Dr Ron Davis’s strategic approach to understand ME/CFS

Posted on 03/16/2017 by wames

Health rising blog post, by Cort Johnson, 8 March 2017: Ron Davis’s Strategic Approach To Understand Chronic Fatigue Syndrome (ME/CFS)

The Open Medicine Foundation released two videos of Ron Davis talking about their work over the past couple of weeks. I got a chance to talk to Davis twice since then and to flesh out a bit more what he’s doing right now.

As most people probably know, the Davis group’s working hypothesis right now is that problems with glycolysis – the process producing many of the raw materials the mitochondria use for energy – is impaired in chronic fatigue syndrome (ME/CFS). Their data is leading them to suspect an enzyme called pyruvate kinase is this issue. The Fluge/Mella group has come to a similar conclusion, but they’re more focused on a different enzyme called pyruvate dehydrogenase.

Both are coming to the conclusions in an indirect sort of way. Fluge and Mella’s amino acid metabolism results suggested problems with glycolysis were present. Davis’ experiments and metabolomics results suggest the same. Davis noted, though, that neither is directly measuring the performance of the enzymes that break down pyruvate.

Davis’s forte is creating new technologies. Named one of the great inventors of the century by the Atlantic, he created many of the tools that made the Human Genome Project possible. George Church, a Harvard professor, called him a “frequent provider of disruptive core technologies”.

It’s no surprise, then, that Davis has been creating new tools to help him better understand the energy depletion process he believes lies at the core of ME/CFS. Davis is guided by two ancillary goals as he does this: to make the tools as cheaply as possible to avoid the problems with funding that come with ME/CFS, and to produce “fast assays” he can use to test as many potential treatments as quickly as possible…

A Strategic Approach
Davis’ strategic approach (so far as I understand it) to understanding and finding ways to impact the energy problem in ME/CFS patients’ cells has been the following:

(1) First he found a way to assess our cells ability to generate energy by putting them under salt stress (the sodium chloride test)

(2) He then created a tool or tools (electrical impedance, magnetic levitation) which he can use to measure their energy status or health (electrical impedance, magnetic floatation).

(3) With these two tools he can put cells under stress, add possible treatments to them and see if they respond.

(3) After tests suggested that something in ME/CFS patients’ blood was inhibiting their cellular energy production, Davis began filtering their blood to see if he could remove the substance. He found that he could and that a large molecule or protein was likely responsible for blocking the cells’ energy.

(4) Using what he’s learned about the energy production problems Davis began to add substances to the serum to see what would allow the ME/CFS cells to tolerate the salt stress. He’s found two substances so far. He’s also begun to test those substances in a wide variety of patients and people with other fatiguing illnesses to determine if the same issues are present in them.

(5) Davis also used the scientific literature to come up with a list of drugs that might help. He’s testing about a hundred of them in the serum now.

(6) A next step is to be able to create the ability to quickly test many numbers of cells and substances at once.

(7) Drugs or substances that pass the test will give him clues about what’s going on and will provide the foundation for further tests. A variety of problems may be found.

Read the full article
Open Medicine video lecture, 20 Feb 2017: An update on ME/CFS research with Dr Ronald W Davis

Open Medicine video lecture, 7 March 2017: Q&A on ME/CFS Research with Dr. Ron Davis

Transcript of Q & A Regarding 21 Feb 2017 Research Update Video with Dr.
Ronald W. Davis

Open Medicine Foundation says:

Dr. Davis’ team has made exciting breakthroughs in understanding the molecular basis of this devastating disease. The team is now poised to unravel the complexity of CFS and start identifying potential treatments. Significant funding is needed for this to happen and your donations at every amount are critical in our mission to find treatments and a cure as fast as possible.  Click to donate online

 

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Patients diagnosed with ME/CFS also fit SEID criteria

Posted on 03/15/2017 by wames

Research abstract:

Background:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains undiagnosed in up to 91% of patients. Recently, the United States-based Institute of Medicine (IOM) developed new diagnostic criteria, naming it systemic exertion intolerance disease (SEID).

Purpose:
We examined how subjects fit SEID criteria and existing ME/CFS case definitions early in their illness.

Methods
A total of 131 subjects fitting 1994 Fukuda CFS criteria at the time of study recruitment completed a survey of symptoms they experienced during their first 6 months of illness. Symptoms were drawn from SEID and existing criteria (1994 Fukuda, 2003 Canadian Consensus Criteria (CCC), and 2011 Myalgic Encephalomyelitis-International Consensus Criteria (ME-ICC)).

We calculated and compared the number/percentage of subjects fitting single or combinations of case definitions and the number/percentage of subjects with SEID experiencing orthostatic intolerance (OI) and/or cognitive impairment.

Results
At 6 months of illness, SEID criteria identified 72% of all subjects, similar to when Fukuda criteria (79%) or the CCC (71%) were used, whereas the ME-ICC selected for a significantly lower percentage (61%, p < .001). When severity/frequency thresholds were added to the Fukuda criteria, CCC and ME-ICC, the percentage of these subjects also fitting SEID criteria increased to 93%, 97%, and 95%. Eighty-seven percent of SEID subjects endorsed cognitive impairment and 92%, OI; 79% experienced both symptoms.

Conclusions
SEID criteria categorize a similar percentage of subjects as Fukuda criteria early in the course of ME/CFS and contain the majority of subjects identified using other criteria while requiring fewer symptoms. The advantage of SEID may be in its ease of use.

Patients diagnosed with Myalgic encephalomyelitis/chronic fatigue syndrome also fit systemic exertion intolerance disease criteria, by Lily Chu, Jane L. Norris, Ian J. Valencia & Jose G. Montoya in Fatigue: Biomedicine, Health & Behavior [Published online: 13 Mar 2017]

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Cellular immune responses in post-giardiasis CFS

Posted on 03/15/2017 by wames

Research abstract:

BACKGROUND:
The role of pathogen specific cellular immune responses against the eliciting pathogen in development of post-infectious chronic fatigue syndrome (PI-CFS) is not known and such studies are difficult to perform.

The aim of this study was to evaluate specific anti-Giardia cellular immunity in cases that developed CFS after Giardia infection compared to cases that recovered well.

Patients reporting chronic fatigue in a questionnaire study three years after a Giardia outbreak were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS and idiopathic chronic fatigue.

Giardia specific immune responses were evaluated in 39 of these patients by proliferation assay, T cell activation and cytokine release analysis. 20 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls.

RESULTS:
Patients were clinically classified into CFS (n = 15), idiopathic chronic fatigue (n = 5), fatigue from other causes (n = 9) and recovered from fatigue (n = 10). There were statistically significant antigen specific differences between these Giardia exposed groups and unexposed controls. However, we did not find differences between the Giardia exposed fatigue classification groups with regard to CD4 T cell activation, proliferation or cytokine levels in 6 days cultured PBMCs. Interestingly, sCD40L was increased in patients with PI-CFS and other persons with fatigue after Giardia infection compared to the non-fatigued group, and correlated well with fatigue levels at the time of sampling.

CONCLUSION:
Our data show antigen specific cellular immune responses in the groups previously exposed to Giardia and increased sCD40L in fatigued patients.

Giardia-specific cellular immune responses in post-giardiasis chronic fatigue syndrome, by K Hanevik, E Kristoffersen, KP Rye, S Sørnes, S Svärd, O Bruserud, N Langeland in BMC Immunol. 2017 Jan 28;18(1):5

 

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WAMES AGM 1 April 2017 – your contribution invited

Posted on 03/14/2017 by wames

The WAMES AGM will take place on 1st April 2017. This will be a short business meeting to report on the activities of the past year and plan the priorities for the coming year. Attracting funding and volunteers is our current priority. Without them we will be unable to maintain and develop all our campaigning, information and support activities.

Contact Jan jan@wames.org.uk if you have any comments about WAMES, issues you would like the committee to consider or ideas for funding and recruitment.

We would love to hear from anyone who would like to take part in our mission to:

make a difference for ME in Wales

as a trustee on the management committee, a volunteer, small steps supporter, fundraiser or donor.

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First Minister’s Question time addresses employment barriers for long term fluctuating conditions

Posted on 03/14/2017 by wames

National Assembly for Wales Recording of proceedings, 7 March 2017:

13:55  Mark Isherwood
3. Sut y mae Llywodraeth Cymru yn helpu i leihau’r rhwystrau i gyflogaeth ar gyfer pobl sydd â chyflyrau iechyd hirdymor cyfnewidiol? OAQ(5)0481(FM)

3. How is the Welsh Government helping to reduce the barriers to employment for people with long-term, fluctuating health conditions? OAQ(5)0481(FM)

13:55 Carwyn Jones  Y Prif Weinidog / The First Minister
We are taking a preventative approach to removing health barriers to work through the Healthy Working Wales programme and our new all-age employability plan will strengthen our approach to supporting low-activity groups, including support for those with longer-term health condition, to access employment opportunities.

Rydym ni’n dilyn dull ataliol o gael gwared ar y rhwystrau iechyd i waith trwy raglen Cymru Iach ar Waith a bydd ein cynllun cyflogadwyedd pob oed newydd yn cryfhau ein dull o gefnogi grwpiau gweithgarwch isel, gan gynnwys cymorth i’r rheini â chyflwr iechyd tymor hwy, i gael mynediad at gyfleoedd cyflogaeth.

13:55 Mark Isherwood
After Action for ME delivered an employment support programme for people with ME with the North Bristol NHS Trust, 72 per cent of clients achieved their employment goals. How will you ensure, therefore, that the Welsh Government, looking at the good practice very nearby across the border, will address the barriers faced by people with long-term, fluctuating conditions such as myalgic encephalomyelitis and ensure that these are produced co-productively in accordance with the Social Services and Well-being (Wales) Act 2014 requirements?

Ar ôl i Action for ME gyflwyno rhaglen cymorth cyflogaeth i bobl ag ME gydag Ymddiriedolaeth GIG Gogledd Bryste, cyrhaeddodd 72 y cant o gleientiaid eu nodau cyflogaeth. Sut y gwnewch chi sicrhau, felly, y bydd Llywodraeth Cymru, gan edrych ar yr arfer da cyfagos iawn ar draws y ffin, yn mynd i’r afael â’r rhwystrau a wynebir gan bobl sydd â chyflyrau hirdymor anwadal, fel enseffalomyelitis myalgig a sicrhau bod y rhain yn cael eu cynhyrchu yn gyd-gynhyrchiol yn unol â gofynion Deddf Gwasanaethau Cymdeithasol a Llesiant (Cymru) 2014?
Senedd.tvFideo Video

13:56 Carwyn Jones Y Prif Weinidog / The First Minister
I’ve already mentioned, of course, the employability plan. I can say that, in terms of Healthy Working Wales, over 3,000 organisations employing around 460,000 people have engaged with Healthy Working Wales. It represents about 33 per cent of the working population with an investment of over £800,000 per year in the programme. We’re also supporting workplaces to tackle the stigma and discrimination associated with mental health problems through the Time to Change Wales organisational pledge.

Rwyf wedi crybwyll eisoes, wrth gwrs, y cynllun cyflogadwyedd. Gallaf ddweud, o ran Cymru Iach ar Waith, bod dros 3,000 o sefydliadau sy’n cyflogi tua 460,000 o bobl wedi ymgysylltu â Chymru Iach ar Waith. Mae hynny’n cynrychioli tua 33 y cant o’r boblogaeth sy’n gweithio gyda buddsoddiad o dros £800,000 y flwyddyn yn y rhaglen. Rydym ni hefyd yn cynorthwyo gweithleoedd i fynd i’r afael â’r stigma a’r gwahaniaethu sy’n gysylltiedig â phroblemau iechyd meddwl trwy addewid sefydliadol Amser i Newid Cymru

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Selection bias & disease misclassification undermine the validity of ME/CFS studies

Posted on 03/13/2017 by wames

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome has been a controversial diagnosis, resulting in tensions between patients and professionals providing them with care.

A major constraint limiting progress has been the lack of a ‘gold standard’ for diagnosis; with a number of imperfect clinical and research criteria used, each defining different, though overlapping, groups of people with myalgic encephalomyelitis or chronic fatigue syndrome.

We review basic epidemiological concepts to illustrate how the use of more specific and restrictive case definitions could improve research validity and drive progress in the field by reducing selection bias caused by diagnostic misclassification.

[After highlighting the danger  in generalising the results of studies using patients with unspecific ‘chronic fatigue’ (which could include people with a range of diagnoses, including mental health conditions) to people with ME/CFS, and proposing that strict selection criteria are used in research trials, the Biobank team go on to recommend specialist services do the opposite and accept a broader range of patients:]

Priorities for clinical practice

Nevertheless, it is important to distinguish research from clinical practice. While the former should focus on better definition of disease status, sub-groups and the trialling of preventative and treatment interventions, the main role of the clinician is to provide the best care and support to their patients, irrespective of a diagnosis or lack of it. Therefore, clinical services should be open to people with a broader range of conditions, presenting with, for example chronic fatigue.

Historically, patients accepted by ME/CFS Specialist Services in the United Kingdom have often been required to meet the centers for disease control and prevention (CDC)-1994 criteria (Fukuda et al., 1994) or even broader case criteria (NICE, 2007). We propose that criteria such as the Institute of Medicine (Institute of Medicine, 2015) or the CDC-1994 could still be used as a guide for primary care professionals to refer patients to Specialist Services, provided an adequate workout of cases conducted in primary care to enable the practitioner to suspect a diagnosis of ME/CFS. This could be the case until we have a better understanding of ME/CFS and are in a position to diagnose reliably and offer specific treatments. It is also important to acknowledge that many with chronic fatigue currently referred to ME/CFS specialist services would benefit from alternative care pathways, avoiding overloading already stretched services. This is particularly important for those with an alternative diagnosis explaining their symptoms, including some chronic medical and psychiatric diseases. It has been suggested that between 40 and 64 per cent of cases referred to CFS Specialist services do not meet diagnostic criteria for CFS, so robust referral procedures need to be established (Devasahayam et al., 2012; Newton et al., 2010).

How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies? by Luis Nacul, Eliana M Lacerda, Caroline C Kingdon, Hayley Curran, Erinna W Bowman in Journal of Health Psychology [Published March 1, 2017]

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NVCBR researchers close in on a diagnostic test for ME/CFS patients

Posted on 03/10/2017 by wames

Nevada Center for Biolomedical Research news item, by Kellen Jones, 28 February 2017: NVCBR researchers close in on a diagnostic test for ME/CFS patients

Physicians lack effective tools to aid in the diagnosis and treatment of those who are impacted by ME/CFS, a complex and often disabling disease.  That could change now that scientists at Nevada Center for Biomedical Research (NVCBR) have taken the first step in developing a clinical assay for diagnosing ME/CFS patients through the creation of an antibody immune signature.

The work was conducted in collaboration with Drs. Stephen Johnston and Phillip Stafford, at Arizona State University’s Biodesign Institute, Innovations in Medicine, and Drs. Karen Schlauch and Richard Tillet, from the University of Nevada, Reno, as well as other researchers from around the world.

The group’s findings recently appeared in the prestigious journal Molecular Neurobiology:

Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity, by  Sahajpreet Singh, Phillip Stafford, Karen A. Schlauch, Richard R. Tillett, Martin Gollery, Stephen Albert Johnston, Svetlana F. Khaiboullina, Kenny L. De Meirleir, Shanti Rawat, Tatjana Mijatovic, Krishnamurthy Subramanian, András  Palotás,  Vincent  C. Lombardi [Published online: 15 Dec 2016]

The immune system produces proteins called antibodies that bind to the surface of pathogens, such as viruses and bacteria, to neutralize the pathogens. Occasionally, this system becomes dysregulated and produces antibodies to our own tissue, resulting in autoimmunity. Utilizing a microchip comprised of thousands of small random protein sequences (referred to as random peptides), researchers at NVCBR, in collaboration with the scientists at ASU’s Biodesign Institute, screened blood sera from ME/CFS cases and healthy controls, from two geographic distinct cohorts, and identified a diagnostic pattern of antibody/peptide binding that identifies ME/CFS patients with high specificity and sensitivity.

“The purpose of screening sera with a random peptide array is to identify things that our body sees as foreign such as the molecules that make up pathogens or the proteins of our own tissue, in the context of autoimmunity,” explained Dr. Vincent Lombardi, NVCBR Research Director. “Now that we have identified a group of random peptides that differentially bind with the antibodies of ME/CFS patients, our next challenge is to figure out what antigens these random peptides represent in the real world. Much can be learned about the causes of this disease once the antigens are accurately identified.”

Dr. Lombardi originally conceived of the project with the aim of identifying potential pathogens associated with ME/CFS as well as autoantigens. In addition to identifying prospective pathogen-associated antigens and autoantigens, the data also produced an immunosignature that can accurately identify ME/CFS patients from healthy controls. Future in-depth analysis of these data will help researchers determine which antigens are most relevant to the disease process and whether or not there are existing treatments available to target the implicated biochemical pathways.

Going forward, NVCBR researchers intend to confirm the work using a larger ME/CFS cohort as well as other disease cohorts with overlapping symptomology such as multiple sclerosis. The immunosignature technology, developed by ASU, has been used successfully with other neuroimmune diseases including Alzheimer’s disease.

“The goal of our research program is to ascertain the underlying mechanisms of neuroimmune disease as well as identify disease-related biomarkers and more effective treatments for the patients,” stated Dr. Lombardi. “A robust immunosignature of ME/CFS would help achieve these goals.”

Comments on paper: Pheonix rising forum

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Anxiety – autonomic nervous system in ME/CFS to blame?

Posted on 03/10/2017 by wames

Health rising blog post, by Cort Johnson, Dec 10, 2016: The Anxiety Question in Chronic Fatigue Syndrome and Fibromyalgia: Is the Autonomic Nervous System to Blame?

Anxiety type symptoms are common in chronic fatigue syndrome (ME/CFS), fibromyalgia, Gulf War Ilness (GWI), and postural orthostatic tachycardia syndrome (POTS). Dr. Baraniuk, an ME/CFS and GWI researcher, has long thought that researchers missed the boat by focusing on depression in ME/CFS; anxiety, he believes is far more prevalent.

That certainly fits my experience. Trouble concentrating, feeling tense or jumpy, anticipating the worst, irritability, restlessness, feeling like your mind’s gone blank, nausea, muscular tension, dizziness, restlessness, fatigue and problems in concentration, headache, abdominal pain, shortness of breath, sweating and frequent urination can all be found in anxiety, ME/CFS and fibromyalgia.

The “anxiety” in POTS, ME/CFS and FM: is it primarily emotional or physical?
The diseases are different. Flu-like symptoms are more common in ME/CFS and pain is much more intense in FM. Post-exertional malaise – a key symptom in ME/CFS – is never mentioned in connection with anxiety and is apparently not present. The crippling feelings of dread and fear often present in anxiety are rarely present in ME/CFS; many studies indicate that emotional issues contribute little to the functional problems in ME/CFS while physical issues dominate.

Still a common core of symptoms – feeling tense, trouble concentrating, muscle tension, dizziness, abdominal pain, shortness of breath, etc. – are found in ME/CFS, FM and anxiety. It’s as if the more extreme emotional symptoms have been stripped away leaving a body and mind on edge.  Emotional issues are often present, but at a “sub-clinical” level. They’re not enough to trigger a diagnosis of anxiety but are enough to be aggravating. Plus, similar problems of catastrophizing and hypervigilance are fairly common.

I recently experienced an ebbing of many of these symptoms – the muscular tension, the trouble concentrating, the restlessness, the chronic pain, the difficulty taking deep breaths- while using a device that stimulates the vagus nerve. That made me wonder if  autonomic nervous system problems could be behind many of these symptoms.

Given the continuing emphasis on behavioral approaches to ME/CFS and FM in some countries it’s an important question. A recent study from Belgium reported that 45% of ME/CFS patients had a mood disorder. A 2013 UK study stated that symptom focusing and beliefs about damage were particularly prevalent in ME/CFS patients with anxiety.

The article goes on to look at a study where the authors hypothesized that the anxiety type symptoms experienced by POTS patients were due to an over-awareness of their physical symptoms. The article then looks at other ways to produce anxiety-like states in ME/CFS. Read more

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The Clinical & Scientific Basis of ME/CFS is now free to download

Posted on 03/09/2017 by wames

A research classic from 1992 is now available to download for free (725 pages – a heavy tome)

The Clinical and Scientific Basis of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Edited by Byron Hyde, M.D. – Nightingale Research Foundation, Ottawa, Canada with editorial and conceptual advice from Paul Levine, M.D., NIH, Bethesda, Maryland, USA and Jay Goldstein, M.D., Chronic Fatigue Syndrome Institute, USA, 1992

Published by Nightingale Research Foundation simultaneously in Canada and the USA, 1992

 

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Collection of writings about the PACE trial

Posted on 03/09/2017 by wames

Investigator bias and the PACE trial, by Steven Lubet in Journal of Health Psychology[Published online: 7 March 2017]

Abstract: The PACE investigators reject Geraghty’s suggestion that the cognitive behavior therapy/graded exercise therapy trial could have been better left to researchers with no stake in the theories under study. The potential sources and standards for determining researcher bias are considered, concluding that the PACE investigators “impartiality might reasonably be questioned.”

Extract: Viewed in this light, Geraghty’s proposal is persuasive. By virtue of their own experience, the PACE investigators were confident in the effectiveness of CBT and GET as ME/CFS treatments. Their earlier public statements— attributing ME/CFS symptoms to “false cognitions”— certainly appeared to dispose them toward a result. Coupled with their mid-trial revision of certain outcome measures—in a direction favorable to their own theories of improvement and recovery—it is reasonable to conclude that non-blinded trials of CBT/GET should be designed and overseen by investigators with no preexisting stake in the outcome.

 

Overview by Family physician Dr Mark Vink from the Netherlands:

Assessment of Individual PACE Trial Data: in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, Cognitive Behavioral and Graded Exercise Therapy are Ineffective, Do Not Lead to Actual Recovery and Negative Outcomes may be Higher than Reported in Neurol Neurobiol 3(1) 2017 (full article)

 

news.com.au article by Jason Murphy, 17 jan 2017: How Alem Matthees’ letter helped solve Chronic Fatigue Syndrome mystery

 

The PACE trial missteps on pacing and patient selection, by  Prof Leonard A Jason in Journal of Neurology and Neurobiology, 10 January 2017

Abstract: As others have pointed out a variety of complicating factors with the PACE trial (e.g. changing outcome criteria), I will limit my remarks to issues that involve the composition of adaptive pacing therapy and issues involving patient selection. My key points are that the PACE trial investigators were not successful in designing and implementing a valid pacing intervention and patient selection ambiguity further compromised the study’s outcomes. [full article available on payment, excerpts available here]

 

Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? by M. Sharpe, T. Chalder, A. L. Johnson, K. A. Goldsmith & P. D. White in Fatigue: Biomedicine, Health & Behavior [Published online: 15 Feb 2017]

Abstract: Wilshire et al. suggest that we have overestimated the number of patients that recover from chronic fatigue syndrome (CFS) after receiving a course of either cognitive behaviour therapy (CBT) or graded exercise therapy (GET), as reported in a secondary analysis of outcome data from the Pacing, graded Activity and Cognitive behavior therapy; a randomized Evaluation (PACE) trial. We provide counter-arguments to this view.

 

Quick thoughts blog post, 20 Dec 2016, by James Coyne: Simon Wessely: Why PACE investigators aren’t keen on handing over the PLOS One data to Coyne

 

Undark podcast no.8, 31 Oct 2016: Worse Than the Disease

Prof David Tuller discusses a therapy commonly prescribed for chronic fatigue syndrome — one for which supporting research is now unravelling.

Undark case studies,  27 Oct 2017, by Prof David Tuller: Worse Than the Disease   [9000+ words]

 

Studies on Cognitive Behavioral Therapy and Graded Exercise Therapy for ME/CFS are misleading, by Sten Helmfrid (Assoc. Prof. of Physics, Member of the Swedish ME Association)

This is a translation of an article published in Socialmedicinsk tidskrift, Stockholm,
Sweden, on September 28 2016. Link to the original article in Swedish:
Citation: Helmfrid  S. Studier  av kognitiv beteendeterapi  och gradvis ökad  träning vid ME/CFS är missvisande. Soc Med Tidskr. 2016;93(4):433–44.

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