IACFSME 2022 Virtual Medical Conference: Day 2 Presentations: 28 July (9 am to 5 pm EDT)

Science For ME

Science For ME

Forum Announcements
We have four threads, one for each day of the conference. Please add the following to these threads:
* reports from forum members attending the conference
* tweets and reports from other social media
* your thoughts about the information presented.
* any questions you would like asked of presenters

IACFSME 2022 Virtual Medical Conference: Day 1 Workshops: 27 July (9 am to 5 pm EDT)
IACFSME 2022 Virtual Medical Conference: Day 3 Presentations: 29 July (9 am to 4.40 pm EDT)
IACFSME 2022 Virtual Medical Conference: Day 4 Presentations: 30 July (9 am to 3.30 pm EDT)
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9.00 am - 9.15 am
Introduction
Fred Friedberg, IACFS/ME
Chronic fatigue self-management in primary care: a randomized trial (2013) Friedberg et al.
Rethinking the Standard of Care for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2019, Friedberg, Sunnquist and Nacul
Editorial: A
utonomic markers, chronic fatigue syndrome, and post-exertion states, 2019, Friedberg
Legitimizing myalgic encephalomyelitis/chronic fatigue syndrome: indications of change over a decade, 2020, Friedberg
Open Fred Friedberg (University of Stonybrook) Hydrogen Rich Water; Heart rate variability biofeedback in CFS
Non-improvement in chronic fatigue syndrome: relation to activity patterns, uplifts and hassles, and autonomic dysfunction, 2022, Friedberg et al

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9.15 am - 10.15 am
Keynote: Pathophysiology of exercise intolerance in ME/CFS & long COVID
David Systrom, Harvard Medical School, USA
Exercise Intolerance in Preload Failure Treated with Pyridostigmine (2018) Faria Urbina et al (mentions ME/CFS & POTS)
Fatigue, Sleep, and Autoimmune and Related Disorders, 2019, Zielinski, Systrom and Rose
Unexplained exertional intolerance associated with impaired systemic oxygen extraction - 2019, by Melamed, Systrom et al
Event: Grand Rounds: Pathophysiology of Exercise Intolerance in Chronic Fatigue Syndrome Event Date: May 5th, 2020 David Systrom, MD
The Exercise Response to Pharmacologic Cholinergic Stimulation in ME/CFS, 2020/21, Systrom, phase2 trial registration
Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing, 2021, Singh, Systrom et al
Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine, 2022, Systrom et al
Other threads about Systrom:
David Systrom, researcher, Brigham and Women's Hospital, USA
Event: Grand Rounds: Pathophysiology of Exercise Intolerance in Chronic Fatigue Syndrome Event Date: May 5th, 2020 David Systrom, MD
 
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10.30 am - 12.30 pm
Provocative Maneuvers: Methods to Induce Symptomatic Features of ME/CFS
Rochelle Joslyn (moderator), IACFS/ME
Mark VanNess, University of the Pacific, USA
Peter Rowe, Johns Hopkins University School of Medicine, USA
Dane B. Cook, University of Wisconsin - Madison, USA
Alain Moreau, Université de Montréal, CHU Sainte-Justine Research Center, Canada
Luis Nacul, MD, MSc, PhD, University of British Columbia, Canada
VanNess
Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in ME/CFS, 2018, Stevens et al
Frontiers review - Chronotropic incompetence an overlooked determinant of symptoms and activity limitation in ME/CFS (prov. 2019) Davenport et al
Reproducibility of Measurements Obtained During Cardiopulmonary Testing in Individuals With Fatiguing Health Conditions - Larson, Snell, Davenport ..
Rowe
"Passive standing tests for the office diagnosis of postural tachycardia syndrome: New methodological considerations" (Peter Rowe team 2018)
Low sensitivity of abbreviated tilt table testing for diagnosing postural tachycardia syndrome in adults with ME/CFS, 2018, van Campen, Rowe & Visser
Physical activity measures in patients with myalgic encephalomyelitis/chronic fatigue syndrome [...], 2020, Rowe et al
Heart Rate Thresholds to Limit Activity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients (Pacing) - 2020 - van Campen, Rowe, Visser
Reductions in Cerebral Blood Flow Can Be Provoked by Sitting in Severe ME/CFS patients, 2020, Van Campen, Rowe, Visser
Deconditioning does not explain orthostatic intolerance in ME/CFS, 2021, VanCampen, Rowe, Visser
Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients, 2021, Van Campen, Rowe, Visser
Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with ME/CFS, 2021, Rowe et al
Compression Stockings Improve Cardiac Output and Cerebral Blood Flow during Tilt Testing in (ME/CFS)Patients: A Randomized Crossover Trial, 2021,Rowe
Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS, 2022, Morrow, Rowe et al
Cook
Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Cook, Light +
Cardiopulmonary, metabolic, and perceptual responses during exercise in ... (ME/CFS): A Multi-site Clinical Assessment, 2022, Cook et al
Moreau
Dr Alan Moreau's new, low-stress protocol for provoking PEM.[Thoughts?]
Webinar : Deconstructing Post-Exertional Malaise in Myalgic Encephalomyelitis: An Exploratory Biomarker Analysis - with Dr A. Moreau Dec 19 2019
Profile of circulating microRNAs in Myalgic Encephalomyelitis......(2020)Moreau et al
Dr Alain Moreau video - developing new test to discriminate between ME & Fibro
UK CMRC 2018 Conference - Prof Alain Moreau
Nacul
Hand grip strength as a clinical biomarker for ME/CFS, 2018, Nacul et al



12.30 am - 1.30 pm Poster session
 
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1.30 pm - 2.30 pm IMMUNOLOGY

Inhibition of autophagy induces chronic fatigue in mice: a potential mouse model to study ME/CFS
Avik Roy, Simmaron Research Inc.,
Animal Models of ME/CFS
Simmaron article

Investigating T cell populations for immune cell exhaustion in ME/CFS using flow cytometry
Jessica Maya, Cornell University, USA
ME/CFS patients exhibit altered T cell metabolism and cytokine associations (2019) Mandarano, Hanson et al

Immune comparison of male and female ME/CFS patients
Kristina K Aenlle, Miami VA Healthcare System, USA
 
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METABOLISM
2.30 pm - 3.30 pm
Feasibility of investigating oxygen consumption (VO2), heart rate variability, blood pressure and lactic acid levels of people with myalgic encephalomyelitis during normal daily activities.
Nicola Clague-Baker, University of Liverpool, England
UK Planned study: Feasibility of investigating VO2, HR, BP, lactic acid and activity of pwME during normal daily activity, 2020/21, Clague-Baker et al

Pre-Illness metabolomics data among college students following mononuclosis and ME/CFS reveals differences in multiple metabolites and metabolic pathways
Leonard A. Jason, DePaul University, USA
Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis, 2022, Jason et al
Cytokine networks analysis uncovers further differences between those who develop ME/CFS following infectious mononucleosis, 2021, Jason et al
Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study, 2020, Jason et al
Seeking the causes of post-Covid symptoms, researchers dust off data on college students with mononucleosis, 2020, David Tuller article (Jason study)


Urine metabolomics exposes anomalous recovery after maximal exertion in ME/CFS female patients
Katherine A Glass, Cornell University, USA

METABOLISM AND CO-MORBID CONDITIONS
3.45 - 4.45 pm
Dysfunctional cerebrospinal fluid metabolites and lipids infer white matter dysfunction in ME/CFS and mitochondrial dysfunction in Gulf War Illness (GWI)
James Baraniuk, Georgetown University, USA
Review of the Midbrain Ascending Arousal Network Nuclei and Implications for (ME/CFS), Gulf War Illness (GWI) and (PEM), 2022, Baraniuk
Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in ME/CFS and GWI in a Model of PEM, 2021, Baraniuk et al
Subcortical brain segment volumes in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2021, Addiego et al
Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and [ME/CFS], Baranuik et al, 2021
Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in ME/CFS, 2020, Narayan et al
More on Baraniuk's research listed here

Gender matters: perceived burdensomeness increased in males with chronic invisible illness
Cathy Pederson, Wittenberg University, USA
Understanding suicidal ideation in people with chronic invisible illness, 2020, Pederson
Commentary: Suicide is a Concern for the Chronic Invisible Illness Community, 2020, Pederson
Note a misuse of statistics here
The Importance of Screening for Suicide Risk in Chronic Invisible Illness (2018)  Pederson


Do people with joint hypermobility represent a subgroup of myalgic encephalomyelitis/ chronic fatigue syndrome?
Kathleen Mudie, Solve ME/CFS Initiative, USA
EDS, hypermobility, and the link, if any, to ME/CFS
 
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cassava7 said:
A request — could you record / quote Dr Systrom’s exact words on graded exercise therapy during his keynote tomorrow, please?
Click to expand...
(this is not all word for word, but pretty much what Dr Systrom said)
"We never ever simply prescribe exercise as a fix. What we do do, and we have had luck with this, and [there's some evidence] is that exercise is judiciously combined with medications. We treat with orthostatic intolerance medications, with pyridostigmine, and then prescribe recumbent cycling, increasing it over time. Patients should not push themselves into a crash.

I would never view a patient with ME/CFS as permanently afflicted. [we've had good success in getting improvements]"


I'll write up my notes on Systrom's talk tomorrow.
 
Thank you @Hutan, I very much appreciate your coverage and the team’s.

I remain concerned by Dr Systrom’s statements. His RCT of Mestinon (pyridostigmine) showed no physiological improvements on pre-post iCPETs. There is no evidence that any medication improves exertion intolerance in ME/CFS nor prevents crashes (PEM).

Dr Systrom seems patently unaware of the low recovery rates of ME/CFS beyond 5 years. I suspect this may be due to sampling bias.
 
Post copied from Elevated ATG13 in serum of pwME stimulates oxidative stress response in microglial cells , 2022, Gottschalk et al

Slides from Dr. Roy's presentation today at IACFS/ME about their work on a mouse model for ME with a drug that acts on mTOR -> ATG13 -> autophagy impairment.

It definitely does something that looks a bit like PEM, if I'm understanding the slides correctly, and much more effectively in female mice.

Did anyone catch the presentation?

[Edit: Thanks to @wigglethemouse for asking Dr. Roy to share these on Twitter (see here).]
 
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Science For ME said:
9.15 am - 10.15 am
Keynote: Pathophysiology of exercise intolerance in ME/CFS & long COVID
David Systrom, Harvard Medical School, USA
Click to expand...

Dr Systrom presented a lot of information in his talk, and probably his recent papers are the best way to approach a lot of it rather than my hasty notes of my incomplete understanding of his verbal summaries.

That said, let's see how we gp.

Pathophysiology of Exertion Intolerance
People with ME/CFS often have a modest decrease in VO2 max. Systrom has looked at what might be causing that. It isn't a Pulmonary Mechanical Limit (as in, I'm assuming happens with lung damage that reduces useful lung volume). It's to do with Impaired Oxygen Flux - the ability to take the oxygen out of the blood.

What can cause the Impaired Oxygen Flux? It could be a General Cardiac Limitation - but it doesn't seem to be related to structural heart disease. A problem in ME/CFS is Preload failure - cardiac filling pressures are low. Systrom has found that 90% of the ME/CFS patients they see.

There also are Peripheral Limitations - e.g. it may be that the body shunts blood from arteries to veins, bypassing capillaries in tissue for some reason. Impaired Systemic Oxygen Extraction


Small Fibre Neuropathy
They did a study in 2021 (Joseph et al) that basically replicated the 2016 Oldham study that found that some patients had exercise intolerance but no usual heart or lung problems. The 2021 study added ME/CFS clinical criteria and a skin biopsy for small fibre neuropathy. 599 patients, 223 had a skin biopsy, 160 met ME/CFS criteria (IOM). They found a 45% prevalence of SFN in ME/CFS from the biopsy. Later work has used deeper skin biopsies that capture sweat glands - the prevalence with that approach is over 60%. SFN has been found to be high in fibromyalgia and POTS.

However, the presence of SFN is not correlated with physiology dysregulation. Systrom speculates that there may also be neuropathy elsewhere in the body, in ganglions.


Inflammasome activation
Systrom has talked with the NIH - there is a group interested in TNF-related apoptosis-inducing ligand (TRIAL) - a ubiquitous cytokine [I'm not sure if this is the NIH group working on ME/CFS, I think it was]. TRIAL activates the inflammasome. TRIAL may be neurotoxic - in the periphery (causing SFN?), and in the CNS?

A study looked at the change in TRIAL an hour after peak exercise - TRIAL was much higher in those with SFN. The relationship between cytokines an hour after peak exercise was different in people with ME/CFS compared to healthy controls. The inflammasome may be abnormally activated after exercise in ME/CFS. The conclusion was that acute exercise activates TRIAL and the inflammasome in ME/CFS and this is related to SFN and PEM.


Skeletal muscle mitochondrial dysfunction
Melamed et al 2019 - 11 patients had a muscle biopsy. 10/11 had a citrate synthase deficiency - a global marker of mitochondrial dysfunction. The higher mutation load in muscles , the lower the oxygen extraction. [sorry about the vagueness there - check out the study if you want more]

This has led them to the Astellas study - more to come on this.

Poor systemic O2 extraction may be related to muscle mitochondrial dysfunction.


ME/CFS and Long Covid - dyspnea
ME/CFS and LC are frighteningly similar
Singh et al 2021 in Long Covid - found low systemic oxygen extraction and preload failure. Systrom thinks it looks just like ME/CFS.
Hyperventilation during exercise is a feature of a subset of people with LC and ME/CFS. It is likely to be associated with the feeling of dyspnea (breathlessness) although it's not yet understood. [Systrom made no suggestion that the hyperventilation was voluntary or a result of emotional stress.]
Novak 2021 et al - tilt table for POTS and LC patients. Cerebral blood flow reduced in both cohorts.
Tooba et al 2021 - Dyspnea in Chronic Preload state


There was a Venn diagram:
Inside a circle of preload failure, were three overlapping circles of ME/CFS, POTS and SFN. Some patients meet criteria for all three, some for just two or one.


Treatment
Joseph et al 2022 - Pyridostigmine (mestinon) improves VO2 peak. They give the treatment and then 45 minutes later do a CPET. Mestinon may be a useful drug in a subset.


Funding
Systrom acknowledged Ron Tompkins contribution to coordinating ME/CFS research.OMF has funded a $700,000 study at the Brigham on PEM.


QUESTIONS
Systrom commented that the dysfunction in the mitochondria could be acquired and affect by autoimmunity.

Does TRIAL actually get through the blood brain barrier? Not sure, but the NIH group were interested in its effect on the CNS.

Ray Perrin - asked about improvement when breathing higher levels of oxygen. Systrom said he remains agnostic about supplemental oxygen. He's not aware of a study. He noted that none of the patients desaturates in O2 - the issue is getting the oxygen out of the blood cell. Red cell defects have been found in ME/CFS and LC - they are bigger and more rigid.

Mestinon - anecdotally with 180mg/day[?] over a couple of months patients report improvements. Suggests that there is ultimately an adrenergic signal. He thinks a subset may have myasthenia of the ganglion caused by an antibody to the ganglion.

Robert Frederiks - asked about the Warburg effect - where cells act as though there is no oxygen even though there is
[i.e. In tumors and other proliferating or developing cells, the rate of glucose uptake dramatically increases and lactate is produced, even in the presence of oxygen and fully functioning mitochondria.]
Click to expand...
could there be an exaggerated extraction of oxygen mediated by a Warburg effect? Systrom- - yes, potentially very much related. Hyperventilation could be mediated by a Warburg effect.

What causes SFN? Might be cause by an autoantibody in some patients (and might also not just be in the periphery, more proximal diseases possible e.g. ganglionopathy.). [Systrom had earlier mentioned TRIAL as being neuropathic]

CGRP - a vasodilator. Much of what has been described is a problem of vasodilation in arteries and veins. Migraines are common in Me/CFS - caused by vasodilation in the head. Some of the latest migraine treatments might help with systemic vasodilation. Anecdotally, there has been a mixed response. About 50% of patients trying these treatments for their migraines report some improvement in fatigue and OI symptoms.

iCPETS, involves about 5 minutes of cycling and it's only the last bit that is challenging. They have done 2000 iCPETS in ME/CFS now, including 50 LC patients in that number. Systrom can count on one hand the number of patients who have had a significant crash afterwards. He is very respectful of PEM, it is probably the major incapacitation of ME/CFS.

"We never ever simply prescribe exercise as a fix. What we do do, and we have had luck with this, and [there's some evidence] is that exercise is judiciously combined with medications. We treat with orthostatic intolerance medications, with pyridostigmine, and then prescribe recumbent cycling, increasing it over time. Patients should not push themselves into a crash.

I would never view a patient with ME/CFS as permanently afflicted. [we've had good success in getting improvements]"
 
LarsSG said:
Post copied from Elevated ATG13 in serum of pwME stimulates oxidative stress response in microglial cells , 2022, Gottschalk et al

Slides from Dr. Roy's presentation today at IACFS/ME about their work on a mouse model for ME with a drug that acts on mTOR -> ATG13 -> autophagy impairment.

It definitely does something that looks a bit like PEM, if I'm understanding the slides correctly, and much more effectively in female mice.

Did anyone catch the presentation?

[Edit: Thanks to @wigglethemouse for asking Dr. Roy to share these on Twitter (see here).]
Click to expand...

1.30 pm - 2.30 pm IMMUNOLOGY

Inhibition of autophagy induces chronic fatigue in mice: a potential mouse model to study ME/CFS
Avik Roy, Simmaron Research Inc.,
Animal Models of ME/CFS
Simmaron article

I watched part of it but found it very hard to follow what he was saying and my lack of knowledge of biochemistry limited my understanding.
Here's the link to Dr Roy's slides from the talk that he has posted:
https://my.theopenscholar.com/files/simmaronlab/files/iacfs_2022_roy.pdf

Here's what I think I learned in the most general terms:
They used a drug that impairs autophagy on the grounds that other research in pwME, listed here on the slides Dr Roy shared:
Potential contributing factors to the pathogenesis of ME/CFS
 mitochondrial toxicity (Hanson et al., 2016)
 upregulations of inflammatory cytokines (Mandarano et al., 2020),
 autophagy impairment (Gottschalk et al., 2022),
 Myelin abnormalities (Morris and Maes, 2013).
Click to expand...
They tested the mice on a treadmill and in a maze and observed them after the treadmill exercise for PEM effects.
The female mice were much more severely affected than the males, though in the males there was a delayed effect observed a month later.
Those affected didn't put on any body weight and lost muscle mass.
After the treadmill exercise those affected moved much less and more slowly and seemed to be struggling.
There was no effect on ability to get through a maze, so apparently no effect on cognition??
Muscle tissue showed infiltration by (I think) T cells. They are currently analysing changes in muscle tissue.

From the slides Dr Roy shared:
Result
 Severe muscle fatigue
 Female ( 90%) vs male (30%)
 Younger (3-4 wks) versus older (5-6 wks)
 Potential Inflammatory demyelination.
 Loss of muscle development and growth.
 Decreased grip strength.
Click to expand...

Dr Roy seemed very excited by the potential of this mouse model for learning more about PEM. He said in the Q&A that this as far as he knows is the only animal model for ME/CFS.

My impression is that they are closer to an animal model that might give useful information than the studies we've seen of rats being made to swim to exhaustion and calling that CFS.

My reservation was that some of the effects of the drug, such as loss of muscle mass and focus on effects on muscles rather than other symptoms such as cognition and OI, mean that it's probably an incomplete model, or may be more like a model of a muscle myopathy rather than of ME. It would be interesting to compare the muscle tissue with that seen in biopsies of pwME. I don't get the impression the same effects are found. If that's the case, it may turn out to be a blind alley without direct relevance to ME.
 
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Investigating T cell populations for immune cell exhaustion in ME/CFS using flow cytometry
Jessica Maya, Cornell University, USA
Jessica Maya is a young PhD researcher at Cornell. She spoke clearly but so fast I couldn't keep up with taking notes. I'll try to watch the talk again later as it looked interesting.
It was a small study (20 MECFS, 20 controls) They studied a particular type of T cells called CD4+ and CD8+ and found some evidence of markers that indicated T cell exhaustion. The blood samples were taken 2 days after an exercise challenge. More studies are planned to learn more and understand better how these findings relate to symptoms.
 
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Immune comparison of male and female ME/CFS patients
Kristina K Aenlle, Miami VA Healthcare System, USA

Again my notes are very sketchy, so this is an interim report.
There were two parallel studies with the same protocol carried out at different centres.
Klimas studied males, Fletcher studied females.
Both had pwME and controls, I think.

Both cohorts did an exercise challenge. Measures included VO2max, flow cytometry and blood tests looked at B, T, NK cells and cytokines.
These were tested 4 hours and 24 hours after the exercise challenge.

Dr Aenlle went quickly through some of the differences found between males and females and between patients and controls at the different time points, but I couldn't keep up with noting them. I think the summary said males had differences in T cells, and females B, NK cells and cytokines. There was an increase in pro inflammatory cytokines in females not in males.
I need to check that by watching again.

Edit:
Summary:
Male ME/CFS change in T cell percentage at baseline
Female ME/CFS changes in B cells and NK cells at baseline and at VO2Max
Both male and female ME/CFS show a decrease in NK cell function
Women show an increase in pro inflammatory cytokines at baseline.

She finished with mention of next steps including targeted treatment.
Edit: she also raised the question of whether ME/CFS cells are showing signs of accelerated aging. Need to look at ages of participants in analysing data.

I think the key takeaway from this study is that male female differences mean they should be studied as separate cohorts within any study of ME/CFS, rather than averaging results of a mixed cohort.
 
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I get a bit suspicious when a whole lot of things are found to differ between males and females with ME/CFS.
Trish said:
males had differences in T cells, and females B, NK cells and cytokines.
Click to expand...
Such differences seem a bit unlikely, given that there's no reason to think the phenotype of the disease is very different in males and females.

I wonder if the blood analysis of the two studies was done in separate labs or at separate times. It's an odd choice to make - one centre studying males and one centre studying females, it increases the chance that some site difference biases the results.
 
METABOLISM
2.30 pm - 3.30 pm
Feasibility of investigating oxygen consumption (VO2), heart rate variability, blood pressure and lactic acid levels of people with myalgic encephalomyelitis during normal daily activities.
Nicola Clague-Baker, University of Liverpool, England

After trying to follow complicated physiology presented very fast in the previous 3 talks, this one came as a relief - I could actually understand it and get excited about it. I think it's one of the most valuable pieces of research for pwME I've seen, as it offers the potential of feasible home testing at most severity levels (not very severe) and should provide useful data for diagnosis, tracking severity and potentially as outcome measures for clinical trials.

It was a feasibility study, though it also gave some potentially useful outcome indicators too.
17 patients, 5 controls.

Patients were 2 mild, 10 moderate and 5 severe.
The researchers visited the patients at home to set up the testing and carry out the first stage.

On the day of testing, participants wore a portable metabolic system (PMS), heart rate variability (HRV) monitor and their blood pressure (BP), heart rate (HR), oxygen saturation (O2 sat) and lactic acid (LA) were taken during lying down, sitting, standing, bathroom activity, going down stairs, kitchen activity, going upstairs and a cognitive activity (maths) each for 5 minutes, or for as long as they could manage, eg some were unable to stand for 5 minutes.

They continued to wear the HRV monitor for up to six additional days and also recorded their BP, HR, O2 saturation and lactic acid.

The participants also recorded their daily activity and symptoms and fatigue questionnaire for the 7 days.

As you can see, they were able to collect a wealth of data while patients were at home and doing normal daily activity. They did find some physiological differences but the study was intended as a feasiblity study, so the focus was on whether the method was acceptable and manageable, not on outcomes. They did find it was highly feasible.

The hope is that this will provide sufficient data to remove the need for the much more physically demanding 2 day CPET, avoiding the need to travel to a testing centre and the likely PEM from that method.

I hope they get funding for a much bigger study and others replicate this too.

I am imagining if this method, or some refinement of it, is found to be useful and provides valid data that differentiates pwME from controls and from other diseases, it could be a hugely useful tool for diagnosis, disablity claims, and as outcome measures for clinical trials.
 
One more to write up. I didn't manage to stay for the last 2. I'll watch those later.
Taking a break before my last report. Just remembered I haven't eaten my breakfast yet!
Edit: 2 more to write up and I missed the last 3. I clearly can't count.
This rapid fire of 3 talks, discussion, 3 more talks, discussion is exhausting.
 
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Pre-Illness metabolomics data among college students following mononuclosis and ME/CFS reveals differences in multiple metabolites and metabolic pathways
Leonard A. Jason, DePaul University,
Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis, 2022, Jason et al
Cytokine networks analysis uncovers further differences between those who develop ME/CFS following infectious mononucleosis, 2021, Jason et al
Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study, 2020, Jason et al
Seeking the causes of post-Covid symptoms, researchers dust off data on college students with mononucleosis, 2020, David Tuller article (Jason study)
I think most of what Prof Jason talked about has already been published in the papers listed in the spoiler above.

They have done a metabolomics study on some of the patients in their original study of students who developed infectious mononucleosis (IM) and those who went on to develop what Jason calls S-ME/CFS ie ones who fit both Fukuda and one of the criteria that require PEM.

Because they had collected data including blood samples in several thousand students before any caught EBV, they were able to look at predisposing factors for those who developed ME/CFS.

There were no psychosocial factors predisposing to ME/CFS.
Predisposing factors were elevations in pro-inflammatory cytokines.

They now have done metabolomics in the blood samples from before infection for 18 S-ME/CFS and 18 matched controls who recovered from IM. They found some significant differences in some pathways including ones related to previous findings in other studies, such as TCA cycle and glutathione. I didn't manage to write down the details.

With computer modelling on the metabolomics data have made a predictive model that they say has over 90% sensitivity and specificity.

They are doing a 6 year follow up study and including data on Covid.

I hope this is accurate. As with other reports, this depends on my sketchy note taking.
 
Urine metabolomics exposes anomalous recovery after maximal exertion in ME/CFS female patients
Katherine A Glass, Cornell University, USA

There has been very limited urine metabolomics in ME/CFS to date, and none after an exercise challenge.

This was a pilot study with 10 pwME and 9 controls.
Urine was collected before and 24 hours after a maximal CPET exercise challenge and tested for over 1000 metabolites.

There were no significant differences between groups at baseline.

There were significant between group differences 24 hours after exercise in 33 metabolites, some realated to fatty acid and amino acid metabolism.

The fascinating thing is that the healthy controls had changes to hundreds of their urine metabolites after exercise, but the ME patients metabolites didn't change after exercise. So the between group difference after exercise was based on changes that happened in healthy people but not in pwME.

This was interpreted as showing that while healthy controls undergo a recovery process that shows up in altered metabolites in their urine, the pwME did not show evidence of this recovery at 24 hours.
The researcher describes this as 'disrupted metabolic recovery'.

I hope this will be followed up with larger trials and longer follow up.
 
During the conference volunteers live-tweeted during several of the conference sessions using the forum's twitter account, s4me_info.

This post is a copy of notes made during the July 28 keynote session at 9:15 AM, Pathophysiology of exercise intolerance in ME/CFS & long COVID, presented by David Systrom.

All notes were taken from this twitter thread (link in quoted section):
Click to expand...

=== start of comments ===

The second day of the IACFS/ME conference is about to start with a keynote lecture by David Systrom (Harvard Medical School) on the pathophysiology of exercise intolerance in ME/CFS and long COVID.

Systrom has a background in pulmonary critical care.

His expertise is [invasive] cardiopulmonary exercise testing (iCPET) where catheters measure blood flow and gasses, both venous and arterial, during an exercise test.

Around 6 years ago his research indicated that there was a subset of patients with exercise intolerance that could not be explained by intrinsic heart or lung problems.

Only later would his team test if these patients had ME/CFS, which was the case for the majority of them.

These patients were characterised by what Systrom calls 'preload failure'. They had a reduced VO2 max and a reduced right atrial pressure.

He is now seeing similar deficiencies in patients with Long Covid: "they are frighteningly similar if not identical."

There was also a smaller subgroup of ME/CFS patients where Systrom suspects skeletal muscle mitochondrial dysfunction and poor systemic oxygen extraction.

A randomised trial is ongoing on 40 patients of this subgroup.

They will be taking the new drug ASP0367 (which targets mitochondrial function) for 6 weeks.

Systrom also found that many (approximately 30-45%) ME/CFS patients had small fiber neuropathy following a skin biopsy. But interestingly there was no relationship between CPET measures such as Peak VO2 and abnormalities of the skin biopsy.

Systrom highlighted that many patients with preload failure have dyspnea. He thinks that
dyspnea and hyperventilation are common in ME/CFS and Long COVID.

Systrom also discussed his recently published trial of Pyridostigmine. It improved VO2 peak but the effect size was small.

He thinks it might be a useful repurposed drug in the (off-label) treatment of exercise intolerance in ME/CFS.
During the Q&A Systrom also touched the controversial topic of exercise for ME/CFS.

He said his team realises that PEM is often the most incapacitating symptom of ME/CFS and that therefore he advises patients to not push themselves into a crash

Systrom says he first prescribes medication so that patients are able to do more and only then let them try (graded) exercise.

He said they had good results with this approach and that it does not seem to result in permanent worsening of symptoms.

=== end of comments ===

My note: Here's a link to the Harvard ME/CFS Collaboration website that I think is relevant for this talk, Heart Preload Failure web page
 
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Continuation of notes from the @s4me_info twitter thread.

This post is a copy of notes made during the July 28 session at 10:30 AM, Provocative Maneuvers: Methods to Induce Symptomatic Features of ME/CFS. There were multiple presenters for this session, see conference schedule for full list.

=== start of comments ===

Mark VanNess (University of the Pacific) is now talking on methods to induce symptoms of ME/CFS (mostly exercise testing) and increase understanding of its pathology.

Next up is Peter Rowe (Johns Hopkins) on the ideal protocol for tilt table testing.

In his talk, Rowe credits the work of Visser/Van Campen in the Netherlands which suggested reduced cerebral blood flow in ME/CFS patients who had neither POTS or hypotension.

Lucinda Bateman (Bateman Horne Center) is now talking on how her clinical team uses the 'NASA lean test'.

The goal is often not to make a specific diagnosis but to provide an objective test of orthostatic intolerance. It can also guide treatment.

There is a risk of the patient fainting during this test but with close monitoring the test can be quickly aborted and safely managed.

Bateman also says that a single NASA lean test is often not sufficient to induce PEM.

The next speaker is Dane Cook (University of Wisconsin).

His talk focuses on cognitive tests such as the paced auditory serial addition task (PASAT).

These are used to induce mental fatigue which is then studied using MRI scans done before and after the test.

Cook showed an interesting slide where healthy controls made less errors on cognitive tests over time.

The ME/CFS patients had the opposite pattern. They started with an equal amount of errors but these increased rather than decreased over time due to mental fatigue.

Alain Moreau (Université de Montréal) explains how his team developed a new stress test, a pressure cuff, because many ME/CFS patients are too ill to do exercise testing.

Luis Nacul (University of British Columbia) is that latest speaker on the topic of “Provocative Maneuvers”. His talk focuses on tests measuring handgrip strength. His team reported this to be a marker for ME/CFS and disease severity.

A German study showed a reduction in hand grip strength of ME/CFS patients over time suggesting a fatiguability that was not seen in controls.

Nacul suggests that handgrip strength has potential as a provocation test in ME/CFS studies as it is inexpensive, readily available, and relatively safe.

Peter Rowe (Johns Hopkins) adds that some of his ME/CFS patients reported that physical therapy (testing range in motion for example in the neck) can also provoke fatigue and other symptoms.

During the Q&A the panellists discuss issues and risks with provocative testing.

Alain Moreau says that some patients are fine 90 minutes after the test but and become only really sick the next day.

Lucinda Bateman says that she knows patients who deteriorated (e.g., chronic pain) following exercise testing, so it is far from an ideal method.

The panellists stress that it important to prepare methods, (e.g., resting room), to alleviate PEM and symptoms afterwards.

Moderator Rochelle Joslyn asked if anyone considered cumulative provocations over time as most tests are limited to 1, 2 or 3 repeats.

The panellists found this interesting but agreed that it would be difficult to translate this into a controlled (and ethical) study design.

Another issue with provocative tests is making sure that patients and controls subjects are similar in fitness.

Bateman argued it is really hard to fully control for deconditioning.

=== end of comments ===
 
Continuation of notes from the @s4me_info twitter thread.

This post is a copy of notes made during the July 28 session at 1:30 PM, Immunology 1. There were multiple presenters for this session, see conference schedule for full list.

=== start of comments ===

Avik Roy of Simmaron Research is now discussing a drug-induced mouse model of ME/CFS.

Jessica Maya, a PhD Candidate from Cornell University found that the CD8+ T cells of ME/CFS patients have an exhausted subset of T cells that were not seen in healthy controls.

The sample size of the study was small though.

In the chat, Maya explains that Dr. [Liisa] Selin and Anna Gil work on very similar things, and "I've seen similar findings in my data that her group has found."

Kristine Aenlle (Miami VA Healthcare System) talks about Immune difference between male and female ME/CFS patients.

Females, for example, showed an increase in pro-inflammatory cytokines that was not the case for male patients.

=== end of comments ===
 
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