[ME/CFS Research Foundation] International ME/CFS Conference 2026 7–8 May

Jonathan Edwards said:
I don't think that is realistic, to be honest. The 'inflammatory markers' posted are obscure proteins not normally used as markers. For peripheral inflammation to inhibit TSPO going in to brain I think one would at least want raised C-reactive protein and other acute phase proteins. I would be a bit sceptical even then. (And of course there is no clinical evidence of peripheral inflammation.) I am not sure how it would relate to schizophrenia or depression, either?
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Per the paper @Murph posted and some others I skimmed, I get the impression that there are some proteins typically upregulated during inflammatory conditions that also bind TSPO. The possibility I’m interested in is that some of these proteins remain upregulated somewhere in the periphery in absence of a full inflammatory response. Most “inflammation-associated” genes have binding sites for multiple cytokine-associated transcription factors (NFkB, all the STATs, CREB, ATFs, etc.)—it takes the full concert to induce peak transcription, but even just one or two of those TFs can noticeably upregulate the gene.

To me it’s the explanation that makes the most sense with the increased signal in the some bones and muscle groups that were highlighted. If that peripheral protein sequestering TSPO could be identified it would be a clue towards the upstream signaling abnormality. Especially if the same upstream signaling pathway also happens to induce upregulation of some lipid pathways in B cells, per the @DMissa findings
 
jnmaciuch said:
To me it’s the explanation that makes the most sense with the increased signal in the some bones and muscle groups that were highlighted.
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For me the explanation that makes most sense is that the data don't mean that much - other than being negative for brain inflammation. I am not sure that there are good controls for body uptake. Uptake in marrow might be what you get when everywhere else is not interested.

I agree that there is a faint possibility of something going on in marrow and muscle - and worth someone pursuing. I think that impacting BBB is pretty implausible though.
 
Jonathan Edwards said:
Uptake in marrow might be what you get when everywhere else is not interested.
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Perhaps, but if that was the case we should be seeing only random variation in all the areas measured on the full body scan compared to the healthy controls, who also don’t have anything interesting going on. Instead there was a trend of signal being higher in ME/CFS in all muscle groups and bone marrow tested (reaching significance in several), but [edit: near identical levels or lower in all organs].

Could still be a confounder, maybe that’s what happens when someone spends more time sitting. All in all the pieces point to something potentially interesting though.

Jonathan Edwards said:
The 'inflammatory markers' posted are obscure proteins not normally used as markers.
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agree. Though, interestingly, I can tell you off the top of my head that at least 4 of these are known NFkB/RELA target genes. All of them might be but I’d have to double check
 
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Sean said:
Most signal is found in the shoulders, postural muscles, the neck,...​

Now that is interesting. It fits my experience of pain distribution.

Also might help explain sleep disturbance and quality problems, via pain in those areas.
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Mine too. I mean diagnosed medical specialist has looked at or diagnosed or suggested an investigation into almost each of those areas. I get pain in other areas (calf and shin was always the thing) but not to the injury sense, in a PEM sense.

Random sidenote, partly because I think this was mentioning in passing on the @James Cox thread about pain

I rely on heat a lot for pain. So have for many years now thank goodness had electric throws and heatpads (before that it was hot water bottles and when you need so many of those it isn't ideal for ME/CFS). Like it being common that most days over the years I might have several heatpads and a throw. Due to injuries etc and even in summer which was frankly horrific if it wasn't better than the summer before with x numbers of even worse in summer hot water bottles meaning I was 'could be worse'.

Recentlyish I for the first time in maybe nearly a decade had a window for more than days where I wasn't using a heatpad in my bed most days, just the throw. For various reasons. But I still use the throw because the bottom half of my legs get ice cold for one, in the last months it has been a joke of it being off and on as well because on the random hot days even the extra layer when it was off was too much,, but as it is only spring night was then cold.

Anyway here is the weird thing after what might seem like preamble but has context. I was getting hot flushes. I'd put the throw on 7 for 2 timer-wise (when I'd previous think nothing of level 9 for the higest time setting) and then even though the throw was mainly from hip down find I was burning up from that known area at the top of the chest just above the breast (isn;t that where the brown fat is and it is know to be a heat thrower area) up neck.

Now I get poor temperature regulation because I've had that for decades but this was different so I was starting to assume maybe it was a sign of my age as a woman and/or medication changes etc. as it had been a few months. And was starting to get cautious with the throw, even though it then happened of course if I put a jumper on because the hotter bit of my body was getting extra cover (where the heating the toes always worked better).

What I hadn't put it together with was that I was getting this at the exact same time I stopped using the heat pads that I often sit on and have on my legs, back etc maybe arms. I assumed adding these back in would be worse.

Until I had to sit somewhere else where, because everywhere in my home is set up as such, I switched on two heat pads in those areas on pretty hot. And I've now done that many times over. And I don't get any more overall hot by those than I did before.

I've now got my large heat pads back in my bed and put the electric throw on my feet on and I'm not getting the 'flush' or sudden burning up under the chin either. So it mainly seems to be a phenomenon that happens when the throw which goes over my quilt and my hip-to-feet is on and nothing else (which tend to be in direct contact, often on my rear side as it is back and legs etc). I mean I might get sweaty in situ but it isn't causing the under the chin flush. Plus I'm so much more comfortable - I forgot what a relief the direct heat round that area is.

You'd think a hotter thing nearer the top of your body would cause that same thing worse but it isn't and actually seems to make it less likely when the throw on the feet is on and warming those from on top (done in that area for warmth of icy toes rather than pain specifically, but it does ease eg calf and shins).

I thought nothing could surprise me anymore re: temp control because I had decades of it (but now those decades seem more logical than this even, at least I could eg trace back to things that made sense to me in a pattern) but there is 'another one'.
 
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My pain is often triggered by getting cold (and after going outside in my wheelchair I often struggle moving at all due to the cold) and sometimes fully disappears if I heat it up enough. Bath is amazing for leg pain but very exhousting.

Its odd. But I will say that I am unsure if I even have ME/CFS due to the number of other conditions I am uncovering this year!!
 
There was an issue that some data/screenshots from the presentations of the Berlin conference could not be made public yet. We have therefore deleted all our posts and our blog article about it. Apologies for the error.

Videos of the presentation will be made available later by the ME/CFS Research Foundation in a correct/vetted format. We will check and see if it's possible to share our summary of some of the talks afterwards.
 
Sorry if this has already been discussed, I don’t have the energy to read the entire thread.

But the impression I got is that after further analyses the DecodeME team seemed very confident in the original MAGMA analysis finding that the gene expression of the affected genes is by far most relevant in the brain.

I’m wondering now that we have “confirmation”, at what point can or should we start calling ME/CFS a neurological illness? At what point can I stop getting annoyed when advocates call it that hahah. I’m pretty sure neuroimmune is still a bit of a stretch given the current evidence. But neurological? Have we reached that threshold?
 
Evergreen said:
In the original trial FAQs (now no longer available on the PACE trial website, for some reason) and in their response to Tom’s comments on the protocol, the investigators stated:
“Although we originally planned to use actigraphy as an outcome measure, as well as a baseline measure, we decided that a test that required participants to wear an actometer around their ankle for a week was too great a burden at the end of the trial. We will however test baseline actigraphy as a moderator of outcome.“
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It is over 20 years ago now, but as I recall when the funding was announced for the study in 2003, one person on a list I was on who seemed to have inside knowledge said that it involved actigraphy as an outcome measure i.e. that was the grant that was approved by the MRC.

But then by the time the protocol was published in 2007, actigraphy as an outcome measure was dropped.

It's very frustrating that, presuming this is the case, they could change this so radically from the multi-million pound grant that was approved.
 
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Utsikt said:
Has the original grant application ever been made public?
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This was an application at one stage, I'm not sure it was the final one:
THE PACE TRIAL IDENTIFIER.pdf

Microsoft OneDrive

1drv.ms 1drv.ms

As I recall, it was obtained using a freedom of information act request. One person editorialises is about it here:

It includes:
Secondary measures:
Efficacy:
[..]
2. Daytime physical movement (an objective measure of activity) will be measured over 48 hours with an Actiwatch attached to the ankle.
 
BrightCandle said:
Low Dose Nextrone trial on ME/CFS patients from Long Covid. 160 LDN/Placebo. Both arms had ~10 drop outs so about 66 ended in each arm. No effect, same reduction seen in placebo and LDN arms on fatigue. About twice as many LDN patients got worse compared to Placebo 8% vs 4%. 4.5mg for 16 weeks.

The questions show that physicians certainly think it works and are looking to see if they did everything right and seems like they did account for all the questions and it still didn't work.
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Not watched any if this in LDN i was told that it takes about 3 months for improvement in people using it for various chronic illnesses. If that were true on average the clock would need to at about three uthen run from there for some months to be sure. So that's 6 months plus all in. Do trials usually give it this?
 
Tom Kindlon said:
But then by the time the protocol was published in 2007, actigraphy as an outcome measure was dropped.

It's very frustrating that, presuming this is the case, they could change this so radically from the multi-million pound grant that was approved.
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Tom Kindlon said:
This was an application at one stage, I'm not sure it was the final one:
THE PACE TRIAL IDENTIFIER.pdf

Microsoft OneDrive

1drv.ms 1drv.ms
As I recall, it was obtained using a freedom of information act request. One person editorialises is about it here:
LISTSERV - CO-CURE Archives - LISTSERV.NODAK.EDU
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Thank you so much for digging these out, @Tom Kindlon! So helpful. I've had a look.

It's unclear when the Pace Trial Identifier was written, but it's after October 2001 as they write
The outline proposal of this study (G010039) was approved for a full proposal in October 2001.
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and well before April 2004, which when Jane Bryant's editorial is dated. @Tom Kindlon, you mentioned that funding was announced in 2003, so some time between late 2001 and early 2003.

In the PACE Trial Identifier, the secondary measures are listed as follows [formatted with each measure on a separate line for ease of reading]:
Secondary measures:
Efficacy:
1. The self-rated Clinical Global Impression (CGI) change score (range 1-7) provides a self-rated global measure of change, and has been used in previous trials.30
2. Daytime physical movement (an objective measure of activity) will be measured over 48 hours with an Actiwatch attached to the ankle.
3. The Hospital Anxiety and Depression scale will measure change in anxiety and depression.31
4. The 36 item short-form health survey (SF-36) measures not only physical but also social and role functioning.24
5. The EuroQOL (EQ-5D) visual analogue scale provides a simple global measure of quality of life.32
6. The Client Service Receipt Inventory (CSRI), adapted for use in CFS,33 will measure hours of employment/study, wages
and benefits received, allowing another more objective measure of function.
7. An operationalised Likert scale (from much better to much worse) of the nine CDC symptoms of CFS.1
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The secondary outcome measures in the published trial per the main paper were:
  1. CGI
  2. Work and Social Adjustment Scale
  3. 6 Minute Walk Test
  4. Jenkins Sleep Scale
  5. HADS
  6. CFS symptom count
  7. Poor concentration or memory
  8. Postexertional malaise
So there are numerous changes from what is stated in the PACE Trial Identifier. I would have thought it would be competely normal for many things to change between a funding application and the protocol, with changes after that needing to be well-justified. Since the protocol was published mid-trial, this case is a little different.

Actigraphy for 48 hours does indeed feature in the Identifier but the 6MWT does not, and the latter was ultimately used.

Let's say for argument's sake that that document is the final version and it was indeed submitted to the MRC. Would the MRC's decision have been different if actigraphy had not been listed as an outcome measure? Or if the 6MWT had been there instead of it? Those are genuine questions, not rhetorical. Was actigraphy a dealmaker?

The Trial Management Group Minutes start in June 2002. Unless I missed it, actigraphy doesn't get a mention until meeting #7 in May 2004, when the minutes note [underlining added]:
Objective Measures of outcome. We had much discussion aboutvarious potential objective measures of outcome, including a six-minute walking test where the patient is timed using a stopwatch and the distance walked is recorded. The possibilities of using actigraphy and the step test for fitness were also discussed. We agreed that we would pilot the use of actigraphy, the step test and the six minute walking test in the first three centres. We had some discussion about whether an objective measure was to be a primary outcome. We had some discussion about the power of the trial to detect clinically significant differences between groups using the six-minute walking test.
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The next mention is in meeting #10 [underlining added]:
Primary outcome(s)
Discussion took place regarding the primary and secondary outcomes – number of outcomes and efficacy. It was decided that it was acceptable to have several primary outcomes for the trial, and that fatigue and disability could be considered separately and in combination. Cost utility could be considered as a fourth primary outcome. Actigraphy was not considered suitable as a primary outcome, but should remain as a predictor only.
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Then in meeting #11, we hear why:
Actigraphy is to be given at baseline only, as a predictor. This is on the basis of research by the Dutch Nijmegen group who found it useful as a predictor (the more passive, the poorer outcome), but not useful for outcome.
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And in meeting #12, we get the clanger:
The issue of using actigraphy as an outcome measure was raised. It was noted that the Dutch study by Bleijenberg and colleagues reported that actigraphy was not a good outcome measure since the majority of patients are reasonably active and there is no change in this in spite of improvement in fatigue. However, pervasively passive people at baseline may do worse on CBT and perhaps better on GET.

A final decision on using this as an outcome has been postponed until we see how much of a measurement load actigraphy is, and it was agreed that this may be changed later next year if desired.
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So whatever was written in the Identifier, according to the Trial Management Group minutes, actigraphy was not a planned outcome measure at any point from 2002. If the MRC required or requested an objective measure of physical activity, and this was supplied with no intention to use it, then that would be deceitful, but I have not seen anything that would suggest that.

I think the thing for advocates to focus on is not that actigraphy appeared in the PACE Trial Identifier as a secondary outcome measure, but their stated reason for not using it as an outcome measure, and the fact that CBT participants did not improve on the objective measure that was used - the 6MWT - any more than those doing SMC or APT, and GET participants' improvement on the 6MWT was statistically significant, but small and unlikely to be clinically significant.

Tagging @V.R.T. @Robert 1973 @Sean @rvallee to make sure you all see this update after Tom's helpful input.
 
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Evergreen said:
I think the thing for advocates to focus on is not that actigraphy appeared in the PACE Trial Identifier as a secondary outcome measure, but their stated reason for not using it as an outcome measure, and the fact that CBT participants did not improve on the objective measure that was used - the 6MWT - any more than those doing SMC or APT, and GET participants' improvement on the 6MWT was statistically significant, but small and unlikely to be clinically significant.
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Not just as an objective outcome measure of immediate improvement, but also critically for the GET arm to test that:

1. Patients did actually follow the full treatment protocol, and did not simply report that they did (which is a serious possibility given how much pressure they were likely under to report that they did).

2. Even if patients did follow it that they did not simply substitute the treatment for their normal daily activities, with no overall increase in activity.

3. The subjective and objective outcome measures correlated.

A strong positive result on actigraphy (including correlations) would have been one of the most powerful pieces of evidence possible in favour of their hypothesis, and they would have been crowing it from the rooftops if it had delivered, and quite rightly so.

But they knew actigraphy could falsify their claim of increased activity (due to treatment), and were likely to do so, and so they made sure it couldn't by the simple but very effective tactic of just not collecting that data in the first place. They deliberately weakened and perverted the trial by refusing to collect some of the most robust and critical data possible.

The excuses given – that actimeters were too much of a burden to patients to wear, and that they failed to report a benefit in the Dutch studies – are utterly appalling, and should have immediately disqualified the study from proceeding any further or being taken seriously.

Actigraphy should also have been a primary outcome measure. No question about that.

This piece of brazen skullduggery and its consequences for us enrages me to this day. It is straight and cruel fraud, as far as I am concerned. They knew what they were doing, had no excuses, and I will never forgive them for it.

:mad::mad::mad:
 
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