The Yale LISTEN Study Town Hall: July 2023
February 28, 2024Information
Drs. Harlan Krumholz and Akiko Iwasaki discuss preliminary findings and answer questions from LISTEN participants.
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- 00:05There you go. OK,
- 00:09so for anyone who's watching
- 00:10this now is being recorded.
- 00:11We've we've we've just welcomed everyone
- 00:14and now we're just starting the recording.
- 00:16So for anyone who's just joining us by video,
- 00:19we welcome you too.
- 00:21But so let me just anyone else got
- 00:26any comments midsubernally if you
- 00:28could go anything else before we go.
- 00:31OK. So again the the I won't take too
- 00:35long on this piece but just to tell you
- 00:38so listen studies consists of of people
- 00:40who are living with long COVID people
- 00:44who are experiencing adverse effects
- 00:48after having had the vaccine and other
- 00:51people controls we call them controls.
- 00:53We really mean are people who aren't
- 00:55suffering from either of those two
- 00:56things because we really in some of
- 00:58the studies are going to need people
- 01:00who are in a similar situation to you
- 01:02with regard to their demographics
- 01:04but are different from you in the
- 01:07sense that they're not suffering
- 01:08from a chronic condition.
- 01:10And so we're also encouraging many people
- 01:13within listen to if they can identify
- 01:15others to join this who can serve as
- 01:18sort of that reference population.
- 01:20Someone said they're they're
- 01:22not hearing the audios,
- 01:24most people hearing the audio.
- 01:25I can see people so I can just
- 01:27tell me so sorry Jose,
- 01:28but we're it seems like it's going so the
- 01:34so right at this point Kindred by the
- 01:37way has over 4000 people who have
- 01:40joined Kindred and I hope that's been
- 01:42a source of support for many people
- 01:43is that information has been passing.
- 01:45Kudos to that team. And the LISTEN study,
- 01:48which you're part of and that's
- 01:50the what we're talking about today,
- 01:53has, believe it or not, 20 / 2100
- 01:56people have joined the listen study.
- 01:58And you know, this is pretty novel in the
- 02:01sense that we didn't go to doctors and said,
- 02:03can you identify people in your practice
- 02:05who might want to join a study.
- 02:07And you know that there can be implicit
- 02:09biases in that where you know,
- 02:11some people are offered the opportunity
- 02:12to join a study and other people
- 02:14don't necessarily get the opportunity
- 02:15to join a study.
- 02:16And and and people may not, you know,
- 02:19come in through that pathway very
- 02:21well or you're not at a center that's
- 02:23been asked to be part of the study.
- 02:24So you're really not possible for
- 02:25you to be part of that.
- 02:27But in this study,
- 02:27what we wanted to do was go straight
- 02:29to people and then let people let
- 02:32other people know and through various
- 02:34mechanisms sort of just grow organically.
- 02:37And again, you know,
- 02:37this study has to be worthy of your trust.
- 02:39So if people are having a bad experience,
- 02:41no one's going to join it.
- 02:42So people have to feel like this
- 02:44is something that's worthy of them
- 02:46being part of.
- 02:47Now everybody came into Kindred and
- 02:50filled out a basic questionnaire to
- 02:53a variable degree of completeness.
- 02:55So one of the things I want to take
- 02:57the opportunity to do is to say we
- 02:59are doing things with the surveys.
- 03:01And I want to encourage everyone
- 03:02to be sure that they have filled
- 03:04out all their surveys.
- 03:05Plus we're going to start getting
- 03:07to the point where we're going to
- 03:08send out more surveys specifically
- 03:10from the listen study.
- 03:11So that's going to be an important
- 03:13part of what we do also.
- 03:14And we're going to be looking to you
- 03:16all as we begin to think about like,
- 03:18what should we be asking,
- 03:19how do we make sure we capture it?
- 03:20How do we in way advocate for
- 03:23what your voice is in this,
- 03:25what your experience has been,
- 03:26in addition to trying to advance
- 03:28the science to figure out how we
- 03:30can relieve some of the suffering
- 03:31or at most of the suffering that's
- 03:33going on out there.
- 03:34So this is another important piece.
- 03:36The connectivity to the medical
- 03:38records is another part.
- 03:39We're just going to start working
- 03:41on that as well.
- 03:42So many of you have connected your records.
- 03:44You know that Hugo is configured so your
- 03:46data doesn't move without your permission.
- 03:48There's no secondary marketplace,
- 03:50the data doesn't get sold it it's
- 03:53this has been like the whole idea
- 03:55was to give people agency over their
- 03:57own data to be able to pull that
- 03:59data together whether by wearables or
- 04:01health systems or insurers and payers.
- 04:04And so you're essentially have you
- 04:06accumulate those data assets and be
- 04:09able to share them into the study.
- 04:11This is a very unusual and novel effort here.
- 04:14And if we can prove that this can be done,
- 04:16I think it will spread as a mechanism
- 04:18to try to accelerate the way in
- 04:21which data can be aggregated,
- 04:23organized and analyzed so that
- 04:25we can learn in almost real time
- 04:27what's going on with people.
- 04:29And because the data streams
- 04:32with your permission,
- 04:32we're able to use it within the state.
- 04:34And again, we,
- 04:35we did agree in the consent that
- 04:38at some point we might allow other
- 04:41investigators to use the data,
- 04:43but we would have to de identify the
- 04:44data but enable other investigators.
- 04:46But what won't ever happen is
- 04:48the data won't be sold.
- 04:49It won't be commercialized in that way.
- 04:52It'll be only used for science to
- 04:54try to advance knowledge to try to
- 04:56make a difference to to what you
- 04:59guys are facing or or what people
- 05:01that you care about are facing.
- 05:03And so that's the configuration of this.
- 05:05So we're urging people to make sure
- 05:07they fill out the whole questionnaire.
- 05:09We we for some of the people we're
- 05:11actually adding some additional
- 05:12questions that are being done.
- 05:14But but we will be increasing I think
- 05:17the cadence of some of the information
- 05:20collection and then the the medical
- 05:22records are another important part of that.
- 05:23And then there's another piece of this
- 05:25study which is that there's a smaller
- 05:27group that we are working on to get
- 05:31to gather blood and saliva so that
- 05:33it can be analyzed in a Kiko's lab
- 05:35where now he's heading this effort to
- 05:37to organize this and it's collecting
- 05:39it in people's homes for a smaller group.
- 05:41And we are going to use that to
- 05:44try to correlate how people are
- 05:46reporting their experiences with
- 05:48what we can do from thousands of
- 05:51measures of of the immune system and
- 05:54and how it's functioning to try to
- 05:57begin to make some progress towards
- 05:59understanding and so quickly.
- 06:01I just also want to say that we we're
- 06:04if I were in your position I might
- 06:06be a little impatient like OK so when
- 06:08stuff going to start moving out the
- 06:10the the vibrations preprint is an
- 06:12example trying to move things out.
- 06:13We've got several other pieces
- 06:15that we want to move into preprint
- 06:17so you can see them.
- 06:18These are going to be basic descriptive
- 06:21studies that just help you understand
- 06:23who's in listen and and so we're
- 06:25going to do that for long COVID,
- 06:27we're going to do that for vaccine injury.
- 06:29We're going to do that for the combination.
- 06:30We're going to look at that all
- 06:32together and apart and and then
- 06:33we're going to look also people who
- 06:35have like we've looked at vibration
- 06:37and not we'd like to do that.
- 06:39Similarly for people,
- 06:40there are a lot of people
- 06:41have tinnitus ringing in
- 06:42the ears and not there's a
- 06:44lot of people who have pots.
- 06:46So they have autonomic dysfunction
- 06:48and we want to like look at that
- 06:51group specifically and we also are
- 06:53interested potentially in talking
- 06:54about people have central nervous
- 06:56system issues especially cognitive
- 06:58dysfunction and how does that look.
- 07:00Now there'll be overlaps in all these,
- 07:01but we're we're trying to
- 07:03characterize the group.
- 07:04So to manage your expectations
- 07:06there's these aren't going to be
- 07:08Nobel Prize winning contributions.
- 07:10What we're trying to do first is
- 07:12explain who's in the study what,
- 07:14what are some of these patterns
- 07:16We're doing some what's called
- 07:17cluster analysis to see, you know,
- 07:19who are what.
- 07:21I'll say like a sort of the what's the map,
- 07:22how are people organized with
- 07:24regard to their symptoms?
- 07:26Where are the areas where there's
- 07:27lots of people who have this cluster
- 07:29of symptoms versus this cluster?
- 07:30Because we believe that this label
- 07:32of law of of whether it's long
- 07:34COVID vaccine injury is too broad.
- 07:36It's it's it.
- 07:38They're probably different mechanisms
- 07:39but awful different manifestations.
- 07:42Just because someone's called long COVID,
- 07:43you may be very unlike some other
- 07:46people who are also called long COVID.
- 07:48And the more specificity we get the
- 07:50more likely we're to make progress.
- 07:52We start to build a a taxonomy around
- 07:54this a way to talk about this it's
- 07:57more sophisticated more precise and
- 07:59and for each of you it helps people
- 08:01understand who what you're experiencing
- 08:03and not putting you under some big
- 08:05categorization that actually doesn't
- 08:07really capture capture who you are.
- 08:09So in some thank you can't
- 08:12we can't thank you enough.
- 08:14Two we're urging you to to as
- 08:17much as you can participate with
- 08:19regard to filling out the surveys
- 08:20to connecting your records and if
- 08:23we're if you're asked about those
- 08:25blood specimens to give it some real
- 08:29consideration that would be great.
- 08:31We're going to start pushing,
- 08:32pushing stuff out.
- 08:33Some of the stuff will be very
- 08:35basic in the beginning.
- 08:36And again this idea of pre printing.
- 08:38So it's an Open Access link,
- 08:40we'll send it out to people and
- 08:42so it's there's no firewall,
- 08:44there's no price to it.
- 08:45It's just posted and it'll look like a paper,
- 08:48but it's there for public comment.
- 08:49It hasn't gone through peer review yet.
- 08:51It's just out there for your comments.
- 08:53So we're going to urge you to make
- 08:55comments and participate that way as well.
- 08:57And if anyone in the group wants to
- 08:58be more involved in studies or more
- 09:00involved in the things that we do,
- 09:02we need help. We're interested.
- 09:03We know you guys,
- 09:04I've got a lot on your plate
- 09:06just to deal with your health.
- 09:08So we don't want to impose or burden you,
- 09:10but I want to really extend the
- 09:12invitation that that many people
- 09:14have different skills in this group
- 09:16that could actually help help us
- 09:18advance and make more progress.
- 09:20So if you think there is a way that you
- 09:22want to be involved,
- 09:23then reach out to us and let us know.
- 09:25We for sure would want to hear that.
- 09:26And meanwhile, by the way,
- 09:27you also know there is a clinical
- 09:29trial we're doing with Pax Lovid,
- 09:3115 days of Pax Lovid versus placebo.
- 09:33It has been limited to three states,
- 09:36but we're about to expand it out.
- 09:39Leslie sent out a note to
- 09:41Kindred members I think today to
- 09:44say we're we're extending it.
- 09:45I hope we're going to extend it to all.
- 09:47There are a lot of exclusion criteria.
- 09:49So it's like any clinical trial,
- 09:51it's like you know there's this
- 09:53is there's certain ways you've got
- 09:55to satisfy to get in but and it's
- 09:57only going to be 100 to start.
- 09:59But again,
- 10:00every one of these people is going
- 10:02to get deep immune phenotyping in
- 10:04the Kiko's lab both before in the
- 10:07middle and at the end of the some
- 10:09of the data collection to help us
- 10:11understand whether one there are
- 10:14people who have maybe viral persistence.
- 10:16Are there people that are really
- 10:18responders to an antiviral like Paxlovid?
- 10:21And what can we learn in general about
- 10:23long COVID through this clinical trial?
- 10:25And I know there are others who may
- 10:27feel like either they don't qualify or
- 10:29they're not in the long COVID group
- 10:30saying when are you going to study us?
- 10:32And we're eager to.
- 10:33We're just need to figure out,
- 10:35hey, brass tacks we got,
- 10:36we have to figure out funding,
- 10:37we have to figure out how to do it.
- 10:38There's lots of stuff to get together.
- 10:39But the more momentum we get,
- 10:41the more we can convince others that
- 10:43this is real. We need to invest in it.
- 10:45We need to get answers and we need
- 10:47to help address the suffering.
- 10:48So with that,
- 10:49let me hand it over to to Tiana,
- 10:51who will just talk a little bit
- 10:53about the preprint and then she'll
- 10:55hand it over to Akiko.
- 10:57I'm here to share a little
- 10:58bit about the preprint.
- 10:59I'll share my screen. So I want to
- 11:02make sure everyone can also see it.
- 11:04Can you see the PowerPoint? OK, good.
- 11:08So this is one of the efforts that
- 11:10is ongoing in the Listen study.
- 11:13Like Harlan mentioned,
- 11:14there's many other avenues of
- 11:16questions that we're exploring,
- 11:19but this is just one of them.
- 11:20And this is specifically about internal
- 11:22tremors and vibrations as a symptom
- 11:25among people with long COVID and Listen.
- 11:29So the preprint is posted on Medarchive.
- 11:32If you want to take a deeper dive,
- 11:34feel free to look it up with this
- 11:36title on Medarchive and send us your
- 11:40comments or additional questions.
- 11:42As a caveat,
- 11:43some of the other results that I'm
- 11:45presenting today are more updated
- 11:47compared to what's posted on here.
- 11:50So if you hear something interesting
- 11:52today but you don't see it
- 11:54on the Med Archive page,
- 11:55it's because we have some new
- 11:57analysis that we haven't posted yet.
- 12:00So the motivating question that we
- 12:03had was this question right here among
- 12:06listen participants with long COVID.
- 12:08How do those with versus without
- 12:11internal tremors and vibrations
- 12:13differ from each other?
- 12:15And what's been described about
- 12:18internal tremors and vibrations has
- 12:21been this emerging definition of
- 12:24movement or a sensation of movement
- 12:26at any location inside the body
- 12:29occurring with or without external
- 12:32visible movement or muscle spasms.
- 12:34And the scientific literature
- 12:36that I've been able to find,
- 12:38we're mostly focused around Parkinson's
- 12:41disease and essential tremor.
- 12:42But I also saw in the chat,
- 12:44I think Angie posted something
- 12:46interesting about this being a
- 12:48perimenopausal or menopausal symptom.
- 12:51So I would love to hear more
- 12:52about what are other situations
- 12:54where this has been described.
- 12:56All of this is contextualized
- 12:59with the caveat that clinicians,
- 13:02researchers,
- 13:02patients might have different definitions
- 13:05for what is a tremor and how to
- 13:09classify different types of tremor,
- 13:11and that's still being actively
- 13:13discussed in the scientific literature
- 13:15about the best ways to approach that.
- 13:17For our methods,
- 13:19we particularly focused on the
- 13:21survey data and for the results
- 13:23I'm about to describe we have not
- 13:26utilized any of the biospecimens
- 13:28data or the electronic health
- 13:30records data that you've shared.
- 13:32And the surveys,
- 13:33if you some of you recall
- 13:35asked about your demographics,
- 13:37socio economic characteristics,
- 13:39pre pandemic medical and psychiatric
- 13:41conditions as well as current conditions
- 13:44at the time of taking the survey.
- 13:47Current health status which was
- 13:49measured by a standardized quality of
- 13:52life question and current symptoms,
- 13:54choosing from a list and having the
- 13:58option to say other or none and long
- 14:01COVID was defined by self report.
- 14:04Do you think you have long COVID without
- 14:06imposing any additional criteria
- 14:08around when the long COVID symptoms
- 14:11started or how long those have lasted?
- 14:14The way that The Who criteria
- 14:18imposes And for internal tremors,
- 14:20The specific phrasing in the
- 14:23questionnaire was internal
- 14:24tremors or buzzing vibration,
- 14:26and if someone checked that
- 14:28box then they were defined
- 14:31as having that symptom.
- 14:32So our statistical analysis
- 14:35took a two pronged approach.
- 14:38We first just simply analyzed a bunch
- 14:41of variables between the two groups.
- 14:43So demographics, socio economics,
- 14:45all the conditions and everything
- 14:48else that I have just mentioned,
- 14:51comparing them between the groups,
- 14:53the two groups,
- 14:54those with and without internal tremors.
- 14:56And two things I want to highlight
- 14:59here are that we also use the symptom
- 15:03questionnaire to calculate an
- 15:05approximation of something that the
- 15:07Recovery Consortium proposed which some
- 15:09of you might have read about in the news.
- 15:11So this is an NIH funded research consortium
- 15:16that suggested a preliminary scoring
- 15:18system for how to define long COVID.
- 15:21And just out of curiosity,
- 15:24not because we explicitly endorse or have
- 15:26any sort of opinion about what they propose,
- 15:30we just wanted to check how their
- 15:33scoring criteria might or might not
- 15:36apply in the listen population.
- 15:38And we also define something
- 15:39called new onset conditions.
- 15:41So that was calculated based on
- 15:43conditions that people reported as
- 15:45having at the time of taking the surveys,
- 15:48but were not reported as something
- 15:50they were having before the pandemic.
- 15:53The second branch of our analysis
- 15:55was a machine learning model.
- 15:58It was a gradient boosted tree machine
- 16:00and the focus of this particular
- 16:03analysis was just to see what symptoms
- 16:06are important for differentiating
- 16:08people with internal tremors from
- 16:11those without internal tremors.
- 16:17Here are some of our results in the
- 16:19overall group of listen participants
- 16:21with long COVID median age was 46 years,
- 16:25a majority were female,
- 16:26a majority were white, and 37%.
- 16:29A substantial minority reported symptoms
- 16:32of internal tremors or buzzing vibration.
- 16:35As a long COVID symptom and
- 16:38comparing the two groups,
- 16:39people with internal tremors were
- 16:41significantly more likely to be female
- 16:44with no significant differences in age,
- 16:47race, marital status,
- 16:49pre pandemic employment,
- 16:52pre pandemic household income.
- 16:55Something really interesting that I want
- 16:57to highlight is that the two groups
- 17:00were not different in their rates of
- 17:02any of the pre pandemic conditions
- 17:04that they had across 30 some pre
- 17:06pandemic conditions that we asked about
- 17:09but for infection characteristics.
- 17:11People with internal tremors were
- 17:13more likely to report it an index
- 17:16infection during the pre delta wave
- 17:21for health status which was measured
- 17:24by the Euro QOL quality of life scale.
- 17:28We found that the overall score that
- 17:31people rated their health status on
- 17:34for the overall group the median was 49
- 17:37and this is on a scale of zero to 100.
- 17:39Zero means the worst and 100 means the best.
- 17:43And we found that people with internal
- 17:47tremors were statistically significant
- 17:49in rating their current health as
- 17:52being worse than the other group.
- 17:55And here's also the recover score
- 17:57that I mentioned before.
- 17:58So it's an approximation because
- 18:01our questionnaire does not match
- 18:04the recover studies questionnaire
- 18:06directly in terms of the symptoms.
- 18:08But to the best of our ability we
- 18:12approximated using their scoring criteria
- 18:14and we found that overall across everyone
- 18:17with long COVID in this and listen,
- 18:20we have a score of around 16,
- 18:23a median score of 16,
- 18:25inter quartile range of 12 to 23 and
- 18:28people with internal tremors reported
- 18:30a median score that was higher than
- 18:33those without internal tremors
- 18:37for a new onset conditions.
- 18:39Comparing all of these conditions,
- 18:41rates of mast cell disorders,
- 18:44neurologic conditions,
- 18:45anxiety disorders,
- 18:46and trauma and stressor related
- 18:49disorders were significantly higher
- 18:51among people with internal tremors
- 18:53versus people without internal tremors.
- 18:55And again, this is new onset
- 18:58conditions that are occurring at
- 19:00the time of taking the surveys
- 19:02as opposed to anything that was
- 19:05reported as a pre pandemic condition.
- 19:10For the machine learning
- 19:11model that was created,
- 19:13here is a list of the top symptoms
- 19:16that were really important for
- 19:17differentiating the two groups.
- 19:19And I want to just highlight
- 19:20the top five right here.
- 19:22So hair loss was the most important,
- 19:24followed by floaters or visual lights,
- 19:28neuropathy, tinnitus and sudden chest pain
- 19:30and the other ones so on and so forth.
- 19:34On this list here,
- 19:37some of the early conclusions that we can
- 19:40draw are that participants with internal
- 19:43tremors and vibrations compared to others
- 19:45in listen who also have long COVID.
- 19:48They had similar demographics,
- 19:50similar health before the pandemic.
- 19:52But something about them might have
- 19:55been correlated with having different
- 19:57new onset conditions at the time of
- 20:00taking the surveys and having worse
- 20:02self reported health status measured
- 20:04by this quality of life scale and
- 20:07the machine learning model helped us.
- 20:10Understand that it is possible to
- 20:13differentiate the two groups from
- 20:15each other on the basis of other long
- 20:17COVID symptoms that people reported.
- 20:20Like Harlan mentioned,
- 20:21there's a lot of other studies that
- 20:23are ongoing right now and I want
- 20:25to specifically thank all of you
- 20:27on this call who participate bar
- 20:29participating in listen and some
- 20:31specific people including Sean,
- 20:33Kelly and Teresa.
- 20:34I want to thank all of you.
- 20:37That's it.
- 20:37Feel free to write more questions in
- 20:39the chat and I'll try to get to them.
- 20:43That was amazing. And for all of you
- 20:46on Tiana's actually medical student.
- 20:49And so we how are so fortunate to have
- 20:51people at all sorts of different levels,
- 20:53but to get a medical student at this
- 20:57caliber to help us is remarkable.
- 20:59Akiko, do you want to take on next?
- 21:03Sure. So I know that some of
- 21:05you have asked questions about
- 21:07what is the updated view of what
- 21:10might be causing long COVID.
- 21:13And so I wanted to just share
- 21:15a couple of slides as to how we
- 21:18are thinking about it. Let's see.
- 21:24OK,
- 21:28can you see this? Yeah, OK, great.
- 21:32So yeah, you know as you have
- 21:35heard me speak about this before,
- 21:37we we had four hypothesis for
- 21:41the root causes of long COVID.
- 21:44The first one being the viral
- 21:47reservoir or viral pathogen associated
- 21:49molecular patterns which is the
- 21:51nucleic acids of the viral genome.
- 21:54And these things can cause persistent
- 21:58symptoms because the either the
- 22:01viral antigen that triggered T or
- 22:05B cells chronically or viral RNA
- 22:08that can trigger this innate immune
- 22:11system to secrete certain types of
- 22:14inflammatory cytokines can both lead
- 22:17to chronic conditions and symptoms
- 22:20That that was our first hypothesis
- 22:23and and this is really related to
- 22:26the source COVID 2 virus that causes
- 22:28COVID 2nd hypothesis was autoimmunity.
- 22:32This is basically T and or B cells
- 22:36that react against self antigens.
- 22:38And we have seen a pretty striking
- 22:41evidence of auto antibody in
- 22:44severe cases of acute COVID.
- 22:47These patients either had prior
- 22:50existing antibodies against the
- 22:52immune factors that render them
- 22:55more susceptible to severe COVID or
- 22:58they developed auto antibody during
- 23:00the course of infection that target
- 23:03very various different tissues and
- 23:06cell types throughout the body.
- 23:08And once these things are triggered,
- 23:11it's it's very difficult to reverse them.
- 23:13And this is the second possibility
- 23:16as to why some people are suffering
- 23:19from the chronic phase of COVID.
- 23:22And the third hypothesis is dysbiosis
- 23:26of microbiome mainly we were thinking
- 23:30about the gut microbiome and potentially
- 23:34causing some leakiness in the gut
- 23:38epithelium that leads to inflammatory
- 23:40conditions and that's certainly been
- 23:42seen in MECFS and other conditions.
- 23:45We we also thought of reactivation
- 23:48of latent viruses that all of us
- 23:51carry a variety of viruses inside
- 23:54of our body which are latent and
- 23:57don't cause any symptoms or disease.
- 24:00But when there is a the immune pressure
- 24:02that's controlling these viruses,
- 24:04when they're lifted or when
- 24:06they're dysfunctional,
- 24:07these latent virus can become reactivated.
- 24:11And the the 4th hypothesis is tissue damage.
- 24:15This is it doesn't have to even
- 24:17occur at the site of infection.
- 24:19We demonstrated using a mouse model
- 24:22of mild respiratory COVID that even
- 24:25a lung infection that's transient
- 24:27in a mice can lead to very long
- 24:31term changes in the central nervous
- 24:33system that is not reversed even
- 24:36after weeks of weeks post infection.
- 24:39And the I've sort of highlighted
- 24:42each of these boxes with different
- 24:45colors to indicate that throughout
- 24:47the research that we've been doing,
- 24:50we are seeing as well as many others
- 24:53that are in investigating the causes
- 24:56of long COVID Viral persistence is one
- 24:59of the key hypothesis that still is
- 25:05supported by over 100 different publications.
- 25:09We still don't know if the virus
- 25:11that's persistent in some people are
- 25:14causing the disease or it's just a
- 25:16sort of what happens with COVID and
- 25:19that it doesn't relate to the disease.
- 25:22And one of the best ways to
- 25:25to figure this out is,
- 25:26is through this back slovid trial
- 25:30that Harlan already mentioned.
- 25:32What this allows us to do
- 25:35is kind of interrogate the immune
- 25:37system in people who have long
- 25:40COVID prior to the treatment with
- 25:43Paxlovid and during the treatment
- 25:45and after the treatment to see how
- 25:48the immune factors change over time
- 25:51and how does that change correspond
- 25:54to benefit for the patients.
- 25:57Since we think that there are
- 25:59multiple root causes of long COVID,
- 26:01we're not expecting everyone to
- 26:04respond positively to Paxlovid.
- 26:06But we're hoping that a subset of
- 26:09people who respond to PAC Slovid
- 26:11will tell us a lot about what are
- 26:13the biomarkers for responsiveness?
- 26:16What are the features that are
- 26:17common in the people who respond
- 26:19positively to PAC Slovid?
- 26:21And in the future trials can we enrich
- 26:24for those people with the biomarkers
- 26:27to provide a sort of better chances
- 26:30of people recovering or feeling
- 26:32better from COVID with PAC Slovid.
- 26:35So, so this is sort of a an area
- 26:38that we're heavily investigating
- 26:39and are very excited to be able
- 26:42to do this with you all.
- 26:45Of course we're recruiting some
- 26:46some of you through the listen
- 26:49study and and hopefully we'll be
- 26:51able to tell you what's going on
- 26:53once the the study's completed.
- 26:54But that that's a huge,
- 26:56I think it will give us a gives us a
- 26:59huge clue as to what might be driving and
- 27:02whether the reservoir has any kind of
- 27:05real evidence for disease autoimmunity.
- 27:08I kind of graded out a little bit,
- 27:10but this I haven't really dismissed,
- 27:13we haven't dismissed this possibility.
- 27:15It's just that in our studies we haven't
- 27:17found any common auto antibodies that
- 27:20are found in people with long COVID.
- 27:23If you look at the number of
- 27:25auto antibodies per person,
- 27:26they're not elevated necessarily in the
- 27:29long COVID participants compared to controls.
- 27:32And this is the study that Doctor David
- 27:35Petrino and our group have done together.
- 27:38It's called the Mylan COVID study and that
- 27:41is has been on Medarchive for almost a year,
- 27:45but it's finally accepted for publication.
- 27:47So we should be able to share
- 27:49the the latest with you shortly
- 27:52in the published version.
- 27:54But in any case,
- 27:55we don't see a clear cut evidence
- 27:57for auto anybody against human
- 28:00proteins that are expressed on the
- 28:02surface or secreted from the cells.
- 28:05However,
- 28:05it doesn't mean that there isn't
- 28:07AT cell mediated autoimmunity and
- 28:10it also doesn't mean there isn't
- 28:12a antibody mediated immunity that
- 28:15targets intracellular antigens.
- 28:16So we're still very much open to
- 28:19this idea and investigating further
- 28:23the the dysbiosis.
- 28:24We haven't really been able to look
- 28:27into the microbiome yet but we are
- 28:30looking at latent virus reactivation
- 28:32and this is showing us that in
- 28:35people with long COVID there appears
- 28:37to be an elevated level of Epstein
- 28:40Barr virus reactivation.
- 28:41As well as potentially there's
- 28:44zoster virus which is the the virus
- 28:48that causes shingles that may be
- 28:51reactivating much more frequently
- 28:53than people without long COVID
- 28:55who recover from COVID.
- 28:57And this has been reported not
- 28:58just by us but
- 29:00at least two other groups and it it's
- 29:02you know again we don't know whether
- 29:05this EBB reactivation is causing
- 29:06the symptom or it's just a sign of
- 29:10a dysfunctional immune response.
- 29:11But it is telling us there's some
- 29:13really biological difference in in a
- 29:15subset of people with on COVID and
- 29:18tissue damage we're we're continuing
- 29:20to use this mouse model and developing
- 29:22other mouse models to be able to
- 29:25look at the you know causal role of
- 29:28these inflammation induced damage.
- 29:30How do we reverse this you know
- 29:32such as the the the CNS impact and
- 29:36memory issues and brain fog and
- 29:38and so on that's reported.
- 29:40So this is sort of like the updated
- 29:43version of what I told you before
- 29:45and then you know ideally right
- 29:47we we we should have clinical
- 29:50trial coupled with deep biological
- 29:52analysis for all of these going on
- 29:55and there are some efforts going on.
- 29:57But I just wanted to kind of highlight
- 30:00I'm sorry the dog what we're doing
- 30:03here and then just sort of taking these
- 30:07insights into sort of the downstream
- 30:12effects and pathology that people are seeing.
- 30:15So the viral reservoir, autoimmunity,
- 30:17latent virus reactivation, tissue damage,
- 30:19this may be kind of happening in in
- 30:22concert within a person or one may be
- 30:24driving the disease in a subset of people.
- 30:27We don't know what the actual sort of
- 30:30connection between these wheels are.
- 30:32But what we do know is that there is also
- 30:36evidence of downstream pathology such
- 30:39as vascular damage that's reported from
- 30:42respiratory and and others including micro
- 30:45clots as well as platelet activation.
- 30:48These are two events that we are
- 30:51investigating in Els and study
- 30:53from participants who provided us
- 30:55blood and saliva.
- 30:57We're also looking at hormonal imbalance
- 30:59because one of the key defining
- 31:02factor that we saw in our long COVID
- 31:05participants was at reduced levels of
- 31:08cortisol as well as potentially other
- 31:10hormones and and so we're really looking
- 31:13into the this hormonal imbalance as a
- 31:17possible downstream sort of mechanism
- 31:20and mitochondrial dysfunction.
- 31:22This is also been reported both
- 31:25for MECFS and long COVID.
- 31:27We're investigating what the causes
- 31:30of a mitochondrial dysfunction might
- 31:31be and it may be triggered by the
- 31:35upstream events such as vascular
- 31:37damage and microcloth formation,
- 31:39which would then impair the ability
- 31:42of cells to acquire oxygen and
- 31:45properly conduct the the mitochondrial
- 31:48function in tissues.
- 31:50So these are sort of the downstream
- 31:52things that we also are looking at
- 31:55through the ELSN study and of course
- 31:58ultimately we'd love to identify
- 32:00biomarkers for different subsets of
- 32:03diseases and of course therapy and
- 32:07cure ultimately depending on what
- 32:09the driver of these diseases are.
- 32:11And so we,
- 32:12we are very excited to be able to
- 32:15do this with all of you and you
- 32:17know we're working very hard,
- 32:18Born Alley is working very hard in,
- 32:20in coordinating collection of
- 32:23biospecimen from a subset of
- 32:26you that's listening in today.
- 32:28So I'm going to just stop sharing.
- 32:30I,
- 32:31I think I took more than my share of time,
- 32:33but I'd be happy to address any questions.
- 32:37Of course
- 32:39we, I think we, we always appreciate
- 32:41when you take more time, it's great.
- 32:45There are questions that are both in the Q&A,
- 32:49but some of that were sent to us before.
- 32:59So this person, there are a couple
- 33:00questions we're going to ask for
- 33:01you and then Bernal can answer one.
- 33:02But because this person said I've been
- 33:05tested and treated for micro clots,
- 33:06is this something that's going to be more
- 33:08readily available in the United States?
- 33:09I've been paying out of pocket
- 33:11to see a doctor.
- 33:12What do you think about microclots?
- 33:15Yeah, so we are also, as I just mentioned,
- 33:19very interested in our investigating
- 33:22microclots and in people.
- 33:23And we are seeing definitely evidence of
- 33:27microclots and platelet activation in some
- 33:30people with long COVID as well as some
- 33:33convalescent people who have recovered
- 33:35from COVID but have had COVID before.
- 33:39And right now I I don't want to make
- 33:41any claims that microclots are causing
- 33:44the disease because we don't know.
- 33:47We see some increases and it's variable.
- 33:50It's not that everyone has microclots,
- 33:52there are it seems to be a more
- 33:56activation in long COVID and and and
- 33:58even in post vaccine adverse events.
- 34:02However, we need to be very careful.
- 34:04First of all we need to have enough
- 34:06control to be able to say statistically
- 34:09significantly is is there an elevation and
- 34:12in the people who have these micro clots,
- 34:15what are the the the common common
- 34:17symptoms and features as well
- 34:18as immune markers do we see.
- 34:20So we we are cautiously approaching
- 34:24this with proper controls and trying
- 34:27to understand what that means.
- 34:29We don't know what it means yet.
- 34:31There are places that are doing
- 34:34the micro clot analysis.
- 34:37You know,
- 34:37I don't know which labs are doing them,
- 34:40but I know that there are some labs doing it.
- 34:42Hopefully they're doing it in a
- 34:44in a standard way because there's
- 34:47also variation between each labs
- 34:49in the outcome of these assays.
- 34:52So, yeah,
- 34:53it's it's very early days and I don't
- 34:57know what to recommend whether you
- 34:59should get the microcloth assay and
- 35:01and then what would be the treatment,
- 35:04you know,
- 35:05and so we're still in the discovery phase.
- 35:08Yeah. And I just endorse that.
- 35:09Also somebody asked me about this
- 35:11today in an e-mail and I said,
- 35:15you know, I think it's promising.
- 35:16I know a lot of people believe in it.
- 35:17I'm not sure about both the validity,
- 35:20the reliability that is test to test place
- 35:23to place because this isn't standardized.
- 35:25Like if you go get a potassium measured
- 35:29at one place and at another place,
- 35:31there are national federal standards that
- 35:33make sure that it should be the same.
- 35:35But you know we don't have those,
- 35:37that oversight right now on the micro clots
- 35:39and then ultimately is it actionable?
- 35:42And you know, some people think it
- 35:43is and some people think it don't.
- 35:45I know how much everyone's suffering.
- 35:46So I don't want to say what people should do,
- 35:50'cause, you know, there's a bit,
- 35:52there's a bit of desperation in all of it.
- 35:53But but just to say,
- 35:54on the science side,
- 35:55it's not there that we could say
- 35:57that with with confidence.
- 35:59Yet
- 36:01a couple other people were
- 36:04asking Akiko whether the damage
- 36:05that they're experiencing now,
- 36:07do they do we think that it can be reversed?
- 36:10Is it permanent? And,
- 36:11you know, my view on is,
- 36:13is I think you and I both heard
- 36:15stories of people who have been
- 36:17suffering for a long time and then it
- 36:19does resolve and they've gotten better.
- 36:21We've heard other people who,
- 36:22you know, it persists in,
- 36:23but I don't think we can say yet
- 36:25for sure what would be considered
- 36:27permanent or what might be reversible.
- 36:30And I I want people to have hope
- 36:32still and there's definitely not
- 36:33evidence to suggest that what
- 36:35lots of people are suffering,
- 36:37you know, wouldn't go away.
- 36:39So I I always try to encourage
- 36:40people to have hope.
- 36:41But I don't know what do you think of Kiko?
- 36:44Yeah, I I think, I I really hope
- 36:47there is a way to reverse it.
- 36:49And and you know certain
- 36:51tissues that are damaged,
- 36:52of course it depends on which organ and
- 36:55how replaceable those cells are and so on.
- 36:58But I definitely,
- 36:58I mean that's why we're doing this research.
- 37:01We really want to find something that
- 37:04would be helpful And we are doing because
- 37:06we have these mouse models of tissue damage,
- 37:09we are able to try all kinds of different
- 37:12agents to be able to reverse the damage.
- 37:15And that's what what some members of my lab
- 37:18are doing right now and we'll let you know,
- 37:21you know, if we find something.
- 37:22But we're doing this in a sort of way,
- 37:25you know, in which science has
- 37:28approached similar kinds of inflammatory
- 37:31conditions before with the drugs that
- 37:34are able to kind of restore and and
- 37:37replenish the damaged cell types.
- 37:39So I'm hopeful,
- 37:40of course we're not going to
- 37:42promise anything because you know
- 37:43that that would be irresponsible.
- 37:45But yeah,
- 37:47I am really hope that we can find something.
- 37:50You know, we know that some days
- 37:51it may be hard to have hope when
- 37:53you're facing all these things.
- 37:54So we, we want to encourage people
- 37:56not to give up and to feel maybe
- 37:58we can together all find answers.
- 38:00Bernal, you know,
- 38:01you answered this on the chat.
- 38:03Some people put it in the Q and AI know,
- 38:05you know, maybe you could just say
- 38:07out loud people listen who have
- 38:10had the deep immuno phenotyping,
- 38:12maybe you can make a comment or two.
- 38:13I'll just say to fit folks that it's
- 38:16not usual for us to be allowed to return
- 38:20research level results to participants.
- 38:23We want to be able to do that.
- 38:24But the the the regulatory
- 38:27bodies are concerned about.
- 38:29By the way Micro Klots is an
- 38:31experimental test as well,
- 38:33but because clinicians are ordering it,
- 38:36they can give it back to you.
- 38:37But when we're doing experimental
- 38:39tests in the lab,
- 38:41that for research there's reluctance
- 38:44because of a fear that people act on
- 38:46them in ways that aren't yet proven out,
- 38:49that even the tests should be acted on.
- 38:51But we think we found a path
- 38:53to share something.
- 38:54So Bernal, do you want to talk about that?
- 38:57Sure.
- 38:57So
- 38:58we right now have approval from
- 39:00the IRB to share research only
- 39:03reports and we are in the process
- 39:06of getting the reports ready,
- 39:08finishing off all the assays first
- 39:10and then getting the reports ready.
- 39:12And once we have them ready,
- 39:13we will reach out to you because
- 39:15that's the protocol that the IRB
- 39:17has proposed for us.
- 39:18We'll send out a mass e-mail to
- 39:21anybody in the study who has
- 39:23contributed biospecimens to our
- 39:25study and once they acknowledge
- 39:27and request for the reports,
- 39:29we'll individually be sending
- 39:30out those reports.
- 39:31But those will be research
- 39:33only reports not actionable.
- 39:35Thank you. A
- 39:38couple people, Akiko were asking about
- 39:41Epstein Barr virus and the reactivation and
- 39:46and and then somebody asked whether
- 39:49or not long COVID they asked whether
- 39:52can reactivate other viruses as well.
- 39:55But I think we're thinking like maybe
- 39:57those are the actual cause of the symptoms.
- 39:59But do you want to just say a minute
- 40:00what are you thinking about Epstein
- 40:02Barr virus Now as I know you mentioned
- 40:04as a mechanism this reactivation of
- 40:06viruses but in in in your lab you are
- 40:09you're you're following the stream,
- 40:10right as a as a way to sort of
- 40:12figure this out.
- 40:14Yeah definitely. So we are.
- 40:17Testing experimentally whether source
- 40:20COVID 2 infection can reactivate
- 40:23EBV in latently infected B cells,
- 40:26for example in the tissue culture.
- 40:28So we can do this just in vitro
- 40:32experiment to see whether there's any,
- 40:34you know interaction between
- 40:36the viruses and that would be
- 40:39a direct path to reactivation.
- 40:42But a indirect path would be that
- 40:44the source COV two infection led to
- 40:47impairment in T cells or B cell immune
- 40:50control of these latent viruses and
- 40:53that would be sufficient to reactivate.
- 40:56So that that's sort of the,
- 40:57the cause for reactivation but also
- 41:00the consequence of reactivation whether
- 41:02EBV treatment of against EBV reacted
- 41:07EBB or monoclonal antibodies or
- 41:10there's some other form of treatment
- 41:13to deal with the reactivated virus.
- 41:16Would that be helpful to people?
- 41:18And these things would obviously
- 41:20require some you know,
- 41:21form of clinical trials to be able to
- 41:24to understand the benefit of these drugs.
- 41:27But yeah,
- 41:28so we are still investigating like you know,
- 41:31what causes it and what is
- 41:32the consequence of it.
- 41:35Somebody was asking how can
- 41:37you tell that it's reactivated?
- 41:41There are two separate evidence.
- 41:44So one is the Cell paper that was
- 41:46published by Jim Heath's group last year
- 41:49where he was able to detect viremia,
- 41:53which means the EBV viral DNA
- 41:55was found in the blood of people
- 41:57during the acute phase of COVID.
- 42:00And when they follow these people over time,
- 42:03the ones that who had viremic EBV were
- 42:07the ones that were more likely to develop
- 42:10long COVID versus those who didn't.
- 42:12So this was a longitudinal
- 42:14study that Jim Heath,
- 42:15this group has done and there are
- 42:18Mike Peluso as well as our lab.
- 42:21We found that elevated antibodies
- 42:23against lytic protein of EBV which
- 42:26is normally hidden in latent cells.
- 42:29They don't express these proteins
- 42:31during latency and the fact that you
- 42:34have elevated IgG against these things
- 42:36are are quite indicative of recent
- 42:39reactivation with with the virus.
- 42:42So we're not saying that people who have
- 42:45these antibodies have live infectious
- 42:47CBB floating around in their blood.
- 42:49We actually can't find, you know,
- 42:52viremia in these people.
- 42:54However,
- 42:55we do see evidence for recent reactivation.
- 42:58So this may have happened during
- 43:00the acute phase of COVID or it may
- 43:03have happened a few months ago.
- 43:04We don't know,
- 43:05we we we don't have the
- 43:07longitudinal samples to,
- 43:08to tell what happened in the
- 43:10intervening time period.
- 43:11But yeah, so that's the evidence we have.
- 43:15Well, that's great.
- 43:18Somebody's asking about auto antibody
- 43:20testing that doctors can do and it it
- 43:24may be just an opportunity to reflect
- 43:26on this paper that's going to come out
- 43:28in nature where there was a panel,
- 43:29what is it more than 2000 auto
- 43:31antibodies that were tested.
- 43:32And and I don't know if you want us
- 43:34to say something about that Akiko,
- 43:36I mean sort of that we weren't
- 43:38able to identify much there,
- 43:41right, exactly. So this is the REAP
- 43:44strategy that was developed by Professor
- 43:47Ringslab and what it contain actually
- 43:51over 6000 antigens from human. Yeah.
- 43:54And of course there are you know several
- 43:58auto antibodies that are found in people
- 44:01with long COVID and people without
- 44:03long COVID and the healthy control.
- 44:05So and in fact all of us carry some
- 44:09form of auto antibodies against
- 44:11you know several auto antigens but
- 44:14they're not pathologic antibodies.
- 44:16And so but even though we didn't find it
- 44:19in that panel like I said you know we,
- 44:21we we haven't excluded the possibility that
- 44:24auto antibody against internal antigens,
- 44:27intracellular antigens or some
- 44:29nucleic acids or something else
- 44:31may be causing the symptoms.
- 44:33So even though you know that REAP didn't
- 44:37find clear pattern of auto antibody,
- 44:40we we certainly haven't given
- 44:42up on that hypothesis
- 44:45and somebody was raising an
- 44:47issue to us asking about you know
- 44:50that study was about long COVID.
- 44:52We also are going to be doing the
- 44:54same kind of analysis for those who
- 44:56are experiencing vaccine injury.
- 44:58I will say one thing about this issue
- 45:01of vaccine injury because somebody,
- 45:03I think you know who had come into the
- 45:05study with long COVID was wondering why?
- 45:08Why are you studying people with
- 45:09vaccine injury and want to say that
- 45:11it's clear to us that there are lots
- 45:13of people who are suffering and and
- 45:15there were a lot was a lot of overlap
- 45:17in terms of a chronic condition that
- 45:18had really unraveled people's lives.
- 45:20And it.
- 45:20It's important to know that these people
- 45:22who are reporting this about the vaccine.
- 45:25You know that most of every one of them
- 45:28that I've talked to like doesn't want to
- 45:30get involved in the politics of this.
- 45:31They're not anti Vaxxers.
- 45:33They got vaccinated.
- 45:34They they,
- 45:35they are people who have found
- 45:37themselves in a position where
- 45:40it's it's inconvenient for anyone
- 45:41to even talk about them because
- 45:43of what the way the politics
- 45:47occurred. And a lot if people with
- 45:51long COVID have found themselves in
- 45:52positions where people don't believe them,
- 45:54I can take it's even more intense
- 45:56for these individuals who are
- 45:58reporting symptoms after vaccination.
- 45:59And so, you know, I think when Akiko and I,
- 46:02you know, became aware of this
- 46:03and started talking about this,
- 46:04we recognized that there was some
- 46:07risk because of the political
- 46:08maelstrom about this. But we're,
- 46:11we wanted to approach us scientifically and
- 46:13we wanted to approach us humanistically.
- 46:15I mean people are suffering and
- 46:17we've developed a platform,
- 46:18we've developed a way to work together with
- 46:21folks and we thought that we should be,
- 46:24you know, we should be willing
- 46:25and interested and we weren't.
- 46:26We are, you know,
- 46:28in trying to find answers there too.
- 46:30So what what really I think in the
- 46:33end was there will be different
- 46:35mechanisms no doubt when we're talking
- 46:37about viral persistence that's not
- 46:38going to be the thing that is we'll
- 46:41we'll find that occurs for people
- 46:42who had problems after vaccination.
- 46:44And I want to say I believe,
- 46:46I know Kiko believes you know
- 46:48vaccinations are modern medical miracle.
- 46:50Millions of lives were saved because of
- 46:52the speed with which vaccines burned out.
- 46:54But it can be true and true that
- 46:57there still were some people who were
- 46:58harmed by the vaccine. You could.
- 47:00Both of those things can be true.
- 47:02The net value of it was immeasurable.
- 47:05And yet and yet there's still
- 47:06some people harmed.
- 47:07If you look at vaccines over the history,
- 47:09it's almost always true that
- 47:11there's some things that happen
- 47:13when people are vaccinated,
- 47:14in this case rare relative to benefit,
- 47:17but important to anyone who's affected.
- 47:20And I think our job is to understand how
- 47:22can we prevent in the future what is this
- 47:24and how do we help alleviate suffering.
- 47:26And again we're trying to to to take
- 47:29this in in a in a broad based way.
- 47:32So you know long COVID an injury there
- 47:35they may unlock some of the mechanisms
- 47:38that by which the immune system is is
- 47:41ends up conspiring against the best
- 47:43interest of the host and of the person.
- 47:46And so you know we're hoping that this
- 47:49all helps unlock this interestingly
- 47:51when we measure the health status
- 47:53in in listen of people with who are
- 47:56reporting vaccine injury and if people
- 47:57are reporting along COVID and by the
- 47:59way even the long COVID group we're not
- 48:01requiring people have had a positive test.
- 48:02We know lots of people got this before
- 48:04tests were available we're we're
- 48:06we're accepting what people say.
- 48:08And when you look at their health both
- 48:11groups are suffering about equally that
- 48:13that score of zero to 100 is is shows
- 48:17severe disabilities severe illness
- 48:19in both both groups about equally.
- 48:22Maybe we can use them to help us
- 48:24understand each each other because
- 48:25they can almost serve as controls
- 48:27for each other because like I
- 48:28said there's some things that
- 48:30would not have happened otherwise.
- 48:32But anyway I just wanted to to mention
- 48:34so we're we're just about a time
- 48:37let me just thank everyone we'll
- 48:38look for we'll look through and see
- 48:41if there are other questions that
- 48:42we can answer that we we missed.
- 48:44I'm going to give Akiko the last word here,
- 48:46but. But I just want to say
- 48:47from the depth of my heart,
- 48:49I want to thank all of you
- 48:50for being part of the study,
- 48:51being part of the team,
- 48:53being willing to come along.
- 48:54We are always interested in your
- 48:56comments and not just positive comments.
- 48:59Tell us what we're doing wrong.
- 49:01Tell us what we can do better.
- 49:02Tell us how we can we, you know,
- 49:04somehow be more responsive to this,
- 49:06how we can accelerate this.
- 49:08And also great deep thanks to
- 49:10the Listen research team at Yale
- 49:12who spent countless hours trying
- 49:13to move this stuff forward.
- 49:15And Akiko,
- 49:16let me hand it back to you for last comments.
- 49:19Yeah. Thank you, Harland. Yeah.
- 49:20It's it's I'm I'm really grateful to
- 49:22be part of this large team including
- 49:25so many participants here today
- 49:28to be able to investigate this.
- 49:30I think it's going to this is already
- 49:33revolutionizing the way we do science
- 49:35and and and and much thanks to Harland
- 49:37and his vision in in allowing this to
- 49:40happen and we're very much committed
- 49:42to figuring out what's going on with
- 49:45people with long COVID and people
- 49:47with post vaccine adverse events.
- 49:50And we we have collected the first
- 49:53set of samples from people with
- 49:55vaccine injury and we are just
- 49:58waiting for the results to come back.
- 50:00And so hopefully next time we can
- 50:02share some of the the collected
- 50:05data from that study.
- 50:07But we're very,
- 50:08very much dedicated to doing this and and
- 50:11we apologize for the slowness of the studies,
- 50:14even though we're doing
- 50:16everything at lightning speed,
- 50:17things take a long time even even with
- 50:20just the regulatory paperwork alone.
- 50:22So it's really,
- 50:23it's not an immediate answer
- 50:25that we can give you,
- 50:26but just know that we are really
- 50:29working hard and we thank you all.
- 50:34Thank you.