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Chris Armstrong's presentation for Solve ME/CFS October 20 2016 (metabolomics)

Neunistiva

Senior Member
Messages
442
Well it's already proven to be a physical illness from research over the past decades, unfortunately people don't always listen to proof, it takes campaigning and marketing I think. I knew it were a physical illness before I started 6 years ago. In our 2015 paper alone we saw 20% of the metabolites to be significantly altered compared to controls. Using unsupervised multivariate analytical techniques the patients were separated from controls. That is, without telling the algorithm the people were different it could tell that they were based on the metabolites alone. This was all published and more telling in our opinion. In the figure below, the top unsupervised plot is in blood and the bottom unsupervised plot is in urine, both showed decent separation, only minor intermingling. We figured our paper did show it was clearly a physical disorder but it didn't seem to get much exposure and I think the marketing of research and big names has really helped recently.

Thank you for the explanation. I agree that there is enough proof that ME/CFS is a physical illness for anyone willing to look at evidence, and that we even have the evidence is all thanks to researchers like you.

But the problem to prove it is on a personal level, as opposed to on a research level.

While there is a lot of research that points to clear abnormalities, most of us, including myself, have tall stacks of medical exams which are all perfectly normal. I have absolutely no proof that I am sick, apart from the logical conclusion that a psychologically healthy person wouldn't be bedbound, completely dependent on the help of others, for 7 years if there wasn't something seriously wrong physically.

The reason why I am considering paying a lot of money for the metabolic test (apart from helping researchers get more information) is for having solid evidence of ANY physical abnormalities, and not having to rely on a few kind doctors to take my word for it.

I'm willing to take the risk of the test not revealing anything, since I am not obligated to show it to anyone else, and whether the results are what I hope for or not, I will take them with a grain of salt.

It's easier remaining hopeful with researchers like you backing us up. Thank you.
 
Messages
67
Thank you for the explanation. I agree that there is enough proof that ME/CFS is a physical illness for anyone willing to look at evidence, and that we even have the evidence is all thanks to researchers like you.

But the problem to prove it is on a personal level, as opposed to on a research level.

While there is a lot of research that points to clear abnormalities, most of us, including myself, have tall stacks of medical exams which are all perfectly normal. I have absolutely no proof that I am sick, apart from the logical conclusion that a psychologically healthy person wouldn't be bedbound, completely dependent on the help of others, for 7 years if there wasn't something seriously wrong physically.

The reason why I am considering paying a lot of money for the metabolic test (apart from helping researchers get more information) is for having solid evidence of ANY physical abnormalities, and not having to rely on a few kind doctors to take my word for it.

I'm willing to take the risk of the test not revealing anything, since I am not obligated to show it to anyone else, and whether the results are what I hope for or not, I will take them with a grain of salt.

It's easier remaining hopeful with researchers like you backing us up. Thank you.

Well then in that case I will talk to my group and the clinic we work with about possibly running samples for people if they wish it. Is there a group that currently does a metabolic test?
 

Neunistiva

Senior Member
Messages
442
Well then in that case I will talk to my group and the clinic we work with about possibly running samples for people if they wish it. Is there a group that currently does a metabolic test?
To the best of my knowledge, OMF is getting an option for international patients metabolic test set up with Metabolon. Dr. Janet Dafoe talked about it in this thread.

There is also Gordon Medical Research:
For a donation of $1500 or more, individuals will receive a Personal Metabolomic Assessment (PMA) report that will show them how their personal metabolomic profile compares to a healthy population and the overall CFS population.
 
Messages
67
To the best of my knowledge, OMF is getting an option for international patients metabolic test set up with Metabolon. Dr. Janet Dafoe talked about it in this thread.

There is also Gordon Medical Research:

Wow that is a lot of money. I suppose it goes back into funding research too though so that's great! In talks to setup funding for our research too, maybe this would be a way to do it as I run the samples myself. All the studies and work we have done to this date has been on a budget of less than $100k USD.
 

Ben H

OMF Volunteer Correspondent
Messages
1,131
Location
U.K.
To the best of my knowledge, OMF is getting an option for international patients metabolic test set up with Metabolon. Dr. Janet Dafoe talked about it in this thread.

There is also Gordon Medical Research:

Hey @Neunistiva and everyone,

Just a small technicality but it is not OMF setting up the metabolomic test, it is Laurel Crosby at Stanford University. When it is ready for commercial release I will create a thread (which should be soonish).

The biggest difficulty we found, and Laurel has since managed to navigate, was how to get international patients blood to the facilities. Laurel came up with the great idea of LN2 shippers which worked great. Upto 32 days of shipping time. Dry ice isnt an option for international patients as if it gets stuck in customs, your sample is pretty much done for. Its only days with dry ice.


Anyway hope that clears that up a bit. I agree that there are lots of patients who want this test, even if its not helpful clinically just yet.


B
 

Hutan

Senior Member
Messages
1,099
Location
New Zealand
My shock index when standing in the morning is over 1.0 about half of the time and is always more than the 0.5 to 0.7 range reported for healthy people. My orthostatic intolerance, PEM symptoms and shock index are all positively correlated.
Yes these symptoms all seem to be somewhat related.

Yes, it makes me wonder if the shock index (heart rate divided by systolic bp) would be useful as a quantitative and easy to measure proxy for PEM. That could potentially be useful when trying to find relationships between PEM and metabolites and when trying to track responses to treatments.

It would be great if someone could study how well correlated shock index is to PEM in ME people with OI and without OI.
 

FMMM1

Senior Member
Messages
513
Wow that is a lot of money. I suppose it goes back into funding research too though so that's great! In talks to setup funding for our research too, maybe this would be a way to do it as I run the samples myself. All the studies and work we have done to this date has been on a budget of less than $100k USD.

Thank you for your earlier reply in which you stated that NMR was the "gold standard" in metabolic testing. If you were to start testing patients would you use NMR or Mass Spectrometry or both? What are the advantages of NMR compared to Mass Spectrometry and vice versa?

I'm wondering e.g. if NMR has lower or higher detection limits compared to Mass Spectrometry or if Mass Spectrometry covers a wider range of metabolites (biochemical pathways) compered to NMR?

Thanks
 

JohnM

Senior Member
Messages
117
Location
West Yorkshire
Yes, it makes me wonder if the shock index (heart rate divided by systolic bp) would be useful as a quantitative and easy to measure proxy for PEM. That could potentially be useful when trying to find relationships between PEM and metabolites and when trying to track responses to treatments.

It would be great if someone could study how well correlated shock index is to PEM in ME people with OI and without OI.

@Hutan
I had never heard of shock index until your post, but it is such an apt description of how I feel at my worst - i.e. in a state of shock. I am in the OI camp, with a narrow pulse pressure most often, but also experience intermittent Orthostatic Systolic Hypotension, and POTS. Perhaps yet more evidence of an inability to maintain homeostasis, and why, as Chris alluded to in an earlier response, longitudinal metabolite profile studies will be required to be meaningful?

As is often the case on PR, yet more information for me to digest, and further motivation for me to better manage my activity/energy levels through monitoring heart rate and blood pressure levels. At a practical level I think it is about the most productive thing I can do to improve my health at the moment. :)

A cursory glance online also turned up this paper - https://www.ncbi.nlm.nih.jgov/pmc/articles/PMC4193151/ - on the correlations of Shock Index and Modified Shock Index, which may also be of interest?

@ChrisArmstrong
Thanks kindly for your research efforts and for your replies to queries raised to date :)

Would it be feasible to incorporate measurements of PEM, HR and BP into any future design study, together with "activity levels (number of daily steps) and body mass index", as outlined by @Sidereal in an earlier post?
 
Messages
67
Thank you for your earlier reply in which you stated that NMR was the "gold standard" in metabolic testing. If you were to start testing patients would you use NMR or Mass Spectrometry or both? What are the advantages of NMR compared to Mass Spectrometry and vice versa?

I'm wondering e.g. if NMR has lower or higher detection limits compared to Mass Spectrometry or if Mass Spectrometry covers a wider range of metabolites (biochemical pathways) compered to NMR?

Thanks

Well NMR is much cheaper and reliable so I'd much prefer a test be conducted on it however it's not as sensitive as MS so there are less metabolites to use in a test. When we get some more funding we will try expand to a much larger cohort to study and validate a test.

@Hutan
I had never heard of shock index until your post, but it is such an apt description of how I feel at my worst - i.e. in a state of shock. I am in the OI camp, with a narrow pulse pressure most often, but also experience intermittent Orthostatic Systolic Hypotension, and POTS. Perhaps yet more evidence of an inability to maintain homeostasis, and why, as Chris alluded to in an earlier response, longitudinal metabolite profile studies will be required to be meaningful?

As is often the case on PR, yet more information for me to digest, and further motivation for me to better manage my activity/energy levels through monitoring heart rate and blood pressure levels. At a practical level I think it is about the most productive thing I can do to improve my health at the moment. :)

A cursory glance online also turned up this paper - https://www.ncbi.nlm.nih.jgov/pmc/articles/PMC4193151/ - on the correlations of Shock Index and Modified Shock Index, which may also be of interest?

@ChrisArmstrong
Thanks kindly for your research efforts and for your replies to queries raised to date :)

Would it be feasible to incorporate measurements of PEM, HR and BP into any future design study, together with "activity levels (number of daily steps) and body mass index", as outlined by @Sidereal in an earlier post?

Yes we can certainly do this, Working on something that could help with collecting some of this information. There is a myriad of tech out there that could make this quite plausible and affordable.
 

Daisymay

Senior Member
Messages
754
Wow that is a lot of money. I suppose it goes back into funding research too though so that's great! In talks to setup funding for our research too, maybe this would be a way to do it as I run the samples myself. All the studies and work we have done to this date has been on a budget of less than $100k USD.

Good grief.....you mean ALL your research over all the years?
 

JohnM

Senior Member
Messages
117
Location
West Yorkshire
Well NMR is much cheaper and reliable so I'd much prefer a test be conducted on it however it's not as sensitive as MS so there are less metabolites to use in a test. When we get some more funding we will try expand to a much larger cohort to study and validate a test.

Yes we can certainly do this, Working on something that could help with collecting some of this information. There is a myriad of tech out there that could make this quite plausible and affordable.

@ChrisArmstrong
Again many thanks for your replies to queries posted to date. I'm in the midst of a real rough patch this past week or so, but knowing people like yourself are working on our behalf to find answers to this awful disease sure helps; such a contrast to the continuing shenanigans and influence of the BPS adherents here in the UK.

I hope that you can get the funding required to expand on your research, and would be happy to contribute the little I can, as and when you're able to set anything up. :)
 

soti

Senior Member
Messages
109
@ChrisArmstrong - thanks for your and your group's work and for taking the time to engage with the PR community. I'm someone whose only abnormal test result was a very high level of serum glutamine "approaching that of ammonemia" as the lab noted, and of course no one could tell me what this meant. Given the close relationship between glutamate and glutamine, and the starring role for glutamate in your paper, I have hope that you guys are on the track of something that may ultimately prove illuminating for my case---as well as for many others. Keep us posted as to where to send funding donations.
 

ZeroGravitas

Senior Member
Messages
141
Location
UK
Thank you so much already @ChrisArmstrong for answering so many questions here (and on other threads), following on from your brave webinar appearance during the zombie hour of the morning, with a cold (man, you sounded so relieved to reach the end of that, lol ;):)).

I'll quickly mention that @Cort covered your work the other day, here on his Health Rising blog (although I'd guess you know that already).

I'd also like to say how much your paper's findings struck a chord with me personally. I mean, I know it's be laboured (above) that:
This is an important point that needs to be understood, individual metabolite profiles aren't going to match what these metabolite studies are showing.
...But aspects of the metabolic picture you found happened to tally well with my own serum amino acids results from 3 years hence (shown in expandable picture, below). Low essential AA across the board with that tell tale very high aspartic acid (from the use of AAs via glutamine as a fuel). A feature I'd not had any explanation for at all before. (Issues with sulphur pathway too, that you may of mentioned in passing.)
2013 Serum AAs.png
It's kind of funny how we patients have been able to get these test for years, but are still extracting possible meaning from them years after the results. And research seemingly only just able to look at things like this in a meaningful way. Kind of backwards, perhaps, from naive expectations of medicinal science.

I'm aware of how these should be taken with a spoon full of salt, in terms of their meaning (enigmatic as they tend to be already) and the isolated nutritional recommendations the commercial ones carry, too. Especially as they will presumably be calibrated on healthy individuals.

Now for some fairly big, open ended questions...:


(1) What trends do you see in the use and effectiveness of the different metabolomic testing technologies (which might we expect to see or have used on us in future)?

My Genova test, for example, will have been done using High-performance liquid chromatography (HPLC), I believe. Which I think essentially separates different sized molecules mechanically, as they move through an adsorbent material at different rates (if I understand correctly). Presumably this produces a kind of bar-code like diffusion pattern that can be read-off, as with those old style genetic tests... Anyway, how does this (older?) technology compare in accuracy and cost to optical and NMR spectroscopy?

You say that NMR is currently much cheaper than MS (mass spectroscopy), but is it likely to scale down in cost much? The setup involves a massive superconducting magnetic chamber, right? Is it the case that whiles that's pretty expensive in itself, the sample measurements are quick and clean (and you just share time on one)? (Sorry, I'm so vague on this, ironic since I did a physics degree, some years ago, at the University of Nottingham, with a tutor based in the Peter Mansfield NMR centre, heh.:oops:)
Cropper2016-11-18-05-11-23-9942501.jpg < From your webinar video (NMR test equipment used?).
I get the impression that optical spectroscopy technologies are really improving rapidly in price-performance and miniaturisation. (Exponential technological advances are a particular interest of mine.) So even if it is more expensive than NMR right now, is it likely to be cheaper (and better in many ways), within the next decade, say? (With NMR reliant on less shrinkable equipment?)


(2) Is there some resource that gives some kind of easily digestible, qualitative (and quantitative) indication of how much and how rapidly each type of metabolite tends to vary (and under what conditions)?
Cropper2016-11-18-05-13-57-8870523.jpg
Its cool that you highlighted this, since when we look at our own results there's no indication or feel for what what the dynamics are like there. The kind of talk I see about people's out of range results tend to be very linear in it's induction. There's often no appreciation for the relative magnitude of the quantities, even, with just a plain number quoted.:confused: Let alone thinking about whether different metabolites will take days or months to slide out of range, or how much they might spike at various times after eating (as you mention).

For example, my nutritionist, at the time, suggested that low serum AA levels across the board like that (it was a fasted morning draw, I think) would likely be the product of months of decline. Is that reasonable? How big might a protein meal AA peak be, by comparison? Fat soluble vitamins (D, K, A, E) are certainly very slow to change, right? On the opposite end of the scale, I was looking up adenosine, and that's stated to have a serum half-life of under 30 seconds!(?) It puzzled me how substances like that are even measured... (Is it all produced locally to the site of the blood draw? Do it's levels reduce in the sample, after draw, to an equilibrium set by enzymes in the blood? Etc.) Where-as, for one thing, people are generally familiar with blood glucose level variations, up and down within a day (from diabetics in trouble on medical dramas).

What I'd really like to see are demonstrative dynamic models of metabolite levels. Preferably interactive ones that you can poke with an input change, to get a feel the pliability/elasticity characteristics and knock effects through the various paths to other metabolites... Although, even a written data repository would be a step up from hit-and-miss Wikipedia pharmacokinetic numbers. Even the human metabolome database often doesn't seem to have the relevant info.


(3) Have you used computational simulation of human metabolism at all, or know much about others who have?


Some years ago I saw a there were various efforts aiming at ultimately creating a totally detailed whole body virtual modelling system of the interplay of metabolites, proteins, genes, etc, across the various compartments and tissue types of the body. Are such things visibly happening or having any impact yet, in your experience?

I envisage this kind of super-detailed simulation being used as in conjunction with data fed in from the various types of testing (and a Watson-like integrated AI expert system), as the new paradigm of medicine (2.0). One that's more preventative and holistic. But before then, I'm wondering if similar approches might get some early action being used for treating us lot, here. I mean, like you've been saying...
Yeah I don't expect there to be a button but it all depends what is occurring in the individual. We will be engaging in genetic profiling during the long-term monitoring to determine if individuals have a genetic issue that is hindering their recovery.
I'm assuming it will take long-term monitoring to bring the metabolism up together.
...It seems unlikely at this point that proper recovery from CFS/ME will be as straight forwards as a drug monotherapy (for most). Might it even be the case that targeting the most derange quantities in a patient, to bring them all up together, may not be effective? (Or a lot less effective than optimum.)

I mean, you talked about (metaphorically) picking up all (or enough) of the fence posts at once, to get it (metabolism) to stand back up. I'd previously thought about things more like an umbrella, blown inside out: the body has seemingly transitioned to a distinct, stable state. But similarly you need to apply force against many of the spokes simultaneously to revert it.

Could it be that, for some, it's going to take a fairly clever, dynamic, tailored set of interventions. Somewhat like an orbital insertion manoeuvre in space, where you can't just aim straight at where you want to go - it's a whole lot more slide-ways and unintuitive than that.

I mean, metabolism is a great big interwoven web of feedback loops, right? Such that I imagine the CFS/ME state as perhaps being an unusual orbit, around some 'strange attractor', if you are looking at what's going on in some abstract multi-dimensional phase space plot of important metrics. That when we are simple looking across things in one dimension, most of the quantities either fall into the normal area, or behave totally incomprehensibly, because we're not aware of the overall dimensions of what's happening.
2013-09-20-7_7cs.jpg <A strange attractor ploted - chaotic behavior can seem random, but will stay within certain bounds.

Or even that (stretching my space comparison) there may exist clever little adjustments to be made that are far cheaper, easier, less problematic, requiring perhaps only over-the-counter nutrients, that will almost miraculously fix things. If one can just figure out some weird way to apply them to the specific individual. In the solar system, it's been found that there is a dynamically changing network of routes between gravitational Lagrange points and such, requiring almost zero thrust to traverse between the orbits of any planet (but a lot of time and finesse).


(4) In your opinion, could it be possible that the X-factor in patient's blood, which Fluge-Mella/Davison say causes healthy cells to konk-out, might not (always) be a distinct factor?
(Like an auto-antibody.) Could it be a profile of the metabolites and factors themselves? That the cell (or mitochondria) is integrating across all these signals it's sensing, not requiring any single one to always be present. (Sorry, rampant half-arsed speculation. I'm sure we'll find out something concrete from them fairly soon.)

@Freddd, in his B-12 protocol [1,2,many other places (I get lost, sorry)], has talked about a 'deadlock quartet', with regards to his supplement treatment protocol, and many complexities with getting the various central wheels of metabolism (particularly methylation) turning properly again. Writing about paradoxically induced 'doughnut hole' folate deficiency, for example, as a very counter-intuitive, emergent problem, that appeals to my conception of chaotic orbits. I see now that he's previously mentioned such things explicitly with regard to 'refeeding syndrome' (e.g. exhausting potassium, also troubles with interrupting the body's nutrient triage system with too small doses of folate, I think).

Also Amy Yasko's work, Rich Van Konynenburg's offshoot of that, etc, I guess they've helped capture my imagination down this route. Although, playing around with B vitamins and such has failed me a number of times.
Maybe this is some direct problem, like gut bacteria getting in the way, or it just not being appropriate for my biology. Frustrating, that there's so much promise there, if I could just see what was going on; trying to implement such complex protocols while unable to measure one's internal state can feel like trying to solve a Rubik cube blindfolded, having never seen one before. No feedback aside from slow dawning realisation that things have been getting gradually worst for weeks. (Since even the limited testing that is on offer is too expensive and hard to access, here anyway.) Hence why talk of longitudinal testing/treatment sounds amazing.
However, well organised longitudinal metabolite profiles I think will be very useful for the individual. We are running a project on this and I think Ron Davis is too.

Or do you think all this complexity that these clever people (mentioned above) have been exploring is likely to turn out to be somewhat of a Gordian knot? One that's about to be cut by discovery of some previously unseen or unconsidered factor... (Sorry, that's a bit of an impossible question.)


Sorry for all the prattle there...o_OI'd appreciate any of your thoughts on any aspect of the above. Having been accumulating thoughts on this for a couple of weeks (of not being able to get myself together enough to post) I've got rather too much in mind. So might make a second (big) follow up post with the rest too, including some more personal perspectives. That's if no one throws me off the forum for trying to waste the valuable resource of your time... :eek::oops: Oops.
 

ash0787

Senior Member
Messages
308
I like this line of research Chris but I am a bit skeptical about the starvation hypothesis, because while it would explain the long term sickness we experience it doesn't seem to provide an explanation for PEM, particularly when it is occuring within the first month of the illness, presumably before such a state of severe deficiency would set in.

In the onset of mine it happened basically overnight, then I recovered enough to exercise within about 5 days, but then the PEM crash cycle started, went to the doctor within a fortnight and they said 'post viral fatigue' rather than a sustained infection or a 'sepsis', blood testing done within 4 weeks found no signs of a known infection or significant change in immune cell counts.
 

FMMM1

Senior Member
Messages
513
(1) What trends do you see in the use and effectiveness of the different metabolomic testing technologies (which might we expect to see or have used on us in future)?

My Genova test, for example, will have been done using High-performance liquid chromatography (HPLC), I believe. Which I think essentially separates different sized molecules mechanically, as they move through an adsorbent material at different rates (if I understand correctly). Presumably this produces a kind of bar-code like diffusion pattern that can be read-off, as with those old style genetic tests... Anyway, how does this (older?) technology compare in accuracy and cost to optical and NMR spectroscopy?

You say that NMR is currently much cheaper than MS (mass spectroscopy), but is it likely to scale down in cost much? The setup involves a massive superconducting magnetic chamber, right? Is it the case that whiles that's pretty expensive in itself, the sample measurements are quick and clean (and you just share time on one)? (Sorry, I'm so vague on this, ironic since I did a physics degree, some years ago, at the University of Nottingham, with a tutor based in the Peter Mansfield NMR centre, heh.:oops:)
View attachment 18344 < From your webinar video (NMR test equipment used?).
I get the impression that optical spectroscopy technologies are really improving rapidly in price-performance and miniaturisation. (Exponential technological advances are a particular interest of mine.) So even if it is more expensive than NMR right now, is it likely to be cheaper (and better in many ways), within the next decade, say? (With NMR reliant on less shrinkable equipment?)
---- even the limited testing that is on offer is too expensive and hard to access, here anyway.) Hence why tal


Hi ZeroGravitas
The first issue is what is the proposed diagnostic test based on. Chris has proposed using allantoin in urine; however, he's pointing out that you need to find something to correct for the variable dilution of urine (your fluid intake). Creatinine levels in urine are normally used to correct for dilution; however, Chris has stated that creatinine cannot be used in this case (see Chris's webinar for an explanation). According to Wikipedia creatinine "is usually produced at a fairly constant rate by the body"; so there would need to be another compound (detectable in urine by NMR) which is produced at a fairly constant rate.

The next issue appears to be the capital cost of an NMR. I've looked briefly online and the cost appears to be in the region of £1 million (wild guess but perhaps better than nothing). A MS-MS (mass spectroscopy - mass spectroscopy) would cost ball park £250,000 (the metabolmics MS-MS instruments used by Open Medicine Foundation - Robert Naviaux, Ron Davis etc. will cost a bit more). However, the MS-MS method used by Robert Naviaux roughly did one analysis per hour while I'm guessing that the NMR will analyse a sample every few minutes (say 4 minutes). Therefore a NMR could do maybe 100,000 samples a year i.e. the entire/most of the UK patient group in 1 year. Even at £100 per sample a single NMR could theoretically generate an income of £10 million a year. If there already is an underutilised instrument (e.g. Peter Mansfield NMR centre) then it could be a cash cow. So NMR stacks up if you have a diagnostic test.

The Government laboratories in the UK [Fera Science Limited (Fera)/VSD AFBI] do statutory EU testing using MS for £250 ish (testing food etc); so MS-MS is a viable option if you have a diagnostic test. Robert Naviaux etc measured sphingolipids etc (in blood) using MS-MS in their proposed diagnostic test.

I'm not aware of any optical spectroscopy technologies, except possibly infrared, which would deliver the required detection limits but I haven't worked in a chemistry laboratory in decades so there may be something I've missed (I also missed the use of NMR).

The key thing is to identify the diagnostic target(s) e.g. allantoin in urine (or possibly blood) or sphingolipids etc in blood; the technology to detect them is already there (NMR and MS). Making the technology cheaper is a longer term goal.

Thanks for pointing out that there is NMR kit out there and I hope the above helps
 

hixxy

Senior Member
Messages
1,229
Location
Australia
@ChrisArmstrong I don't know if you're continuing to check your account here at all, but I have a question. Do you know of any studies showing localised depletion as a result of immune activation and/or inflammation? For example from what would happen in EGID or IBD which is uncontrolled over a long period of time?
 
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