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By David Tuller, DrPH

Yet another interesting development has taken place at Cochrane—and this new development again suggests that things there might be moving in the right direction. On Friday, the organization withdrew a protocol for what is called an “individual patient data” review of exercise therapy for the illness it has referred to as chronic fatigue syndrome.

Given recent related news involving Cochrane, this development led to some understandable confusion. So just to clarify: This is NOT the exercise review that has been the subject of controversy over whether it would or would not be temporarily withdrawn. That basic exercise review focused on the published data from the papers included. Just ten days ago, Cochrane rejected a revision of this basic exercise review and announced the upcoming development of a plan for a “full update.”

An IPD review is a more in-depth analysis than a basic review because it uses the actual trial data from the included studies rather than relying on the published numbers. The goal of an IPD review would be to provide what could be portrayed as even more authoritative findings to bolster those arising from a basic review. In any event, no IPD exercise review has been published. What has just been withdrawn is the protocol for such an IPD exercise review, which Cochrane published in 2014.

The lead author of the IPD exercise review protocol was also the lead author of the currently contested basic exercise review. More controversially, the co-authors included the three main PACE investigators as well. These circumstances triggered a public debate between Cochrane and critics about appropriate standards for assessing conflicts of interest. Cochrane’s policies allow those who contribute trial data for use in IPD reviews, as the PACE investigators were doing in this situation, to be included as co-authors.

Based on the IPD exercise review protocol, the authors produced the IPD exercise review, which was expected to be published last year. Perhaps because of the growing international controversy over PACE and other GET/CBT studies, Cochrane wisely decided to consult with a wider group of readers than usual and sent out this IPD exercise review to experts not affiliated with the GET/CBT ideological brigades. At least some of these outside reviews were scathing. By last summer, the apparent delay in publication of the IPD exercise review had already led people outside Cochrane to assume that it was unlikely to be published—an assumption confirmed by the new statement.

Here’s the notice that appeared on the site of the IPD exercise review protocol on Friday:

“This protocol has been withdrawn and it is no longer being progressed to a Cochrane review.
This protocol was published in 2014 and a new protocol is required for any future individual participant data (IPD) meta‐analysis on this topic. 
The editorial group responsible for this previously published document have withdrawn it from publication.”

Significantly, the statement indicates that the withdrawal was made by the “editorial group” that prepared the document. That presumably means the Common Mental Disorders group, which has long owned this illness at Cochrane. If that’s the case, it means that those in charge at the Common Mental Disorders group now accept that Cochrane will not be publishing the actual IPD exercise review. That in turn would leave no reason for the IPD exercise review protocol to remain in the literature.

Certainly the IPD exercise review protocol withdrawal is very different from this fall’s messy almost-withdrawal involving the basic exercise review. To recap: In October, Reuters broke the story that Cochrane planned to temporarily withdraw the review, pending a revision to be submitted by the authors. Cochrane had based its decision on the basic exercise review’s unacceptable methodological and scientific failings, which a patient had authoritatively documented in a formal complaint. Yet Reuters largely portrayed Cochrane as having caved under belligerent pressure from an aggressive patient lobby.

After the Reuters article appeared, Cochrane backed away from its apparent decision to temporarily withdraw the review. While leaving the review in place, it announced that the authors were nonetheless pursuing a revision in response to the concerns raised. This was the revision rejected by Cochrane late last month. Given that editors considered the revisions necessary in the first place because of the inadequacies of the published basic exercise review, the fact that it remains in the Cochrane library raises continuing questions about its status as a credible and legitimate piece of scientific research.

In any event, figuring out exactly what is transpiring within Cochrane’s inner sanctum is challenging—especially since it appears difficult for the organization to withdraw a review without the consent of the authors. My hope is that these recent steps are all part of a slow but deliberate plan to finally transfer the illness from the Common Mental Disorders group to a more appropriate department. The withdrawal of the IPD exercise review protocol will help facilitate such a move, since this also eliminates any expectation that Cochrane will publish the actual IPD exercise review from the Common Mental Disorders group.

Along with these recent positive actions, I hope that everyone involved—including those who have worked hard producing the multiple iterations of these reviews—can amicably agree that anything else previously generated by the Common Mental Disorders group related to this illness should also be withdrawn. That would allow whatever new group at Cochrane takes on the challenge to start its investigations with a clean slate.

At the University of Zürich, Vincent speaks with virologists Cornel Fraeful, Urs Greber, and Silke Stertz about their careers and their work on AAV2, adenovirus entry, and influenza virus.

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By David Tuller, DrPH

Earlier today, I sent the following e-mail to Dr Fiona Godlee, editorial director of BMJ. I cc’d Carol Monaghan MP, Darren Jones MP, and Nicky Morgan MP. I also cc’d Teresa Allen of the Health Research Authority.

**********

Dear Dr. Godlee—

As you know, I have spent some time criticizing a 2011 BMJ Open study involving the use of school absence records to identify children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME, or what many now refer to as ME/CFS). The investigators exempted the study from ethical review on the false grounds that it was “service evaluation” rather than “research.” To support this claim, they cited an unrelated 2007 letter from the regional research ethics committee.

The school absence study was conducted by investigators from the University of Bristol. As it turns out, members of this team of investigators have cited the same 2007 REC letter to exempt ten other studies (or parts of studies) from ethical review on similar grounds. Five of them, including the school absence study, were published in BMJ journals—two in BMJ Open, and three in Archives of Disease in Childhood. The first was published in 2009, with others following in 2011, 2013, 2015 and 2017.

(I am cc-ing Carol Monaghan MP, Darren Jones MP, and Nicky Morgan MP. All three are involved in parliamentary inquiries into issues related to ME/CFS, including some of the questionable research that has characterized this field. I am also cc-ing Teresa Allen from the Health Research Authority.)

None of these five BMJ papers appear to meet the criteria for “service evaluation” studies, which are generally designed solely to assess the provision of services through the use of anonymized databases. The BMJ Open school absence study, in contrast, featured a formal hypothesis, in-person collection of participant data, and generalizable conclusions. These are all hallmarks of “research” and not “service evaluation,” according to the UK Health Research Authority, the relevant government agency. Studies defined as “research” require ethical review.

Here are the five Bristol studies that cited the 2007 REC letter to exempt themselves from ethical review and were published in BMJ journals:

Association between school absence and physical function in paediatric chronic fatigue syndrome/myalgic encephalopathy. Archives of Disease in Childhood, 2009.

Unidentified Chronic Fatigue Syndrome/myalgic encephalomyelitis (CFS/ME) is a major cause of school absence: surveillance outcomes from school-based clinics. BMJ Open, 2011.

Depression in paediatric chronic fatigue syndrome. Archives of Disease in Childhood, 2013.

Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts. BMJ Open, 2015.

Obesity in adolescents with chronic fatigue syndrome: an observational study. Archives of Disease in Childhood, 2017.

Here is the background:

In 2007, the North Somerset and South Bristol REC approved a request to add questionnaires to those already being used during pediatric care at the Bath CFS/ME clinical service. At the time, the clinical service was conducting assessments with several questionnaires at entry and at twelve months. The REC application sought approval for the Bath CFS/ME clinical service to collect further assessments at six weeks and six months, explaining that the extra data would be useful for measuring and improving the delivery of care.

The title of the research project associated with the application was: “What happens to children with CFS/ME? The study of a longitudinal cohort of children who access a paediatric CFS/ME service.” After reviewing the application, the REC responded in a letter dated May 1, 2007. The letter stated: “Members [of the REC] considered this project to be service evaluation. Therefore it does not require ethical review by a NHS Research Ethics Committee or approval from the NHS R&D office.”

The 2007 REC letter referred to “this project”—i.e. the expanded schedule of questionnaires for children at the Bath CFS/ME clinical service designed to assess health care delivery. The five BMJ studies that cited the letter to exempt themselves from ethical review would seem to fall beyond the scope of that particular “project.”

Besides the school absence study, BMJ Open published a paper including data from adults patients as well as children. It is hard to understand how an REC letter specifically about pediatric questionnaires could be cited to exempt from ethical review a study involving adults. And the three studies published in Archives of Disease in Childhood did not focus on the evaluation of services. Instead, they presented generalizable conclusions about the illness and its links to other factors, such as depression and obesity.

The pediatric depression study in Archives of Disease in Childhood, for example, concluded the following: “Depression is commonly comorbid with CFS/ME, much more common than in the general population, and is associated with markers of disease severity. It is important to screen for, identify and treat depression in this population.” Studies with generalizable conclusions are normally categorized as “research,” not “service evaluation,” and require ethical review.

It is incumbent upon Bristol University to conduct a thorough examination of this matter. Whatever Bristol does, however, BMJ itself must investigate how it published five studies that exempted themselves from ethical review on questionable grounds, with no apparent oversight–all citing the same 2007 REC letter.

BMJ editors need to ask themselves questions such as:

*What lapses in procedures for assessing and reviewing manuscripts might have allowed these studies to slip through? What red flags were missed?

*What is current policy about fact-checking ethics declarations, especially if they are used to exempt studies from ethical review?

*Have editors been particularly lax in their oversight in cases involving this specific illness? Have editors put too much trust in this particular research team?

*In the case of the 2011 school absence study, the abstract itself provided sufficient information to determine that this was “research” requiring ethical review. Why did editors fail to recognize this? Why hasn’t the journal addressed the issue honestly and apologized for this mistake?

*How does BMJ plan to prevent similar embarrassments in the future? After this misstep, how can BMJ ensure public confidence in its editorial decision-making?

Dr Godlee, since I first wrote to BMJ Open about the school absence study more than a year ago, the journal has dissembled, obfuscated, and evaded responsibility for having published research that inappropriately exempted itself from ethical review. Such a lack of transparency and accountability is unacceptable; it is also antithetical to robust scientific debate. Now it appears that your journals have published four other Bristol studies in a similar predicament as the first.

These editorial lapses are especially troubling when issues involve the health and wellbeing of children. To rectify the problems in this instance, BMJ needs to: 1) Review the facts related to the publication of these five papers; 2) take any necessary corrective action in each case to ensure the accuracy and integrity of the published literature; and 3) make the necessary changes in editorial and reviewing processes and policies.

Best—David

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

By David Tuller, DrPH

In what can only be characterized as a welcome surprise, Cochrane has rejected the revision of a 2014 review of exercise treatments for chronic fatigue syndrome, stating that the work does not meet the organization’s “quality standards.” Cochrane revealed the decision late Friday in a statement appended to the review, which itself was a revision of a review first published years earlier.

That review reported that exercise therapy, most often graded exercise therapy, was effective. Yet the review was a methodological mess. Two patients–Tom Kindlon and the late Robert Courtney—wrote extensive and cogent critiques after it was published. When the lead author of the review provided inadequate responses, Courtney filed a formal complaint with Cochrane.

Cochrane found merit in the complaint and had recently given the authors a chance to revise their work accordingly. This was the revision that Cochrane has now deemed unsatisfactory.

Why did Cochrane’s announcement surprise me? I had assumed the revision would be unsatisfactory. But Cochrane had initially decided to withdraw the review pending these revisions, and had backed down from doing so under what must have been enormous pressure from the CBT/GET ideological brigades and their defenders. So the review has not been withdrawn during this revision process.

Given that early retreat on Cochrane’s part, I was concerned the editorial team would require the authors to make only a few tweaks but no substantive changes to the review. Luckily, I was wrong. Here’s the statement Cochrane posted on Friday:

“The author team has re‐submitted a revised version of this review following the complaint by Robert Courtney. The Editor in Chief and colleagues recognise that the author team has sought to address the criticisms made by Mr Courtney but judge that further work is needed to ensure that the review meets the quality standards required, and as a result have not approved publication of the re‐submission. The review is also substantially out of date and in need of updating. 

Cochrane recognises the importance of this review and is committed to providing a high quality review that reflects the best current evidence to inform decisions. 

The Editor in Chief is currently holding discussions with colleagues and the author team to determine a series of steps that will lead to a full update of this review. These discussions will be concluded as soon as possible.”

The suggestion that the review is out of date is interesting. This could be referring to the fact that raw PACE trial data were released two years ago, and there are now published reanalyses of the findings. Perhaps Cochrane recognizes that these reanalyses, which refute the positive results reported by the PACE team, would need to be included in any credible “full update.”

The Cochrane statement does leave some questions unanswered. Given that a revision was deemed necessary in the first place, the current published version is obviously unsatisfactory as is. Will this published but unsatisfactory version be withdrawn? If not, why not? If so, when?

Moreover, the Cochrane statement seems conveniently ambiguous on a key point. Will the authors of the current review be asked to develop the “full update” themselves or will they just be participating in discussions of what steps should be taken going forward? Until given reason to think otherwise, I will interpret that ambiguity as deliberate and therefore as a positive sign.

Perhaps this is the moment when all, including the authors, will agree that the time has come to remove this illness from the Common Mental Disorders group. In conjunction with that, perhaps all will agree as well to withdraw the reviews conducted under the auspices of this group—the exercise review as well as an older review of cognitive behavior therapy for the illness.

In fact, the response to a comment posted on the review in October suggests that transferring the illness elsewhere could be a real possibility. A reader raised once again the concern about the illness being housed within the Common Mental Disorders group, citing the 2015 report from the Institute of Medicine and the WHO’s categorization of it as neurological. Cochrane’s response was not from the lead author of the review but from two representatives of the Common Mental Disorders group itself. Here’s part of what they wrote:

“In response to concerns raised by members of the CFS/ME community, Cochrane has been considering repositioning the editorial oversight of CFS/ME reviews. The Cochrane CMD Review Group currently sits within the Brain, Nerves and Mind (BNM) Network. In the future, reviews on this topic might sit with another Cochrane Review Group within the BNM Network, or they might transfer to another Network altogether…Please be reassured that this is currently under consideration and a decision is anticipated before the end of 2018.”

Given the source, perhaps this response is a signal that the Common Mental Health Disorders group has agreed to a collegial and imminent hand-off of responsibilities and that an acceptable biomedical home will be found for ME/CFS. That would indeed be an excellent development.

The TWiVsters review isolation of a naturally occurring DNA virus from fruit flies, and the cell-type specific function of a small transmembrane protein encoded in an open reading frame upstream of the enterovirus polyprotein.

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The lost picornavirus ORF

For over 50 years the RNA genome of picornaviruses (illustrated below for poliovirus) was thought to be translated into a single, long polyprotein. All this time a very small upstream open reading frame (uORF) has gone undetected – until now.

Picornavirus-UP

Analysis of over 3000 picornavirus genomes revealed a small ORF, beginning with an AUG codon, in the 5-untranslated region of the genome. This uORF (pictured above as a red line) is in a different reading frame from that of the polyprotein. The putative protein, called UP, could be detected in cells infected with the picornaviruses echovirus 7, poliovirus 1, and enterovirus A71.

UP is required for efficient replication in intestinal epithelial cells but not in laboratory cell lines. The protein contains a transmembrane domain, and is associated with the endoplasmic reticulum. A function of UP is to disrupt cell membranes and allow the release of virus particles entrapped in vesicles.

Curiously, UP is only found in the genomes of some enteroviruses, and not in rhinoviruses or other picornaviruses that cause respiratory infections. The protein might be specifically required for replication in intestinal epithelial cells.

When I saw this manuscript a few days ago, it reminded me of work we had done in the 1980s. We had just completed the nucleotide sequence of the poliovirus genome and found clear evidence for a single polyprotein initiated by an AUG codon at nucleotide 742. We were surprised to find 7 other AUG codons in the putative 5’-noncoding region, and were interested in determining whether these were initiators of protein synthesis.

We mutated each of the 7 AUG codons in the poliovirus genome to UUG and found that 6 of the 7 viruses replicated normally. The exception was a virus with a mutation of AUG #7: this virus formed small plaques on HeLa cells and replicated poorly. We surmised that this mutation somehow affected translation of the polyprotein.

Why didn’t we see the UP uORF back in 1988? Our experiments were done with type 2 poliovirus, not type 1. The former has a very short open reading frame after AUG #7 and consequently we did not think it was important. AUG #7 of poliovirus type 1, in contrast, has a longer reading frame, encoding UP, that overlaps the polyprotein reading frame (see illustration below).

uORFs of P1/Mahoney and P2/Lansing polioviruses. Amino acid codons are shown. uORF of P1 is longer than that of P2 as seen by the locations of the UGA termination codon. The AUG of the polyprotein is in a different reading frame as shown.

We were studying type 2 poliovirus because it could paralyze mice, allowing us to study the determinants of neurovirulence. Had we used type 1 poliovirus, we might have seen the UP uORF and detected its encoded protein back in 1988.

Team TWiV cover the discovery of another giant virus from 30,000 year old Siberian permafrost, and how viral aggregation accelerates the production of new infectious viruses and increases fitness, demonstrating an Allee effect.

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Paul Has Measles

pablotieneSusana López, Martha Yocupicio, Selene Zárate, virologists from Mexico, together with graphic illustrator Eva Lobatón, have teamed up to produce Paul Has Measles, a children’s book about viruses and vaccines.

Paul Has Measles is available in English (download link) or Spanish (download link).

Please share!

paulhasmeasles

By David Tuller, DrPH

The UK’s National Institute for Health and Care Excellence (NICE), which develops clinical guidelines for a range of medical conditions, is currently selecting a committee to develop a new guidance for the illness it refers to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The new guidance will replace one written in 2007, when the organization was calling the illness CFS/ME. That 2007 guidance recommended graded exercise therapy (GET) and cognitive behavior therapy (CBT) as standard-of-care interventions and has been routinely cited as evidence that these treatments are effective.

[continue reading…]

TWiV 520: This old mouse

The TWiVidae review universal influenza vaccines that are in clinical trials, and discovery of an atypical parvovirus that causes chronic kidney disease in middle aged, immunocompromised laboratory mice.

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