By David Tuller, DrPH

As I mentioned in my six-month review, I always feel that there are lots of issues I don’t get to. To broaden the blog’s range a bit and, hopefully, increase its usefulness to readers, I figured it was a good idea to post the weekly round-up of news posted on the invaluable Science For ME forum. (Thanks, @Trish and @Kalliope for compiling the round-ups and S4ME for allowing me to re-post them.)

I am on the forum regularly and find that the smart, free-ranging discussions, comments and updates are critical for my own understanding of events. I recommend it highly to anyone with an interest in this issue.

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Week beginning 14th January 2019

Headline News

UK Parliamentary Debate this Thursday. Contact your MP.
House of Commons backbench debate on ME/CFS will take place on Thursday 24th January led by Carol Monaghan.

Motion to be debated and voted on:

That this House calls on the Government to provide increased funding for biomedical research into the diagnosis and treatment of ME, supports the suspension of Graded Exercise Therapy and Cognitive Behaviour Therapy as means of treatment, supports updated training of GPs and medical professionals to ensure they are equipped with clear guidance on diagnosis of ME and appropriate management advice to reflect international consensus on best practice, and is concerned about the current trends of subjecting ME families to unjustified child protection procedures.

#MEAction: links for contacting your MP here article here
ME Association article with links to contact your MP here
Parliamentary briefing here
Article in The Canary here Thread here
……………………………………………………

News

Belgium – Extension of the ME/CFS convention.
@Michiel Tack has summarized the Belgian assessment report. On the positive side, the report highlights biomedical findings and acknowledges problems with the PACE-trial, GET and the oxford criteria. The negative side is that the authors cling on to CBT, despite their results being rather poor.
Thread with summary here

Invest in ME and European ME Alliance are facilitating the formation of the European ME Clinicians Council (EMEC)
It will bring together clinicians in the field of ME and form a network that can improve the knowledge of clinicians in Europe and act as a focal point for healthcare agencies, doctors and media outlets who wish to learn more from experienced clinicians.
Presentation from Invest in ME here Thread here
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Letters, talks …

UK – Open letter to AfME @Trish has written a personal open letter to Action for ME asking them to withdraw their document ”Support, empower and employ people with M.E. A toolkit for professionals”.
Concerns are detailed about inaccuracies and the emphasis on rehabilitation and goal setting, especially as the document has been circulated to DWP staff who deal with unemployment and disability benefits.
AfME have replied saying they will not withdraw the document but it will be reviewed as part of their ongoing reviews process.
AfME ‘Toolkit’ here Thread with letter here Reply from AfME here

David Tuller’s lecture: The PACE Trial: “Thing of beauty or Pile of Crap” from a seminar in Norway in November 2018 is now available on YouTube.
Thread with link to video here
…………………………………………

Biomedical Research

Nature Genetics
”Repurposing large health insurance claims data to estimate genetic and environmental contributions in 560 phenotypes” by Lakhani et al.
Data from twins suggests a large genetic component in ME/CFS and very little environmental influence (with some caveats).
Paper here Thread here

International Journal of Immunopathology and Pharmacology
”Changes in the transcriptome of circulating immune cells of a New Zealand cohort with ME/CFS” by Sweetman, Tate et al.
Small study showed molecular changes including relating to inflammation, cellular stress response, metabolism, mitochondria and circadian clock.
Paper here Thread here

Clinical Therapeutics
“Relationship Between Exercise-induced Oxidative Stress Changes and Parasympathetic Activity in CFS: An Observational Study in Patients and Healthy Subjects” – Andrea Polli et al
Data from 36 participants (women with CFS and healthy controls) performing exercise test. Oxidative stress showed an association with pain symptoms in people with ME/CFS, but no exercise-induced changes in oxidative stress were found. The change in parasympathetic activity following exercise partially accounted for the change in oxidative stress in healthy controls.
Paper here Thread here
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Other research

Frontiers in Pediatrics
”Onset patterns and course of ME/CFS” by Chu, Montoya et al
Results from survey with 150 ME patients (Fukuda criteria) from USA. Most findings consistent with prior studies, but also explores new topics including evolution of symptoms.
Article here Thread here
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Psychosocial news

Denmark – Journal of Psychosomatic Research
Letter to the editor by director of Danish Health Authority where he argues that it makes sense for the Danish Health Authority to accept the diagnostic umbrella term of “functional disorders”. ME belongs under this umbrella according to him. Not a recommendation.
Letter to the editor here Thread here
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Coming Events

Norway ME-conference March 26-27
“A health political, biomedical ME conference” with Norwegian lecturers.
Website to conference here Thread here

NIH conference April 4-5th ‘Accelerating Research on ME/CFS’
The goal is to present high-quality studies of ME/CFS to better understand the state of science and help drive the field forward. For scientists, clinicians, patients and other ME/CFS stakeholders. Conference will be webcast and publicly available.
More information here Thread here

By David Tuller, DrPH

So it’s time again to review my work and figure out what I’ve been doing. My crowdfunding from last April has been covering my half-time position at Berkeley since July 1, so December 31 marks the end of the first six months. The Berkeley fiscal year ends June 30th, so I will need to decide soon if I am going to crowdfund again this spring and continue this project for another year.

I posted 42 times from July 1st through December 31st. A third of these posts–14, if I counted correctly–involved the terrible pediatric studies coming out of the University of Bristol. The lead investigator of the Bristol group, of course, is the former vice chair of the CFS/ME Research Collaborative. Many members of the CMRC now appear to have recognized that the Bristol work is sub-par and does not warrant much consideration.

Many of these 14 posts concerned either the Lightning Process study or the school absence study, both of which are rife with methodological and ethical missteps and need to be retracted. I also reported how Bristol was advertising its FITNET-NHS trial by essentially promising that two-thirds of those who got the treatment would recover—a great way to bias the results. And I exposed how the Bristol team decided to cite the same research ethics committee letter to exempt at least 11 studies from ethical review—some of them clearly under false pretenses. Five of those studies were published in BMJ journals, yet BMJ has stonewalled rather than taking any corrective action.

Many of these posts were open letters to people who should know better. The most frequent recipient was Dr Fiona Godlee, the editorial director of BMJ, to whom I sent four of these missives. So far, for reasons I fail to understand, Dr Godlee has been either unwilling or unable to fulfill her obvious professional responsibilities in this matter. Rather, her journals seem to be doing everything they can to avoid cleaning up their messes—including accusing me of misreporting the facts. One of my open letters to Dr Godlee was a request for an apology from BMJ for this false claim from the journal BMJ Open, which published the school absence study.

Other topics also warranted multiple posts. These included the Cochrane situation, the Mayo Clinic’s continued reliance on stupid and unscientific recommendations, and the disturbing invitation to Professor Per Fink to speak at a conference on psychosomatic medicine at Columbia. The Cochrane posts included a statement in support of the decision to temporarily withdraw the deeply flawed exercise review. That letter was signed by more than 40 scientists and experts from many leading academic centers.

In addition, Virology Blog’s new open letter to The Lancet garnered even more signatures– from 114 experts, ten members of Parliament, and several dozen patient and advocacy organizations from around the world. I posted this letter first in June, and then reposted it twice more—in July and August—with more signers for each iteration. The August version received news coverage in The Times (UK), followed the next day by a story on BMJ’s site.

In response, the head of the UK Medical Research Council, Dr Fiona Watt, issued a laughable statement in defense of PACE. Not surprisingly, she cited the Cochrane reviews to back her claim. Of course, Cochrane subsequently made clear that it believes the exercise review needs to be withdrawn and revised—even though it has not yet managed to make this happen. So Dr Watt really needs to come up with a better defense of PACE if she hopes to keep justifying her agency’s seriously flawed perspective.

I wrote only one blog on the situation with NICE and one on the UK’s problematic Improving Access to Psychological Therapies program. I had intended to devote more time to both these issues during this time period but did not manage to do so; other events kept intervening. I hope to do better on these topics in the next six months, given their importance.

In non-Virology Blog efforts, I co-wrote a piece about disability insurance issues for STAT, the well-regarded health reporting site, with my friend and colleague Steve Lubet, a law professor at Northwestern University. And for BerkeleyWellness.com I conducted a Q-and-A with journalist Maya Dusenbury about her book on medical discrimination against women–Doing Harm: The Truth About How Bad Medicine and Lazy Science Leave Women Dismissed, Misdiagnosed, and Sick. The Dusenbery interview included some discussion of a key issue—so-called “medically unexplained symptoms.”

I continued my traveling and public outreach efforts. I spent time in the Netherlands and the UK in September and October, and five days in Norway in November. I was interviewed at length in both Amsterdam and Oslo. During my time in England, I attended the annual gathering of the CFS/ME Research Collaborative for the first time, pleased to note that it seemed to me to be a BPS-free zone this year. Although I wasn’t officially on the schedule, I was asked to say something at the end of the first day—so I gave a little rant along predictable lines.

In Newry, Northern Ireland, I was delighted to share the podium with Professor Brian Hughes, a psychologist at National University of Ireland Galway. My presentation wasn’t that different from usual, but I did happen to compare the peer-reviewing and self-congratulatory behavior of the PACE authors and their colleagues to a “circle jerk”—an American summer-camp expression that speaks for itself. (The only problem is that it’s a guy term, so I’m not sure it would be understood to include the many women among the GET/CBT ideological brigades.)

I also gave two talks in Sheffield and two in Norway. I think I might need to vary my act soon! Everyone’s heard it already. It might be time to develop a new talk focused on non-PACE aspects of the situation, although ripping up PACE provides me with great pleasure—even when the shredding is just metaphorical.

As always, I didn’t get to lots of things I hoped to cover. I always feel like I’m way, way behind. I still have a couple of interviews from Australia I haven’t written up, plus interviews with two patients from the Royal Free outbreak. When I started this project, there was much less news! With so much going on now in so many different countries, it seems to be more and more difficult for me to keep up with it all–much less comment on everything.

By David Tuller, DrPH

Carol Monaghan, a member of Parliament from the Glasgow area, has done it again. This week she is spearheading a three-hour debate in the House of Commons about the awful situation confronting ME patients in the UK. (The organizers of this debate are using ME, not CFS or ME/CFS or CFS/ME. As readers know, the issue of what to call the disease or cluster of diseases is fraught.)

This will be the third parliamentary debate she has organized in the last year. The difference this time around is that the debate will be held in the House of Commons itself, not in Westminster Hall like the first two. House of Commons debates are a much bigger deal. They tend to receive more press attention and have a greater potential impact on policy developments going forward. They also allow for a vote on a motion put forward by the organizers. (Of course, given Brexit insanity, it’s unclear how much coverage anything else will get, just as Trump insanity overwhelms every other issue in U.S. news coverage.)

The first two debates were held in February and June. In these initial forays, Monaghan focused on the PACE trial, among other issues. In doing so, she provided the single most damning quote about the study that I’ve heard from anyone in UK politics. “I think that when the full details of the trial become known, it will be considered one of the biggest medical scandals of the 21st century,” she declared. 

(I have suggested that this claim is too modest. When the full details become known, it could be considered one of the biggest medical scandals of the millennium—even though the millennium is only 19 years old.)

Along with three other MPs, Monaghan presented her case for the new debate in late October. More than 30 MPs overall supported the call for the House of Commons debate, so the push is a cross-party affair, not a partisan issue. Apparently members from across the political spectrum have recognized the stunning failures of the UK medical and academic establishments in this particular situation. Many undoubtedly became aware of the problems through contact with constituents suffering from the illness, which is how Monaghan stumbled onto it. Before that, she said, she knew next to nothing about the issue or about the PACE trial.

(Here is a Q-and-A with Carol Monaghan I posted last March.)

The motion proposed for consideration touches multiple important bases. Here it is:

“That this House calls on the Government to provide increased funding for biomedical research into the diagnosis and treatment of ME, supports the suspension of Graded Exercise Therapy and Cognitive Behaviour Therapy as means of treatment, supports updated training of GPs and medical professionals to ensure they are equipped with clear guidance on diagnosis of ME and appropriate management advice to reflect international consensus on best practice, and is concerned about the current trends of subjecting ME families to unjustified child protection procedures.”

In addition to these critical issues, it is my hope that one of the presenting MPs specifically calls out both the University of Bristol for its scientifically invalid research into pediatric manifestations of the illness and BMJ for publishing these bogus studies. I have documented over and over that this research violates multiple core methodological and ethical principles and should never have been published in the first place. Yet instead of taking action to correct the scientific record, BMJ has stonewalled and, in some instances, conveyed false information or absurd arguments in its defense. The Bristol University vice chancellor, for his part, has filed multiple complaints with Berkeley to try to shut me up. That obviously hasn’t worked.

TWiV 531: Circ du RNA

Patrick Moore returns to TWiV to discuss the discovery from the Chang-Moore laboratory of circular RNAs in cells infected with herpesviruses.

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RNA in circles

circRNAThe diversity of cellular RNA structure and function has progressed from the early days of molecular biology, when we thought only about mRNA, tRNA and ribosomal RNAs. Then RNA splicing was discovered along with the many small nuclear RNAs that mediate that process. Next came small interfering RNAs and microRNAs and long noncoding RNAs, master regulators of cell processes. The latest addition to the RNA toolbox are circular RNAs (circRNA), first found in viroids, then cells, and now encoded in the genomes of two herpesviruses.

Circular RNAs were first found to constitute the genetic information of viroids, unusual pathogens of plants that encode no protein. Later circular RNAs were found in uninfected cells, where they are produced by backsplicing: a downstream 5’-splice donor joins an upstream 3’-splice acceptor (illustrated). They have a number of diverse functions in cells, including acting as miRNA sponges, sequestering miRNAs so that they cannot degrade target mRNAs; regulating transcription, splicing, translation, and ribosomal RNA processing, and acting as adaptors for protein-protein interactions. They have been implicated in neuronal and cardiovascular diseases and cancer.

Circular RNAs have recently been discovered in cells infected with two different DNA tumor viruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV). These two herpesviruses account for about 2% of all human cancers, including lymphoid and non lymphoid malignancies (EBV), Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease (KSHV). Outbreaks of Kaposi’s sarcoma in the US in the early 1980s were the first signs of the emergence of a new immunosuppressive disease, AIDS, caused by HIV-1.

circRNAs from several regions of the EBV genome were detected in infected cells and in post transplant lymphoproliferative disease, Burkitt lymphoma, nasopharyngeal carcinoma, and AIDS-associated lymphoma. circRNAs were also detected in some KSHV infected primary effusion lymphoma cell lines and from some (but not all) Kaposi’s sarcomas.

The contribution of these newly discovered viral circRNAs to tumorigenesis is unknown. One type of circRNA was found in all EBV-associated tumors examined, suggesting that at least for these cancers, they might have some role in tumor development or maintenance. Because circRNAs are very resistant to exonuclease degradation, they might be more useful than viral DNA detection for predicting disease.

I wonder how many other DNA viruses encode circRNAs in their genomes, and what are their contributions to viral replication and pathogenesis.

TWiV 530: Quiet please!

Steve Goff returns to TWiV to discuss the work of his laboratory on how retroviral genomes are silenced in infected cells.

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Toll to the Rescue

prion conversionby Gertrud U. Rey

Transmissible spongiform encephalopathies (TSEs) include a variety of fatal neurodegenerative diseases caused by infectious proteins called prions. Although prions are not viruses, their ability to self-propagate without a nucleic acid intermediate has always fascinated virologists, causing them to adopt prions into their repertoire of pathogenic agents. Common TSEs comprise scrapie in sheep, bovine spongiform encephalopathy (“mad cow disease”) in cattle, Creutzfeld-Jakob disease in humans, and chronic wasting disease in deer.

[continue reading…]

TWiV 529: Rueckert Road

At the University of Wisconsin-Madison, Vincent meets up with one of his virology heroes, Roland R. Rueckert, to talk about his research and his second career as a forest manager.

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By David Tuller, DrPH

I was surprised recently when the UK press made a big splash about what was, in the end, a modest study from a team led by Carmine Pariante, a professor of psychiatry at Kings College London. I was less surprised when I realized that the Science Media Centre was involved in disseminating the news. The coverage generated by the SMC’s efforts largely paralleled the overblown claims made by the study authors themselves in linking this paper about hepatitis C patients to possible biological mechanisms underlying what they call “chronic fatigue syndrome.” (The same illness or cluster of related illnesses is also referred to as myalgic encephalomyelitis, CFS/ME and ME/CFS, among other names.)

[continue reading…]

By David Tuller, DrPH

Alan Montgomery is a professor of medical statistics and clinical trials at the University of Nottingham’s School of Medicine. He is also the senior author of the Lightning Process study published in 2017 in Archives of Disease in Childhood, a BMJ journal. Professor Montgomery formerly worked at University of Bristol, along with Professor Esther Crawley and the other co-authors of the Lightning Process study.

[continue reading…]