Astounding Norwegian research breakthrough with Rituximab can solve CFS mystery!!!

[mellster]

Great post - agree on LDN as a must-try for at least 30+ days if possible - but I'm obviously biased

Just adding my post from the Research forum here in case anyone can help:

Has anyone thought about how the autoimmune aspect might be reconciled with the gene expression alterations detected by Light et al?



At first glance I can't see an obvious way that the two could fit together, ACA autoantibodies attacking mitochondria can explain a portion of the symptomatology but not all, and I struggle to see how pain/fatigue receptors would be upgregulated as a result of these autoantibodies. That said, my knowledge of autoimmune diseases is very limited so I'd love it if someone could enlighten me.

Also something I noticed regarding LDN:

Another thing I just realised, if this is indeed getting close to the central pathological mechanism of the illness, then Low Dose Naltrexone surely becomes a must-try treatment for anyone that believes they may fit within that subgroup:



LDN might be having the same effects as Rituximab but obviously in a less drastic way.

 

[SilverbladeTE]

Like ME itself, it's harder to be pericse on effects due to the distance in time between cause and effect

ie
ME diagnosis is oftne not given to many months, often years after the trigger,, so finding out the trigger/data from such is nigh impossible and part of what's kept us in the dark
with this study though you have months to effect but it is clinically observed, big difference.

And yes I highly doubt this will be the "magic bullet" drug, as they've just hit on, by chance and ye olde trial and error/hard work, of a new avenue of treatment, NOT the "magic bullet"
I'd suspect 10 or 15 years down the line they'll identify a SPECIFIC treatment that has best effect with less side effects/better costs

In other words, this is standard good experimental clinical work, with a little twist (time to effect and still not udnerstanding precisely why)

The parallels between this and HIV treatment should be obvious and should put a huge boot right up the cojones of the psychobabblers though
ie, to both public and clinicians, invovlment of an immune cell can be grasped and severity of threat/suffering to ME victim therefor understood

remember, we've got thirty years of devious, sly manipulation via PublicRelations jiggery-pokery of ME to the Public, showing ME patients as young, beautiful and dozing asleep...
So the public AND clinicians (who aren't immune ot this crap either) get brainwashed into accepting that ME = sleepy/lazy folk who aren't suffering!
Showing though that either the immune system is attacking the body OR infected like HIV, that is huge breakthrough itself, as most folk can udnerstand HIV, multiple sclerosis etc
People will now question an dbe suspicious of the psychobabblers' garbage.

As a wise man once said:
"You can fool some of the people all of the time..but you can't fool all of the people, all of the time!"
The worm has turned.


two points
1) Many in the "professional" classes, like doctors, think they are "better" than the "common herd" and cannot be conned...um, con artists would beg to differ
As I keep saying, "smarts" and intelligence are two different things
Hence they fell easy and hard for the psychobabble spiel on ME.

2) "boot up the cojones", this is purely a humorous figure of speech, not a call for really doing the Cossack Dance on their family jewels!

 

[richvank]

Just adding my post from the Research forum here in case anyone can help:

Has anyone thought about how the autoimmune aspect might be reconciled with the gene expression alterations detected by Light et al?



At first glance I can't see an obvious way that the two could fit together, ACA autoantibodies attacking mitochondria can explain a portion of the symptomatology but not all, and I struggle to see how pain/fatigue receptors would be upgregulated as a result of these autoantibodies. That said, my knowledge of autoimmune diseases is very limited so I'd love it if someone could enlighten me.

Also something I noticed regarding LDN:

Another thing I just realised, if this is indeed getting close to the central pathological mechanism of the illness, then Low Dose Naltrexone surely becomes a must-try treatment for anyone that believes they may fit within that subgroup:



LDN might be having the same effects as Rituximab but obviously in a less drastic way.

Hi, Vitalic.

In the Lights experiment, the expression of certain genes in peripheral mononuclear cells (lymphocytes and monocytes) is measured before and after a period of strenuous exercise. In my opinion, what happens there is that the exercise generates oxidative free radicals in the mitochondria of the skeletal muscle cells, and these lower the body-wide glutathione status, which is already somewhat depleted in PWMEs. The body-wide glutathione status (acting through the blood plasma) lowers the glutathione status of the peripheral mononuclear cells, and this raises their state of oxidative stress. This is sensed by the cobalt ion in the cobalamin coenzyme of the methionine synthase enzyme, which increases the partial block in the methylation cycle and thus lowers the methylation capacity of these cells. This lowers the methylation of the DNA composing certain genes, and that increases their expression.

In the Rituximab trial, the Rituximab knocks out the B cells (which also happen to be among the mononuclear cells in the blood). In doing so, I suspect that it also lowers the inflammation and thus the state of oxidative stress, allowing glutathione to rise. In some of the patients, this rise is sufficient to break the vicious circle involving glutathione depletion, the B12 functional deficiency, the partial block in the methylation cycle, and the draining of folates from the cells. When the immune system recovers, it likely no longer has a Th2 shift, and the inflammation stops, in these patients, so they recover. In some other patients, when the B cells come back up, the imbalance is still present, and the resulting oxidative stress re-establishes the vicious circle, so that they relapse. In the patients who didn't experience any benefit, even temporary, from the Rituximab treatment, I suspect that other stressors that are placing demands on glutathione are dominant over the inflammation. I think that toxins would be good candidates in this subgroup.

Best regards,


Rich

 

[Vitalic]

Like ME itself, it's harder to be pericse on effects due to the distance in time between cause and effect

ie
ME diagnosis is oftne not given to many months, often years after the trigger,, so finding out the trigger/data from such is nigh impossible and part of what's kept us in the dark
with this study though you have months to effect but it is clinically observed, big difference.

And yes I highly doubt this will be the "magic bullet" drug, as they've just hit on, by chance and ye olde trial and error/hard work, of a new avenue of treatment, NOT the "magic bullet"
I'd suspect 10 or 15 years down the line they'll identify a SPECIFIC treatment that has best effect with less side effects/better costs

In other words, this is standard good experimental clinical work, with a little twist (time to effect and still not udnerstanding precisely why)

The parallels between this and HIV treatment should be obvious and should put a huge boot right up the cojones of the psychobabblers though
ie, to both public and clinicians, invovlment of an immune cell can be grasped and severity of threat/suffering to ME victim therefor understood

remember, we've got thirty years of devious, sly manipulation via PublicRelations jiggery-pokery of ME to the Public, showing ME patients as young, beautiful and dozing asleep...
So the public AND clinicians (who aren't immune ot this crap either) get brainwashed into accepting that ME = sleepy/lazy folk who aren't suffering!
Showing though that either the immune system is attacking the body OR infected like HIV, that is huge breakthrough itself, as most folk can udnerstand HIV, multiple sclerosis etc
People will now question an dbe suspicious of the psychobabblers' garbage.

As a wise man once said:
"You can fool some of the people all of the time..but you can't fool all of the people, all of the time!"
The worm has turned.


two points
1) Many in the "professional" classes, like doctors, think they are "better" than the "common herd" and cannot be conned...um, con artists would beg to differ
As I keep saying, "smarts" and intelligence are two different things
Hence they fell easy and hard for the psychobabble spiel on ME.

2) "boot up the cojones", this is purely a humorous figure of speech, not a call for really doing the Cossack Dance on their family jewels!

It's funny you should mention that, did you see the picture attached to the der spiegel article about the Norwegian study?

Once you've been awakened to the political undercurrents involved in this condition all these subtle little manifestations become incredibly obvious. It's not like there is some conspiratorial regime in place to purposefully represent CFS sufferers in this way, but there is clearly some kind of manufacture of consent or other phenomenon involved which have gradually evolved over time due to continual misinformation. How about showing someone in a bed attached to drips looking like they are on the verge of death, which is the situation many sufferers are faced with, instead you get some fit and healthy looking woman that's woken up feeling a bit down in the dumps.

 

[floydguy]

It's funny you should mention that, did you see the picture attached to the der spiegel article about the Norwegian study?

Once you've been awakened to the political undercurrents involved in this condition all these subtle little manifestations become incredibly obvious. It's not like there is some conspiratorial regime in place to purposefully represent CFS sufferers in this way, but there is clearly some kind of manufacture of consent or other phenomenon involved which have gradually evolved over time due to continual misinformation. How about showing someone in a bed attached to drips looking like they are on the verge of death, which is the situation many sufferers are faced with, instead you get some fit and healthy looking woman that's woken up feeling a bit down in the dumps.

Or a hottie with a hangover

 

[Vitalic]

Hi, Vitalic.

In the Lights experiment, the expression of certain genes in peripheral mononuclear cells (lymphocytes and monocytes) is measured before and after a period of strenuous exercise. In my opinion, what happens there is that the exercise generates oxidative free radicals in the mitochondria of the skeletal muscle cells, and these lower the body-wide glutathione status, which is already somewhat depleted in PWMEs. The body-wide glutathione status (acting through the blood plasma) lowers the glutathione status of the peripheral mononuclear cells, and this raises their state of oxidative stress. This is sensed by the cobalt ion in the cobalamin coenzyme of the methionine synthase enzyme, which increases the partial block in the methylation cycle and thus lowers the methylation capacity of these cells. This lowers the methylation of the DNA composing certain genes, and that increases their expression.

In the Rituximab trial, the Rituximab knocks out the B cells (which also happen to be among the mononuclear cells in the blood). In doing so, I suspect that it also lowers the inflammation and thus the state of oxidative stress, allowing glutathione to rise. In some of the patients, this rise is sufficient to break the vicious circle involving glutathione depletion, the B12 functional deficiency, the partial block in the methylation cycle, and the draining of folates from the cells. When the immune system recovers, it likely no longer has a Th2 shift, and the inflammation stops, in these patients, so they recover. In some other patients, when the B cells come back up, the imbalance is still present, and the resulting oxidative stress re-establishes the vicious circle, so that they relapse. In the patients who didn't experience any benefit, even temporary, from the Rituximab treatment, I suspect that other stressors that are placing demands on glutathione are dominant over the inflammation. I think that toxins would be good candidates in this subgroup.

Best regards,


Rich

Thanks Rich, interesting explanation. I have questions I'd like to ask but I feel they would probably best be answered by more in depth research into the methylation cycle.

It sounds like you are sceptical about the prospect of there being any specific auto antibodies involved in the pathology of CFS, certainly the fact only some people improved has to be explained and if you are postulating that auto-antibodies are causal then it becomes somewhat harder to explain, but it could also be down to the heterogeneous nature of the condition and only certain sub-types responding, or sub-optimal infusion rates/dosages.

 

[SilverbladeTE]

Vitalic
BBC
http://www.bbc.co.uk/news/health-14883651

image title is "weary woman"
see what I mean?

social manipulation has become endemic and monstrous since the Cold War.
Western version of propaganda is far more effective and subtle.

that pic has a relation to ME, like a person with a small, dark bruise on their arm has to the Black Death!

 

[richvank]

Thanks Rich, interesting explanation. I have questions I'd like to ask but I feel they would probably best be answered by more in depth research into the methylation cycle.

It sounds like you are sceptical about the prospect of there being any specific auto antibodies involved in the pathology of CFS, certainly the fact only some people improved has to be explained and if you are postulating that auto-antibodies are causal then it becomes somewhat harder to explain, but it could also be down to the heterogeneous nature of the condition and only certain sub-types responding, or sub-optimal infusion rates/dosages.

Hi, Vitalic.

Yes, it's true that I'm skeptical about there being specific autoantibodies in ME/CFS. Of course, I could be wrong, but there have been efforts in the past to find them, and as far as I know, these efforts have not paid off. There is some elevation of ANA, there is some anticardiolipin antibody in some cases, and there are Hashimoto's antibodies in quite a few PWMEs, but I haven't heard of any specific ones in ME/CFS.

I think the ANA and the anticardiolipin antibodies are the immune system's response to fragments of cells that have had an early death.

I recall going to an NIH CFS workshop in Bethesda, MD, several years ago at which Prof. Dan Clauw, the rheumatologist from U. of Michigan, made the statement that one thing we don't see in these patients is autoimmune disease. I raised an objection: "What about Hashimoto's?" He essentially said that he did not consider Hashimoto's to be in the same category as autoimmune disorders such as rheumatoid arthritis or lupus. In my hypothesis, I have adopted the Duthoit model in which the thyroid's own hydrogen peroxide attacks its proteins in the absence of enough glutathione to protect them, and the immune system mounts an immune response to these altered proteins. Wikland found Hashimoto's in 41% of the patients he studied using fine needle biopsy.

I think it makes sense to think more generally about what would happen when there is a Th2-shifted person with a dysfunctional HPA axis who then has their B cells knocked out. I think the inflammation that was present will go down, taking down the oxidative stress, which is a major factor in the abnormal biochemistry of ME/CFS. I hope that people who do Rituximab trials will monitor glutathione. I expect that it would be very revealing.

I'm certainly open to other explanations, but so far I think this one fits pretty well, when we consider everything else we know about ME/CFS.

Best regards,

Rich

 

[Andrew]

At the rate this thing is moving forward, I'm going to be dead before they figure it out. I made a big mistake by letting this study get my hopes up.

 

[SOC]

It's funny you should mention that, did you see the picture attached to the der spiegel article about the Norwegian study?

Once you've been awakened to the political undercurrents involved in this condition all these subtle little manifestations become incredibly obvious. It's not like there is some conspiratorial regime in place to purposefully represent CFS sufferers in this way, but there is clearly some kind of manufacture of consent or other phenomenon involved which have gradually evolved over time due to continual misinformation. How about showing someone in a bed attached to drips looking like they are on the verge of death, which is the situation many sufferers are faced with, instead you get some fit and healthy looking woman that's woken up feeling a bit down in the dumps.

I don't see your objection. I look EXACTLY like that when I'm in bedbound with ME.

 

[Vitalic]

Hi, Vitalic.

Yes, it's true that I'm skeptical about there being specific autoantibodies in ME/CFS. Of course, I could be wrong, but there have been efforts in the past to find them, and as far as I know, these efforts have not paid off. There is some elevation of ANA, there is some anticardiolipin antibody in some cases, and there are Hashimoto's antibodies in quite a few PWMEs, but I haven't heard of any specific ones in ME/CFS.

I think the ANA and the anticardiolipin antibodies are the immune system's response to fragments of cells that have had an early death.

I recall going to an NIH CFS workshop in Bethesda, MD, several years ago at which Prof. Dan Clauw, the rheumatologist from U. of Michigan, made the statement that one thing we don't see in these patients is autoimmune disease. I raised an objection: "What about Hashimoto's?" He essentially said that he did not consider Hashimoto's to be in the same category as autoimmune disorders such as rheumatoid arthritis or lupus. In my hypothesis, I have adopted the Duthoit model in which the thyroid's own hydrogen peroxide attacks its proteins in the absence of enough glutathione to protect them, and the immune system mounts an immune response to these altered proteins. Wikland found Hashimoto's in 41% of the patients he studied using fine needle biopsy.

I think it makes sense to think more generally about what would happen when there is a Th2-shifted person with a dysfunctional HPA axis who then has their B cells knocked out. I think the inflammation that was present will go down, taking down the oxidative stress, which is a major factor in the abnormal biochemistry of ME/CFS. I hope that people who do Rituximab trials will monitor glutathione. I expect that it would be very revealing.

I'm certainly open to other explanations, but so far I think this one fits pretty well, when we consider everything else we know about ME/CFS.

Best regards,

Rich

Well presumably knocking out the B-cells would temporarily halt production of the pro-inflammatory cytokines that are found to be up-regulated in PWCs and thus reduce inflammation, but I wonder if this fits with the fairly dramatic variation in response times? In other words, how can some people respond immediately but others take 6 months, presumably it might be related to the severity of the methylation cycle block in each particular case but the variation is quite perplexing. I'm also aware that improper activation of the 2-5A/RNase L/PKR pathway can lead to inflammation and production of NO (mediated by NF-kB) which in turn leads to oxidative damage, so knocking out B-cells might have an influence on that too.

Also what of the findings by Hokoma et al. (http://www.ncf-net.org/pdf/AnticardiolipinAntibodies.pdf), specifically that 95% of patients were detected as having ACA autoantibodies - this is more than just a few cases, and while it is not something specific to CFS the fact they actually postulated Rituximab might be a viable treatment is quite surprising given the recent Norwegian study. I don't think Fluge/Mella are certain that there is an autoimmune component, but they are keeping that option on the table, what they are certain of is that there is some immune component x which is having a delayed reaction to the B-cell depletion, the main priority has to be finding that because it could tell us a lot about what is causing the illness.

 

[globalpilot]

Hi Rich,
The one problem I have with your idea about the oxidative stress going down when B cells are depleted is that other aspects of the immune system produce oxidative stress and these may not be affected by the Ritifimub.

GP

Hi, Vitalic.

Yes, it's true that I'm skeptical about there being specific autoantibodies in ME/CFS. Of course, I could be wrong, but there have been efforts in the past to find them, and as far as I know, these efforts have not paid off. There is some elevation of ANA, there is some anticardiolipin antibody in some cases, and there are Hashimoto's antibodies in quite a few PWMEs, but I haven't heard of any specific ones in ME/CFS.

I think the ANA and the anticardiolipin antibodies are the immune system's response to fragments of cells that have had an early death.

I recall going to an NIH CFS workshop in Bethesda, MD, several years ago at which Prof. Dan Clauw, the rheumatologist from U. of Michigan, made the statement that one thing we don't see in these patients is autoimmune disease. I raised an objection: "What about Hashimoto's?" He essentially said that he did not consider Hashimoto's to be in the same category as autoimmune disorders such as rheumatoid arthritis or lupus. In my hypothesis, I have adopted the Duthoit model in which the thyroid's own hydrogen peroxide attacks its proteins in the absence of enough glutathione to protect them, and the immune system mounts an immune response to these altered proteins. Wikland found Hashimoto's in 41% of the patients he studied using fine needle biopsy.

I think it makes sense to think more generally about what would happen when there is a Th2-shifted person with a dysfunctional HPA axis who then has their B cells knocked out. I think the inflammation that was present will go down, taking down the oxidative stress, which is a major factor in the abnormal biochemistry of ME/CFS. I hope that people who do Rituximab trials will monitor glutathione. I expect that it would be very revealing.

I'm certainly open to other explanations, but so far I think this one fits pretty well, when we consider everything else we know about ME/CFS.

Best regards,

Rich

 

[Snow Leopard]

f course, I could be wrong, but there have been efforts in the past to find them, and as far as I know, these efforts have not paid off.

I believe I have read almost all of the studies on autoantibodies. I can say that the efforts so far have actually been pretty weak, just a handful of studies and none that have tried to look for novel antibodies.
The lack of a good search is due to the fact that high ANA is atypical in CFS, but not all autoimmune conditions have high ANA all the time.

 

[floydguy]

I don't see your objection. I look EXACTLY like that when I'm in bedbound with ME.

 

[richvank]

Hi, Vitalic, globalpilot and Snow Leopard.

I think all of you have made some good points. I also think that it is going to take more research to answer the issues that we have raised. I hope that glutathione measurements will be part of the ongoing studies in this area, because I think that would help to sort things out. I guess I've speculated about as far as I can at this point, and time will tell whether there is any validity to the speculations. I'm glad this study was done, because I think it is likely to stimulate progress in the ME/CFS field.

Best regards,

Rich

 

[fla]

I recall going to an NIH CFS workshop in Bethesda, MD, several years ago at which Prof. Dan Clauw, the rheumatologist from U. of Michigan, made the statement that one thing we don't see in these patients is autoimmune disease.

But Fluge made this comment on PloS ONE and I've seen large numbers of PR posts mention comorbid autoimmune conditions. Montoya mentions vitiligo as being of particular interest in one of his youtube videos.

van der Meer et al. comment on the high rate of other autoimmune diseases in the patients and their relatives in this series. This is not an original observation and has been noted also by others. One of the senior authors of our manuscript, prof. H. Nyland, is the single physician in Norway who has seen and systematically registered most CFS/ME patients and he confirms this finding his patients.

I see M.E. as a body state kind of like homelessness is a life state. Glutathione is the bank account balance which when depleted causes a huge amounts of misery in all aspects of health/life. The M.E/homeless state is held in place by a vicious circle mechanism. The original cause for the depletion of the bank account/glutathione must be dealt with otherwise getting out of the M.E./homeless state is next to impossible.

Glutathione levels in non-M.E. people with autoimmune conditions and IBS should be tested to see if it could be used as a predictor for M.E. should an oxydative stressful immune event come along to break the camel's back.

 

[Klmrav]

I was wondering if anyone thinks it might be helpful to do a poll on ANA, ACA, NK cell function and B cell levels. I haven't had the ACA tested yet, but ANA pos, NK cell function low normal, B cells low. Too bad we didn't have an Access database to collect datapoints. In my previous life I designed a large one for employee training.

 

[redo]

Hi, still to read the full paper but I wanted to note odds. Two thirds respond to the drug. One in five are in full CFS remission after only two treatments, although with a long wait till full response? Two treatments are less than a month's wages for most people. Bye, Alex

PS We don't know why one in three don't respond. It could be that they require more treatments. It could also be that there are two different diseases (or more) and that one responds and the other doesn't.

The authors write that they think that there's a significant chance many of the remaining patients will get an effect if they just continue with the infusions. They have written this after they are done with the study, and do have experiences with more infusions... So that's good news. :Retro smile:

 

[SilverbladeTE]

I don't see your objection. I look EXACTLY like that when I'm in bedbound with ME.

Lucky you!
I look more like this old chap....

http://www.flickr.com/photos/lupinehorror/3979679246/sizes/m/in/photostream/

(link, as Flickr doesn't allow direct links, grr)


*chants*
Gordon! Gordon! Gordon!

 

[Dolphin]

I'm a latecomer to the Rituximab party and don't have the energy to read the 370-odd preceding posts so apologies if this has been covered already

I think the SF36 data in the Fluge paper gives a useful insight on how big an effect Rituximab has:

van der Meer and colleagues criticised the fatigue scale used in the trial both because it was unvalidated and because it focused on change from baseline rather than absolute scores. They also say the effect on fatigue is small, pointing to the best change score of just under 4 (mean score for all particpants at 24-32 weeks), consistent with "slight improvement"

Fluge and colleagues pointed out that patients peaked at different times reducing the mean peak score, and that scores included non-responders as well as responders.

The SF36 physical function data (Table 4) can get round some of these problems. First, it's a widely used and validated (if imperfect scale), and measures total activity not change scores, both of which should keep van der Meer et al happy. Second, the authors reported peak SF36 change, ie is based on the maximum change for each individual (I think) so should be more to Fluge et al's liking.

Baseline SF36 Physical Function score = 34 (Standard Deviation 6) for Rituximab

Maximum change=39% (Rutiximab group vs 11% for control group)
Net maximum change = 28% (ie RXB change less control change)

Mean net maximum change=9.5 points (0-100 scale)

As far as I know, the maximum change is calculated per individual, so an improvement of 15 points is 50% for someone with a baseline score of 30 but only 25% for a patient with a baseline score of 60. However, to get a useable figure here I applied the mean maximum change to the mean baseline score.

For comparison, the PACE trial found a SF36 score change of 7.1 for CBT and 9.4 for GET. However, the enormous difference with PACE is that it was unblinded so the SF36 scores there might be biased by participants in the treatment groups (the 'therapeutic alliance' between patients and therapists was rated 'very high' so patients might unconsciously boost their scores to make their therapist look good). In the Fluge trial all particpants were blinded to which treatment they had.

So, 9.5 is a pretty good improvement, and in most trials that would cause a stir - but it isn't absolutely enormous either.

Of course, the maximum change figure includes non-responders as well as responders so if we pro-rata all the improvement to the responders (9 ex 13 with SF36 data), we get a score of 13.8 for responders, which begins to look pretty good. However, trials generally don't report mean scores for responders and non-responders separately.

I don't claim this is mathematically rigorous but I think the numbers give probably give a reasonable feel for the effects of the study, using different data. The results appear to be good if not awesome.

Maybe I should add that I think the Fluge study is tremendously exciting. I don't know if rituximab will prove to be a magic bullet for CFS, even if they tweak the dosage, but I do think the study provides striking evidence of an immune system role in the illness. As the authors say:

the presented findings may have a major impact on the direction of biomedical research in CFS.

[STRIKE]Just to confuse things: occasionally SF-36 scores are seen as percentage points (they are scored 0-100). So percentage changes may actually mean the actual number of points changed. Just as if somebody got 40% on an exam and somebody said they improved by 20% in the next exam - that could mean a score of 60% (rather than 48%).

I don't have time to check the paper now to see what is the more likely meaning. Although maximum variations of 11% in the control group makes me think that one is talking about numerical changes i.e. a change of 11% equals 11 points; otherwise the maximum changes for the control group look small.[/STRIKE]
ETA: I have looked at the paper again. They use normalised SF-36 scores not just for PCS and MCS but also the 8 SF-36 subscales. So one can't make direct comparisons with the PACE Trial.