Profile of circulating microRNAs in Myalgic Encephalomyelitis......(2020)Moreau et al

[rvallee]

Forgive me, but I have trouble imagining how a very severely ill patient, who is often bed bound, could tolerate 90 minutes of cuff pressure on their arms. Perhaps I am missing something....

The pressure is much less than what a blood pressure cuff does and it's mostly off, that is there is zero pressure, then very mild pressure, then off again. Very severe patients would be a problem but only at the worst end, there's plenty of severe patients in that space of severe cases that can endure it.

 

[Helene]

I may be wrong here but an increase or decrease in mi-RNAs following a post exertional challenge may still be the cause of PEM. It probably takes some time for these miRNAs to influence gene expression and then go on to cause symptoms. So testing them for longer than 90 minutes as they did in this study may not be necessary. But I don’t know how long these mi-RNAs need to be altered for, for them to cause symptoms if that makes sense. I guess having more time points would allow you to see how long they are altered for at least.

They said they tested housebound patients but was the test conducted in their homes? Otherwise getting to the university in itself would surely cause a change in mi-RNAs. Although they did measure these at baseline and found a difference between ME/CFS vs controls and after 90 minutes and also ME/CFS compared to themselves at baseline and again at 90 minutes.

Yes- I believe they tested at least some of the patients in their homes. The nurse working on the study was willing to come from Montreal to a home in Ottawa, about a two hours drive, to test our family but we didn't end up doing it due to the logistical problems of getting family members from BC & the US to Ottawa.

 

[leokitten]

Someone please correct me if I’m wrong, but there are currently zero validated and approved miRNA tests done by major labs for any disease or condition outside of research settings?

Sorry every time “diagnostic test” is mention I get uncomfortable. I scanned the paper and no this won’t ever be a diagnostic test that a major lab can run (unless I totally missed something). It requires not only a research level wet lab protocol but also a trained ML model on way more cases to get the decision boundary.

This is a research diagnostic/severity biomarker discovery paper, not a diagnostic test development paper (like for example the nanoneedle paper).

 

[Mij]

I've re-read the paper and while the patients report suffering from PEM after the use of the cuff, I still have my doubts about whether the study proves that what they are measuring is necessarily what causes PEM. It could be, there is nothing that proves that it isn't, but I don't see the evidence to be able to say definitely it is. So, as is often the case, I think there is a bit too much hype about this.

I wonder if it's measuring/detecting orthostatic intolerance instead?

 

[Ravn]

Just for information, some nuance seems to have been lost in translation in some of the English language coverage. Nothing critical but if you're wondering about insipid expressions like 'discomfort after effort', that was 'malaise après effort' in the original French, which basically means PEM.

For the purpose of a diagnostic test it probably doesn't matter whether the microRNAs they're measuring reflect PEM or some ME-specific fatiguability, as long as it's ME specific.

But since they're claiming it is PEM it would have made a lot of sense to take another sample at 24 hours, just to be sure. They asked participants about PEM symptoms later and PEM symptoms were indeed reported by pwME but not controls. Fine, but here we're back in questionnaire territory which is what we're trying to get away from with a diagnostic test. And it doesn't tell us if those symptoms were also reflected in microRNA.

Also, looking at the supplementary data, the PEM symptoms reported were largely fatigue (72%), headache and muscle pain (16% each) and only a few reports of other symptoms. This could be interpreted as very mild PEM, something the researchers were aiming for as they wanted their participants to suffer as little as possible, but it could equally be fatiguability rather than PEM.

Jumping ahead of myself here but a clinical diagnostic test that requires a health professional to travel to patients to perform a 90 minute test - just ain't gonna happen most places. Even if there was ready access to the type of lab required to run this sort of analysis. Would still be good to have a research diagnostic test of course, to ensure participants actually have ME, or a certain subgroup of ME.

The differences between the four clusters look interesting but each cluster has only between 5 and 11 people in it. Assuming the results can be replicated on a larger scale, it seems a significant finding that in some clusters microRNAs are upregulated and in others downregulated. Certainly would have the potential to confound research if not taken into account.

 

[dreampop]

I've re-read the paper and while the patients report suffering from PEM after the use of the cuff, I still have my doubts about whether the study proves that what they are measuring is necessarily what causes PEM. It could be, there is nothing that proves that it isn't, but I don't see the evidence to be able to say definitely it is. So, as is often the case, I think there is a bit too much hype about this.

Looking back, https://www.s4me.info/threads/dr-al...ess-protocol-for-provoking-pem-thoughts.6329/, I see my thoughts on this method aren't exactly new.

I totally agree. Isn't it too short a timeframe for PEM?

 

[butter.]

I think before putting any particular interpretation on this we need to see the difference between a group of PWME before and after cuff massage, and a group of PWME before and after a similar period of no massage plus a dose range in between so that there is a dose response curve indicating what aspect of the procedure is producing an effect.

I worry a bit that they think they are 'stressing' people. It is easy to induce a physiologic stress response just by putting people in a room and saying something of importance is going to happen. The problem is that the stress response for patients and healthy volunteers are likely to be very different because volunteers are just having a day off being guinea pigs.

If there is a consistent dose-dependent effect in PWME then this looks quite interesting, but I would like to be sure.

In case this is significant, could a treatment be as „easy“ as blocking these miRNA or us this wishful thinking?

 

[Perrier]

Found it:

https://www.nature.com/articles/s41598-020-76438-y

The full study title is
Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology. Moreau et al, Nature November 2020.

Every Sunday morning on Radio Canada (French language CBC) they invite Dr Quach Than researcher in microbiology and immunology to speak about the latest development in Covid research. This morning, when they were speaking about the fact that Covid strikes some folks very mildly and others severely, she said: perhaps the work of Dr. Moreau will help us to understand why.

She did not explain further, but did mention that he had just published regarding Syndrome de Fatigue Chronique. It's not quite clear to me how his findings will impact the severity levels of Covid, but clearly Dr Moreau is making headlines here in Quebec.

 

[Bombino]

I emailed the federal government to provide increased funding to their small group because clearly they did a lot with such a tiny budget.

 

[Perrier]

I emailed the federal government to provide increased funding to their small group because clearly they did a lot with such a tiny budget.

I have written to the Prime Ministers office during the pandemic, and indicated that his subsidies ignored those who were disabled. I was happy to receive a long kind letter, and eventually 600$ was offered to those who are 'disabled.' I think Bombino you should fall on receptive ears. AT least, I hope you do. Stay well.

 

[Perrier]

Seems Radio Canada had even more about Dr Moreau. Around lunch time they have a science programme, and today there was a discussion about Dr. Moreau's work and his publication. There was even a brief interview with him. What most impressed me was that the word 'fatigue' was only used with regard to the name: syndrome de fatigue chronique. Throughout the programme they talked about exertion intolerance. They also pointed out that there is no way to cheat on this test, and it is illness specific. Wonderful work. How far away are we from treatments???

 

[Milo]

For the purpose of a diagnostic test it probably doesn't matter whether the microRNAs they're measuring reflect PEM or some ME-specific fatiguability, as long as it's ME specific.

But since they're claiming it is PEM it would have made a lot of sense to take another sample at 24 hours, just to be sure. They asked participants about PEM symptoms later and PEM symptoms were indeed reported by pwME but not controls. Fine, but here we're back in questionnaire territory which is what we're trying to get away from with a diagnostic test. And it doesn't tell us if those symptoms were also reflected in microRNA.

It reminds me of this paper: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2796.2011.02405.x
I am not exactly sure how the results compare, but perhaps the novelty is all about trigger PEM from arm stimulation+sensory triggers from presence of someone, and having a conversation with that person+ sitting up.

At this point, do we have a biomarker, is it feasible in clinical setting, is the test ready to be commercialized (probably not) and is the test sensitive enough to rule out other diseases such as lupus and other rheumatologic diseases, multiple sclerosis and those recovering from infectious diseases such as COVID?

 

[Andy]

it is illness specific

[Not aimed at Perrier] Is it? I've just tried to check back and, from what I've seen, this hasn't been tested on subjects with other illnesses, so not sure how it can be claimed to be illness specific.

 

[butter.]

I hope they make the connection between thrombospondin, EBV duptase and ADAMTS16 gene which has been found to be „off“ in me/cfs.

 

[Sly Saint]

syndrome de fatigue chronique

why aren't they using 'encéphalomyélite myalgique' ?

 

[Perrier]

why aren't they using 'encéphalomyélite myalgique' ?

They are using both; sometimes a journalist will just lapse into the fatigue name. At lease that is what I noted on Radio Canada.

 

[Perrier]

[Not aimed at Perrier] Is it? I've just tried to check back and, from what I've seen, this hasn't been tested on subjects with other illnesses, so not sure how it can be claimed to be illness specific.

In the interview, Moreau gave a figure for the number of micro RNA s there were, and then he stated that there were some very specific ones, and he gave a figure for the number, that are common to folks with ME. But Andy, your point is well taken. But Moreau did emphasise that the test was ME specific. That was what I picked up from the short interview Sunday at noon on Radio Canada.

 

[rvallee]

why aren't they using 'encéphalomyélite myalgique' ?

I'd say it's about half and half in most communications but physicians here only know of CFS so in aiming to reach physicians it's a lot like why OMF uses CFS often too, otherwise physicians don't know what they're talking about.

Exhausting...

 

[Jim001]

"But Moreau did emphasise that the test was ME specific."

Could Moreau have meant that the test was ME specific relative to the controls? I dont know what is standard language in this respect but this seems unintentionally vague.

 

[Perrier]

"But Moreau did emphasise that the test was ME specific."

Could Moreau have meant that the test was ME specific relative to the controls? I dont know what is standard language in this respect but this seems unintentionally vague.

Dear [Guest]..., yes he said it was ME specific relative to controls. He pointed out the micro RNA s he consistently finds in ME patients, are not presenting in the controls. But you might want to glance at his paper; it's not that long and 'abordable,' as we say.