Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

Yea, but I think Jonathan's point was that the evidence is there that CBT &/or GET don't work ---. Logical inference is they don't work so don't fund them ---

 

Ethanol Levels (presumably in mg/dL).

HV 180.0145
HV 0.2219
HV 0.5629
HV 0.0669
...

Spoiler: Remainder all normal

HV 0.1789
HV 0.0948
HV 0.5878
HV 0.1228
HV 0.1256
HV 0.5782
HV 0.2124
HV 0.0915
HV 0.8194
HV 0.1329
HV 0.0835
HV 0.4338
HV 0.057

PI-ME/CFS 0.234
PI-ME/CFS 0.154
PI-ME/CFS 0.2627
PI-ME/CFS 0.059
PI-ME/CFS 0.0799
PI-ME/CFS 0.1656
PI-ME/CFS 0.6207
PI-ME/CFS 0.11
PI-ME/CFS 0.1183
PI-ME/CFS 0.0522
PI-ME/CFS 0.1416
PI-ME/CFS 0.0953
PI-ME/CFS 0
PI-ME/CFS 0.128
PI-ME/CFS 0
PI-ME/CFS 0.3376
PI-ME/CFS 0.1654542

 

Um isn't that like 4 times the legal limit for driving?

 

Someone emailed Dr Walitt about the reason for choosing a single rather than a 2-day CPET and got this response back from the NINDS’ Office of Neuroscience Communications and Engagement on behalf of the NIH ME/CFS working group. Bolding mine:

https://twitter.com/user/status/1761135302473609475

 

I've now read the main parts of the study. It comes across like a messy political compromise, as in everybody had to do trade-off deals to get their particular view inserted with the inevitable result that the paper is bedeviled with incoherent non sequiturs. I would love to have been a fly on the wall during the writing negotiations. I'm sure at least some of the authors were trying in good faith to do rigorous science; I feel for them.

I hope outside researchers can do something useful with the raw data, tiny as the cohort is. Or that the buzz around the study sparks some good ideas to be investigated.

If anyone here has any good ideas you can submit them to the NIH NINDS ME/CFS Research Roadmap project (deadline 8 March 2024) discussed here

 

Someone asked for my response...and my current response is that I'm not interested in providing a full response...I have a lot of thoughts on the paper and I'm not really interested in sharing them all at this time for a bunch of different reasons.

However, I would like to point out that, yes, all study participants had PEM and PEM after CPET was explored in a previous paper:

https://pubmed.ncbi.nlm.nih.gov/38352048/

As for patient selection, the communtiy was involved in picking the 5 outside adjudicators who had to unanimously agree to include each study participant.

And I believe that one reason only 9 people were included in the final CPET analysis is that several patients who returned to the NIH for their second visit declined to take the test. So...those results would probably look a little different if the patients who felt too ill to exercise had exercised. There's a catch-22 with all inpatient ME studies...of course the sickest people can not participate so we don't learn aboout them. It's a problem without a good answer as MRI machines etc don't travel.

Also, more papers will be published delving into specific sub-studies. I don't know when/what/etc but several have been ready to go and were waiting for this main paper to be published.

 

So basically they couldn't be bothered to slightly alter their protocol to include the 2 day CPET. Talk about effort preference. I guess they have CFS too!

 

This may be an unpopular opinion but I understand why they used a 1-day CPET. It makes sense that by taking measurements when PEM is induced on the 2nd day, they were trying to find the cause of the lower 2nd day CPET results, not validate them. I think it is relatively well known that the 2nd day CPET results are worse but we need to figure out why this happens. I guess they could have run the 2nd day CPET, but I think this would have just confirmed what is already known. Perhaps having the 2-day CPET results might have changed the overall study narrative, but the point still stands that finding the cause is what is important. To me the bigger issues with the 1-day CPET were the fact that the patients seemed to have less severe PEM, the small sample size and not running extensive enough testing to find the causes. If they had found the cause of PEM I would be applauding them, but unfortunately they didn't.

Also, given that the 2 day CPET is more taxing on the participants it is arguable if that is worth validating an already known result.

 

See my response just above...I believe several patients opted out of the CPET. I would not have enjoyed being asked to do a second one. I think the team was also trying to balance demands on patients with data collection. A 2-day CPET along with everything else they asked us to do would've been...no bueno. For me, the worst part of the study was the 4 nights in the metabolic chamber after the CPET...and if it had been after a second CPET...(barfing noises).

 

Thank you, are intramural data indicating whether low levels of catechols correlated with severity of ME patients?

The potential overlap with synucleinopathies is interesting. There are researchers (Avik Roy?) thinking that a subgroup of ME patients might suffer from a synucleinopathy, as far as I can recall. Also, there is Abilify, which seems to help some patients, and is known to be a 'dopamine stabilizing' agent.

 

Upon further reflection, I think my biggest gripe with the paper (besides the small sample size and BPS influences) is it took so long to come out that much of what was done seems outdated now.

• The CPET work is outdated by Systrom's invasive CPET test and many of the two day CPET's that have been done.
• The genetic testing will soon be outdone by the GWAS study.
• The autonomic testing is outdone by more advanced SFN testing, QSART and wearable HRV devices.
• The fMRI brain imaging may be somewhat interesting but IMO it seems less important than Younger and VanElazkker's PET/more advanced scanning techniques and some of the Long Covid scanning work.
• The muscle biopsy's are being outdated by Wust's work in Long Covid and ME/CFS.
• The microbiome testing has been outdone by several larger studies.
• As far as I can tell, much of the proteomics, mitochondrial, immune, cortisol and CSF testing has and is being run on larger cohorts but some of this may be new.
• The one thing that I don't think has been outclassed is the modified effort expenditure for rewards task which is the one thing I am sure is almost entirely useless.

That's not to say there isn't useful material in here, but it does feel like it too so long to run and come out that it got left behind. Hopefully the upside is that it helps other researchers make better decisions about what to focus on in the future.

 

What's your point here exactly? Can you spell it out?

 

Thank you!

PS: Quite often I find your 'summaries' very enlightening and helpful.

 

Sure! They state that there is no evidence of deconditioning: maximum grip strength and arm muscle mass are normal.

There is no sign of muscle atrophy on biopsy, no shift from mitochondrial-heavy / fat burning aerobic / fatigue-resistant / slow twitch type 1 fibres to mitochondrial-light / anaerobic sugar burning / fatiguable / fast-twitch type 2 fibres. (Note that the opposite was shown by Rob Wüst in LC and likely to be replicated in ME in coming months).

(Vastus lateralis is your big outer thigh muscle. pH 9.4 is to stain the type I fibres. I presume they're tagging ATP synthase ie mitochondrial complex V, which is a type of ATPase that makes ATP rather than degrading it for energy. Edit: no, see this ref: "Reportedly the speed of muscle fiber contraction is directly proportional to relative myosin ATPase activity (at pH 9.4) while fatigability relates to relative oxidative capacity. Type I fibers have low ATPase activity (at pH 9.4), are slow twitch, have high oxidative and low glycolytic capacity, and are relatively resistant to fatigue. Type IIA fibers have high myosin ATPase activity (pH 9.4), are fast twitch, have high oxidative and glycolytic capacity, and are relatively resistant to fatigue. Type IIB fibers have high myosin ATPase activity (pH 9.4), are fast twitch, have low oxidative and high glycolytic capacity, and fatigue rapidly.")

But then they find fatiguability, which they claim is both not peripheral, but at the same time is due to deconditioning in the muscles (and cardiovascular system).

Not peripheral / (neuro-)muscular —

But it's due to deconditioning —

Concluding

---
Perhaps I am not following the logic, but as written this seems contradictory.

 

The 2-day CPET literature isn’t clear-cut at all and different studies have reported different abnormalities (and lack thereof). This has been discussed at length in different threads. I do think this was a missed opportunity, as 2-day CPET findings require independent replication. Though with the tiny sample size they had of patients able and willing to undergo CPET, it wouldn’t have been useful anyway.