This Week in Virology
Host: Vincent Racaniello
Guest: Daniel Griffin
Aired 6 March 2021
Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick.
From MicrobeTV, this is TWiV, This Week in Virology, Episode 727, recorded on March 4th, 2021. I’m Vincent Racaniello, and you’re listening to the podcast all about viruses. Joining me today from New York, Daniel Griffin.
Daniel Griffin: Hello, everyone.
VR: This is COVID-19 update #52. Before you start, Daniel, let me ask you a question. Is it a good idea for certain states to abandon the masking regulation?
DG: [laughs] Let’s start with the politics right away. It is a little too soon, I think. Many of us are saying, “Give us a little more time.” Peter Hotez is the nicest. He’s like, “Give me two weeks. I would like two months.” We’re really making progress here. This is interesting, and this is a political decision. I will say this, we talk about an infectious disease that our society, in the United States here, we are willing to tolerate 100 flu deaths per day. I guess we’re willing to tolerate 2,000 COVID deaths per day. This is tough.
What I say is, and I love to use my buddy Gareth’s dad as an example, because his dad’s always, “Whatever Boris says.” Whatever Boris Johnson, U.K., tells him, he’s ready to do. Gareth always says, “Really, because you always were so trusting in the government and you always thought they were so wise before the pandemic. Suddenly, in the pandemic, if they tell you you’re allowed to go to the pub, you believe them.” Just because the state says, “Hey, we’re lifting mask mandates,” they might be lifting a mandate, but they’re not saying you have to go out maskless.
You could still protect yourself. You could still protect others. You could still be part of the solution. I actually would prefer a society where you didn’t have to have mask mandates because everyone listened to the science and did the right thing and no one needed to force them to do the right thing.
VR: Okay, good. I’m glad to get that out right at the beginning. All right, Dan.
DG: All right. We’ll start with my quotation. “Do what you feel in your heart to be right – for you’ll be criticized anyway.” That’s another Eleanor Roosevelt. Perhaps people know that this is Women’s History Month. Eleanor Roosevelt is actually one of my favorites. My dad tells the same stories over and over again. One of the stories I love to hear is the time he was the high school photographer, and actually, got to meet Eleanor Roosevelt. Very jealous. What a just tremendous, bright, intelligent woman. I would have loved to have had the opportunity to meet her if she was still with us.
My quotation is not quite as powerful, but hopefully, appropriate. “Never miss an opportunity to vaccinate, never miss an opportunity to test, never waste a vaccine dose.”
Let’s start off with testing. I keep bemoaning the fact that the testing rates are going down. This is not good. If you’re not doing enough testing, you’re not keeping the lights on, so it’s hard to keep track of things. Just resist this temptation to stop testing. We’re in the middle of a pandemic, we’re still in the middle of a pandemic. We need to keep the lights on. We need to continue to test.
There was an interesting article just published in CID, Clinical Infectious Disease, and it was entitled, Difference in SARS-CoV-2 attack rate between children and adults may reflect bias. That was like when the title tells you what it’s all about. This actually described this phenomenon where children were less likely to be tested. They might also have more asymptomatic disease. They also referenced a few papers on Long COVID in children. I’m going to actually return to that in the end because that actually was part of what caught my eye.
I think it’s fair to say that most of us no longer believe that children are less likely to get, less likely to spread COVID. It is, I think the evidence is pretty good, that the severity is usually less in children as far as the acute COVID. The mortality is lower in this age group. We’re actually seeing cases of post-acute COVID syndrome, so Long COVID in children. I’ll actually return to some of the data we have on that out of the U.K., because I think that’s really critical when we make some decisions here.
Active vaccination. This was an exciting week. I’ve been waiting for this for many, many months actually. It’s the J&J data. Perhaps some of our listeners know that in my role as a senior fellow infectious disease for United Health Group, we created this concept of a readiness cohort. What happened is when J&J was waiting to get to Phase III, we set up about a million people ready, excited to be part of that trial. Then as soon as they got approval, we shot out emails targeted to areas where we thought there would be high incidents of COVID, and then this was actually the fastest-recruited, largest vaccine trial in history.
If you want to get a really good deep dive and discussion on the J&J data, I’m actually going to tell people to listen to the most recent TWiV that was dropped on Thursday, the day we are recording this, a really nice discussion, about one hour and 15 minutes into that show. Just to give a brief for our clinical update listeners, the data was submitted, safety and efficacy data from an ongoing, still ongoing multinational Phase III randomized, double-blind placebo-controlled trial of a single dose Ad26.COV2.S vaccine in approximately 40,000 participants submitted to the FDA for EUA.
We now know that that has been granted. The primary analysis evaluated co-primary efficiency endpoints of molecularly confirmed, PCR confirmed moderate-to-severe critical COVID-19 with an onset of at least 14 and 28 days post-vaccination, respectively. Now, I’m going to go a little bit into these endpoints. They were looking at the co-primary efficacy analysis, and they included 39,321 individuals randomized 1:1 with a median follow-up time of two months post-vaccination, and across all the areas, they reported a 67% effective as early as 14 days after vaccination.
There’s a lot of weeds here. Again, that’s why I’m recommending people listen to the prior TWiV. I want to get to I think the critical data here. In the vaccine group, there were no COVID-19 cases requiring medical intervention, hospitalization, death after 28 days. One hundred percent effective against COVID-related hospitalization or death as early as 28 days after that single shot. I want to just talk a little bit about that, because there’s a lot of discussions. I’ll get into this about, “Boy, if I’ve got an option, which vaccine am I going to choose?”
A couple of things I want to say about the J&J vaccine. One, is it’s a single shot, second, as we learned from this trial, very limited reactogenicity, this is very much similar to that normal vaccine that you’re used to, arm is a little sore, people are not down for a day or two like we’re seeing with some of the other vaccines. The others, I also like to say that the mRNA vaccines were tried early on. They had endpoints there of a little over 100 cases for the Moderna and the Pfizer.
This vaccine was tried during, I’ll say our current conditions, full-blown pandemic, lots of transmissions, lots of variants, it was looked at in South Africa, it was looked at in Brazil, it was looked at in the United States, it was looked at in a lot of different places, and in a sense, you could say they were playing against the A Team. J&J did great, 100% at keeping people from dying, 100% at keeping people from ending up in the hospital. The other, and I think this is really interesting data that we saw here, the most robust data that we’ve seen presented to the FDA was the vaccine efficacy against asymptomatic infections.
I mentioned that we were expecting to hear this. What they reported is they looked at day 29 with observation out to day 71. What they were doing, it was a combination, most of it was zero conversion for antibodies to the nuclear capsid, so directed at the N-protein. They also were actually including your positive PCR, so when you put all that together, they’re reporting a 74% reduction in asymptomatic COVID-19. I think that’s actually pretty impressive.
I think we’re moving towards that direction where we’re really starting to have a growing amount of evidence saying that these vaccines, so we call this sterilizing immunity, but the idea that they actually prevent you from getting infected. It looks like they’re interrupting transmission. This feeds right into our next question. I get a lot of questions about, “Will the vaccines keep me from getting Long COVID?” Because people say, “I don’t know. I’m looking at 94. I’m looking at 95. I’m looking at these numbers in the 60s and 70s. Maybe I want a certain vaccine over another because I don’t want to get that Long COVID, maybe a mild case with the vaccine.” At present, we do not know, but I will say this is feeding into this thing.
If you cannot even be infected with COVID, this really looks like you’re not going to end up with Long COVID. So, promising that the vaccines are really going to reduce the number of people that go on to develop Long COVID.
One of the things we really liked as providers was just how easy this vaccine is going to be to work with. It’s one and done. It’s also something that is provided just as a refrigerated suspension. You could put it in a normal medical refrigerator and leave it there for three months. It comes in multi-dose vials, so five doses per vial.
You draw up a half an ml, you inject that, and just like the others, there is– Once you take it out of the fringe, you can let it sit there on the counter for up to 12 hours. Once you puncture and start drawing out your doses, they recommend getting all those doses out before six hours. Why is that? Does it magically go bad at six hours? There’s no preservatives in here, so it’s really an infection risk. After six hours, there’s a concern that now you might have introduced a low level of some bacteria. That’s really the six hours here. Much easier to work with here, single 0.5ml intramuscular injection.
A few questions I’ve been getting now. I hit back on this, people– “Now that there are several vaccines, which vaccine should I choose?” I’m going to start with the end. Don’t give up your shot, get whatever shot you can get. There are a few exceptions, or say subtleties here, if a person has that same-day access to either J&J or one of the mRNA, and let’s say this is a very frail individual, they’re on dialysis, they’re already on oxygen, that might be a person where that reactogenicity gets us into trouble with the mRNA vaccines, maybe that’s the time you think of the J&J.
Questions about G6PD deficiency in vaccines. I don’t know how many of our listeners are familiar with G6PD. It’s an enzyme deficiency that evolved in a lot of areas in the world where there was malaria. These people can be at risk with some of the anti-malarial drugs, and also could be at increased risk of oxidative stress. One of the nice things about J&J is we know that this platform was used over 200,000 people, 193,000 people got the Ebola vaccines in an area with about a 20% incidence of G6PD. They did very well.
We’re not seeing any specific concerns. Again, there will be potentially a time in the future when people will say, “Well, I’d rather have one vaccine than have to go through two.” It’ll be interesting to see what comes out as the person’s favorite vaccine. Before we move on to passive vaccination, I’ll say, looking at surveys among potential vaccinees, there looks like there’s a little bit of favoritism towards J&J. A tremendous vaccine, in no way inferior to any of the others, and I look forward to seeing even more exciting results as we get more experienced with this platform.
Passive vaccination. I was talking about monoclonals, but let’s talk a little bit about convalescent plasma. We had some new publications. The Association of Convalescent Plasma Treatment with Clinical Outcomes in Patients with COVID-19, A Systematic Review and Meta-analysis was published in JAMA.
They looked at a total of 1,060 patients from four peer-reviewed randomized control trials, another 10,722 patients from six other publicly available randomized control trials. They looked at all-cause mortality, length of hospital stay, need for mechanical ventilation and data on clinical improvement, clinical deterioration, and serious adverse events. Really, the conclusion from looking at all this data was that treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes.
Along the same lines, this has not been a great week for convalescent plasma, the NIH did announce on Tuesday, March 2nd, that it was halting its trial of COVID-19 convalescent plasma in emergency room patients.
An independent data and safety monitoring board met for the second planned interim analysis. They basically said that they felt it was unlikely that this therapy was going to benefit this group of patients. A little bit about this trial, it was a good trial. I think it was well thought out. It was conducted at 47 hospital ED departments across the U.S. They had already enrolled 511 patients.
They were specifically looking at the effectiveness of COVID-19 convalescent plasma. This was blood plasma derived from patients who recovered from COVID-19. They were targeting this to adults who came to the ED with mild to moderate symptoms that they had had for a week or less. They were trying to get it in the first seven days. They were looking at a higher-risk group. These patients had at least one risk factor. Obesity, hypertension, diabetes, heart disease, chronic lung disease. None were ill enough to require hospitalization, so none were in week two.
As pointed out, they did not get any signal to suggest that this was going to be beneficial. Little balance here. I’ve mentioned the large MAYO access program where they tried to tease out maybe a little bit of benefit, high titer neutralizing antibody versus low titer. We had that study out of Brazil where if you could get it, high titer within the first 72 hours, there may have been a reduction in people progressing.
I think convalescent plasma is really coming to an end, being replaced with monoclonals with the data suggesting a really robust benefit in that group. I think we’re moving into the days of the monoclonals.
Period of detectable viral replication. There’s a lot of studies that we actually have been hearing about in peer review, but they finally got published. I think interesting for how many months now we’ve been using steroids, embracing that, and actually, that was based upon a preprint from the recovery collaborative group.
We saw on the 25th of February, Dexamethasone in Hospitalized Patients with COVID-19, the RECOVERY Collaborative Group. This was published in The New England Journal of Medicine. This is the giving dexamethasone in COVID. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation, 29.3 versus 41.4, among those receiving oxygen without mechanical ventilation, 23.3 versus 26.2.
We’re seeing a rate ratio of 0.82 in those individuals, 0.64 in mechanical ventilation. We’ll say a 36% reduction in incidence of death in the focus on mechanical ventilation, and 18% reduction in those not on mechanical ventilation. Here is something that I want to point out. This is critical that we see in this data, it really echoes something we’ve been saying for a long time.
Among those individuals on no respiratory support, so individuals with a room air oxygen saturation of 94% or higher, those in the first seven days, if those individuals received steroids, there was actually a trend towards increased mortality. A rate ratio of 1.19, so about a 19% increase towards doing worse. I just want to put this. This reinforces that steroids are not the first week, it’s the second week, in individuals who have an early inflammatory phase that is actually resulting in hypoxemia.
Don’t give steroids in that first week to someone with a headache and a fever. The timing, the right patient selection, you can do harm, you can do good, but it’s going to take some decision-making here.
Early inflammatory phase. Still in this phase now, we actually have the IL6 Receptor Inhibitor data. We’ve talked about this in the preprint format. Now we have the two papers published in The New England Journal of Medicine.
Tocilizumab in Hospitalized Patients with Severe COVID-19 Pneumonia. This was the COVACTA trial. This was a Phase III trial, 452 patients with severe COVID-19 who were hospitalized, randomly assigned in a 2:1 ratio to receive a single intravenous infusion of tocilizumab. This was weight-based, 8mg per kilogram versus placebo. About a quarter of the participants got a second dose within the next 18 to 24 hours.
This was only 19% of the patients who received steroids prior to tocilizumab. This was prior to the recovery data. Giving tocilizumab without steroids– in this randomized trial, the use tocilizumab without a background of steroids did not result in lower mortality than placebo at 28 days. The only encouraging suggestion from the subgroup analysis was about a 40% reduction in need for mechanical ventilation.
My takeaway from this is it really confirms not using IL6 Receptor Inhibitors without a background of steroids. You actually see a separation and then you see it come back together if you look closely at the Kaplan Meyer curves. There was also not much attention to timing. The only exclusion was imminent death within the next 24 hours. If you look at the timing, some of these patients were receiving tocilizumab as late as 49 days after symptom onset. Some of these individuals receiving tocilizumab during the first week of illness, some of the individuals were receiving it during the second month of illness while they were sitting on a ventilator, so timing and a lack of background of steroids here.
We also saw Interleukin-6 Receptor Antagonists in Critically Ill Patients with COVID-19, the REMAP-CAP Investigators. This is an ongoing international, multifactorial, adaptive platform trial. Adult patients with COVID-19 within 24 hours after starting oxygen or organ support in the ICU were randomly assigned to receive tocilizumab, again, weight-based, sarilumab, or standard care, and the primary outcome was respiratory and cardiovascular organ support-free days, ordinal score, also looking at days of free of ordinal support to day 21. This was really focused on timing.
Ninety-three percent of the patients who are receiving dexamethasone, and again, about 29% of the folks got a second dose of tocilizumab; 353 patients were assigned to tocilizumab, only 48 to sarilumab, 402 to control. The median number of organ support-free days was 10 in the toci group, 11 in the sarilumab group, and zero in the control group. The median adjusted cumulative odds ratio was 1.64 for toci, 1.76 for sarilumab, as compared to controls, and the probability of superiority compared to control was reported at between 99.9% and 99.5% respectively.
An analysis of 90-day survival showed improved survival in the interleukin-6 receptor recipients compared to controls with a hazard ratio of 1.61. This had a probability of superiority of more than 99.9%. Critically-ill patients, COVID-19 within that first 24-hours of organ support in the ICU, treatment with the IL6 receptor antagonists improved outcomes including survival. This all comes together with the paper that we did discuss before, the recovery trial data that’s still in a pre-print. So, what we see here with toci given with the background of steroids is a reduction in mortality and a reduction in the risk of being intubated.
I was on a call, I think earlier today, where an ACTEMRA slide came up, and the person apologized and I said, “No. Actually, we’ve gone full circle, and I think we’re back to– In a sense, back to where we were in April.” Steroids first, the right time. It is not easy to manage COVID. You want to get someone expert in this involved, because we do have interventions with mortality and morbidity reduction.
The tail phase. This is a little tricky part, but I’m going to go into this, anticoagulation. What do we do when someone has been in the hospital, maybe someone hasn’t been in the hospital?
Back in September, we saw the Brief Report in Blood, Post discharge thrombosis and hemorrhage in patients with COVID-19. They concluded that COVID-19 hospitalization did not appear to have an increased risk of post-discharge hospital-associated venous thromboembolism compared with hospitalization with other acute medical illness. Story moves a little forward. In December, we saw the article in blood advances, Incidents of symptomatic, image-confirmed venous thromboembolism following hospitalization for COVID-19 with 90-day follow-up. They were describing a rate of 2.6% out past 42 days, so a high bar, these had to be image-confirmed clotting complications.
Now, in January 2021, for hospitalized patients, the WHO suggested the use of low-dose anticoagulants for preventing blood clots formed in blood vessels. The NIH is recommending targeted anticoagulation for higher-risk patients at discharge. We really don’t have great evidence-based guidance. Much of medicine, much of COVID here needs to be individualized. I’ll say, here in New York, a lot of systems are using Xarelto, Eliquis, these direct, oral anticoagulants, and we’re still trying to sort this out. Someone comes in during that first week, and number one, neglect the outpatient management.
We talk about, maybe they get anticoagulation then, maybe it’s aspirin. Again, really a lot of judgment, because we do not have great data to guide us. We do know that individuals with COVID are at risk of clotting complications. Then, I want to get back to children and Long COVID before I tell a couple of stories. The article I mentioned before in CID Differences in SARS-CoV-2 attack rates between children and adults may reflect bias. They referenced some of the publicly available U.K. data. They were looking at five-week prevalence of persistent symptoms in different age groups.
When they looked in children, aged 2 to 11, these are young kids. They were seeing persistent symptoms in 12.9% of the children, compared to about 22% in adults. We are seeing Long COVID, post-acute COVID complications in children as well. When we think about children, and we say that, “Oh, they’re less likely to die, they’re less likely to end up in the hospital.” If 13% of our children end up with Long COVID, this is a disaster.
Before I talk about our fundraiser, I just want to bring people a story I recently had, which I was not happy about. It was a couple which I just admitted to the hospital today in their 80s. They went out and had a meal with some friends. The husband had actually had COVID six months ago. It was not a terrible case, he recovered. They got a call on Monday, “Hey, we’re so sorry, but we were just diagnosed with COVID,” the couple that they had lunch with. The woman got a test on Monday, it was negative, so we’re all good. You can predict the future with a negative test. Apparently not.
On Wednesday, she and her husband started to feel poorly. On Sunday, day five of illness, they went to an urgent care center, they were both diagnosed with COVID. How were they treated? Were they offered access to monoclonal antibodies? No. Instead, they were offered vitamin D and zinc, they were sent home, and now both of them, in their 80s, are in the hospital. Remember what we’ve been reiterating, really good evidence for those monoclonals during the first week, excellent access here in New York. It’s as simple as making a phone call on the behalf of your patient.
Our fundraiser, through the months of February, March– Actually, we’re going to extend this into April, we’re going to continue to support the American Society of Tropical medicine. What we’re looking to do, as part of this support, is to create annual meeting travel awards. We’re targeting this to early-career investigators, women from areas of the world, low-income countries. Help us support American Society of Tropical Medicine. Drop what you’re doing, unless you’re driving, and go to parasiteswithoutborders.com, and please donate and help in our efforts here.
VR: All right. Time for some email for Daniel. If you want to send in a question, email@example.com. Stewart writes, “I am treating a 65-year-old gentleman with a history of Guillain-Barré in the last five years. Does that remain an absolute contra-indication to the Moderna and Pfizer vaccines? Will any of the newer vaccines be considered safe? The complication is that this individual needs to be in the OR for his job, and the ORs where he works are demanding vaccination before granting access. I would appreciate any advice you might offer.”
DG: The nice thing, I think I said this last time, is as we move forward, as we get more data, it’s easier for me to answer these questions with a little more certainty. We’re not seeing signal, we’re not seeing an increased risk of Guillain-Barré or Bell’s palsy, of any of these concerns. So, I don’t think there is a reason to miss your shot, not get this. If the person is concerned and wants to use J&J versus the mRNA vaccines, I think that’s, I’m going to say reasonable, not encouraging that. All the vaccines, what I like to reinforce is, there is no side effect you’re going to get from the vaccine that compares to getting COVID and continuing to be at risk.
VR: Sara in Tallahassee writes, “What are the timing recommendations for other vaccines, flu, HPV during and after the Moderna vaccination series?”
DG: I was on a call with the American College of Immunization Practices, and they were actually talking a little bit about the timing here. We are recommending about a two-week gap between vaccines, but what they reiterated is this is qualified. If that’s going to stand in the way of a person getting a vaccination, this is a soft recommendation. We don’t have any particular concerns that getting a concomitant flu shot and your COVID vaccine will cause an issue, we actually anticipate in the future that they may be given at the same time. The general recommendation is two weeks apart, but if that is going to interfere with a scheduled COVID vaccination or interfere with the opportunity to get a flu shot or another vaccination, this is a soft recommendation. Go ahead, get your shot.
VR: Sandy writes, “I live in Texas and after the storm, I went for my second shot sponsored by our health department and the local hospital. They had 150-plus people packed in a high school halfway for one and a half hours before we got the shot. Zero ventilation.” Well, that is Texas for you. “I have self-isolated since October. This is the only exposure I’ve had. I’m 70, really quite scared. I’ve taken vitamin D for 30 years. I’ve been waiting for the vaccination before I went for a checkup. I was thinking about getting a COVID test but I live in a rural area. I don’t know how to find a doctor to treat this. What kind of doctor do I look for? I would appreciate any comment.”
DG: Okay. Yes, this is not great. You’re not alone. I’m rather upset how the vaccinations are rolling out. I had an individual from the east end of Long Island. I think I may have related this story before. This gentleman was in his 80s, he’d been really good, staying home and not going out. He went to one of these mass vaccination sites, was in a room with a lot of other people for a very long period of time. He got his vaccine, got the normal reactogenicity. Then about six days later, started feeling crummy, and, yes, he got COVID, and the suspicion is, that that was his only exposure that made sense.
I do think it’s a bit of a disaster when we turn a vaccination opportunity into an exposure risk. Every fall, right, we give 200 million influenza vaccines. We do it through doctor’s offices. We do it through pharmacies. We do it in a lot of different venues. I’m not really sure why this vaccine rollout had to be done so poorly. That’s my criticism of the rollout. Hopefully, we’re not going to do this next time. Let’s learn from our mistakes. Let’s say you start to get symptomatic, right? It’s been more than four or five days. You are concerned, “I actually have the COVID.” Then you want to go and get tested. If you do, we have access to monoclonals. That’s the most effective thing we can offer during that first week.
There are national numbers. You just go to United in Research, there’s a number. It’s fusion centers throughout the country that can come to your home and administer to you within 24 hours for free, it’s already been paid for. There also are Eli Lilly and Regeneron where you can go online and find a local hospital facility that might do this as well.
Unfortunately, you’re going to have to be proactive, because a lot of physicians I’ve even described here in New York, where they should know better, don’t pick up the phone, don’t make this happen for people. Just the fact that you’re in a rural area, if you do end up with COVID, all the science is growing and continues to support this as our most powerful tool.
VR: One more from Gene, “What about it? I hear repeated claims that snippets of RNA viruses and COVID vaccines can alter human DNA. You’ve been the star of my lockdown life. Thanks. I will be vaccine liberated in about a week.”
DG: No, the mRNA vaccines will not change your DNA. They will not get into the nucleus. They will not change your genetic code. There’s actually one of the local infectious disease physicians was joking that he was planning on getting vaccinated. I don’t know if he’s gotten vaccinated already. He was saying that he was bemoaning the fact that he still was bald and short and the vaccine had not helped him. It did not rewrite his DNA in any helpful or deleterious manner. Unfortunately, or fortunately, depending on how you look at it, how happy you are with your current genetics, none of our vaccines’ technologies have the ability to rewrite anyone’s genetics.
They are safe that way. We also get the question about, “Oh my gosh, fertility?” I’d like to point out, tens of thousands of women who have been vaccinated have now gotten pregnant. We are encouraging women, actually, I should say encouraging women who are pregnant or plan on getting pregnant, to get vaccinated. It’s in a sense, two for one.
Protect yourself and the baby. We do know, this is different than when I was first on CNN, that pregnant women are a higher risk population, 20 times more likely to end up in the ICU. We have ongoing trials looking specifically at this, but these vaccines are the safest, most effective vaccines we’ve ever had. You’re safe there.
VR: That’s COVID-19 clinical update number 52 with Dr. Daniel Griffin. Thank you, Daniel.
DG: Thank you so much, and everyone, be safe.