NIH: Accelerating Research on ME/CFS meeting, 4th and 5th April 2019

[Andy]

Day two now available, https://videocast.nih.gov/launch.asp?27424

 

[Alvin]

The entire first day is available to stream on demand, https://videocast.nih.gov/launch.asp?27422

No individual talks or timestamps for individual talks available yet.

Day two now available, https://videocast.nih.gov/launch.asp?27424

They can also be downloaded for offline viewing

 

[Andy]

New Findings Elucidate Potentially Treatable aspects of ME/CFS

Bethesda, MD — New evidence of cardiopulmonary and nervous system abnormalities in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) yields clues to the etiology of their exercise intolerance and points to potential treatments.

The findings were presented during the 2-day Accelerating Research on ME/CFS Meeting sponsored by the National Institutes of Health (NIH) and held on its main campus. The meeting brought together researchers from a range of scientific and clinical disciplines along with patients and patient advocates.

https://www.medscape.com/viewarticle/911666 - may need free sign up to view.

 

[Hoopoe]

@Jonathan Edwards remember that you were skeptical about IV saline?

During cycling, many ME/CFS patients will have relatively normal VO2 max levels but abnormally low filling pressure, particularly the right atrial pressure. That phenomenon, which Systrom and colleagues have called "preload failure," is seen in nearly all patients evaluated with iCEPT who meet ME/CFS criteria.

In a study Systrom and colleagues published in 2016 on 49 patients with this phenomenon, giving two saline boluses corrected the problem in most cases. The authors concluded that inadequate ventricular filling related to low venous pressure is a clinically relevant cause of exercise intolerance. "In retrospect, most of those patients had evidence of ME/CFS," he observed.

(I'm not sure if you were concerned about potential harm from having an infusion as opposed to just drinking salt water, or skeptical about the idea that salt water would be genuinely helpful)

 

[Jonathan Edwards]

@Jonathan Edwards remember that you were skeptical about IV saline?


(I'm not sure if you were concerned about potential harm from having an infusion as opposed to just drinking salt water, or skeptical about the idea that salt water would be genuinely helpful)

I remain sceptical and I would expect Systrom to be as well. An IV bolus will raise central venous pressure (sometimes called preload) for about twenty minutes, until it is peed out. So it is no use as a treatment. Saline might stay in the body longer if given at a time of day when CVP is especially low, as in first thing in the morning, but two cups of tea would be as good.

 

[Hutan]

Cort's summary of the conference - Day 1:
Accelerating ME/CFS: The NIH Conference Day 1

 

[mariovitali]

I just posted some comments regarding the presentations given at the NIH and the hypotheses being generated by Machine Learning.


As an example, regarding Dr Ron Davis's mentions on exosomes (which are a type of Extracellular Vesicles - EVs, shown below) we have the following where we can see GAS6, MFGE8, MER (=MERTK) :

Source : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208672/



The potential relevance was picked up by Machine Learning, here is the relevant Tweet in August 2017 (observe MERTK, GAS6 and also FASLG) :

Note the relationship of FAS Ligand and TRAIL (mentioned by Dr Systrom) and mentions on plasma membrane below :

Surface interactions of EVs with the plasma membrane are of outstanding importance since such interactions mediate binding of EVs to cells resulting in signal transduction or uptake of EVs by cells. It is now established that EV-target cell interactions involve tetraspanins, integrins, ECM proteins, immunoglobulin superfamily members, proteoglycans, and lectins [21, 22]. Details of EV docking and entry to cells are not in the focus of this review, as these interactions have recently been reviewed elsewhere [21, 22]. To illustrate the outstanding functional significance of the interaction of EV surface molecules with those of the plasma membrane, here, we only refer to the plethora of EV-immune cell interactions including cell-free antigen presentation by EVs [23], Fas ligand or TRAIL-mediated cell death induction by EVs
[24–26], or the transfer of immune checkpoint molecules (PD1, PDL-1) by EVs

for MFGE8 :






More here :


https://www.s4me.info/threads/machine-learning-assisted-research-on-me-cfs.5015/page-4#post-159640

 

[FMMM1]

I personally think there was really nothing there in the Montoya cytokine results... all moderate patients were no different than controls. I’m not sure I buy this bimodal explanation either.

What do people think? I’m sure it was talked about here when the paper came out. Cytokines are a tricky business to measure accurately and reproducibly and technology might need to improve before we see anything.

When I looked at one of the slides Ron Davis presented (of Montoya's cytokine study) I thought I don't get this i.e. the results aren't that different for ME Controls/moderately ill/severely ill. Perhaps the P values indicated a significant difference between the controls and those with ME; however, visually they didn't look that different.

Cort Johnson, from memory, highlighted that the 2015 Hornig/Lipkin cytokine study had to use very rigorous measures to establish a difference between control and ME groups (controlling the time of day samples were taken etc.). I think someone, possibly @Jonathan Edwards said that the elevated cytokine levels were an echo of a problem i.e. inflammation somewhere in the body.

We then had rituximab; which didn't confirm B-cell autoimmunity. @Jonathan Edwards from memory said that the results for the autoantibodies (against adrenergic receptors, and muscarinic and acetylcholine receptors?) didn't look convincing - it looks like he was correct.

Then we had Fluge and Mella who found something in the blood which affected cellular metabolism. That something was originally thought to (potentially) be an autoantibody - even though rituximab hadn't worked.

I'm guessing that:

• the reason why the cytokine results in blood were not that different (controls versus people with ME) is that the cytokines are in the exosomes - not the blood;
• the reason why the autoantibody results were not that different is that the inflammation in ME is not in general due to autoimmune - autoantibodies;
• micro-RNAs (controlling genes) --- in the exosomes?

I assume that we need a large scale trial i.e. to establish whether these cellular energy problems (reversed by removing the exosome fraction in the blood) are widespread in ME. That way we may be able to get a diagnostic test (nano-needle?) and treatments for those with this form of the disease (ME) e.g. SS-31. Also, it might help some people, currently incorrectly labelled as having ME, to get a proper diagnosis and treatment.

@alex3619 once wrote that the cause of type 2 diabetes is not understood; however, there is a diagnostic test and treatments - perhaps that is now deliverable for some people with ME.

I watched Bhupesh Prusty's talk. I'm very impressed (prior to viewing it I though no virus's). He seems to have a similar problem to Ron Davis. Bhupesh seems to think 1 in 1000 peripheral blood monocyte has HHV-6 (or another type of virus/bacteria which causes mitochondrial fragmentation); Ron reckons that only some dendric(?) cells are caught in the trap. I think testing for virus might be easier than the dendric cells. Great work from Bhupesh on the mechanism - guess the Lyme folks should take interest.

@Snow Leopard I think some dots may have been joined up this week.

A diagnostic test is urgently needed -

• the UK Government, supported/ably assisted by Action for ME, found 5 million pounds for PACE - how about the same for a biomedical diagnostic test?
• The EU Commission provided 33.9 million euros in biomedical grants for Lyme in the last 10 years (development of a diagnostic test etc) and zero for ME.

I suggest that you make your voice heard in the forthcoming EU elections - and also to your UK MP (remind them of public money and PACE).

 

[Trish]

@FMMM1 on a minor point of accuracy, the UK had a Labour Government from 1997 to 2010, and the PACE trial ran between 2005 and 2010, so I assume the funding was agreed while Labour was in power, not the Conservatives.

 

[FMMM1]

@FMMM1 on a minor point of accuracy, the UK had a Labour Government from 1997 to 2010, and the PACE trial ran between 2005 and 2010, so I assume the funding was agreed while Labour was in power, not the Conservatives.

I hadn't known that i.e. that the PACE trial was funded by a Labour government, or, as @Andy has pointed out, that NICE guidance regarding CBT/GET predated the publication of the PACE trial [Lancet in February 2011 [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext].
I have edited my post above. Thanks.

Action for ME acted as the secretariat to the all party parliamentary group on ME and supported the implementation of GET/CBT as a treatment for ME - stating that there was evidence that GET/CBT helped some people.

 

[Andy]

I hadn't known that. However, the decision to implement policy (GET/CBT), based on the PACE trial, was I assume made after the publication of the trial results - in the Lancet in February 2011 [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext].
The decision to implement a policy/not to implement a policy (GET/CBT) was therefore made by the incoming Conservative Government.
Action for ME acted as the secretariat to the all party parliamentary group on ME and supported the implementation of GET/CBT as a treatment for ME - stating that there was evidence (PACE) that it helped some people.

The NICE guidelines, in their current format i.e. CBT and GET as treatments, come from 2007, so before PACE. PACE will have reinforced the thinking behind them but it didn't result in any change of policy by itself.

The guidelines are determined by NICE, theoretically an independent body, so to claim that any UK government, Conservative or Labour, implemented treatment policy will be an unhelpful statement to make, in my opinion.

 

[Sly Saint]

2019 Valedictorian Eva Jazbec | Sierra Nevada College
April 12, 2019

During the past four years, I spent 7 semesters tutoring math and science at SNC. I interned at the UC Davis TERC Chemistry Lab for 9 months, where I contributed to the long-term monitoring dataset on Lake Tahoe water quality. For the past 12 months, I’ve been conducting clinical research on patients with Chronic Fatigue Syndrome at Simmaron Research.

Simmaron is an Incline Village scientific non-profit which focuses on identifying promising new avenues for CFS research. I was fortunate enough to receive the National Institute of Health (NIH) travel award to attend a workshop for young/early career ME/CFS investigators. I also presented my data as a poster co-author at the NIH conference: “Accelerating Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)”.

https://www.sierranevada.edu/2019-valedictorian-eva-jazbec/

 

[FMMM1]

The NICE guidelines, in their current format i.e. CBT and GET as treatments, come from 2007, so before PACE. PACE will have reinforced the thinking behind them but it didn't result in any change of policy by itself.

The guidelines are determined by NICE, theoretically an independent body, so to claim that any UK government, Conservative or Labour, implemented treatment policy will be an unhelpful statement to make, in my opinion.

Noted and edited.

 

[Roy S]

 

[dreampop]

Cort's summary of the conference - Day 1:
Accelerating ME/CFS: The NIH Conference Day 1

I know this probably makes no sense scientifically, but whenever I read about tgf-b being high it makes me think there is a post-inflammation immune response to a infection that never got properly turned off.

Could MR1 mistakenly direct MAIT cells to non-infectious riboflavin producing bacteria in the gut? Thereby conjuring more MAIT cells that don't actually have anything to do.

My mind is wandering.

 

[FMMM1]

Is this serum switching (healthy cells in sick serum vs sick cells in healthy serum) independent of Davis' research? Would be pretty strong boost to have honed in on the same observation.

Yes.

The first group who identified this were, as Bhupesh Prusty acknowledges earlier in his talk, Fluge/Mella (December 2016). Fluge/Mella used a Seahorse analyser which measures cellular energy metabolism i.e. by measuring "oxygen consumption rate (OCR) and extracellular acidification rate (ECAR)". Subsequently Ron Davis found the same effect using the nano-needle (which measures impedance).

What Bhupesh has done is measured this in an entirely different way i.e. by measuring mitochondrial fragmentation - in that sense it is entirely different from the Seahorse analyser/nano-needle.

What he also appears to have done is established what changes in the cells mitochondria (i.e. mitochondrial fragementation) and suggested the mechanism(?) i.e. microRNA. So presumably everyone is now going to try to get money to look for microRNAs (i.e. which fragment mitochondria) in exosomes - is Maureen Hanson already doing this?

Also, Chris Armstrong's 2015 paper highlighted this metabolic shift/Naviaux joined in highlighting a mitiochondrial problem (2015?) ---

Also note that Bhupesh in his slide on "Future Directions" that potentially the consequence of this is an increase in reactive oxygen species (ROS). A drug Naviaux highlighted to Ron Davis "SS31 is a mitochondria-targeted antioxidant" could help to mop up those ROS and help some people with ME.

I guess Lyme might just be the same i.e. the result of mitochondrial fragmentation - Bhupesh mentions that bacteria may have developed this mitochondrial fragementation i.e. to evade the immune response.

Can we/should we/will we now start lobbying, e.g. through ME Action - Millions Missing, for the development of a diagnostic test based on this and the assessment of potential treatments (SS31)? The people who influence health research spending aren't likely to read what's on this site; we should try to speak to those people i.e. EU MEPs/UK MPs

 

[Andy]

Can we/should we/will we now start lobbying, e.g. through ME Action - Millions Missing, for the development of a diagnostic test based on this and the assessment of potential treatments (SS31)? The people who influence health research spending aren't likely to read what's on this site; we should try to speak to those people i.e. EU MEPs/UK MPs

Each demonstration should decide what targets (it can be general or specific) will be most impactful for drawing attention at your location. We aren’t dictating specific targets this year by country as we did in previous years. In the UK and Scotland, the #MillionsMissing campaign will focus on increasing funding for biomedical research into the diagnosis and treatment of ME.

https://www.meaction.net/2019/02/26/announcing-millionsmissing-2019-join-us/

 

[Sean]

The first group who identified this were, as Bhupesh Prusty acknowledges earlier in his talk, Fluge/Mella (December 2016). Fluge/Mella used a Seahorse analyser which measures cellular energy metabolism i.e. by measuring "oxygen consumption rate (OCR) and extracellular acidification rate (ECAR)". Subsequently Ron Davis found the same effect using the nano-needle (which measures impedance).

What Bhupesh has done is measured this in an entirely different way i.e. by measuring mitochondrial fragmentation - in that sense it is entirely different from the Seahorse analyser/nano-needle.

What he also appears to have done is established what changes in the cells mitochondria (i.e. mitochondrial fragementation) and suggested the mechanism(?) i.e. microRNA. So presumably everyone is no going to try to get money for looking for microRNAs (i.e. which fragment mitochondria) in exosomes - is Maureen Hanson already doing this?

Three independent teams, using three different methods, with the same result.

Given the methodologies are sound (including statistical power), then this is looking like the best possibility so far for both a specific and unique (?) biomarker, and a leading research clue.

 

[wigglethemouse]

Lets not forget Karl Mortens plasma swap too. This is slide 44 from his presentation in NZ.

Thread on his presentation here
https://www.s4me.info/threads/dr-ka...ealand-about-his-research-december-2018.7287/

 

[Kalliope]

Excellent article in Medscape: "Milestone" Meeting Highlights NIH Efforts to Combat ME/CFS
by Miriam Tucker

The National Institutes of Health (NIH) held a 2-day conference on high-level science that is beginning to yield clues to understanding and ultimately treating the complex, multisystem illness now known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
...
Koroshetz noted that ME/CFS is a challenging area of research for the NINDS "because of the stigma of the illness and the lack of commitment from the medical community.... We really need people to see this is a problem and attract researchers to follow these threads that are appearing from the research. Eventually, I think we're going to figure this out."