What research do you want to see? (study ideas)

I see that point.
But I think there’s a counterpoint in that society and medicine does not take PEM seriously at all, or even really believe it exists. And pwME are constantly forced into PEM through interacting with these two systems.

If we’re gonna have people in PEM we may aswell advance the research on it, in order for society to eventually take it seriously. Valudating/invalidating diagnostic criteria will have an enormous long term benefit until there is a reliable (non-CPET) biomarker.

Obviously though informed consent is an absolute **must**. And I like Trish’s version of the study too.
 
Yann04 said:
Valudating/invalidating diagnostic criteria will have an enormous long term benefit until there is a reliable (non-CPET) biomarker.
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But CPET is neither validated nor a biomarker. That's part of the problem.

People giving detailed accounts of the symptoms they experience in PEM is as reliable as anything we have, and we don't need to expose them to the risks of CPET to provoke those symptoms.
 
Yann04 said:
I see that point.
But I think there’s a counterpoint in that society and medicine does not take PEM seriously at all, or even really believe it exists. And pwME are constantly forced into PEM through interacting with these two systems.

If we’re gonna have people in PEM we may aswell advance the research on it, in order for society to eventually take it seriously. Valudating/invalidating diagnostic criteria will have an enormous long term benefit until there is a reliable (non-CPET) biomarker.

Obviously though informed consent is an absolute **must**. And I like Trish’s version of the study too.
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I agree.

The question to me however is whether more 2-day CPET studies will really lead us to understanding anything about more pathology. Because several 2-day CPET studies have been published, thousands of patients have gone through the procedure and Workwell has data on several hundreds of patients (that for whatever reason they don't publish). So I sceptical whether there'll ever be an "aha moment" from these studies. Society/medicine doesn't take ME/CFS any more serious after those studies have been published. An argument can be made that one needs more "response to exertion" studies, for example the one by Rob Wüst.
 
RCT of Low Dose Apiprazole. Small cohort of severe people.

Follow patient made protocol. Titrate from 0.1mg - a couple mg as tolerated. Don’t increase activity levels for first 6 months.

Long trial, 1.5+ years, to measure “poop out” effect some describe.

Primary outcome measure = Fitbit activity data + FUNCAP
 
Wouldn't it make more sense for all 2-day CPET research to be done 48 hours apart instead of 24?

Correct me if I'm wrong, but most people's PEM lasts at least a few days. And while some will already be experiencing PEM after 24 hours, for many others, it's closer to 48. Doing the second test at 48 hours would ensure that most people's PEM is high without being so long that many are recovered.
 
For me average peak PEM is probably around 24 hours, ± a few hours. But can certainly go longer if severe.

How much of that is decades of learning to identify and manage it, and avoid the worst of it, is another question.

I would expect it to be much more variable (and hence more difficult to discern) for the more inexperienced patient still in the steep part of that learning curve.
 
A combined lower dose Aripiprazole and lower dose Naltrexone trial.

Gradual titration up but to patient tolerated maximum to allow for sensitivity especially in severe patients. Eg I only tolerate 1.7mg of ldn and 0.65mg of lda way below the prevailing wisdom. I think alot of people don't succeed because they are started on or forced up to too high a dose for their phenotype .

Also a big, focussed biomarker program that collates all the possible candidates from studies (I've seen so many studies mentioning things), triages them and takes the most viable ones through to validation into a diagnostic or diagnostic set to take to the NHS. This would sooo take the wind out from under the BPS argument's sails.
 
Ideas arising from a recent van Campen study:
  • undertake analysis of cerebral brain flow (CBF) and cardiac output (CO) upon orthostatic challenge in all ME/CFS patients, not just those reporting orthostatic symptoms and not just those with a normal HR and BP response to tilt testing.
  • compare CBF and CO measurements on good and bad days
  • investigations into the mechanisms of the CBF and CO reductions
  • investigations of possible treatments, including compression garments and drugs with a plausible mechanism
  • validate the CBF measurement technique of extracranial Doppler flow
  • replicate the study using different methods of measurement of CBF
  • more studies on non-cerebral blood flow in relation to orthostatic stress and good day/bad day comparisons e.g. is there blood pooling?
  • differences in ME/CFS severity in males and females
Thread here:cerebral blood flow relation is abnormal in most ME/CFS patients with a normal heart rate and blood pressure response, 2024, van Campen et al
 
I'd like to see a study on energy expenditure in ME/CFS or long COVID vs healthy controls, larger than the NIH deep phenotyping study, possibly before and after exercise.

The differences weren't statistically significant, but it was a bit higher in ME/CFS, at least after the CPET. All days when normalized for body weight, and it seems there might be a trend of the difference increasing in the days following a CPET.

forestglip said:
I was curious about energy expenditure after looking at my own food tracking over the past six months, which shows I ate an average of 2,950 calories per day, yet have gained at most, maybe five pounds, if any. There's a chance the recorded intake is a bit higher than reality, as I was eating beef from the farmer's market often, and I probably guessed too high for the fat content. But at most it'd be about 150 calories too high per day.

So I'm wondering if my body is burning tons of energy for some reason, even though I'm mostly sedentary. Average 2,800 steps per day over the past month. I think a typical energy expenditure for someone my size and age and activity is around 2,250, according to a calculator on Mayo Clinic's website. 2850 for "very active" which is quite far from my activity level.

Looking at the data from the study, it doesn't look like that's a universal thing, if my own recorded calorie count is even accurate for me. The average intake seems to be similar for both groups. There are some outliers both high and low, but their body weights are also pretty high and low, respectively, compared to most of the other participants.
View attachment 23038
Definition of the metric: "total energy expenditure in kcals/day from the full whole room indirect calorimeter measurement on the Baseline chamber night". So that was before the CPET.

Looks like it's maybe trending up in the three days after the CPET:
View attachment 23039 View attachment 23040 View attachment 23041

Largest difference seems to be during sleep on the third day after CPET:
View attachment 23044

The study says no differences found, although a p-value of 0.07 for that last sleep measurement.


S12:
View attachment 23042

Fig S9A-D:
View attachment 23043


I might try to see what the data looks like if the energy expenditure is normalized to body weight.
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forestglip said:
Difference might be a little more visually apparent if normalizing based on fat free mass (order is baseline total, baseline sleep, day 1 total, day 1 sleep, day 2 total, day 2 sleep, day 3 total, day 3 sleep)

View attachment 23056 View attachment 23057 View attachment 23058 View attachment 23059 View attachment 23060 View attachment 23061 View attachment 23062 View attachment 23063

Here's the fat free mass for each group:
View attachment 23068
(Edit: I accidentally posted the wrong mass chart at first.)

I did notice the study's figure in the post above has one feature that is statistically significant for the metabolic chamber study, respiratory quotient on the 3rd day (p=0.01). (MECFS: 0.87 +- 0.04, HV: 0.89 +- 0.01)
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Could it be that people with ME/CFS are so tired because the body is burning as much fuel as possible on some internal body process, like fighting pathogens, and there's none left over for normal life?

I tried searching for other metabolic chamber or energy expenditure studies on ME/CFS or long COVID, or even any disorder involving chronic fatigue, but couldn't find anything relevant other than the NIH study, which only had 21 people on the first day and 17 on the following days.

Edit: Oh, I found one:
Increased Resting Energy Expenditure in the Chronic Fatigue Syndrome, Watson, 2011
It has been suggested that resting energy expenditure may be raised in chronic fatigue syndrome due to an upregulation of transmembrane ion transport. We measured resting energy expenditure by indirect calorimetry in 11 women with chronic fatigue and in 11 healthy women. Total body potassium, by whole body counting, and total body water, extracellular water and intracellular water, by a bioelectrical impedance method, were also measured.

When individual resting energy expenditure was predicted on the basis of total body potassium values for the chronic fatigue group, 5 out of 11 of these subjects had resting energy expenditure above the upper limit of normal as defined by the control group data. This is consistent with the hypothesis that there is upregulation of the sodium-potassium pump in chronic fatigue syndrome.
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Preprint Medrix: Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in ME/CFS - Helliwell, Tate et al -2022
I'm not sure if we have mentioned epigenetic studies on this thread yet, although I think we have seen other published epigenetic studies. This linked one is very small, just two female patients and one female control. But the design is longitudinal, looking at epigenetic expression during a bad health period and a good health period, with each individual serving as their control.

There's lots of scope to replicate this in larger cohorts, with variations on the theme e.g.:
  • different tissues/fluids/specific cell types
  • male cohort
  • pre and post exertion; PEM and not PEM
  • controls could be required to restrict their activity levels to be approximately the same as the ME/CFS participants; all participants could follow a similar diet for a month prior
  • different levels of ME/CFS severity
 
Hutan said:
Preprint Medrix: Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in ME/CFS - Helliwell, Tate et al -2022
I'm not sure if we have mentioned epigenetic studies on this thread yet, although I think we have seen other published epigenetic studies. This linked one is very small, just two female patients and one female control. But the design is longitudinal, looking at epigenetic expression during a bad health period and a good health period, with each individual serving as their control.

There's lots of scope to replicate this in larger cohorts, with variations on the theme e.g.:
  • different tissues/fluids/specific cell types
  • male cohort
  • pre and post exertion; PEM and not PEM
  • controls could be required to restrict their activity levels to be approximately the same as the ME/CFS participants; all participants could follow a similar diet for a month prior
  • different levels of ME/CFS severity
Click to expand...
This sounds like an interesting approach. Would it mean that rather than just PEM it’s possible to see if there are differences when someone is on the way down / it feels like a deterioration is ‘active’

I don’t know enough about what epigenetics can cover to imagine what it could pick up and how careful the method can be to this but I think the more longitudinal the better, and of course it needs to be within patients rather than just between in order to see pattern of what is going on.

it’s not like we aren’t forced over threshold all the time anyway in daily life so as useful as / an important approach to add rather than the focus on an arbitrary objective ‘amount’ to trigger a ‘reaction’ eg from cpet when I think most of us can feel there is also a cumulative element
 
For the proposed study by @Hutan above I would also find it sensible to have one group of ME/CFS patients that has reported a variable status of ill health, i.e. better periods followed by worse periods etc, vs one group of ME/CFS patients who has reported no change in health, i.e. a rather constant period of ill health. I think that could be helpful in understanding whether one is actually measuring what one thinks one is measuring.

Hutan said:
  • controls could be required to restrict their activity levels to be approximately the same as the ME/CFS participants; all participants could follow a similar diet for a month prior
  • different levels of ME/CFS severity
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I wonder if that isn't sort of a contradiction itself?

I think it may be very hard or even impossible to recruit healthy controls that reduce their activity levels to that of a severe or very severe person. I know Rob Wüst has done studies on bedbound healthy controls but that was for a couple of weeks, rather than several months.

I wonder if maybe there isn't even larger problem here, which makes means that controlling for activity between pwME/CFS and HCs in previous studies could have been skewed with the reason simply being we have no metric to control for such activity.

Some studies use average step count, but even when 2 people have the same average step count the one person might have paced whilst the other one wouldn't have which could impact muscle composition etc. For someone who struggles with OI, step count might not be an adequate metric in the first place, with hours of being upright being potentially more crucial and so on.

I wonder if it is sensible to first study, how should one control for activity in different ME/CFS study setups (arguably a microbiome study will have to control for different factors than a skeletal muscle study or a metobolimics study) to be able to set some minimally required standard in the field.
 
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EndME said:
I wonder if that isn't sort of a contradiction itself?

I think it may be very hard or even impossible to recruit healthy controls that reduce their activity levels to that of a severe or very severe person. I know Rob Wüst has done studies on bedbound healthy controls but that was for a couple of weeks, rather than several months.
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My list of possibilities wasn't meant to all happen in one study. For a study where activity was kept within a range, you would probably want to have patients with mild severity.

For sure, it's not possible to make everything the same, but an attempt to reduce the amount of noise could be help find something interesting.
 
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