Netherlands: PAIS [Post-Acute Infection Syndromes] Conference, 26th to 29th August, 2026, Amsterdam

DMissa said:
To start with I am skeptical that ME/CFS is a primary mitochondrial disease despite this idea remaining in vogue for decades, and in spite of my PhD being on it and my career track record partly depending on it
Click to expand...
Hey, if you have some time, since you’re interested in energy production, metabolism, and stress signalling in cells, maybe you could take a look at this video. I’d be really interested to hear your thoughts on it.

Interestingly, the only two drugs being developed specifically for ME right now, MDC001 and IVO-21, both target mitochondrial function.
 
Dude said:
Hey, if you have some time, since you’re interested in energy production, metabolism, and stress signalling in cells, maybe you could take a look at this video. I’d be really interested to hear your thoughts on it.

Interestingly, the only two drugs being developed specifically for ME right now, MDC001 and IVO-21, both target mitochondrial function.
Click to expand...
I don't have the hour needed to watch the whole thing but I have tried to give it as detailed a skim as I can.

While I am not as keen on broad use of the term inflammation I do think that mtDNA getting into the cytoplasm or out of the cell is a plausible avenue to investigate. It is more plausible to me than the typical "not enough energy being made by respiration" idea. It links to things that could easily trigger symptoms, and it links to time course of symptoms through some innate immune mechanisms. @jnmaciuch has expressed more detailed ideas about this to me in the past that I won't elaborate on unless she chooses to share but I am convinced by her ideas that it is a worthwhile lane to try looking at.

I also think the FBXL4 association in DecodeME supports this but then I also wonder why it is the only gene that seems to.

I am not sold on the bits about respiration itself and that are predicated on the WASF3 findings. The WASF3 paper is a very good paper and it does a very good job of showing what a potential role for WASF3 in a mitochondrial respiratory issue could be. The remaining question is whether there is a mitochondrial respiratory issue that is a central feature of ME/CFS. Based on all other evidence I am aware of outside of this paper I weigh the likely answer to be "no". Please bear in mind I have very likely spent the most time of anybody on earth directly assaying this so if anything I should be biased towards believing the opposite. That should tell you how clearly I think the evidence base is speaking.

If there is really anything to this (a specific issue with respiration), the final part of the WASF3 paper where they measured respiration in skeletal muscle cells needs to be replicated. I am not convinced by one paper because I have seen a lot of negative data in other tissues, and skeletal muscle is really hard to interpret for these kinds of assays because there are all sorts of sampling effects and variations that are possible and muscle mitochondrial content and activity is necessarily tied strongly to activity levels. Those who have done seahorse on muscle samples can tell you what a messy pain in the bum it is as well - and this is in the view of someone with thousands and thousands of hours of respirometry experience across different sample types and different instruments. A finnicky experiment with a necessarily limited amount of sample material, upstream sources of potential variation, and in-assay sources of potential variation is not something to run away with from one report, in my view.

I should elaborate that when I said primary mitochondrial disease in the last comment I meant so in the most commonly thought of sense: a respiration defect. I am very open to possibilities that a) don't have a body of inconclusive evidence b) clearly link to relevant illness dynamics.

I hope the WASF3 muscle findings are replicated well, but until then I'm cautiously interested rather than convinced.
 
Last edited:
Actually, I should also mention one lane I think being largely overlooked is mitochondrial calcium sequestration. A major priority area that may be indicated by DecodeME is synaptic maintenance. Mitochondrial calcium ion storage and movement is essential for synaptic function, particularly under high activity. There are also relevant roles in membrane dynamics (such as synaptic vesicle recycling) which ties directly into this as well. This is where imbalances in membrane lipid composition or handling could easily factor in as well. If the wrong part of the wrong membrane is too fluid or stiff or reactive or charged or whatever else, you could have all sorts of synaptic consequences.

Really all I hope for is that future projects get more creative than the done to death energy thing and to incorporate important pieces of evidence that we do have already (eg: the negative stuff and the recent genetic stuff).
 
Last edited:
DMissa said:
I don't have the hour needed to watch the whole thing but I have tried to give it as detailed a skim as I can.

While I am not as keen on broad use of the term inflammation I do think that mtDNA getting into the cytoplasm or out of the cell is a plausible avenue to investigate. It is more plausible to me than the typical "not enough energy being made by respiration" idea. It links to things that could easily trigger symptoms, and it links to time course of symptoms through some innate immune mechanisms. @jnmaciuch has expressed more detailed ideas about this to me in the past that I won't elaborate on unless she chooses to share but I am convinced by her ideas that it is a worthwhile lane to try looking at.

I also think the FBXL4 association in DecodeME supports this but then I also wonder why it is the only gene that seems to.

I am not sold on the bits about respiration itself and that are predicated on the WASF3 findings. The WASF3 paper is a very good paper and it does a very good job of showing what a potential role for WASF3 in a mitochondrial respiratory issue could be. The remaining question is whether there is a mitochondrial respiratory issue that is a central feature of ME/CFS. Based on all other evidence I am aware of outside of this paper I weigh the likely answer to be "no". Please bear in mind I have very likely spent the most time of anybody on earth directly assaying this so if anything I should be biased towards believing the opposite. That should tell you how clearly I think the evidence base is speaking.

If there is really anything to this (a specific issue with respiration), the final part of the WASF3 paper where they measured respiration in skeletal muscle cells needs to be replicated. I am not convinced by one paper because I have seen a lot of negative data in other tissues, and skeletal muscle is really hard to interpret for these kinds of assays because there are all sorts of sampling effects and variations that are possible and muscle mitochondrial content and activity is necessarily tied strongly to activity levels. Those who have done seahorse on muscle samples can tell you what a messy pain in the bum it is as well - and this is in the view of someone with thousands and thousands of hours of respirometry experience across different sample types and different instruments. A finnicky experiment with a necessarily limited amount of sample material, upstream sources of potential variation, and in-assay sources of potential variation is not something to run away with from one report, in my view.

I should elaborate that when I said primary mitochondrial disease in the last comment I meant so in the most commonly thought of sense: a respiration defect. I am very open to possibilities that a) don't have a body of inconclusive evidence b) clearly link to relevant illness dynamics.

I hope the WASF3 muscle findings are replicated well, but until then I'm cautiously interested rather than convinced.
Click to expand...

Thanks for your assessment!
 
Thanks for the shoutout @DMissa . I’ve talked about my thoughts on how mtDNA release might fit into the picture in bits and pieces across the forum (was thinking of writing up a hypothesis paper at one point but got sidelined by PhD work and grant applications). I agree with your thoughts about the mitochondrial calcium sequestration in neurons—if the signals from DecodeME point broadly towards the balance of excitatory and inhibitory input to neurons, then mtDNA release downstream of calcium flux seems like the most direct link from the brain signals in DecodeME to a clinical profile that fits with interferon signaling in both presentation and timing. (and I’ll note, interferon signaling is not equivalent to “inflammation”, per the video’s oversimplification)

I might be chasing clouds here, of course. But insofar as this theory does yield some direct testable hypotheses, I’m committed to chasing it down to the best of my (unfortunately limited) ability.
 
Last edited:
jnmaciuch said:
was thinking of writing up a hypothesis paper at one point but got sidelined by PhD work and grant applications
Click to expand...
If at one point, you have the time and energy to do so, I’d be interested. I find hypothesis discussions helpful for me to learn about what the science means and how it can apply clinically. For example, the synaptic pruning thread got me to understand things that I otherwise would not get.

On another note, I love how you and @DMissa are always thinking about how the DecodeME findings can fit into your ideas and research. Sometimes it feels like researchers are not considering them enough. I’m very grateful to have researchers on the forum like both of you.
 
SugarSquared said:
On another note, I love how you and @DMissa are always thinking about how the DecodeME findings can fit into your ideas and research.
Click to expand...
Outside of the few things I have been touching on recently I do feel that I am not best placed to answer some of the main questions from it as I am not a neuroscientist or an imaging person or a mouse person who would be better able to address salient questions about the brain.

If the questions raised here and in my recent postings don't lead anywhere (such as lipids, calcium) I would honestly be content to conscientiously withdraw from the field and let better placed people use the funding to make a real dent.

It is less about how evidence like DecodeME can fit into my ideas and more about how I can actually be useful in getting people better ASAP.
 
The culture around biomedical research and funding sometimes seems to emphasize extensive domain experience above other qualities that I'd argue matter even more, such as:
- a focus on how their research could lead to understanding that matters to understanding and to treatments, not just conducting research in a certain direction because it's convenient or popular
- a tendency to think hard before starting a project, to ensure the work is actually conducted in a way that has a chance of giving a clear answer
- a willingness to falsify hypotheses and pivot focus

Right now a lot of ME/CFS funding goes towards projects that, at least to my non-expert eye, lack the above qualities.

In my past life, in math, there is this concept of 'mathematical maturity' where after a certain amount of time working in one narrow field of math people develop these generalizable skills, which translate to other fields of math even if they know none of the particulars. My sense is people doing biological research the way you do (i.e. trying things out and learning from their own and others' mistakes) have a similar kind of transferrable skill set. (Learning from false steps is the critical factor, which I suspect is why it seems like some folks can work for decades in a field, never really testing their ideas, and thus never really gaining these skills..)

So you will know best @DMissa, and I completely understand if there just isn't a project fit that feels right for you someday, but at the same time don't underestimate how valuable every person contributing this kind of 'research maturity', sanity and clear-eyed thinking to the ME/CFS landscape is.
 
Last edited:
ScoutB said:
So you will know best @DMissa, and I completely understand if there just isn't a project fit that feels right for you someday, but at the same time don't underestimate how valuable every person contributing this kind of 'research maturity', sanity and clear-eyed thinking to the ME/CFS landscape is.
Click to expand...

You are 100% correct and I agree completely. The problem is that a) I am junior and b) indeed, there are transferrable skills and knowledge but only to an extent. I can't yet only be overseeing the big picture at the project design level, I have to provide technical expertise and do work myself on the front lines. If I was 10 years further into my career I could hire subject matter experts as postdocs and be paid to be the hands-off big boss and focus on making sure it is all scientifically productive and on track. But I just I can't do that at this earlier stage. Sure, I can learn new things - but nobody is going to fund me doing eg: hands on brain imaging in ME/CFS with no experience - rightfully so because it would be inefficient and something that, in reality, somebody else would be doing 90% of workload for even if it was in training me.
 
Last edited:
ME Research UK:

Exciting research funded by ME Research UK was showcased at the ISLC-PAIS 2026 conference.

Topics included muscle and blood-vessel abnormalities, post-exertional malaise (PEM), cellular waste, gene regulation, fat metabolism, and changes in brain tissue.

This international event on Post-Acute Infection Syndromes took place in Amsterdam from August 26 to 29.

Discover more about the presentations here: https://tinyurl.com/246rj47b

This is part 1 of three articles on the ISLC-PAIS conference - more to follow over the coming weeks.
 
ME Research UK:

ISLC-PAIS 2026: Systems thinking, terminology, and negative trials.

Last week ME Research UK posted part 1 of a series of articles reflecting on the ISLC-PAIS conference which took part in Amsterdam 26 – 29 August, 2026. In part 2, notable presentations on research not funded by ME Research UK are discussed.

Here, speakers raised broader questions about how PAIS and ME/CFS research is framed and communicated. The presenters explored whether systems thinking could provide a more complete understanding of post-exertional malaise (PEM), why the term ‘PAIS’ may not encompass all cases of ME/CFS, and why publishing null or negative findings is essential for reducing bias (systematic errors that can occur at any stage of the research process, affecting the reliability and validity of findings) and strengthening the evidence base.

Read more: https://tinyurl.com/2fw5rt95
Read Part 1: https://tinyurl.com/246rj47b
 
From Bluesky about a poster for the conference:
Check out our conference poster on defining PEM:
positivenutrition.ie/wp-content/u...

Coauthors: @naomidharvey.bsky.social@ciarawrightphd.bsky.social@sunsopeningband.bsky.social

Full paper currently in draft!

positivenutrition.ie/wp-content/uploads/2026/08/Ciara-Wright-Poster-ISLC-PAIS-Final.pdf


In the paper, we argue that PEM is characteristic of and unique to ME, and is equivalent to PENE as defined by the ICC. Required to be prolonged, disproportionate, systemic, may be delayed, can cause lasting functional decline



If you have x condition + PEM, then this is proposed as comorbid ME eg Lyme disease + ME/CFS. You can ofc have Lyme without ME/CFS.

PESE is symptomatic exacerbation post exertion which is a subset of PEM and can happen in other diseases. Eg fatigue, SOB, pain in cardiac diseases



A clearer definition will help phenotype patients in research and in treatment, hopefully leading to better science for everyone.

Recognising PEM and tailoring management will reduce risk of iatrogenic injury to pwME



Summary stolen from Ciara's thread on the other place:
x.com/CiaraGlenvil...
Click to expand...

Poster title: A Clearer Definition of PEM: Why It Matters for Everyone

Authors:
Naomi D. Harvey, Harriet A. Carroll, Ciara Wright, Todd Davenport
 
Chandelier said:
From Bluesky about a poster for the conference:


Poster title: A Clearer Definition of PEM: Why It Matters for Everyone

Authors:
Naomi D. Harvey, Harriet A. Carroll, Ciara Wright, Todd Davenport
Click to expand...
It is good that they clearly distinguish between post exertion symptom exaggeration/exasperation and the abnormal features of PEM.

PEM may involve PESE whereas in general many other conditions display PESE, that is an exaggeration of a normal response whilst lacking the pathological aspects of ME/CFS PEM.

Many, including the BSP advocates who still mistakenly focus on ME/CFS as just fatigue, cofound PEM and PESE in their research. Though because of the overlap the two will correlate, it is important the distinction is accounted for.
 
thesicktimes.org

Biological pathways and mechanistic trials centered at new Long COVID conference in Amsterdam - The Sick Times

Researchers, clinicians, and advocates gathered for the inaugural conference of the International Society for Long COVID and Post-Acute Infection Syndromes in the Netherlands in late August. The four-day event featured hundreds of presentations and posters about trials and disease mechanisms.
thesicktimes.org thesicktimes.org


Biological pathways and mechanistic trials centered at new Long COVID conference in Amsterdam
Written by David Tuller
October 6, 2026

Key points you should know:
  • In late August, the International Society for Long COVID and Post-Acute Infection Syndromes hosted its inaugural gathering in Amsterdam. Hundreds hobnobbed in the H’ART Museum, a major cultural and conference facility in the heart of the city.
  • Presenters acknowledged that a series of clinical trials had produced disappointing results. They focused on seeking lessons from the null findings and called for more smartly designed trials targeting the pathological mechanisms believed to be involved.
  • Some presenters highlighted innovative use of electronic wearables and remote monitoring in an effort to improve research and accurately track biological events, such as the occurrence of post-exertional malaise.
  • PROBE-PASC, a program centering mechanistic trials for Long COVID funded by the U.S. Department of Defense, was revealed during the conference.
 
Thank you for that report, @dave30th.

At the same session, Mark Faghy, professor of clinical exercise physiology at Loughborough University in the U.K., noted that PEM can appear in multiple phenotypes, including “metabolic dominant,” characterized by physical fatigability and delayed recovery; “anatomic dominant,” by orthostatic intolerance, dizziness and cardiovascular issues; and “cognitive dominant,” by impaired memory, concentration, and executive function. Another variant, “multisystem” PEM, involves the “simultaneous exacerbation” of a broad spectrum of symptoms.
Click to expand...

Mumble mumble. :grumpy:

Very concerned about this kind of expansion of the PEM concept.

Far as I am concerned PEM has a very specific meaning, in particular the importance of the delayed component, which I regard as one the most important clues we have. Diluting out the significance of that is not a good development, in my view.

I am not saying there are no non-delayed consequences from activity/exercise. But I am very far from convinced they are safely subsumed into a broader PEM concept. If anything they should be a separate category, until otherwise proven. The PEM label should be restricted to features associated with the delayed component.

That distinction must be very carefully controlled for in studies.
 
Last edited:
The questions I have is how many patients has he seen that fit into these 'phenotypes', and how much overlap is there in the symptoms actually reported by those patients. I would suspect that he's only seen a relatively small number of patients, and that there is a considerable overlap.
 
Sean said:
Thank you for that report, @dave30th.
Click to expand...

It is a good summary. It brings across the mood of the community. The pity is that this community is all facing the wrong direction.

Putrino says:
“We need to run toward complexity, not run away from it,” he concluded. “Anyone who is trying to look for the one magic bullet that will solve all of this is bound to be disappointed, because they’re trying to squeeze a square peg in a round hole.”

No, they are trying to do science rather than pretend everyone is right and deserves that $3M grant.

Peluso says:
When such mechanistic trials yield null results, Peluso suggested, investigators should consider multiple circumstances that could possibly explain the findings. Perhaps the drug didn’t reach the target, or the dose was too low, or the intervention too late. After those and other factors are taken into account, said Peluso, should investigators entertain “the last option”— that the mechanism itself is wrong.

No, you focus on whether the mechanism wrong from the start. Rather than waste another $30M.
 
Andy said:
The questions I have is how many patients has he seen that fit into these 'phenotypes', and how much overlap is there in the symptoms actually reported by those patients. I would suspect that he's only seen a relatively small number of patients, and that there is a considerable overlap.
Click to expand...
I don't think he was really saying they were mutually exclusive phenotypes but that PEM could be thought of to be made up of different sub-components that in different cases might be more or less dominant than others. I assumed delay would be featured in all of them, although it's true that is only specifically mentioned in one domain. So yeah, I would think there would be considerable overlap, which is how he framed the "multi-system" PEM and why he was making the argument for "systems-level" approaches.

Or as Jo would say, he's trying to "shore up the multi-system folklore." Maybe Jo's right that it's folklore. I don't know. I can't adjudicate that one. This was definitely a multi-systems-friendly crowd.
 
Last edited:
You must log in or register to reply here.
Back
Top Bottom