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The Road to Safety: Understanding the Common and Less Common Side Effects of COVID-19 and Other Vaccines

Authors: Barbara Rath, MD, PhD; Paolo Bonanni, MD; Federico Martinón-Torres, MD, PhDFaculty and Disclosures


Activity Transcript

Barbara Rath, MD, PhD: Hello, I'm Barbara Rath, co-founder and chair of the Vaccine Safety Initiative, and I'm research director at the University of Bourgogne Franche-Comté in Besançon, France. Welcome to this program titled, "The Road to Safety: Understanding the Common and Less Common Side Effects of COVID-19 and Other Vaccines."

Joining me today are Federico Martinón-Torres, who is head of pediatrics and director of translational pediatrics and infectious diseases at the Hospital Clínico Universitario de Santiago in Santiago de Compostela, Spain, and Paolo Bonanni, who is professor of hygiene and director of the Department of Health Sciences at the University of Florence in Italy. Welcome, both of you. Thank you for coming here.

Federico Martinón-Torres, MD, PhD: Thank you.

Paolo Bonanni, MD: Thank you. Thank you, Barbara.

Dr Rath: Unlike most medicines, vaccines are administered usually to healthy individuals, including infants and children. And because you give something to healthy people means you don't really want to see side effects. In other words, our tolerance to seeing side effects is very low following vaccination.

The safety assessment of vaccines is continuous and exhaustive. It begins during the nonclinical studies and evaluation and then continues throughout studying individual components, the effects on particular cells, and continues throughout the clinical development phase, where we have clinical trials, phase 1, 2, and 3. Then once the vaccine is in use, the safety assessments continue, which is called postmarketing surveillance after approval of a new vaccine.

This is where your role comes in as a physician. In other words, your observations as a clinician are important throughout your career and throughout the postmarketing surveillance of vaccines.

Now, this is not a random surveillance, but it follows very strict rules. And in order to start pulling large numbers of data, because once a vaccine is approved, it is given to millions of people, we have to have an international agreement on what constitutes, let's say, fever, following a vaccine. Unless we agree on these definitions, we cannot compare data coming from different settings, from different studies, or from pre- vs postmarketing surveillance.

How do we define adverse event following immunization? The WHO has defined it as any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine. In other words, did the vaccine cause a problem, or was there a vaccination given, and something happened later that has nothing to do with the vaccination?

So, Federico. How do you think we would separate those questions?

Dr Martinón-Torres: Well, thanks, Barbara. I think that one of the main problems we face every day with regards to vaccine safety, safety alarms, are the coincidental events. Good things, bad things, even disease, constantly happen all the time, and vaccines are very common things. In broad vaccination, in mass campaign vaccination like we have just done with COVID-19, it's easy that these good things and bad things happen related in time with the vaccination itself, but not meaning that there is any true causal relationship.

Of course, vaccines can actually cause adverse events, and this is something we will discuss in later on. But most of the times, these adverse events are very rare, and most of the times will be observed as reactogenicity, or the expected self-limited reactions that you can get after vaccination.

But what more often happens is that we wrongly link what is actually happening to the subject with the fact of having received a vaccine immediately, just after a few days or a few weeks later, which is the temporary association that often leads to misconceptions, to fear to vaccinate, and other social alarms related to vaccination.

But if we put that into perspective, just to give an idea to the audience, if we think about anaphylaxis, which can be 1 in a million doses, and we put on the other hand, I don't know, any national Lotto prize, you have 1 in a million chances of getting an anaphylaxis after vaccination, and 1 in a 100,000 to get, I don't know, the prize of the Lotto, no? Which seems impossible, but it's much, much higher, the possibility, than having severe adverse events with vaccines.

And there are several examples in that regard. If we just consider, for example, the mortality rate in children, the normal mortality rate, where we can say that if we vaccinate, considering a mortality rate of around 3 per 1000 children a year, just in the day of vaccination, we can find 8 deaths. Not related to the vaccine, but because they were children that were going to die with or without vaccination.

But it's normal that even the physician that is witnessing that tries to relate what has just happened with the fact of having received the vaccine. And this is quite normal when we talk about vaccines, because the perception about vaccines, the perception about the benefits, and the acceptability of the risk of vaccines, are totally different as compared to those of drugs or other medicines.

There are interesting examples in the literature, and I like very much one from a paper in Pediatric Infectious Disease Journal (PIDJ) data we have discussed several times, Paolo and myself, from Claire-Anne Siegrist, where she states exactly the numbers of what is expected of a certain disease in a certain population. In this example, she knows that there will be 50 to 60 adolescents per 100,000 that will be admitted to the hospital because of diabetes debut. She represents that in a graph, 100,000 women in a full year. And then now let's imagine that that population is vaccinated. After the year, we will be seeing 50 to 60 cases of debut diabetes that are admitted to the hospital, and some of them will be just after the first dose, 1 week after the second dose.

And it's quite easy that, of course, the girl and the family will think that it's related to the vaccine, but even the physician. But the real truth is that if we look at the surveillance and the total number of cases at the end of the year, it's no different. There is no reason to think that there is any even observational or logical association. So I think it's very important, and sometimes even for the healthcare provider, it's very difficult to differentiate what is a pure coincidental event in time with vaccination with a true adverse event.

Dr Rath: To make it very simple, this is fairly complex if you look it up in the literature, but there are different situations that we can see that can cause something that looks like an adverse event following vaccination. There are things that are pure coincidences. There are things that are truly caused by a vaccine. There are also things that just happen whether you vaccinate or not, or independent of even the disease, the vaccine-preventable disease that you're trying to address. And then there are the things that we may induce as a procedural discomfort, or as something else untoward, because we haven't administered the vaccine correctly.

Dr Bonanni: And let me say that also, the fact that we do not expect the effect of the vaccine immediately makes us concentrate on the side effects. When you are taking a drug, for instance, for headache, you expect the effect immediately, and so you are less concentrated on side effects. But the side effects after therapeutic drugs are more than when you get the vaccine.

Dr Rath: And it may make people deemphasize the benefit of a vaccine, right? People say, "I got the flu vaccine and now experience the flu of my lifetime 5 days later," the benefit of the vaccine is not there yet fully.

And then it becomes difficult to understand, is the flu-like symptom now an adverse event following immunization, or is it vaccination failure, or is it a natural disease that just happened in a more diminished form because some of the vaccine has started to work? These are the things we need to understand, which is part of why we've studied a lot how to measure disease severity consistently, so we can understand when vaccines are taking away some of the severity of the illness, but they don't stop the illness completely.

And then some people interpret that as an adverse event following immunization, even though it's the actual exposure to the disease, which is less severe because you have been vaccinated. And we'll talk a little bit more about that, but before vaccine is administered to humans, there's a lot of work going into this, and there are decades, often, leading up to a new vaccine.

I've heard the complaint many times from patients, they say the COVID vaccine was suddenly developed so rapidly, and this is not trustworthy. Most people do not see the big foundation that is underneath the peak of that iceberg that leads to the final few vaccines that ever make it to market. The decades of work in the construction of the vaccine, the general disease studies, and then the design of a vaccine and all of these things coming together.

Paolo, can you give us some more details on how cumbersome and elaborate the development of a vaccine actually is?

Dr Bonanni: Yes, yes, Barbara. Before a vaccine is given to human beings, the manufacturers of vaccines undertake extensive safety evaluation of any individual vaccine component, and also of the final formulation, so both the components and the final mixing of these components.

These components are tested in the laboratory for purity, sterility, potency, which means the ability to generate a strong response; the consistency, so the fact that when you produce more lots of the vaccine, they are similar in their characteristics; their activity and stability. Many of these tests are conducted in labs, and many, such as the test for efficacy, toxicity, safety, and effects on reproductive health, are also tested on animal models before they are taken to the test in human beings.

If we look at what is done during the lifetime of the development of a vaccine, there are some tests that are performed in labs as to the pharmaceutical quality. Then, we have the nonclinical studies, where, for instance, the toxicity is evaluated both in cell cultures, but also on animal models. And then if everything is okay, we go on testing and making the experimental studies in human beings.

And I would like to stress the fact that starting from phase 1 studies, going to phase 2 and phase 3, which are the efficacy studies, we involve tens of thousands of people who are involved in these preassessment, preevaluation studies. And then after these studies are finished, there is the filing for approval. But what is important is that sometimes we do not see all the rare events that could follow immunization in these clinical trials, and so the evaluation of safety is continuing for all the lifetime of the vaccine.

So we have the so-called postmarketing safety monitoring, as you underlined before, and this is collected at the European level with surveillance systems that can collect all single data. So this is really a reassurance for our safety.

And the other important thing, I think, is regarding the role of the healthcare professionals in monitoring vaccine safety. In this sense, we should underline that the manufacturers themselves have a duty to give a notification of any side effects they are coming to know, but also the general practitioner (GP), the nurses, and the pharmacists and the public itself has a role, because we are prompted by the health authorities to notify any adverse events occurring after vaccination.

After this, there is a validation of what happens after the vaccine. If this is not connected with the vaccine, we go on. But if there is something that makes us think that there is a connection, a causal connection, then we have to interpret the result, and there might be some changes in the use of the vaccine or the indication, so some action is taken. But then we have to start detecting again what happened.

So there is a circle, in a way, of surveillance, action, surveillance and action. However, what is important to know is that even very rare adverse events are detected because this system of surveillance can cover all the use of the vaccine during the lifetime of the vaccine.

Dr Rath: So you don't need to worry about every detail of that, but your responsibility as a physician is to encourage your patients to let you know if anything went wrong, and then to discern that and make a report whenever possible when you think something is real, and then leave it up to the regular authorities to go and dig deeper.

Most vaccines are provided as injections, as we mentioned earlier, and the most common AEFI are symptoms that occur at the injection site, meaning pain, redness, swelling. These events are reported as side effects of most injected vaccines, and are generally mild and self-limiting. There are some discussions whether you could recommend giving paracetamol or something to limit the pain if it's getting much worse.

Occasionally, unexpected AEs or AEFI, or rare, serious AEFI may occur. Some events, such as anaphylaxis, usually occur rapidly after immunization, so the time window may also depend on the AEFI you're describing. For anaphylaxis, you expect that to happen within a very short time window right after vaccination, if you think the vaccination has been the cause, and it requires very swift recognition and management on the side of the medical team. Others may occur days or weeks after immunization.

Anaphylaxis, therefore, is actually a good one to monitor, because as you can remember from the introduction of the COVID vaccine, there was the instruction that even if you get the vaccine at a pharmacy, which is possible in some countries, you would want to monitor the patient for about 15 to 20 minutes. If nothing has happened until then, anaphylaxis is almost ruled out, and the patient can safely go home, or the vaccine recipient.

So, Federico, what do you think? How would you manage the monitoring for AEFI in your practice?

Dr Martinón-Torres: Well, I think that the challenge when we think about safety of the vaccines are the more rare adverse events. Because usually, and as Paolo perfectly explained, the phases of phase 1 to 3 trials allow us to detect not only the minor safety issues, but also the common adverse events, and of course the efficacy of the vaccines. But even with the large trials, there can be rare conditions which are difficult to detect, even in big trials, as those we have performed for COVID vaccines, which are among the largest trials where we included millions of patients, but rare conditions below 1 in 20,000 or in 10,000 can just be omitted.

That's why it's so important, the postmarketing surveillance and all the networks that are doing continuous surveillance postimplementation that provide us with the necessary information to detect safety signals and to go through them and ascertain if they are true or not adverse events following immunization. So I think we need to really reinforce the importance of that and the transparency of the process.

And when we think about what happened in the large-scale implementation of the COVID-19 vaccines is that some alarms arose. That's pretty obvious, no? And I think for few vaccines, we have accumulated so much safety information in such a short period of time, and I think that has been shared with total transparency with everybody, not only among the professionals. And I think that it's a good take-home message about how this actually works, and how reassuring is the process of evaluation of the safety of the vaccines, even for the newest vaccines.

Dr Rath: Which means you should communicate that to your patient, because otherwise the false impression may arise among patients who say, "Something was put out to the public, and then they discovered something."

It's good to preempt that when you talk to your patients, or to your vaccine recipients, and say, "We are now certain down to 0.1%," or, "The studies were such and such, but anything below that is not ruled out. It can happen. And if we vaccinate millions of people, there may be 1 or 2 or 3 who may experience this. But the chances of just walking across the street and being hit by lightning are many times bigger." So give a comparator, give something like the Lotto numbers that you were talking about, whatever, to put that into perspective.

Dr Martinón-Torres: Yes, I think that the accumulated experience so far in general is reassuring. We are talking about billions of doses, more than 12 billion doses of COVID-19 vaccines administered worldwide. And beyond the effectiveness, which is out of discussion . . .

Dr Rath: Multiple times over.

Dr Martinón-Torres: Exactly. So I think that the safety in that regards is guaranteed. But it doesn't mean that vaccines cannot actually have adverse events. That's a reality. Any biological product may have. But most of the times they are exceptional, very rare in frequency. And what we often observe are just what we mentioned before, situations where we find coincidental events in time, but not true casual relationships. So I think that this is something we need to really keep in mind when talking about safety of the COVID-19 vaccines, as for other vaccines in general.

Dr Rath: Yes, and on the other hand, we put the bar intentionally low to be good safety surveillors, right? We don't say, "Oh, unless this big, dramatic event has happened, we don't want to hear from you." It's the other way around. Every small thing, we want you to report. But be aware that in the vast majority, things may be very coincidental.

Now, there were certain things that really came into the public and caused concern in people who were already vaccinated or those planning to get vaccinated. For example, myocarditis. What is your take on that after COVID vaccine?

Dr Bonanni: Yes, we know that myocarditis is not so frequent. It's rare in the pediatric population, and when it occurs, we can find the presence of some viruses, like enterovirus, adenovirus, parvovirus B19, Epstein-Barr, and so on. But when the COVID pandemic started, we very early understood that the multisystem inflammatory syndrome in children linked to SARS-CoV-2 was one of the causes of myocarditis.

And we have to also understand the numbers. Because there were about 192 million people who received a total of 354 million COVID-19 vaccines based on the mRNA technology, so an impressive number in the short time. And there were only less than 2000 reports of myocarditis, and only in 1600 cases, the report met the definition of myocarditis. This occurred mainly in the young male population. The median age was 21 years, and the median time from the vaccination to the onset of symptoms was 2 days on average.

Dr Rath: And it's a population that usually doesn't go see the doctor.

Dr Bonanni: So they were mainly male because they were 82% male. And the peak of this occurrence of postvaccination myocarditis was in those who were 16 years old. So it was between 12 and 24 years, with an incidence that was between 5200 per million doses, which is rare, we can say. But all the same, we have to concentrate and to understand well what is happening with those cases.

So what happened with these cases was that between December 2020 and August 2021, there were around 800 cases of myocarditis among those under 30 years. They had troponin levels which were higher than normal; 72% had abnormal electrocardiogram, and 72% also had a magnetic resonance which was not normal for the heart. But very reassuring was that 96% of people were hospitalized, but 87% of them had a resolution very, very quickly, and the most common treatment for these cases was nonsteroidal anti-inflammatory drugs.

The other experience that we had with these cases was that while when you have a classical myocarditis, you have a long time to recover and a long time to go back to the normal ejection fraction of the heart, in these cases, in the postvaccination cases, it took 1 to 2 days to go back to the normal ejection fraction. So it means that not only this is not very frequent, but it's also a very mild case of myocarditis after vaccination.

So we can say for sure that the ratio of benefits to risks is much, much more favorable than not being vaccinated, because we have to remember that myocarditis can occur during COVID-19.

Dr Rath: It can occur in the context of most viral infections, in fact, especially in the pediatric population, exactly. And again, I am not sure how good our baseline numbers are, in fact.

Dr Bonanni: Yes. So, in summary, we can say that a significantly higher risk of getting myocarditis from SARS-CoV-2 infection is there compared to COVID-19 vaccine administration, and most cases of myocarditis following COVID-19 vaccines are mild and self-limiting.

Dr Rath: So as you mentioned before, there are a number of AEFI where you can document the physical finding by measuring ejection fraction with an echocardiogram or with imaging procedures, etc. What's more difficult, I think, are psychological adverse events following immunization. Things where people report on a mood change, or some level of anxiety. What's your experience with that, Federico?

Dr Martinón-Torres: Well, I think that the stress-related immunization reactions are a well-defined group of AEFIs, very well-defined and very important group. There are many factors surrounding the actual case of an immunization or stress-related reaction after immunization that it may take us all of the day to discuss. But I think it's important to keep in mind that this happens, and happens quite often, and it's important to distinguish these specific AEFIs, because the management and the prognosis is totally different than the alternative differential that we may have.

It's very common after vaccination to suffer from fainting, hyperventilation, even compulsions, what it's called hypoxic seizures, or vomiting, among other reactions to the immunization itself, to the stress of the immunization. This is particularly frequent in children in adolescent age, but also this can go beyond, and lead to rumors and to mass reaction when these situations, these specific reactions, are witnessed by other vaccinees, or the situation is spread through social media or through Twitter or the internet or the press, which can generate a true cluster of stress-related disorders related to immunization.

So I think that the most important thing to do in this regard is to prevent them. Because most of the immunization events that are related to stress, related to anxiety, can be prevented with adequate measures before vaccination. From the position to adequate information, to their risk assessment of the specific vaccine. You can perceive in the clinic if the patient is nervous or if the person is prone to, I don't know, to faint or if he has already antecedents of syncope.

So these are important things that we can already understand in the anamnesis before vaccination. But it's also important to vaccinate the patient in a lying down or sitting position, and to do the vaccination in the proper conditions to ensure the safety of the patient, and very importantly, to observe the patient for at least 15 minutes after vaccination. With all these measures, you can really decrease, dramatically decrease, the possibilities, the odds, of witnessing stress-related immunization reactions.

Dr Rath: I think as pediatricians, we may be more familiar with this concept, but there's this whole setting in which you vaccinate, and I think we need to spend more time thinking about how we create a comfortable setting that's not threatening. So you have to work with the family also, to prepare them. When they come in for the visit, let's be relaxed. Let's not have too much of a waiting period. Let's create a situation where this is a comfortable place. I don't appear rushed as a physician. I answer questions, I listen.

If we talk about these risks, what I found interesting during the pandemic is that suddenly in my coffee shop, there wasn't just the question, "Did you get the COVID vaccine, yes or no?" It was the question, "Which vaccine did you get?" Particularly because mRNA vaccines were brand new as a vaccine design, as a revolutionary step forward, even though this was the result of decades of research into mRNA vaccines, which most people didn't know.

So, what in your mind is the risk of an mRNA vaccine, as opposed to a non-mRNA, conventional vaccine, let's say?

Dr Martinón-Torres: Well, I'd say that although new, the mRNA vaccines are no different in terms of safety as compared to, let's say the classical vaccines. We have been discussing this already today. Billions of doses administered, globally at the same time and everywhere with different surveillance systems. So I think it's very reassuring all the information we have after billions of doses in a short period of time, repeated doses, and the message is the same. These vaccines are safe, and they can actually have rare adverse events like any other vaccine, any biological product, but not at a different rate than the conventional, let's say, or more classical vaccine approaches. What we can expect is reactogenicity and the usual self-limited events.

As a matter of fact, if we really focus on the very severe adverse events that have been described and accepted to be related to COVID-19 vaccines, there's a very short list. And in many cases these will be the usual that you can find very rarely also for other vaccines, like anaphylaxis or thrombosis with thrombocytopenia syndrome. Some cases described, as Paolo has been already discussing, myocarditis with some of the vaccines in a specific condition in very low rates, Guillain[-Barré] syndrome, capillary leak syndrome.

The thing is that totally, they are very rare, a very low rate of adverse events. Well described, not during the clinical trials, but after the rollout and the implementation of billions of doses.

Dr Bonanni: Let me make a comment on anaphylaxis, because we have also to understand that when you speak about anaphylaxis, when you are anaphylactic, you have an anaphylactic reaction after a bite of an insect, you are on a mountain and you are in trouble there. But when we have a very rare anaphylactic case during vaccination, we are ready to fight that. So that there are no deaths after anaphylactic reaction, even if they are very rare. I haven't heard of an anaphylactic death in Italy for the last 40 years after vaccination, while I have heard of people who died after a bite of a wasp or something like that. So it's a totally different situation.

Dr Martinón-Torres: No, I think it's a very good point, and I agree that these contraindications are very rare. Most of the times what we'll be facing are relative contraindications or precautions to vaccinate that you can't really understand looking at the label of the vaccine, talking with the patient, and trying to establish the risk-benefit ratio for that particular individual to vaccinate. But as a default in general, vaccination always has more benefits than risk, and this is what we need to keep in mind.

Dr Rath: Physicians often think that if they mention even the remote chance of an AEFI to their patient while they're giving the vaccine consultation, that this may scare their patient away. Research has shown that it's exactly the opposite. The more I'm upfront with things and tell people, "Okay, this is this rare," compared to, let's say, a Lotto win or something else that you can put into perspective, "and this is what we do if, and this is what you will do if," then people feel confident, they understand that you've been open and upfront with things, and they don't feel like you're withholding information.

So from a risk communication viewpoint, being honest and well informed and well trained as a clinician always pays off.

Dr Martinón-Torres: Well, but sometimes it's also a question of probabilities and perceptions, no? Because I think we discussed that when you take a paracetamol, you are taking a risk of 5% bleeding in your stomach, and you don't consider that, you just take your acetaminophen. And your chances of having a thrombotic event with the COVID vaccine is 1 in 300,000 to 1 in a million. And despite that, vaccines have included that possibility into their labels, and has really blocked or impacted the rollout of these vaccines in Europe and in many areas of the world.

And we have to be ready for more alarms. As this evolves, new warnings or new safety signals may arise, not necessarily evidence based, and we have to carefully approach them, and as healthcare providers, to analyze them carefully. We know that there will be transparent information coming from the regulatory agencies. If it is necessary, the labels of the vaccines will be updated accordingly.

But in the meanwhile, we have to really transmit calm to the population, to the vaccinees. Otherwise what can be just a rumor or just a coincidental event can really lead to a problem in vaccine trust and can really block the rollout of the vaccines. So we have to be very careful how we deal with our daily AEFIs and how we interpret the cases we see of potential adverse events during our clinical practice.

Dr Rath: So what should physicians be worried about in clinical practice now, in conclusion?

Dr Martinón-Torres: Well, I think that if we need to some take-home messages of what we have been discussing, it's that adverse events following immunization can happen anytime, anywhere, and it's part of our duty to be alert and to try to understand.

Most of the times they will be self-limited, short-term, reactogenic problems, but there may be true, serious adverse events, or really even rare adverse events, and they are well described. And even we have to report it, to analyze that, and to have precaution to draw conclusions, with the specific relation that what we are witnessing may be or not related to the vaccine itself.

I think that after the experience we have accumulated during these years, we know that vaccine trust is a very valuable thing. Before the pandemic was already in the top 10 list of WHO threats to global health, and all the rumors, all the noise that something comes from safety silos or some hesitant or antivaccine lobby, etc, messages can really be difficult and diminish the rollout of any vaccine, and also specifically COVID-19 vaccines.

Dr Rath: WHO has summarized a number of key messages of COVID-19 vaccine safety. Would you want to give the audience a summary?

Dr Martinón-Torres: Sure. I think that after the extensive review and the accumulated evidence we have so far, the top 10 or the top 5 messages are first that the serious reactions are really, really very rare, and treatable when they're diagnosed early. Paolo mentioned a good example. When anaphylaxis happens following vaccination, it happens in the clinical side, so you are ready to treat it.

That the benefits of COVID vaccines really outweigh by far the risk, even the risk that have been ascertained and detected related to the vaccination. That the risks are higher, always, with COVID-19 disease than following vaccination. Even for those rare events, we mentioned myocarditis and Paolo discussed that, but other rare adverse events that we just mentioned, and that could be related to vaccine, are more frequent when you suffer the natural disease than when you are vaccinated. So again, the benefits are clearly balancing towards vaccination.

And that serious adverse events may happen, even rarely, and when this happens, they may contraindicate the vaccine in those specific subjects, but in those subjects you may have also the chances of alternative vaccines from different platforms to get them vaccinated. So I think as a method, COVID-19 vaccines are as safe as any other vaccine.

Dr Rath: As I said to patients during the pandemic, there's not a world without COVID. You're in a world with COVID, and you pick your choices of how to get through that most safely, and that's what you just said very nicely.

So in summary, just remember that proactive communication is important. Ask where you have questions, go to the literature, talk to regulatory agencies if you're uncertain. Distinguish adverse events following immunization from coincidence, and especially first and foremost, remember that good pharmacovigilance starts with a vigilant physician, and that's you.

We thank you very much for your attention, and especially I'm thanking both the experts who were invited today for their lively comments and informed teachings today. Thank you very much, and thank you for participating in this activity. We look forward to discussing this a bit more in the future. Thank you.

This transcript has not been copyedited.

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