Open UK - Recruiting: Novel Dynamic Proteomics Approaches to Investigate the Systems Level Pathology of ME/CFS

Exercise stress tests aren’t for the mild or moderate, either. It was one of those that gave me my first proper experience of PEM crashing. I’d only really noticed mild energy depletion before that. Really not sure this is a great idea.

 

Two muscle biopsies is tough. Obtaining a sample worth analysing is a pretty invasive procedure. The scars are likely to be permanent.

I would like some sort of reassurance that this is more than just blind hope that something will turn up.

 

From the Patient Information Sheet page 3, Screening Visit:

From page 5, Exercise Stress Test and Assessment Visit 2:

 

"Your ratings of perceived exertion and leg muscle pain will be monitored every 5mins. " does not sound relative to their stated investigation. personal perception is a bps kind of nonscience .

 

Also, how realistic is it that pwME could maintain their heart rate at 70% of the expected age matched heart rate for as long as 25 minutes?

I think it could be interesting to compare perception and objective measures, but if they don't have other objective measures than heart rate that doesn't seem a valuable approach to me.

I see they have another focus, but I don't understand, if they do exercise testing, why they don't take into account the 2 days CPET research?

Edit: I find it strange that on the one hand, they refer to the CCC and PEM and offer accommodations like breaks, but on the other hand think they need 25 minutes high intensity heart rate is needed to provoke PEM.

Edited for clarity and to delete redundant sentence.

 

So, if there’s a strong consensus on this board that recruiting pwME into exercise stress tests is a Very Bad Idea, what the blazes is the ME Association doing promoting it with a “come to sunny Nottingham!” puff piece?

I don’t know much about the ME Association, but several of their communications choices in the last couple of months seem very poor. Mad scientists will always do mad things, but I’d expect better of a reasonably-resourced patient organisation.

 

Though welcoming more biomedical research I echo others’ concerns.

Even, if ignoring the risks of significant PEM and the likelihood that abnormalities in an exercise test only show in activity undertaken on a second day in such as the two day CPET test, it is also necessary to know the total activity levels undertaken around any exercise based provocation, but in the information so far available there is no mention of use of electronic activity monitoring during the research period.

 

Rate of perceived exertion (RPE) is one of the measures used in a CPET. It's part of how they assess if it was truly 'maximal' effort. That in itself isn't problematic if it's just part of a range of measures used.

A bigger problem will be the exercise and travel required for the study, and the two biopsies. It seems like only the mildest patients could take part!

 

I never had a muscle biopsy but since having ME I had severe 'Postoperational Malaise' for several months after every minor operation. I think it was sometimes even worse as an outpatient than as an inpatient, so without pwME-sufficient time to rest immediately before and afterwards in a proper bed.

Also, I had three lumbar punctures because of a suspected other (treatable) condition, and while I needed some weeks to recover from the first when my ME was still 'mild', the other two procedures left me not only bed-bound for weeks but with a permanent deterioration.

 

I had a muscle biopsy, and to be honest i would submit to another one just to find out if the results are changed in microscopy and respiratory chain findings.

The scar is minimal, barely visible after all the years. I remember though that it was painful to walk for a few days after the procedure. I had some kind of spasm. The tissue was sampled on my upper thigh.

Of course the procedure is not without risk, infection being one of the major risk.

Between a muscle biopsy, a spinal tap and the CPET, the one that is sure to make us crash is the CPET; the other 2 will depend on the amount of travelling and exertion compared to what the patient’s threshold is. There are risks for all, and i am glad that the researchers are up front about it.

 

Not sure that if they are recruiting people who actually have ME anyone would be able to actually complete it either. I hope that their criteria for entry are including PEM and very rigid, otherwise this is basically a way of filtering out people with ME.

Unless it was one of the psychology experiment type things where they hide the agenda, and they are actually only going to look at those who don't complete it so really are using it as a filter to make sure people have ME. I'd add laughy face emoticons because of the ridiculousness, but it isn't really very funny when you consider all the past research mostly doing the opposite.

Even those who think they understand ME on paper, don't get its brutality - in fact even those with it don't and try and fight it hence the issue of never finding your baseline except by breaking it (which often gives you a new lower baseline).

I think the fact they've specified it will be at 70% HR sounds to me like they think that will keep it 'safe' because I've heard that advice in gyms before now. Sadly they don't realise that isn't quite how ME works. Although it will be interesting to see how the actual HR level goes over that space of time and what that translates to regarding exertion to keep it there. I don't fully know how the HR will react over time if you keep on going and how you can adjust exercise to keep it at 70% without allowing breaks over the space of 25min in someone with ME. Is that likely to be one of the issues of the illness, my brain is trying to compute integration of the various things I know because noone would normally try or measure this bit.

What is the Workwell Methodology for finding thresholds - does this exceed past that point for most? ie do they/can they provide data on something comparable to this test and when the majority of their participants would cark out into creating PEM? Would they really not be better science-wise measuring 'how far past that individually' based on physiological measures, rather than using objective distance or time measures across persons if they are trying to - I assume - see what happens as muscles and body and systems become more and more over-exerted?

Are they confusing objective with 'arbitrary' re: measures? This will always be one of the primary debates if proper scientific research is being done using exertion or anything else stressing the body in ME. Being able to see what 'stage' being are in re: their baseline/PEM (inc ensuring that people are rested after journey to get there if comparing across people and wanting to assume they are all in the same stage). Otherwise it is like thinking you are measuring physiological responses for people running 800m, except some turn up having done 1500m before they get there.

 

Which will skew their perception even further. They've clearly underestimated how brutal ME is given their conception that 25mins at 70%HR is suitable. Then use completion of that as a boundary for acceptance into the study. I'm rather worried we have another 'drop-outs not being presented in the data' issue here. And the fact that there is no follow-up of the PEM in the days after they've done all of this will misguide them further into not realising what they are asking people to do potentially.

Why did they not design the experiment to fit the condition, rather than try and skew the sample to fit the methodology they have chosen?

 

I think we need to know there will be some independent oversight of the medical impact for those participating. So that anyone who experiences significant issues short-term, medium-term, long-term isn't disappearing - it is a matter of ethics that is documented and treated by someone not involved with the study or conflicted.

There are alos implications for this needing to be oversighted because if these things become 'ideas' for future studies then we need to be logging the adverse effecs and how serious they are. My suspicion is that currently these will only be using 'normal person' data for these procedures. Part of the data that goes alongside the outcomes for this, if people really are risking their health doing this, is detailed documentation of the effects of each of these.

I also don't know how you can separate the impacts of each of these on someone's ME/health from whatever they think that they are measuring. It shows distinct misunderstanding of the condition that you put people through procedures that cause relapses, exercise that causes relapses and think that you are measuring anything constant if you are not studying these events and impacts to 'control for' them in your results?

 

At a guess, two reasons.

One, a repeat CPET wouldn't add anything significant to this particular study. The purpose of the 2-day CPET is to measure the impact of day 1 on performance on day 2. This study doesn't concern itself with exercise performance, they just need a stressor to induce PEM once so they can get their proteomics samples while the pwME is in a state of PEM.

Two, they're asking an awful lot of participants as it is so don't want to add unnecessary burden and risk.

A lot of the other comments here raise concerns about the risk of cycling for 25mins. Looking at the protocol I think they're quite aware of this and are looking for people who are not too severely affected for this reason.

When my ME was very mild I could easily cycle 25mins without PEM, my threshold was pretty high then. Good for me, not so useful for research.

I also had a period of several years when 25mins cycling would have cost 2 or 3 days of relatively mild PEM without any deterioration of the underlying ME. Would have been ideal for this sort of research but may be difficult to recruit enough people in this 'sweet spot'.

This all raises the question, again, what type and level of stressors are acceptable in research? We need studies that look at us when we have PEM. How do we achieve this with the least risk?

Also wondering, is a fixed stressor for everyone, like the 25mins at 70%HR, sensible in ME? It's clearly an attempt to control as many variables as possible but does this work in ME? If one person exceeds their PEM threshold at 10 mins and ends up with severe PEM and another person exceeds theirs only after 20 mins and only gets mild PEM, what effect does this have on the resulting data?

What alternative stressors do we have that reliably induce mild PEM? There was Moreau's arm cuff, does anyone know if this is being developed further? Any other methods?

Maybe we should have longitudinal studies where patients message whenever they think they've overdone it in the course of their normal life and PEM is likely to follow and the researchers rush off to collect samples at the patients' homes. Can't see that happening any time soon.

 

So I assume the controls are going to have to go through all the exercise and the biological sampling also, because who knows what that stress does to protein levels even when you're healthy.

Those will have to be pretty dedicated controls to sign up for two muscle biopsies a week apart as well as two spinal taps a week apart.

I forget if I was given a local anesthetic when I had my one lumbar puncture. I do remember feeling like my lower back had been hit by a baseball bat, though.


[ETA: The sensation of being struck was only present during the procedure. It went away when the needle was removed.]