virology blog

Trial By Error: Psychosomatics Journal Linked to PACE Authors Highlights Bias from Subjective Outcome

7 March 2021 by David Tuller 1 Comment

By David Tuller, DrPH

The Journal of Pyschosomatic Research, a high-profile publication from Elsevier, has recently published an article relevant to long-standing arguments about trials that are both unblinded and reliant on subjective outcomes–like, say, the PACE study and related research into psycho-behavioral treatments for ME/CFS. This specific question–how to assess research quality when subjective outcomes are involved–is at the core of ongoing debates over both draft guidelines for ME/CFS from the UK’s National Institute for Health and Care Excellence and Cochrane’s contested review of exercise therapies for chronic fatigue syndrome.

The authors of the article in the Journal of Psychosomatic Research are the current editor (Jess Fiedorowicz, of the University of Ottawa) and two former editors (James L. Levenson of Virginia Commonwealth University, and Albert Leentjens of Maastricht University Medical Centre). The two former editors currently sit on the journal’s advisory board. I assume that the article thus reflects the journal’s own perspective. And that perspective would seem to contradict claims made by some of the journal’s prominent advisory board members, including two of the lead PACE investigators.

The article, first available online in early March, is called “When is lack of scientific Integrity a reason for retracting a paper? A case study.” It discusses a 2004 paper published by the journal–a study investigating homeopathic treatment for what the investigators called chronic fatigue syndrome. Treatment allocation—to a homeopathic preparation or a placebo—was blinded to both participants and their providers. Not surprisingly, the findings did not support the notion that homeopathy was an effective treatment for chronic fatigue syndrome.

In 2019, the Journal of Psychosomatic Research received a request to retract the 2004 study. The request was based on the public admission by one of the homeopaths involved that she had engaged in actions meant to undermine the blinding of the treatment allocation. In the recent article, the three editors explain why they do not believe retraction is warranted in this case, despite what is a clear lapse in scientific integrity. The editors report that, after investigating the matter, they are convinced that the study findings remain robust and that any efforts to influence the outcomes did not work. They attribute this success to the rigor of the process of blinding everyone who was involved in the study.

So…the point of all this is not to report that homeopathy is not an effective approach for chronic fatigue syndrome (and presumably for the other clinical states grouped under that term, the name myalgic encephelomyelitis, and ME/CFS). It is to note that this team of top editors at a major psychosomatics journal places a great deal of value on the role of blinding in ensuring the integrity of research results. Their “case study” includes this significant passage:

“Reporting on the integrity of the blind has merit and is especially valuable when dealing with subjective outcomes for which there is a greater risk of bias due to any unblinding…. Un-blinded assessors of subjective binary outcomes may exaggerate odds ratios by an average of 36%. Subjective outcomes are frequently used in studies that fall within this journal’s scope, at the interface of psychology and medicine. We recommend assessing the integrity of the blind for any clinical trial, particularly those utilizing subjective outcomes akin to the primary outcomes of the…study in question.”

This passage does not directly address the problem of unblinded trials and subjective outcomes. But the editors certainly make no bones of the fact that subjective outcomes, absent blinding, are at “a greater risk of bias.” And they recommend that checking the “integrity of the blind” is of particular importance for trials “utilizing subjective outcomes”–like the various questionnaires chosen for the homeopathy study in question. It is understandable that these issues are important to these editors, given that, as they note, “subjective outcomes are frequently used in studies that fall within this journal’s scope.”

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Who is on the journal’s advisory board?

A corollary to the message of the cited paragraph is that trials “utilizing subjective outcomes” that are not blinded at all are at even greater risk of bias. It is therefore interesting that the Journal of Psychosomatic Research’s roster of advisory board members includes Professors Michael Sharpe and Peter White—two leading proponents of the view that subjective outcomes in unblinded trials are not a problem to interpretation, at least when it comes to their own research.

Colleagues of Professors Sharpe and White who hold similar views are also members of this journal’s advisory board: Professors Per Fink from Denmark, Judith Rosmalen from the Netherlands, and Jon Stone from the UK. These professionals are all experts in the field of so-called “medically unexplained symptoms,” or MUS–in which they place ME/CFS as well as irritable bowel syndrome and other entities of unknown etiology. Yet the body of MUS research is riddled with studies that are unblinded and rely on self-reported outcomes.

Despite the lack of objective support for many of their findings, investigators in this field routinely overlook the role that bias plays in research relying on subjective outcomes in unblinded studies. That role has now been highlighted in a very prominent manner by a journal that these same investigators serve as editorial advisory board members. Hm.

A leading example of this combination of being unblinded and relying on subjective outcomes is the PACE trial, with Professors Sharpe and White as two of the three lead investigators. PACE included four objective measures—a six-minute walking test, a step-test for fitness, whether people were employed, and whether they were on social benefits. All failed to meet the subjective reports of improvements on questionnaires about physical function and fatigue. Rather than acknowledging this fact forthrightly and discussing the implications of the poor results for the validity and reliability of their subjective measures, the PACE authors scattered these findings across multiple papers—a decision that helped minimize any attention to the collective failure of all of them.

The PACE investigators also questioned the objectivity of their own self-selected objective outcomes. They claimed they implemented the six-minute walking test differently than other investigators, so the disastrous results could not be compared to those from studies of people with a variety of conditions. They claimed that independent economic factors and changes during the period of the study meant that whether people got back to work or got off benefits would not be an objective measurement of the success or failure of treatment.

They had also dropped a key objective measure—wearing a movement monitor known as an actimeter for a week at the end of the trial. However, they retained it as a baseline measure, meaning participants wore it for a week at the start. Publicly, the investigators claimed they dropped it as an outcome because they believed that wearing it for a week would be too much of a burden for participants at the end of the trial. They did not explain why it would be more of a burden at the end of the trial than at the beginning.

When trial minutes were released after a freedom of information request, they revealed that the PACE team dropped the actimeters as an outcome after learning that Dutch colleagues had found their own results from this measure did not meet their positive subjective reports. In other words, retaining the measure did not appear to be a useful way to do what they seemed determined to do: “prove” their therapies worked. So they disappeared it.

Now the current and former editors of the Journal of Psychosomatic Research have made declarative statements about about blinding and subjective outcomes. So I’m curious: What is their opinion of the PACE trial? Do Fiedorowicz, Levenson and Leentjens know that this debacle was unblinded and relied on subjective outcomes, and that the investigators assessed their objective findings as irrelevant? Do they care about this contradiction between their own pronouncements on research integrity and the apparent belief by members of their advisory board that combining unblinded studies and subjective findings does not present a problem to proclaiming treatment success?

One and Done

4 March 2021 by Gertrud U. Rey 4 Comments

by Gertrud U. Rey

On February 27, 2021, the FDA issued an emergency use authorization for a third SARS-CoV-2 vaccine. The vaccine was developed by Janssen Pharmaceutica, a Belgium-based division of Johnson & Johnson, in collaboration with Beth Israel Deaconess Medical Center in Boston. Perhaps the most exciting feature of this new vaccine is that it only requires one dose to be effective in inducing an immune response.

The vaccine is named Ad26.COV2.S because it consists of a human adenovirus vector, with a DNA genome, into which has been inserted the gene that encodes the full-length SARS-CoV-2 spike protein (pictured). Ad26.COV2.S is similar to AstraZeneca’s vaccine, based on a different adenovirus, and with a slightly different version of spike, which is not yet authorized in the U.S. The notion of using a virus as a vector to deliver vaccines to humans is based on the ability of viruses to enter cells by attaching to host cell receptors and releasing their genome into the cell. Upon injection into a vaccine recipient, the vaccine vector should enter cells and serve as a code for host proteins to synthesize the SARS-CoV-2 spike protein from the inserted gene. Ideally, the spike protein will then act as an antigen to prime the immune system to recognize SARS-CoV-2 if it infects the body at a later time.

Adenoviruses are particularly suitable as vectors for delivering foreign genes into cells because they have a double-stranded DNA genome that can accommodate relatively large segments of foreign DNA, and because they infect most cell types without integrating into the host genome. However, because of the prevalence of adenovirus infections in humans, most people have adenovirus-specific antibodies that could bind and neutralize these vectors, thus rendering them less effective at stimulating antibodies to the inserted gene product. AstraZeneca circumvented this issue by using an adenovirus of chimpanzee origin that does not normally infect humans. The adenovirus used to make Ad26.COV2.S (Adenovirus 26) is of human origin; however, when tested, most people have very few antibodies that inactivate this adenovirus, compared to antibodies against other adenoviruses. Thus, potential Ad26.COV2.S recipients are less likely to have pre-existing antibodies to the adenovirus vector itself. To optimize Adenovirus 26 for use as a vaccine vector, Janssen investigators deleted the gene that regulates viral replication, thus ensuring that the virus vector cannot cause an infection in human cells.

During infection, the SARS-CoV-2 viral particle fuses with the host cell membrane; a process that is mediated by two main events: 1) a structural rearrangement of the spike protein from its pre-fusion conformation; and, 2) cleavage of the spike protein by a cellular enzyme called furin. Based on the knowledge that the pre-fusion, uncleaved form of spike is more stable and immunogenic, Janssen investigators also inserted two mutations into the spike gene: one that locks the translated spike protein into its pre-fusion conformation, and one that prevents its cleavage by furin.

The FDA’s decision to issue an emergency use authorization for Ad26.COV2.S was based on safety and efficacy data from an ongoing Phase III clinical trial done in 39,321 participants who received either a single dose of Ad26.COV2.S or a placebo control. The trial was randomized, meaning that participants were randomly assigned to the experimental group receiving the Ad26.COV2.S vaccine, or the control group, so that the only expected differences between the experimental and control groups were the outcome variables studied (safety and efficacy). Randomizing trial participants eliminates unwanted effects that have nothing to do with the variables being analyzed. The trial was also double-blinded, meaning that neither the investigators nor the subjects knew who was receiving a particular treatment. Double-blinding leads to more authentic conclusions because they reduce researcher bias.

The basic findings of the trial were as follows:

side effects related to vaccination were mild to moderate; and
the vaccine was
- 66% effective at preventing moderate to severe COVID-19 across all geographic areas and age groups (U.S., South Africa, and six countries in Latin America);
- 72% effective at preventing moderate to severe COVID-19 across all age groups in the U.S.;
- 85% effective at preventing severe disease; and
- 100% effective at preventing COVID-19-related hospitalization and death as of day 28 after vaccination.

The apparently reduced efficacy of Ad26.COV2.S compared to the Moderna and Pfizer vaccines has led to considerable public skepticism. However, this is an unfair comparison for several reasons. Ad26.COV2.S was tested at a time when more variants were in circulation, including in places where the Moderna/Pfizer vaccines are thought to be less effective against locally circulating variants. Some limited data also suggest that Ad26.COV2.S might protect from asymptomatic infection and may thus prevent transmission from vaccinated individuals to non-vaccinated individuals. Although there is some evidence to suggest that the Pfizer vaccine has a similar effect, no such data exist yet for the Moderna vaccine.

The most critical measure of a vaccine’s efficacy is how well it prevents severe disease, hospitalizations, and deaths, and in this regard, all three vaccines are comparable. Moreover, Ad26.COV2.S has at least two advantages over the Pfizer/Moderna vaccines: 1) it does not require a freezer and can be stored in a refrigerator for up to three months; and, 2) it can be administered in a single dose. This will increase vaccine uptake, because people won’t have to get two shots and/or remember to get the second shot. It also makes it easier to immunize people with limited access to healthcare, such as the homeless and people living in remote areas. When all these factors are considered together, it is clear that Ad26.COV2.S will be a crucial additional tool in the fight against this pandemic.

Trial By Error: A Q-and-A with Tracie White, author of The Puzzle Solver

3 March 2021 by David Tuller 2 Comments

By David Tuller, DrPH

Tracie White, a science writer at Stanford University, first stumbled across the story of Whitney Dafoe as an assignment from one of her editors. That initial encounter ultimately turned into The Puzzle Solver: A Scientist’s Desperate Quest to Cure the Illness that Stole His Son, an account that Kirkus called “a complex, well-related story of medical detective work.”

The story of Stanford geneticist Ron Davis and his son Whitney’s severe case of ME/CFS was certainly not unknown, given previous coverage–starting with Miriam Tucker’s excellent 2015 feature in The Washington Post. White’s is the first full-length account. During the reporting of the book, she grew close to the family, which included psychologist Janet Dafoe, Whitney’s mom, and his sister Ashley. I asked White a few questions about the process of writing the book.

Understanding virus isolates, variants, and strains

25 February 2021 by Vincent Racaniello 7 Comments

Many virology terms are being used these days by people who do not understand their meaning. Included are journalists, medical doctors, scientists, lawyers, and people from all walks of life. In normal times this word mis-usage would be so rare that it would not matter. However, because we are in a viral pandemic that affects nearly everyone, I will attempt to explain the meaning of virus isolates, variants, and strains.

Many of the terms used in virology are ill-defined. They have no universally accepted definitions and there is no ‘bible’ with the correct meanings. As each of us are trained by other virologists, we hear them using terms in certain contexts and we copy their usage – whether or not it is correct. I learned many good things from my mentors but also many things that are wrong.

Nevertheless, certain terms should have specific meanings. Some of my colleagues will certainly disagree with some of my definitions, others will agree. Kudos to the latter. I also recognize that few will read this post and it will have little impact. Perhaps one day a high school student will search for some of the terms and come across it. It is mainly meant for me to put my thoughts down in an orderly manner.

The virology terms I have in mind all have to do with attempts to place order on the huge varieties of viruses in the virosphere. Most of them today derive their meaning from the viral genome: the DNA or RNA that encodes the production of new virus particles. This reliance on the genome is relatively recent: until the 1980s we had no genome sequences; hence most categories were based on other properties, such as the size of the virus particle, whether or not it has a membrane, its type of symmetry, and much more. Today it’s all about the genome. Whether or not you think this myopia is a good idea is not the topic of this post.

Let’s start with the term virus isolate, because it’s the easiest to define. An isolate is the name for a virus that we have isolated from an infected host and propagated in culture. The first isolates of SARS-CoV-2 were obtained from patients with pnemonia in Wuhan in late 2019. A small amount of fluid was inserted into their lungs, withdrawn, and placed on cells in culture. The virus in the fluid reproduced in the cells and voila, we had the first isolates of the virus.

Virus isolate is a very basic term that implies nothing except that the virus was isolated from an infected host. An isolate comes from a single host. We can have my virus isolate, or yours, or the neighbor’s down the street. Most patients do not get to have virus isolates taken from them. Even though SARS-CoV-2 has infected millions, we do not have millions of isolates, probably just thousands. We do have genome sequences from many people, and those can be inferred to represent the isolate from each person – however in most cases infectious virus is not isolated from individual patients.

Isolates are given names so that their origin is known. For example, one of the early isolates of SARS-CoV-2 is called BetaCoV/Wuhan/WIV04/2019. This isolate name consists of the genus, Betacoronavirus, followed by the city of origin, the isolate number, and the year. SARS-CoV-2 is the name of the virus; it is not an isolate name. Isolates of other viruses are also precisely named. I’m a big fan of the very detailed influenza virus nomenclature, which is as follows: Virus name/antigenic type/host of origin if other than human/geographical origin/serial number/last two digits (or all four digits) of year of isolation/hemagglutinin subtype neuraminidase subtype. Examples include influenza A virus A/duck/Germany/1868/68 (H6N1) or influenza A virus A/chicken/Vietnam/NCVD- 404/2010 (H5N1).

A virus variant is an isolate whose genome sequence differs from that of a reference virus. No inference is made about whether the change in genome sequence causes any change in the phenotype of the virus. The meaning of variant has become clouded in the era of whole viral genome sequencing, because nearly every isolate may have a slightly different genome sequence. Such is the case for SARS-CoV-2: nearly every sequence from a different person is slightly different. Up until the end of 2020, any SARS-CoV-2 sequences from any two individuals differed by about ten nucleotide changes out of 30,000. They are all variants, but the term is rarely used in this context. However since then viral genomes with many more changes have been identified. These have been called ‘variants of concern’ (VOC) because it is thought that the changes confer new phenotypic properties such as increased fitness. British scientists did a good deed by calling them VOCs, because now the press must call them variants.

Unfortunately mainstream media, following in the footsteps of scientists who really should know better, have been using the term ‘strain’ to describe what are actually variants. This practice emerges in every viral outbreak: there is a new, more (fill in the blank with your favorite phenotype) strain of Ebolavirus, of Zika virus, and now of SARS-CoV-2. It began early in 2020 with the finding of variants with a single amino acid change in the spike protein, from D to G at position 614. The press called this a new strain that was more transmissible. But the use of strain was incorrect: it is a variant and remains so to this day.

A virus strain is a variant that possesses unique and stable phenotypic characteristics. Such characteristics can only be ascertained by the results of experiments done in the laboratory, in cells in culture and in animals, coupled with observations made in infected humans. The name strain is not easily earned: certainly it cannot simply be given by journalists! As Jens Kuhn has written, “The designation of a virus variant as a strain would be the responsibility of international expert groups”. No such designation of strain has been given more than once to SARS-CoV-2: there is one, and only one strain of this virus. No incorrect usage of that term will change this fact. As you might imagine, it can take some time for an international group of experts to agree on anything.

Viral strains are few and far between: it is a designation highly desired but given sparingly. A retrovirologist recently assured me that there is only one strain of HIV-1. The Lansing strain of poliovirus is derived from a human isolate that was passaged 99 times in mice until it acquired the ability to infect that species. That strain has demonstrably different properties from the human strain.

There are other terms to describe viruses but they are more confusing than contentious, and they are not used universally. The term serotype is used to describe viruses of the same species that are antigenically different. There are three serotypes of poliovirus; if you are infected with type 1, then immunity you generate will not protect you against infection with types 2 or 3. Same for the four serotypes of dengue virus, and the hundreds of rhinovirus serotypes. These days, the genome sequence of the virus is used to infer whether isolates are serologically different. The term genotype is used to describe the genetic makeup of a virus. For example, hepatitis C viruses are placed in different genotypes depending on the overall identity of their genomes. For other viruses, the term clade is used. A clade is a group of organisms composed of an ancestor and its descendants, as illustrated by the phylogenetic tree below. SARS-CoV-2 isolates and HIV-1 isolates are placed in clades based on phylogenetic trees constructed from their genome sequences.

I believe that the terms of virology should be used accurately and consistently. The terms isolate, strain, and variant have been frequently and incorrectly misused during the pandemic, which generates confusion. I have little faith that either the general public or the scientists will agree on any nomenclature. Rest assured that if you misuse isolate, variant, or strain, I will correct you according to my lexicon.

Trial By Error: National Institutes of Health Director Francis Collins on Plans for Long COVID Research

24 February 2021 by David Tuller 12 Comments

By David Tuller, DrPH

The US government seems to be taking Long COVID seriously. In December, Congress allocated $1.15 billion over four years for research into the issue. This week, Francis Collins, director of the National Institutes of Health, announced the agency’s plans for that funding. (I’ve posted his announcement in full below.) In a post last month he highlighted the plight of the long-haulers and praised the most extensive report yet on their situation. That well-received research report was spearheaded and produced by a patient-led team from the Body Politic COVID-19 Support Group, an online community.

The relationship between what is generally being called ME/CFS and what is generally being called Long COVID is unclear. A number of high-profile news articles–including ones published by The New York Times, The Guardian, and Kaiser Health News–have noted the apparent overlaps in symptoms and in possible or hypothesized causes. These articles have taken at face value the notion that ME/CFS patients are suffering from a serious disease and have not presumed that psychotherapy and exercise are the optimal approaches to treatment.

Both ME/CFS and long COVID are complex phenomena–as is evident from confusion and disagreement over the appropriate nomenclature. ME/CFS is an unsatisfactory hybrid term used to refer to a range of described clinical entities. Long COVID is a convenient and easy-to-understand term but it conveys nothing about the condition’s expansive range of presentations. That variety is better expressed through the scientific name it has been given: Post-Acute Sequelae of SARS-CoV-2 infection (PASC). In other words, there are lots of different sequelae–not just one entity called Long COVID.

Ramped up funding for research into Long COVID could be beneficial for ME/CFS patients. My sense is that many of the latter are hopeful that these investigations could reveal biological mechanisms and pharmaceutical treatments that could be relevent for them as well–especially given apparent similarities in symptoms like post-exertional malaise and cognitive impairment. (I never expected to see the phrase “brain fog” in news headlines all around the world.)

At the same time, there is cause to be wary. This pandemic is now early in its second year, so so-called Long COVID is still a relatively short phenomenon–especially when compared to the decades of illness experienced by many with ME/CFS. Reports of persistent symptoms are known to be common after many viral infections. It is also known that these cases self-resolve most of the time–even if it can take a year or more in some cases.

If it is asserted prematurely or simplistically that Long COVID and ME/CFS are somehow the same, what happens if most of these legions of Long COVID patients get better in the next few months or over the next year? It could easily be presumed that the “multi-disciplinary rehabilitation”–or any number of helpful or non-helpful interventions–led to improvements, even if the recoveries would have happened in any event. In such a scenario, that advice could be presumed to be applicable to ME/CFS patients. Before declarative statements can be made, we need to see a lot more data.

In the meantime, it’s great that NIH has found more than $1 billion to investigate Long COVID. It certainly suggests that more money could have been found ten or twenty years ago to study ME/CFS than the pittance that has historically been allocated. While the amount has increased significantly in recent years, two or three times a pittance is still a relative pittance. (Jennie Spotila provides regular analyses of NIH funding at Occupy M.E., her blog)

Below is the announcement from NIH Director Francis Collins:

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NIH launches new initiative to study “Long COVID”

I write to announce a major new NIH initiative to identify the causes and ultimately the means of prevention and treatment of individuals who have been sickened by COVID-19, but don’t recover fully over a period of a few weeks. Large numbers of patients who have been infected with SARS-CoV-2 continue to experience a constellation of symptoms long past the time that they’ve recovered from the initial stages of COVID-19 illness. Often referred to as “Long COVID”, these symptoms, which can include fatigue, shortness of breath, “brain fog”, sleep disorders, fevers, gastrointestinal symptoms, anxiety, and depression, can persist for months and can range from mild to incapacitating. In some cases, new symptoms arise well after the time of infection or evolve over time. In December, NIH held a workshop to summarize what is known about these patients who do not fully recover and identify key gaps in our knowledge about the effects of COVID-19 after the initial stages of infection. In January, I shared the results from the largest global study of these emerging symptoms. While still being defined, these effects can be collectively referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC). We do not know yet the magnitude of the problem, but given the number of individuals of all ages who have been or will be infected with SARS-CoV-2, the coronavirus that causes COVID-19, the public health impact could be profound.

In December, Congress provided $1.15 billion in funding over four years for NIH to support research into the prolonged health consequences of SARS-CoV-2 infection. A diverse team of experts from across the agency has worked diligently over the past few weeks to identify the most pressing research questions and the areas of greatest opportunity to address this emerging public health priority. Today we issued the first in a series of Research Opportunity Announcements (ROAs) for the newly formed NIH PASC Initiative. Through this initiative, we aim to learn more about how SARS-CoV-2 may lead to such widespread and lasting symptoms, and to develop ways to treat or prevent these conditions. We believe that the insight we gain from this research will also enhance our knowledge of the basic biology of how humans recover from infection, and improve our understanding of other chronic post-viral syndromes and autoimmune diseases, as well as other diseases with similar symptoms.

Some of the initial underlying questions that this initiative hopes to answer are:

What does the spectrum of recovery from SARS-CoV-2 infection look like across the population?
How many people continue to have symptoms of COVID-19, or even develop new symptoms, after acute SARS-CoV-2 infection?
What is the underlying biological cause of these prolonged symptoms?
What makes some people vulnerable to this but not others?
Does SARS-CoV-2 infection trigger changes in the body that increase the risk of other conditions, such as chronic heart or brain disorders?

These initial research opportunities will support a combination of ongoing and new research studies and the creation of core resources. We anticipate subsequent calls for other kinds of research, in particular opportunities focused on clinical trials to test strategies for treating long-term symptoms and promoting recovery from infection.

Research Studies: A SARS-CoV-2 Recovery Cohort—the central program of this initiative—will leverage ongoing COVID-19 studies, long-term cohort studies established well before the pandemic began, and new studies of people with Long COVID. These studies aim to characterize the long-term effects of infection in a diverse set of people and the trajectory of symptoms over time. The initiative will support a multidisciplinary consortium of investigators who collaborate and coordinate across studies. The initiative also will support two complementary studies: 1) large data studies from resources such as electronic health records and health systems databases that will be critical to understand how many people are affected and what factors contribute to recovery; 2) studies of biological specimens to understand injury to the brain and other organs.

Core Resources: A clinical science core, data resource core, and biorepository core will provide overall consortium coordination, clinical expertise in post-acute COVID symptoms, and facilitate the use of standardized data and biological specimens collected from the consortium studies by consented volunteers.

Our hearts go out to individuals and families who have not only gone through the difficult experience of acute COVID-19, but now find themselves still struggling with lingering and debilitating symptoms. Throughout this pandemic, we have witnessed the resilience of our patient, medical, and scientific communities as they have come together in extraordinary ways. NIH deeply appreciates the contributions of patients who have not fully recovered from SARS-CoV-2 infection and who have offered their experiences and insights to lead us to this point, including those with other post-viral infections. Through the PASC Initiative, we now ask the patient, medical, and scientific communities to come together to help us understand the long-term effects of SARS-CoV-2 infection, and how we may be able to prevent and treat these effects moving forward.

Francis S. Collins, M.D., Ph.D.
Director, National Institutes of Health

SARS-like bat coronaviruses are not only in China

18 February 2021 by Vincent Racaniello 7 Comments

It is well past the time to stop blaming a laboratory in China for the release of SARS-CoV-2. Such fallacies reflect an ignorance of scientific facts, including the recent finding of closely related coronaviruses in bats in Thailand.

The bat CoV RatG13, sampled in 2013 in Yunnan province, shares 96% whole genome identity with SARS-CoV-2, suggesting a likely bat origin of the pandemic virus. To identify other possible sources for highly related viruses, a colony of 300 bats in eastern Thailand, consisting only of one species, Rhinolophus acuminatus, was sampled in June 2020. Thirteen of 100 bat rectal swab samples were positive for a single PCR amplicon with 95.86% sequence identity to SARS-CoV-2 and 96.21% identity to bat CoV-RaTG13. This virus, named RacCS203, appears to be the dominant coronavirus circulating in this bat colony. Phylogenetic analyses indicate that RacCS203 is a new member of the SARS-CoV-2 related CoV lineage (SC2r-CoV).

Trial By Error: Happy Tenth Anniversary, PACE Trial!

18 February 2021 by David Tuller 6 Comments

By David Tuller, DrPH

It’s been ten years since The Lancet published the first results of the PACE trial. Wow!

Ten years ago, I was 54 and still a graduate student in public health at UC Berkeley. I was also busy writing stories for The New York Times about the mouse retrovirus study that had roiled the field of research into chronic fatigue syndrome—the then-standard name for the illness now referred to as ME/CFS by US government agencies. The mouse retrovirus, XMRV, turned out to be a lab contaminant. The story had struck such a nerve at least in part because of long-standing and lingering speculations that a retrovirus could be involved—a position that retains some strong adherents.

Trial By Error: Hughes-Tuller Comment on Wessely-Chalder CBT Study Rejected by Journal, Posted Here

15 February 2021 by David Tuller 10 Comments

By David Tuller, DrPH

Last fall, Professor Sir Simon Wessely and Professor Trudie Chalder were among several co-authors of a study published in the Journal of the Royal Society of Medicine. The study purported to prove that years of provision of cognitive behavior therapy (CBT) to patients with “chronic fatigue” and “chronic fatigue syndrome” proved that the intervention was a success. I previously pointed out myriad problem in this post last August.

An antiviral to prevent or treat SARS-CoV-2 infection

11 February 2021 by Vincent Racaniello 4 Comments

Vaccine development has far outpaced antiviral discovery for COVID-19. Hydroxychloroquine was a disaster, and the repurposed remdesivir, which must be administered intravenously, has modest effect when given to hospitalized patients. The situation is unfortunate because antiviral drugs may be used to either prevent infection (prophylactic) or treat infection (therapeutic). A promising antiviral drug candidate is EIDD-2801/MK-4482 which has been shown to block SARS-CoV-2 transmission among ferrets, and more recently, to treat or prevent infection in mice. In both cases the drug is active after oral administration.

Trial By Error: New Biopsychosocial Paper on Long-Covid and Somatic Symptom Disorder

9 February 2021 by David Tuller 13 Comments

By David Tuller, DrPH

Biopsychosocial Campaigners Target Long-Covid

New papers from the biopsychosocial campaigners often provide opportunities to highlight unwarranted assertions, misleading use of data, and—in particular–associations interpreted as if they were causal relationships and not, well, associations. An article co-authored by Trudie Chalder, a professor of cognitive behavioural therapy at King’s Collge London, and published recently in the Journal of Mental Health, deploys such strategies in its efforts to suggest that large swaths of those experiencing what is being called long-Covid are suffering from “somatic symptom disorder” (SSD).