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

[FMMM1]

On the NIH study and this paper potentially being of use to BPS interests and specifically their desired outcome in the new Cochrane Exercise Therapy Review:



Oh, I can imagine that there are plenty of ways for that to happen - 'more research is needed on how to tweak things exactly right, but given the lack of documented harm, patients who want to explore ways to get better should not be denied the GET option'....

This is the NIH's considered opinion of what ME/CFS is:

They suggest that the functional disability only results from deconditioning produced by the reduction in physical activity. Of course it's ridiculous, as others have pointed out - most of us could give examples of why this is not true. There's that early Newton study that found that the people with mild ME/CFS were not drastically deconditioned. But there it is.

All that needs to happen for the BPS people to keep winning the Cochrane war is for there to be ongoing disputes about what the new Exercise Therapy Review concludes. So long as that happens, and surely it will, then the 2019 review stands, and continues to be cited. And there's no loss of BPS reputations.

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 ---

 

[SNT Gatchaman]

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

 

[Eddie]

Ethanol Levels (presumably in mg/dL).

HV 180.0145

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

 

[cassava7]

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:

Your email to Brian T. Walitt, M.D., at the National Institute of Neurological Disorders and Stroke (NINDS) concerning myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been forwarded to the National Institutes of Health (NIH) ME/CFS Working Group for reply.

Thank you for your comments about the recently published NIH ME/CFS study. You asked Dr. Walitt what informed his decision to use a 1-day cardiopulmonary exercise test (CPET) instead of a 2-day CPET. We hope the information provided below is helpful.

The NIH study sought to study the phenomenon of post-exertional malaise (PEM) in multiple dimensions as it occurred. The NIH investigative team wanted to use a single stress to induce PEM and take serial measurements from each participant as PEM was occurring. A single stress model was preferred, as a second stress would interfere with the evolving biological process that corresponds to the experience of PEM.

After reviewing the literature and NIH’s focus group work (https://pubmed.ncbi.nlm.nih.gov/33071931/) and discussing with experts in the field, a single CPET was determined to be adequate for inducing post-exertional malaise. Measurements of bioenergetics, mitochondrial function, questionnaires, and a PEM interview tool developed for the study (https://pubmed.ncbi.nlm.nih.gov/38352048/) were collected prior to CPET and at multiple intervals over 72 hours.

The single CPET protocol was successful in inducing PEM in each of the participants. It was also successful in demonstrating impaired cardiopulmonary performance between the PI-ME/CFS and Healthy Volunteer groups (Figure 5 in the Nature Article at https://www.nature.com/articles/s41467-024-45107-3). While no bioenergetic or mitochondrial changes were noted (Figure S9), further work is planned with stored samples collected over the CPET experiment.

The NIH did consider the 2-day CPET protocol. The 2-day CPET protocol is currently used in clinical practice for documentation of non-recovery of anerobic metabolism after the second CPET. The primary community use of the 2-day CPET is for establishing a ME/CFS diagnosis, which can be important for individual patients in obtaining medical care and disability benefits. As the NIH study was using a wealth of information for diagnostic purposes, including an expert panel of clinical adjudicators to establish the ME/CFS diagnosis, a 2-day CPET was not felt necessary.

The addition of a second CPET would confound the desired experiment by adding a ‘second hit’ of stress into an otherwise straightforward experimental model. A 2-day CPET would have also added a great deal of lasting discomfort to the participants in the study who already had given so much of themselves to the research study already. Some of the participants may not have been willing to participate in the 2-day CPET.

In summary, a single CPET was selected as the most ideal model for studying the evolution of PEM. From all the data collected in the new study, it appears that that selection has successfully achieved its objectives.

We hope this information is helpful.

Office of Neuroscience Communications and Engagement
National Institute of Neurological Disorders and Stroke on behalf of the Trans-NIH ME/CFS Working Group

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

 

[Ravn]

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

 

[B_V]

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.

 

[Hubris]

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

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!

 

[Eddie]

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

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.

 

[B_V]

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 was 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.

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).

 

[Sean]

We know that there are likely sub-sets within ME,

I remain unconvinced about that. There might be, or might not. Just isn't enough evidence either way, at this point.

They certainly leave the door more than ajar but I cannot see this as being cited in a Cochrane review in a conclusion that says 'Even if the efficacy data look dismal some very clever scientists think it should work so we conclude it probably does'.

I fear you under estimate Cochrane's demonstrated ability and preparedness to do exactly that.

Those declines have a lot to do with 'effort preference', only it is the other way around - the decline in performance and afferent feedback (sensations associated with fatigue) causes the 'reduced effort preference'.

Exactly. The assigning of that causal pathway is arbitrary, and inappropriate for an observational study. Not to mention simply not in accord with the broad body of evidence for ME.

Thanks. I guess regardless of its purpose, the battery of testing is also likely to be more challenging for PwME than for healthy volunteers, which might well add to the stress.

Plus, IIRC, the participants had to stay at the research facility for a week. If so then I am pretty sure that would be quite stressful for most ME patients.

Or put another way, why doesn't every other limiting condition cause a syndrome similar to ME, complete with PEM. Why doesn't MS have this? Why not everyone who has been in a coma for an extended period?

Astonishing. Again: why does this not happen in every other disabling illness?

More pertinently, they collected no evidence that allowed them to plausibly speculate along these lines. What they could easily have done is asked their participants if disability or deconditioning came first as some kind of sensible check - since the patients were there. But they chose not to. It's not science, it's bar room opining.

One of the very few things I am sure of about ME is that deconditioning is not a primary feature, and plays no role in etiology nor perpetuation, and trying to treat it as if it does will just make things worse.

My own personal history completely rules out deconditioning having any primary causal role. I was simply too active in the early stages for that to be true. I know that, because I checked with several physios and doctors (including a sports doctor) about how much activity was required to prevent deconditioning, and I was well above that level. And paying for it big time, I might add.

If anything, following their advice to avoid deconditioning may well have contributed to a worse outcome for me. By which I mean it almost certainly did.

Some patients may well become at least somewhat deconditioned, and that may well be an additional complicating comorbidity. But a secondary contingent one, over which they likely have little say.

There is a good term for this: bootstrap pseudoscience. It's pseudoscience that somehow keeps rising by climbing itself again and again, even though doing it even once is physically impossible.

Bootstrap antiscience. They are doing the opposite of what is required by robust scientific method, and doing it deliberately.

I worry about a research template of sorts being passed down. There is also the Lyme group. And isn't there a new overarching group that looks at several diseases in tandem?

This. It is a huge cultural problem in medical science at the moment. It is quite clear that the BPS school have been deliberately and systematically lowering methodological standards for decades, and that it has worked very well, for them.

 

[Sean]

I was initially unhappy about them only using a single CPET measure, not the 2-day test-retest version, and thought it a serious lost opportunity and weakness.

But now I am inclined to accept their reasons for doing so, including the burden on patients.

 

[Hutan]

I was initially unhappy about them only using a single CPET measure, not the 2-day test-retest version, and thought it a serious lost opportunity and weakness.
But now I am inclined to accept their reasons for doing so, including the burden on patients.

Yes, me too. Except that the 2 day CPET differences in ME/CFS are still not entirely beyond question - a replication in a very well conducted, adequately sized NIH investigation would have been extremely helpful.


DOPA, DOPAC and DPHG
Re Evergreen's query above:

In cerebrospinal fluid, the PI-ME/CFS group had statistically significant decreased levels of DOPA, DOPAC, and DHPG (Fig. 6a–c)...These results did not change after excluding data from participants taking central-acting medications.

L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine(adrenaline), which are collectively known as catecholamines.
In the neuronal cytoplasm dopamine undergoes not only enzymatic oxidation to form DOPAC but also spontaneous oxidation to form 5-S-cysteinyl-dopamine (Cys-DOPA).

DHPG is a metabolite of norepinephrine.
Norepinephrine is more commonly known as noradrenalin in the UK, it is a catecholamine. It mobilises the body for action, and is increased at times of stress.

In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the rest of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility.

norepinephrine acts on target cells by binding to and activating adrenergic receptors located on the cell surface.

Lower levels of these catecholamines are a key part of the exertion preference story:

The catecholamine nuclei release lower levels of catechols, which impacts the autonomic nervous system leading to decreased heart rate variability and decreased baroreflex cardiovascular function, with downstream effects on cardiopulmonary capacity. Concomitant alteration of hypothalamic function leads to decreased activation of the temporoparietal junction during motor tasks, leading to a failure of the integrative brain regions necessary to drive the motor cortex. This decreased brain activity is experienced as physical and psychological symptoms and impacts effort preferences, leading to decreased engagement of the motor system and decreases in maintaining force output during motor tasks. Both the autonomic and central motor dysfunction result in a reduction in physical activity. With time, the reduction in physical activity leads to muscular and cardiovascular deconditioning, and functional disability. These features make up the PI-ME/CFS phenotype.

So, yes, first, how strong is the evidence of lower levels in ME/CFS?

In cerebrospinal fluid, the PI-ME/CFS group had statistically significant decreased levels of DOPA, DOPAC, and DHPG (Fig. 6a–c). Levels of norepinephrine, cys-DOPA, and dopamine did not differ between the groups. These results did not change after excluding data from participants taking central-acting medications.

Figure 6a-c
21 healthy volunteers; 16 ME/CFS
The paper notes that some of the participants were taking central-acting medications, but it doesn't say if the charts and significance analysis exclude the data from these participants, and it does say that excluding them didn't change the results. It could be worth checking out the analysis using the source data.



DOPA - 6a
summary - most ME/CFS data points looked like healthy control data points. no good evidence of a problem
the p value of 0.02 indicates significance but not strong significance. Regardless of cohort, most of the values are in the range 550 to 800 pg/ml. There are a few outliers in both cohorts that are making most of the difference to the p value. Given that most of the ME/CFS results look like most of the HV results, it's hard to make a story of lower levels of DOPA being an important part of ME/CFS pathology. That's particularly true given the levels of dopamine and norepinephrine which are downstream of DOPA weren't different.

I found a reference suggesting that a low level of DOPA is less than 2.62 pmol/mL and that level increased the risk of developing Parkinsons. I think that makes for a value of 518.6 pg/mL. In that case, most of the participants with ME/CFS did not have abnormally low levels of DOPA, maybe 2 did. Obesity and stress are said to reduce DOPA levels - the ME/CFS cohort had higher BMIs. a larger proportion of people with BMIs >30.

DOPAC - 6b
summary - ME/CFS data points essentially fall within the range of healthy control data points. no good evidence of a problem
the p value of 0.02 indicates significance but not strong significance. The ME/CFS values are almost entirely within the range of the healthy controls. So, yes, the median is lower, but I don't think it's possible to make much of a story out of it. Also, DOPAC is a metabolite of dopamine, and dopamine levels were found to be normal.

I found a reference with a mean level of DOPAC in controls of 2.15 nmol/L. I make that 362 pg/mL, which is close to the median reported for the healthy controls. So, yes the ME/CFS results may be mostly on the low side of average, but not abnormally so.

DHPG - 6c
summary - ME/CFS data points essentially fall within the range of the healthy control data points, although on the low side. Interesting
the p value is a bit stronger for this molecule, but still, the ME/CFS data points fall pretty much within the range of the healthy controls. So, again, there's really no basis here for saying that lower levels of catechols are causing problems with cardiovascular function.

Again, the control's median here matches the mean value I found via google for healthy controls. So again, the ME/CFS results are on the low side of average, but there are plenty of healthy controls with similar levels. The upstream molecule, norepinephrine, was reported as being not different from controls.

I did however find a paper that reported levels of DHPG associated with what they called synucleinopathies - Parkinsons, multiple system atrophy and pure autonomic failure (the latter features prominent orthostatic hypotension from sympathetic noradrenergic denervation). Mean levels (as I calculate them from the nmol/L in that paper) were 1615, 1419 and 1065 pg/mL respectively. There is a group of ME/CFS participants with values in that low range - could they be misdiagnosed? The people in that synucleinopathies paper were on a whole range of medication which might have affected results.

My conclusion
So.. I think the findings are interesting and it would be good to find out more about the molecules, and diseases where the molecules are low. I think it's a stretch to say low levels of these molecules are a problem in ME/CFS when there is so much overlap with the healthy controls. It would be very nice to have these investigations replicated in larger cohorts with better matched controls, as well as in people who have had ME/CFS for longer or who have more severe disease.

It would also be good to check the technique used to determine the molecule levels. Edit - I'd like to know if the data was analysed in batches - there look to be two separate groups in each of the DHPG cohorts, maybe corresponding to some variation in technique?

It would also be good to know how the levels of the various catechol molecules related to each other in individuals. e.g. were there people with reliably low levels of a number of molecules, perhaps identifiable in a PCA?

 

[butter.]

Yes, me too. Except that the 2 day CPET differences in ME/CFS are still not entirely beyond question - a replication in a very well conducted, adequately sized NIH investigation would have been extremely helpful.


DOPA, DOPAC and DPHG
Re Evergreen's query above:



L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine(adrenaline), which are collectively known as catecholamines.
In the neuronal cytoplasm dopamine undergoes not only enzymatic oxidation to form DOPAC but also spontaneous oxidation to form 5-S-cysteinyl-dopamine (Cys-DOPA).

DHPG is a metabolite of norepinephrine.
Norepinephrine is more commonly known as noradrenalin in the UK, it's is a catecholamine. It mobilises the body for action, and is increased at times of stress.


Lower levels of these catecholamines are a key part of the exertion preference story:


So, yes, first, how strong is the evidence of lower levels in ME/CFS?


Figure 6a-c
21 healthy volunteers; 16 ME/CFS
The paper notes that some of the participants were taking central-acting medications, but it doesn't say if the charts and significance analysis exclude the data from these participants, and it does say that excluding them didn't change the results. It could be worth checking out the analysis using the source data.

View attachment 21174

DOPA - 6a
summary - most ME/CFS data points looked like healthy control data points. no good evidence of a problem
the p value of 0.02 indicates significance but not strong significance. Regardless of cohort, most of the values are in the range 550 to 800 pg/ml. There are a few outliers in both cohorts that are making most of the difference to the p value. Given that most of the ME/CFS results look like most of the HV results, it's hard to make a story of lower levels of DOPA being an important part of ME/CFS pathology. That's particularly true given the levels of dopamine and norepinephrine which are downstream of DOPA weren't different.

I found a reference suggesting that a low level of DOPA is less than 2.62 pmol/mL and that level increased the risk of developing Parkinsons. I think that makes for a value of 518.6 pg/mL. In that case, most of the participants with ME/CFS did not have abnormally low levels of DOPA, maybe 2 did. Obesity and stress are said to reduce DOPA levels - the ME/CFS cohort had higher BMIs.

DOPAC - 6b
summary - ME/CFS data points essentially fall within the range of healthy control data points. no good evidence of a problem
the p value of 0.02 indicates significance but not strong significance. The ME/CFS values are almost entirely within the range of the healthy controls. So, yes, the median is lower, but I don't think it's possible to make much of a story out of it. Also, DOPAC is a metabolite of dopamine, and dopamine levels were found to be normal.

I found a reference with a mean level of DOPAC in controls of 2.15 nmol/L. I make that 362 pg/mL, which is close to the median reported for the healthy controls. So, yes the ME/CFS results may be mostly on the low side of average, but not abnormally so.

DHPG - 6c
summary - ME/CFS data points essentially fall within the range of the healthy control data points, although on the low side. Interesting
the p value is a bit stronger for this molecule, but still, the ME/CFS data points fall pretty much within the range of the healthy controls. So, again, there's really no basis here for saying that lower levels of catechols are causing problems with cardiovascular function.

Again, the control's median here matches the mean value I found for healthy controls. So again, the ME/CFS results are on the low side of average, but there are plenty of healthy controls with similar levels. The upstream molecule, norepinephrine, was reported as being not different from controls.

I did however find a paper that reported levels of DHPG associated with what they called synucleinopathies - Parkinsons, multiple system atrophy and pure autonomic failure (the latter features prominent orthostatic hypotension from sympathetic noradrenergic denervation). Mean levels (as I calculate them from the nmol/L in that paper) were 1615, 1419 and 1065 pg/mL respectively. There is a group of ME/CFS participants with values in that low range - could they be misdiagnosed? The people in that synucleinopathies paper were on a whole range of medication which might have affected results.

My conclusion
So.. I think the findings are interesting and it would be good to find out more about the molecules and diseases where the molecules are low. I think it's a stretch to say low levels of these molecules are a problem in ME/CFS when there is so much overlap with the healthy controls. It would be very nice to have these investigations replicated in larger cohorts with better matched controls, as well as in people who have had ME/CFS for longer or who have more severe disease. It would also be good to check the technique used to determine the molecule levels.

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.

 

[Eddie]

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.

 

[Hutan]

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

There doesn't seem to be any analysis of that. It's possible that there isn't a sufficiently wide or reliable difference in severity among the ME/CFS participants to find significant relationships with levels of molecules.

 

[dave30th]

Yeah. The paper's quotes are —

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

 

[butter.]

There doesn't seem to be any analysis of that. It's possible that there isn't a sufficiently wide or reliable difference in severity among the ME/CFS participants to find significant relationships with levels of molecules.

Thank you!

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

 

[Sean]

Yes, me too. Except that the 2 day CPET differences in ME/CFS are still not entirely beyond question - a replication in a very well conducted, adequately sized NIH investigation would have been extremely helpful.

No argument there.

 

[SNT Gatchaman]

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

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).

Compared to HVs, PI-ME/CFS participants failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass.

The groups did not differ in composition by wholebody dual energy X-ray absorptiometry or in slow-to-fast muscle fiber atrophy as measured by Type 2: Type 1 muscle fiber median Feret diameter ratio (Type2:1 mFd) using ATPase pH 9.4 stain of the vastus lateralis.

(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.")

Six slides of frozen sections were taken to Johns Hopkins University, Neurology department, Neuromuscular Laboratory for ATPase pH 9.4 stain, which can identify Type II muscle fibers.

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 —

a relative decrease in the slope of the Dimitrov index 17,18(Fig. 4b) occurred inPI-ME/CFS participants but both remained constant in HVs, suggesting that the decline of force was not due to peripheral fatigue or a neuromuscular disorder.

But it's due to deconditioning —

At maximal performance, a substantial group difference in cardiorespiratory capacity became apparent, which was related to both chronotropic incompetence and physical deconditioning.

With time, the reduction in physical activity leads to muscular and cardiovascular deconditioning, and functional disability. All these features make up the PI-ME/CFS phenotype.

Concluding

Physical deconditioning over time is an important consequence.

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

 

[Sid]

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.