By David Tuller, DrPH

This week, the Journal of Health Psychology published a special issue containing a raft of commentaries on the PACE trial. Most of them slammed the study for its many, many unacceptable flaws. Not surprisingly, Sir Simon Wessely’s lackeys at the Science Media Centre immediately posted three comments from “experts” lauding the trial and criticizing the JHP commentaries. I thought it might be helpful to deconstruct these rather pathetic efforts at defending the indefensible.

I’ve posted all three statements below, followed by my comments. I decided to keep them relatively brief, although I could have gone on much longer.

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Prof. Malcolm Macleod, Professor of Neurology and Translational Neuroscience, University of Edinburgh, said:

“The PACE trial, while not perfect, provides far and away the best evidence for the effectiveness of any intervention for chronic fatigue; and certainly is more robust than any of the other research cited. Reading the criticisms, I was struck by how little actual meat there is in them; and wondered where some of the authors came from. In fact, one of them lists as an institution a research centre (Soerabaja Research Center) which only seems to exist as an affiliation on papers he wrote criticising the PACE trial.

“Their main criticisms seem to revolve around the primary outcome was changed halfway through the trial: there are lots of reasons this can happen, some justifiable and others not; the main think is whether it was done without knowledge of the outcomes already accumulated in the trial and before data lock – which is what was done here.

“So I don’t think there is really a story here, apart from a group of authors, some of doubtful provenance, kicking up dust about a study which has a few minor wrinkles (as all do) but still provides information reliable enough to shape practice. If you substitute ‘CFS’ for ‘autism’ and ‘PACE trial’ for ‘vaccination’ you see a familiar pattern…”

Professor Macleod’s comments reflect a lack of understanding of both the illness itself and the fatal flaws of the PACE study. In his first sentence, he refers to “chronic fatigue.” As I and others have noted about 7 million times, “chronic fatigue” is a symptom of a great many illnesses; “chronic fatigue syndrome,” or “myalgic encephalomyelitis,” or ME/CFS or CFS/ME, or “systemic exertion intolerance disease,” is a specific disease entity.

Although there is still no universally accepted case definition, calling it “chronic fatigue” is a clear indication that Professor Macleod does not have a firm grasp on what he is talking about. The same could be said for the Science Media Centre’s failure to correct this phrasing. If they can’t even properly cite the illness in question, how can anything they claim about it be viewed as authoritative?

Professor Macleod does not engage in any substantive discussion about the criticisms outlined in the JHP commentaries. Instead, like other PACE defenders, he chooses to insult the authors. He notes that he “wondered where some of the authors came from” and suggests that some are of “doubtful provenance,” whatever that means. If he is still wondering who the commentary authors are, I can clue him in: They include experts from University College London, Northwestern University, DePaul University, the University of Hertfordshire, Victoria University of Wellington in New Zealand, UC Berkeley (that’s me), and the ME Association. Others are from patients and independent scholars who have proven themselves time and again to be expert researchers with more integrity and honesty than the entire cabal of PACE defenders.

Professor Macleod also states this about the rampant outcome-switching in PACE: “The main think (sic) is whether it was done without knowledge of the outcomes already accumulated in the trial and before data lock – which is what was done here.” This further demonstrates that he does not understand what happened in PACE. There are, in some cases, legitimate reasons to change outcome assessment methods in clinical trials. However, simply deciding mid-trial that you like other outcome methods better is not a legitimate reason—especially when every single change allows the researchers to report more impressive results.

Moreover, in an open label trial with subjective outcomes like PACE, investigators should have a pretty good idea which way things are trending before seeing the actual results. It is specious to assume that the PACE investigators were “without knowledge of the outcomes already accumulated”—they could have easily known things were not going well and relaxed all their outcome measures as a result.

Furthermore, while they obtained oversight committee approval for changing the primary outcome in the 2011 Lancet paper, they apparently received no approval for their overhaul of the definition of “recovery”—at least, no such approval is cited in the 2013 Psychological Medicine paper. And two of the four “recovery” criteria—the physical function and fatigue outcomes—were from post-hoc analyses, so they were obviously not generated before “data lock.” Professor Macleod does not mention this issue; like the PACE authors themselves, he would prefer to ignore the embarrassing fact that 13% of participants were already “recovered” for physical function at baseline.

Finally, it is rich that he brings up the analogy of anti-vaccination campaigners. Given that it was The Lancet that dramatically spurred that movement with its publication of the now-discredited 1998 Andrew Wakefield paper linking autism to vaccines, Professor Macleod’s statement just makes him appear clueless about The Lancet’s egregious behavior in both cases. I hope someone lets him know, sooner rather than later, that he has made a fool of himself.

Lancet editor Richard Horton vigorously defended the Wakefield study for years, just as he has defended PACE. And just as The Lancet finally retracted that paper, it will ultimately have to retract PACE as well.

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Dr Neha Issar-Brown, Programme Manager, Population and Systems Medicine at the Medical Research Council (co-funders, along with the National Institute for Health Research, of the PACE trial), said: 

“The Medical Research Council funded and supported the PACE trial after subjecting the research proposal to a robust peer-review process involving experts in the field, as is the case with all our funding decisions.  This included ensuring adherence to standardised trials methodology and design principles. The researchers’ findings were then peer-reviewed before publication in journals. All research evolves by continually re-evaluating existing evidence and looking for new knowledge and we would always welcome high-quality research applications to better understand the underlying disease mechanisms, causes, prevention and treatments for this extremely debilitating condition.”

This statement from the Medical Research Council is not in fact a defense of PACE or a response to any of the criticisms. It is simply a statement of the MRC’s role and an explanation of the process of publication. Yet it is simply false that the PACE trial was conducted according to “standardised trial methodology and design principles,” as the commentaries make abundantly clear. Repeating this claim without engaging critics does not alter the facts.

Moreover, the published studies are so full of flaws that it is absurd to cite the fact that they were peer-reviewed as evidence of their validity and reliability. Any study in which participants could meet outcome thresholds at baseline—and that includes both the 2011 and 2013 papers—should obviously never have passed peer review. What we know about The Lancet publication, in particular, is that the paper went through “endless rounds of peer review,” per editor Horton’s words, yet was simultaneously fast-tracked to publication. Despite my many efforts to extract an explanation from Dr. Horton, he has never bothered to explain how many “endless rounds of peer review” it is possible to complete during a fast-track peer review process.

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A spokesperson for University of Oxford said:

“The PACE trial of Chronic Fatigue Syndrome treatments was conducted to the highest scientific standards and scrutiny. This included extensive peer review from the Medical Research Council, ethical approval from a Research Ethics Committee, independent oversight by a Trial Steering Committee and further peer review before publication in high-impact journals such as The Lancet. 

“The allegation that criteria for patient improvement and recovery were changed to increase the reported benefit of some treatments is completely unfounded. As the study authors have repeatedly made clear, the criteria were changed on expert advice and with oversight committee approvals before any of the outcome data was analysed.

“Oxford University considers Professor Sharpe and his colleagues to be highly reputable scientists whose sole aim has been to improve quality of life for patients with ME/CFS. While scientific research should always be open to challenge and debate, this does not justify the unwarranted attacks on professionalism and personal integrity which the PACE trial team have been subjected to.”

Finally, this statement from Oxford’s unnamed “spokesman” is just a jumble of public relations nonsense. It is always suspicious when an institution declines to put a name to a statement—it often means no individual is willing to take responsibility for what is being said. In the case of this utterly vacuous statement, it makes sense that smart communications professionals would not want to have it attributed to them.

Let’s take this paragraph in particular: “The allegation that criteria for patient improvement and recovery were changed to increase the reported benefit of some treatments is completely unfounded. As the study authors have repeatedly made clear, the criteria were changed on expert advice and with oversight committee approvals before any of the outcome data was analysed.”

The claim that the PACE investigators obtained “oversight committee approvals” for the wholesale redefinition of “recovery” is a lie. They did not obtain any committee approvals for this; at least, that’s the only conclusion that can be drawn from the fact that no such approvals were mentioned in the Psychological Medicine paper. It is perplexing to see an official statement from Oxford—presumably vetted by Professor Sharpe and the SMC (or perhaps not)—contain such a blatantly false claim.

Moreover, it is silly to argue that boosting outcomes was not the aim of the PACE investigators. Obviously, it was. The PACE investigators themselves have argued repeatedly that they relaxed outcome measures, particularly for “recovery,” because they decided mid-trial that the original measures were too stringent. So they clearly knew that the changes they made would improve the reported findings. In that sense, it doesn’t really matter whether they examined the data beforehand; if you make it easier to meet outcome measures by lowering your standards, then you obviously know you will achieve better results.

So this Oxford statement is laughable. If these are the best defenses the Science Media Centre can concoct at this stage of the controversy, then PACE is really in big, big trouble.

 

By David Tuller, DrPH

The National Institute for Health and Care Excellence, the U.K. organization that develops clinical guidelines for medical conditions, has rejected my freedom-of-information request for the names of the experts involved in the reassessment of the guidance for the illness it calls CFS/ME. This isn’t surprising, since the agency also recently rejected similar requests from the Countess of Mar and the ME Association. However, NICE’s response to the FOI request, which I received on Friday, contains some useful information and clarifies the decision-making process. I have included the NICE response below, but here are some key observations.

The 2007 guidance, called CG53, endorsed cognitive behavior therapy and graded exercise therapy as the treatments of choice. According to the FOI response, the surveillance team that drew up the recently published “consultation document,” which recommends no change in this guidance, includes four NICE staffers: a technical analyst, a technical adviser, a clinical adviser and an associate director. In developing their proposal, they consulted with seven “topic experts”–three psychiatrists, two neurologists, a pediatrician and a patient representative. The surveillance team’s provisional decision to leave the guidance as is triggered this month’s two-week period for receiving comments from stakeholders. The final call will now be made by a group of eight top NICE employees, collectively called the “guidance executive.” Among the eight are Sir Andrew Dillon, NICE’s chief executive; Mark Baker, director of the Centre for Clinical Practice; and communications director Jane Gizbert.

According to the FOI response, four of the topic experts consulted were members of the committee that developed the guidance in 2007. That list included Professor Esther Crawley of Bristol University, who could presumably be the pediatrician among the topic experts. (For those who have not followed this saga closely, Professor Crawley falsely accused me of libeling her in two high-profile lectures this year—her inaugural address at her own institution and a talk to the British Renal Society. Despite my multiple efforts to extract an explanation from her, she has failed to provide any documentation for this ridiculous allegation.)

It is inappropriate and unsatisfactory that psychiatrists were the largest group represented among the topic experts. Apparently NICE still fails to recognize that the disease in question is most emphatically not a psychiatric or psychological disorder; the agency apparently accepts without question the specious perspective of the cabal of U.K. psychiatrists, psychologists and others who have hijacked the debate for the last three decades. The 2015 reports from the U.S. National Institutes of Health and the Institute of Medicine (now the National Academy of Medicine) authoritatively documented that ME/CFS, as American government agencies now generally call the illness, is an actual organic disease and not a figment of patients’ fevered imaginations.

The PACE/CBT/GET counter-narrative—that deconditioning alone accounts for the perpetuation of the symptoms, and that patients harbor “unhelpful beliefs” about having a medical condition—is not grounded in legitimate scientific research. Despite the desperate attempts by the PACE investigators to defend their pet theoretical framework, it is now clear to the international scientific community that the study’s reported findings in The Lancet (2011) and Psychological Medicine (2013) were wildly inflated—the result of rampant outcome-switching and other egregious methodological lapses.

In addition to PACE and other Oxford criteria studies, the NICE document cites the Cochrane reviews of CBT and GET in support of its conclusion. First of all, Cochrane includes the illness it calls CFS in its mental health disorders section, which immediately raises questions about the organization’s biased perspective. Moreover, given the inclusion of PACE and other studies using overly broad case definitions in the Cochrane analyses, the NICE consultation document is seriously misguided to cite these reviews as reliable evidence. After all, the Cochrane analyses cannot be legitimate and accurate when the studies they include are not. (I plan to take on Cochrane in an upcoming post.)

Both CBT and GET involve telling patients that these approaches will help them get better—an obvious method of biasing the results, especially given that the study was not blinded. The treatments appear to provide modest boosts in subjective measures but no long-term benefits over other treatment or management approaches. Neither PACE nor other studies from this group of researchers have documented objective improvements to match these subjective results; indeed, objective measures have consistently failed to support the claims of improvement and recovery. The significance of these salient facts appears lost on the NICE surveillance review team, which apparently suffers from the same “dysfunctional cognitions” as the PACE investigators about the efficacy of their strategy.

In normal circumstances, it might be appropriate to include committee members who worked on previous guidance as topic experts in the review process. But these are not normal circumstances. With this illness, relying on these committee members is a bad move. It stands to reason that those who developed the utterly inadequate and potentially dangerous 2007 guidance would be unwilling to challenge their own past perspective that GET and CBT are effective. This is especially true given that the PACE authors and other adherents of the biopsychosocial approach have consistently demonstrated their unwillingness to accept any criticism that challenges their viewpoint. They refuse to acknowledge, for example, that any study in which participants can meet outcome thresholds at baseline, before any treatment at all, has no place in the scientific literature, as many dozens of well-known experts have made clear in open letters to The Lancet and Psychological Medicine.

In Professor Crawley’s case, her research on the prevalence of the illness among children consistently conflates the symptom of “chronic fatigue” with “chronic fatigue syndrome.” This conflation serves to dramatically inflate the numbers of those purported to be afflicted. Her work, such as her proposal for the FITNET-NHS study of online CBT for kids, also misrepresents the NICE guidance that she herself was involved in developing, in ways that appear to render post-exertional malaise as an optional symptom rather than a required one. When called to account for these distortions, she chooses to insult her critics rather than provide satisfactory explanations of her flawed methodological choices. It is therefore highly troubling that the NICE consultation document cites FITNET-NHS as important new research that will inform future guidance.

The NICE response to my FOI request indicates that the agency reached out to the topic experts seeking their opinions on being identified. Three of them expressed concerns about having their names made public; a fourth could not be reached. The response does not indicate the answer, if any, from the remaining three; perhaps they didn’t object at all. Nevertheless, based on the responses from the three who objected, NICE has decided to keep all the names secret.

According to the NICE response, here’s why the three topic experts objected: “Reasons given include their experience, and that of other experts in the field, of being connected with this topic area. These included concerns about personal harassment, previous abuse and threats they have been subjected to when involved in work on this topic.”

It needs to be stated clearly that the PACE authors have routinely wielded this overhyped claim as a way of discrediting critics. However, the tribunal decision last summer that ordered Queen Mary University of London to release the raw trial data dismissed the claims as unfounded. The tribunal decision noted pointedly that the only reliable evidence presented to the court about such behavior involved an incident in which Professor Trudie Chalder, one of the three main PACE investigators, was heckled at a lecture. Professor Chalder herself acknowledged in her testimony at the tribunal that none of the investigators had received death threats, despite their habit of hyperventilating about the issue of abuse from patients. As has been previously documented, the wave of news stories about these purported death threats was a public relations stunt organized by the Science Media Centre.

So have some CBT/GET investigators received offensive e-mails or other communications that have upset them? I have no reason to doubt it. Perhaps some of these messages have even contained what could be construed as threats. But Professor Crawley and her colleagues have routinely deflected attention from the defects of their research by wrapping themselves in martyrdom, complaining vociferously that even the filing of freedom-of-information requests constitutes harassment—a preposterous argument, given that patients have a legal right to seek key information about publicly funded trials. And these researchers also frame accurate criticism as vexatious and illegitimate. That’s what Professor Crawley did earlier this year when she accused me of “libelous blogging” in a slide shown during her two speeches.

So despite its claims of valuing an open and transparent process, NICE is allowing the topic experts involved—including four whose names are already public as part of the 2007 guidance committee–to cloak themselves in anonymity. That is not acceptable. Given the enormous importance of this reassessment of CG53 and the huge public interest in understanding how the decisions are being made, NICE should reconsider this rejection of my request.

I am appealing to the agency to overturn its initial decision. Following the agency’s expected rejection of my appeal, I will then appeal to the Information Commissioner’s Office. Whatever the ultimate outcome of my request, the FOI response suggests that it is critical that the members of the guidance executive recognize that a pro forma ratification of the 2007 guidance will be a public relations disaster. More than 15,000 people signed the ME Association petition protesting the NICE provisional decision; that’s a lot of very, very unhappy patients. With PACE now exposed as a dishonest and even fraudulent piece of research, the ground in the debate has shifted. It is no longer time for business as usual.

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Here is the substantive part of the NICE response to my FOI request:

Thank you for your request for information under the Freedom of Information Act (FOIA), received at this office on 07 July 2017. You requested the following information about the review of the CFS/ME guideline (CG53):
 
1.       The number of people on the expert panel who will review input from stakeholders
2.       The number, if any, of these people who are the same as those who were on the panel that developed the 2007 guidelines
3.       The names of the people on the expert panel reviewing the CFS/ME guidelines, those currently serving and those who have served in the past year.
 
Background

There is no expert panel which reviews input from stakeholders in our review process. You can read more about how we check that published guidelines are current and accurate in our guidelines manual.
 
For this review we followed the process for the 4 and 8 year checks. It includes extensive searches to identify any new primary and secondary studies, including any economic studies. The focus is on the scope of the published guideline, but any additional areas or changes in practice that are identified are also considered if they fall within the referral of the published guideline. A literature search is conducted across a range of sources. These may vary from topic to topic. They are selected according to their relevance to the topic and are based on those used in the published guideline.
 
Topic experts and members of the original guideline committee are asked for their opinion, in their personal capacity, on the relevance of the published guideline, recent developments in the topic area and their knowledge of any new important evidence since publication of the guideline. Guideline committees are responsible for the recommendations made and we publish the membership of them. We do not routinely publish the identities of topic experts because while they may express an opinion they are not part of the decision making body. 
 
NICE’s surveillance review team summarises the relevant evidence and highlights any studies that may have an important impact on our recommendations. The main themes of new, relevant evidence across the guideline are also summarised, along with any other identified information (such as changes in licensing indications for a medicine or updated national policy). The surveillance team is made up of NICE employees – a Technical Analyst, Technical Adviser, Clinical Adviser and Associate Director.
 
The information identified as part of the surveillance review forms the basis of a review proposal for NICE’s Guidance Executive. In this case the review proposal was a public consultation document. When the information summarised in the review indicates that a ‘no update’ decision should be considered there is a 2‑week consultation with stakeholders who are registered for the published guideline.
 
The final decision about whether an update is need is based on a balanced assessment of new relevant evidence published since guideline publication, the views of the topic experts, feedback during consultation and other sources of information on the continued relevance of the guideline. The findings of the check on the need for an update are discussed with topic experts. All proposals go through an internal validation process (including sign‑off by the Associate Director and Director) before submission to NICE’s Guidance Executive. It is Guidance Executive that takes the decision to update the guideline or not.
 
Response to your request under the FOIA

Given the background above, in responding to your request, I have assumed that by ‘expert panel’ you mean the topic experts who were asked for their opinion on the relevance of the published guideline.
 
1.       The number of people on the expert panel who will review input from stakeholders.
Seven topic experts were asked for their opinion on the relevance of the published guideline.
 
2.       The number, if any, of these people who are the same as those who were on the panel that developed the 2007 guidelines.
Four of these people were also members of the original guideline committee.
 
3.       The names of the people on the expert panel reviewing the CFS/ME guidelines, those currently serving and those who have served in the past year.
We hold the names of the topic experts who were asked for their opinion on the relevance of the published guideline. For your information the topic experts are from the following fields: neurology (2), psychiatry (3), paediatrics (1), patient representative (1). However, we consider that the names are exempt from disclosure under 2 sections of the FOIA. We explain these exemptions and why we have applied them below.
 
Section 40 – personal information

Section 40 provides an exemption from the right to know where the information requested is personal data protected by the Data Protection Act. Personal data is data that relates to a living individual who can be identified from that data. The names of these individuals is clearly personal data.
 
Under section 40(2) we are withholding the names of the topic experts because we consider that to release it would contravene the principles of the Data Protection Act. In reaching this decision we considered whether disclosure would be fair to the individuals concerned, the consequences of disclosure, the reasonable expectations of the individuals and any legitimate public interest in disclosing the information.
 
NICE does not routinely publish the names of topic experts who contribute to the review process therefore the individuals had no expectation that this information would be made public. We wrote to the topic experts to ask them if they had any objections to their identities being disclosed to the public, and if so, what those objections were. Three of them were strongly opposed to their identities being made public in this context and one could not be contacted within the time available.
 
Reasons given include their experience, and that of other experts in the field, of being connected with this topic area. These included concerns about personal harassment, previous abuse and threats they have been subjected to when involved in work on this topic. We were sent a link to a news story from the Guardian describing threats and abuse directed at researchers and professionals in this field.
 
NICE is also concerned that disclosing the identities of the topic experts would have a significant impact on our ability to get experts to contribute to our work on this topic in the future. This point was supported by Mr Justice Simon in the judicial review that followed the publication of the original guideline. While Mr Simon was referring to guideline committee members in his judgement we consider that the impact would be the same if the identities of the topic experts asked for their opinion in the review process were made public.
 
When individuals are members of a guideline development group (also known as a guideline committee) their identities are publicly available on our website because the membership, as a whole, is responsible for the recommendations made. As described above, in the review process, the topic experts are asked for their opinion but the review decision is taken by NICE’s Guidance Executive whose membership is publicly available on our website.
 
As 3 of the topic experts expressed concerns over their identities being made public and 1 could not be contacted we consider that it would not be fair to make the remaining names public as this could have the effect of unreasonably focusing activity on these individuals. 
 
We recognise the public interest in ensuring public authorities remain transparent, accountable and open to scrutiny. We also recognise that disclosure would enable individuals to understand decisions made by public authorities in more detail, however on balance we do not consider the public interest in disclosure overrides the interest in maintaining these individuals’ privacy.
 
We therefore conclude it would not be fair to disclose the information under section 40(2) of the FOIA.
 
Section 38 – health and safety

Section 38 states that information is exempt from disclosure if its disclosure would, or would be likely to
(a)    endanger the physical or mental health of any individual, or
(b)   endanger the safety of any individual
 
The topic experts, and other experts in the same field, have specifically referenced threats and harassment they have been subject to in the past, as described above.
 
We have also considered if some of this information is already in the public domain because of the individuals previous work in this or other fields. As 4 of the topic experts were also on the guideline committee, their interest in this field is already in the public domain. However, in the context of the review, consultation and the campaigning activity around NICE’s proposal, we consider that releasing the information at this time would create a direct link between the experts and the review proposal and would raise their profile. Therefore disclosure at this time is likely to increase the risk that these individuals would be targeted and that this could lead to additional harm.
 
Mr Justice Simon also referenced unfounded allegations made against guideline committee members and his judgement stated that ‘unfounded as they were, the allegations were damaging to those against whom they were made; and were such as may cause health professionals to hesitate before they involve themselves in this area of medicine. A perception that this is an area of medicine where contrary views are not to be voiced, and where scientific enquiry is to be limited, is damaging to science and harmful to patients.’
 
Given the volume and nature of the correspondence (enquiries, petitions, letters, activity on message boards, Freedom of Information requests) we have received to date we are concerned that the experts may be targeted individually by any campaign and that such activity would impact on experts’ wellbeing and on their and others’ willingness to contribute to the work of NICE in the future, especially when they are not part of the decision making body.
 
We can’t be certain that the release of the withheld information would put the individuals at risk but we consider that there is sufficient evidence to conclude that they would be singled out for harassment, intimidation and possibly threats of violence. 
 
This exemption is subject to the public interest test. We accept that there is significant public interest in being accountable and transparent for the decisions we take and for individuals under understand how we make our decisions. However, NICE also has a duty to protect the physical and mental wellbeing of the individuals concerned.
 
In this case the makeup of the decision making body, Guidance Executive, is already in the public domain. The review proposal is also publicly available and contains comprehensive discussion of the evidence including the feedback from the topic experts.
 
NICE operates openly and transparently. All of our guidance development processes are published in detail on the website. We believe the process and information on which the proposal is based is publicly available and subject to consultation. We consider that those with an interest in this guideline have sufficient information to be able to understand both the process and consideration of the evidence.
 
Given the concerns raised by the individuals and other evidence of previous incidents of experts in this field being targeted for harassment, including threats of violence, in the past we conclude that the public interest in disclosing the information does not outweigh the interest in maintaining the exemption in light of the likely risks to the health and safety of the individuals.
 
We therefore conclude it would not be fair to disclose the information under section 38 of the FOIA.

Lynda Coughlan joins the weekly virtual bus companions for a discussion of a host defense peptide from frogs that destroys influenza virus, and mouse models for acute and chronic hepacivirus infection.

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Kermit’s urumi

Hydrophylax bahuvistaraFrogs don’t get flu (as far as I know) but their skin contains a peptide that inhibits the replication of influenza virus (link to paper).

Frog skin contains host defense peptides (HDPs), part of the innate immune defenses of many species. They were first found in amphibians by Michael Zasloff, who, as part of his research, performed surgery on frogs and then returned them to an aquarium – which was not sterile. He wondered why the frogs always healed without signs of infection, which lead him to discover the antimicrobial peptides, called magainins, in frog skin. HDPs had been first discovered years earlier in the silk moth.

Amphibian HDPs are active against bacteria, fungi, viruses, and protozoa. To discover HDPs that inhibit influenza virus, 32 HDPs from skin secretions of the Indian frog Hydrophylax bahuvistara were screened by mixing them with virus followed by a plaque assay. One peptide was found to potently inhibit influenza virus replication without cell toxicity. It was called urumin, after the whip sword known as urumi.

Urumin inhibits infectivity of influenza H1N1 viruses far better than H3N2 viruses. The reason is that the peptide targets the viral H1 hemagglutinin, one of two glycoproteins in the viral envelope. Furthermore, the peptide appears to interact with the conserved stalk region of the HA glycoprotein, and not with the globular head.

Currently two different antiviral drugs, oseltamivir and relenza, are used to control influenza virus infection. Viruses resistant to these drugs were still inhibited by urumin, indicating that should urumin ever be licensed, it would be useful in the event that oseltamivir and relenza resistant viruses became more common.

Examination of urumin treated virus particles by electron microscopy revealed that they are disrupted by the peptide. How urumin breaks influenza virus particles is not known. However, the HDP nisin destroys bacteria by first binding to a bacterial membrane component, then moving into the membrane. After binding to HA, urumin might in a simlar way disrupt the membrane of influenza virus particles.

Urumin also reduced disease, death, and the amount of virus in the lung in mice intranasally infected with influenza virus.

These observations suggest that urumin is worthy of additional study as an influenza virus inhibitor. HDPs are attractive antimicrobial compounds because resistance to their mechanisms of action is lower than for other types of inhibitors. However, enthusiasm for urumin is dampened because, despite extensive study, no HDP has yet been approved by the US Food and Drug Administration for use in humans. The obstacles to therapeutic success of HDPs have not been identified.

By David Tuller, DrPH

The Countess of Mar, a well-known advocate for ME/CFS patients in the House of Lords, has received a negative response to her request for the names of the experts involved in the review of the NICE guideline for CFS/ME. The ME Association has not yet received a response related to the same question, nor have I. But the response to the countess indicates that the process is proceeding with a lack of full transparency.

Here’s the response from the Department of Health:

“The National Institute for Health and Care Excellence (NICE) routinely consults a range of topic experts as part of its surveillance review process. NICE is currently consulting on a review proposal for its clinical guideline on the diagnosis and management of chronic fatigue syndrome and myalgic encephalomyelitis. NICE does not routinely publish the names of topic experts as they are not part of the decision making [sic] process for the surveillance review.”

This answer is of course unsatisfactory. The last sentence is the operative one, so let’s deconstruct it. In the first part of the sentence, NICE is telling us that it does not routinely publish the names of topic experts. But just because it doesn’t routinely do something is not necessarily relevant to whether it should take this step now. Perhaps no one has asked for these names before. Presumably the development or review of most guidelines is not so controversial as this particular one for CFS/ME. (The patient-preferred name for the illness, and the most appropriate one, is of course just ME, without the CFS tacked on.)

It is also not routine that more than 15,000 people sign petitions expressing serious dissatisfaction with existing clinical guidelines. But that’s how many have put their names to the petition launched by the ME Association. That’s a huge number of unhappy patients and advocates; NICE would be well-advised not to ignore them. Perhaps the strict adherence to routine measures—like not disclosing the names of topic experts involved in the process—should be reconsidered in the current urgent context. (The petition drive closed today to coincide with the deadline for the stakeholder comments on the NICE guidelines.)

The second part of the sentence explains the purported reason for not sharing the topic expert names: they are not part of the decision-making process. First of all, what does that mean? Given that topic experts have been consulted in this instance, it is bizarre to read that they are “not part of the decision-making process”? Is their advice then ignored completely? Are they just a fig leaf to create the appearance of consultation while NICE does what it wants? If their advice is reviewed and considered rather than tossed right in the trash, why does the statement declare that they are not part of the decision-making process?

Perhaps the statement means that the topic experts are not officially in the room or on the conference call when the final approval is made. But even if that were the case, why would that mean their names should be kept from the public? Is the development process of NICE guidelines an official state secret that demands utmost protection?

And if the topic experts are not involved in the decision-making, as the statement asserts, then what exactly is their function? And who are the people involved in making the decision? Are they themselves experts, or just functionaries listening to others? Is it the group that originally developed the 2007 guideline? That group includes Professor Esther Crawley [Correction–see below], a close colleague of the PACE authors-—so that’s not a particularly good sign. Given the enormous impact of these guidelines, it is imperative that the process be conducted as openly as possible—which, given the response to the Countess of Mar’s question, is so far not the case.

Correction, July 24th: In the initial post, I mistakenly wrote Professor Trudie Chalder.

T7-like virusCould ancient host proteins contribute to the replication of a modern virus? The answer is, not very well (link to paper).

Viruses are obligate intracellular parasites, which means that they have to get inside of a host cell to produce more viruses. The genomes of all viruses, even the biggest ones, do not encode anywhere near the number of proteins that are needed to replicate. The cell provides thousands of proteins that are involved in energy production, membrane synthesis, protein synthesis, transport, and so much more.

The difficulty in studying ancient proteins is that none of them exist. But we can make good guesses about what very old proteins might look like, by examining modern proteins, seeing how they vary among organisms, and calculating how they might look like billions of years ago. The field of predicting what ancient proteins might look like is quite active.

Investigators have predicted what ancient versions of a cell protein called thioredoxin might have looked like. They have synthesized such ‘ancient’ thioredoxins and shown that they are stable and active. Thioredoxins are found in nearly all organisms, where they act as antioxidants.

Ancient thioredoxins that have been synthesized include those from the last common ancestors of bacteria; of archaea; and of archaea and eukaryotes (all around 4 billion years old); the last common anestor of cyanobacterial, deinococcus, and thermus groups (about 2.5 billion years old);  the last common ancestor of gamma-proteobacteria; of eukaryotes; and of fungi and animals (around 1.5 billion years old).

These ancient thioredoxins work in a modern E. coli. This bacterium has two thioredoxin genes, and if they are both deleted, growth occurs, but very slowly. If genes encoding ancient thioredoxins are introduced into these mutated bacteria, they can compensate for the growth deficiency. The older thioredoxins (4 billion years) compensate less well than ones that are closer in time (1.5 billion years).

It’s amazing that an ancient protein can work in a modern E. coli. But could ancient thioredoxins support viral growth?

Thioredoxin from E. coli is an essential part of the DNA polymerase complex of the bacteriophage T7 (pictured – image credit). This virus does not form plaques on E. coli lacking the two thioredoxin genes. The only ancient thioredoxin gene that allows phage T7 plaque formation is from the last common ancestor of cyanobacterial, deinococcus, and thermus groups, which is about 2.5 billion years old and has 57% amino acid identity with the E. coli enzyme. But the effienciency of plaque formation was very poor – about 100 million times worse than on regular  E. coli. None of the older thioredoxins worked.

Why would an ancient thioredoxin work for E. coli but not for bacteriophage T7? Over billions of years, thioredoxin evolves but it must still be able to carry out its function for E. coli. The viruses that infected bacteria 4 billion years ago were very different from contemporary viruses, and so the ancient thioredoxin does not work for modern viruses. Today’s thioredoxin could change so that it would not support T7 replication – as long as the enzyme still works for E. coli.

The authors of this work view it as a proof of principle: that virus growth is not supported by an ancient version of a modern protein required for virus replication. They would like to apply this approach to produce plants that are resistant to viruses, which have serious effects on global agricultural productivity.

I think the work is amazing not only because an ancient protein can be made, but it supports growth of the host and not that of a virus. It might therefore be possible to reconstruct the host-virus arms race, starting from ancient proteins. In this race, the gene encoding an essential cell protein can evolve so that it no longer supports virus replication. Next, the viral genome changes to adapt to the altered cell protein. And so the game goes back and forth.

The authors have shown that they can select mutant bacteriophage T7 isolates that replicate in the present of an ancient thioredoxin. This result suggests that it might be possible to reconstruct host-virus arms races beginning with an ancestral host protein. If we can make an ancient protein, could we also make an ancient virus? Why not?

By David Tuller, DrPH

This month, the U.K. organization currently assessing whether to update the clinical guidelines for the illness it calls CFS/ME is seeking input from “stakeholders” in the process. Unfortunately, that’s not good news—it’s bad news.

Why? The National Institute for Health and Care Excellence, or NICE, is an independent body that operates under the sponsorship of the U.K. Department of Health and establishes guidelines for clinical practice. NICE created its current guidelines for CFS/ME, called CG53, in 2007. These were heavily influenced by the cognitive behavior therapy/graded exercise therapy (CBT/GET) paradigm, which was already dominant in Britain before the first PACE results were reported in The Lancet in 2011.

NICE is in the process of reviewing whether it should take a fresh look and update CG53. The guidelines cover a range of areas, including clinical presentation and diagnosis as well as management strategies. The organization has asked those who have registered as stakeholders, such as advocacy groups, to submit comments between July 10th and July 24th.

But in a recent exchange of e-mails with NICE, the ME Association clarified that the request for stakeholder input means the organization has already reached a preliminary decision that no revisions to the 2007 guidelines are necessary at this time. The two-week comment period therefore offers, at best, a formal opportunity to change the minds of people who have already indicated that their minds are made up. Since the available evidence has not yet persuaded them that recent events have rendered obsolete the old recommendations for CBT and GET, stakeholders have an enormous challenge in seeking to effect any change in their perspective.

The NICE solicitation of input from stakeholders comes right as the U.S. Centers for Disease Control has suddenly stopped recommending CBT and GET for what it calls ME/CFS. In early July, mention of the two treatments vanished from the CDC website. The website still suffers from multiple issues; the agency says more changes are forthcoming. But the removal itself should signal to NICE that the tide has shifted against both the CBT/GET ideology and the science purportedly proving that these treatments are effective. A decision to ratify the current NICE guidelines, as if nothing has changed since they were promulgated, will be greeted with dismay from many in the international scientific community.

What is obvious, but what NICE appears to overlook, is that the CBT/GET literature is plagued by two overarching flaws. The first is that these are mostly open-label trials with subjective outcomes—a study design rejected in other fields of medicine because it is so prone to bias. The second is that many of the studies, especially older ones, rely on the use of the Oxford criteria or other broad case definitions that yield heterogeneous samples because they conflate chronic fatigue and chronic fatigue syndrome. These studies simply cannot provide credible evidence about treatments for the specific disease that patients prefer to call ME. (PACE, of course, suffers from many other flaws besides these two.)

Some have argued that it is better to be able to provide patients with some recommendations rather than none. It is therefore important to stress that a recommendation should not be kept just because there are no better recommendations to make. If a recommendation is based on results from studies that promote bias, or on results that have been inflated through outcome-switching or have been derived from heterogeneous samples or are inaccurate for other reasons, then the recommendation needs to be rescinded, even if there is not sufficient current evidence to suggest other proven treatment approaches. That is especially the case when patient surveys and biomedical evidence raise concerns that a recommended strategy—in this instance, a steady increase in activity levels–is causing serious harm rather than benefit.

The fact that NICE decided to reconsider the 2007 guidelines this year seemed like a potentially promising development, but it was unclear what new information the agency would consider. For example, would the surveillance review include only reports from clinical trials of therapeutic interventions? Or would it also include findings of physiological abnormalities, most from research produced outside the U.K., which undermine the deconditioning theory that supports use of CBT and GET?

Other questions: Would the review consider the conclusion of the 2015 report from the U.S. Institute of Medicine (now the Academy of Medicine) that “exertion intolerance” was a cardinal symptom, which raises questions about whether GET is contra-indicated? Would it consider that the U.S. Agency for Healthcare Research and Quality found little or no evidence for CBT and GET after removing Oxford criteria studies from its analyses? And would it include the reanalyses of the reported PACE “recovery” and “improvement” findings, which were dramatically boosted by post-hoc outcome changes?

NICE’s “surveillance proposal consultation document” for CG53, recently posted on its website, provides answers to many of the questions. This 56-page report offers details about the NICE surveillance review and the reasons for the agency’s provisional decision not to change the guidelines. The review was apparently conducted by a NICE “surveillance team” with input from an unidentified number of unidentified “topic experts.” (I have filed a freedom-of-information request with NICE for the names of the experts it consulted. NICE has 20 working days to respond. The ME Association is also seeking the names, and the Countess of Mar has asked the Department of Health for the same information.)

The consultation document indicates that the surveillance team and topic experts did in fact take notice of the recent controversies and the new literature, including the reanalyses, before concluding that the guidelines should remain the same. The document noted that some upcoming research could impact the guidelines down the line, and identified specifically a study of online CBT for kids—an apparent reference to FITNET-NHS. This study exemplifies some of the problems common in this field of research, as I described on Virology Blog months ago. (Professor Esther Crawley of Bristol University, the trial’s lead investigator, subsequently referred to that blog post as “libelous” in a slide she showed during at least two speeches. She has not documented her charge.)

The consultation document also notes that only study abstracts, not the studies themselves, were reviewed. This is a surprising methodological choice given the significance of the issue. Abstracts can be seriously misleading and incomplete; studies themselves obviously provide a much more authoritative and nuanced picture. It does not seem too much to expect that those responsible for establishing enormously influential clinical guidelines should have taken the time to examine the actual research on which they were basing their recommendations. To learn that they did not is rather shocking.

In response to the controversy over the PACE trial, the document notes more than once that the investigators themselves have responded to criticisms, citing the FAQ on the trial website and other publications. The surveillance team appears to accept these responses at face value–as thorough and honest explanations. Perhaps no one has examined them closely enough to realize how empty and full of half-truths they are. The PACE investigators have certainly tried to defend their work. But there are no reasonable answers to many of the concerns, so their responses to date have only satisfied their ideological companions and those who know little about the debate.

The consultation document contains some troubling inaccuracies in its discussion of the PACE trial. For example, it reports that “the PACE authors note that…changed thresholds for recovery were pre-specified.” But it is simply false to call the revised thresholds “pre-specified.” The recovery thresholds for physical function and fatigue—two of the four recovery criteria in the 2013 paper published in Psychological Medicine–were the same as the “normal range” thresholds included in the 2011 Lancet paper. In that earlier paper, these thresholds were presented as part of post-hoc analyses, so it is hard to understand how the same thresholds could also be “pre-specified” under any standard definition of the term.

Besides that, all four recovery criteria were weakened, so it was self-evident that each change, whether pre-specified or not, would boost the numbers that the investigators could report had achieved “recovery.” Moreover, the 2013 paper does not cite any oversight committee approval for the major changes to the “recovery” definition–an oversight that should have raised alarm bells for Psychological Medicine. (Since the NICE surveillance team only reviewed abstracts and not actual papers, it would not have noticed this unusual lack of oversight committee approval.) And the consultation document fails to mention the fact that 13 percent of the PACE participants were already “recovered” for physical function at entry—an anomaly that should have prevented publication.

In another inaccurate (or at least highly disingenuous) statement, the consultation document notes that the investigators “have re-analysed the main outcome measures according to the original protocol with similar results to those in the primary PACE results paper i.e. reduced fatigue and increased physical function.” But it is stretching the truth beyond recognition to claim that the results of the reanalysis were “similar.” In the 2011 Lancet paper, the investigators reported that around 60 percent “improved” with CBT and GET; in the 2016 reanalysis, which used the original PACE protocol’s definition of “improvement,” the figure fell to around 20 percent.

Proponents of PACE have cited the 60 percent improvement rate as evidence of the effectiveness of CBT and GET. So a two-thirds decline in improvement rates should change any reasonable observer’s assessment of the effectiveness of the interventions. For NICE to accept the PACE investigators’ argument that this dramatic drop represents “similar results”–presumably because they were still able to report some very modest “improvement”–suggests that the surveillance team and topic experts are assessing the data with preformed opinions.

The topic experts seem to have enabled some of the NICE surveillance team’s own poor instincts. For example, after noting concerns raised about the Oxford criteria, the consultation document dismisses the significance of the issue this way:

“Trials using Oxford criteria were eligible when developing NICE guideline CG53, and topic experts had no concerns about the inclusion criteria of trials in CFS. It was also noted by topic experts that there is no gold standard definition of chronic fatigue syndrome. There is currently insufficient consistent evidence about diagnostic methods for CFS/ME to determine an impact on the guideline recommendations.”

Hm. So they used these studies the first time around ten years ago, and therefore it must be okay to use them again; something about that logic escapes me. And the topic experts expressed “no concerns,” shrugging off the case definition problem because there is “no gold standard.” But this thorny issue is at the core of the current controversy, and failure to address it is not a viable option. Scientists outside the influence of the CBT/GET ideological brigades understand very well that the populations generated with the Oxford criteria cannot yield actionable findings about an illness that should be defined much more specifically.

The consultation document also states that NICE will encourage Cochrane to update a 2008 review of CBT so that it can include the reported results from the PACE trial. “A further review of the guideline may be considered following publication of the updated Cochrane review,” stated the document. In other words, the NICE surveillance team is not only not deterred from considering the PACE results but is taking steps that would amplify their impact on the recommendations.

In fact, by citing Cochrane’s reviews as key evidence to support keeping the guidelines in place, the consultation document highlights the major role of these analyses in bolstering the entire CBT/GET enterprise. Cochrane takes the same problematic approach to assessing studies as NICE, accepting the results of open-label trials with subjective outcomes even though these are known to suffer from serious bias. In addition, Oxford criteria studies dominate the Cochrane reviews. In short, the body of research being used by both Cochrane and NICE, including but not limited to PACE, suffers from fundamental flaws. (Perhaps if Cochrane removed responsibility for the illness from the “common mental disorders group,” where it doesn’t belong, a new set of reviewers would demand higher-quality evidence.)

The provisional decision to not revise the guidelines at present has alarmed patients and advocates. The ME Association has launched an online petition, which notes that the intention is “to offer the patient community the chance to demonstrate to NICE just how unhappy it is with the current guideline.” The petition states:

“As stakeholders, the ME Association believes that the current guideline is not fit for purpose and that we are not being afforded a fair opportunity to help produce a better version.

We believe the guideline should be improved to reflect international biomedical research and medical opinion and the overwhelming evidence against current treatment recommendations – specifically in relation to graded exercise therapy.

We also feel recent re-analysis of PACE Trial data and growing international concern about the efficacy of this research, and those therapies it examined, should result in a reappraisal of their use in this guideline.”

The petition’s specific demands include, among others, a “complete and proper review” of the current guidelines, recognition of CFS/ME as a neurological disease in accordance with UK health agencies, removal of the GET recommendation in particular, and the highlighting of pacing as a strategy widely used by patients. The ME Association petition has so far collected more than 11,600 signatures.

NICE will presumably consider the stakeholder input before making its final decision. I guess the topic experts will also be given another chance to weigh in. I hope there’s a real chance to change the outcome.

**********

The CDC (Sort of) Explains

I sent the CDC a few questions last week after the agency had removed CBT and GET from its web pages, among other changes. I wanted to know what had prompted the changes, whether the removal of CBT and GET constituted an acknowledgement that there was no reliable evidence to support recommending the therapies, and whether the agency would apologize for having gotten it wrong. I also asked if the CDC would actively disseminate information about the changes.

Here’s what I heard back:

Dear Dr. Tuller,

Thank you for your interest in CDC’s recently updated ME/CFS web pages.

In follow-up to the IOM report, CDC hosted a roundtable meeting with a variety of stakeholders including ME/CFS patients, advocates, clinicians with ME/CFS expertise, healthcare professional organizations, medical educators, researchers/foundations, and other government agencies. The goal of this face-to-face meeting was to provide an opportunity for individuals to share their thoughts about how the IOM report could best be communicated through the CDC ME/CFS website and our educational materials for a variety of audiences.

During the website revision process, our staff focused on conveying information in plain language that would be understandable to the general public, regardless of the viewer’s background knowledge of ME/CFS. Part of this process included removing jargon and medical terms that we know are not widely understood by the general public and could be confusing.

As you will see on the website’s “treatment” tab, we suggest that patients with ME/CFS be careful about how they incorporate exercise into their lives. Every person’s experience with ME/CFS is unique so we continue to recommend that patients and their loved ones work closely with their doctor to determine the best course of management for themselves. We continue to believe that exercise can be useful for some ME/CFS patients, and also are trying to emphasize that people need to be careful not to overdo it and push themselves so far that it harms their health. We also state that talking to a therapist to help find strategies to cope with their illness may be helpful. We know from our past discussions with patients and their loved ones that there has been confusion about what we recommend related to exercise and therapy. We hope that the updated website provides more clarity.

CDC staff are currently developing the web pages for healthcare professionals. We plan to use social media and established partner communications channels to ensure that the general public and healthcare providers are aware of the new site once the healthcare pages are completed. In addition, we are collaborating with the CFSAC education workgroup on ways to disseminate information about ME/CFS to medical professionals and the general public.

Thanks again for your continued interest in this important public health topic.

This statement from the CDC is disappointing. The agency apparently does not plan to make a public announcement at this time that it has dropped CBT and GET, even though these therapies remain widely prescribed in the U.S. The agency will also not acknowledge that there is little or no credible evidence to support the treatments, and that it was wrong to recommend them for so long. The most it will concede is that “there has been confusion about what we recommend related to exercise and therapy.”

This is nonsense. Patients and advocates did not complain about the CDC website because they didn’t understand what it was recommending. They complained because it specifically recommended GET and CBT, citing PACE. After removing references to PACE from the website, the agency then claimed that CBT and GET were generic management strategies, unrelated to PACE. This claim was untrue. What other illness is GET recommended for? In what other illness is CBT supposed to alleviate you of the misguided belief that you have the illness in the first place?

Until early July, that is where things stood. Now the CDC seems to want to pretend it was all a big misunderstanding. To be clear: Patients are not against activity or exercise per se. They recognize that people with the illness should move their bodies to the extent they can without over-exerting themselves; that is a basic concept behind the self-management strategy called pacing. It is the “graded” aspect that patients find alarming—the idea that activity levels need to be steadily increased to reverse the deconditioning that is wrongly hypothesized as causing the symptoms. Similarly, patients are not against psychotherapy as a tool for coping with the demands and stresses they confront. They are against the specific form of CBT that has been created to treat their illness.

So patients were never confused by what the CDC’s recommendations meant. They understood that the recommendations meant the CDC bought into the CBT/GET paradigm, despite the PACE trial’s glaring flaws. In maintaining that it made the changes to prevent “confusion,” the CDC is weaseling out of admitting the obvious–the country’s top public health officials got this one wrong for years. The PACE trial–the crown jewel of CBT/GET research–has been authoritatively discredited. But the CDC won’t say so.

CBT and GET have been the de facto standards of care for this illness in the U.S. A major reason is that the CDC endorsed the therapies. Now the agency has abruptly un-endorsed them. That’s a big, big deal, not a minor tweak. For the sake of public health awareness and understanding, CDC officials have an obligation to provide a direct, transparent, and credible account of why they made these major changes. The statement I received from them does not demonstrate those qualities.

Ben tenOever joins the TWiVoli to discuss the evolution of RNA interference and his lab’s finding that RNAse III nucleases, needed for the maturation of cellular RNAs, are an ancient antiviral RNA recognition platform in all domains of life.

 

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PoxvirusI just love it when long standing mysteries in virology are suddenly solved, typically by the use of new technologies. In this story, the long standing mystery was why poxvirus mRNAs have a stretch of poly(A) in their 5′-noncoding regions. The answer is that it allows the ribosome to preferentially translate these viral mRNAs over those of the host (link to paper).

Ribosomes, the sites of protein synthesis, are very large assemblies of RNAs and proteins. A ribosome-associated protein called RACK1 is the major player in this story. This protein was previously found to be important for translation of viral RNAs by internal ribosome entry, a process in which ribosomes bypass the 5′-cap structure on mRNAs.

Cells lacking the gene encoding RACK1 seem to be just fine – they grow normally. This result would suggest that RACK1 is not needed for translation of mRNAs via the 5′-cap structure. But the translation of mRNAs of vaccinia virus, a poxvirus, is blocked in cells lacking RACK1. More specifically, the viral mRNAs produced later in infection cannot be translated.

This effect of RACK1 on vaccinia virus mRNA translation prompted a closer look at the protein in virus infected cells – which revealed that it is phosphorylated by a viral protein kinase. Phosphorylation of RACK1 makes the ribosomes preferentially translate vaccina virus mRNAs – an effect that is completely dependent upon the poly(A) in the 5′-untranslated region! Transfer of this poly(A) sequence to a non-viral mRNA enhanced its translation in cells in which RACK1 is phosphorylated.

The amino acid sequence of RACK1 that is phosphorylated is within a loop that contacts the 18S ribosomal RNA subunit. An examination of RACK1 proteins from different species reveals that in plants, unlike in mammals, this loop contains a stretch of negatively charged amino acids. Because a phosphate is negatively charged, it made perfect sense to see if the plant loop sequence, when transferred to mammalian RACK1, could stimulate translation of poly(A) containing mRNAs. It did!

In other words, phosphorylation by a vaccinia virus protein kinase makes RACK1 plant-like! Which is why the authors called their paper ‘Trans-kingdom mimicry underlies ribosome customization by a poxvirus kinase”. Exactly what RACK1 protein is doing in plants is a burning question, as is how RACK1 recognizes mRNAs containing a poly(A) leader.

Phosphorylation of RACK1 by the vaccinia virus kinase explains why viral mRNAs with poly(A) leader sequences are preferentially translated in infected cells (late viral mRNAs have this unusual leader). The presence of poly(A) in the 5′-ends of late vaccinia virus mRNAs is considered to be a consequence of polymerase slippage – but it is clearly not a mistake. At one time, long ago, a polymerase might have slipped for the first time, but the resulting poly(A) in the mRNA conveyed a selective advantage that remained. Today I would no longer call the addition of poly(A) to vaccinia virus mRNAs an error!

Why did it take so long to figure out the role of poly(A) at the 5’-end of vaccinia virus mRNAs? The right technology was not available – the key ones were the ability to knock out specific genes in cells, to knock down mRNA levels with RNA interference, and to identify the sites of RACK1 phosphorylation by mass spectrometry. These are not only recently developed techniques, but they have become widely accessible. But don’t forget the use of long-ago isolated vaccinia virus mutants of the protein kinase that were an essential part of this story.

Rich Condit, a poxvirologist, joined Nels Elde (also a poxvirologist, though he dabbles in other systems) and me to discuss this very cool paper on episode #21 of TWiEVO, This Week in Evolution. Rich had some very good insight on this paper; plus he bristled twice during the episode. You’ll have to listen to find out why.

Image credit.

 

By David Tuller, DrPH

This is the beginning of a new phase for “Trial by Error.” I initially assumed that my work on PACE and ME/CFS (or ME, or CFS/ME, or CFS) would be a one-off investigation, and then I’d move on to other projects. But after my 15,000-word series was posted on Virology Blog in October of 2015, the story kept going and going. I couldn’t stop myself—there was always more to write about. But it was all very complicated and I didn’t know where it would lead.

And then the issue gained traction and momentum, especially after the release last year of the trial data, which revealed how much the investigators had inflated their findings by relaxing their outcome measures. The data release itself occurred thanks to the heroic efforts of Australian patient Alem Matthees, who doggedly pursued his freedom-of-information request and defeated Queen Mary University of London’s high-powered legal team. Despite this success, there’s still more work to do, and I’m glad to have the opportunity to pursue the issue further. I owe that opportunity to all the amazing contributors to the crowdfunding campaign, and to the support of Professor Vincent Racaniello, the host of Virology Blog, and my colleagues at the School of Public Health at the University of California, Berkeley.

Going forward, I will drop the word “Continued” from the headline of this series and just use “Trial by Error.” I decided to keep “Trial by Error” because, well, I really like the name. And I think it accurately describes both the PACE trial specifically and the larger effort to impose the CBT/GET paradigm on this patient population. I have relied on my friends Valerie Eliot Smith and Robin Callender Smith for their legal insight throughout this effort, but I also need to thank them again for suggesting this perfect title two years ago.

Other than that, I expect things will more or less continue as before–some investigating/blogging on Virology Blog, some writing for other publications, some orchestration of open letters from academics, some use of social media, etc. Overall, the project should cover about half my work time. I have previously mentioned some things I want or plan to examine. Unforeseen topics will also emerge, of course—before Esther Crawley libeled me, who knew I’d write multiple blogs about her unscholarly behavior?

I won’t manage to do everything, but I hope to get enough done to help further blunt the authority and credibility of the CBT/GET ideological crusaders. Their position has been considerably weakened, given the willingness of many in the international scientific community to criticize the PACE study’s conduct and methodology. Yet the PACE investigators still present themselves as victims of an organized campaign of anti-science zealots, as Professor Michael Sharpe implied recently in his abstract for an “ethics” talk at Oxford. (Professor Sharpe’s position was artfully deconstructed last week on Virology Blog by Northwestern University law professor Steven Lubet.)

I can understand why the PACE investigators might have trouble acknowledging that the theory to which they have devoted decades of their lives has been undermined by the evidence of their own highly promoted trial. But the dereliction of editorial responsibility by The Lancet and other prestige journals, which have enabled the PACE/CBT/GET charade by publishing poor-quality work, is perhaps even more disturbing. It is not surprising that The Lancet has just published another flawed study from this school of research, a trial of self-help graded exercise for what the researchers still call “chronic fatigue syndrome.” In effect, The Lancet was doubling-down on its defense of PACE.

The Lancet editor, Richard Horton, has invested his reputation in the proposition that the PACE trial was methodologically sound and that the critics were not only wrong and irrational but were in fact harming the scientific enterprise. Yet he has also recently positioned himself as a high-profile scourge of poor-quality science. Given that, his refusal to acknowledge the flaws with the PACE/CBT/GET approach promoted by his journal represents enormous hypocrisy or a great talent for self-delusion.

In fact, The Lancet’s publication of the self-help graded exercise paper has occurred as the CBT/GET paradigm continues to lose ground elsewhere. Early this month, the Centers for Disease Control revised its website for the illness, in the process eliminating recommendations for these therapies (more on that below). In contrast, Dr. Horton and his journal remain mired in this swamp of bad science. So does the rest of the U.K. academic and medical establishment.

**********

Just as The Lancet has published more “evidence” for graded exercise, the CDC has moved decisively in the opposite direction. In revamping the information on the part of its website geared toward the general public, the agency has “disappeared” all mention of CBT and GET as treatment or management strategies. Patients and advocates have long pushed for this step, as did Julie Rehmeyer and I in a New York Times opinion piece in March. Although the revised text is dated as having been reviewed on May 30th, it apparently went live sometime during the first week of July. (The CDC has still not revised the pages designed for health care providers, although old information has been removed. The agency calls the illness ME/CFS.)

For advocates, the CDC’s removal of the CBT/GET recommendations represents a major victory. “I think it’s huge,” said Mary Dimmock, an advocate who has long pressured the CDC to revise its website. Given the agency’s stature, she added, the decision could have widespread impact, not just in the U.S. but internationally as well. Many health care providers and institutions here and abroad look to the CDC for guidance in public health matters.

“So many patients have been made worse by the treatments,” said Dimmock, who became an advocate after her son became seriously ill several years ago. “While there is more to be done, removing these recommendations is a significant step forward in protecting ME patients from harm.”

In the revision, the CDC website has dropped the agency’s 1994 definition of the illness. The new definition, based on the one proposed in a 2015 report from the Institute of Medicine (now the Academy of Medicine), requires the presence of “post-exertional malaise.” In the 1994 definition, that was only one of eight optional symptoms. The immediate implication of the shift is that GET should likely be considered contraindicated, given the premium this intervention places on steadily boosting activity levels. The form of CBT prescribed in PACE could also be contraindicated, since the ultimate goal of that intervention is likewise to increase activity. (The CDC has not adopted the name proposed by the IOM report, “systemic exertion intolerance disease.”)

In addition to symptomatic relief, the revised CDC website suggests such management strategies as a balanced diet, nutritional supplements and complementary medicine. Here’s some of the new language on managing the illness that has displaced the previous sections on GET and CBT:

*Avoiding ‘push-and-crash’ cycles through carefully managing activity. “Push-and-crash” cycles are when someone with ME/CFS is having a good day and tries to push to do more than they would normally attempt (do too much, crash, rest, start to feel a little better, do too much once again). This can then lead to a “crash” (worsening of ME/CFS symptoms). Finding ways to make activities easier may be helpful, like sitting while doing the laundry or showering, taking frequent breaks, and dividing large tasks into smaller steps.

*Talking with a therapist to help find strategies to cope with the illness and its impact on daily life and relationships.

Of course, avoiding “push-and-crash” is what patients already do when they practice pacing. The “push-and-crash” language itself appears to be closely aligned with the arguments provided by the PACE investigators and their colleagues; many patients might describe their experiences differently. Nevertheless, removing the CBT/GET recommendations is a welcome step, if overdue. For years, patients and advocates pointed out the problems with PACE and related research, and also cited the evidence that too much exertion caused harm because of physiological abnormalities, not the deconditioning presumed by CBT and GET. But until now, the agency refused to make the necessary changes.

The CDC’s longtime promotion of these therapies has had a widespread negative impact, as I reported at length last fall in the MIT-based online magazine Undark. So it is not enough now to merely tweak the website quietly. The agency should publicly announce the changes and explain the reasons for making them. By removing CBT and GET, the CDC is conceding the truth of what patients and advocates have repeatedly told them—the evidence does not support recommending these therapies for this illness, either as treatments or as generic management strategies. Agency officials should now apologize for having gotten it so wrong and for having failed to address these legitimate and often-expressed concerns.

Many U.S. health care organizations continue to recommend CBT and graded exercise for ME/CFS, in part or in whole because of the CDC’s guidance. This approach still causes many patients to suffer serious and permanent deterioration along with the stigma and blame that come with the illness, said Mary Dimmock. She hopes CDC officials will now strongly promote awareness of the changed recommendations not just among the public but specifically among medical societies, medical education providers, state health commissioners and others involved in health care delivery.

“I want them to take a leadership position to disseminate this information proactively,” said Dimmock. “They have a responsibility to reach out and fix this problem.”

The CDC has another urgent obligation: To communicate with the U.K.’s National Institute for Health and Care Excellence, which develops clinical guidelines for various medical conditions. NICE is currently debating whether or not its recommendations for the illness—which it calls CFS/ME–need to be reviewed; of course, these recommendations include CBT and GET as indicated treatments. NICE is soliciting input this month from stakeholders, but the expert panel assessing the situation has apparently made a provisional decision that no review is required.

The CDC has a long history of collaborating with key members of the PACE team and others in the U.K. medical and public health establishments; it is not surprising that prescribing CBT and/or GET should have become standards of care in both countries. It is now incumbent on U.S. public health officials to alert their British colleagues, including those at NICE, that they have just abandoned these longstanding recommendations. They should also explain why they have taken that major step, and why NICE should consider doing the same. (More on the NICE guidelines later this week.)