New Australian genetic marker detection study

ME Research UK blog post, 6 November 2016: New study – Genetic marker detection

Prof Brett Lidbury and colleagues at the John Curtin School of Medical Research, Australian National University in Canberra are conducting an ongoing programme, funded by charities in Australia, which aims to find biomarkers for ME/CFS using a range of sources – bioinformatics, genetics and pathological testing.

lidbury-group-good

ME Research UK has provided funding to the group to acquire additional genetic data using DNA pooling. It will then be possible to apply machine learning techniques and statistical analyses to an integrated data set combining genetic, clinical and pathological information.

As Prof Lidbury explained in a recent interview,

“We’re looking for patterns in the data which can help with biomarker pattern detection and provide clues to disease mechanisms. With complex diseases like this, we need to look at many factors simultaneously, and cross-disciplinary studies are necessary to integrate the findings from different avenues of research investigation.”

Read more at MER UK’s specific project page, Two dimensional sequencing and machine learning to maximise genetic marker detection

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Hypothalamic-Pituitary-Adrenal Hypofunction in ME/CFS

Review abstract:

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels.

This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity. Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS.

Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-?, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-?, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms. HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.

Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways by Gerwyn Morris, George Anderson, Michael Maes in Mol Neurobiol. 2016 Oct 20. [Epub ahead of print]

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Studies on CBT & GET for ME/CFS are misleading, says Swedish prof

Article abstract:

There have been a number of studies on Cognitive Behavioral Therapy (CBT) and Graded Exercise Therapy (GET) for ME/CFS based on a treatment model where the disease is perpetuated by cognitive processes. Although the studies are flawed and the model lacks scientific support, the treatments are described as evidence based.

The studies are non-blinded and rely on subjective outcomes. There are no objective measures of adherence. The diagnostic criteria vary, and the participating patients often have one or several psychiatric diagnoses apart from suffering from chronic fatigue. The underlying model has no theoretical foundation and is at odds with physiological findings. Surveys suggest that the efficacy of CBT is no better than placebo and that GET is harmful. Therefore, cognitive behavioral therapy and graded exercise therapy for ME/CFS are not evidence based.

More info:

This is a translation of an article published in Socialmedicinsk tidskrift, Stockholm, Sweden,by Assoc. Prof of Physics & Member of the Swedish ME Association, Sten Helmfrid  on September 28th, 2016. http://socialmedicinsktidskrift.se

Download the article in English: Studies on Cognitive Behavioral Therapy and Graded Exercise Therapy for ME/CFS are misleading

Link to the original article in Swedish (vol. 93, issue 4, pp. 433 -44): http://socialmedicinsktidskrift.se/index.php/smt/article/view/1450/1255

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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Dr Keith Geraghty requests experiences of CBT & GET

Dr Keith Geraghty, researcher at the University of Manchester (@keithgeraghty) has tweeted at 6:09 p.m. on Mon, Nov 07, 2016:

Ever experience adverse reactions to CBT or GET in CFS treatment – email me @ Keith.geraghty@manchester.ac.uk – we want to hear your story.

About Keith:

Keith Geraghty is an Honorary Research Fellow within the Primary Care Section of the Institute of Population Health. His role is to support current grant applications and research projects and to conduct independent work in the area of public health, health services research and primary care.

Keith has a special interest in medically unexplained symptoms, patient safety issues, doctor patient relations, and Chronic Fatigue Syndrome/ME.

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Activity patterns in response to symptoms in patients being treated for CFS

Research abstract:

Objective:
Cognitive-behavioral models of chronic fatigue syndrome (CFS) propose that patients respond to symptoms with 2 predominant activity patterns-activity limitation and all-or-nothing behaviors-both of which may contribute to illness persistence. The current study investigated whether activity patterns occurred at the same time as, or followed on from, patient symptom experience and affect.

Method
Twenty-three adults with CFS were recruited from U.K. CFS services. Experience sampling methodology (ESM) was used to assess fluctuations in patient symptom experience, affect, and activity management patterns over 10 assessments per day for a total of 6 days.

Assessments were conducted within patients’ daily life and were delivered through an app on touchscreen Android mobile phones. Multilevel model analyses were conducted to examine the role of self-reported patient fatigue, pain, and affect as predictors of change in activity patterns at the same and subsequent assessment.

Results
Current experience of fatigue-related symptoms and pain predicted higher patient activity limitation at the current and subsequent assessments whereas subjective wellness predicted higher all-or-nothing behavior at both times. Current pain predicted less all-or-nothing behavior at the subsequent assessment.

In contrast to hypotheses, current positive affect was predictive of current activity limitation whereas current negative affect was predictive of current all-or-nothing  behavior. Both activity patterns varied at the momentary level.

Conclusions
Patient symptom experiences appear to be driving patient activity management patterns in line with the cognitive-behavioral model of CFS. ESM offers a useful method for examining multiple interacting variables within the context of patients’ daily life.

Activity patterns in response to symptoms in patients being treated for Chronic Fatigue Syndrome: An experience sampling methodology study by Band R, Barrowclough C, Caldwell K, Emsley R, Wearden A. in Health Psychology, 7 Nov 2016 [Preprint]

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Postexertion ‘crash,’ not fatigue per se, marks CFS

Medscape Medical News article, by Miriam Tucker, November 04, 2016: Post exertion ‘Crash,’ not Fatigue per se, Marks Syndrome

Article extract:

The name “chronic fatigue syndrome” is being phased out not just because it is viewed as trivializing a condition that renders many patients completely or nearly bedbound but also because it gives the misleading impression that the illness is characterized simply by prolonged unexplained fatigue.

In fact, ME/CFS is characterized by multiple heterogeneous symptoms, with PEM, often described as a “crash” or a significant worsening of already-present symptoms, being a near-universal experience.

“Many studies show that physical exertion can help with insomnia in healthy people, and even people with other medical conditions such as depression, anxiety, or even heart failure. But in ME/CFS patients, physical exertion exacerbates their symptoms,” conference cochair Lily Chu, MD, from Stanford University, Palo Alto, California, told Medscape Medical News.

“The way these patients present is very different from healthy people or people with other medical conditions.”

Indeed, recent diagnostic criteria for the illness, including the February 2015 Institute of Medicine report, require PEM among other symptoms to make the diagnosis of ME or ME/CFS as opposed to older definitions of CFS. However, the Centers for Disease Control and Prevention continues to endorse a 1994 CFS definition that lists PEM as an optional criterion, but does not make it mandatory for the diagnosis.

What Is PEM?

At the IACFSME conference, Dr Chu presented findings from her group’s study of 150 patients diagnosed with the 1994 criteria who completed a survey about their symptoms after physical or cognitive exertion or emotional distress.

The majority (89%) reported experiencing PEM after both types of triggers, but 10% reported no effect after emotional distress, whereas overall physical exertion elicited significantly more symptoms than did emotional distress (seven vs five; P < .001).

Although fatigue was the most commonly exacerbated symptom, more than 30% of patients also reported cognitive difficulties, sleep disturbance, headache, muscle pain, and influenza-like feelings. Some also reported gastrointestinal, orthostatic, and mood-related exacerbations.

Timing and duration of symptoms varied among respondents and per respondent, but 11% reported a consistent post trigger delay of at least 24 hours, whereas 23% said that their symptoms typically lasted for 3 or more days.

 “PEM consists of more than just fatigue and pain. It’s an exacerbation of multiple symptoms, some of which are atypically associated with exertion,” Dr Chu told Medscape Medical News.

She added, “PEM can be difficult for clinicians and patients to identify. We suggest patients keep a diary for a week or two, documenting symptoms and activity so we can look at and see relationship of activity and timing, duration, and intensity of symptoms.”

Read full article, including overview of other biological studies into PEM [you will need to register with Medscape]

 

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PACE-gate: when clinical trial evidence meets open data access

Article abstract:

Science is not always plain sailing and sometimes the voyage is across an angry sea. A recent clinical trial of treatments for chronic fatigue syndrome (the PACE trial) has whipped up a storm of controversy. Patients claim the lead authors overstated the effectiveness of cognitive behavioural therapy and graded exercise therapy by lowering the thresholds they used to determine improvement. In this extraordinary case, patients discovered that the treatments tested had much lower efficacy after an information tribunal ordered the release of data from the PACE trial to a patient who had requested access using a freedom of information request.

‘PACE-Gate’: When clinical trial evidence meets open data access, by Keith J Geraghty, in J Health Psychol, 1 November 2016 [Published online before print]

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The most extreme consequence of ME/CFS – trauma & premature death

Livets bilder (Life images) blog post, 25 October 2016: The most extreme consequence – trauma and premature death  (Originally written in Swedish)

In this post I will write about something that I see as the most extreme consequence of what I call secondary system related stress. Something that is not “just” about worsening an existing condition, but when the system-related stress, adding to a person such damage that it could be counted as an additional condition. A new diagnosis. And a risk of a premature death.

When I wrote an earlier post about how my own emotional reactions have changed over time due to the cumulated stress, I remembered that I somewhere read about ME/CFS and PTSD (Post Traumatic Stress Disorder) triggered by healthcare.

I found an interesting article describing how Dr. Nancy Klimas found her way into further research about ME/CFS. In the 1990s, she studied how people with chronic diseases were affected by a natural disaster. One of the patient groups were people with ME/CFS. The study showed that people with chronic disease developed PTSD in a higher level than those without any chronic disease. People with ME/CFS also showed an exacerbation in their chronic condition. But she discovered something else as well: Even those ME/CFS sufferers who were not at all affected by the trauma during the natural disaster had higher rates of PTSD. This was something that differed from the other groups of chronically ill. After further investigation, she found an explanation in the patients’ healthcare situation:

“Yet compared with people with other chronic diseases, CFS patients, even those who hadn’t lived through the trauma of a hurricane, had notably higher PTSD rates, she found. Digging deeper, she found that CFS patients had actually been distressed by their medical experiences. A common theme in the trauma was an exposure to a health-care situation that was demoralizing and demeaning, she says.”

Dr. Nancy Klimas also said in an interview in the Miami Herald 2009:

“I’ve had patients who met posttraumatic stress disorder criteria, where their trauma was their interaction with their physician around this illness. They came to a doctor with Chronic Fatigue Syndrome; they left the doctor with PTSD.”

So, it is a long known fact that people with ME/CFS are at risk of developing PTSD related to community support systems. I have not found any specific studies on ME/CFS and healthcare triggered PTSD. However, right now there is an important survey study in progress, designed to investigate secondary mental illness in people with ME/CFS linked to external factors, such as how healthcare personnel treat their patients. It is web based and open to everyone with ME/CFS to join.

Read more

 

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ME researchers identify danger of contamination in ME/CFS genomics study

Research abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease causing indefinite fatigue. ME/CFS has long been hypothesised to have an infectious cause; however, no specific infectious agent has been identified.

We used metagenomics to analyse the RNA from plasma samples from 25 individuals with ME/CFS and compare their microbial content to technical controls as well as three control groups: individuals with alternatively diagnosed chronic Lyme syndrome (N = 13), systemic lupus erythematosus (N = 11), and healthy controls (N = 25).

We found that the majority of sequencing reads were removed during host subtraction, thus there was very low microbial RNA content in the plasma. The effects of sample batching and contamination during sample processing proved to outweigh the effects of study group on microbial RNA content, as the few differences in bacterial or viral RNA abundance we did observe between study groups were most likely caused by contamination and batch effects.

Our results highlight the importance of including negative controls in all metagenomic analyses, since there was considerable overlap between bacterial content identified in study samples and control samples. For example, Proteobacteria, Firmicutes, Actinobacteria, and Bacteriodes were found in both study samples and plasma-free negative controls.

Many of the taxonomic groups we saw in our plasma-free negative control samples have previously been associated with diseases, including ME/CFS, demonstrating how incorrect conclusions may arise if controls are not used and batch effects not accounted for.

Metagenomic investigation of plasma in individuals with ME/CFS highlights the importance of technical controls to elucidate contamination and batch effects, by  Miller RR, Uyaguari-Diaz M, McCabe MN, Montoya V, Gardy JL, Parker S, Steiner T, Hsiao W, Nesbitt MJ, Tang P, Patrick DM, for the CCD Study Group in PLOS One 2 Nov 2016

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Which countries conduct ME/CFS research?

Phoenix rising forum post, by HIP, January 2016: Why so little ME/CFS research from France and Germany?

There seems to be little ME/CFS research done in France and Germany, relative to their overall scientific output. Why is this?

Using a rough method, I found that the number of ME/CFS scientific research papers published by each country is the following:

research-by-country

 

France and Germany, along with the UK, are the leading countries in Europe in terms of publishing scientific papers. Yet Germany and France seem to have published very few ME/CFS papers. In fact Norway, a country of just 5 million inhabitants, has produced more ME/CFS papers than France or Germany.

I wonder why this is. Moreover, shouldn’t ME/CFS patients in France and Germany be advocating for more ME/CFS research? These countries are leading forces in science and technology, so it would be good to have them onboard.

The following diagram shows the number of scientific papers (of any sort) published by different countries around the world. As you can see, France and Germany are leading nations in terms of their overall scientific output. Yet they do very little ME/CFS research…

I just modified the search parameters to exclude any UK papers containing the phrases “graded exercise” and “cognitive behavioural therapy”, and with these GET/CBT papers excluded, it brings the UK total number of ME/CFS papers down from 595 to 480.

Similarly for the Netherlands, another country with a lots of psychobabble ME/CFS research, modifying the search to exclude GET/CBT brings to the total number of Dutch ME/CFS papers down from 173 to 112.

Read the full blog post and comments

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