires strict vigilance to prevent the possibility of bias. Yet PACE suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings.[3] Despite these flaws, White et al.’s claims of recovery in Psychological Medicine have greatly impacted treatment, research, and public attitudes towards ME/CFS.

According to the protocol for the PACE trial, participants needed to meet specific benchmarks on four different measures in order to be defined as having achieved “recovery.”[4] But in Psychological Medicine, White et al. significantly relaxed each of the four required outcomes, making “recovery” far easier to achieve. No PACE oversight committees appear to have approved the redefinition of recovery; at least, no such approvals were mentioned. White et al. did not publish the results they would have gotten using the original protocol approach, nor did they include sensitivity analyses, the standard statistical method for assessing the impact of such changes.

Patients, advocates and some scientists quickly pointed out these and other problems. In October of 2015, Virology Blog published an investigation of PACE, by David Tuller of the University of California, Berkeley, that confirmed the trial’s methodological lapses.[5] Since then, more than 12,000 patients and supporters have signed a petition calling for Psychological Medicine to retract the questionable recovery claims. Yet the journal has taken no steps to address the issues.

Last summer, Queen Mary University of London released anonymized PACE trial data under a tribunal order arising from a patient’s freedom-of-information request. In December, an independent research group used that newly released data to calculate the recovery results per the original methodology outlined in the protocol.[6] This reanalysis documented what was already clear: that the claims of recovery could not be taken at face value.

In the reanalysis, which appeared in the journal Fatigue: Biomedicine, Health & Behavior, Wilshire et al. reported that the PACE protocol’s definition of “recovery” yielded recovery rates of 7 % or less for all arms of the trial. Moreover, in contrast to the findings reported in Psychological Medicine, the PACE interventions offered no statistically significant benefits. In conclusion, noted Wilshire et al., “the claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments.”

In short, the PACE trial had null results for recovery, according to the protocol definition selected by the authors themselves. Besides the inflated recovery results reported in Psychological Medicine, the study suffered from a host of other problems, including the following:

*In a paradox, the revised recovery thresholds for physical function and fatigue–two of the four recovery measures–were so lax that patients could deteriorate during the trial and yet be counted as “recovered” on these outcomes. In fact, 13 % of participants met one or both of these recovery thresholds at baseline. White et al. did not disclose these salient facts in Psychological Medicine. We know of no other studies in the clinical trial literature in which recovery thresholds for an indicator actually represented worse health status than the entry thresholds for serious disability on the same indicator.

*During the trial, the authors published a newsletter for participants that included glowing testimonials from earlier participants about their positive outcomes in the trial.[7] An article in the same newsletter reported that a national clinical guidelines committee had already recommended CBT and GET as effective; the newsletter article did not mention adaptive pacing therapy, an intervention developed specifically for the PACE trial. The participant testimonials and the newsletter article could have biased the responses of an unknown number of the two hundred or more people still undergoing assessments—about a third of the total sample.

*The PACE protocol included a promise that the investigators would inform prospective participants of “any possible conflicts of interest.” Key PACE investigators have had longstanding relationships with major insurance companies, advising them on how to handle disability claims related to ME/CFS. However, the trial’s consent forms did not mention these self-evident conflicts of interest. It is irrelevant that insurance companies were not directly involved in the trial and insufficient that the investigators disclosed these links in their published research. Given this serious omission, the consent obtained from the 641 trial participants is of questionable legitimacy.

Such flaws are unacceptable in published research; they cannot be defended or explained away. The PACE investigators have repeatedly tried to address these concerns. Yet their efforts to date—in journal correspondence, news articles, blog posts, and most recently in their response to Wilshire et al. in Fatigue[8]—have been incomplete and unconvincing.

The PACE trial compounded these errors by using a case definition for the illness that required only one symptom–six months of disabling, unexplained fatigue. A 2015 report from the U.S. National Institutes of Health recommended abandoning this single-symptom approach for identifying patients.[9] The NIH report concluded that this broad case definition generated heterogeneous samples of people with a variety of fatiguing illnesses, and that using it to study ME/CFS could “impair progress and cause harm.”

PACE included sub-group analyses of two alternate and more specific case definitions, but these case definitions were modified in ways that could have impacted the results. Moreover, an unknown number of prospective participants might have met these alternate criteria but been excluded from the study by the initial screening.

To protect patients from ineffective and possibly harmful treatments, White et al.’s recovery claims cannot stand in the literature.

Therefore, we are asking Psychological Medicine to retract the paper immediately. Patients and clinicians deserve and expect accurate and unbiased information on which to base their treatment decisions. We urge you to take action without further delay.

Sincerely,

Dharam V. Ablashi, DVM, MS, Dip Bact
Scientific Director
HHV-6 Foundation
Former Senior Investigator
National Cancer Institute
National Institutes of Health
Bethesda, Maryland, USA

James N. Baraniuk, MD
Professor, Department of Medicine
Georgetown University
Washington, D.C., USA

Lisa F. Barcellos, MPH, PhD
Professor of Epidemiology
School of Public Health
California Institute for Quantitative Biosciences
University of California, Berkeley
Berkeley, California, USA

Lucinda Bateman, MD
Medical Director
Bateman Horne Center
Salt Lake City, Utah, USA

Alison C. Bested, MD, FRCPC
Clinical Associate Professor
Faculty of Medicine
University of British Columbia
Vancouver, British Columbia, Canada

Molly Brown, PhD
Assistant Professor
Department of Psychology
DePaul University
Chicago, Illinois, USA

John Chia, MD
Clinician and Researcher
EVMED Research
Lomita, California, USA

Todd E. Davenport, PT, DPT, MPH, OCS
Associate Professor
Department of Physical Therapy
University of the Pacific
Stockton, California, USA

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

Simon Duffy, PhD, FRSA
Director
Centre for Welfare Reform
Sheffield, UK

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

Derek Enlander, MD
New York, New York, USA

Meredyth Evans, PhD
Clinical Psychologist and Researcher
Chicago, Illinois, USA

Kenneth J. Friedman, PhD
Associate Professor of Physiology and Pharmacology (retired)
New Jersey Medical School
University of Medicine and Dentistry of New Jersey
Newark, New Jersey, USA

Robert F. Garry, PhD
Professor of Microbiology and Immunology
Tulane University School of Medicine
New Orleans, Louisiana, USA

Keith Geraghty, PhD
Honorary Research Fellow
Division of Population Health, Health Services Research & Primary Care
School of Health Sciences
University of Manchester
Manchester, UK

Ian Gibson, PhD
Former Member of Parliament for Norwich North
Former Dean, School of Biological Sciences
University of East Anglia
Honorary Senior Lecturer and Associate Tutor
Norwich Medical School
University of East Anglia
Norwich, UK

Rebecca Goldin, PhD
Professor of Mathematics
George Mason University
Fairfax, Virginia, USA

Ellen Goudsmit, PhD, FBPsS
Health Psychologist (retired)
Former Visiting Research Fellow
University of East London
London, UK

Maureen Hanson, PhD
Liberty Hyde Bailey Professor
Department of Molecular Biology and Genetics
Cornell University
Ithaca, New York, USA

Malcolm Hooper, PhD
Emeritus Professor of Medicinal Chemistry
University of Sunderland
Sunderland, UK

Leonard A. Jason, PhD
Professor of Psychology
DePaul University
Chicago, Illinois, USA

Michael W. Kahn, MD
Assistant Professor of Psychiatry
Harvard Medical School
Boston, Massachusetts, USA

Jon D. Kaiser, MD
Clinical Faculty
Department of Medicine
University of California, San Francisco
San Francisco, California, USA

David L. Kaufman, MD
Medical Director
Open Medicine Institute
Mountain View, California, USA

Betsy Keller, PhD
Department of Exercise and Sports Sciences
Ithaca College
Ithaca, New York, USA

Nancy Klimas, MD
Director, Institute for Neuro-Immune Medicine
Nova Southeastern University
Director, Miami VA Medical Center GWI and CFS/ME Program
Miami, Florida, USA

Andreas M. Kogelnik, MD, PhD
Director and Chief Executive Officer
Open Medicine Institute
Mountain View, California, USA

Eliana M. Lacerda, MD, MSc, PhD
Clinical Assistant Professor
Disability & Eye Health Group/Clinical Research Department
Faculty of Infectious and Tropical Diseases
London School of Hygiene & Tropical Medicine
London, UK

Charles W. Lapp, MD
Medical Director
Hunter-Hopkins Center
Charlotte, North Carolina, USA
Assistant Consulting Professor
Department of Community and Family Medicine
Duke University School of Medicine
Durham, North Carolina, USA

Bruce Levin, PhD
Professor of Biostatistics
Columbia University
New York, New York, USA

Alan R. Light, PhD
Professor of Anesthesiology
Professor of Neurobiology and Anatomy
University of Utah
Salt Lake City, Utah, USA

Vincent C. Lombardi, PhD
Director of Research
Nevada Center for Biomedical Research
Reno, Nevada, USA

Alex Lubet, PhD
Professor of Music
Head, Interdisciplinary Graduate Group in Disability Studies
Affiliate Faculty, Center for Bioethics
Affiliate Faculty, Center for Cognitive Sciences
University of Minnesota
Minneapolis, Minnesota, USA

Steven Lubet
Williams Memorial Professor of Law
Northwestern University Pritzker School of Law
Chicago, Illinois, USA

Sonya Marshall-Gradisnik, PhD
Professor of Immunology
Co-Director, National Centre for Neuroimmunology and Emerging Diseases
Griffith University
Queensland, Australia

Patrick E. McKnight, PhD
Professor of Psychology
George Mason University
Fairfax, Virginia, USA

Jose G. Montoya, MD, FACP, FIDSA
Professor of Medicine
Division of Infectious Diseases and Geographic Medicine
Stanford University School of Medicine
Stanford, California, USA

Zaher Nahle, PhD, MPA
Vice President for Research and Scientific Programs
Solve ME/CFS Initiative
Los Angeles, California, USA

Henrik Nielsen, MD
Specialist in Internal Medicine and Rheumatology
Copenhagen, Denmark

James M. Oleske, MD, MPH
François-Xavier Bagnoud Professor of Pediatrics
Senator of RBHS Research Centers, Bureaus, and Institutes
Director, Division of Pediatrics Allergy, Immunology & Infectious Diseases
Department of Pediatrics
Rutgers New Jersey Medical School
Newark, New Jersey, USA

Elisa Oltra, PhD
Professor of Molecular and Cellular Biology
Catholic University of Valencia School of Medicine
Valencia, Spain

Richard Podell, MD, MPH
Clinical Professor
Department of Family Medicine
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey, USA

Nicole Porter, PhD
Psychologist in Private Practice
Rolling Ground, Wisconsin, USA

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

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

Anders Rosén, MD
Professor of Inflammation and Tumor Biology
Department of Clinical and Experimental Medicine
Division of Cell Biology
Linköping University
Linköping, Sweden

Peter C. Rowe, MD
Professor of Pediatrics
Johns Hopkins University School of Medicine
Baltimore, Maryland, USA

William Satariano, PhD
Professor of Epidemiology and Community Health
University of California, Berkeley
Berkeley, California, USA

Ola Didrik Saugstad, MD, PhD, FRCPE
Professor of Pediatrics
University of Oslo
Director and Department Head
Department of Pediatric Research
University of Oslo and Oslo University Hospital
Oslo, Norway

Charles Shepherd, MB, BS
Honorary Medical Adviser to the ME Association
Buckingham, UK

Christopher R. Snell, PhD
Scientific Director
WorkWell Foundation
Ripon, California, USA

Donald R. Staines, MBBS, MPH, FAFPHM, FAFOEM
Clinical Professor
Menzies Health Institute Queensland
Co-Director, National Centre for Neuroimmunology and Emerging Diseases
Griffith University
Queensland, Australia

Philip B. Stark, PhD
Professor of Statistics
University of California, Berkeley
Berkeley, California, USA

Eleanor Stein, MD, FRCP(C)
Psychiatrist in Private Practice
Assistant Clinical Professor
University of Calgary
Calgary, Alberta, Canada

Staci Stevens, MA
Founder, Exercise Physiologist
Workwell Foundation
Ripon, California, USA

Julian Stewart, MD, PhD
Professor of Pediatrics, Physiology and Medicine
Associate Chairman for Patient Oriented Research
Director, Center for Hypotension
New York Medical College
Hawthorne, NY, USA

Leonie Sugarman, PhD
Emeritus Associate Professor of Applied Psychology
University of Cumbria
Carlisle, UK

John Swartzberg, MD
Clinical Professor Emeritus
School of Public Health
University of California, Berkeley
Berkeley, California, USA

Ronald G. Tompkins, MD, ScD
Summer M Redstone Professor of Surgery
Harvard Medical School
Boston, Massachusetts, USA

David Tuller, DrPH
Lecturer in Public Health and Journalism
University of California, Berkeley
Berkeley, California, USA

Rosemary A. Underhill, MB, BS, MRCOG, FRCSE
Physician and Independent Researcher
Palm Coast, Florida, USA

Rosamund Vallings, MNZM, MB, BS
General Practitioner
Auckland, New Zealand

Michael VanElzakker, PhD
Research Fellow, Psychiatric Neuroscience Division
Harvard Medical School & Massachusetts General Hospital
Instructor, Tufts University Psychology
Boston, Massachusetts, USA

Mark VanNess, PhD
Professor of Health, Exercise & Sports Sciences
University of the Pacific
Stockton, California, USA
Workwell Foundation
Ripon, California, USA

Mark Vink, MD
Family Physician
Soerabaja Research Center
Amsterdam, Netherlands

Frans Visser, MD
Cardiologist
Stichting Cardiozorg
Hoofddorp, Netherlands

Tony Ward, MA (Hons), PhD, DipClinPsyc
Registered Clinical Psychologist
Professor of Clinical Psychology
School of Psychology
Victoria University of Wellington
Wellington, New Zealand
Adjunct Professor, School of Psychology
University of Birmingham
Birmingham, UK
Adjunct Professor, School of Psychology
University of Kent
Canterbury, UK

William Weir, FRCP
Infectious Disease Consultant
London, UK

John Whiting, MD
Specialist Physician
Private Practice
Brisbane, Australia

Carolyn Wilshire, PhD
Senior Lecturer
School of Psychology
Victoria University of Wellington
Wellington, New Zealand

Michael Zeineh, MD, PhD
Assistant Professor
Department of Radiology
Stanford University
Stanford, California, USA

Marcie Zinn, PhD
Research Consultant in Experimental Electrical Neuroimaging and Statistics
Center for Community Research
DePaul University
Chicago, Illinois, USA
Executive Director
Society for Neuroscience and Psychology in the Performing Arts
Dublin, California, USA

Mark Zinn, MM
Research Consultant in Experimental Electrophysiology
Center for Community Research
DePaul University
Chicago, Illinois, USA

New individuals added 23 March 2017

Norman E. Booth, PhD, FInstP
Emeritus Fellow in Physics
Mansfield College
University of Oxford
Oxford, UK

Joan Crawford, CPsychol, CEng, CSci, MA, MSc
Chartered Counselling Psychologist
Chronic Pain Management Service
St Helens Hospital
St Helens, UK

Lucy Dechene, PhD
Professor of Mathematics (retired)
Fitchburg State University
Fitchburg, Massachusetts, USA

Valerie Eliot Smith
Barrister and Visiting Scholar
Centre for Commercial Law Studies
Queen Mary University of London
London, UK

Margaret C. Fernald, PhD
Clinical and Research Psychologist
University of Maine
Orono, Maine, USA

Simin Ghatineh, MSc, PhD
Biochemist
London, UK

Alan Gurwitt, M.D.
Former Clinical Child Psychiatry Faculty Member
Yale Child Study Center, New Haven, Connecticut
University of Connecticut School of Medicine, Farmington, Connecticut
Harvard Medical School, Boston, Massachusetts
Co-author of primers on Adult and Pediatric ME/CFS
Clinician in Private Practice (retired)
Boston, Massachusetts, USA

Geoffrey Hallmann, LLB, DipLegPrac
Former Laywer, (Disability And Compensation)
Lismore, Australia

Susan Levine, MD
Clinician in Private Practice
New York, New York, USA
Visiting Fellow
Cornell University
Ithaca, New York, USA

Marvin S. Medow, Ph.D.
Professor of Pediatrics and Physiology
Chairman, New York Medical College IRB
Associate Director of The Center for Hypotension
New York Medical College
Hawthorne, New York, USA

Sarah Myhill MB BS
Clinician in Private Practice
Knighton, UK

Pamela Phillips, Dip, Dip. MSc MBACP (registered)
Counsellor in Private Practice
London, UK

Gwenda L Schmidt-Snoek, PhD
Researcher
Former Assistant Professor of Psychology
Hope College
Holland, Michigan, USA

Robin Callender Smith, PhD
Professor of Media Law
Centre for Commercial Law Studies
Queen Mary University of London.
Barrister and Information Rights Judge
London, UK

Samuel Tucker, MD
Former Assistant Clinical Professor of Psychiatry
University of California, San Francisco
San Francisco, California, USA

AM Uyttersprot, MD
Neuropsychiatrist
AZ Jan Portaels
Vilvoorde, Belgium

Paul Wadeson, Bsc, MBChB, MRCGP
GP Principal
Ash Trees Surgery
Carnforth, UK

 ME/CFS Patient Organizations

25% ME Group
UK

Emerge Australia
Australia

European ME Alliance

Belgium ME/CFS Association
Belgium

ME Foreningen
Denmark

Suomen CFS-Yhdistys
Finland

Fatigatio e.V.
Germany

Het Alternatief
Netherlands

Icelandic ME Association
Iceland

Irish ME Trust
Ireland

Associazione Malati di CFS
Italy

Norges ME-forening
Norway

Liga SFC
Spain

Riksföreningen för ME-patienter
Sweden

Verein ME/CFS Schweiz
Switzerland

Invest in ME Research
UK

Hope 4 ME & Fibro Northern Ireland
UK

Irish ME/CFS Association
Ireland

Massachusetts CFIDS/ME & FM Association
USA

ME Association
UK

ME/cvs Vereniging
Netherlands

National ME/FM Action Network
Canada

New Jersey ME/CFS Association
USA

Pandora Org
USA

Phoenix Rising
International membership representing many countries

Solve ME/CFS Initiative
USA

Tymes Trust (The Young ME Sufferers Trust)
UK

Wisconsin ME and CFS Association
USA

New Organizations added 23 March 2017

Action CND
Canada

Associated New Zealand ME Society
New Zealand

Chester MESH (ME self-help) group
Chester, UK

German Society for ME/CFS (Deutsche Gesellschaft für ME/CFS)
Germany

Lost Voices Stiftung
Germany

M.E. Victoria Association
Canada

ME North East
UK

ME Research UK
UK

ME Self Help Group Nottingham
UK

ME/CFS and Lyme Association of WA, Inc.
Australia

ME/CFS (Australia) Ltd
Australia

ME/CFS Australia (SA), Inc.
Australia

ME/CVS Stichting Nederland
Netherlands

ME/FM Myalgic Encephalomyelitis and Fibromyalgia Society of British Columbia
Canada

MEAction
International membership representing many countries

Millions Missing Canada
Canada

National CFIDS Foundation, Inc.
USA

North London ME Network
UK

OMEGA (Oxfordshire ME Group for Action)
UK

Open Medicine Foundation
USA

Quebec ME Association
Canada

The York ME Community
UK

Welsh Association of ME & CFS Support
UK

[1] White PD, Goldsmith K, Johnson AL, et al. 2013. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine 43(10): 2227-2235.

[2] White PD, Goldsmith KA, Johnson AL, et al. 2011. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 377: 823–836

[3] Racaniello V. 2016. An open letter to The Lancet, again. Virology Blog, 10 Feb. Available at: http://www.virology.ws/2016/02/10/open-letter-lancet-again/ (accessed on 2/24/17).

[4] White PD, Sharpe MC, Chalder T, et al. 2007. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 7: 6.

[5] Tuller D. 2015. Trial by error: the troubling case of the PACE chronic fatigue syndrome trial. Virology Blog, 21-23 Oct. Available at: http://www.virology.ws/2015/10/21/trial-by-error-i/ (accessed on 2/24/17)

[6] Wilshire C, Kindlon T, Matthees A, McGrath S. 2016. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior; published online 14 Dec. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1259724 (accessed on 2/24/17)

[7] PACE Participants Newsletter. December 2008. Issue 3. Available at: http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter3.pdf (accessed on 2/24/17)

[8] Sharpe M, Chalder T, Johnson AL, et al. 2017. Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior; published online 15 Feb. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1288629(accessed on 2/24/17).

[9] Green CR, Cowan P, Elk R. 2015. National Institutes of Health Pathways to Prevention Workshop: Advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Annals of Internal Medicine 162: 860-865.

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BBC’s Week in week out reports on the crisis in home care in Wales

BBC Wales TV show Week In Week Out: The Real Cost of Caring

The pressure is on our social services to deliver care to some of the most vulnerable in society. Week In, Week Out investigates the challenges facing those on the front line of a system struggling under the strain. Filming behind the scenes with a Welsh care company, reporter Sian Lloyd uncovers a recruitment crisis which impacts on people needing care in their own homes.

Watch the 30 minute show

Broadcast on BBC One 20 March 2017. Available online for 12 months.

See also:

BBC TV show Panorama: Britain’s home-care crisis   Watch the 30 minute show

Broadcast on BBC One 20 March 2017. Available online for 11 months.

Daily post article, 19 March: North Wales home care budgets for elderly in crisis

Companies providing home care service are struggling to stay in business in the face of financial pressure

 

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Cognitive neuroscientists use electrical imaging to search for cause of CFS

DePaul University press release, by Jordyn Holliday, 16 March 2017: Cognitive neuroscientists use systems level approach to search for cause of chronic fatigue syndrome

Using electrical neuroimaging, a team of cognitive neuroscientists at the Center for Community Research at DePaul University, is working to determine the reasons for the brain problems commonly seen in chronic fatigue syndrome. In order to gather data for their current study, the research team assesses results from individual 30-minute electroencephalograms (EEGs), a test that measures brain waves.

This is an example of a deregulated network seen in people with chronic fatigue syndrome. Note that nearly all the connections are deregulated, producing a wide range of symptoms. (DePaul University/Center for Community Research)

CHICAGO – A team of researchers from the Center for Community Research at DePaul University are on a mission to better understand why the brain is less efficient in people with chronic fatigue syndrome (CFS), a disease that many patients refer to by its original name, myalgic encephalomyelitis (ME). This illness is characterized by extreme muscle
exhaustion, cognitive deficits, as well as unrefreshing sleep. The innovative systems level approach utilized by the research team may lead to important answers about this disease, they note.

Using electrical neuroimaging, research scientist Marcie Zinn, senior research associate Mark Zinn and professor Leonard Jason, are working to determine the reasons for the brain problems commonly seen in this disease. Their research could potentially lead to improved diagnoses and understanding of the disease, which has debilitated over 17 million people worldwide.

‘People become traumatized by a debilitating illness and then become traumatized again by the reaction to them by people who don’t understand,’

said Jason, professor of psychology and director of the Center for Community Research at DePaul. In addition to finding the source of many chronic fatigue syndrome symptoms, their research focuses on debunking the stigma surrounding the disease. ‘This research will examine biological issues involved in this illness,’ Jason said.

‘We know that different regions of the brain have to work together to process information, and problems in those networks can produce many symptoms in patients,’ said Marcie Zinn. ‘These brain problems in CFS could be the result of bad and/or slow connections,’ she noted.

EEG versus functional MRI

In order to gather data for their current study, the research team analyzes responses from online surveys and assesses results from individual 30-minute electroencephalograms (EEGs), a test that measures brain waves.

‘With the approach we use, we can see the brain at the millisecond level, which is 1,000th of 1 second. That’s the timeframe your brain works in. In contrast, there is about a 2 or 3 second delay with the functional MRI,’ Marcie Zinn said.

The researchers’ hope is that their work will help gain a better sense of the possible causes of chronic fatigue syndrome. Physicians, psychologists and other health care professionals then may be better equipped to target treatments to help correct deficits.

Mark Zinn also compared their quantitative EEG approach to social networks.

‘We’re studying interactions in the system of the brain,’ he  said. ‘We are studying relationships between neurons,’ he explained, adding that a major advantage of their approach is that they examine the brain on a systems level. ‘Our focus is to link patients’ signs and  symptoms to functional systems in the brain, which contrasts with  traditional attempts to link patients’ symptoms to brain lesions and other physiological abnormalities,’ Mark Zinn said.

Their innovative  systems level approach has been previously published in Applied
Psychophysiology and Biofeedback in 2016.

Center for Community Research

Jason said DePaul’s Center for Community Research has been researching and addressing chronic fatigue syndrome and myalgic encephalomyelitis for 25 years. ‘We have had years of experience in this area, and the nature of our work provides us at DePaul unique opportunities to better understand its etiology and pathophysiology,’ he said.

The results of this latest research may shed light on how brain function relates to the symptoms confronted by patients. It involves studying patients and controls.

More info about the Centre

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Do graded activity therapies cause harm in CFS?

Article abstract:

Reporting of harms was much better in the PACE (Pacing, graded Activity, and Cognitive behavioural therapy: a randomised Evaluation) trial than earlier chronic fatigue syndrome trials of graded exercise therapy and cognitive behavioural therapy.

However, some issues remain.

The trial’s poor results on objective measures of fitness suggest a lack of adherence to the activity component of these therapies.

Therefore, the safety findings may not apply in other clinical contexts.

Outside of clinical trials, many patients report deterioration with cognitive behavioural therapy and particularly graded exercise therapy.

Also, exercise physiology studies reveal abnormalities in chronic fatigue syndrome patients’ responses to exertion.

Given these considerations, one cannot conclude that these interventions are safe and risk-free.

Do graded activity therapies cause harm in chronic fatigue syndrome?, by Tom Kindlon in Journal of Health Psychology [First Published March 20, 2017] Full article is behind a paywall

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PACE trial claims of recovery are not justified by the data: a rejoinder to Sharpe, Chalder, Johnson, Goldsmith & White

Following a response from the PACE trial researchers to their re-analysis from the PACE trial researchers Wilshire et al have published a reply:

Article abstract: 

BACKGROUND: Recently, we critically evaluated the claim from the PACE trial that cognitive behavioural therapy (CBT) and graded exercise therapy (GET) can lead to recovery from chronic fatigue syndrome.

We showed that the trial’s definition of recovery was so loose it failed to capture the term’s core meaning. Also, this definition was substantially loosened very late in the trial, in ways that favoured the study hypotheses. The investigators do not acknowledge any of these criticisms and stand by their original analyses.

PURPOSE: To examine the arguments advanced in defence of PACE’s recovery claims.

METHODS: Drawing on various sources of evidence, we consider three major arguments raised in defence of PACE’s recovery claims: 1) that since there is no agreed definition of recovery, it comes down to a matter of opinion; 2) that the original definition was “too stringent”; and 3) the revised definition generates results that align with previous studies.

RESULTS: We find that: 1) “recovery” is a strong claim, which implies evidence a return to health, and that the trial’s final definition did not preserve this core meaning; 2) there is no evidence to suggest that the original protocol-specified definition was “too stringent”; 3) absolute recovery rates from other studies are not a legitimate source of support for the recovery definition used.

CONCLUSIONS: The PACE trial provides no evidence that CBT and GET can lead to recovery from CFS. The recovery claims made in the PACE trial are therefore misleading for patients and clinicians.

PACE trial claims of recovery are not justified by the data: A Rejoinder to Sharpe, Chalder, Johnson, Goldsmith and White, by Carolyn Wilshire Tom Kindlon and Simon McGrath,  [Published: 22 March 2017] Full text available on open access

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The full independent re-analysis of the PACE Trial now available on open access

ME Association blog post, 22 March 2017: Thanks to the MEA, you can now read the whole independent re-analysis of the PACE Trial recovery paper, 22 March 2017

The independent re-analysis of the PACE Trial recovery paper emerged from behind the publisher’s paywall today – after the ME Association paid US$2,000 for the paper to be switched to Open Access so that academics and clinicians can read it in full.

We used funds in our Medical Education Programme to enable this exercise in transparency to take place.    Read more from the MEA.

Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial, by Carolyn Wilshire, Tom Kindlon Irish ME/CFS Association, Dublin, Alem Matthees & Simon McGrath in Journal Fatigue: Biomedicine, Health & Behavior [Published online: 14 Dec 2016]

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Clinically proven mtDNA mutations are not common in CFS

Research abstract:

Background:
Chronic Fatigue Syndrome (CFS) is a prevalent debilitating condition tat affects approximately 250,000 people in the UK. There is growing interest in the role of mitochondrial function and mitochondrial DNA (mtDNA) variation in CFS. It is now known that fatigue is common and often severe in patients with mitochondrial disease irrespective of their age, gender or mtDNA genotype. More recently, it has been
suggested that some CFS patients harbour clinically proven mtDNA mutations.

Methods:
MtDNA sequencing of 93 CFS patients from the United Kingdom (UK) and South Africa (RSA) was performed using an Ion Torrent Personal Genome Machine. The sequence data was examined for any evidence of clinically proven mutations, currently; more than 200 clinically proven mtDNA mutations point mutations have been identified.

Results:
e report the complete mtDNA sequence of 93 CFS patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations. This finding demonstrates that clinically proven mtDNA mutations are not a common element in the aetiology of disease in CFS patients. That is patients having a clinically proven mtDNA mutation and subsequently being misdiagnosed with CFS are likely to be rare.

Conclusion:
The work supports the assertion that CFS should not be considered to fall within the spectrum of mtDNA disease. However, the current study cannot exclude a role for nuclear genes with a mitochondrial function, nor a role of mtDNA population variants in susceptibility to disease. This study highlights the need for more to be done to understand the pathophysiology of CFS.

Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome by Elizna M. Schoeman, Francois H. Van Der Westhuizen, Elardus
Erasmus, Etresia van Dyk, Charlotte V. Y. Knowles, Shereen Al-Ali, Wan-Fai Ng, Robert W. Taylor, Julia L. Newton, Joanna L. Elson in BMC Medical Genetics Vol. 18, #1, p 29 [Published: 16 March 2017]

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