MRC-funded grant proposals on ME/CFS by year, 2003–2023, along with the total number of proposals received that year.

There are some significant differences there. Altmann is talking of LC proposals that might include ME/CFS I suspect. Almost everything that could be measured in ME/CFS has been measures and found normal. There may well be room to measure some of these things for the first time in LC but the chances that will tell us much about ME/CFS wouldn't be good.

He talks there of approaching UKRI, which is a new high level research pot linked to science and technology. Why apply there rather than MRC? UKRI is almost certainly driven by politics rather than science. It has a picture of Patrick Vallance on the about page!!

I have not heard of any proposals from Altmann that would immediately strike me as fundable. Enthusiasm is fine but we need good ideas - like DecodeME. Why isn't Altmann here on the forum debating the science where we have so many experts on the disease??

 

Unfortunately, going down that route is of starting observations and hypothesis hasn’t got us very far. We have the prospect of DecodeME reporting fairly soon, and, hopefully, that will provide some causal clues. It will also provide evidence ruling in or ruling out other hypothesis (Even if things don’t reach the strict threshold for genetic statistical significance, it will give a good pointer to whether or not there is or he’s not likely to be a signal).

Whatever it finds (or doesn’t find) should help clear away some of the research smoke.

 

Is he still on Twitter? Maybe someone could send him some tempting links to threads for paper discussions...

 

I wouldn't dismiss @Sasha's suggestion, @Simon M.

It took me twenty years to work out the critical steps in rheumatoid and the solution was driven by very detailed clinical observation. The clincher was that I had gradually whittled down the pathology of RA to nine specific and apparently unrelated lesions. Away Bhatia in my lab was then able to show that the immunoglobulin receptor that Vikki Abrahams showed triggered TNF production was only expressed in the normal body at those nine 'unrelated' sites. And we worked out a plausible reason. That made it vanishly unlikely that immune complexes of a certain size were not the key mediators. And the prediction worked.

But it took me twenty years to hone the clinical analysis to that level. Nobody else had been doing anything like that, since Eric Bywaters, who by then was 92. Eric set up UK rheumatology in the 1950s and was a seriously intelligent man, but by the time we had mediators to fit his observations he was too old. Eric had made many of the crucial pathological observations that allowed me to whittle down the lesions to nine.

 

Maybe he doesn't know S4ME exists, or what it is. Can he be invited?

 

This is fascinating. I didn't even know there were lesions in RA (nodules?). That's a really extraordinary achievement, and with a huge impact on the lives of thousands of very ill people. What a fantastic thing!

But is our problem in ME/CFS that we don't have signs that are physically observable, such as these lesions? Could clinical observation of symptoms alone (the need to lie flat, PEM, etc.) do anything to move us forward? And if so, is there something we can do here on the forum to provide useful information about those symptoms in a way that would be helpful?

 

Apologies, I phrased that rather badly. I certainly didn’t mean to dismiss that approach. But I do think it would make sense to wait until we see the DecodeME results before starting a big effort to generate new hypotheses from careful observation. I’m hopeful those results will be published in a preprint in the relatively near future (though I have no idea of time scale – Chris Ponting and told Dave Tuller he might be able to give one once the imputation analysis is complete, since that could potentially take a very long– and uncertain length of – time).

 

Things are an order of magnitude more difficult, it might seem. But science is always about solving a problem that is an order of magnitude more difficult than the last one, except that the difficulty remains much the same because you can benefit from what you learnt last time and technological advances. Rheumatoid was as difficult in 1990 as ME/CFS is today. Rheumatoid became tractable through molecular biological advances 1985-95, to add to the genetics data we had had in the 1070s. We need some similar lead in ME/CFS to make sense of the symptom patterns but it may well be that we should be honing our understanding of the symptom patterns in the way we did for RA pathology.

 

The effort of sorting out the nine lesions in RA consisted merely of me lying on a sofa for 2 hours and pondering many hundreds of times over a twenty year period!! And some reading of Bywaters and Gardiner. The forum is an ideal place to get lots of people lying on sofas thinking.

They should be available to some of us very soon - those who are in the project or on the advisory board. Confidentiality will obviously be respected until a formal preprint is out but we should not have to wait too long now.

 

This is very cheering.

I'm struck by how much variation there is on the forum concerning symptom patterns. I'll often read an account of someone's symptoms here that I don't recognise from my own experience (as well as a lot of commonalities, of course). I'm wondering how that can be tackled, given that we've talked for years about how there may be a dozen different diseases going on here.

Is there a specific research methodology for looking at symptom patterns? Or is it basically asking questions, thinking, asking some more questions...?

 

I think most people on this website usually criticise studies that don't recruit patients according to criteria that are deemed as somewhat meaningful (the CCC or similar). Questions and feedback shouldn't have to be equivalent to a study especially not on a forum where people should like they can express themselves freely, but I wonder whether when asking questions about this illness one should also specify by what one means with "ME/CFS". It's a bit hard because a website shouldn't have to require a diagnosis, not everybody has access to a diagnosis, most don't have access to regular testing for other pathologies that might develop, without clues to pathology anybody can argue that their definition of ME/CFS is "better", others will have been diagnosed according to criteria that aren't used anymore nowadays and most importantly this forum is supposed to be inclusive, but perhaps it would be sensible to know when some heterogenity and variation described on this forum is due to differing definitions of ME/CFS or whether things are heterogeneous independent of which definition is being used (I don't have any reason to think it would matter as people on this forum seem to be extremely educated on almost all matters surrounding ME/CFS but it is something I have thought about especially after the intramural study arguably showed a somewhat high rate of misdiagnosis)?

 

Do you think continuing to explore some of the symptoms that aren't typical of acute illness could be useful?

What struck me about discussions of the drive to lie or sit down, the alcohol intolerance, the burning muscles, the poisoned feeling, etc., is that we need to work harder at describing them to get them across. Symptoms like intolerance to light and noise are familiar to almost everyone, at least at some level, so we tend to default to comparisons.

Or is the whole pattern more revealing than individual symptoms? Do we need to poke around more at what might be different between the mild/moderate and severe/very severe illness categories?

 

That's interesting - I've not been aware of having this symptom except when I'm in the run-up to a migraine or already have one. I didn't have this even when I was 95% confined to bed. From what I've read, I thought it was only something that affected the most severely ill patients.

That's an interesting question of whether certain symptoms only turn up in the most severely ill - and if so, what that means in terms of mechanism. Ron Davis was doing a study of the most severely ill patients at one point (can't remember what happened to it), with the idea of getting the 'strongest signal' of the disease but maybe 'strongest signal' isn't the way to think of it. Maybe 'illuminating downstream consequence' is.

 

I certainly think that there may be a completely ne layer of problems for the severe/VS.

What I would look for are clues that quite different symptoms might be versions of the same thing (as turned out in RA) or versions of one symptom that turn out to be quite different things.

I thin we should look into the alcohol thing more. I would want to know what the intolerance consists of. Is it a worse hangover? It is a dislike of the taste? Is it an indefinable 'being put off' thing that might be a silent hypothalamus signal - like not wanting to eat more meat after you have had some fruit? Is it pain or discomfort somewhere? Or are there different effects indicating quite different mechanisms for different individuals?

 

Would you like to start a new thread on it, to get attention? This sounds like a very good idea.

 

Yes, OK, if I can remember how to do that.

 

One study is discussed here - the study author joins the thread and comments on some of the possible mechanisms
https://www.s4me.info/threads/alcoh...ic-fatigue-syndrome-2023-maciuch-jason.33560/

 

@Jonathan Edwards's new thread specifically about alcohol intolerance is here.

@Eleanor, I've copied your post onto the new thread, hope that's OK!

 

Thanks!