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Sept 10: CDC 'conference call' including Unger and Lipkin

heapsreal

iherb 10% discount code OPA989,
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I don't know, but I tested negative to hhv6/PCR when I was tested in the USA too...I don't remember seeing any large community based studies testing for HHV6 (I could be wrong). There are tales and then there is science.

unfortunately the science is lacking for many of us, as firestormm as said hopefully lipkin and other scientist step up and provide more science relevant to us.
 

Ember

Senior Member
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2,115
She's also carrying out post-exertion resting heart rate tests, with the theory that ME patients' heart rates don't follow a normal course after exertion.
Dr. Unger doesn't mention using resting heart rate tests in her “Auugust 30” response. She writes, “Our primary objective is to measure the exercise capacity in as many of the enrolled patients as possible using a standardized protocol, and to monitor the post-exertional response for 48 hours with online cognitive testing and visual analogue scales of fatigue, pain, and symptoms.”
 

jspotila

Senior Member
Messages
1,099
Thanks for the insight.

Was the testing itself excruciating, or was it the PEM, or both?

I've been confounded by Klimas/Sol patients here making it sound like an AT bicycle test was wasn't very taxing and didn't seem come with much of a post-test price. "Excruciating" is much more what I would expect of an exercise challenge test.

The testing itself is very difficult because you pedal a bike until you literally can't do it anymore. It's unpleasant, but then you get to stop.

Excruciating was the PEM, the pain, the cognitive decline, the orthostatic intolerance, and on and on. Sometimes when I am really severely crashed, I feel like I might die (although never having had any critical injury I don't have anything to compare it to). I was afraid for the first couple weeks that maybe I permanently broke myself. But IV fluids, and three weeks of bed rest, helped me come back up out of it. So "excruciating" is my shorthand for all of that.
 

biophile

Places I'd rather be.
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8,977
I think someone mentioned MS earlier on this thread. A recent study using cerebrospinal fluid from MS patients:

What Schutzer found startled another of his co-investigators, Patricia K. Coyle of Stony Brook University in New York, one of the leading MS clinicians and researchers in the country. The proteins in the CSF of the new MS patients suggested physiological disruptions not only in the white matter of the brain where the myelin damage eventually shows up. They also pointed to substantial disruptions in the gray matter, a different part of the brain that contains the axons and dendrites and synapses that transfer signals between nerves.

Several scientists had in fact hypothesized that there might be gray matter involvement in early MS, but the technology needed to test their theories did not yet exist. Schutzer's analysis, which Coyle calls "exquisitely sensitive," provides the solid physical evidence for the very first time. It includes a finding that nine specific proteins associated with gray matter were far more abundant in patients who had just suffered their first attack than in longer term MS patients or in the healthy controls. "This evidence indicates gray matter may be the critical initial target in MS rather than white matter," says Coyle. "We may have been looking in the wrong area."

http://www.sciencedaily.com/releases/2013/09/130910205241.htm

Grey matter pathology is not a new topic in MS. Grey matter atrophy occurs in ME/CFS, and other studies have found protein abnormalities in our cerebrospinal fluid. Makes me wonder how all this ties in with Lipkin's preliminary findings.
 

Nielk

Senior Member
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6,970
Wasn't Dr Enlander doing a study of response to exercise? Was that a 2-day test? If we can get more data, that might help convince Dr Unger.



Dr. Enlander's study involves a one day test with a three day subsequent return of the patient to take vitals and bloodtests.
 

Nielk

Senior Member
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6,970
Dr. Unger doesn't mention using resting heart rate tests in her “Auugust 30” response. She writes, “Our primary objective is to measure the exercise capacity in as many of the enrolled patients as possible using a standardized protocol, and to monitor the post-exertional response for 48 hours with online cognitive testing and visual analogue scales of fatigue, pain, and symptoms.”


Ember - where can I see the Aug 30th Unger response?
 

Bob

Senior Member
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England (south coast)
Dr. Unger doesn't mention using resting heart rate tests in her “Auugust 30” response. She writes, “Our primary objective is to measure the exercise capacity in as many of the enrolled patients as possible using a standardized protocol, and to monitor the post-exertional response for 48 hours with online cognitive testing and visual analogue scales of fatigue, pain, and symptoms.”

That's a shame. It was at the most recent CFSAC meeting that they were discussing CPET testing, and she was urged to get in touch with Dr Snell about two-day CPET testing, and to test for resting heart rates. She made some notes at the time, and looked like she might be listening. Well, it seems that she did contact Dr Snell, but hasn't yet incorporated two-day CPET testing. With regards to monitoring post-exertion resting heart rate, she also seemed receptive but didn't commit to it. So I was wrong, again, to say that she is including post-exertion resting heart rate, because I don't have any evidence for it.

I guess I was hoping that it was a commitment, and got over-excited that she would be including these tests. I get the feeling that the study is a work in progress for Unger, and she seems receptive to a certain extent, but extremely slow to make changes. Perhaps well targeted correspondence might encourage her to include tests for these biomarkers.

In this CFSAC video (0.43.50), Beth Unger states, in relation to exercise tests:
"We are going to be doing cognitive testing afterwards, to show that change, and the suggestion of looking at resting heart rate, we can easily incorporate that into that post monitoring as well."

Perhaps I've been over-enthusiastic about the thought of the CDC carrying out a proper study at long last.

When Dr. Snell speaks here of "failure to reproduce," he's speaking of the patients' failure to reproduce on day two the CPET results that they achieved on day one. He isn't referring to other researchers' failure to replicate his research. In fact, he challenges other researchers to find out why patients can't reproduce their day one results. He suggests "lots of reasons" for his findings and lists on his accompanying slide (177) inflammatory cytokine elevation (Klimas et al., 2007), neuroendocrine dysfunction, cardiovascular abnormalities and mitochondrial abnormalities (Whistler et al., 2006, Wong et al., 1992).

Ah, now I understand. Thanks for that, Ember. I totally misinterpreted it, didn't I. I just couldn't work out what he meant when I looked at it again yesterday.

Apologies again for my misinformation, and thanks for correcting me.

However, I still think that Dr Snell has not replicated his own research. I think his earlier study found useful differences in the VO2 max test, but VO2 max did not provide useful results in his latest study, unless I've misinterpreted it. I might have got this wrong, so I'm happy to be corrected, if anyone can interpret his latest paper. But, in any case, his latest results definitely suggest a great deal of potential in a two-day CPET test.


These are the Snell exercise studies that I can find on Google: 2005, 2007, 2013.
 

SOC

Senior Member
Messages
7,849
Thanks for the insight.

Was the testing itself excruciating, or was it the PEM, or both?

I've been confounded by Klimas/Sol patients here making it sound like an AT bicycle test was wasn't very taxing and didn't seem come with much of a post-test price. "Excruciating" is much more what I would expect of an exercise challenge test.
I've done the full 1-day CPET and the Klimas/Sol test about 5 years apart and at different stages of illness. The one-day CPET was much, much more demanding. I was not yet housebound at that time, but I felt awful at the end of the CPET, but recovered partially within hours. I was able to travel home by plane (with hubby, not on my own). The PEM hit about 4 days later, which is typical for me. I had the full PEM -- flu-like symptoms, exhaustion, joint aches, swollen glands. :ill: It was weeks before I felt anything close to baseline again. The testing and the PEM were both excruciating.

That said, I was willing to do it again 5 years later when I was housebound, but better managed, to see if my AT had changed. (It hadn't). The Klimas/Sol AT test was extremely easy. The whole thing was less than 6 minutes, I think. No PEM.

I suspect that the AT test will not give as much information as a 2-day CPET, which is why I think the 2-day CPET should be the gold standard for research. OTOH, if our exercise problems are as severe as they seem to be, it shouldn't require maximal exercise should show abnormalities, so there may be some instances where the lesser test might be appropriate.
 

Andrew

Senior Member
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2,513
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Los Angeles, USA
I'm afraid Lipkin's initial findings are starting to look familiar to me. I was always told by my immunologist that there was no active virus in ME, but the immune system was subtly malfunctioning and was activated despite there being no pathogen. No causative pathogen that is. The wide variety of viruses associated with ME could just be opportunist passengers, as the immune system is disordered.

The only new thing I see is the difference between patients with less than versus more than three years. There have been a number of studies in the past pointing to cytokine irregularities. The big frustration, though, it the studies don't all find the same pattern. And I also have a vague recollection of Klimas finding that the cytokine irregularities vary from day to day. OTOH, I could also wonder if this variation in irregularity is not a pattern in itself. IOW, an immune system that keeps firing in different directions for no apparent reason.
 

Gemini

Senior Member
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East Coast USA
As far as I understand at present, all we know is that Dr Lipkin's team has not found a smoking gun -- a causative agent -- for ME/CFS. That doesn't mean that infections -- different ones in different groups maybe -- aren't 1) causing us a lot of misery, and 2) treatable. Nor does it mean that there is not a single causative infectious agent. They're still looking.

A question I submitted to the call & not answered was:

Drs. Unger and Lipkin,
Will your laboratories be attempting to replicate Dr. Chia's finding of enterovirus in stomach lining? If not, explain please? Patients with severe gastro symptoms are prescribed endoscopies-- can you set up a procedure for them to forward tissue samples to your labs for analysis if they wish to do so?

Lobbying for funding as Dr. Lipkin suggests could cite the need for replication studies like this & the importance of research into previous infections. Not clear to me if he was referring to microbiome research only when he mentioned having 10% of needed funding or if he meant for all of his remaining pathogen work. Anyone know?
 

vli

Senior Member
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Not clear to me if he was referring to microbiome research only when he mentioned having 10% of needed funding or if he meant for all of his remaining pathogen work. Anyone know?
Yeah the way he said it I didn't think was clear either.

I am not American and have no Congressman who represents me (I'm a Hong Kong resident). Who should I contact on here to try to put together a fundraising effort for Dr Lipkin?
http://forums.phoenixrising.me/inde...h-raising-funds-for-prof-lipkins-study.25213/
 

Ember

Senior Member
Messages
2,115
Ember - where can I see the Aug 30th Unger response?
Jennie posted and explained the relevant excerpt:
Dr. Unger responded in writing on August 30th, but for unknown reasons the advocates did not receive her response until today. Both the letter and Dr. Unger’s comments on the call today explain why CDC has chosen to do one day of maximal effort testing, followed by 48 hours of cognitive testing and symptom measurements. Especially important (and highlighted in the excerpt below) is Dr. Unger’s representation of Dr. Snell’s opinion on the protocol:

"To address concerns regarding the cardio-pulmonary exercise testing (CPET) in the second stage of the study, I would like to share additional details, and the rationale that we used to select the one-day maximal exercise test. Our primary objective is to measure the exercise capacity in as many of the enrolled patients as possible using a standardized protocol, and to monitor the post-exertional response for 48 hours with online cognitive testing and visual analogue scales of fatigue, pain, and symptoms. Maximal CPET with one day of testing and 48-hour follow-up of cognition was developed in consultation with Dr. Gudrun Lang (cognition) and Dr. Dane Cook and Connie Sol (exercise). The exercise protocol was discussed also with Dr. Chris Snell. Dr. Snell favors the two-day test because it gives more information, however he believes the one-day maximal CPET will provide useful information. We chose the one-day test so that more patients could be tested. The two-day test would require an additional overnight stay for those patients who travel long distances to attend clinic and excludes those who are most severely affected because of the heavy physical toll. In developing the protocol, we strived to find a balance between testing that would yield meaningful data in the broadest representation without placing an unnecessary burden on the patients."
Jennie commented, “The excerpt I posted is the only portion of the letter that pertains to CPET.”
 

Ember

Senior Member
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2,115
However, I still think that Dr Snell has not replicated his own research.
When Dr. Snell discusses his own replication study, he describes “slightly different results:”
Our first attempt at doing this, we saw significant difference in oxygen consumption, CFS compared to controls. Controls usually do a little better on the second test; CFS did considerably worse. We replicated that with a larger population. That first study was an n of 6 for CFS and 6 controls. We replicated it with 51 CFS and 10 controls.

Slightly different results. We didn't get such a dramatic drop-off in oxygen consumption, but one of the measures we did look at was workload. We get that on a bike; it's exclusive really to a bike. And we saw a big drop-off on second test workload at ventilatory or anaerobic threshold in the CFS population that wasn't apparent in the CFS (sic) population. What that suggests is a big drop-off in efficiency in utilizing oxygen post-exercise. So now, at a much lower level of work, I have to start relying on my anaerobic energy system. So I'm starting to get less work for more effort and greater build-up of metabolites.
 

Otis

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USA
I've done the full 1-day CPET and the Klimas/Sol test about 5 years apart and at different stages of illness. The one-day CPET was much, much more demanding. I was not yet housebound at that time, but I felt awful at the end of the CPET, but recovered partially within hours. I was able to travel home by plane (with hubby, not on my own). The PEM hit about 4 days later, which is typical for me. I had the full PEM -- flu-like symptoms, exhaustion, joint aches, swollen glands. :ill: It was weeks before I felt anything close to baseline again. The testing and the PEM were both excruciating.

That said, I was willing to do it again 5 years later when I was housebound, but better managed, to see if my AT had changed. (It hadn't). The Klimas/Sol AT test was extremely easy. The whole thing was less than 6 minutes, I think. No PEM.

I suspect that the AT test will not give as much information as a 2-day CPET, which is why I think the 2-day CPET should be the gold standard for research. OTOH, if our exercise problems are as severe as they seem to be, it shouldn't require maximal exercise should show abnormalities, so there may be some instances where the lesser test might be appropriate.

Thanks for the insight in the differences between the two tests but I've got one clarification I'd like to make.

There seems to be persistent confusion that because the test is one day that is an AT test and not a CPET test. This is incorrect. The one day test will be a CPET test, not an AT. It just not the two day CPET that Dr. Snell and most patients would prefer.

I'm making this distinction because I believe it's important for patients/advocates to object to the one day CPET and to demand they follow the full Snell/Stevens protocol (two day CPET) and it's critical that our objections are accurate.

From @jspolita's blog, this is the written response from Dr. Unger regarding the one day test where she clearly states they are running a one day CPET test. I see this was posted above but I'm posting it here for completeness.

To address concerns regarding the cardio-pulmonary exercise testing (CPET) in the second stage of the study, I would like to share additional details, and the rationale that we used to select the one-day maximal exercise test. Our primary objective is to measure the exercise capacity in as many of the enrolled patients as possible using a standardized protocol, and to monitor the post-exertional response for 48 hours with online cognitive testing and visual analogue scales of fatigue, pain, and symptoms. Maximal CPET with one day of testing and 48-hour follow-up of cognition was developed in consultation with Dr. Gudrun Lang (cognition) and Dr. Dane Cook and Connie Sol (exercise). The exercise protocol was discussed also with Dr. Chris Snell. Dr. Snell favors the two-day test because it gives more information, however he believes the one-day maximal CPET will provide useful information. We chose the one-day test so that more patients could be tested. The two-day test would require an additional overnight stay for those patients who travel long distances to attend clinic and excludes those who are most severely affected because of the heavy physical toll. In developing the protocol, we strived to find a balance between testing that would yield meaningful data in the broadest representation without placing an unnecessary burden on the patients.

This is a very good blog entry on the subject and I highly recommend reading the entire thing because it also contains comments from Dr. Snell on the decision to reduce the CPET testing to one day.
 

SOC

Senior Member
Messages
7,849
Thanks for the insight in the differences between the two tests but I've got one clarification I'd like to make.

There seems to be persistent confusion that because the test is one day that is an AT test and not a CPET test. This is incorrect. The one day test will be a CPET test, not an AT. It just not the two day CPET that Dr. Snell and most patients would prefer.

I'm making this distinction because I believe it's important for patients/advocates to object to the one day CPET and to demand they follow the full Snell/Stevens protocol (two day CPET) and it's critical that our objections are accurate.

From @jspolita's blog, this is the written response from Dr. Unger regarding the one day test where she clearly states they are running a one day CPET test. I see this was posted above but I'm posting it here for completeness.



This is a very good blog entry on the subject and I highly recommend reading the entire thing because it also contains comments from Dr. Snell on the decision to reduce the CPET testing to one day.

I think Dr Unger has been clear that the one day test is a CPET, not an AT only. I don't see any confusion in the patient community about that.

I, like Dr Unger, have concern about severely ill patients being able to perform the two day CPET. However, unlike Dr Unger, I also have concern about those same patients doing the one day CPET. It is not an easy test, even for the moderately ill. I also have concern about whether online fatigue self-evaluation is any kind of reasonable measure. I would much prefer objective measures. I'm also not convinced that 48 hrs is long enough to capture the full effect of exercise, although I think it is likely to show some significant effects. Using the one day test looks like half-assed science to me, but I'm not making the decisions.
 

Ember

Senior Member
Messages
2,115
Perhaps I've been over-enthusiastic about the thought of the CDC carrying out a proper study at long last.
What we don't need from the CDC is another obsolete case definition. Dr. Unger stated her research goals in November 2011, shortly after her Ottawa rebuttal of the ICC:
“We are planning to collect standardized data on all the domains of illness included in the Canadian Consensus Criteria of CFS/ME, the 1994 CFS definition and the newly proposed International ME definition,” she wrote. “We anticipate that this data will assist researchers and clinicians in considering further refinements of the case definition.”
Last spring, Dr. Unger added:
I want the data to show us what it is. I am hearing regularly from the patients that this is one of the biggest problems they have. Malaise, I'm told, is the worst word in the world to use—that's it's post exertional exacerbation or relapse. At the same time, I've asked clinicians, “Is this unique to CFS?” Some of them say yes and some of them say no. We need the data to really look at this. If a patient doesn't have that, would you not manage them as a CFS patient? There again, I'm getting mixed answers from clinicians.
Without ever naming it, Dr. Unger is referring to the ICC domain of post-exertional neuroimmune exhaustion: “When an exercise test was given on two consecutive days, some patients experienced up to a 50% drop in their ability to produce energy on the second evaluation [62].” PENE is described as the cardinal feature of ME, a subset that should be treated as separate and distinct from CFS. Dr. Unger must be familiar with the test for PENE prescribed by the ME Primer:
PENE: A 2 consecutive day comprehensive 8-12 minute cardiopulmonary exercise stress test (measuring heart, lung, and metabolic function) - only ME patients have significantly worse scores the second day & abnormal recovery from exertion. * Exercise tolerance test with expired gas exchange - (2 consecutive days) – measure cardiovascular, pulmonary & metabolic responses at rest & during exercise: □ peak oxygen consumption VO2 or VO2 at anaerobic threshold (AT) - decline of 8% or greater on test 2 indicates metabolic dysfunction, □ post-exercise blood analysis - increase in sensory, adrenergic and immune genes - increase in metabolite receptors unique to ME
Dr. Unger could address her research questions by gathering the data that the Stevens Protocol provides. Instead, she's opting to measure exercise capacity, along with post-exertional cognitive function, fatigue, pain and "symptoms." By tapping the domains of earlier case definitions, Dr. Unger is turning the clock back a decade, despite professing:
I share your concern about patient heterogeneity. My question is whether any one case definition is going to solve the problem. Part of what I think we need to do is decide what the measures are that are going to yield us meaningful subgroups of this illness. I think even the Canadian case definition allows for heterogeneity.
Prior to developing the Stevens Protocol, didn't Staci Stevens use the kind of soft post-exercise measures that Dr. Unger has chosen? Dr. Snell comments:
One of the things that surprised me when I got into the field that nobody really had an objective measure of fatigue. You know, “I'm tired. I feel fatigued.” So I say, “How much?” “Oh well, 5 on this scale.” Well that doesn't mean anything to me. I need some hard numbers. You know, that's not real science, as far as I'm concerned. We have tests out there that we use all the time with athletes who are so concerned about their performance that they'll take it over and over again. They use it to monitor their training. Interestingly, they have their own off-label drug trials going on that they assess through exercise testing and physical function. And they get way more publicity than any drug trials in any mainstream illnesses, let alone chronic fatigue syndrome. It applies equally well to high-level athletes as it does to people with certain pathologies. It's just a matter of asking the right questions.
Dr. Snell remembers the early days:
We connected with a group of people that were involved with chronic fatigue syndrome research, and we actually got a contract to do exercise testing for a major drug trial. And we thought well, here we've got a condition where fatigue is a primary symptom, and how are they measuring fatigue? “Oh, I'll give you a questionnaire.” That doesn't really work for athletic performances, and so it was nothing that we were ever familiar with: “Let me give you a questionnaire to see how you're going to do in the Olympics. No, that's not going to work. Let me stick you on this treadmill, and let's look at your performance, and then we can predict what we need to do to get you to win a gold metal in the Olympics.” Everything's objective; everything's data driven. So we tried to bring that approach to understand fatigue primarily in chronic fatigue syndrome, but also across a whole range of conditions. Because the symptom is the same. Fatigue is fatigue. Let's see how it manifests itself; let's quantify it; let's measure it. Then maybe we can start trying to understand what the underlying cause for that fatigue is.
Back in 2009, Staci Stevens testified before CFSAC:
CFS is a physical disease, and we can identify, characterize, and measure its most distinctive and disabling features. The gold standard in medicine is to identify and employ objective measures to evaluate disease and illness severity. That is what we do at the Pacific Fatigue Laboratory; evaluate multisystem function and impairment in CFS. A medically determinable impairment requires objective evidence. For example, we have developed an objective serial cardiopulmonary exercise test protocol using AMA guidelines that measures functional impairment as well as the metabolic, cardiovascular and pulmonary systems both at rest and during exercise. The protocol elicits and measures both fatigue and post-exertional malaise, considered to be a hallmark symptom of CFS. By contrast, the CDC recommends the use of self-report questionnaires to diagnose and quantify this illness. Questionnaires simply do not provide the evidence required by the Social Security Administration or long term disability carriers to diagnose medical illness or to determine a disability claim. That questionnaires have become the standard of diagnosis for CFS at the CDC shows how little progress they have made in the last 25 years in characterizing this disabling syndrome....

Without a sensitive and specific case definition, how can future research hope to uncover the biomedical underpinnings of this disorder for the benefit of those who suffer?
 

Bob

Senior Member
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16,455
Location
England (south coast)
When Dr. Snell discusses his own replication study, he describes “slightly different results:”

Yes, I know, but thanks for looking into it.
I was referring to the published data, in his 2005, 2007 & 2013 papers.
In his past studies (2005/2007), which I gave links to earlier, Snell got significant results for VO2 peak tests, as stated in the abstracts of those papers.
But in his latest study (2013), he doesn't appear to have got significant results for VO2 peak, as far as I can understand it.
Looking at the latest results, there seems to be no difference between test 1 and test 2 for VO2 peak, when comparing the difference between CFS patients with controls between each test.

I haven't read the paper in full, and the text is difficult to interpret, but the results section states:

"Test 2 [...]
Univariate analyses comparing group means for each variable generally concurred with this interpretation although the group means for VO2 peak were not significantly different at the Bonferroni-adjusted alpha level (p=.026; Table 3)."

And in table 2, and Figure 1A, there is almost the same difference between CFS patients and controls in both test 1 and test 2. So the change for CFS patients was not significantly different to the change in the control group, between test 1 and test 2, for VO2 peak, if I'm interpreting it correctly.

The paper is difficult to interpret, and so I may be wrong about this, but I think I'm right.

The results from the latest study were nonetheless exceptionally interesting, esp for VTWL (aka ATWL).
All I'm pointing out is that Dr Snell's research seems to be exploratory at this stage, but with some very interesting, and potentially transformative, results. It's definitely something that should be followed up.