For joining us to this webinar jointly hosted by New York City Department of health and mental hygiene, and the infectious diseases Society of New York I’m Adam Ratner president intellect of ideas and why and I’m joined by Josh current president and Dr Mary foot from New York City We’re grateful for the enthusiasm that the community has had for the last few months for these webinars And our goal is to continue them on a quarterly basis with topics, expanding beyond uncovered as the situation permits one quick reminder before we start anyone who has been an member in the past, should’ve received an email, notice with a reminder to pay dues and vote in the X and Y, elections before the July thirty deadline so please do so, to help keep the society strong the links for both of these are on the societies homepage it Y dot Org resting each talk tonight soon be twenty five minutes with five minutes for questions Please submit your questions via the Q and a feature and one of us will ask the speaker at the conclusion of their talk. We apologize in advance. We don’t get all the questions because we’re going to try our best to stay on schedule So to that end, I’m delighted to introduce our first speaker Dr married Dr foot is a senior health security specialist and health systems planning and strategy lead at the New York City Department of health and mental hygiene and she will be talking to us today on update coded nineteen in New York City Alright, thank you so much Adam and I did pay my dues already, so thank you for the reminder. So thank you so much for for everybody for joining us in the evening session. We are very excited to be here as always So this is just a quick outline where we’re mainly going to be presenting are epidemiology updates than a couple updates on our guidance and the test entries program So, of course, where we now, unfortunately, we are up to thirteen million cases worldwide with over five hundred and seventy two thousand destitute coca sites many of the US states are now, unfortunately delayed But are now starting to implement base, covering requirements, another restrictions after seeing a dramatic increase in transmission and many parts of the country and New York City We are fortunately still plugging along and we have been watching things very, very closely as we officially entered phase, three of reopening onto life. So that was just last week So we’re keeping a very close eye on things and our current, New York City response strategy We are keeping a close eye on what’s going on in the rest of the country, maintaining very close vigilance on our surveillance numbers and continuing our suppression measures, efforts and monitoring, you know, the impact of everything going on around that So cobit, nineteen transmission worldwide We’re up to over three, thirteen million cases that took about six weeks to double the amount of cases that we had had previously and we’re over five hundred and seventy two thousand deaths And that is to say And we’re definitely starting to see hotspots that have been picking up, especially unfortunately, in, in, in our neighbors, to the South and Latin America, also, Middle East and definitely South Asia have have really been picking up a lot in South Africa It’s been much more heavily impacted of late And this is just a really nice map if you haven’t seen it, this is by the New York Times, and this is really a good visualization. That’s sort of where things are across the country. It’s a bit of a heat map So, you can see in the areas that are red are where they’re having significant, rising levels of cases And then the blue, the light blue is where we’re having decreasing number of cases So, as you can see, you know, we’re actually doing, okay, the former epicenter around the Northeast, but unfortunately we’re starting to become surrounded by these hotspots that really seem to be wanting to close them on that So, hopefully, you know, things will continue where we are in the blue So, looking at again, the US data, this is a visualization of the cumulative cases and that’s something us above the ninth of July. And overall, the US is being over three point, four million cases And that accounts for about twenty six percent of confirms global cases. And we are at over a hundred and thirty seven thousand and that is accounting for about twenty four percent of reporting

And where we are in New York City, that’s unfortunately a little more encouraging. And what we’ve just just mentioned. We are cumulatively at a case Council of about two hundred and fifteen thousand actually almost two hundred and sixteen thousand We had had had overall throughout the course of this, so far about fifty, five thousand hospitalizations confirmed, that’s over eighteen thousand, and adding on another almost five thousand, a probable depth And the probable depth are counted from death certificate report. And that was largely sorted from the earlier phase of the surge before we had widespread testing available So that is how those are categorized and just looking at this. So, again, you’ll see a case counts at the top hospitalization, which is, you know, a little bit lagged behind the cases And then, because it takes a little while before some of these diagnosed before the end up getting hospitalized up in time And again, the desks that you’ll see, also there’s about a two week lag behind hospitalization with the desk, but in all measures, we happen in a steady state of decline And this is a newer visualization that we have been monitoring closely. This is looking at So, basically, you know, this is as everybody’s talking about oh, work cases are growing up because we’re testing more and that’s not really the whole story Of course, you need to look at your percentage of testing positive so we’ve had a steady increase in the number of testing and you don’t see sort of on the far. Right? There’s a bit of it reporting lag So so that’s why, you see, the lower number at the far right? And then we’ve had a very study decline in the percentage testing positive, which is exactly where we want to be So so just to talk about some of our more recent updates, it pertains to healthcare partners We had a recent guidance, come out on number twenty, a couple of weeks ago that gives some new recommendations on personal, protective equipment and identifying and managing corporate exposures in the workplace and exclusion after a potential workplace exposure to cope it So really, this is based on during suppression where, you know, really focusing on identifying and excluding now, healthcare personnel amount that staffing shortages has been a relatively stabilize We’re asking to move back towards excluding potentially expose patients to, to limit as best. We can a potential asymptomatic a spread And so, and again, these guidance that we’re gonna be talking about is aligned with a recently updated CDC guidance as well So the PV guidance again, I’m sure everybody, at this point has already well, well, implemented this but again, we’re continuing to recommend the universal source control So anyone entering healthcare facilities should be wearing a face covering your face mask If they do not have one, they should be offered one and all healthcare staff of the facility should be wearing a medical grade face mask unless they’re, you know, far, far away from interacting with a patient or in the patient not in the patient care areas with their colleagues, so, in addition, and this is this was kind of a, a bigger shift is in addition to universal face messing, the CBC has recommended that In areas of moderate to severe transmission to use universal eye protection as well as mask for all patient encounters. And we have adapted that recommendation for New York City and part of the reasoning behind that You know, there’s several reasons one of courses that we want to make sure that we’re protecting our healthcare workers from potential presence medic or asymptomatic transmission. And we just given everything around us one. You know, we have reopening Reopening is going on the, as you saw on that map, we’re being pretty bombarded by the rest of the country increase in transmission and we’re expecting of course and spill over into New York And also we’re really hoping to get this equipment and these guidelines in place. And have healthcare workers used to this kind of protection, getting us ready for going into flu

And respiratory viral season is really, you know, multiple recommendations, just really ensure optimize our workforce, healthcare, workforce protection as best. We can And this will probably continue on at least through the winter and cold season And then again, are otherwise R E, recommendations have stayed the same in terms of, for care of stable routine care of confirmed or suspected we do So recommends gloves gown, face mask, or an, and ninety five respirator eye protection And the additional change was that the CDC had recommended using basically full covet P. E for any kind of aerosol generating procedure, just again to unless you have a, you know, very recent tests that your confidence in are very low suspicion We really recommend to just make sure everybody’s protected during any kind of air procedure to avoid also furloughs So looking at our updates in the exposure and exclusion guidance the now that staffing shortages are easily mitigated We’re hoping to go back to this To a more cautious containment approach. So I encourage you if you haven’t looked at it to look at the CDC health worker, risk, risk, exposure, risk assessment guidance. But this is basically the summary of it So and exposure to a health workers defined as any of the following scenarios So, basically, the health care workers been in prolonged contact with a patient that’s becoming diagnosed as positive to cope in prolonged close contact is now standardized to the definition of greater than or more more than fifteen minutes But then sixty two per person. So that is a healthcare worker with in prolong close contact, but a patients or coworker that ends up being positive for focus nineteen That would be considered an exposure and also if the patient was not or the person with was not wearing any kind of source control and the healthcare provider was not wearing face masks and the eye protection So, full of mucosal protection, that would also be considered an exposure if the person with coma was not wearing a face mask or face covering And then also, again, this is this is kind of the basis for the aerosol generating procedure recommendations. If A healthcare provider was not wearing all the recommended, and during the procedure, regardless of contact time, that would be considered an exposure as well. And with the recommended logos staff Or two weeks, and then the Segways into our test trace and take care many of you, I’m sure have heard something about this At this point, this is our contact tracing initiative that is being run out of New York City, help them hospitals and it has, of course, the multi problems attack of a really optimizing and expanding testing capacity in New York city through, you know, not only free testing sites for New York City, helping hospitals, but we’re going to be also running pop up testing sites and high priority neighborhoods throughout the summer in addition to supporting expansion of testing and other settings, other medical settings And so that’s the test portion of it And then those get reported over to the trace program, any positive results that is a lab, or send out or a lab diagnosis, they will get that automated do not need to report But if you are using a point of diagnostic test, and we do ask, if there is a positive such as the energy test, then we recommend that you please call and report the case to our reporting central or the provider access line is listed And when you are testing and evaluating patients, that is potentially has been You know, tell them prepare them as you’re doing the testing and evaluation that if they do test positive, this is kind of the sequence of events they would be asked to isolate develop a list of their contacts and they should be getting a call from our trace program if the test is positive and

ask them to please pick up the phone And also it’s really, really important to make sure that you’re communicating to your providers. That it’s really important That the patient contact information is complete and accurate and up to date, because that’s how so, when you’re filling out the lab requisitions it’s really important that we have that information Because that is how the trace program is able to reach out and contact the patient and again, just let them know it’s really important to anybody with the positive results should isolate for the full, ten days from the start of their symptoms, or from the data about their first positive test results to stay at, were diagnosed and systematic patient And test take care if we went through most of this a so we have the call center with the contact racers that we’ll be reaching out once they have elicited the contact history and they will be able to follow up with any identified context for symptoms And also give instructions or or guidance on where to obtain testing. So anybody that has been identified as a contact we recommend testing regardless of symptoms And that’s where the take care part of our program of the program is that they will offer anybody that needs to isolate or quarantine based on contact or diagnosis They can be offered wraparound services to safely isolate at home. For example, they live alone and can’t leave We can provide food services and other support services and if they are unable to isolate safely home, such as the, the, you know, or the high density living situation, congregate, living or have a high risk family member and left alone to home, then they can also access the free hotelling program, and that is all the information is all offered to the patient once they’re contacted by the trace program And just an update on the whole warning So that is the based on the executive order from New York state, where that was initially issued on six, twenty, four and the list of impacted States, or that are eligible for the trouble restriction, continue to expanse We encourage you to continue to look on the New York state website or the updated list and the implications are that anybody returning from one of these states, then it will be requested quarantine regardless of whether or not, you’re in New York city residents or just a visitor you’ll be asked to isolate for quarantine for fourteen days and there is the exception to this for the central workers and healthcare workers to fall under that exceptions So the recommendation is, you know, if they, if the facility is okay with it, they can continue to work. They need to be cope it tested within twenty four hours of returning to New York City And in addition, they need to be self monitoring their symptoms at least twice a day and they need to be actively monitored for a symptoms and temperature check before any shift. And every twelve hours after that If they were staying on for longer than the twelve hours Is it a current recommendation and just kind of to answer some questions that we’ve gotten about? You know so how, how to, how is this being enforced? It’s really not being enforced It’s more in good faith on our system. However, we do If we do get the names of people flying in, we didn’t get the names and contact information and so those that are identified as arriving from these identified States will get a series of robo calls That will I give them instructions about how to of what the expectations are about isolation and how to isolate safety, and give them information on how to access services that they need while they’re eating And so, okay, so we talked about this and so all of this is laid out nicely now on the New York state in the New York state guidance And we have an epic queue on our website, so if you needed additional information on the details, so you can take a look at that Oh, oh, okay

And just so, you know, again, this guidance is the healthcare worker exception is applicable to healthcare workers, except for in nursing homes to the current nursing home guidance and orders about staying out of work If any potential exposures does still apply. So, just as another, another bit of information for you, so that’s if for our public health update. So I’m happy to answer any questions Great, thank you. Very. That was terrific. One question. So I know this that this goes beyond, but I think that’s something that’s on many people’s minds Now, is the, the plan for school reopening, and I’m not going to ask you about policy on school reopening, but just so, what is current thinking about the schools? And how does how does the testing tracing plan impact that what do you, what do you see looking forward to when schools? Yeah. So, I mean, it’s, it’s certainly as you can imagine So, in progress, and I think they’re, I think we had to have some pretty solid plans and then just over the last couple of days, there’s been indication of some shifting guidance from the federal level that we will have to comply with So, how that’s all, gonna play out will hopefully be more clear in the next couple of weeks But, you know, certainly, the plan is to mainly focus on reducing classroom, crowding through shifting schedules, rotating children that are coming in for classroom versus remote learning And, of course, there’s very, very detailed safety plans being developed in terms of infection control, environmental cleaning and screening the children And also, you know, how to identify if they had potential exposures, how to ensure that those children are not coming into school or work. And that’s also part of the collaboration with the trace program Okay, thank you. Yeah, absolutely. I’m looking at the queue and they do any of the other panelists have questions Okay, not seeing or hearing other questions I think we can move on to our next speaker. Thank you. Alright, thank you. So we should be transitioning over to Dr can you get control of the screen now for you? Yes, so we’re really very excited to have Pre speak tonight. In fact, speaking of schools has been helping with reopening of a few universities and so she’s a great resource if you need to run anything by I’m sure she’d be happy to speak with you. But tonight, Pre is gonna be speaking about antimicrobial stewardship during the in nineteen era. Thank you for Yeah, I think she’s nude. Muted. Yeah. Yeah I think keep yourself on mute on the computer And there you go. Okay, good. Gotcha. Perfect good thumbs up. Alright So, first of all, thank you to the Department of health, and to and why for this this invitation, I’m really excited to speak with you all about stewardship what went well, what, perhaps didn’t go so well, and what do we know about perhaps early trends in antimicrobial? Resistance so far, so no disclosures of any sort today But as far as disclaimers, I should mention that, while mine to share, I’m signed specific rates are not really the subject of this up tonight discussion I will be referencing some of our, our local microbiology, including multi drug resistance and So, as far as the framework for for this evening discussion on stewardship, I will be spending the initial part of the evening on sort of a scaffolding of what your chips can do and has traditionally done for pandemic response and then looking at antibiotic use metrics for our own institution, and if these closely mirror what you are experiencing at your own facilities,

that would be great to hear about and looking and taking a deeper dive into things Like, what specifically were the pathogens we isolated in this timeframe and then finally, all mentioned a very nice collaboration that we have planned between the health department, and many of the York city health system, as pertains to a coded specific anti diagram Okay So, speaking for the Bronx in particular by now, this is fairly common knowledge, but because of the types of patients we care for the generational sort of poverty and issues related to that and comorbidities we had unfortunately the highest hospitalizations in depth Of any borough, and this is, of course, some data straight from the health department timeframe I’m gonna be focusing on this evening is really our shared pandemic surge, which is sometime between early March and may So, historically, stores programs have done certain kind of discrete have performed certain discrete functions for pandemic preparedness as part of the larger hospital response The stems back in my memory At least as far back as two thousand and nine with each one in one a pandemic where our job specific to store chip became really allocation of the inhibitors vaccines and the, we are sort of the guidelines people So, we’re the ones who quickly are able to they just the literature and spit out. What makes the most sense for our prescribers and patients fast forward to a bullet while there weren’t specific stewardship issues. You know, mainly Because we didn’t really see the patients. We did have a lot of hypothetical materials set up in the event that we did admit a patient with with true. Ebola One thing that was an instrumental part of the stewardship response though was identification of alternative diagnosis of which self malaria was really number one in the Bronx because of our large West African population We saw a ton of this, and so by we were using between the health department, the patient and the Michael lab We were able to very quickly get a diagnosis, treat the patient and often times, send them back home. So, of course, a lot of this was applied to legionnaires And then, as far as diagnostic stewardship, and then finally, most recently with measles where, you know, it’s less clear how to Stuart should play a role in that But as pertains to treatment with there was a well known what established a shortage going on at the time So really, our role was in in screening the right patient’s developing guidelines and determining the allocation paradigm for for our hospitals So, going back to mid February, when we were just starting to hear about covet nineteen crossing, the Pacific Ocean, the Atlantic Ocean, and establishing a presence in the United States, several stewards and I, from from around the country, put our heads together and this, just kind of came from a place of of wanting to be led into the party or having a seat at the table of the pandemic preparation and what we did was we, we’ve laid out this framework of what are we good at What do we do all the time. And how can we assist you to prepare for what what inevitably became this, this gigantic surge of of coded patients? And so a lot of these things actually came through, which I’ll show shortly where am I here? So what about the outpatient role covet nineteen very quickly? Established as a, as a viral respiratory infection and at first, I think that the thinking was that patients will not really require antimicrobials is a classic, you know, viral pneumonitis and respiratory failure. And so Antibiotic should I really have a role, and this actually played out in terms of outpatient prescriptions for antibiotics

There was this very brief, but very nicely done study of prescription data from fifty seats And they showed that, and amoxicillin really took a nosedive in terms of people filling prescriptions and doctors actually prescribing these drugs And so, you know, a small Twitter war was waged in which certain steward said, okay, we’re gonna this is great We’re gonna see, antimicrobial resistance, go down and then other folks and other parts of the country like, Michigan, New York City said well, hold on a sec. Let’s wait and see what happens on the inpatient side And as is probably no news to any of you. All who, who have been experiencing this for many months now antibiotic use, went way up. And I’ll show you exactly what up needs in a second first, though Let’s establish some of the definitions of stewardship in case. The audience numbers are not familiar So, we usually think in terms of this ratio, this is very similar to the standardized infection ratio So ours is a standardized anti microbial administration ratio, which means that basically speaking This is a rate of antibiotics administered to all the patients in a certain location in a certain hospital over a denominator, which is a thousand patient days in that location just like for data There’s a risk adjustment provided by enage, which has to do with the hospital location bed, size, size, medical school, affiliation, location within the country, and a lot of other fairly sophisticated things with the intention of spitting out a benchmark for us to kind of try to adhere to the benchmark is basically observed, you know, what are you allowed being a health system in New York City or, you know, Utah, or or Florida and what are you actually administering? And this gives you a, a ratio, unfortunately, because of everything that went on and a very rapid opening and closing closing of search. There was not a predictable risk adjustment And so all we have to go by right now is just a rate specific to our own region, perhaps, and our own facilities. So, let’s take a look starting with the ARS A lot of these patients received community acquired pneumonia coverage Upfront and this is because this is a totally unknown entity It looked a lot like community acquired pneumonia patients for often walking in from home and they have multi focal infiltrates the often that success criteria And so they just looked very ill, and you can see here that starting about late February, the amount the, the rate actually of subtract some use across all of our, including our pediatric just skyrocketed there was maybe a lower rise in the winter months And this is predictable, because this would have reflected pneumonia season You can see very clearly in the spring when things really should’ve started to come down there instead going up, keep in mind, though that this is not a raw amount. This is not a volume But this is a rate, so if the overall number of patients presenting to the goes up, the antibiotic use rate should actually go down And what we’re seeing is that this is the opposite, the opposite phenomenon of what what we would expect So, I’m sorry, these are appear to be PDF or not flashing in in the way that I hoped, but essentially these curves for broad spectrum anti antibiotic use looks identical to what I just showed you for subtract on which is that right? About the end of February, early March, there was a drastic increase in the rate of prescriptions within our of K, though separate team and vancomycin that all kind of tracked together in all of our emergency departments, including Pediatrics Probably reflecting the fact that we were starting to admit adult patients to our children’s hospital

What about a typical coverage is a little bit of a different story in that while initially a typical coverage was highly counted as having potential, either anti inflammatory properties possibly antiviral properties We, we really only saw the rate of prescriptions increase at one of our emergency departments, and this tracks basically one to one with the campus where we do not have an ID pharmacist And so therefore we did not place restrictions on these agents During the pandemic we had to loosen restrictions of the broad spectrum agents, and we tighten restrictions for anything that we thought would be given by by prescribers for their anti, inflammatory or anti viral properties And so we kind of shut those down immediately. And you can see, they actually, in the case of visits are missing, they declined accepted the one one campus I mentioned So, then taking it a step further to the inpatient setting, probably less of a increase reflecting the overall patient denominator, which we all know, exploded Nevertheless, there was a predictable rise, every canvas throughout the month of April, starting with March, but then a really nice decline in May as a pandemic wind it down to a low grade level And as it looks very identical to what we see year after year around this time of year, which is that hospital’s not as full or not as many admissions for pneumonia in general hospital senses and antibiotic use tends to go down in concert with us as you can see while a lot more patients were initiated on these agents The average days of therapy, or the durations that patients receive these did not change significantly And same goes for vancomycin and several other of the drugs that we, we have been using heavily during the pandemic, our number one agent, even before the pandemic was IV subtract from, because is not restricted Very easy to dose frontline Prescribers love it, because there are fewer perceived renal toxicities and the like, and you can see that the use went up dramatically days of therapy stayed consistent but we, if there was one agent, we were overdoing It was subtraction And this is, because again, going back to the, the underlying, prevailing thought process of prescribers, which is that patience may concurrently, have community, acquired pneumonia This is historically are number one drug associated with C, depth and monitor here. And I will show you the see the story a little bit later on, but spoiler alert It turns out that actually didn’t didn’t really happened. Thankfully, I just wanna mention the healthcare association of New York state Which does provide us with some comparative data of Downstate hospitals versus upstate hospitals, teaching hospitals versus not And here we can see that while we kind of overdue the potential use we, all in our region. We’re overdoing The the recession is probably, for the reasons, I just mentioned so now why this happened there are I like to like to break this down into patient and provider specific factors and then stewardship specific factors so fundamentally patients sick enough to be admitted often We’re having rapid responses in the are, they are often integrated in the, and they’re syndrome was indistinguishable from traditional bacterial or fungal festive and so it was very easy to sort of bundle the care to include antibiotics that we would traditionally give for services We all know that there are many many issues related to deployment of nontraditional frontline providers, a healthcare work or stream burnout

Increased ratios of patients to providers less time actually, set with patients picking up on physical exam findings and so pursuing somewhat of a bandage approach of just giving antibiotics Empirically. Interestingly, while there were very well described shortages of crash current medication Sedatives, I think several, we did not actually experience antimicrobials shortages We had prepared for this in advance, but we, a stewardship kind of made it very easy for people to give these drugs. So, we were somewhat complicit in these curves, like, skyrocketing in the way that I should. I just showed you So looking at our traditional functions within the hospitals and what happened to some of these You can see where some of the places or some of the things that slipped through the cracks and taking it a step further You can see where those things need to be built back up very quickly in the event of a either second wave or just a continual hamster wheel of of coven infection So, the important ones of these are really our audit and feedback mechanism where normally, we would call prescribers would institute time out at about forty, eight or seventy two hours This was not happening because we were all pretty much diverted to other functions within the pandemic So, whether that was clinical trials or emergency use authorization or testing, or you name it, we were not doing what we were essentially hired to do Our formulary restrictions were totally relaxed during this timeframe This was both to make it easy for prescribers to provide the care that that we felt was needed and also to alleviate some of the strain on our trainees overnight, both the front line in terms of residents and our, our fellows and then clinical pathways where we really Excel or chip we, you know, we can write multiple guidelines in no time at all This admittedly was you’re very late to the party with this, but, you know, to tell a truth idea, say H, W, and none of those professional societies release anything Related to empiric antibiotic, prescribing for patients with severe quoted. So health systems left to our own devices to create these and well, we did end up creating them. Sometime in May a little late to the game Eventually they did come and hopefully optimistically. They helped a lot of people. So, what do we know about Super infections? We’ve established that antibiotic uses through the roof We know which agents we know how many days, but what about the actual documentation and diagnosis of superinfections or Co infections? Basically, bacterial and fungal infections that occur at some interval after the initial SARS Coby to infection in multiple risk factors Several of them are very predictable having to do with prolonged hospitalization, a severe immune dysfunction because of the virus itself. Fair use six an inhibition, diabetes age Nevertheless turns out that at least an existing publish literature, which is not a lot less than ten percent of total hospitalized patients actually, developed documented Co, infections are super infections. Unfortunately, the ones that get these are the six, of course intubated lined up echo All of these types of events secondary infections are thought to be often terminal events meaning that whether patient may initially improve or stabilized from the coded itself, they may come to the secondary either that, or cloud Fi or something else But this is not new. This is, this is actually rather predictable, because it as it turns out this also happened in the original source and immerse as well also related to the degree of critical illness on these patients

There was actually a recent survey I don’t know if audience numbers had a chance to participate in that, but across the country few ID physicians actually felt that Super infections were happening. Frequently Most of them responded that they were either rarely or occasionally observed very predictively happening in the most vulnerable patients mechanically ventilated in So there’s not we don’t have a lot of data to draw from as far as what pathogens are Appearing what day into the hospitalization? What are these patients look like and what is their outcome? But we have a ton of letters to the editor perspective pieces, viewpoints, speculating on this. And this is kind of what we’ve been going by so far So here and Monte, we decided to take a look for ourself, our frontline ID clinicians, and a few providers were alerting us and our infection prevention colleagues to some concerning activities in a certain units Maybe clusters of certain infections. Some of them being. So we decided to take a look at this ourselves and really digging deep to our own ecology And so we did a retrospective look back between March, first in April, eighteen. So, period of about six to seven weeks we excluded any contaminants So the negative staph, the skin flora, anything that didn’t grow on a repeated basis we excluded oral flora Canada from respiratory cultures And so we tried to be as pure as possible and that a definition of infection, rather than colonization So, I’m tracking along with what is known about this illness in New York City The majority of our patients were Hispanic and non Hispanic, black, sixty years and above, and as far as distinct patients who developed coinfection, it was a very small percentage of total by that time time point So, more than four thousand covet patients had been cared for in our system at that point. And only a hundred and fifty two had very clear, clinical superinfections And so, this was a very low rate at three point six percent. Which is pretty reassuring However, when you when you take a look at their host factors and their outcomes, it’s, it is pretty concerning. So A hundred and fifty two distinct patients, but twenty one of them had both positive respiratory and blood cultures and often with different organisms So they may have grown saying the respiratory, but grew candid on the blood, or or something. Totally unrelated Nearly half of them received either Biologics or acute systemic IV steroids of some, sort, the length of stay was was pretty long, was at least thirteen days and unfortunately fifty seven percent were deceased Very, a, pretty soon into their hospital stay. So, I’m within about six to eight weeks, the point at which we, we conducted the analysis fifty seven percent We’re already to see the median time from positive. Two positive culture was about six to seven days I don’t want to ignore that twenty six percent or twenty two percent twenty two distinct patients with positive blood cultures, or clinical bacteremia actually had positive cultures at the same time as there covet presentation. And this is what? The variety of of stuff, not just staff or strep we see in influenza, but there was some gram negatives and there were some other other bacteria that we wouldn’t necessarily expect somewhere community members Others had previous recent admissions. Others were long term care residence. So it was sort of a mix of everything There was a small, but again, concerning amount of multi drug resistant as already observed within a week, a presentation, both for the patients with pneumonia and bacteremia is and for the bacteremia is more than half had a centralized But again that any just send Class seats definition is sort of a different story as far as source of bacteremia. There are multiple

The one thing I should take the time to mention here and I would love to hear if some of you are observing a similar phenomenon, which is that the negative staff transi bacteremia, increased by nearly two and a half percent in this timeframe And we think this is because of probably a decline in sterile technique provider, fear and anxiety strain in terms of time spent with the patient and, and just multiple factors that, where I need it very difficult for providers to, to maintain the usual standards of care that they would have before the pandemic, comparing respiratory patients So, those respiratory contractions to bloodstream infections obviously, nearly all of the, those with pneumonia, how we’re integrated and about half of those bacteremia is the, why counts? And the were very elevated as expected, but we don’t know at this point. Is this because of the secondary infection or is this because of advanced illness that we know that both of those Increase significantly the Pro calcitonin story from the small group of patients we looked at. Admittedly it’s less clear. It’s not apparent to us At this point, it distracts along with the overall date of hyper inflammation or if this is actually a harbinger of some sort of a secondary infection What we do know though, is that a length of stay was dramatically prolong because of these secondary events And that whether you looked at zaps or bacteremia is more than half expired, and this was, you know, only within six weeks of presentation So if we extended that a little bit further, this may be an even more frightening rate Okay, so as far as the micro organism specifics, there were pretty much typical expected hospital associated flora of a variety, but with special mention of staff, aureas and Pseudomonas there weren’t a lot of multi drug resistant isolists I think about seventeen to twenty and all, but these seem to occur mostly in our intro bacterias Unfortunately, there were an increased number of series, and among those there were class B, carpet, enemies, producing E, coli in particular and this is not to implicate us or to out us in any specific way Because, of course, at this point, the health department is well aware of these infections, but really to try to figure out some of the risk factors in these patients and how these may have been prevented So, all of these were community dwellers. Actually, none of them had either long term care, say, or travel to the typical areas And the, the shortest interval was about, I think three or four days that they developed one of these patients developed An ndm infection, and they were almost invariably terminal events One patient was ultimately chronically vented discharge to a event facility and then readmitted and is still so on half unfortunately, they grew the, as part of almost like a poly microbial just flop So to speak, unfortunately, their teams, there may have been also some, some transfer of resistance elements to closely related species, like, club, a ton of antibiotic exposure, proceeding infection and then, even after targeted broad spectrum and antimicrobials Unfortunately, patients still to come to septic shock for the most part this prompted us to take a look at our own antibody grams for this period of time And it, no surprises as pertains to staff or is except to say that if we continue at the current rate, we would’ve way out pace The number of we had for the entire year in the ice, using the year proceeding. Likewise For gram negative while we didn’t have a huge number of of the increase in isolists. You can see there’s a lot of red here

Indicating that, for, for most of these species against most of our common antibiotics, there was a more than ten sometimes twenty percent decline and susceptibility So of course Super concerning this prompted us to collaborate with our local search programs and the health department within New York City Due to the pandemic as far as see this I had mentioned earlier that it appear to actually have gone down and this may be due to increase hand hygiene and just increase the in personal use of personal protective equipment But also, we, we can’t dismiss the fact that fewer tests were being sent and this may be due to diagnostic confusion, with related back diary So, in summary, certain things went Well, a stewardship was mobilized to do the things that we do really well, in a number of ways is pertaining to diagnostic sewer chip shortage, mitigation, helping with clinical trials in creation of guidelines But a lot of things also suffered And the cost of all this of this kind of deployment of stewardship expertise with that, we loosened restrictions. We did not have the ability to perform auditing feedback We were losing track of our antibiotic use rates, and we’re sort of lead to the party as far as guideline creation. Although those is ultimately come out. So, the remaining questions include are these truly terminal events Although the rate that we observed was less than five percent of total covet patients are the secondary septic events from bacteremia from that are these, the cause of these patients, ultimate demise So, in order to do that, of course, we’re in the process of looking at a a set of match controls, who did not develop these infection and then finally, what is the deal with pro calcitonin and and cobit previously we thought, okay, this is very specific to bacterial infection this is going to help us and then with Colgate, I think a lot of that went out the window that remains to be seen And so with that, I just do want to take a minute to think the entire torture program at the. We are many members deep as you can see A special shout out to our founding member Dr, Bill Windows trust use of course, with the CDC now and then all these wonderful people at on the right the health department Y, pathology, micro pharmacy, our infection prevention and control and epidemiology colleagues the ID division special shout out to the ID fellows and welcome to any new ID, and then finally, I can, I can’t walk away from this without a special mention to our spiritual colleagues at Mount Sinai and and mass Simon who we’ve been collaborating with just constantly, constantly throughout the whole thing and really nice friendships and long lasting relationships And Bonds has informed, so we were very grateful. So with that, I’ll turn it back over to our modern moderators and thank you once again. Thank you for you. That was terrific. Really broad and an amazing data We’re running a little behind time. Actually. We’re almost exactly on time, but I don’t want to keep us from hearing Mark’s talks. So I’m gonna turn over to Adam to introduce mark Great thanks. So I am delighted to introduce my colleague and friend Mark Mulligan. He is the director of the ongoing vaccine center, which is now, and I funded site He is also the director of the division of infectious diseases and immunology at MIT and the Thomas s. Murphy senior professor of medicine and microbiology He will be speaking to us today about covet nineteen immunity and vaccine trials. Mark. Alright, thank you very much Adam. And thank you, Josh. I really appreciate this Invitation this opportunity to talk about community and vaccine trials. I’ll I’ll talk, I’ll show you my conflicts and then we’ll get right into things

Now, acknowledge a lot of people doing the work here are the conflicts and they’ll be there. I think you’re gonna get a copy of the slides and then we’ll labor those, but some government funding some industry funding So the virus makes its impression on the immune system, just as it did, and this called the sack, and you see those large protrusions and that’s the main target of immunity the viral spike And so here’s another version of the virus with that viral. Spike, are you able to see my arrow when I move it? Oh, yeah. Adam. Can you see my arrow when I’m moving it? No, okay, well, nevermind, then that’s fine So that you see that at the top middle that the virus and binding to the well known receptor, Ace two, and as a positive strand virus, once it enters the cell and releases it’s genome into the cytoplasm, it can start translation and transcription of a and it will then make new virus particles which can be released in and all of this is contributing both the incoming virus, and the newly released virus to the immune response and down at the bottom, right? dendritic cells, doubling up virus, presenting to T, helper cells, and eventually help provided to a cytotoxic T cells and B cells And the ultimate objective then is to have an immune response is shown in the top right here where infected cells are destroyed antibodies produced in We get memory B T cells and I’ll show you evidence for for all or most of these we are learning more and there’s not a lot published about cellular immunity thus far, but we, we’re, we’re beginning to get a good feel for things So, let’s let’s take a look at a couple of patients. So these are the first, two weeks after hospitalization for two patients that we saw in our hospital. We had an opportunity to sample essentially daily plasma or serum samples from them And if you just focus, let’s say, on the patient on the left, this is the alive binding antibody against the spike protein. The s, one protein is worked on by lead ally in our lab But you can see that the, the blue line with the triangles goes up and peaks around eight, fifteen, sixteen, and starts to come down and then and green in and red peak a little later, and then continue more flatlined out through day roughly three weeks here And kind of the same story on the right? So these are two patients with significant illness in the hospital and there’s certainly mounting what looks like a a robust initial antibody response over the first, two weeks of infection So binding antibodies against the spike. Well, let’s look a little further out These are thirteen patients for whom we have multiple time points and we’re running again alive Kind of a standard bench top align against the s, one protein, which is the, the terminal part of the entire s protein, and you can see on the left hand panel the, and now we’re, you know, we’re kind of going out a little further, maybe three weeks Four or five, six weeks in the middle panel and right. Hand panel So now we’re bringing in multiple isotypes not just and you can see the even by four to six weeks is already starting to come down. Some of those curves look like they’re coming down So let’s look a little further out looking at another six weeks and now you can see on the left hand panel. The some of them of return negative Most, all of them are heading down for, as we get out towards day seventy, eighty after infection You can see that now we’re starting to see some declines, although some people are still stay flat, an, even more declined seeing So after two to three months, we’re starting to see a antibody drifting down again. This is binding antibody Well, let’s look at what what I’ve been showing you as the target, the spike protein and Letter be down here is, is just a graphic display, so this is the C terminus of the spike about twelve hundred amino acids. There’s a short cytoplasmic tail

There’s trans, membrane anchor domain here and then this would be the s, two protein, and there’s a cleavage side in this area and then you have the one protein and this red areas, the receptor binding domain That’s the part of the spike that latches onto the ace two molecule, which is the receptor for the virus. This is a graphic display of the spike timer Is this as a primer on the surface of the very on and one single monomer of the driver is shown in this dark blue, and then there are two more light blue and going with this a single dark blue monomer is the receptor binding domain It’s about two hundred and twenty amino acids in length its relatively small part of the spike protein, but a very important part in most of the neutralizing antibodies and epitope are directed it in, or founded in this part of the molecule So, this is a very important target for antibody for vaccine development I mentioned memory, so, of course, with vaccines, what we’re trying to do is this memory, well, this memory memory B, cells, in this case occur after natural infection. So again, this is worked from my lab unpublished Lila my and colleagues, and you can see in red convalescent patients. So these patients are a one to two months after their infection And they are making a Emory B cell response in the range of point, five to one one, and a half percentage of all the producing B cells that we we can detect after six days stimulation are producing specific antibodies to, in this case the entire spike Ecto domain as one, and this two, interestingly, people that had a asymptomatic infection that seemed to have maybe a little bit lower levels of memory B, cells, and then healthy controls or influenza patients that we had collected in Pre coded times I’m really not not having any a memory B cells specific for the spike protein So, this is actually encouraging, given all the talk, given what I showed you above here, that, you know, that the antibody levels may be starting to decline a bit very important to keep in mind that we’ve got memory B, cell responses That are appear to be present in convalescing patients This is more recent work in our lab from Dr Murray amount of at Goldman and colleagues, and we’re using a published reporter virus That makes a green color with the virus infect cells. The unaffected cells are blue as is shown over there on the top. Right? And you can see here and this is a single patient at two different time points So I’m sorry I don’t have a pointer, but in the top three rows day post onset twenty eight So that’s twenty eight days after symptom onset the next three rows down fifty three are the fifty three days after I’m said, and you can see if you look where the blue transitions to green, you can kind of get a sense that you might have an IC fifty fifty percent loss of the green dots about one, sixty, the title of one sixty, a twenty eight and already a fifty three That’s probably down to one eighty or something like that. We’re still working to a little bit, but it’s, it’s actually looking quite nice. Initially Down at the bottom are the binding antibody tyres and clearly has gone down is was pretty stable actually, and has gone down just as a comparison In general may groups that have published, and certainly what we’ve seen so far in the lab, there’s a pretty nice correlation between binding antibody and neutralizing antibody So, again, this neutralizing antibody will prevent the virus, probably through attaching to the receptor, binding domain, present, prevent virus from attaching to its receptor and a avoid infection of cells This is a paper from long at all recently published and it’s showing sort of the same thing that I’ve shown you already either in the left hand panel for binding antibodies, or in the right hand panel for neutralization the pink dot, the acute phase blue triangle

The convalescent phase so the acute phase would probably be in the first ten to fourteen days convalescent phase one to two months after symptom onset And you can see finding antibodies start to come down a bit as to the neutralizing antibodies. One point The office made in the papers that the asymptomatic patients, if you look at binding antibodies, in particular seem to have lower levels, compared to the symptomatic patients, and more people who actually were antibody negative So, that that is something that will they’re watching. I think people who have milder infections or asymptomatic infection A little bit of data suggesting they, they may have lower magnitude, immune response. What about cellular immunity? So, this was a recent paper from Alex and Shane and was the first author in the primary report in sale and they just come out with an editorial nature reviews And Immunology, but the main point in the paper was yes, you can see in a dozen or so convalescent patients. You can see evidence of T, cell activation And they also looked at normal volunteers who were samples from Pre, covet times people. That had not had infection And they can actually see some T, cell activity up to twenty to fifty percent of an exposed study participants had a significant reactivity again stars Coby to peptide cools Interestingly non spike was greater than the spike targeted that makes some sense these non spike proteins or less subject to innovation and then mutation this is an so prone to mutation and probably more conserved So, what this probably represents is, as the second bottom up second bullet up from the bottom says, is T, cell memory Two common cold viruses, the, for seasonal corona viruses, which have listed here. Now that we’ve all heard so much about there There may be, this is the some evidence for cellular across a community that has the potential as we say, in the last bullet here to impact either disease or vaccine And so there’s a lot to be learned about this. So this is a slide about preexisting cellular immunity from seasonal corona viruses and also just mentioning that in this paper They published some of the first evidence for a T, cell responses during infection with the current virus. Not surprisingly but they’ve, they’ve shown that Alright, so I’ve spoken a bit about immunity and clearly there is a robust immune response. We’ve got to learn about the duration of that immune response We have some subjects now that are about one hundred and ten days out, and we’re following overtime and will continue to follow that in our natural history studies that we’re doing All of this is very important for the vaccine field, and I’m gonna spend the last part of my time talking about vaccine. The phase two shown here also part. Two of my top There are a variety of platforms for vaccines a variety of immunogens. I’m not going to go through this whole slide, but you’ll have this up in the very top. Right? You see that I point out that the viral sequence was published on January eleven since the very first vaccines out of the gate, where the genetic vaccines this is a flexible Rapids available platform So our DNA, so in March, and then in April, the army and the DNA studies were begun, and we already have some information coming out about these phase one trials Now just a couple of months later. It’s actually quite amazing. And I’ll share some of that information with you, third bullet down with common viral vectors, another platform as the viruses generally And then there’s the subunit proteins, and, of course, whole kill viral vaccines the immunogens, all of these thus far that I’m going to talk about tonight and that we have some human data for all Spike proteins directed either the whole spike or the receptor binding domain Here’s an overview, a quarterly of these platforms. So again, the double stranded DNA closed circular plasma in the top left, the lipid nanoparticles and casing in the middle on the left. And then the spike protein Usually, the protein based vaccines are being given with adjuvants

And then the, the viral vectors showing them that in the panel, a kind of the top half, and the inactivated virus is down to bottom that, right? After this slide the showing over a hundred candidate vaccines in various stages in the pipeline, and we’re gonna focus on those for which we’re beginning to see some clinical trial data This is the first the first one to have a report in the literature. This is published in LANCE it last month and this is the recombinant add five viral vector expressing the spike protein study done in in China This is can sign up Biologics and the second column from the right there just call your attention there There they produce in the top White row, allies and antibodies, and in the bottom, right? Neutralizing antibodies receipt They also we looked at detail responses and by both at least spot Assays and intracellular side of time staining. They demonstrated modest T, cell response for both CD, four, and the top panel and CD eight in the bottom panel I won’t go through all these limitations but there are a number of limitations to this work And this is a vaccine candidate that I think could could be improved further, perhaps with the boost it might need to be a different type of viral vector to to boost But it’s also a, perhaps a different end of our syrup type since add five. There’s a significant amount of Pre, existing immunity, and they showed that that damp and the immune response here So this is a candidate that I would have modest enthusiasm for I think, at best. Now, my enthusiasm goes up when we get to the vaccine So, Madonna partnered with and really, incredibly, you know, within a couple of months of the sequence, becoming available, had begun a first in human study So this is in a lipid Nano particle, which helps the, or they get into the self and once in there’s a fusion in the zones and release of the into the side is all that’s like, I showed you with the virus Itself in this case, you’re coating just a piece of the virus so there’s no risk of infection. That is spike protein here They’ve actually made a couple of protein additions or mutations to protein in the like to stabilize it in a profusion configuration So that antibodies can be more effective and and point out in the middle of the panel on the left, no base vaccine has been licensed But it is a very attractive platform again, because it’s flexible once you have the platform, you can stick in any gene of interest for any future outbreak. It’s a rapid So, these, these vaccines are produced by in vitro transcription and so free systems and you can really scale these up as well There’s promise in an animal model with this vaccine again, the first human vaccines down the bottom left of this panel, and the were in March They gave two injections and over on the right hand side, you’ll see that they issue the press release on the eighteen. Th, and now they have a paper impressed and doing with Journal, which supposed to come out this week may even have come out by. Now I’m not sure, but very soon you’ll be able to we’ll all be able to see the data for this. But what they said in the press release that was that they and they only looked at neutralizing antibodies in eight of the forty five study participants I suppose just because of access to Bsl three to do that was limiting for them, but they do see levels of binding and neutralizing antibodies that we’re equal to or perhaps a little higher than convalesce and patients want to pause here and just say that we don’t know what is required or immune protection against this virus, what we should be targeting with our vaccines, but for antibodies, one reasonable thing to say should be a target lacking any better target is the level of antibodies seen in convalesce and patients that those patients who have successfully fought off the infection and are about one to two months out, and those levels could be compared to the levels of antibody one to two months out after vaccination to let us know that we should be finding antibody Sure. But most importantly, the neutralizing antibody. So, phase one has been completed and in the second bullet down on the right hand half here phase two is now

A fully rolled with six hundred participants and phase three is slated to start later this month. So, again moving very quickly through phase two, two phase, three given the initial, somewhat encouraging results. astrazenica This is a non replicating or weekend add no virus. It’s a chimpanzee and a virus so remember, I mentioned the Pre existing immunity problem for ad five you get away from this by using an Enda virus from a different species So humans haven’t seen this before There’s very little if any cross reactivity, and they have some animal model data that they protected mcat’s against lung disease did not reduce on days of faring geo colonization, viral loads in pigs They showed that a second antibiotic a second dose of the vaccine boosted neutralizing antibody This is in phase two and even phase three, very early phase three now in UK and this is slated to start in the US and a phase, three trial next month and then also a phase three trial in Brazil So, a non replicating viral vector expressing again. The spike, the entire spike protein, I wanna talk about a study that we participated in and contributed to. This is the Pfizer beyond to collaboration Again, I’m a lipid nanoparticles Messenger and, like, the Dana, this Pfizer beyond is modified. What does that mean? It means that, because we are a single stranded and seen by the system, is that almost like a viral or an, a, a TL, or seven or eight are triggered and you get quite an innate response So it’s a self platform You can think of a modified that way, but it might actually be a little too strong, a little bit too much of inflammatory response, and so modified or in a mesilate Some of the yearning nucleus sides to try to reduce detection by Taylor, seven, eight the image in here not the full spite, but receptor binding donate domain timer Here are some reactive. We call it data for these are the systemic events, and just stepping. Aside. For a minute I’ll mentioned that the local reactions work generally injection site pain in many participants not all mild to moderate And if you read or swollen reactions, but not very many, but more more impressive where some of the systemic reactions with the first, those not so much. So Particularly with the second dose, we, we saw fevers shown in the left hand. Bottom part of the panel in seventy five percent of people getting a second dose at the thirty microgram level We didn’t give the second dose of the hundred microgram based on what we had seen with first dose of a hundred microgram and second dose of thirty So, for for this project, most likely somewhere, ten, twenty, thirty micrograms will be the dose to go forward with and from a D*** it’s looking to be fifty micrograms. Maybe twenty five. They’re, they’re looking at that So, and these are the antibody results at the top panel The binding antibodies, the bottom panel, the neutralizing antibodies, and I’ll just point out that the magnitude of these in green are the low medium and high dose of the, and in black or the health of the human convalescent Sera So, again, maybe a benchmark we’d like to equal or exceed that and you can see providing antibodies. We do exceed that. Remember here for the high dose on the far right? Green There was no second dose given, but for the the two left parts of the panel, a second dose was given a day twenty one and you can see a nice boosting response for binding antibodies. Maybe more importantly, let’s call your attention to the lower panel The neutralizing antibodies again on the far right of the lower panel The ninety four being the human convalescent zero geometric mean, and you can see that after two doses of thirty micrograms even two weeks after the second dose in this middle part of the lower panel a geometric means tighter A four hundred and thirty seven about roughly a four to five fold higher, then with the health with the human convalescent zero So, I think that’s encouraging that either at the ten or the thirty microgram does proceed two to two to four to five fold, hire of neutralizing antibody So, I think for a first in human study, we showed here that and it does the vaccine. That was tolerable

And safe we were, we were able to induce antibodies that would appear to be of a magnitude and a quality that would be of interest. I’m just gonna close by talking about the process and organization of the vaccine effort In the US you’ve heard about it It’s called Operation works, work, speed, a government, private partnership, and there’s a code prevention network that many sites in New York will be participating in using harmonized vaccine protocols to compare probably five different vaccines in phase three advocacy trials Each of which will have thirty thousand participants And this coping prevention network has its own logo now and they have a website now that’s up and going, which is a blue down the bottom of this slide. So I won’t belabor this given the time But July, Madonna, August astrazenica, that’s the Oxford vaccine. Then we can add the virus soon after that. J and J with another ad, new virus spike candidates and sanity A couple of Soviet proteins with adjuvants. I mentioned Pfizer. They’re doing this, not in inside the government network. But an industry sponsored trial and phase two will launch likely next week and the phase three a little bit later, July or early August I think I really want to pause on the second bullet up from the bottom. Just for a few seconds Can say that we must enroll in these phase three trials people groups, communities with higher than average risk for covet nineteen infection or disease And so we need to be enrolling the groups that you just heard about in some of the earlier talks Minority ethnic and racial minorities, certain occupations, such as the central workers that have to go to work in grocery stores or transit workers, older individuals, individuals with chronic conditions, that stable, chronic conditions Those are the people that all of us who will be looking to enroll hundreds and hundreds of participants in these phase three trials that are coming up We’ll need to be reaching out to starting right now for community engagement and education, and then ultimately to talk about the R word recruiting Once we have a trust and a relationship established with these communities, occupational groups unions, etc. There’ll be a clinical trial participant registry at the website So participants can go in there and potential participants can go in there and leave their information and then it’ll hook them up to the nearest site. And here are the sites I’ve shown you for the Madonna trial. Starting this month, besides that, I’m aware of that will beginning So while Cornell, uptown, Cornell, Chelsea meridian clinical in the Bronx And then starting next month for the astrazenica, Oxford, Rochester in upstate New York blood center about holla Bronx, prevention, Colombia point out that both Magda and and in Rochester are the national study So, we’re very proud of that. We have them both here in New York and then we’ll have up to five exclamation locations in the vaccines center and last but not least Just my plea for adherence and I won’t read through all this. But I’ll just point out this interesting name on this beer. Which I won’t say in the public environment, but you can read it yourself and, you know, let’s stay strong I think the key question is, is it essential? And if it’s not, we shouldn’t be doing that, particularly in the, in the many many states, where they have a real problem still. And with that, I’ll move to my knowledge in slide And thank you for your attention. And thanks to the organizers for this chance Mark, thank you, that was fantastic, given the time, I think, that we’re gonna forgo questions, but I want to take this moment to thank all of our speakers and to thank everyone for attending we’re hoping to do these webinars quarterly going forward And so there will be news of more of these sure. So thanks to everyone. And goodnight, thank you guys. Very much. I was terrific. Thank you for you, mark. Good to see you Adam Yep. Great to see all of you. Yeah, thanks everyone. Thanks