Shamus/multimed_short · Datasets at Hugging Face

audio audioduration (s) 3.17 30.4	transcription stringlengths 18 455	duration float64 3 30
	autonomic symptoms using the compass questionnaire, ME/CFS patients are clearly and significantly different than controls. Not only that, the degree of autonomic dysfunction on	13
	the compass correlates with the fatigue impact scale. Peter Rowe: We know that orthostatic stress can impair neurocognitive function.	12
	One of the studies that help really bring this out was done by Marvin Medow and Julian Steward, who had been important investigators in orthostatic intolerance.	12
	They showed that as you gradually increase the angle of the tilt test, ME/CFS patients had different problems on the n-back tests.	11
	As you increase the complexity of the n-back test, they made more errors and had slower reaction time. We often hear about cognitive dysfunction as an independent symptom,	12
	but it clearly can also be aggravated by orthostatic stress. I want to highlight a few papers from Linda Van Camp and in France visitor's data in the Netherlands.	12
	I've helped with some of the writing of these papers, but the data are entirely theirs and they deserve the bulk of the credit for this. But they looked at the influence of the tilt test	12
	on cognitive scores using a two back and a three back-test. As you can see here, after the tilt test, immediately afterwards, patients had worse scores on their cognitive studies.	11
	They also looked at what happened seven days after the tilt test. You can see that ME/CFS patients had worse scores on numeric rating scales for concentration.	14
	This is suggestive of orthostatic intolerance being capable of provoking PEM. The symptoms of orthostatic intolerance are largely due to reductions	12
	in blood volume and venous return to the heart when people are upright. That leads importantly to under perfusion of the cerebral circulation.	10
	If we look at this slide, it summarizes the main pathophysiologic influences on patients. They have an increase in the amount of pooling	10
	possibly due to a defect in vasoconstriction. There's about a 10% reduction in intravascular volume in people with orthostatic intolerance.	9
	These two things combined, so that when they stand in upright tilt position, they get a marked reduction in cerebral blood flow.	10
	As David Goldstein at the NIH has termed it, they get an increase in the sympathetic adrenal response, a big increase in catecholamines and adrenal release.	10
	That can lead to a variety of different phenotypes of orthostatic intolerance at the bottom. One is classical orthostatic hypotension, delayed orthostatic hypotension that occurs beyond the three-minute point.	12
	What we term neurally mediated or reflex hypotension, postural tachycardia syndrome. Then some people can have low orthostatic intolerance with a normal heart rate and blood pressure response.	13
	When we tried to measure the cerebral blood flow differences, we initially began with transcranial Doppler, but could not identify differences between	11
	healthy controls and patients during a head-up tilt test. I know that Dr. Novak, who will be speaking later, has had better success with this technique.	9
	But Van Campen and Visser came up with a method of measuring brain blood flow by putting their Doppler probe on each internal carotid artery for about 20 or 30 seconds,	12
	and then each vertebral artery for the same amount of time. So that over a two or three minute timespan, they can tell you by adding the flow through those vessels,	11
	the total cerebral blood inflow. We obviously don't know what is happening within the brain, but that's the amount of blood that is pumped to the brain.	11
	Studies have shown that you don't really need to be an ultrasonographer to see the difference between the flow through each vessel when	8
	the person is supine and then when they're standing. I want to show you the data from their very large study of adults with ME/CFS during head-up tilt testing using this technique.	13
	This study enrolled 429 adults, which was almost as many as the cumulative published research	9
	that we had summarized in the Institute of Medicine report. This is a very large study. Notice that 28% of these patients after 30 minutes upright met	10
	criteria for POTS,14 had delayed orthostatic hypotension. But the vast majority of adults had a normal heart rate and blood pressure response, 58%.	11
	They might have been at risk for being told there's nothing wrong. But when you employ the cerebral blood flow measures, here are the key findings from that paper.	10
	Healthy controls have a 7% reduction in brain blood flow compared to their supine values after they'd been up for 30 minutes. In contrast, the entire group of ME/CFS patients had a 26% reduction in brain blood flow.	14
	So I think you could reasonably conclude that it's no wonder that these patients have difficulty with processing as Vergheut was talking about thinking of the right words and concentrating.	11
	When you break that group of all patients down, 90% of them had objectively measured reductions in brain blood flow,	11
	significantly different than controls. The ones with POTS or delayed orthostatic hypotension were worse. But the group that could have been dismissed as normal,	10
	the ones who had a normal blood pressure and heart rate response nonetheless had a 24% reduction in brain blood flow over threefold greater than what you'd see in healthy controls.	11
	When these patients were all measured supine, the ME/CFS and healthy control groups did not differ with regard to their brain blood flow.	11
	This slide from that paper shows that midway through the tilt at the 10th minute, the degree of cerebral blood flow reduction was correlating	10
	well with the number of orthostatic symptoms that patients reported. This paper is more recent from their work, they looked at a group of people with	10
	normal heart rate and blood pressure responses to the tilt. They were interested in looking at the relationship between heart rate and stroke volume. That relationship should mean that if stroke volume goes down,	13
	we compensate with an increase in heart rate. In healthy controls, you see the 95th percentile prediction interval here with the blue line of the slope of	15
	the change in stroke volume and the change in heart rate. What you see in the gray area is that close to 40% of adults with ME/CFS,	11
	typically the ones with more severe symptoms, were unable to elevate their heart rate during the tilt test in accordance with the drop in stroke volume.	10
	Suggesting and consistent with what's called chronotropic incompetence, something that had previously been identified during exercise testing of people with	10
	ME/CFS but we think this was the first demonstration of this during orthostatic testing. What else do we know? We know that the risk factors for orthostatic intolerance	11
	can include seemingly disparate conditions. Trisha was talking about a number of other co-morbid problems. I think we have come to appreciate that mass cell activation, joint hypermobility,	13
	vascular compression syndromes, and in a small subset, neuroanatomic problems can accompany the autonomic nervous system dysfunctions. Here's an example of one of the large studies comparing	13
	the hyper mobile Dutch ME CFS patients with the ones who didn't have hypermobility. Notice that the ones who are hypermobile had a far greater reduction in	11
	brain blood flow regardless of the type of hemodynamic response they had to the tilt test. This slide is meant to illustrate some of these other conditions	11
	we know from the work at Vanderbilt by Cyndya Shibao and Italo Biaggioni that postural tachycardia syndrome can occur in people with mast cell activation disorders.	12
	In the Theohirades a review paper in the New England Journal, you can see I think here that many people with mast cell activation have cardiovascular problems and many of the other symptoms	11
	of mast cell activation can mimic those of ME/CFS. On the bottom left is a patient we had cared for Johns Hopkins who had some rather refractory symptoms of PO and ME/CFS.	15
	We found later when her reflexes became abnormal, that she had congenital narrowing of the cervical spinal canal and a disc bulge at C67,	11
	which her spine surgeon replaced, and within less than six months, her ME/CFS symptoms have resolved,	9
	her POTS had disappeared, and she's now well into her eighth year of follow-up, having had previously refractory ME/CFS symptoms, now entirely healthy.	11
	On the bottom right is some work from Stephen Smith and his colleagues pointing out that abnormalities that involve vascular compression in this case May–Thurner syndrome,	11
	where you get the right iliac artery compressing the left common iliac vein, that these problems are associated with POTS and treatment of these pelvic venus abnormalities can be associated	13
	with a nice improvement in overall symptoms, including the chronic pelvic pain. We also know from the past that	9
	orthostatic intolerance is one of the most treatable components of ME/CFS. This was a slide from one of our earlier papers showing that with open treatment, not blinded therapy,	12
	but open treatment of orthostatic intolerance with floor and FMI, migraine, and Beta-blockers and others, the patients who had volunteered for	9
	this study came in with a wellness score of 35 out of 100, where 100 means optimal health, zero means dying,	8
	and over four months of therapy, they increased to a mean of 70. This is, in many ways, still the data that we find clinically,	11
	perhaps a little bit better now that we have medications like ivabradine and a couple of others that can be used to treat orthostatic intolerance. Well, what do we still need to know about dysautonomia in ME/CFS?	15
	Well, we need better diagnostic tools, including as the Common Data Elements Committee concluded that we'd have to have	10
	better questionnaires that focus on orthostatic intolerance. We need, as anyone who's had a tilt test knows more easily available, less taxing and less expensive orthostatic tests.	13
	I think it's important to have a better ability to identify both for clinical care and for research studies, the patients who have refractory dysautonomia as a result of	10
	other structural problems that probably would not respond to medication intervention. These include cervical stenosis, crania cervical instability, and some of these vascular compression problems.	12
	We need to know more about mechanisms. We don't know what initiates the circulatory dysfunction and whether it's one thing or multiple hits.	10
	It could be that the autonomic nervous system disturbance is a consequence of something else at a more central level with downstream, autonomic, and circulatory control dysfunction.	11
	We don't know how infection triggers dysautonomia. We need to look at the genetic factors that influence its development since there's a heritable component to ME/CFS.	12
	It may be that the dysautonomia is triggered by a peripheral phenomenon. This is a slide on the mechanisms of POTS from a paper that was published after an NIH meeting.	12
	Connective tissue laxity may play a role in POT by making the vessels more compliant and allowing more blood to pool when the venous hydrostatic pressure is higher.	11
	There is interest in what role small fiber neuropathy plays in leading to excessive pooling. There's been a lot of interests in whether auto-immune antibodies that can block	14
	the ability to vasoconstrict or can activate cardiac receptors increasing tachycardia. There might be a variety of reasons for	10
	It's been thought to be the case as the part of the pathophysiology for ME/CFS in the past. But there's nice work from Van Camp and investors	9
	suggesting that the CPEC results have nothing to do with the cerebral blood flow raising the question of whether deconditioning plays a big role or not.	9
	Then we know there is an inadequate aldosterone response to standing that's clearly understood. These are among the mechanisms that need to be looked at.	11
	I think we also need to ask what other symptoms are impacted by the circulatory dysfunction? There's a lot of interests in neuro inflammation,	9
	but could it be the result of this sub-optimal blood flow that we see in ME/CFS patients, when they're upright? Is there some reperfusion injury that is taking place?	14
	Then separately, we often think about immune dysfunction in this illness independently, but anything that elevates catecholamines and	11
	orthostatic intolerance will provoke adverse sympathetic immune interactions. We know that each of the lymph nodes, it has sympathetic innervation and could	11
	these problems be secondary to the orthostatic intolerance, but nonetheless effect viral reactivation or responses to infection. Along those lines, I wanted to show two models for how symptoms might occur.	15
	This is from Klaus Wirth and Carmen Scheibenbogen in Germany. With upright posture you get a reduced pre-load, orthostatic stress, increased sympathetic activity,	12
	which leads to tachycardia but also to vasoconstriction, and they pause it that this leads to under perfusion of skeletal muscles and a variety of vasodilators spilling out of there.	12
	Also reducing renal function and leading to various pain and other symptoms. Then this slide is a reminder that a variety of problems with	15
	increased sympathetic activation can have immediate impact on a variety of immune functions, including factors that might affect the enteric nervous system.	14
	We have a number of treatments that have been available in treating orthostatic intolerance. But very few studies that have looked at these comprehensively in people with ME/CFS.	10
	This includes vasoconstrictors, volume expanders and drugs that control heart rate or catecholamine release or effect. But in addition, I think we need to think about: whether you	11
	can address the dysautonomia using therapies used, for example, for mass cell activation syndrome, notably famotidine or chromolyn.	9
	I mentioned chromolyn because we've been treating a young man from Maine who has been refractory to all of the medications on the previous slide, but had a lot of facial erythema and cutaneous erythema,	14
	and when we put them on chromolyn, he started being able to sit upright rather than being forced to lie down all day. My colleagues at Hopkins,	10
	to mention another example, Malcolm Brock and his Belgian colleague Frank Boltzmann's, are looking at the combination of hyperhidrosis in POTS.	10
	They've found that a proportion of these patients have a defect in a mutation in one of the sodium channels. When they use sodium channel blockers like guanfacine,	11
	they can see improvements in symptoms and overall function. This leads to some mechanism based treatments that might be fruitful. I want to end with a couple of points about the challenge of heterogeneity in ME/CFS.	16
	Originally I had presented this at the FDA conference, I think 10 years ago. But it's important to recognize that flares in co-morbid illnesses can occur during	10
	randomized trials and they have the potential to obscure the treatment effect of the drug under study. That heterogeneity can be reduced by careful subject selection, clear case definitions,	13
	eligibility criteria, especially for these subsets, and studies have single agents for ME/CFS and orthostatic intelligible need large sample sizes.	11
	I think ultimately that's going to necessitate a much greater devotion of resources to clinical trials, including support for clinical trial networks so that we can do	10
	these studies efficiently and in a timely manner for the people who are desperate for help. Some of the strategies that can be employed	9
	include stratification to address duration of illness, since that seems to be a factor in at least the chronotropic incompetence, different pathophysiologic subsets.	11
	One thought is that we should have run in periods for treating some of the co-morbid disorders and controlling them as much as we can. Or, another strategy is to identify the people who respond to the drug under study,	13
	then remove people from that medication and only randomize the responders. People have thought about randomized trials of	9
	withdrawing the extensively effective therapies, crossover designs might be effective for some conditions and as N-of-1 trials. I'm going to stop there and thank those who've made our work	13

autonomic symptoms using the compass questionnaire, ME/CFS patients are clearly and significantly different than controls. Not only that, the degree of autonomic dysfunction on

13

the compass correlates with the fatigue impact scale. Peter Rowe: We know that orthostatic stress can impair neurocognitive function.

12

One of the studies that help really bring this out was done by Marvin Medow and Julian Steward, who had been important investigators in orthostatic intolerance.

12

They showed that as you gradually increase the angle of the tilt test, ME/CFS patients had different problems on the n-back tests.

11

As you increase the complexity of the n-back test, they made more errors and had slower reaction time. We often hear about cognitive dysfunction as an independent symptom,

12

but it clearly can also be aggravated by orthostatic stress. I want to highlight a few papers from Linda Van Camp and in France visitor's data in the Netherlands.

12

I've helped with some of the writing of these papers, but the data are entirely theirs and they deserve the bulk of the credit for this. But they looked at the influence of the tilt test

12

on cognitive scores using a two back and a three back-test. As you can see here, after the tilt test, immediately afterwards, patients had worse scores on their cognitive studies.

11

They also looked at what happened seven days after the tilt test. You can see that ME/CFS patients had worse scores on numeric rating scales for concentration.

14

This is suggestive of orthostatic intolerance being capable of provoking PEM. The symptoms of orthostatic intolerance are largely due to reductions

12

in blood volume and venous return to the heart when people are upright. That leads importantly to under perfusion of the cerebral circulation.

10

If we look at this slide, it summarizes the main pathophysiologic influences on patients. They have an increase in the amount of pooling

10

possibly due to a defect in vasoconstriction. There's about a 10% reduction in intravascular volume in people with orthostatic intolerance.

9

These two things combined, so that when they stand in upright tilt position, they get a marked reduction in cerebral blood flow.

10

As David Goldstein at the NIH has termed it, they get an increase in the sympathetic adrenal response, a big increase in catecholamines and adrenal release.

10

That can lead to a variety of different phenotypes of orthostatic intolerance at the bottom. One is classical orthostatic hypotension, delayed orthostatic hypotension that occurs beyond the three-minute point.

12

What we term neurally mediated or reflex hypotension, postural tachycardia syndrome. Then some people can have low orthostatic intolerance with a normal heart rate and blood pressure response.

13

When we tried to measure the cerebral blood flow differences, we initially began with transcranial Doppler, but could not identify differences between

11

healthy controls and patients during a head-up tilt test. I know that Dr. Novak, who will be speaking later, has had better success with this technique.

9

But Van Campen and Visser came up with a method of measuring brain blood flow by putting their Doppler probe on each internal carotid artery for about 20 or 30 seconds,

12

and then each vertebral artery for the same amount of time. So that over a two or three minute timespan, they can tell you by adding the flow through those vessels,

11

the total cerebral blood inflow. We obviously don't know what is happening within the brain, but that's the amount of blood that is pumped to the brain.

11

Studies have shown that you don't really need to be an ultrasonographer to see the difference between the flow through each vessel when

8

the person is supine and then when they're standing. I want to show you the data from their very large study of adults with ME/CFS during head-up tilt testing using this technique.

13

This study enrolled 429 adults, which was almost as many as the cumulative published research

9

that we had summarized in the Institute of Medicine report. This is a very large study. Notice that 28% of these patients after 30 minutes upright met

10

criteria for POTS,14 had delayed orthostatic hypotension. But the vast majority of adults had a normal heart rate and blood pressure response, 58%.

11

They might have been at risk for being told there's nothing wrong. But when you employ the cerebral blood flow measures, here are the key findings from that paper.

10

Healthy controls have a 7% reduction in brain blood flow compared to their supine values after they'd been up for 30 minutes. In contrast, the entire group of ME/CFS patients had a 26% reduction in brain blood flow.

14

So I think you could reasonably conclude that it's no wonder that these patients have difficulty with processing as Vergheut was talking about thinking of the right words and concentrating.

11

When you break that group of all patients down, 90% of them had objectively measured reductions in brain blood flow,

11

significantly different than controls. The ones with POTS or delayed orthostatic hypotension were worse. But the group that could have been dismissed as normal,

10

the ones who had a normal blood pressure and heart rate response nonetheless had a 24% reduction in brain blood flow over threefold greater than what you'd see in healthy controls.

11

When these patients were all measured supine, the ME/CFS and healthy control groups did not differ with regard to their brain blood flow.

11

This slide from that paper shows that midway through the tilt at the 10th minute, the degree of cerebral blood flow reduction was correlating

10

well with the number of orthostatic symptoms that patients reported. This paper is more recent from their work, they looked at a group of people with

10

normal heart rate and blood pressure responses to the tilt. They were interested in looking at the relationship between heart rate and stroke volume. That relationship should mean that if stroke volume goes down,

13

we compensate with an increase in heart rate. In healthy controls, you see the 95th percentile prediction interval here with the blue line of the slope of

15

the change in stroke volume and the change in heart rate. What you see in the gray area is that close to 40% of adults with ME/CFS,

11

typically the ones with more severe symptoms, were unable to elevate their heart rate during the tilt test in accordance with the drop in stroke volume.

10

Suggesting and consistent with what's called chronotropic incompetence, something that had previously been identified during exercise testing of people with

10

ME/CFS but we think this was the first demonstration of this during orthostatic testing. What else do we know? We know that the risk factors for orthostatic intolerance

11

can include seemingly disparate conditions. Trisha was talking about a number of other co-morbid problems. I think we have come to appreciate that mass cell activation, joint hypermobility,

13

vascular compression syndromes, and in a small subset, neuroanatomic problems can accompany the autonomic nervous system dysfunctions. Here's an example of one of the large studies comparing

13

the hyper mobile Dutch ME CFS patients with the ones who didn't have hypermobility. Notice that the ones who are hypermobile had a far greater reduction in

11

brain blood flow regardless of the type of hemodynamic response they had to the tilt test. This slide is meant to illustrate some of these other conditions

11

we know from the work at Vanderbilt by Cyndya Shibao and Italo Biaggioni that postural tachycardia syndrome can occur in people with mast cell activation disorders.

12

In the Theohirades a review paper in the New England Journal, you can see I think here that many people with mast cell activation have cardiovascular problems and many of the other symptoms

11

of mast cell activation can mimic those of ME/CFS. On the bottom left is a patient we had cared for Johns Hopkins who had some rather refractory symptoms of PO and ME/CFS.

15

We found later when her reflexes became abnormal, that she had congenital narrowing of the cervical spinal canal and a disc bulge at C67,

11

which her spine surgeon replaced, and within less than six months, her ME/CFS symptoms have resolved,

9

her POTS had disappeared, and she's now well into her eighth year of follow-up, having had previously refractory ME/CFS symptoms, now entirely healthy.

11

On the bottom right is some work from Stephen Smith and his colleagues pointing out that abnormalities that involve vascular compression in this case May–Thurner syndrome,

11

where you get the right iliac artery compressing the left common iliac vein, that these problems are associated with POTS and treatment of these pelvic venus abnormalities can be associated

13

with a nice improvement in overall symptoms, including the chronic pelvic pain. We also know from the past that

9

orthostatic intolerance is one of the most treatable components of ME/CFS. This was a slide from one of our earlier papers showing that with open treatment, not blinded therapy,

12

but open treatment of orthostatic intolerance with floor and FMI, migraine, and Beta-blockers and others, the patients who had volunteered for

9

this study came in with a wellness score of 35 out of 100, where 100 means optimal health, zero means dying,

8

and over four months of therapy, they increased to a mean of 70. This is, in many ways, still the data that we find clinically,

11

perhaps a little bit better now that we have medications like ivabradine and a couple of others that can be used to treat orthostatic intolerance. Well, what do we still need to know about dysautonomia in ME/CFS?

15

Well, we need better diagnostic tools, including as the Common Data Elements Committee concluded that we'd have to have

10

better questionnaires that focus on orthostatic intolerance. We need, as anyone who's had a tilt test knows more easily available, less taxing and less expensive orthostatic tests.

13

I think it's important to have a better ability to identify both for clinical care and for research studies, the patients who have refractory dysautonomia as a result of

10

other structural problems that probably would not respond to medication intervention. These include cervical stenosis, crania cervical instability, and some of these vascular compression problems.

12

We need to know more about mechanisms. We don't know what initiates the circulatory dysfunction and whether it's one thing or multiple hits.

10

It could be that the autonomic nervous system disturbance is a consequence of something else at a more central level with downstream, autonomic, and circulatory control dysfunction.

11

We don't know how infection triggers dysautonomia. We need to look at the genetic factors that influence its development since there's a heritable component to ME/CFS.

12

It may be that the dysautonomia is triggered by a peripheral phenomenon. This is a slide on the mechanisms of POTS from a paper that was published after an NIH meeting.

12

Connective tissue laxity may play a role in POT by making the vessels more compliant and allowing more blood to pool when the venous hydrostatic pressure is higher.

11

There is interest in what role small fiber neuropathy plays in leading to excessive pooling. There's been a lot of interests in whether auto-immune antibodies that can block

14

the ability to vasoconstrict or can activate cardiac receptors increasing tachycardia. There might be a variety of reasons for

10

It's been thought to be the case as the part of the pathophysiology for ME/CFS in the past. But there's nice work from Van Camp and investors

9

suggesting that the CPEC results have nothing to do with the cerebral blood flow raising the question of whether deconditioning plays a big role or not.

9

Then we know there is an inadequate aldosterone response to standing that's clearly understood. These are among the mechanisms that need to be looked at.

11

I think we also need to ask what other symptoms are impacted by the circulatory dysfunction? There's a lot of interests in neuro inflammation,

9

but could it be the result of this sub-optimal blood flow that we see in ME/CFS patients, when they're upright? Is there some reperfusion injury that is taking place?

14

Then separately, we often think about immune dysfunction in this illness independently, but anything that elevates catecholamines and

11

orthostatic intolerance will provoke adverse sympathetic immune interactions. We know that each of the lymph nodes, it has sympathetic innervation and could

11

these problems be secondary to the orthostatic intolerance, but nonetheless effect viral reactivation or responses to infection. Along those lines, I wanted to show two models for how symptoms might occur.

15

This is from Klaus Wirth and Carmen Scheibenbogen in Germany. With upright posture you get a reduced pre-load, orthostatic stress, increased sympathetic activity,

12

which leads to tachycardia but also to vasoconstriction, and they pause it that this leads to under perfusion of skeletal muscles and a variety of vasodilators spilling out of there.

12

Also reducing renal function and leading to various pain and other symptoms. Then this slide is a reminder that a variety of problems with

15

increased sympathetic activation can have immediate impact on a variety of immune functions, including factors that might affect the enteric nervous system.

14

We have a number of treatments that have been available in treating orthostatic intolerance. But very few studies that have looked at these comprehensively in people with ME/CFS.

10

This includes vasoconstrictors, volume expanders and drugs that control heart rate or catecholamine release or effect. But in addition, I think we need to think about: whether you

11

can address the dysautonomia using therapies used, for example, for mass cell activation syndrome, notably famotidine or chromolyn.

9

I mentioned chromolyn because we've been treating a young man from Maine who has been refractory to all of the medications on the previous slide, but had a lot of facial erythema and cutaneous erythema,

14

and when we put them on chromolyn, he started being able to sit upright rather than being forced to lie down all day. My colleagues at Hopkins,

10

to mention another example, Malcolm Brock and his Belgian colleague Frank Boltzmann's, are looking at the combination of hyperhidrosis in POTS.

10

They've found that a proportion of these patients have a defect in a mutation in one of the sodium channels. When they use sodium channel blockers like guanfacine,

11

they can see improvements in symptoms and overall function. This leads to some mechanism based treatments that might be fruitful. I want to end with a couple of points about the challenge of heterogeneity in ME/CFS.

16

Originally I had presented this at the FDA conference, I think 10 years ago. But it's important to recognize that flares in co-morbid illnesses can occur during

10

randomized trials and they have the potential to obscure the treatment effect of the drug under study. That heterogeneity can be reduced by careful subject selection, clear case definitions,

13

eligibility criteria, especially for these subsets, and studies have single agents for ME/CFS and orthostatic intelligible need large sample sizes.

11

I think ultimately that's going to necessitate a much greater devotion of resources to clinical trials, including support for clinical trial networks so that we can do

10

these studies efficiently and in a timely manner for the people who are desperate for help. Some of the strategies that can be employed

9

include stratification to address duration of illness, since that seems to be a factor in at least the chronotropic incompetence, different pathophysiologic subsets.

11

One thought is that we should have run in periods for treating some of the co-morbid disorders and controlling them as much as we can. Or, another strategy is to identify the people who respond to the drug under study,

13

then remove people from that medication and only randomize the responders. People have thought about randomized trials of

9

withdrawing the extensively effective therapies, crossover designs might be effective for some conditions and as N-of-1 trials. I'm going to stop there and thank those who've made our work

13