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 onApril 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.)

By David Tuller, DrPH

From the start, one of my strategies for this PACE-debunking project was to draw in outside experts–people with no ax to grind and no pre-conceived notions about the trial and its methodology–and encourage them to scrutinize the matter. It was telling that many well-regarded scientists and researchers were willing to make scathing public comments about PACE and the related claims being made by the CBT/GET ideological brigades. When Bruce Levin, a professor of biostatistics at Columbia, calls something “the height of clinical trial amateurism,” people should pay attention and stop maligning PACE critics as being irrational, anti-science or vexatious.

That’s why I’m delighted that Simon Wessely himself, in a recent Twitter exchange, invited Mike Godwin, an American attorney and social commentator, to review the PACE trial controversy. After scrutinizing the published record, including the PACE research and the special issue of the Journal of Health Psychology dedicated to the issue, Godwin pronounced PACE to be “so profoundly flawed that it cannot be trusted.” In response, Sir Simon attempted to re-direct the narrative, reiterating his own positive beliefs about the trial. What he fails to understand is that, despite his knighthood and his widely hailed courage in “standing up for science,” his beliefs and opinions are irrelevant here. In this case, the facts are what count.

And when outside observers assess the facts about PACE, they see what the critics see–an uninterpretable mess. Mike Godwin is known for the so-called “Godwin’s Law of Nazi Analogies,” a trenchant observation that he described this way in a 1994 article in Wired: “As an online discussion grows longer, the probability of a comparison involving Nazis or Hitler approaches one.” Almost 25 years later, this observation has retained its relevance and social currency.

In any event, the embroilment of Godwin in the PACE debate can be traced to Professor Michael Sharpe. He has been engaged for weeks in a relentless but ultimately incoherent pro-PACE tweeting campaign that has once again exposed his inability to defend the study’s methodological flaws. Recently, in response to something someone tweeted in one of these tweet-chains inspired by yet another Sharpe head-scratcher, a PACE critic referenced “the banality of evil”—the brilliant but exhausted Hannah Arendt phrase that emerged from the philosopher’s coverage of the Eichmann trial in Jerusalem. At that point who should jump into the tweet-fray but Sir Simon himself.

(I can’t see Sir Simon’s tweets. He blocked me a year or two ago when I tweeted that some drivel and nonsense he’d tweeted was in fact “drivel and nonsense,” or it might have been “nonsense and drivel.” Screen-shots of his recent tweets were posted on a patient forum.)

Apparently triggered into action by the Holocaust allusion, Sir Simon tweeted out to Godwin with an oblique reference the Nazi-analogy “law” that bears his name. As it turns out, the two became chums decades ago when the young Simon attended an American high school as an exchange student. Who knew? Alas, bonds forged back then in chem lab or drama club were not enough to prevent Godwin from offering a blunt appraisal of the £5,000,000 garbage heap that Sir Simon has called “a thing of beauty.” (Godwin assured me that the two men remain friends despite their disagreement about PACE.)

Sir Simon has defended PACE up and down the queen’s realms, and he appears convinced of his own correctness. As he is fond of reminding people, he wrote the book on clinical trials so he knows something about them. (Can someone check whether Sir Simon’s book covers whether investigators can weaken outcome thresholds after data collection in ways that dramatically boost reported results?) But he appears blind to how others view the study. Did Sir Simon think his school buddy would end up bolstering his side of the argument? If so, he miscalculated.

Godwin did more than declare the trial to be “profoundly flawed.” In his comments, he touched on one of the main negative consequences of the PACE debacle—the fact that the trial and/or its CBT/GET recommendations have influenced how disability insurers and government social welfare agencies make their determinations. Here’s what Godwin, who also watched some of the recent Scottish parliamentary hearings on the issue, tweeted about that aspect of the debate: “It seems clear to me that the PACE trial will continue to be used to deny patients benefits. That sucks.”

Since Sir Simon invited Godwin into the conversation in the first place, the quick smack-down of PACE likely stung. But he managed to present a brave front in the face of the humiliation. In a series of tweets, he wrote back: “You won’t be surprised mike to find that I don’t agree with this…I continue to believe they did a good job with the trial and that it was carried out to a high standard the data is sound even if the results are relatively modest.”

Sir Simon even tweeted to Godwin the “ocean-liner PACE defense” essay posted by The National Elf website in late 2015, shortly after Virology Blog published my 15,000-word investigation. Despite his apparent fondness for this essay, the ocean-liner metaphor is a disaster for his argument, as Northwestern law professor Steven Lubet has noted. It is not just because of the inevitable Titanic association, although that’s a problem. But his account of how the navigators made mid-trip adjustments so the ocean-liner called PACE could reach its pre-determined destination raises further questions. To extend the metaphor, the goal of a clinical trial is to reach whatever destination you reach by following the course you committed to at the outset, not to reach a pre-determined destination by changing your course mid-way through—which is of course what happened in PACE.

Poor Sir Simon. He’s a smart guy but appears to remain mired in misconceptions. He doesn’t grasp that his defense of the PACE trial is intellectually and ethically bankrupt. Now he has unwittingly solicited some unvarnished comments about the trial from a childhood friend. Perhaps Godwin’s honest assessment will finally help Sir Simon accept with grace and humility what experts around the world have recognized: PACE is a piece of crap.

(Post-script: I wrote most of the above on Saturday. Afterwards, Professor Sharpe rejoined the conversation. I responded to his absurd comments in several tweets, which only reinforced my conviction that he is unable or unwilling to understand the legitimate concerns about PACE. In such circumstances, efforts at dialogue and communication seem pointless. On top of that, Professor Sharpe has now blocked me on Twitter, like his colleague Sir Simon.)

This morning I sent the following e-mail to key NICE executives involved in the effort to overhaul the clinical guidance for ME/CFS. I cc’d several stakeholders in the process as well.

**********

Dear Sir Andrew and Professor Baker (and others)—

In an e-mail to Sir Andrew last year, I posed some questions concerning the involvement of NICE with the Improving Access to Psychological Therapies program being rolled out across England by the National Health Service. According to the NICE website, the organization is working with IAPT to “assess digitally enabled therapies for anxiety, depression and medically unexplained symptoms which offer the potential to expand these services further.”

Here is part of that e-mail from last fall:

Chronic fatigue syndrome is included in the list of thirteen conditions identified by “the NICE expert IAPT panel” as appropriate targets for interventions developed through this program. The IAPT site indicates that these interventions need to be consistent with NICE guidance. The site then refers readers to CG53 [the 2007 NICE guidance for CFS/ME] but makes no mention that this guidance is undergoing a full update.

Why is chronic fatigue syndrome still listed under the IAPT program? Does the Guidance Executive agree that it should be removed, since it is not a psychological or psychiatric disorder and the use of CBT and GET is very much under question? If it is not removed from under the auspices of IAPT, does that mean NICE intends to encourage the development of digital methods of delivering CBT and GET to people with CFS/ME, even as the guidance itself undergoes a full update?

Despite positive developments in the NICE process since then, these questions remain. IAPT’s interest in digitally delivered therapies raises particular concern among ME/CFS patients and advocates because it suggests the possible or even likely adoption or endorsement of some version of FITNET-NHS. That is the Bristol University trial investigating online CBT for children, based on the purported success of earlier Dutch research. Critics of the PACE trial, including me, have documented serious methodological weaknesses in both the Dutch study and the U.K. version.

Last year, before NICE announced its decision to pursue a full update of the guidance for this illness, FITNET-NHS was being cited as a study of interest to be considered in a future review. But given the identified deficiencies of this research into online CBT, it has no place being considered during the development of health policy or clinical guidelines for ME/CFS.

As the NICE process for producing the new ME/CFS guidance moves forward, so does IAPT’s implementation of its expansion strategy. IAPT’s recent publications contain no indication, as far as I can tell, that anyone from NICE has communicated with anyone from IAPT about the paradigm shift occurring in perceptions about and treatment of ME/CFS. Those involved with IAPT seem not to have noticed yet that the CBT/GET approach is rapidly losing credibility worldwide.

Does NICE have any current plans to communicate with IAPT about ME/CFS, and specifically about IAPT’s ongoing roll-out of CBT and GET services for these patients? Or will such communications need to wait until the new guidance is released in 2020? Does NICE at least plan in the interim to suspend its cooperation with the NHS on developing digitally enabled or non-digitally enabled IAPT services related to ME/CFS? Since a new NICE guidance is in the works, developing any ME/CFS services for IAPT based on what will soon be an outdated document would seem to be a questionable way to invest limited public resources.

Thanks for your attention to this matter.

Best–David

David Tuller, DrPH
Senior Fellow in Public Health and Journalism
Center for Global Public Health
School of Public Health
University of California, Berkeley

Vincent, Kathy and Rich travel to ASM Microbe 2018 in Atlanta where they speak with Stacy Horner and Ken Stapleford about their careers and their research.

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IFN signaling

Type I IFN receptor binding and signal transduction.

By Gertrud U. Rey

Zika virus (ZIKV) infection causes microcephaly in newborns and is causally associated with Guillian–Barré syndrome in adults. To date, there are no drugs available to prevent or treat ZIKV infection. ZIKV vaccine research is challenging because adult immunocompetent mice are resistant to ZIKV infection and disease.

The primary immunologic response to ZIKV infection is the production of type I interferon, which binds to the interferon alpha/beta 1 receptor (IFNAR1) and activates signal transducer and activator of transcription (STAT) complexes (illustrated). Activation of this pathway leads to the production of hundreds of antiviral and immunomodulatory interferon-stimulated genes and a general antiviral state. In humans, ZIKV evades the innate immune response by degrading STAT2, thereby antagonizing type I interferon (click here for a review of how viruses interfere with interferon). However, in mice ZIKV is incapable of binding STAT2 and triggering its downstream transcriptional effects, possibly explaining the resistance of immunocompetent mice to ZIKV. Consequently, most mouse studies of ZIKV pathogenesis have been done in mice with genetic or acquired deficiencies of interferon signaling. Unfortunately, such models don’t mimic human disease sufficiently to make them suitable for evaluating vaccines and therapeutics.

Using a two-step approach, a group at Washington University School of Medicine has developed a new system to study ZIKV infection in mice (link to paper). First, they generated a mouse-adapted ZIKV strain by passaging the African strain ZIKV-Dak (parental strain) in mice that have an intact type I interferon response but lack mature B and T cell responses. Second, they developed a fully immunocompetent mouse model of ZIKV infection by introducing human STAT2 into the mouse Stat2 locus.

After passaging the parental virus strain four times, the authors obtained ZIKV-Dak-MA (MA indicates mouse-adapted), a strain containing three mutations. The first was a silent mutation in the nucleotide sequence coding for E protein, while the other two were non-synonymous mutations of lysine to arginine, and glycine to arginine at positions 399 and 18 of the NS3 and NS4B proteins, respectively. To test the infectivity of this mutated viral strain, wild type mice were first treated with an anti-Ifnar1 monoclonal antibody and then infected. Compared to the parental strain, ZIKV-Dak-MA was more lethal, with a higher level of replication in the mouse brains.

This higher infectivity in brains may be due to an increased ability of the mutant virus to cross the blood-brain barrier or because it can replicate better in neurons. To test these possibilities, the authors infected mice intracranially with mutant or parental virus in the absence of anti-Ifnar1 antibody treatment. Intracranial infection would bypass the blood-brain barrier, and omitting anti-Ifnar1 antibody would lead to cessation of viral replication before systemic dissemination. Although neither virus caused a lethal infection, mutant viral RNA accumulated to greater levels in multiple regions of the brain, compared to parental virus RNA. In contrast, intracranial infection of mice deficient in IFNAR1 receptor with either strain resulted in minimal differences in viral RNA produced by the two strains. This result suggests that the difference in replication between the two viruses is likely mostly due to different abilities to evade type I interferon responses.

To determine which of the two non-synonymous mutations was responsible for enhanced infection and disease, the authors engineered viruses with the non-synonymous mutations in either NS3, NS4B, or both. Mice were then treated with anti-Ifnar1 monoclonal antibody and challenged with either of the mutant viruses. Viruses with mutations in either NS4B or both NS3 and NS4B were about 95% lethal in mice, while the virus with the NS3 mutation only caused about 5% mortality. The authors obtained the same result in mouse and human neural stem cells, suggesting that the NS4B mutation is necessary and sufficient for enhanced virulence.

Single-cell RNA sequencing analysis of neural stem cells infected with the parental or the NS4B mutant virus revealed that the NS4B mutant is less effective at inducing interferon-stimulated genes and type I interferon responses compared to the parental virus. To determine whether ZIKV modulates type I interferon signaling responses, the authors pre-treated murine neural stem cells with either anti-Ifnar1 antibody or exogenous IFN-b and then infected the cells with parental or NS4B mutant virus. Viral yields produced by the NS4B mutant were higher in the absence, and lower in the presence of anti-Ifnar1 antibody. However, pre-treatment of cells with IFN-b caused the two viruses to replicate to similar levels, suggesting that the NS4B mutation likely results in diminished levels of IFN-b. The fact that the NS4B mutant was still sensitive to exogenous interferon suggests that it may be unable to bind to and degrade mouse STAT2.

In the second major part of this study, the authors generated a fully immunocompetent mouse model of ZIKV infection by introducing human STAT2 into the mouse Stat2 locus. Infection of these human STAT2 knock-in mice with ZIKV-Dak-MA led to 30% mortality, with higher viral levels observed in the spleen and brain. In contrast, none of the mice inoculated with parental virus died. In addition, pregnant ZIKV-Dak-MA recipients passed the virus to their babies. Higher levels of ZIKV-Dak-MA were detected in the placenta and fetal heads of STAT2 knock-in mice. The authors concluded that combining the adapted ZIKV strain with human STAT2 knock-in mice produces a model system that mimics the human mechanism of ZIKV pathogenesis.

The lack of a suitable immunocompetent mouse model for ZIKV infection has been an impediment to research progress in this field. The model system presented here has drawbacks, such as the need to use a specific viral mutant, and a disparity of phenotype observed in peripheral organs and the brain following subcutaneous inoculation with either mutant and parental strains. However, it presents an additional resource for determining mechanisms of pathogenesis, defining correlates of innate and adaptive immune protection, and for developing drugs.

By David Tuller, DrPH

Ten years ago, the National Health Service began rolling out across England a program called Improving Access to Psychological Therapies, or IAPT. This program arose out of the notion that many people were suffering from untreated depression, anxiety and other psychiatric disorders. In parallel with that, research suggested that treating these ailments would not only be good for public health but would in turn help restrain overall medical costs. The most common but not the only psychotherapeutic intervention offered by IAPT services is cognitive behavior therapy.

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By David Tuller, DrPH

This morning I sent three more e-mails alerting interested parties to my concerns about two BMJ studies of children with ME/CFS. When it comes to research, kids are already a vulnerable population, and those with a stigmatizing illness even more so. That’s why it is both surprising and troubling that BMJ appears to have little interest in addressing the ethical and/or methodological violations that Virology Blog has documented in these pediatric studies.

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TWiV 497: Europic 2018

At Europic 2018, a meeting on picornaviruses in the Netherlands, Vincent speaks with Sasha Gorbalenya, Jim Hogle, Ann Palmenberg and Frank van Kuppeveld about their careers and their research.

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N-terminal myristoylation

N-terminal myristoylation. An amide bond links myristate to an N-terminal glycine in the myristoylation site consensus sequence.

The common cold is an infection of the upper respiratory tract that may be caused by many different viruses, but most frequently by rhinoviruses. A compound that inhibits a cell enzyme and blocks rhinovirus replication has the potential to be developed into an antiviral drug (link to paper).

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By David Tuller, DrPH

I have sent the following e-mail to Edward Sykes, the head of mental health and neuroscience at the Science Media Centre. The e-mail concerns the Lightning Process study published last year in Archives of Disease in Childhood. The SMC promoted the findings, which received widespread media coverage.

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