#12 "Chronic Overlapping Pain Conditions" in ME/CFS, new insights with the C.D.C’s Dr Elizabeth Unger, Yang Chen & Elizabeth Fall

[Music] Welcome to Make Visible, the podcast shining a light on complex chronic illness. I am your host Emily Kate Stevens and I've been living with an energy limiting condition since 2020. Here I will speak to the world's leading experts to bring you the latest science research and insights into invisible illnesses, including MCFS, EDS, fibromyalgia, pots, long COVID and more. Welcome to Episode 12 following a short hiatus where I was focusing on maintaining my health and traveling to gather some fantastic interviews that we have upcoming. This week I am bringing you a conversation that I had with members of the US Center for Disease Control, the CDC. I had the pleasure of talking to Dr. Beth Unger who has been researching MCFS for several decades, along with Yang Chen and Elizabeth Fawl who are all part of the MCFS programme there. And our conversation focused on their recent paper looking at chronic overlapping pain conditions that occur in MCFS. There are quite a few factions that probably need explaining and I don't know if we might actually just take it back slightly from the study about which I approached you because we should probably talk about the CDC's MCFS programme and the MCAM which was initiated in 2012 I believe and ran the actual study ran through until 2020. I think you've all been involved in MCAM almost since its inception. So could you just give me a little overview for our audience of what MCAM was set up to do? And the way in which it works. Yang, sure, of course. So let me talk about MCAM study. The full name is the multi set a clinic assessment of magic in sub-malatism, chronic fatigue syndrome, short for MCAM study. This study was conducted across seven specialized clinic in the United States from you mentioned from 2012 to 2020. This project has our study of MCFS and by using the expertise from the leading clinics in this field. I'm starting to rely on those MCFS clinical expertise to decide who will qualify for MCFS group based on their clinical expertise with these units. We did not use any specific case definition. So our study in population includes people diagnosis with CFS, ME or post-infection fatigue and also some of those managers like other MCFS patients. So we published the details of those study design in 2017. Since then we also published nine papers from the MCAM study, including one way we were talking today later, the crank overlapping pin conditions. So we also have a more than 17 data set and the best specimen from MCAM study ran out available on some website that include map, ME, CFS and search ME, CFS. If anyone or any investigator who are very interested in using our data and best specimen from MCAM study, they can apply and get approval through those data use of agreement for the MCAM study. So that's fascinating. So your study which was retrospective and prospective, people can still go back and use that data for new studies in the future via application to you. That is correct. I would say it's not really a retrospective study. I mean we did use the medical records from the past but the baseline data is what's available right now and so that's a cross-sectional view. We are going to be adding the longitudinal data which we're looking at. So most of the study, most of the data that we've published so far has been from the first look, what we call the baseline as people were enrolled. And the design was for a rolling enrollment. So people's baseline could occur at different times as they were eligible for enrollment. Which is quite important with this. Because you're watching them from the time that they enrolled. Yes. And that is one of the features of using the specialty clinics. They're very well-defined patients. These are experts in the illness. But the patients by the time they get to them have all been ill, a lot of them have been ill for many years. And so the average duration of illness in our patients is significant. It's on the order of seven years. We made a special effort in some of the phases of the study to try to enroll newly diagnosed patients with an onset of illness less than three years. But those numbers are relatively small. Is that to do with the nature of ME/CFS and its diagnosis? So it's almost, these people have been going through years of not necessarily having a diagnosis or being treated for the CIPCs that we will talk about without actually necessarily having a concrete diagnosis of ME/CFS. Yes. That's one of the problems that patients with ME/CFS have faced for years is the ability to get diagnosed. And many patients go years without a diagnosis. And of course, in order to get to a tertiary care clinic, which all of these are that had participated in this study, it takes a number of years and referrals and many other clinicians to get there. So and it's also I think that people can't underestimate how involved that process is for people with complex chronic illness with conditions such as ME/CFS. On a daily basis, even just trying to see your general practitioner or your local health care provider, before you even get down the road to going to a specialist clinic, which might be some distance away. I think that you have all been involved in a study as well that looks at the cognitive impact, cognitive assessment of actually going through those processes. You were all three involved in that study, were you? Yes. And Yang and Liz, me want to comment on their educational initiatives, two clinicians that we've worked at because we are trying to target primary care positions. Right. So let us talk about that now. And that is one of the things behind the CDC's ME/CFS program in general. One of your primary focuses is the education of primary health care providers. Liz, do you want to talk about how you do that and how you make that happen? Yeah, of course. So CDC has a number of different initiatives aimed at providing health care education. One in particular, we have a collaboration with MedScape where we offer continuing medical education courses, specifically tailored toward primary care physicians, nurses, nurse practitioners, pharmacists, other healthcare professionals. And these continuing medical education courses have information specifically on diagnosing ME/CFS, managing clinical care for patients with ME/CFS, among other important information that healthcare providers should take a look at. And is that your primary route into educating healthcare providers? Obviously you are part of the CDC, you are visible. Are you able to influence policy or government in other ways or is the primary route through that primary healthcare? I would probably let that answer that one. It's a little complicated. Yeah, I would say there isn't a specific policy, but CDC does advocate and raises the issue of ME/CFS at every possible opportunity. And I would say our web pages that we've spent a lot of time and a lot of collaboration with our persons with lived experience to get into really good shape. Our is really another important outreach. And the web page has sections for healthcare providers, as well as for medical students. We have a special section on ME/CFS in the pediatric population. Also some toolkits for patients as they go to attend their clinical visit to help them ask some questions and provide guidance. So our web page is really, I think, one of our primary outreaches. We continue to update that. Yeah. And so, you know, the whole government, I mean, it's not just CDC and IH is involved in addressing ME/CFS through their research component and we collaborate, very, or you know, try to integrate our programs and have very close communication with them. So. And in terms of the funding model for such, a large project as the MCAM project, is that something that you have had to fund independently, or have to seek funding for and for its continuation? Or was that something that from its initiation was guaranteed funding? CDC's ME/CFS program is funded through Congressional appropriations. There is a special line item for ME/CFS and that is determined each year. So with a year-by-year determination. And the MCAM study was funded through CDC's funding line that Congress approved. All right. And just while we are sort of talking about an overview of the of the CDC's ME/CFS program, Beth, you are chief of the Chronic Viral Diseases Branch. So you don't only look at ME/CFS. You have a broader remit. Am I right in that? Well, you know, it's really interesting how things are organized at CDC. And the two major focuses of our branch are ME/CFS and HPB. We have an HPB laboratory. We're very active in supporting monitoring of HPB vaccine impact in the U.S. as well as pathogenesis of HPB. And of course, HPB is a chronic virus that has a very different kind of a chronic outcome in that it can result in cancer. And with the coming of the COVID-19 pandemic, we work already alerted to the fact that there was likely to be a long-term outcome of this. And so while we are not responsible for long COVID, we have been very active in working with cross-center groups to establish a working group on infection associated chronic conditions and illnesses that includes ME/CFS as well as long COVID and post-treatment line disease and the other post-infection conditions that happen following Dengue or any of the pathogens that CDC is studying. And that's why we have a cross-center working group. Progress in all of these illness post-infection conditions and illnesses has been, I think, limited by the small numbers of people involved in the kind of siloed approach, each organism's group, kind of looking at it in isolation. And the huge number of people affected by COVID kind of changed that and helped everyone recognize that it's very important to look at all of these conditions together to understand the similarities, differences and try to understand the underlying pathogenesis. Yeah, absolutely. And I think that's one of the fascinating things if we look at something like your paper into chronic overlapping pain conditions and actually looking at your all three of your work historically, you can see this huge overlap between some of these chronic overlapping pain conditions and ME but also many of the other post-infectious conditions and in that I mean long COVID, of course, but there's also chronic Lyme. I think also there's possibly conditions that don't necessarily have any kind of specific definition they've all within, within one or all of them. And it's for all of us to work out this where we overlap and where we don't. So let's talk about this paper. You wrote this paper with some of the people who have always been involved in your MCAM study but some of the biggest researchers and people who are most visible on ME/CFS. So I've spoken to this in debate and I've previously spoken to Benjamin, Natalie Surn and Nancy Climars. These people who have been working for decades collaborated with you looking at the chronic overlapping pain conditions. Liz, would you first of all like to tell me the definition of those chronic overlapping pain conditions? Yeah, so chronic overlapping pain conditions also COPCs for short. They're a group of pain-related conditions that frequently occur together in the same person. And these conditions include chronic low back pain, chronic migraine headache, fibromyalgia, interstitial cystitis, which causes pain in the bladder and pelvic area, temporal mandibular disorder, which affects the jaw joint and can lead to pain and difficulty with jaw movement. And also two female specific conditions endometriosis and vulvodemia. And vulvodemia for those who are unfamiliar is a condition that leads to chronic pain in the vulvar area. And ME/CFS is actually considered a chronic overlapping pain condition as well because those affected with ME/CFS often experience pain as a symptom. And just overall, these conditions are frequently seen in ME/CFS and having one of these conditions can increase the likelihood of experiencing others. And I think that you found that almost 75% of the people involved in your study did have a COPC. Is that the correct figure? Yes, that's right. One of the questions that this raises is what comes fast or how do these things into relate? Is it that people with the propensity, for example, for me, grain, therefore have a propensity to move into ME/CFS when they have a viral insult? Or do you believe that the ME/CFS then leaves you open to a lower pain threshold? Or I think that's a really negative way of putting it as a difference in pain perception? I think the term that's commonly used is central sensitization. So it's this overactivity in the central nervous system that leads to pain amplification. That's one of the theories anyway that may be common among these chronic overlapping pain conditions is that there is this overactive pain response in response to pain stimuli. But to be clear, you're not saying that these people are somehow making this up, generating it. No, not at all. So in terms of the order of things, do you have any idea what comes first, whether people had an underlying pain condition, price the ME/CFS or whether it came in after? Well, that's a good question. I think in most cases it's not always easy to tease out the timing which condition came first. I think in a lot of cases having one condition may lead to complications later on, but I would say research in this area is still emerging. So there's a lot more information that we need to figure out about these conditions for sure. I think one of the interesting things to come out of this paper is this idea that if you treat some of these things for which we already have some kind of management. So if you are able to provide some kind of pain relief or treat migraine, if we treat the symptoms of the COPCs, you actually alleviate some of the symptoms of ME/CFS. Is that something that you found in this study? Well, it's not something that we directly studied in this particular analysis, but I would say that given that the chronic overlapping pain conditions did exacerbate certain symptoms in people with ME/CFS, it would be, it's possible that by treating these chronic overlapping pain conditions, we may be able to alleviate different symptoms like pain, for instance. And I just want to point out that a lot of these chronic overlapping pain conditions do have their own FDA-approved treatments. So that's one thing that healthcare providers should understand is that there may be options to help improve quality of life for patients with ME/CFS by treating these other conditions. Okay, I think that we could say that all of the COPCs, along with the ME/CFS, have inflammation in common, is that one of the things that is driving all of this? We did not look at mechanisms in this particular study. Yeah, it's a little bit outside the scope of what we were looking at specifically. There has been a lot of research in the chronic overlapping pain sealed about what the mechanisms may be. And so there's a lot of question and understanding the role of the immune system in ME/CFS and all the post-acute infection syndromes is really basic. It's central. Inflammation and the autoimmune and all of that is just, it's still a very big question and very much an area that's likely to yield answers, but it's very complicated and it's not something we examined in this study. We just looked at the conditions here. Okay. Young, tell me about what you found from the study and looking at these COPCs with MECFs. Yeah, sure. Of course, the first one we found, as you mentioned, we found that the CILPC are very extremely common among the people with MECFs, much more than those health controls. From our study, we found over 75% of MECFs reported to have at least one COPCs, but only 70% of control reported to have a CILPC. When we looked at each CILPC, we found the chronic migraine handache was most common COPC reported from the MECF patient. 48% closer to half MECF patient had the chronic migraine handache. And the phabermagia, chronic low back pain, and the uid bubble syndrome are also very common with the rate 30 to 40% of MECF patients reported to have this one. People with one CILPC are more likely have another one. So, as Lisa mentioned earlier, that is from some literature. Also, our study also found the most common combination of two CILPC chronic migraine handache and phabermagia. And from the impact, we found people with those additional pain conditions, those tend to have a worse pain, and that can reduce the physical function and lower quality of life. So, these suggest the overlapping pain condition may contribute to the very higher level of pain among the people with MECFs. That is why we said that is important to identify and the managers COPC. That could have to improve the outcomes among MECF patients. It's interesting, isn't it, because they are all in completely different regions of the body, localized, the majority of them, not fibromyalgia, and some people might say migraine is not just in the head. But several of them are localized, whereas MECFs tends to be a full body condition. Is it easy to separate each of them out from the MECFs to identify as ACIPC instead of a symptom of the MECFs? For our study, we use the medical history form, so have those patients reported if they have a pain on their hand, cover the pain on their low back, and we also use the breath pain even to rebody map to ask them to identify which their pain area, you know, if they in the shoulder hand or low back, and we also ask a highlight of those pain lasted. We only select those last three months. That is the standard definition for chronic pain. So in this way, we can identify those chronic pain in different kinds of locations on their body and for those chronic pain conditions. Okay, and I will say we relied on the clinicians to make the distinction, and there are case definitions for each of the chronic overlapping pain conditions, and sometimes it takes a good clinician to be able to try to distinguish and separate. And so I think that what's important is to look for them and to recognize those that may be amenable to some therapies. Yeah, some kind of treatment. Are there other CIPCs that are not concurrent with MECFs, or do the majority of CIPCs appear in MECFs patients? In our study, we did find that at least one patient had each of the chronic overlapping pain conditions, although as Yang mentioned, you know, there were certain COPCs that were represented at a, yeah, more prevalent than others. But are there any other COPCs that are not included in here in terms of the definition of COPCs? So I think the fjeld of chronic overlapping pain conditions is kind of evolving over time, and new conditions are being considered COPCs. So it is possible that there are additional conditions since the time that we conducted this study. So that would definitely be an area for future research is to include any additional conditions that have emerged as part of the definition. Okay, I wasn't sure if you had taken all of them and tried to assess whether they were concurrent with MECFs, or if you had just looked at the various conditions that were appearing in MECFs patients. I didn't know which way around it was. It's the first way. We had the list and we looked for them in the patients. Okay. Yes, that's right. The endometriosis that is a female only condition. That's an area that you've been looking at for a long time. And I think in 2015, you published a paper about early menopause and gynecological changes in MECFs. Can you tell me a little bit more about that because I don't think it's something that has very much been discussed in relation to some of these conditions, one possibly because it is a female only condition. But two, also, I just think it's one of those things that is not necessarily as easily discussed. I think people can talk about migraine headache because it's one of those things that is more commonly discussed. But can you tell me a little bit about endometriosis? Sure. And actually endometriosis is in and of itself is a very challenging diagnosis for clinicians to make. It causes a lot of symptoms and sometimes infertility in women. And what it is, it's just implantation of the endometrium outside of the endometrial cavity. And so you have these little implants of tissue kind of growing that can cause severe pain and is cyclic manner. And there are treatments and approaches for it, sometimes some hormonal therapies and sometimes people even have surgery. Now what we found, there's so many things about MECFs that not every study can go into detail in every possible connection and medical condition. And most of these don't take a detailed gynecologic history for some reason. And that's what it takes in order to really find out if a patient has had endometriosis. And what we found was combination of endometriosis, heavy menstrual bleeding, and fibroids often led to surgery when the uterus and the ovaries were removed and that contributed to early menopause. And this was much more common in women with MECFs and those that did not have MECFs. But again, it takes looking at a very careful gynecologic history in order to tease out that information and you needed in both the patients and the comparison group. And in this particular case, we looked at endometriosis, we didn't look at menopause at all because that wasn't sort of the feature of the paper. And then because we wanted to look at all of the patients together, we ended up not focusing as much on endometriosis because we were just trying to overall look at those that could have affected all of the patients, male, son, females. I don't know very much about endometriosis, but a lot of the THOPCs seem to be primarily pain, although the mechanism or the root is not necessarily apparent or there's nothing necessarily physical. Whereas endometriosis does that always have some kind of change in the physicality of the endometrium? Right. In order to make a diagnosis of endometriosis, there has to be some evidence of this implantation of the endometrium outside of the uterus. So it's not just the pain? No, it's not just the pain, although sometimes pain and imaging, they can kind of put the two together in evaluating women for this. This is a gynecologic condition really needs experts to look at. In terms of your demographics and in terms of your data on ME/CFS, what is the prevalence of male versus female? And do you have data on the age ranges? And that sort of demographic data from these studies that you've been doing? That's not necessarily related to this paper, but I just thought it's relevant because of the female-only conditions that you have included in the ECOPC paper. And there's a difference between the population that we have in our study and the population that estimates that we have for the United States. Right. Right. So you want to pull, you mentioned those. I mean, would you, is your question about who is in our study or what we think ME/CFS is in the United States? It was both. It was both, because I thought, well, your study has pulled up to female-only COPCs that are quite relevant. But I think it's interesting when you say that those things are not necessarily so heavily studied. And I just ask this female only group because obviously there are a lot of concerns historically about some kind of patriarchal medical system that possibly we are missing things that are only related to women. And so I think some of these gynecological things possibly fall within that. When you say that a detailed gynecological history was not necessarily taken every patient, I'm interested to find out whether that is symptomatic of the number of people who have MECFS, whether it's symptomatic of our medical systems. So in general what I meant was a lot of studies of MECFS don't focus on the gynecologic conditions. And the NIH did a whole series of trying to come up with what are the current research questions. And they had a series of webinars covering various topics. And the gynecologic question came up in a webinar series that was called lesser studied pathologies because it just doesn't come up. There are so many things to address about MECFS that I'm just saying that it happens that the including the gynecologic history doesn't come up. Right? If you're focusing on cognition you might not be collecting a gynecologic history. And a lot of studies do focus on one thing or the other. If you're focusing on exercise you may not take a detailed gynecologic history. So it's not I'm not saying that the women didn't have appropriate care or diagnosis. I'm saying the studies didn't necessarily collect the information. Now the whole question about how MECFS being a female predominant condition and whether that's contributed to the under diagnosis I think we could agree that that's likely. Just like my brain is the same thing. All of these conditions that are difficult to localize or identify a routine simple test that shows its presence. And women complain of it, it's very easy to write it off as anxiety or depression or whatever. So which is interesting in itself though because you know I would say that the thing that we all have in common is women is the gynecological element. Right. The hormonal element of that obviously has in my understanding has a huge impact in things such as the migraine and in pain perception. Well and you think of patients when what they're dealing with and living with MECFS thinking about their gynecologic issues might not be top of the mind. We have not actually looked at how women keep up with their screening and all of the things that should happen if you're a healthy person, mammography and regular pelvic examinations. But if you're having trouble just even getting to out of bed that's not first of mind. You sort of deal with the priority, what you have to have to. It's another factor that can kind of contribute to the problems. I mean this is a very, very challenging illness. Yeah. Yeah. I mean that is so true that you, especially the way that the healthcare systems are set up that you tend to focus on what is the absolute most important thing that I need to address. And I imagine for a lot of people that is simply, am I getting out of bed to have some kind of functional, consistent, obviously there are hugely varying degrees in terms of people's severity. But it comes down to that, doesn't it? What's the most important right now? And yeah, you're right. The things that fall by the wayside will be the things that you're not necessarily thinking about on a daily basis. Yeah. Yang, did you have some data on the demographics? Yes, I just found some. And for the sex difference with all the CIPC conditions are higher, rate with higher rate among the female, the male and even with all of the CPCC, with RPCC, not just family CFS, with all the CIPC among the MSFF females, they have higher rate than those MSFFs in male. So if we look at only those female only condition, you know, other CIPC, not even could endometriosis and voodemia, we found 87% of MSFFs female had at least one CIPC. And where only 65% of MSFs male have at least one CIPC? That is a big difference over the 20% difference. Yeah, a huge difference. Yes. To put that in perspective in terms of MSFs figures in general, what is the prevalence in male versus female? Okay. I think she's asking in the US, what is our estimate of males versus females? That in my corrects, that's what you're asking? Yeah, I'm just interested to know, like if we then compare that against the CIPC figures, just the MECFS prevalence in female versus male. And now in it, it varies on the approach that's used to come up with the estimate and it's usually on the order of three to one or two to one. Yeah. So that is not dissimilar from the long COVID prevalence, female to male ratio, isn't? Not, no. And actually, I think that is kind of a characteristic of a lot of the infection associated chronic conditions in illnesses, seems to be a female predominance. And that has raised a lot of questions about why and autoimmune conditions, again, are much more predominant. If you know, predominantly female. So, yes, coming back to the whole question about inflammation and immunity, a plan is central role in this condition. I mean, that's why people have looked again and again at this. What is triggering it? It could be different in different situations, but there does something, it's a good place to look, right? Beth, I know that historically that you've done studies in so many different things, but one study that came up that I was reading was a study in 2014 that you did into the Basel Ganglia that suggested there's dopamine dysfunction in MECFS. Just related to what we were just saying is there a difference in dopamine production or receptors in male versus female? I don't know. Okay. That's been documented. Okay. And you know, this raises, there are a lot of really intriguing studies. It raises this question and that question and this abnormality. And I think we're just starting to get pieces of the puzzle to try to see how these things all interface. You know, you ask about which came first. And that's one of the most intriguing things is that the inflammation or genetics about your inflammatory response that primes you to something or is it the environment as far as the data on the dopamine receptors. I am not up to date on male versus female differences. Yeah. Not everything that we have we discuss has to be male versus female, but I just thought that was an interesting point that there are two female only conditions included on your COPC paper. But in terms of the design and implementation of the M CAM study, one of the things that I wanted to ask about is that in your principal objectives, it says to collect biospethamins for future hypothesis testing and for evaluation of morning cortisol profiles. What is the relevance of cortisol, morning cortisol profiles in your MECFS studying? So cortisol changes cyclically with time and the morning profile is one of the best ways to get sort of a snapshot of a person's usual cycle of cortisol. And there have been prior studies that indicate that MECFS patients have kind of a flattened cortisol profile. And that may be an indication of how they respond to stress and interaction with the immune system. So we in prior studies used salivary salimets to actually at different time points right as a person wakes up. So the kid is male to them and then they kind of stick this little cotton plug in their cheek for a certain amount of time and allow it to collect saliva every. 15 minutes, I think, up to, you know, spaced out for two hours, approximately. And then you can sort of plot, you know, how the court is all. It should show a change with time. And we are still analyzing that data. Okay. Okay. I just thought that was because it's one of the things that has been looked into with it and they've started to look into it in Long Cave, it as well. Oh absolutely. And I was curious as to what a person's cortisol is supposed to be doing first thing in the morning versus what changes there might be in people with ME/CFS. Right. And the hypothesis is there at least will be a subgroup with a flattened cortisol response, so a less cortisol being produced. And that in turn does what? Less cortisol. Yeah. So cortisol does influence the immune system in very complex ways. It's not like you can say, boom, it's going to do this. But it's an indication that there could be a less of a modulating effect, of course, on the inflammatory and immune response. Okay. Does it also have an impact on the stress response? Oh yes. It's a sort of vital flight. Right. So that idea that possibly people are shunted into some kind of freeze mechanism that their immune system can't fight? Yeah. The cortisol is part of the stress response, interacts with hypothelanic pituitary axis. And there's in one sense, you would think maybe people would have a heightened cortisol response because we know that there's evidence for some increased epinephrine and sympathetic activities. But with chronic stress, there actually can be a sort of a flattening of that whole response. So again, it's a very complicated picture. It won't be a straightforward, this is the answer kind of a thing because there's a spectrum of people's responses. And that's part of the challenge of analyzing that data. Well, in terms of what is coming up for the three of you for your program, I'm excited about hearing about this cortisol. Can you each tell me what you're excited about in terms of research, in terms of the data that you're either analyzing, driving, or hoping to gather. I'd love to hear what you're looking forward to and excited about in terms of this research in this space. Liz, do you want to go first? Yeah, sure. As Beth mentioned earlier, a lot of the studies that we have published to this point have been using the baseline data. So in the future, I'm really looking forward to delving more into the longitudinal data from the MKM study of the multi-site clinical assessment of MECFS. Just so we can get a sense of the illness over time as that is really important to look at given all the fluctuations that are common with MECFS. So understanding more of the time course of the illness, I think will be very insightful. And that must be something that is not data that's accessible to any other study. The majority of people certainly to have that longitudinal data. That is something that's fairly unique to your center. Yes, that's right. Yeah, so very exciting. Yang, tell me what you're excited about. Yes, some similar with Liz mentioned the continued the get the longitudinal data ready and we can use and also release for any other university use. And we can use this data to compare other studies or other units, let's long call that you mentioned earlier. And we also can look at some time relationship as you mentioned which come first, which condition, which condition come first, which condition, can later is also good way to use the longitudinal study data to explore. Additionally, the MECFS starting click so many information, concurrent with just explore some part, we can use our data to continue explore other part other units, like the sleep part and sleep impact for the MSF and as you mentioned for the cortisol, we're also working on that and link some best specimen data with our clinical data and look at their relationship. And of course, release our information for public has to use and then maybe we can compare with other conditions. Yeah. Fabulous. And Beth. I'm excited about subgrouping of these patients to identify a biologic basis because I think that's been one of the big problems with MECFS. There's so much heterogeneity in the illness. And we're seeing the same thing with long COVID when we know there's one infection and it's such a pleomorphic illness. So there are different pathways we think involved. They could be different kinds of illness that all appear the same clinically. So I think identifying biologic subgroups that are going to be responsive to therapies, that's the thing that's most exciting to me. And I don't see that as unique to CDC. I see that as CDC contributing to the broader field that's going to advance this kind of work. That's amazing. Thank you so much and thank you so much for your collaboration with all of these people who hopefully are the people together with you that could make a difference for patients. I really appreciate your time. Thank you. I look forward to hearing more from the team at the CDC as they explore that longitudinal data and start to drill down into some of the aspects that have arisen from looking at these chronic overlapping pain conditions. There are conversations to be had and research to be done around whether it is that ME/CFS changes pain perception or is it indicative of an inflammatory response that increases likelihood of further inflammatory response? More broadly, what is the mechanism behind those chronic overlapping pain conditions? And really what is the mechanism that is driving this heterogeneous collection of symptoms that form ME/CFS and other post viral conditions? I hope that like me you are learning as we go through these interviews and as ever I would love to hear what you're taking from the conversations. And what you're still wanting to hear more about, I assure you every single request that is sent into me I add to my list and I am slowly working through them one by one. I really, really appreciate all of your feedback and I'm striving to bring you more of what you need wishing you a lovely week. Thank you for listening to Make Visible. Please do like, follow or subscribe to listen to our next episode where we'll be uncovering more insights into complex chronic illness. 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