Upper Airway Resistance Syndrome (UARS): a common underlying cause for all "chronic complex illnesses"? (ME/CFS, fibro, GWI, etc.)

[nataliezzz]

Thanks, I get the picture @nataliezzz.

There is no harm in airing your thoughts here because we are well versed in critical scientific thinking

Also, one more thing @Jonathan Edwards, since the evidence for UARS is so flimsy and weak, maybe you can ask @ME/CFS Skeptic to do one of his epic takedowns of it so everyone can see just how flimsy and weak the evidence is. That way anyone coming to this thread later on who may actually find this information compelling will be able to see what a "nonsense quack theory" it is. @ME/CFS Skeptic surely you would agree to that, right? If there really is nothing to see here, I suspect you could do a good job actually explaining why.

 

[ME/CFS Skeptic]

I already have a list of topics I would like to analyze and write about and not enough energy to do them all, unfortunately.

 

[EndME]

Hi @nataliezzz I have not had the time to go through everything that is written here, but I had a look at the study you shared as you mentioned it several times: https://link.springer.com/article/10.1007/s11325-010-0386-8.

It would appear the protocol was never preregistered anywhere, at least it is not mentioned in the paper as far as I can tell, can you confirm this? If that is the case do you know more about the recruitment process (which typically might bias the study itself, people with sleep problems are more likely to enrol in a sleep related study without that necessarily having anything to do with GWI etc).

There is an additional risk of bias in this study that is of concern and for me it's hard to think of a reason any serious researcher would engage in such a practice: The data from the GWI group was analysed unblindely by the people running the study before recruitment of the control group was even completed (and certainly not analysed). This to me appears to be an extremely serious concern for risk of bias (especially with there being seemingly no prespecified protocol and/or outcome measures), do you see any reason why one should approach a study in such a fashion (the later blinded analysis that was performed wouldn't counter the bias already introduced)? I think most people would stop reading the study now, maybe that's why the work has received any attention.

According to Table 1 pwGWI are essentially more ill than HC's (as one would suspect), however according to Table 2 the authors found no meaningful differences in sleep patterns between the groups that would pass a strongly adjusting multiplicity test (the p-values mentioned are all non-adjusted, so it's impossible to say what's just a chance findinging especially with there being no prespecified protocol). No relationship between GWI symptoms and any sleep patterns is analysed. You mentioned to have a look at the p-values but none of those are adjusted. The only p-value worth mentioning is that of "Arousals/hour". It wouldn't pass a strongly adjusted test but could pass a weaker one, but given that there is no prespecified protocol even that isn't clear.

Table 3 suggests a group association between limited flow and GWI status of the 2 groups. That in turn means that the authors provide no evidence that limited flow impacts any of the other parameters, nor any evidence to suggest it impacts symptoms of GWI, do you agree with this?

So to sum up the findings: There’s a handful of negative findings and one association between GWI status and limited flow (without any way of knowing how many things had been tested for). Unfortunately, there isn't a more sophisticated analysis of this data. This is very unfortunate as the authors claim a relationship between arousals and apneas, hypopneas, and mild inspiratory airflow limitation but provide 0 evidence for such a relationship as they didn’t even analyse whether there is any relationship it all, which makes the claim rather dubious itself (especially when arousals doesn’t pass an adjusted test). If anything a first and naive look at the data would suggest that there is no relationship (all pwGWI have limited flow and healthy controls don't but they look fairly similar in terms of arousals at least from the very limited data the authors provide with several HCs having the same amount of arousals as pwGWI).

I'm trying to understand how you claim causality from this especially since the authors themselves mention “However, a difference in sleep-disordered breathing between groups does not establish that sleep-disordered breathing contributes to the symptoms of GWI. Moreover, even if sleep-disordered breathing does contribute to the symptoms of GWI, our comparing a group with three symptoms to a control with no symptoms does not allow us to determine which of the symptoms of GWI are related to sleep-disordered breathing”. Surely you didn’t confuse correlation with causation, so could you please help me understand your thought process?

Measuring limited flow in GWI would be a fairly simply easy and cheap process. Have there been any other such findings in GWI?

 

[EndME]

I've had a very quick gimpse of the treatment study which is a follow-up study of the above study using the same GWI patients.

I couldn't find any information on how randomization occured, do you know anything on this (I'm asking as the groups don't appear to be evenly matched w.r.t. to perceived physical health)? Secondly, the authors seem to provide no evidence that the sham actually served it's purpose and that partcipants couldn't differentiate between sham and treatment, is that correct (compare that for example Fluge and Mella's RTX trials where the authors provide data that tells us that the patients couldn't differentiate between drug and placebo)? That unfortunately is quite standard in treatment trials so can't be specifically scrutinised here.

I've tried to quickly glimpse over the data but it seems the measure from the previous study that was different between the 2 groups (limited flow and perhaps even arousals) isn't analysed as it was in the first study. That is we don't know whether limited flow as measured in the first study, improves with the treatment and whether that correlated with symptoms. Is that correct?

 

[Trish]

Hi @nataliezzz. I see you have edited the opening post to provide a large amount of text and links to research papers and to your social media threads.

Just working through all that would take me several months of concentrated effort. I don't have the capacity to do that, but would like to understand the logic and evidence base for your hypothesis.

Would it be possible to write a short summary with headings that shows the logical pathway that leads from UARS to ME/CFS, indicating the type and strength of evidence for each step in the pathway, and where you are making assumptions, and without any links or screenshots? A sort of intelligent lay person's summary?

 

[Utsikt]

Yeah, it's kind of funny. @Jonathan Edwards was basically making the argument above that fibromyalgia is a nebulous concept because it's just based on subjective symptoms.

JE has already answered on his behalf, but I echo what he says. I have never said the issue is that all of the symptoms are subjective per se. I have the issue is the combination of objective symptoms, that are very loose, and very loosely applied by clinicians.

So let's presume that UARS is not directly causing low BP. I'm curious if you can think of any correlational factor that could account for 93/400 UARS patients having low BP? This factor would also need to correlate with having an abnormally small oral cavity (based on objective measurements) since 400/400 randomly selected people would not have an abnormally small oral cavity.

You’ve got it backwards. You’re the one making claims, the burden of proof is on you to demonstrate the observed measurements can’t be explained by anything other than the mechanisms you propose. If you can’t do that, you can’t claim causation.

And I don’t understand your request for a «correlating factor» - that is simply a statistical measure that quantifies the strength and direction of a linear relationship between two variables. It does not say anything about the causal relationship between the variables.

Are you asking for an alternative explanation for why there is a degree of correlation between the data? If so, I refer to the paragraph above about where the burden of proof lies.

 

[Sasha]

And I don’t understand your request for a «correlating factor» -

'Confounding factor', possibly?

 

[Utsikt]

'Confounding factor', possibly?

Thank you, that’s the term - it’s what I mean by «alternative explanation». There could be one or many of those, I don’t know. But the burden of proof lies with the one making claims about causation. It doesn’t matter that I don’t know what else might explain the relationship between the variables, what matters is that they can’t demonstrate that there are no alternative explanations based on the evidence they have.

 

[nataliezzz]

Hi @nataliezzz I have not had the time to go through everything that is written here, but I had a look at the study you shared as you mentioned it several times: https://link.springer.com/article/10.1007/s11325-010-0386-8.

It would appear the protocol was never preregistered anywhere, at least it is not mentioned in the paper as far as I can tell, can you confirm this? If that is the case do you know more about the recruitment process (which typically might bias the study itself, people with sleep problems are more likely to enrol in a sleep related study without that necessarily having anything to do with GWI etc).

There is an additional risk of bias in this study that is of concern and for me it's hard to think of a reason any serious researcher would engage in such a practice: The data from the GWI group was analysed unblindely by the people running the study before recruitment of the control group was even completed (and certainly not analysed). This to me appears to be an extremely serious concern for risk of bias (especially with there being seemingly no prespecified protocol and/or outcome measures), do you see any reason why one should approach a study in such a fashion (the later blinded analysis that was performed wouldn't counter the bias already introduced)? I think most people would stop reading the study now, maybe that's why the work has received any attention.

According to Table 1 pwGWI are essentially more ill than HC's (as one would suspect), however according to Table 2 the authors found no meaningful differences in sleep patterns between the groups that would pass a strongly adjusting multiplicity test (the p-values mentioned are all non-adjusted, so it's impossible to say what's just a chance findinging especially with there being no prespecified protocol). No relationship between GWI symptoms and any sleep patterns is analysed. You mentioned to have a look at the p-values but none of those are adjusted. The only p-value worth mentioning is that of "Arousals/hour". It wouldn't pass a strongly adjusted test but could pass a weaker one, but given that there is no prespecified protocol even that isn't clear.

Table 3 suggests a group association between limited flow and GWI status of the 2 groups. That in turn means that the authors provide no evidence that limited flow impacts any of the other parameters, nor any evidence to suggest it impacts symptoms of GWI, do you agree with this?

Hi @EndME , thank you for actually taking a look at it and making some of these critiques, I appreciate that. I plan to go back and read it again in detail so I can respond to them. For right now, I am just going to try to convey why I think flow limitation is the relevant factor to focus on when discussing the strength of the evidence this paper (even though the authors did not provide a rationale for why it would be when they wrote it). If people want to have a productive discussion about this, they must try to develop an understanding of the stress response to inspiratory flow limitation (IFL) theory of sleep-disordered breathing (doesn't mean you have to agree with the theory, but you can't argue against a theory you haven't tried to understand), otherwise these discussions will go nowhere.

Sleep fragmentation by (apnea/hypopnea/RERA-related) arousals is not the primary cause of sleepiness/fatigue in sleep-disordered breathing patients, so there is no reason to focus on arousals as the relevant factor. It is well recognized that the majority of people with obstructive sleep apnea (OSA) - who have arousals related to apneas and hypopneas - are asymptomatic, so arousals simply can't be the primary cause of symptoms or everyone with OSA would be symptomatic. Healthy controls without OSA have plenty of arousals too.

The data from the first large population-based sleep studies (Sleep Heart Health Study, Wisconsin Sleep Cohort Study) show that snoring (which almost always = inspiratory flow limitation [IFL], though many people have IFL without audible snoring) is associated with sleepiness independent of OSA (apnea hypopnea index [AHI] ≥ 5) and that arousals are not the cause of snoring-related sleepiness (by the way, almost everyone with OSA snores, so which is more associated with sleepiness: OSA, or snoring?). There does seem to be a contribution to daytime sleepiness from AHI/arousals when you get into the severe OSA range (AHI >45), but it seems modest and perhaps only captured my multiple sleep latency testing and not self-report measures as many people with an AHI >45 report no significant daytime sleepiness/fatigue. I have summarized the evidence re: this in detail in this Bluesky thread below (sorry, but it would be impossible for me to convey it all here):



The authors of the GWI study did not understand the importance of IFL when they conducted this study (Dr. Gold just noticed "functional somatic syndrome" symptoms in many of his UARS patients, so he decided to investigate the presence of sleep-disordered breathing in "functional somatic syndrome" patients; he developed his theory about the stress response to IFL driving the sleepiness/fatigue and other symptoms in sleep-disordered breathing patients based on the finding of this study and others). So in order to consider the relevance of IFL, you need to take into account the evidence from these large population-based re: snoring (again, snoring almost always = IFL).

So to sum up the findings: There’s a handful of negative findings and one association between GWI status and limited flow (without any way of knowing how many things had been tested for). Unfortunately, there isn't a more sophisticated analysis of this data. This is very unfortunate as the authors claim a relationship between arousals and apneas, hypopneas, and mild inspiratory airflow limitation but provide 0 evidence for such a relationship as they didn’t even analyse whether there is any relationship it all, which makes the claim rather dubious itself (especially when arousals doesn’t pass an adjusted test).

I'm not sure what you mean by "the authors claim a relationship between arousals and apneas, hypopneas and mild inspiratory airflow limitation." A relationship to GWI? Like I said, yes, the data from this study indicate a relationship between IFL and GWI (we can simply ignore the apneas and hypopneas as they are largely irrelevant, as I have argued above).

If anything a first and naive look at the data would suggest that there is no relationship (all pwGWI have limited flow and healthy controls don't but they look fairly similar in terms of arousals at least from the very limited data the authors provide with several HCs having the same amount of arousals as pwGWI).

Yes, you can't just come at this with a "naive look at the data" (you are literally just writing off the finding of "all pwGI have limited flow and healthy controls don't" - which is the relevant finding here - as irrelevant); you have to take the time to develop an understanding of the larger theory for how IFL may be related to not only fatigue, sleepiness and cognitive dysfunction (all well established symptoms of both UARS/OSAS and disorders like GWI, ME/CFS, fibromyalgia), but also symptoms such as body pain and IBS associated with "chronic complex illnesses" (which if you read my full OP you will see there is supporting evidence for).

I'm trying to understand how you claim causality from this especially since the authors themselves mention “However, a difference in sleep-disordered breathing between groups does not establish that sleep-disordered breathing contributes to the symptoms of GWI. Moreover, even if sleep-disordered breathing does contribute to the symptoms of GWI, our comparing a group with three symptoms to a control with no symptoms does not allow us to determine which of the symptoms of GWI are related to sleep-disordered breathing”. Surely you didn’t confuse correlation with causation, so could you please help me understand your thought process?

The findings from the CPAP treatment study (which came after the study quoted above) are also relevant. 18 GWI patients had 96%±5 of their breaths flow limited while 11 age/BMI-matched asymptomatic Gulf War vets had 36±25% of their breaths flow limited (p = <.0001). According to Dr. Gold's theory, a stress response to IFL is the primary driver of symptoms such as fatigue, pain, cognitive dysfunction, insomnia, etc. in "chronic complex illness" patients, so according to this theory, we should see the symptoms of GWI improve with a treatment that ameliorates IFL. The GWI patients treated with CPAP (which was specifically titrated to eliminate IFL) experienced subjective improvements in the symptoms of GWI (fatigue, pain, cognitive dysfunction, etc.) which were highly and significantly correlated with changes in an objective finding (decreased sleep stage shifts) in all patients (GWI patients on sham CPAP did not experience decreased sleep stage shifts and got slightly worse).

I have provided a screenshot below with an explanation of why I believe it does not make sense to claim that UARS/OSAS is just a comorbidity worsening the symptoms of GWI (FSS = "functional somatic syndromes," "anxiety disorders" refers to research re: sleep-disordered breathing & PTSD), and in my OP I have a link to a thread explaining why people with "chronic complex illnesses" typically only experience partial symptom improvement rather than cure on CPAP (likely because CPAP also acts as a stressor).

Measuring limited flow in GWI would be a fairly simply easy and cheap process. Have there been any other such findings in GWI?

No (but if you see anything of value here once you have read through all of the information I shared [not just this one study], maybe you could help call for such a study!). Like I have repeatedly said in this thread, sleep medicine ignores the fact that the sleep fragmentation paradigm of sleep-disordered breathing literally makes no sense, with eminent sleep doctors like Naresh Punjabi claiming that "there is no need for experimental or even observational data on whether sleep fragmentation from recurrent arousals in sleep apnea causes daytime sleepiness." They do go on to make some weak arguments in that paper as I discuss here. Sleep medicine rejects the stress response to IFL paradigm without actually meaningfully engaging with the evidence (you can see an example of a doctor in this thread doing the exact same thing by the way), despite the fact that their own data from the first large population-based sleep studies showed that snoring - not sleep fragmentation by arousals - appears to be the primary driver of sleepiness in sleep-disordered breathing patients.

Thanks again for meaningfully engaging with me on it. I plan to take the time to look into the critiques of the GWI study you have raised, so I hope you will take some time to read through my OP and try to develop an understanding of the stress response paradigm of sleep-disordered breathing.

 

[Hoopoe]

@nataliezzz I think many patients here have been through the phase you're in right now. Patients without answers and solutions, often set out to find the answers and treatments themselves. They are highly motivated, willing to take risks, and looking for a solution. They fear the possibility of having to live without treatment and don't want to hear anything that diminishes their motivation and hopes and are also inexperienced. In this state, it's easy to convince yourself that you've found the answer. It's what everyone wants to hear in this situation. It's possible that you've found something that's relevant to your personal health situation but the way your posts come across is that you're seeking validation for these ideas. You want the validation to have that feeling of having found the answer. It's very difficult to remain objective in this situation and one can easily end up believing in ideas that don't really make sense and I think this is most likely the case here (although some of it may be relevant to your own personal combination of health issues).

 

[nataliezzz]

@nataliezzz I think many patients here have been through the phase you're in right now. Patients without answers and solutions, often set out to find the answers and treatments themselves. They are highly motivated, willing to take risks, and looking for a solution. They fear the possibility of having to live without treatment and don't want to hear anything that diminishes their motivation and hopes and are also inexperienced. In this state, it's easy to convince yourself that you've found the answer. It's what everyone wants to hear in this situation. It's possible that you've found something that's relevant to your personal health situation but the way your posts come across is that you're seeking validation for these ideas.

I'm not seeking validation, I am asking people to actually engage with theory and evidence (Jonathan Edwards openly admitted he wrote it off as a "nonsense quack theory" without reading any of the evidence, and @EndME wrote off the finding of "all pwGI have limited flow and healthy controls don't" - which is the relevant finding here - as irrelevant (I do appreciate @EndME making some real critiques of the study though, which I plan to respond to), but if people won't even attempt to understand the theory they won't be able to argue against it.

CPAP is an almost no-risk treatment. I'm just not going to buy arguments that encouraging people to pursue evaluation/potential treatment for UARS/OSAS is in some way unethical. Fatigue, unrefreshing sleep and cognitive dysfunction are all established symptoms of both UARS/OSAS and disorders like ME/CFS, fibromyalgia, & GWI, so even if UARS/OSAS is not causing these disorders (which is the evidence I am here to debate), there is nothing unethical or controversial about me encouraging people to get evaluated for UARS/OSAS; perhaps it's just a comorbidity for some people and they could experience improvement in symptoms and quality of life with an almost no-risk treatment (CPAP). Regardless, I haven't actually been telling people to pursue evaluation treatment for UARS/OSAS in my post/comments, I'm here to discuss the evidence (really discuss it!)

 

[EndME]

Hi @nataliezzz I will take some time to respond to your points at a later time point but wanted to quickly clarify some points that were seemingly misunderstood.

I'm not sure what you mean by "the authors claim a relationship between arousals and apneas, hypopneas and mild inspiratory airflow limitation." A relationship to GWI? Like I said, yes, the data from this study indicate a relationship between IFL and GWI (we can simply ignore the apneas and hypopneas as they are largely irrelevant, as I have argued above).

I mean exactly what the authors are saying for which they seemingly don't provide any evidence, the authors write "Compared to controls, veterans with GWI had an increased frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation". The authors have provided only negligible evidence that there is an increased level of arousals but have provided no evidence that arousals are related to apneas, hypopneas, and mild inspiratory airflow limitation because they didn't even analyse this (that's what my reference of unsophisticated analysis was refering to). Do we agree that the authors provide no evidence for their claims they are making here?

Yes, you can't just come at this with a "naive look at the data" (you are literally just writing off the finding of "all pwGI have limited flow and healthy controls don't" - which is the relevant finding here - as irrelevant)).

I didn't write of this finding as irrelevant, I'm not sure how you concluded that. It's simply a correlation, that's all I mentioned about it. As mentioned in my initial comment this correlation can be driven by an abundance of different factors. Relevance of a correlation typically comes from understanding the linear relationship of a correlation not from the strength or non-strength of a correlation (of course you can have a causal relationship between two variable witout any correlation being present), which is of course not part of the study. As you are aware you can find hundreds of studies, of a similar quality as the above study, finding a correlation between pwME/CFS some measurements, without this correlation being meaningful.

(doesn't mean you have to agree with the theory, but you can't argue against a theory you haven't tried to understand)

I wasn't arguing for or against a theory. I was just looking at the data you had pointed at as evidence for your theory.

What I find quite interesting is that you sensibly argue that arousal cannot be the cause of symptoms because plenty of people with arousals don't have symptoms and plenty of people without arousals do have symptoms. However, in the same general context we also know that plenty of people with IFL don't have symptoms whilst plenty of people with symptoms have no evidence of IFL. You can try resolving that by making a vague reference to HPA-Axis but I think people on S4ME will quickly see through that as there is an interest in specifics.

so we should see the symptoms of GWI improve with a treatment that ameliorates IFL

Which is why it is so contradictory, which as I mentioned in my second post, that seemingly no relationship between the originial IFL measures and symptom improvement are reported in the trial. That would be very easy to establish and if I thought it was the missing piece then that's what I would look to establish as evidence! You mention the reference to decreased sleep stage shifts but that is of course something different and as mentioned above after a quick glimpse it looks like outcome measures etc were later adapted quite possibly after data has been analysed, but as mentioned above I have only quickly looked at things and you should have the expertise here, so I'll be waiting for your comments.

On a more handwavy level: If IFL drives increased sleepiness then it's hard for me to see any relevance of IFL for ME/CFS as there is no increased sleepiness in ME/CFS.

 

[Utsikt]

If people want to have a productive discussion about this, they must try to develop an understanding of the stress response to inspiratory flow limitation (IFL) theory of sleep-disordered breathing (doesn't mean you have to agree with the theory, but you can't argue against a theory you haven't tried to understand), otherwise these discussions will go nowhere.

I believe you have got it all backwards. It is not anyones job to argue against the theory in itself. It is the proponent of the theory’s job to argue for its validity and plausibility with concrete evidence.

You have not shown any concrete evidence. All you have are severely flawed studies and correlations. That is not evidence by any reasonable standards.

There is no reason to engage with a theory built on nothing, because most of those will be completely wrong. And there is no reason to start large studies on a specific theory when the basic science hasn’t been done adequately yet.

This is a massive issue in most of science. It is not unique to ME/CFS even though it’s especially bad here. Established truths are often false or built on air. Plenty of scientists and doctors get this wrong all the time.

 

[Hoopoe]

I'm not seeking validation, I am asking people to actually engage with theory and evidence

You're making it hard to engage with the theory and evidence when it's loosely connected thoughts and bits of information scattered across various social media and studies that seem to have little relevance or are of poor quality. It's not even clear what your main hypothesis is. I haven't looked at everything because quite frankly the appearance is that of disorganized thoughts that don't merit more than a quick glance. If you want a serious conversation, then it's your responsibility to organize the information, focus on a single claim and then cite the strongest evidence you can find in support of that claim. And then you also have to listen to people telling you that you're wrong because you almost certainly are, simply because figuring out the causes of these illnesses is a very hard problem.

 

[nataliezzz]

Hi @nataliezzz I will take some time to respond to your points at a later time point but wanted to quickly clarify some points that were seemingly misunderstood.

I mean exactly what the authors are saying for which they seemingly don't provide any evidence, the authors write "Compared to controls, veterans with GWI had an increased frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation". The authors have provided only negligible evidence that there is an increased level of arousals but have provided no evidence that arousals are related to apneas, hypopneas, and mild inspiratory airflow limitation because they didn't even analyse this (that's what my reference of unsophisticated analysis was refering to). Do we agree that the authors provide no evidence for their claims?

No, the data show there were increased arousal related to apneas, hypopneas and mild inspiratory airflow limitation (RERAs are arousals related to mild inspiratory airflow limitation). The p-value for AHI is .006 (the majority of apneas/hypopneas terminate in an arousal). Mean arousals/hour were 34 in GWI patients vs. 10 in controls (p<.006). They didn't state specifically exactly how many arousals were related to apneas & hypopneas (but this is not usually stated in sleep research as it is recognized that the vast majority of apneas/hypopneas terminate in an arousal). Anyways, why should any of this matter if we both agree that (apnea/hypopnea-related) arousals are not the factor of interest here?

I wasn't arguing for or against a theory. I was just looking at the data you had pointed at as evidence for your theory.

What I find quite interesting is that you sensibly argue that arousal cannot be the cause of symptoms because plenty of people with arousals don't have symptoms and plenty of people without arousals do have symptoms. However, we also know that plenty of people with IFL don't have symptoms whilst plenty of people with symptoms have no evidence of IFL. You can try resolving that by making a vague reference to HPA-Axis but I think people on S4ME will quickly see through that as there is an interest in specifics.

Ok, so let's discuss some of the evidence supporting the theory. If a stress response to inspiratory flow limitation is not causing symptoms like sleep-onset insomnia, headaches and IBS in sleep-disordered breathing patients, what other factor do you propose could be responsible for the inverse relationship identified between AHI and these symptoms in sleep-disordered breathing patients? (A stress response to IFL can explain it because there is less exposure to inspiratory flow limitation as apneas [complete cessation of airflow] increases).

Some additional data supporting the theory:

Which is why it is so contradictory, which as I mentioned in my second post, that seemingly no relationship between the originial IFL measures and symptom improvement are reported in the trial. That would be very easy to establish and if I thought it was the missing piece then that's what I would look to establish as evidence!

Like I said, the CPAP pressure was specifically titrated to eliminate inspiratory flow limitation. So they started with 96%±5 of their breaths flow limited and presumably went to (close to) 0% of their breaths flow limited on CPAP - do you want to see graphs of their breathing curves to prove it? I'm not sure what evidence you require on that front.

You mention the reference to decreased sleep stage shifts but that is of course something different and as mentioned above after a quick glimpse it looks like outcome measures etc were later adapted quite possibly after data has been analysed, but as mentioned above I have only quickly looked at things and you should have the expertise here, so I'll be waiting for your comments.

Decreased sleep stage shifts may be a downstream effect of removing the stressor of inspiratory flow limitation during sleep with CPAP; the state of nervous system hypervigilance during sleep decreases and sleep stage shifts decrease. Nervous system hypervigilance during sleep is also supported by the objective finding of alpha delta-delta sleep (abnormal intrusion of alpha waves - associated with relaxed wakefulness - into delta wave/deep sleep) in many fibromyalgia & UARS patients (& I have cited a case report of a fibromyalgia cure where the woman's alpha-delta sleep disappeared along with fibromyalgia symptoms with treatment of sleep-disordered breathing with a mandibular advancement device).

On a more handways level: If IFL drives increased sleepiness then it's hard for me to see any relevance of IFL for ME/CFS as there is no increased sleepiness in ME/CFS.

Try telling that to me who used to sleep for 10+ hours every night (and when in PEM I would often sleep for up to 16 hours a night) and having severe daytime sleepiness in addition to fatigue earlier on in my illness (it eventually went away). Sleepiness is definitely a symptom in many ME/CFS patients (just like headaches, IBS, insomnia, etc.) - it is just not a required symptom.

The large population-based sleep studies only looked at sleepiness, not other symptoms well recognized to be associated with OSA like fatigue/headaches/insomnia, so that is all we have data on when it comes to the relationship of snoring to symptoms in sleep-disordered breathing patients.

 

[nataliezzz]

You're making it hard to engage with the theory and evidence when it's loosely connected thoughts and bits of information scattered across various social media and studies that seem to have little relevance or are of poor quality. It's not even clear what your main hypothesis is. I haven't looked at everything because quite frankly the appearance is that of disorganized thoughts that don't merit more than a quick glance. If you want a serious conversation, then it's your responsibility to organize the information, focus on a single claim and then cite the strongest evidence you can find in support of that claim. And then you also have to listen to people telling you that you're wrong because you almost certainly are, simply because figuring out the causes of these illnesses is a very hard problem.

Thanks for the feedback. As stated at the top of my post, I am in the process of updating it with a better explanation of the theory. However, I think I have done a decent job explaining it so far in the OP (obviously I didn't at first - I thought just linking my Bluesky thread was the way to go). Even if you just stick to the content in my OP without clicking on any of the outside links, I think you will come to a decent understanding of the theory.

 

[nataliezzz]

Hi @nataliezzz. I see you have edited the opening post to provide a large amount of text and links to research papers and to your social media threads.

Just working through all that would take me several months of concentrated effort. I don't have the capacity to do that, but would like to understand the logic and evidence base for your hypothesis.

Would it be possible to write a short summary with headings that shows the logical pathway that leads from UARS to ME/CFS, indicating the type and strength of evidence for each step in the pathway, and where you are making assumptions, and without any links or screenshots? A sort of intelligent lay person's summary?

Sorry, Trish, I am trying my best. I put the links to the supporting studies upfront at the beginning since I am being accused of providing no supporting evidence. I did go back and write up (what I thought was) a fairly condensed explanation of the theory with a few supporting visuals (I was trying not to overwhelm it with visuals, but there are some things that a graph can convey that would take a lot of writing to explain). But I understand that even what I have now is too much/too confusing for many people. @forestglip has offered to get an AI summary generated.

 

[Trish]

I am asking people to actually engage with theory and evidence (Jonathan Edwards openly admitted he wrote it off as a "nonsense quack theory" without reading any of the evidence, and @EndME wrote off the finding of "all pwGI have limited flow and healthy controls don't" - which is the relevant finding here - as irrelevant (I do appreciate @EndME making some real critiques of the study though, which I plan to respond to), but if people won't even attempt to understand the theory they won't be able to argue against it.

Hi @nataliezzz. I see you have edited the opening post to provide a large amount of text and links to research papers and to your social media threads.

Just working through all that would take me several months of concentrated effort. I don't have the capacity to do that, but would like to understand the logic and evidence base for your hypothesis.

Would it be possible to write a short summary with headings that shows the logical pathway that leads from UARS to ME/CFS, indicating the type and strength of evidence for each step in the pathway, and where you are making assumptions, and without any links or screenshots? A sort of intelligent lay person's summary?

Crosssposted with your previous post.

I have attempted to begin to understand your theory by reading your opening post earlier today. I went back a bit later and found you had edited it again, but with no indication of which bits have changed.

In the space of 2 days we already have over 100 posts, with most of your posts being very lengthy, and no indication of which bits are repetitions of things already posted and which are new information. It feels like a deluge. I simply can't keep up.

And then you berate us for not engaging with the material and tell people off and make digs at individuals for not trying hard enough.

This is simply not how forum discussions work. They are not seminars where the tutor can tell off students for not doing their homework, they are conversations where anyone can join in in any way they wish to address the thread topic. We are free to get things wrong, or say we think your theory doesn't make sense. We are under no obligation to read everything before we are allowed to draw conclusions, we often gradually get to grips with a topic by making mistakes and others patiently explaining.

Most of us are sick, some very sick, and have very limited reading capacity. If you want us to engage with the material, help us along gently, write simple summaries and outlines, introduce ideas gradually, write shorter posts. Don't answer questions with a whole heap of links and expect us to do the work of deciphering them. Don't say it's too much for you to copy your Twitter threads here yet expect us to do the work of trying to follow them.

I say all this not to tell you off, but to help you understand how forum discussions work, to accept that not all of us have the capacity to read great swathes of text, or to follow your thought processes unless you help us gently and slowly through the material.

 

[nataliezzz]

Crosssposted with your previous post.

I have attempted to begin to understand your theory by reading your opening post earlier today. I went back a bit later and found you had edited it again, but with no indication of which bits have changed.

In the space of 2 days we already have over 100 posts, with most of your posts being very lengthy, and no indication of which bits are repetitions of things already posted and which are new information. It feels like a deluge. I simply can't keep up.

And then you berate us for not engaging with the material and tell people off and make digs at individuals for not trying hard enough.

I criticized Jonathan Edwards for writing it off as a "nonsense quack theory" while openly admitting that he did not even read any of the supporting evidence. I think that was deserved.

My responses to @EndME may have been too harsh; it seemed like they were looking pretty closely at the data in the GWI study, so I was confused why they were not attending to the relevant finding (GWI patients having high % flow limitation while controls didn't) as I thought I had made it clear in my OP that flow limitation is the proposed key factor in the whole theory (but maybe they hadn't read the post again since I updated it) - sorry @EndME

This is simply not how forum discussions work. They are not seminars where the tutor can tell off students for not doing their homework, they are conversations where anyone can join in in any way they wish to address the thread topic. We are free to get things wrong, or say we think your theory doesn't make sense. We are under no obligation to read everything before we are allowed to draw conclusions, we often gradually get to grips with a topic by making mistakes and others patiently explaining.

Most of us are sick, some very sick, and have very limited reading capacity. If you want us to engage with the material, help us along gently, write simple summaries and outlines, introduce ideas gradually, write shorter posts. Don't answer questions with a whole heap of links and expect us to do the work of deciphering them. Don't say it's too much for you to copy your Twitter threads here yet expect us to do the work of trying to follow them.

I say all this not to tell you off, but to help you understand how forum discussions work, to accept that not all of us have the capacity to read great swathes of text, or to follow your thought processes unless you help us gently and slowly through the material.

Thank you, you are right. I'm sorry. I think I was just really put off by Dr. Edwards' response, especially because one of the reasons I specifically came to this forum (after almost everyone has been ignoring me on Twitter - including someone on this forum who has intentionally and repeatedly ignored me) was because I thought he would probably pay attention to it/see some value in this theory, so I was pretty crushed when he reacted the way he did.

Give me some time to try to organize all of this into a more comprehensible format; in addition to the AI summary that @forestglip is working on, it has also been suggested to me to create multiple threads with sub-topics (that way I can link to each of them rather than having it all crammed into one post).

@EndME thank you for engaging meaningfully with some of the evidence on it. I think I should probably take a break from back and forth discussion for several days (and I can work on organizing this into a more comprehensible format in the meantime), so if we do want to continue our discussion (which I would like), maybe we can both take some time to look into the other person's critiques (I will look into the criticisms you raised of the GWI study, and maybe you can go back and re-read my OP which I have updated with a better explanation of the theory)

 

[EndME]

@EndME thank you for engaging meaningfully with some of the evidence on it. I think I should probably take a break from back and forth discussion for several days (and I can work on organizing this into a more comprehensible format in the meantime), so if we do want to continue our discussion (which I would like), maybe we can both take some time to look into the other person's critiques (I will look into the criticisms you raised of the GWI study, and maybe you can go back and re-read my OP which I have updated with a better explanation of the theory)

That sounds like a good idea!

Notably there have been studies that have used a Polysomnography in ME/CFS, including the intramural study. There were no findings of relevance. Moreover a subset of those participants even underwent a 6 week trial of CPAP without there being any relevant improvements!

Generally speaking about some of the engagement that might be frustrating for you: I must have seen similar approaches to theories for ME/CFS upwards of 50 times. Bits and pieces taken from here or there with a lot of "presumably". If one is convinced of any idea, one can always accrue evidence from different places to make a story, but that does not make said evidence convicing. In this case it seems to me that an array of different studies have been posted (I only had time to even look at 2 studies somewhat closer and I suspect to look at the full evidence more closely will take anybody several days). This is an array of different studies that are all on somewhat related topics but that all have different results on differing conditions with different criteria and outcome measures and then making causative claims based on different correlations quickly becomes dubious.

I think the following would be helpful to know for people part of the discussion: Are there any results that are consistently replicated across studies (including accounting for all those studies with negative results, some of which will have never been published) and I'm not taking about somewhat related findings, I'm talking about consistent replication? And what is the evidence for those replicated findings being of relevance to ME/CFS beyond there being an overlap of symptoms and how do the negative findings fit into that?