TWiV 632 Countering a miasma of anti-think

This Week in Virology

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Kathy Spindler,

and Brianne Barker

Guests: Daniel Griffin and Chuck Knirsch

Aired 28 June 2020

Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick. [Music] From MicrobeTV, this is TWiV, This Week in Virology, Episode 632, recorded on June 26th, 2020. I’m Vincent Racaniello and you’re listening to the podcast all about viruses. Joining me today from New York State, Daniel Griffin.

Daniel Griffin: Hello, everyone.

VR: And Chuck Knirsch.

Chuck Knirsch: Hi, folks.

VR: Chuck, someone wrote in and said, “Who’s that ghost in the background?” [laughter] He’s not a ghost, I introduce him every time.

CK: Not a ghost.

VR: Chuck Knirsch is a member of Parasites Without Borders and a clinical researcher and MD and highly expert. That’s why we have him here and he’s a good friend of Daniel’s, as well.

CK: Passionate about international/national health. I’ve been writing about and teaching 25 years.

VR: He was on TWiP, which is, of course, the greatest qualification. Just joking. All right, Daniel, how things going this week?

DG: Things are going well in the New York area. At some point, we’ll talk about how they’re going in other areas. Let me get going. I know Vincent shared with me there are people that just want us to get straight to it and get to the meat of it. Let’s do that. First, I’ll start off with my quotation to set the tone. “It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epic of belief, it was the epic of incredulity, it was the season of light, it was the season of darkness, it was the spring of hope, it was the winter of despair.” That was Charles Dickens, A Tale of Two Cities. He was actually describing the COVID pandemic a little bit before it actually happened. I think there was a lot in there.

I remember very well. I think people have a short attention span or some people do. I remember very well, just a few months ago when I was beside myself with what I referred to at the time as the kitchen sink approach. Let’s just try everything and hope something sticks and hope we don’t kill everyone in the process. We are making a lot of progress. I will start off with my review of current management where I’m going to basically go through everything, but hitting what we now know. We have learned a lot. I recently did an interview where people have gotten a little frustrated, we had this big shutdown.

Actually, I think Vincent, you expressed a little frustration on the most recent TWiV about like, “We had all this time. What did we do?”

VR: Exactly.

DG: We did some stuff. I’m going to go through from soup to nuts about how to approach COVID and what we now know because this is not what we were doing back in March. The first is the really critical thing we’ve learned about with testing. Number one is we actually have tests. There was the recent FRONTLINE special, “The Virus: What Went Wrong?” And my biggest frustration back in February when we were seeing what we now realize was clear community spread in New York area, we had no tests. We had this very circular, “Well, if they haven’t come from Wuhan, we’re not testing them because we’re only seeing positive tests in people from Wuhan,” and we’re like, “You’re only testing people from Wuhan tautology.”

We ramped up, we now have a lot of testing, not as much, nowhere close to as much as we need, but this is key to the whole Tetris that we all talk about. The testing, the tracing, the isolating, the whole contact approach to opening back up. Just to let people know, there has been such a surge in the southern part of our country, that we are having issues with access to swabs and the reagents we need to do the testing. This is a problem. I know there’s always been this, “Anyone who wants a test can get one.” Yes, if you’re willing to wait on getting the test and if you’re right now, if you’re willing to wait on those results. Even in our hospitals, we’re having unless we really prioritize it a 24-hour turnaround. This is a problem. We are still not there.

Our organization just bought a machine that can do another 1,000 tests per day. It’s not enough. We need lots of those. Testing is critical and also the public, people who listen, this is mostly clinicians, a lot of clinicians that I encourage to listen, but a lot of people who’ve been longtime TWiV listeners and new TWiV listeners or not, we need to change that mentality. If you think you’ve got COVID-19, let’s find out, so that we can stop the spread.

What do we do once we find out someone has COVID-19? There’s actually a lot we can do. We now understand a lot about the clinical course. As far as what do we do, we can follow up with our patients, we can perform a repeat outpatient evaluation, either in-person or we can do it through telehealth, which is, I think, here to stay. Detailed history with a real focus on where we are in the clinical course. What’s critical to me is the date of symptom onset. We can identify when that critical second week is going to occur, so we have the timing of the different complications. We’ve been through this a few times but that second week is when we see the respiratory issues, followed by a lot of clotting issues during week three, and then we watch for week four for this post-viral infection bacterial superinfection phase. There’s a lot we can do.

I think, Vincent, you asked last time about pulse oximeters. We recommend now that you can get pulse oximeters, they’re about $30 that you can buy these, that’s $30 well spent. What we’ve seen is as you get close to that second week, people who start to have their level of oxygen drop into the 80s are higher risk. That can be followed the next day by an increase in respiratory rate, and then, this is the frightening, within 24 hours the people who will decompensate, can basically need hospital-level care. That pulse oximeter, that keeping in touch with patients, counting that respiratory rate, which you can actually do just looking at someone over a Zoom call or a telemedicine visit.

We don’t really know what labs are so critical at this point, but we’re still learning a bit about complete blood counts with differentials, so we can calculate that neutrophil-lymphocyte ratio. People whose neutrophils go up and lymphocytes go down, we’ve seen that there are higher risk of poor outcomes. D-dimer, this is something we’ve talked about for a while. These people are at increased risk of doing poorly, but we also think that ties in with an increased risk of thromboembolic complications.

IL-6 levels, there’s a bit of data on that helping us. Chest x-ray, and this is going to tie in, what we’re doing with the chest x-ray is not so much diagnosis, but we’re trying to get a sense of which small subset of patients might need antibiotics. There’s a very limited role of antibiotics, only about 10% of patients. We now have a lot of experience, millions of people have been infected, only about 10% of patients have a secondary bacterial infection. If you’re using antibiotics or you’re receiving antibiotics more than 10% of the COVID 19 cases, you’re overusing those antibiotics.

We often see people show up in the hospital, they’ve got their augmentin, their doxycycline, their minocycline, their azithromycin, whatever else. Be careful with those because we’ve seen a lot of antibiotic-associated diarrhea get admitted to the hospital, the clostridium difficile. Make a careful decision. We’re starting to recommend against drawing a lot of procalcitonin. This is an inflammatory marker that a lot of people and clinicians associate with bacterial infections that goes up in COVID-19. An elevated procalcitonin may encourage you to use antibiotics, don’t. This part of the disease, it doesn’t tell you that there’s a bacterial infection. Look at sputums, look at chest x-rays, do that detailed physical exam.

Decision to recommend hospitalization, we’ve now learned quite a bit about this clinical course. I know early on, there was just a mix of practice styles. We saw young people with no oxygen needs, not much really going on, getting hospitalized just because they had COVID-19. We now have a better sense as I’ve talked about, about this follow-up and better deciding who may benefit from hospitalization. Again, it’s going to be people who are at higher risk, people who have that hypoxemia and an oxygen requirement.

Initial hospital evaluation, really much like we talked about, we’re going to be going through identifying that date of symptom onset, so you know where you are, looking at age and comorbidities that helps us quite a bit. Same blood testing that we talked about, that complete blood count with differential, to calculate that neutrophil-lymphocyte ratio. D-dimers, maybe not procalcitonin. Chest X-ray, but rarely CAT scans. We don’t necessarily need to expose everyone to these people. Pulmonary support, and this has been exciting because we’re starting to see a little bit more, and I say this with tongue in cheek, a little bit more of low-quality evidence helping us in this area. Low-quality evidence is, I guess, better than no evidence. But confirming what we were seeing, where if you keep people off of the ventilators and you use our other tools, high-flow oxygen, biphasic, so I’ll say BiPAP and CPAP, and these are ways of creating pressure, either just one constant continuous positive airway pressure or a biphasic positive airway pressure.

These are ways of getting the oxygen up without putting someone on a ventilator. We talked a little bit about proning before, having patients lay on their belly. Now, they’re coming out with a little bit of data showing that, yes, this actually may improve outcomes. But they’re also demonstrating that this may also increase the risk to healthcare workers. Some of the hospitals in our area are actually putting up extra glass slider doors, trying to create more negative pressure room, so we can provide all these types of pulmonary support, and at the same time, keep our staff safe.

The antibiotics and antivirals as mentioned, limited use for antibiotics, but remdesivir has a limited, minor role. I’m trying not to get too unexcited there. Exciting, the steroids, the dexamethasone, the actual preprint is now out, so people can read the whole study. I think I’d mentioned, I think it’s going to take some of our senators a little while to pivot their thinking because of the dogma anti-steroids, that we discussed the last time, but now we’re actually seeing the full article. It’s very solid, very encouraging, clearly no evidence of harm, and looks like a pretty dramatic improvement.

Some more encouraging news about tocilizumab, I’m going to hit each of those individually what that is. And then anticoagulation, thrombotic complications are very common, and now we’re seeing evidence for benefit of treating people in hospital and actually for treating people post-hospital discharge up to 45 days.

Let’s talk a little bit about each one of these in more depth. Pulmonary support, so we know a bit about proning. We’ve been talking about that for a while, where people are laid down on their belly, and the World Health Organization basically created a group to provide a living systemic review. They’re going to keep us updated as more data is available, but they’ve published their first update in the Annals of Internal Medicine, “Ventilation Techniques and Risk for Transmission of Coronavirus Disease.” Basically, they’re giving us some support to the idea that non-invasive ventilation and they say, “Probably reduces mortality, but may increase the risk of transmission.” That’s nice to be getting some data out there.

The steroids, we mentioned quite a bit last time, and actually, there has been such an uptake of the dexamethasone of the steroids, that now it’s actually hard to get dexamethasone in our country. We have shortages. That was the 35% mortality, 28-day mortality reduction in patients requiring mechanical ventilation, and a 20% reduction in patients with hypoxemia, so anyone requiring oxygen. No benefit, as I think we’ve suspected in first week in patients without disease that makes them require oxygen.

CK: You could probably substitute other steroid equivalents, SOLU-MEDROL, SOLU-CORTEF, if you’re really low on dexamethasone.

DG: I actually in my consults, I give a layout of what would be the equivalents of other steroids, so dexamethasone, we have our glucocorticoids or mineralocorticoids. There’s several different steroids. Dexamethasone of 6 milligrams is probably equivalent to about 32 milligrams of SOLU-MEDROL, or about 40 milligrams of prednisone, so you don’t need necessarily dexamethasone, we don’t think, but that was the study drugs, at least at our centers.

I’m a big fan of whatever was studied. Let’s try to use that if we can, but I think that people were seeing, I think, similar benefits to the other steroids that they were using. Some of the stuff out of China that came out early after The Lancet piece, where they said, “I don’t know about that opinion piece on don’t use steroids because we’re using them and they seem to help,” they were not all done with dexamethasone. It’s actually SOLU-MEDROL in some of those studies.

CK: I was told by an endocrinologist today that there is differences in salt retention, but, otherwise, when you make the adjustments, you get the anti-inflammatory effect that you want by adjusting as you just laid out.

DG: That’s good. I think a little sidebar here, we break down some of our steroids into the glucocorticoid and mineralocorticoid activity, and the glucocorticoid we think of as being mainly the anti-inflammatory aspect, and the mineralocorticoid is that salt fluid retention part, so, yes, there’s going to be a little variation here. It’ll be interesting to see if it’s significant enough that one steroid is better than another. Maybe those will be some of the next trials. The nice thing I like about dexamethasone or prednisone are these are inexpensive therapies.

I did an analysis with the FMRC, one of the prior managers, with the number needed to treat out of the study, how much would it cost us per life saved in Sub-Saharan Africa, in Uganda, based upon current pharmacy prices? About $5 per life saved. This is the kind of stuff you want. You don’t want, let’s say, interventions that are out of the reach of the people that need them the most.

CK: Tocilizumab will be out of reach probably?

DG: Yes. What are the encouraging news about tocilizumab? “Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes.” This was accepted into CHEST. This was basically the observational study of the patients up at Yale. It was 239 patients. They basically looked at how they were doing before, but then they show us how they do after they instituted a protocol, whereby they give steroids and then, tocilizumab. They had an impressive 75% survival for patients on ventilators, so you can think about what you’ve been hearing about how well people usually do on ventilators, and a 93% survival for patients not on ventilators. That was an impressive outcome based upon them embracing the steroids, tocilizumab approach.

We’ll hear from RECOVERY, an actual proper randomized controlled placebo arm trial, and we’ll also hear about the French data, but this was quite impressive and similar to the improved survival we saw. Maybe more interesting, I found, was that it actually looked like the African-American patients and the Hispanic patients did even better or even doing better with these treatments than the Caucasian population. Historically, without these interventions, their chance of death has been about twice of that of the Caucasian. Interesting, and this will be something to think about when we get the RECOVERY data, “Are different therapies more or less effective in different genetic backgrounds?”

A couple updates on anticoagulation, and I don’t want to underplay this. I mean, anticoagulation, what are virologists and ID docs talking about anticoagulation for? We realized early on, and I think I’ve said about half of our patients in the hospital, particularly the critically ill patients, were developing thromboembolic complications. There are a couple studies that just came out. One was right here at Northwell, and it was sort of a reanalysis of the Mariner. This is a large thromboembolic data observation, where they were looking at major thrombotic events over the 45 days post-hospitalization. These patients were admitted, ended up out there, and about a 28% reduction in major thrombotic events using a medicine, XARELTO. I’m going to give you the brand name because I have trouble pronouncing, rivaroxaban.

Then there was one, actually, an observational study specifically, this is the Mount Sinai data. This was an observational study, “Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19.” And this was 2,773 patients at Mount Sinai. Basically, if you looked at patients requiring mechanical ventilation, there was a mortality of 62.7 with no anticoagulation, 29.1 with full anticoagulation, so cutting that more than in half just by using full dose anticoagulation, and a very low risk of bleeding was reported.

Still a bunch of pressing questions, “When patients get admitted should they all get anticoagulation or not? Should it be at these higher doses or just prophylactic doses? When they go home, what’s the best thing to give them when they go home?” Then, there actually is a study going on right now I’m very curious to see the results from. Actually, it was by the first author in the mariner data reanalysis and this is patients who never get sick enough to go into the hospitals, because we see strokes and clots and issues there, trying to look at what is the best approach for them.

Then I’ll just finish on the last note is sort of a little disturbing, just came out in the MMWR, that’s the Morbidity and Mortality Weekly Report and just came out. It has the publication date of June 26, which is going to be after this has been recorded, but it’s already out. I already have access to it. Its volume nine, number 25 and it was looking at women of reproductive age and hopefully, this is not going to be true, but they were actually showing that pregnant women were significantly more likely to require hospitalization should they be infected with COVID-19. It was pretty large. They looked at over 300,000 women of reproductive age. They didn’t have data on everyone, which I have to say. They had pregnancy status available on about a third of these women, so about 91,000 actual. Actually unfortunately, it looked like pregnant women had a higher incidence of hospitalization and also, more likely to be admitted to the intensive care unit.

So far, I hadn’t really seen a signal in pregnant women and I was reassured as time went by, and we didn’t see that, but this is the first report I’ve seen that maybe pregnant women are at significantly more risk than their non-pregnant counterparts.

CK: Not for death, though, that’s a good thing from this study. Right?

DG: Yes. Actually, and I have to say, there was not a significant number of deaths in pregnant women. They’re more likely be hospitalized, increased risk for ICU admission.

VR: You mentioned earlier, in the South the number of cases are going up substantially. Do you expect now some to be imported into the New York area and result in an uptake?

DG: We were starting to see what I was referring to, I think last time, as the back door’s wide open. What was happening is the snowbirds were returning from Florida, Texas, Arizona. A lot of people in New York, it gets cold here and, particularly, if you’re an older individual and have the ability, you might go spend the winter down in Florida and then come back in the summer. We were starting to see that, actually, Wednesday, the governor created a 14-day quarantine for people returning. If you come back from one of those hot zones, and it’s defined as incidence or prevalence above a certain level, then you are required to do 14 days of home quarantine before you’re allowed to enter the general population and pretty stiff fines, like $2,000 first time you’re caught, $5,000 the second time, $10,000 if you spread the virus to someone.

What I think has happened is people are now driving back to New York with New York license plates, so they don’t know. Unfortunately, that was what I was–

CK: Some of the New England states have handouts like Vermont. If you want to enter Vermont, you have to do a 14-day quarantine and they have reciprocity with Maine, New Hampshire, even though there are cases of uptake in Maine. When you started with A Tale of Two Cities, I thought they were going to load to New York and Houston. Houston’s becoming what New York looked like a couple months ago and our friend Peter Hotez has been talking about the parabolic rise in cases, which is quite concerning if they’re going to exceed their ICU capacity, etc. in Houston right now.

DG: I’ve been, I’ve been watching. Peter is very active on social media. I don’t know if our listeners know Peter Hotez, but he is very active and he’s been pointing out for a while that is really a sort of a rocket trajectory to out of control down there in Texas. People have talked about waves and everything else and I know people have said, “We’re still in the first wave. It didn’t go away, and if anything, we had reached a peak in our country of about 38,000 as sort of a single day high. We’re back at that again.” I’m still hoping that the virus’ ability to spread better indoors, or I should say the reverse of that its inability to spread well outdoors, may save us. We haven’t seen a huge uptick after a lot of the protests, but we are seeing a big uptick in areas that have gotten so hot that everyone’s indoors together in the air conditioning. I’m hoping that we have sort of a flat summer, but we’re already seeing a rise in local cases.

CK: It’s clear, Daniel, but from the expert experience and now that some of the case series are being published in the randomized control trials, that if you don’t exceed the ICU capacity or the hospital capacity, care will be better now?

DG: I have to say, I am optimistic because I think we have learned a lot and the mortality– if you get COVID now, your chance of survival is much better than it was, if you got COVID in March. We know what not to give, that’s number one, and we actually have learned quite a bit about what to give, and when, when to worry about you, when you might need hospital level care and we can do all this as long as we don’t get overcapacity. Right now, we are in good shape as far as our ability to deliver care.

This gentleman that I described who came up from Florida, he was very straightforward, very calm, he came in, he escalated to the Venturi mask, he was started on steroids. He was worsening. We followed this up with Tocilizumab, he was on full-dose anticoagulation the whole time and now, we’re just looking at discharge on four liters of nasal cannula. It was all very calm, all very systematic, such a different experience than early on.

VR: I don’t doubt that you have learned things. My question is, “Not every hospital will have learned things, or are they going to learn from your experience and others in these high numbers areas where you’ve been able to do this?”

DG: I think that’s a challenge. I was actually thinking we would talk about this next time, but I’ll jump in with it now, “How do doctors decide what to do? How do they come up with the way they practice?” It had one point been, you learn what you’re going to learn in medical school and residence and that’s what you do forever. But then, we started having the introduction of evidence-based medicine. I think I’ve described that during my training, it was still actually controversial. If you can imagine that you would use evidence to guide your practice, that you would dare use evidence over the eminence-based practice of medicine that had been what had happened for hundreds, if not thousands of years. But it takes a little while.

I talked about the data just came out on Dexamethasone, and the studies there, you can sit down, you can make some time in your day and look through it, decide as a clinician, does this make sense to you. And, hopefully, infectious disease doctors that are guiding patient care, take the time to read through it. But it’s interesting, it takes a little bit of time, there’s almost like an inertia to what we’ve been doing before it changes, and maybe the first thing starts to happen is you see a gradual change in a particular institution. Then you start seeing guidance and graded guidance, where there are certain groups– and I talked about the group that the WHO had formed regarding pulmonary support. Now you start getting guidance, you start seeing guidance coming out.

Sometimes that guidance is occurring at a local level, at a different health system, and those people putting out the guidance are not necessarily trained in how to do this guidance, so there can be a little bit of a delay, unfortunately, before something goes from good evidence to, actually, a properly-graded guideline that helps people take care of patients. My hope, maybe someone will give us enough money we’ll put an ad in the national media, but my hope is actually people listening to TWiV are learning quite a bit about the New York experience and, hopefully, this allows them to do a better job in all the different parts of the country that are just seeing now what we’ve been seeing for many, many months.

VR: We seem to have a lot of physicians listening. I know one won’t be because he feels we have too much banter. I think that’s a loss, especially, you could listen to Daniel’s part at least, right?

DG: I think they could do that, yes. Hopefully, my part is quick to the point, everything you need to know. If you want the banter, I enjoy the banter. You can stay tuned in. I guess I should say before I close out, thanks to everyone who’s been going to Parasites Without Borders and helping us support FIMRC, the Uganda site. Actually, people have been doing a great job. You say, “Hey, we might be able to save a life for $5.” As COVID continues to create food insecurity and all kinds of issues in Sub-Saharan Africa, thank you for everyone going to parasiteswithoutborders.com donating and helping us to support that clinic.

VR: All right. We have two emails for you, Daniel. First from Kathy who writes, “I just wanted to write and thank you for this podcast. While appropriately fearful of the COVID virus, as a 70-plus person, I had also been missing the exciting science that always comes with these events. As a very young medtech working at the city hospital with physicians from Fox Chase Cancer Institute, I did Hepatitis B agar gel diffusion tests, though at that time, it had not yet been identified as the Hep B virus. Using a double-blind study, we tested pints of blood intended for transfusion, a drop of serum from the donor unit tested against the antigens here, and looking for lines of identity when there was an antigen-antibody reaction. The study was quickly interrupted when all of the transfusion from units of blood with lines of identity caused hepatitis. Heady stuff for a 20-year-old.”

“In the ’80s, I had a ringside seat for HIV as I worked in the Red Cross Blood Program as a lab director. We all learned immunology as we muddled our way through that crisis. Do you think the COVID testing is problematic? You should have seen the lack of specificity that came with the early HIV ELISA tests differing blood donors with a positive ELISA test, but negative Western blot ranks right up there with the all-time difficult conversations you can have with a volunteer blood donor. Despite all the headaches that this virus caused, the advances that were made in understanding the immune system were truly amazing.”

“By the time I retired a few years ago, my experiences included testing for the transfusion-transmitted infectious agents, HTLV-1, Hepatitis C, Zika virus, and West Nile. I thought I’d seen it all until COVID came along. Finally, to my question. Is SARS-CoV-2 a transfusion-transmitted disease? Thanks again for this excellent podcast. Stay well.”

I thought you’d enjoy that story, Daniel.

DG: I do, actually. I think maybe some of our listeners know that I had that personal experience of growing up in Greenwich Village in the ’80s. My mother was actually on a panel with the now famous Anthony Fauci up at New York Hospital, as they worked to create relationships between the researchers and the affected population. Oh, I remember. I remember how difficult it was in the early days of HIV. As pointed out, we’re still in the middle of the COVID pandemic, we’re still in the middle of the HIV pandemic.

VR: That’s right. We sure are.

DG: I think the only difference is how many zeros and how many people have HIV and how many people get COVID every day.

VR: Is SARS-CoV-2 a transfusion-transmitted disease? I don’t think so.

DG: We don’t have any evidence. There never tends to be any, I’m going to quote, “significant viremia.” That doesn’t seem to be a big part of this disease.

CK: It’s more spillover, I think, isn’t it?

DG: That’s what we think, yes.

VR: Brian writes, “I’ve been seeing a growing number of stories about COVID-19 patients who have not fully recovered from their illness and are suffering from debilitating fatigue, brain fog, and muscle pain, such as discussed in the article on long-haulers in The Atlantic. What are your thoughts on this? Do you know of these symptoms lingering in any of the patients you have treated?”

DG: Yes. I think I’ve started talking about this the last couple of TWiVs. We’re now seeing a number of these long-haulers. Mount Sinai actually developed a chronic COVID clinic and be careful about the word ‘chronic.’ We’re seeing a number of patients who have a very long duration to their COVID-19 symptoms. They originally signed up for two weeks and still sick at eight weeks. Some of these patients do get better. There’s a long-haul form of COVID, where or maybe they’re sick for 8, 9, 10 weeks, but finally, that fever goes away. Then, they’re left with the fatigue. I don’t know when the fatigue goes away. Just I haven’t been able to follow these people long enough.

We started seeing it in March and here we are, April, May, June, we’re three months out and I still have patients that are in that lingering fatigue, that burning chest period of time. We don’t know if there will be, I’ll call it, a post-viral COVID syndrome that has been described for some of our other viral illnesses. This is something we’re seeing and, I think, Vincent, you’ve asked a few times what percent? I don’t know yet, but we’re definitely seeing this quite often.

VR: Okay. All right, Daniel. Thank you again.

DG: Thank you. It’s always a pleasure. Hey, I appreciate all the great work you guys are doing.

VR: Chuck, thanks a lot.

CK: Good talking with you both.

VR: See you both next week. Take care. Have a good weekend.

DG: Thank you.

[00:36:00] [END OF AUDIO]