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

ScoutB said:
I wonder if they've gone down the classic smart person trap of spending so long with a complicated thing (checking for sex bias on the autosomes) that the related simple thing (Y chromosome, or lack of second X, is protective) has kind of fallen by the wayside. Or else I am totally missing something.

For comparison, the DecodeME preprint cites a paper looking at sex bias in genetic loci of various traits. And that paper also says they found no sex bias for height or weight -- meaning, the same loci on autosomes make both men and women taller. I assume, though, that the Y chromosome (which carries the sry gene and kicks off a whole gender differentiating cascade iirc) is still to blame for men being taller on average.
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That reason may be true, but I think that part of the reason why they say there is no sex biased genetics is because they have not completed the X chromosome analysis. It may completely change once they are done that part, but they can’t say so yet because they haven’t looked at it.

At least, as @Jonathan Edwards says, that statement likely means that the disease process is the same in men and women and we aren’t dealing with two different diseases. I’m sure the reason that ME/CFS is more prevalent in women will become clear with time and more analysis.
 
SugarSquared said:
That reason may be true, but I think that part of the reason why they say there is no sex biased genetics is because they have not completed the X chromosome analysis.
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But the irony is, as I see it, that the X chromosome analysis will tell us nothing about the reason for the female bias - other than that if you have two you are more at risk.They may find genes on the X whose variants contribute significantly to risk and if partial inactivation is a real issue this is quite likely, but it would not explain the sex ratio, it would help explain why some people have ME/CFS, whichever sex they are.

For the question "Why do women have more ME/CFS than men?" the comparator groups are all women and all men. The difference is simple (or fairly simple). For the question "Why do some people get ME/CFS and not others?" the comparator groups are people with ME/CFS and people who do not, irrespective of, or controlling for, sex. The latter will pick up GWAS variants. The former will not. (I may be wrong and I have already been wrong once on this, but if ScoutB's analogy is right this is the situation.)
 
Jonathan Edwards said:
For the question "Why do women have more ME/CFS than men?" the comparator groups are all women and all men. The difference is simple (or fairly simple).
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I'm not sure where to go from there. I'm not disagreeing with you, just brainstorming about how this should be tackled.

Saying an extra X chromosome increases risk is almost synonymous with saying being a female increases risk. Anything downstream of having XX vs XY, so virtually any difference between males and females, could theoretically be responsible. It could be increased estrogen, decreased testosterone, or different immune system patterns, for example.

If the mouse study of X chromosome dosage increasing risk of post-infectious SARS-CoV-2 symptoms is robust and actually relevant to ME/CFS, then that at least probably suggests that the increased risk is not due to the different environments that females and males experience throughout their lives. Maybe we can narrow it down further if we know what exactly differs and what does not between mice that have XX and X0 (females with only one X) or between XY and XXY (males with extra X). Is testosterone lower in XXY mice than in XY mice? Do XXY mice have increased type 1 interferon response compared to XY mice?

I guess a hope is that if being female increases risk because a specific gene on the X chromosome is expressed at higher levels, then a GWAS or whole genome study might pick up a mutation which decreases function of the gene and decreases risk of ME/CFS.

It might make sense to review what all is known about sex bias in autoimmune diseases, and how they're trying to figure out specifics there.
 
fst said:
For completeness' sake, it may be worth noting that the recent study also had a potentially ill-chosen endpoint (Chalder Fatigue scale after two months), that might obscure smaller effects.
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Are you referring to this study: https://s4me.info/threads/immunoads...lled-crossover-trial-2026-stortz-et-al.50743/

I haven't read it in detail, but I think they looked at several different outcomes:
The primary outcome was the impact of IA on PCS symptom severity measured by changes in:

- Post-COVID Functional Scale (PCFS) ranging from 0 to 418
- Chalder Fatigue Scale (CFS) ranging from 0 to 3320
- Bell Score ranging from 0 to 10021
- Multidimensional Fatigue Inventory (MFI-20) ranging from 20 to 10020
- Montral Cognitive Assessment (MoCA) ranging from 0 to 3022
- Hand-grip strength23 before and two weeks post IA and sham apheresis.
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forestglip said:
I guess a hope is that if being female increases risk because a specific gene on the X chromosome is expressed at higher levels, then a GWAS or whole genome study might pick up a mutation which decreases function of the gene and decreases risk of ME/CFS.
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Yes, the conclusion from previous discussion for me was that this is an interesting possibility, but it remains independent of the way sex confers risk. There might be variants with reduced risk. there might not. And variants of all sorts of other genes on X may confer risk despite those not being inadequately silenced. The risk conferred of any variant of a gene on X might be the same for men and women but there is an interesting possibility that if it is an inadequately silenced gene that the risk pattern might be different - because of some synergistic effect of both variant and increased expression. It is all fascinating and worth knowing but answers different questions from those answered by autosomal variant patterns in the two sexes i think.
 
forestglip said:
I'm not sure where to go from there. I'm not disagreeing with you, just brainstorming about how this should be tackled.

Saying an extra X chromosome increases risk is almost synonymous with saying being a female increases risk. Anything downstream of having XX vs XY, so virtually any difference between males and females, could theoretically be responsible. It could be increased estrogen, decreased testosterone, or different immune system patterns, for example.

If the mouse study of X chromosome dosage increasing risk of post-infectious SARS-CoV-2 symptoms is robust and actually relevant to ME/CFS, then that at least probably suggests that the increased risk is not due to the different environments that females and males experience throughout their lives. Maybe we can narrow it down further if we know what exactly differs and what does not between mice that have XX and X0 (females with only one X) or between XY and XXY (males with extra X). Is testosterone lower in XXY mice than in XY mice? Do XXY mice have increased type 1 interferon response compared to XY mice?

I guess a hope is that if being female increases risk because a specific gene on the X chromosome is expressed at higher levels, then a GWAS or whole genome study might pick up a mutation which decreases function of the gene and decreases risk of ME/CFS.

It might make sense to review what all is known about sex bias in autoimmune diseases, and how they're trying to figure out specifics there.
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For looking at hormones, it may be interesting to study the difference between women with PMOS and those without. I have PMOS, so I have more elevated testosterone than those without. Not everyone with PMOS has elevated testosterone (it is one of three diagnostic criteria, and you only have to meet two to be diagnosed), but you could look at those with more testosterone and see if it changes the risk for developing ME/CFS.

Another idea would be to look at people who are on hormonal birth control, comparing between estrogen+progesterone, just progesterone, and no hormonal birth control. When I developed ME/CFS, I was on progesterone only birth control (Nexplanon arm implant). I can't take estrogen-containing birth control because I have genetic risk factors for blood clotting and a strong family history.

Both of these ideas also come with the assumption that I have XX chromosomes. I don't know if I've ever had my chromosomes tested (it's not part of PMOS diagnosis if I remember correctly), so there's possibly a small chance I have some chromosomal sex difference I am unaware of. It would probably be important to test for it in a study.

But still, it could be interesting, and possibly not too hard to look at. Just recruit people with PMOS and without or people on hormonal birth control and those not. Does anyone know if studies like this have been conducted?
 
SugarSquared said:
Not everyone with PMOS has elevated testosterone (it is one of three diagnostic criteria, and you only have to meet two to be diagnosed), but you could look at those with more testosterone and see if it changes the risk for developing ME/CFS.
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I would think that you don't even need PMOS for this. You could just measure testosterone or estrogen in people with vs without ME/CFS. Which I would assume has been done many times and not shown much.

SugarSquared said:
Another idea would be to look at people who are on hormonal birth control, comparing between estrogen+progesterone, just progesterone, and no hormonal birth control. When I developed ME/CFS, I was on progesterone only birth control (Nexplanon arm implant).
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There was this study finding decreased ME/CFS symptoms in those taking birth control: Preprint Digital health app data reveals an effect of ovarian hormones on long COVID and myalgic encephalomyelitis symptoms, 2025, Male+

But from what I remember, I think there's risk of reverse causality: are people feeling better due to taking birth control, or taking birth control because they feel better?
 
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forestglip said:
But from what I remember, I think there's risk of reverse causality: are people feeling better due to taking birth control, or taking birth control because they feel better?
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You did write this on the thread you linked to:
forestglip said:
Or people who feel better have more sex, thus are more likely to take birth control?
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I think that accounts for some of the uses of birth control, but not all of them.

I left a comment just recently on somebody’s post on r/cfs that was asking about advice on which contraceptive to take. I don’t remember them making any mention of having sex. They were considering this option because their menstrual pain is so bad and always leads them to PEM. Hormonal contraceptives can reduce menstrual pain, especially for those with endometriosis and adenomyosis (my gynaecologist told me that the main treatment for adenomyosis is progesterone). My sister started taking the pill before she was having sex. There are many people that start hormonal contraceptives either before they start having sex or for another reason than avoiding pregnancy.

There’s definitely a proportion of people who are taking hormonal contraceptives for the birth control aspect, and that goes in line with people who are healthy enough to have sex that puts them at risk for unwanted pregnancy will want to take contraceptives. But there is also a proportion of people who take hormonal contraceptives because they feel bad and want to feel better.

For me, naproxen was enough to deal with my menstrual pain. I began taking contraception because I started having intercourse with my partner, and don’t want to get pregnant. Nexplanon has had the welcome but unintended side effect of reducing my menstrual pain to the point that I no longer need to take as much naproxen. Of course, this was all before my ME/CFS started.

One thing that could be done to reduce the risk of reverse causality is asking people when they started taking hormonal contraceptives. There is still probably that likelihood that people who feel good enough to have sex will be taking contraceptives, but it will better show the relationship or lack there of between ME/CFS development and severity.
 

  • "Distinct white matter impairments were observed in ME/CFS patients with different onsets." Post-infectious had inflammation-related swelling associated with worse physical health while gradual onset had neural fibre atrophy associated with worse mental health. (Citation at the bottom is Yu et al., Scientific Reports 2025, 15: 24256.)
  • The limitations of this study include the method used that does not have enough specificity for neuroinflammatory processes. A better technology is the novel advanced diffusion model (NII) that can properly investigate white matter inflammation.
  • (Multiple slides were dedicated to the mathematics and biology underlying the NII model and the MH-NMSS-PSO model that he used in the first study mentioned, but I do not understand it well enough to provide a summary.)
  • Qiang Yu's 2026 study on neuroinflammation (Yu et al., Human Brain Mapping 2026, 47: e70505) uses the NII model and does not group by ME/CFS onset to get an understanding of the common underlying pathology. There were 67 ME/CFS patients and 67 controls that were age and sex matched. The groups did not have any statistically significant differences in BMI, metabolic equivalent rates, or MRI scan time.
  • His study had three main results: "Reduced hindered water ratio of non-restricted isotropic diffusion" which may indicate "a form of cellular swelling or 'cytotoxic-like' edema;" "reduced hindered fraction of restricted isotropic diffusion" which may indicate "the shape changes of activated microglia or a chronic depletion of microglia;" and "increased fibre fraction" which may indicate "increased apparent axonal density or a reduced extracellular space due to neuroinflammatory processes."
  • They also had other results from both NII metrics and DTI-derived metrics. Some NII metrics were associated with worse mental health, greater disability, and lower disease severity. Compared to the control group, "ME/CFS patients exhibited widespread white matter abnormalities."
  • The two main limitations for this study are that the NII model is still an indirect measure of inflammation without any specificity for cell types or processes and that there was no biological samples collected which leaves out potential peripheral biomarkers. Validation from other neuroimaging techniques would strengthen the results from this study.
  • This study potentially offers biomarkers for neuroinflammation in ME/CFS and furthers the understanding of ME/CFS neuropathology.
  • One participant remarked on his microglial findings in light of the recent TSPO study that was unable to reach the brain. Qiang Yu responded by saying that future studies would benefit from cell studies in addition to the NII model as the model only provides indirect information about neuroinflammation on its own. The participant brought up the Amsterdam post-mortem study that found microglial fragmentation. He hopes he can collaborate with that study on that front. Qiang Yu doesn't have enough time to respond and just says thank you.
Edit to add the threads about Yu's 2025 paper and his 2026 paper.
2025: Distinct white matter alteration patterns in post-infectious and gradual onset chronic fatigue syndrome revealed by diffusion MRI, 2025, Yu et al
2026: Evidence of White Matter Neuroinflammation in [ME/CFS]: A Diffusion-Based Neuroinflammation Imaging Study 2026 Yu et al
 
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forestglip said:
Are you referring to this study: https://s4me.info/threads/immunoads...lled-crossover-trial-2026-stortz-et-al.50743/

I haven't read it in detail, but I think they looked at several different outcomes:
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No, have missed that, thanks for the hint!

I was referring to the Charité trial that was discussed during the conference.

PS:
In my impression Charité has moved from "gprc antibodies cause mecfs" to "gprc aab can select an autoimmune subset". Not that it changes much, the evidence speaks against that.

Dolphin

Protocol Thread 'IA-PACS-CFS: a double-blinded, randomized, sham-controlled, exploratory trial of immunoadsorption in CFS including PACS-CFS, 2024, Preßler'

https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-024-07982-5
IA-PACS-CFS: a double-blinded, randomized, sham-controlled, exploratory trial of immunoadsorption in patients with chronic fatigue syndrome (CFS) including patients with post-acute COVID-19 CFS (PACS-CFS)
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Jonathan Edwards said:
No. Science is not about how well you have managed to show what you wanted to show but might actually not be there. It is about describing what is actually there.
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This is really frustrating. We so rarely see the data presented as just data, and very little time and effort is spent on trying to just describe what you’ve actually measured and with which tools.

«We found impaired metabolism».

No, you measured a lower oxygen extraction rate in a cell culture where you don’t even know exactly which cells the different ones contained.

Imagine if we tried to build cars based on that kind of precision. We’d have spherical wheels because those are rounder, and all roads would be downhill because those result in a lower fuel consumption.
 
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