Wednesday, 27 June 2018

OMF: HealthRising: Ron Davis (Finally) Gets His Big Grant!

https://www.omf.ngo/2018/06/26/davis-nih-grant/

June 26, 2018

This #OMFScienceWednesday we share the exciting news that Dr. Ron Davis and his team have received an NIH award for 5 years, $3.9 million total grant of which $2.5 million goes to research and the rest goes to Stanford University overhead. (NIH always pays universities their “overhead or indirect” costs on top of the grant amount that was applied for.)

The grant is to study the “Molecular and Single Cell Immunology of ME/CFS.” Thank you Cort Johnson for writing this wonderful article to explain the grant.

by Cort Johnson

“This proposal aims to uncover the immunological basis of ME/CFS”. Ron Davis – Grant application

Sometimes the third time is the charm. Ron Davis has gotten (and been turned down for) many NIH grants but even he was shocked by the response to his first couple of attempts to get an NIH grant for chronic fatigue syndrome (ME/CFS).

This time, though, the NIH came through. Davis’s first try at a NINDS review panel was rejected by reviewers who refused to even assess the grant. His second try for an NIH ME/CFS research center was met with such a weird response that he went before an NIH committee to protest. His third try, the first apparently through the grant review panel for ME/CFS (Special Emphasis Panel [ZRG1-CFS-M (80)S]), thankfully, met with success.

The big multi-year, multi-million dollar RO1 grant to the Stanford Genome Center titled “Molecular and Single Cell Immunology of ME/CFS” lasts for five years and pays out a cool $745,000 this year.

Remarkably, Davis, at 76, was the first and is still the only ME/CFS research center grant applicant to flip his big, NIH Center’s grant application into a smaller – but still quite hefty – grant application since the Research Centers were announced in the fall of last year.

This was a grant application, in truth, that one would have expected to succeed. It ticked all the boxes; it features cutting-edge technologies featuring two highly respected researchers from a top academic institution. It’s the kind of application the NIH has said it’s wanted from ME/CFS researchers for years.

A rejection would have raised a big red flag about bias, but this time the grant review panel came through giving Davis’s application extremely high scores and the NIAID funded it.

The grant combines Stanford immunologist Mark Davis’s work on T-cells with Ron Davis’s work on HLA genes.  Mark Davis is a T-cell expert – he’s spent 35 years studying these prime movers of the immune system. T-cell and B-cells are the big guns of the adaptive immune response which swoop in later in an infection to clear it out. T-cells are unique in their refined approach to pathogens; while other immune cells react to whole antigens, T-cells need only a fragment of an antigen to respond. Their job is a staggeringly complex one; to produce literally billions of potential binding sites that are able to capture small bits of pathogenic proteins and then lift them to the surface of the cell so that the immune system can respond to them.

Once a pathogen is found, T-cells create specially designed copies (clones) of themselves that swarm through the body targeting infected cells or the actual pathogen itself. As Mark Davis explains in the video below, that process is occurring in ME/CFS; ME/CFS patients’ T-cells are busily churning out identical copies of themselves; they’ve responded to something with a fury.

The best candidate is a pathogen – a virus, bacteria, fungus, etc. – which may be gone, but which has ticked off an overactive immune response that is now attacking the body, producing an autoimmune disease.

In this study, Mark Davis will look at an array of T-cells to determine the breadth and extent of the T-cell activation in ME/CFS. He’ll pair that with new technology developed by Ron Davis which gives researchers a better handle on the genes used to capture those pathogenic antigens. They’re found in the most mysterious part of our genome in the HLA locus.

Because the HLA genes also help the immune system differentiate “self” from “non-self” cells, they also play a major role in autoimmunity. Studies indicate that people with certain HLA types are more at risk for autoimmune diseases such as type I diabetes, lupus, myasthenia gravis, Sjögren’s syndrome, narcolepsy, and others. This study will assess the HLA locus of a large number of ME/CFS patients.

Finally, the study will use new techniques developed at Stanford to try and determine what those activated T cells in ME/CFS are targeting.

By the time the study is done, we could know if ME/CFS is an autoimmune disease or is caused by a pathogen (or both!); plus, we could know what specifically has tweaked our immune systems. Plus, Ron Davis, in a section of the grant, and which shows his predilection for long-term thinking, envisions the study as the opportunity to build a new (and precise) molecular framework for understanding, diagnosing and treating ME/CFS.

“This project will build a precise framework for ME/CFS as a molecular and immunological disease, opening up broad new possibilities for research, diagnosis, and treatment.”

Davis is all about getting at the molecular nature – the very basic building blocks – of ME/CFS – a pursuit he believes will illuminate other diseases.

“Moreover, the similarity of ME/CFS to other medically challenging diseases like Lyme disease, multiple sclerosis, Gulf War Illness, fibromyalgia, and more means that the insights derived here could be relevant to many millions of patients.”

Mark Davis on his T-Cell Research in ME/CFS

A Remarkable Six Months

The NIH grant tops off a remarkable first half of the year for Ron Davis, the Stanford ME/CFS Collaborative Research Center and Open Medicine Foundation. First came the $5 million Pineapple Fund donation, then the $1 million donation to support work into Robert Phair’s Metabolic Trap hypothesis, and now the multi-million dollar NIH grant to Davis’s Stanford ME/CFS Research Center.

The Stanford ME/CFS Collaborative Research Center is a research center in the best sense of the word. From the Severe ME/CFS study, to the nanoneedle work, to the big omics study in Mike Snyder’s Stanford lab, to Robert Phair’s metabolic trap hypothesis, the red blood cell deformation studies, Mark Davis’s five year exploration of T-cells, and Ron Tompkins’s muscle cell work, the OMF is now funding a staggering amount of research.

Three years ago, I was at a fundraiser Ron Davis held at his house trying to raise some money for ME/CFS. The future did not look promising. Persistence, however, has paid off and three years later he, Linda Tannenbaum and their ever increasing cohort of workers and volunteers are on a research roll the likes of which we have never seen before.

Original post on HealthRising. Reprinted with permission.


Tuesday, 19 June 2018

Trial By Error: An Open Letter to The Lancet, Two Years On

http://www.virology.ws/2018/06/19/trial-by-error-an-open-letter-to-the-lancet-two-years-on/ 

19 June 2018

By David Tuller, DrPH

This morning, Professor Racaniello sent the following e-mail to Richard Horton, editor of The Lancet. The subject heading: “Another open letter about the PACE trial.” He cc’d the three lead PACE investigators and the public relations office at Queen Mary University of London. Virology Blog’s previous open letter to The Lancet about the PACE trial was sent and posted in February, 2016.

**********

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.” [1] The article reported that two rehabilitative approaches, cognitive behavioural therapy (CBT) and graded exercise therapy (GET), were effective and safe treatments for chronic fatigue syndrome, also often referred to as myalgic encephalomyelitis, ME/CFS and CFS/ME. The PACE study received international attention and has had widespread influence on research, treatments prescribed for patients, and attitudes toward the illness of both the medical community and the public at large.

At the press conference promoting the Lancet paper, one of the lead investigators stated that twice as many participants in the treatment groups got “back to normal,” compared to those in the other study arms. [2] An accompanying Lancet commentary similarly claimed that these “back-to-normal” participants had met a “strict criterion for recovery.” [3]

In fact, we now know that 13 % of the participants qualified at baseline as “recovered” or “within the normal range” for one of the study’s two primary measures, self-reported physical function–even as they were simultaneously classified as disabled enough on the same measure to enter the study. [4] This anomaly, which occurred because the investigators weakened key outcome thresholds after data collection, invalidates any claims that patients “recovered” or got “back to normal.” The overlap in entry and outcome criteria is only one of the trial’s unacceptable methodological lapses.

The treatments investigated in the PACE trial were based on the hypothesis that ME/CFS patients harbor “unhelpful” convictions about having an ongoing organic disease and that the perpetuation of their devastating symptoms is the result of deconditioning. In contrast, a 2015 review from the U.S. Institute of Medicine (now the National Academy of Medicine), reported that ME/CFS is a complex, multi-system illness characterized by neurological, immunological, autonomic, and energy metabolism dysfunctions. [5] The cardinal symptom, noted the review, is a systemic intolerance to exertion; if patients exceed their available energy resources, they can suffer serious and prolonged relapses.

After The Lancet published the first PACE results, ME/CFS patients and advocates immediately pointed out major flaws. But few people outside the field took notice until the science site Virology Blog published a 15,000-word investigation by David Tuller, a public health researcher and journalist at the University of California, Berkeley, in October of 2015. [6] Subsequently, in February of 2016, many of us signed an open letter to The Lancet requesting an independent investigation of the study. [7]

Since then, much has happened:

* In August of 2016, a U.K. tribunal, citing that open letter, ordered Queen Mary University of London to release raw trial data from the PACE study, sought by Australian patient Alem Matthees in a freedom of information request so that he and others could calculate the outcomes promised in the PACE trial protocol. [8]

* Analyses of these data [9], including a study published in BMC Psychology in March [10], have confirmed what has long been argued: The PACE investigators engaged in such extensive outcome-switching that they were able to report dramatically better findings than the null or minimal results obtained under the original measures they promised in their protocol.

* The U.S. Agency for Healthcare Research and Quality (AHRQ) downgraded its recommendations for CBT and GET. [11] This downgrading occurred after the agency removed from its analysis the PACE trial and other studies using overly broad selection criteria that generated cohorts of patients with a grab-bag of fatiguing conditions. And while the PACE trial claimed that GET is safe, AHRQ found that the therapy was associated with more adverse events.

* Last summer, the U.S. Centers for Disease Control abandoned the recommendations that ME/CFS patients be treated with CBT and GET [12], having already removed references to the PACE trial. A couple of months later, the U.K. National Institute for Health and Care Excellence announced that it would pursue a full update of its 2007 guidance, citing concerns about the reliability and validity of the evidence base. [13]

* Earlier this year, a report from the Dutch Health Council recommended that GET should not be used in the Netherlands as a treatment for the illness. [14]

* In March, a group of leading American clinicians who specialize in ME/CFS unanimously agreed that the two PACE treatments are inappropriate and possibly harmful for patients with the illness and should therefore not be prescribed. [15]

Given the worldwide impact of PACE, we urge The Lancet to do what the open letter two years ago requested: commission an independent re-analysis of the individual-level 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 domains of psychiatry and psychological medicine and predominantly from outside the U.K. 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 for your quick attention to this matter.

Sincerely,

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

Michael Allen, PhD
Clinical Psychologist (retired)
San Francisco, California, USA

Christopher Armstrong, PhD
Bio21 Molecular Science & Biotechnology Institute
Department of Biochemistry and Molecular Biology
University of Melbourne
Melbourne, Victoria, Australia

James N. Baraniuk, MD
Professor of Medicine
Georgetown University
Washington, DC, USA

Lisa F. Barcellos, 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

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

John Chia, MD
Clinician and Researcher
EV Med Research
Lomita, California, USA

Lily Chu, MD, MSHS
Independent Researcher

Burlingame, California, USA

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

Janet L Dafoe, PhD
Child Psychologist in Private Practice
Palo Alto, California, USA

Todd E. Davenport, PT, DPT, MPH, OCS
Professor & Program Director
Department of Physical Therapy
Thomas J. Long School of Pharmacy & Health Sciences
University of the Pacific
Stockton, California, USA
Workwell Foundation
Ripon, California, USA

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

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

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

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

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

Derek Enlander, MD
Clinician in Private practice
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, MPH, PhD
Honorary Research Fellow
Division of Population Health, Health Services Research & Primary Care
School of Health Sciences
University of Manchester
Manchester, England, UK

Simin Ghatineh, MSc, PhD
Biochemist
London, England, 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, England, UK

Mike Godwin, JD
Attorney and Author
Distinguished Senior Fellow
R Street Institute
Washington, DC, USA

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

Alan Gurwitt, MD
Clinician in Private Practice (retired)
Associate Clinical Professor, Yale Child Study Center (retired)
New Haven, Connecticut, USA
Associate Clinical Professor, University of Connecticut Dept of Psychiatry (retired)
Storrs, Connecticut, USA
Lecturer, Harvard Medical School (retired)
Boston, Massachusetts, USA

Geoffrey Hallmann, LLB, DipLegPrac
Former Lawyer (Disability and Compensation)
Lismore, New South Wales, Australia

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

Malcolm Hooper, PhD, BPharm, MRIC, CChem
Emeritus Professor of Medicinal Chemistry
University of Sunderland
Tyne and Wear, England, 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
Center for Complex Diseases
Mountain View, California
Member, The ME/CFS Collaborative Research Center at Stanford
Palo Alto, California, USA

Betsy Keller, PhD, FACSM
Professor, Department of Exercise & Sport 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
Open Medicine Institute
Mountain View, California, USA

Richard Kwiatek, MBBS, FRACP
Rheumatologist and Independent Researcher
Northern Adelaide Local Health Network
Adelaide, South Australia, Australia

Eliana M. Lacerda, MD, MSc, PhD
Clinical Assistant Professor
International Centre for Evidence in Disability
Faculty of Infectious and Tropical Diseases
London School of Hygiene & Tropical Medicine
London, England, UK

Charles W. Lapp, MD
Medical Director
Hunter-Hopkins Center
Charlotte, North Carolina, USA

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

Donald Lewis, MBBS, FRACGP, DRACOG
Medical Director
CFS Discovery
Melbourne, Victoria, Australia

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

David F. Marks, PhD
Editor
Journal of Health Psychology
& Health Psychology Open
London, England, UK

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

Marlon Maus, MD, DrPH, FACS
DrPH Program Director
School of Public Health
University of California, Berkeley
Berkeley, California, USA

Neil R McGregor. BDS, MDSc, PhD
Clinical Associate Professor
Faculty of Medicine, Dentistry and Health Sciences
Bio21 Molecular Science & Biotechnology Institute
University of Melbourne.
Melbourne, Victoria, Australia

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

Marvin S. Medow, PhD
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

Jose G. Montoya, MD, FACP, FIDSA
Professor of Medicine
Division of Infectious Diseases and Geographic Medicine
Stanford University School of Medicine
Stanford, California, USA
Director, Palo Alto Medical Foundation Toxoplasma Serology Laboratory
National Reference Center for the Study and Diagnosisof Toxoplasmosis
Palo Alto, California, USA

Sarah Myhill, MBBS
Clinician in Private Practice
Knighton, Wales, UK

Luis Nacul, MD, PhD
Clinical Associate Professor
International Centre for Evidence in Disability
Faculty of Infectious and Tropical Diseases
London School of Hygiene & Tropical Medicine
London, England, UK

Heidi Nicholl, PhD
Chief Executive Officer
Emerge Australia
Melbourne, Victoria, Australia

James M. Oleske, MD, MPH
François-Xavier Bagnoud Professor of Pediatrics
Senator of RBHS Research Centers, Bureaus, and Institutes
Director of 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

Nigel Paneth, MD, MPH
University Distinguished Professor
Depts of Epidemiology & Biostatistics and Pediatrics & Human Development
College of Human Medicine
Michigan State University
East Lansing, Michigan, USA

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

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

Michael Scott, PhD
Clinician/Researcher
Psychological Therapies Unit
Liverpool, England, UK

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

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

Nigel Speight, MA, MB, BChir, FRCP, FRCPCH, DCH
Pediatrician
Durham, England, UK

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

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

Barbara True, MD, FRACP
Private Practice
Wakefield Rheumatology
Adelaide, South Australia, Australia

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

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

Rosemary A. Underhill, MBBS, MRCOG, FRCSE
Physician, Independent Researcher
Palm Coast, Florida, USA

Derya Unutmaz, MD
Professor
The Jackson Laboratory for Genomic Medicine
Farmington, Connecticut, USA

AM Uyttersprot, MD
Neuropsychiatrist
AZ Jan Portaels
Vilvoorde, Belgium

Rosamund Vallings, MNZM, MBBS
General Practitioner
Auckland, New Zealand

Linda van Campen, MD
Cardiologist
Stichting Cardiozorg
Hoofddorp, The Netherlands

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, The Netherlands

Frans Visser, MD
Cardiologist
Stichting Cardiozorg
Hoofddorp, The 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, England, UK
Adjunct Professor, School of Psychology
University of Kent
Canterbury, England, UK

William Weir, FRCP
Infectious Disease Consultant
London, England, UK

John Whiting, MD
Specialist Physician in Private Practice
Brisbane, Queensland, Australia

Sadie Whittaker, PhD
Chief Scientific Officer
Solve ME/CFS Initiative
Los Angeles, California, USA

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

Marcie Zinn, PhD
Cognitive Neuroscience and Data Science
Center for Community Research
DePaul University
Chicago, Illinois, USA
Associate Editor, BMC Journal of Translational Medicine

___________

[1] White PD 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

[2] Boseley S. 2011. Study finds therapy and exercise best for ME. The Guardian, 18 Feb. Available at: https://www.theguardian.com/society/2011/feb/18/study-exercise-therapy-me-treatment (accessed on April 23, 2018)

[3] Bleijenberg G, Knoop H. 2011. Chronic fatigue syndrome: where to PACE from here? The Lancet, 377: 786-788

[4] Wilshire C et al. 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, 14 Dec. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1259724 (accessed on April 23, 2018)

[5] U.S. Institute of Medicine (now National Academy of Medicine). 2015. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. The National Academies: Washington, DC, USA.

[6] Tuller D. 2015. Trial by error: the troubling case of the PACE chronic fatigue syndrome trial. VirologyBlog, 21-23 Oct. Available at: http://www.virology.ws/2015/10/21/trial-by-error-i/ (accessed on April 23, 2018)

[7] Racaniello V. 2016. An open letter to The Lancet, again. VirologyBlog, 10 Feb. Available at: http://www.virology.ws/2016/02/10/open-letter-lancet-again/ (accessed on April 23, 2018)

[8] Rehmeyer J. 2016. Bad science misled millions with chronic fatigue syndrome. Here’s how we fought back. STAT, 21 Sept. Available at: https://www.statnews.com/2016/09/21/chronic-fatigue-syndrome-pace-trial/ (accessed on April 23, 2018)

[9] Geraghty K. 2017. ‘PACE-Gate’: when clinical trial evidence meets open data access. Journal of Health Psychology, 22: 1106-1112

[10] Wilshire C et al. 2018. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology; published online 22 March. Available at: https://bmcpsychology.biomedcentral.com/articles/10.1186/s40359-018-0218-3 (accessed on April 23, 2018)

[11] Smith M et al. 2016. Diagnosis and treatment of myalgic encephalomyelitis/chronic fatigue syndrome; addendum. U.S. Agency for Healthcare Research and Quality. July. Available at: https://www.ncbi.nlm.nih.gov/books/NBK379582/ (accessed on April 23, 2018

[12] Rehmeyer J, Tuller D. 2017. Why did it take the CDC so long to reverse course on debunked treatments for chronic fatigue syndrome? STAT, 25 Sept. Available at: https://www.statnews.com/2017/09/25/chronic-fatigue-syndrome-cdc/ (accessed on April 23, 2018)

[13] Whipple T. 2017. Mutiny by ME sufferers forces a climbdown on exercise treatment. The Times, 25 Sept.

[14] Health Council of the Netherlands. 2018. More scientific research on ME/CFS is needed to serve patients better. 19 March. Available at: https://www.gezondheidsraad.nl/en/news/more-scientific-research-on-mecfs-is-needed-to-serve-patients-better (accessed on April 23, 2018)

[15] Tucker M. 2018. Much can be done to ease ‘chronic fatigue syndrome’ symptoms. Medscape, 12 March. Available at: https://www.medscape.com/viewarticle/893766 (accessed on April 23, 2018)

(Many thanks to Mary Dimmock for helping to contact the signatories.)

Thursday, 14 June 2018

ME Association: The 2018 Invest in ME Research Conference Report – Dr Charles Shepherd

http://www.meassociation.org.uk/2018/06/the-2018-invest-in-me-research-conference-report-dr-charles-shepherd-14-june-2018/

The 2018 Invest in ME Research Conference Report – Dr Charles Shepherd | 14 June 2018

Dr Charles Shepherd provides a summary report of the 13th Invest in ME Research Conference that took place in London on 1st June - 

http://www.meassociation.org.uk/wp-content/uploads/Dr-Shepherd-IiMER-Conference-Report-2018-13.06.18.pdf

“The conference again took place at One Great George Street – an impressive Edwardian building, with equally impressive conference facilities, that sits opposite St James’s Park in London.

“As usual, the audience consisted of people with ME/CFS, carers, charity representatives, health professionals and researchers, from the UK and overseas. The conference was chaired by Dr Ian Gibson with his usual wit and enthusiasm.

“Overall, this was an interesting and enjoyable meeting that covered a number of important overseas research initiatives, as well as some clinical presentations that are more relevant to the here and now situation facing people with ME/CFS.

“Thank you to everyone who was involved in the organisation of the conference.”

To read and download Dr Shepherd’s report - 

http://www.meassociation.org.uk/wp-content/uploads/Dr-Shepherd-IiMER-Conference-Report-2018-13.06.18.pdf

To order the DVDs from Invest in ME of all the conference talks, go to - 

Monday, 11 June 2018

We love Him because He first loved us

http://bible.christiansunite.com/Morning_and_Evening/chme0611.shtml

C H Spurgeon's Morning Devotional for 11th June

"We love Him because He first loved us.”

1 John 4:19

There is no light in the planet but that which proceedeth from the sun; and there is no true love to Jesus in the heart but that which cometh from the Lord Jesus himself. From this overflowing fountain of the infinite love of God, all our love to God must spring. This must ever be a great and certain truth, that we love Him for no other reason than because He first loved us. Our love to Him is the fair offspring of His love to us. Cold admiration, when studying the works of God, anyone may have, but the warmth of love can only be kindled in the heart by God's Spirit. How great the wonder that such as we should ever have been brought to love Jesus at all! How marvellous that when we had rebelled against Him, He should, by a display of such amazing love, seek to draw us back. No! never should we have had a grain of love towards God unless it had been sown in us by the sweet seed of His love to us. Love, then, has for its parent the love of God shed abroad in the heart: but after it is thus divinely born, it must be divinely nourished. Love is an exotic; it is not a plant which will flourish naturally in human soil, it must be watered from above. Love to Jesus is a flower of a delicate nature, and if it received no nourishment but that which could be drawn from the rock of our hearts it would soon wither. As love comes from heaven, so it must feed on heavenly bread. It cannot exist in the wilderness unless it be fed by manna from on high. Love must feed on love. The very soul and life of our love to God is His love to us.

"I love thee, Lord, but with no love of mine,
For I have none to give;
I love thee, Lord; but all the love is thine,
For by thy love I live.
I am as nothing, and rejoice to be
Emptied, and lost, and swallowed up in thee."

Friday, 1 June 2018

What Doctors Don’t Tell You: ME: the cure that went away


Bryan Hubbard

June 2018

Chronic fatigue and ME could be dramatically improved with exercise and therapy, a landmark study discovered. But it was bad science, and the cure was never there.

Controversy has always dogged chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME), the mysterious condition that leaves a patient tired all the time and exhausted from the slightest exertion. The minority of doctors who even believed their patient had an actual physical problem—as opposed to the rest who suspected it was more to do with mind than matter—were perplexed. Then, seven years ago, medicine thought they'd finally figured out how to treat it: patients could get better by combining exercise and cognitive behavioral therapy (CBT), the 'talking cure.'

It was as if a light had been switched on in a darkened room, and it all came from one 2011 study, called the PACE trial, which concluded that the two approaches dramatically improved the sufferers' fatigue—and around 22 percent went on to achieve a full recovery, the researchers claimed in a press conference. 1

But it's all unraveling. Another research team has looked at the raw data that underpinned the PACE study and found that the therapies had "no long-term benefits at all." The 60 percent improvement reported by the PACE researchers was reduced to just 20 percent in the reanalysis, and the 22 percent who had experienced a full recovery evaporated to just 8 percent. 2

To make matters worse, the data had to be crow-barred from the PACE research team. Freedom of information requests had been ignored, and it took two tribunals to get the researchers—who had recruited a $285,000 legal team to defend them—to conform with the request.

In a separate move, WDDTY columnist Dr Sarah Myhill is calling on the General Medical Council (GMC), which regulates the conduct of doctors in the UK, to mount an investigation. She is accusing the PACE researchers of scientific fraud and breaching 'good medical practice.'

Out-paced

Looking at the raw data of the PACE study, researchers from the University of Wellington in New Zealand discovered that almost all the benefits of graded exercise—where the intensity and duration of activity slowly increase—and CBT disappear when the definition of 'patient recovery' is adhered to throughout the duration of the trial and when assessing patients' outcomes afterwards.

The PACE researchers established what they meant by patient 'improvement' and 'recovery'—which included established thresholds that were statistically measurable—before the study began. However, once the study was underway, they weakened their own protocols dramatically, and a patient would be considered to have 'recovered' even when their symptoms had worsened during the trial. The bar for good physical function was lowered so far that even an 80-year-old would have passed, other researchers noted.

Ultimately, the assessment of whether a participant had recovered was determined entirely by the patient—and this was after they had been shown glowing testimonials about the therapies they were getting halfway through the study.

When the original protocols for recovery were reapplied—along with other everyday measures such as returning to work—all the benefits announced by the PACE researchers disappeared. Rates of recovery were "consistently low," the researchers said, and were hardly better than those being achieved by standard treatment. As lead researcher Carolyn Wilshere put it, the PACE researchers had "moved the goalposts."

Legal pace

In Dr Myhill's call to the GMC to investigate the PACE researchers, she is claiming that they have committed 'scientific fraud.' In a letter to Sir Terence Stephenson, GMC chairman, she cites three definitions laid out by the UK Fraud Act of 2006—fraud by false representation, fraud by failing to disclose information and fraud by abuse of position—which she wants the GMC to investigate.

She also argues that CFS/ME patients have been harmed by the therapies promoted by the PACE researchers, and she is urging them to also write to the GMC. "The PACE trial has effectively determined CFS/ME as a psychological condition. As a result, patients who suffer what is, in fact, a serious and debilitating physical condition have been subject to therapies which at best are ineffective and at worse exacerbate the condition," she writes.

Keeping pace

Within months of the PACE results being published, doctors had quickly embraced the dual approach. In the UK, the National Institute for Health and Care Excellence (NICE) established it as the standard treatment, and, more bizarrely, the government's Department for Work and Pensions (DWP) was also recommending it. But the DWP wasn't an innocent bystander: it was shelling out millions in benefits to the country's 250,000 ME sufferers, and it also happened to have funded the PACE trial to the tune of about $7 million. In the US, the Centers for Disease Control and Prevention (CDC), which had worked closely with two of the PACE researchers, Peter White from Queen Mary University in London and Michael Sharpe from Oxford University, also recommended the therapy as the way forward.

The PACE results had pleased both camps in medicine: those that believed that ME was 'all in the head' and others who suspected there had to be a viral cause. The PACE researchers were acolytes of psychiatrist Simon Wessely at King's College London, who squared the circle with his hypothesis that a virus or some organic trigger may have kick-started the problem, but it was prolonged by the morbid thoughts of the sufferer. "The symptoms and disability of CFS are perpetuated predominantly by dysfunctional illness beliefs and coping behaviors," he said. 3

While doctors celebrated, the analysis just wasn't ringing true for many sufferers, who couldn't believe that either approach was of much use. In fact, whenever they exercised, they collapsed with exhaustion immediately afterward, and were often confined to bed, as ME sufferer Sally Burch related after she had been advised by her doctor to take three brisk walks a day. "Those short walks were causing me to get out of breath, and to feel light-headed and dizzy. As the days went by, I found I was able to walk shorter and shorter distances before I ended up in a heap on the ground, trying to make the world stay still. Something was very wrong." 4

Pace of change

Other sufferers thought there was something very wrong with the findings of the PACE trial, too. CFS sufferer Alem Matthees in Australia put in the first freedom of information request to see the underlying data, and he was soon joined by six scientists from Stanford University, who demanded a full independent investigation.

Even though the raw data was being kept under wraps, other researchers were able to spot anomalies. David Tuller at the University of California, Berkeley, discovered that 13 percent of the 641 CFS/ME sufferers recruited into the original trial had 'recovered' even before the trial had started, at least according to the very loose definition of 'recovery' the researchers were using.

Stung by the mounting criticism, the PACE researchers claimed that their critics were "young men, borderline sociopaths or psychopathic"—hardly a fitting description of scientists from Stanford University—before claiming they had been threatened and harassed, which was later found to be untrue.

Finally, they issued a new analysis of their original data, in which they concluded that the participants who hadn't improved were simply afraid of exercise. 5

All of this puts our understanding about CFS/ME—what it is, what causes it and how it can be treated—back to square one. It's clearly not 'all in the mind'—or 'yuppie flu,' as it was once disparagingly described—and this acceptance is at least allowing new theories about what it might be to flourish.

References

1              Lancet, 2011; 377: 823-36

2              BMC Psychol, 2018; 6: 6

3              Gen Hosp Psychiatry, 1997; 19: 185-99

4              www.sallyjustme.blogspot.co.uk

5              Lancet Psychiatry, 2015; 2: 141-52