As Colorado’s High Ozone and Air Pollution Days Climb, So Do Health Dangers

On this episode, Fernando Holguin, MD, professor of medicine and 
pediatrics in the Division of Pulmonary Sciences and Critical Care Medicine 
at the University of Colorado School of Medicine, shares insights into the 
health risks posed by increasing levels of air pollution. Dr. Holguin talks 
about what happens when people are exposed to fine particulate matter, 
how socioeconomic disparities contribute to greater exposure to air 
pollution, coexisting conditions that put people at higher risk of being 
affected by air pollution, the relationship between the gut microbiome and 
lung health, and the ways climate change impacts cardiovascular and 
respiratory diseases.

Transcript

Chris Casey:

Welcome to another episode of Health Science Radio where we talk with researchers at the University of Colorado Anschutz Medical Campus about the ways they are innovating and advancing healthcare. My name is Chris Casey, and I'm the director of digital storytelling in the Office of Communications at CU Anschutz. It's a pleasure as always to be joined by Dr. Thomas Flaig, our Vice Chancellor for research, here in our studio in the historic Fitzsimons Building.

Dr. Thomas Flaig:

It's good to be here, sir.

Chris Casey:

How are you today?

Dr. Thomas Flaig:

I'm very well today, thank you.

Chris Casey:

Very good, very good. Well, we have beautiful conditions outside today, nice kind of almost fall day, but we will be talking today about air quality, an issue that affects nearly all of us. And we'll be talking about the increasing problem of air pollution and the danger it poses to public health. Our guest is Dr. Fernando Holguin, a Pulmonologist and Professor of Medicine and Pediatrics in the division of Pulmonary Sciences and Critical Care Medicine at CU Anschutz. He is the pulmonary division head at the University of Colorado School of Medicine.

Dr. Holguin grew up in Mexico and became a physician in Mexico City. He moved to the United States to train in internal medicine, pulmonology and critical care at Emory University in Atlanta. Dr. Holguin joined the faculty at the CU School of Medicine in 2016. He is director of the University of Colorado Asthma Research and Education program, which primarily focuses on understanding how obesity and changes in metabolism influence airway function in asthma. Dr. Holguin is also currently serving as the co-chair of the American Thoracic Society and European Respiratory Society task force on severe asthma. He has authored or co-authored more than 170 papers, and is internationally known for his research on asthma, COPD and air pollution. Tom, would you like to take us away?

Dr. Thomas Flaig:

Absolutely, I've been looking forward to this topic. So here we are, as you mentioned, the historic Fitzsimons building in the beautiful Rocky Mountain West, and many of us live in this part of the country and enjoy the outdoors and being outside. It seems to me over the last few years in our neck of the woods, there's been more and more focus on air quality and wildfires to some extent. But just more broadly, is it safe to be outside? Am I in a high-risk patient population? Can a young runner go and run 10 miles safely today, or do we have to cancel the track meet and the cross-country meets, all these different things happen. So, it'd be very interesting to get your perspective. Do you think this is a local phenomenon? Is it more broad or what's been happening to our air quality in the Colorado area and more broadly?

Dr. Fernando Holguin:

It's a great question. Thank you Tom, and thank you Chris for inviting me, it's a pleasure to be here with you today. I think it's both things, Tom. It's a broad phenomenon, but it's also a local phenomenon. Broad in the sense that Denver, like most other major cities, I think suffers from vehicle induced air pollution and other emission sources, so we have a high ozone particulate base like most places, particularly in the summer when it's hot, and in the winter with particulate matter when it's cold. But we also get these additional exposures that come from the forest fires that bring a very heavy exposure in terms of particulate matter.

Now, particulate matter, it's small particles that are many times smaller than human hair, that can come deeply into your lungs and cause all kinds of problems, including inflammation. Beyond that, Tom, one of the things that particulate matter does is not only affects the lungs, but it can affect your cardiovascular system as well. So these things have a wide range of health effects in human population. So unfortunately for Colorado, we have sort of a double whammy – both the city and the pollution that it produces, and also what comes from the fires.

Dr. Thomas Flaig:

How do we measure air quality? And as we're talking about, you mentioned particulate matter, sometimes we hear ozone reported, how do we think about air quality and measure that?

Dr. Fernando Holguin:

It's a great question. The Environmental Protection Agency has a set of pollutants that are called criteria air pollutants that it monitors pretty carefully. And we have national standards both for daily averages and for annual metrics that are thought to protect health. And this include things like particulate matter, both fine and larger particulate matter, nitrogen dioxide, also sulfur dioxide and other pollutants.

So those are monitored throughout the United States and in many different parts of the country. So many cities utilize that information to create these composite indices that are called air quality metrics, that you can see through apps, or on the radio, on the newspaper that you can use, because they usually use colors. So for example, green, it's a great day to go outside and exercise, whereas if it's yellow you have to be careful, particularly if you are someone in a sensitive group, like if you have cardiovascular disease, or if you have lung disease. And if it's red, you may be one of those individuals that needs to consider staying indoors where there's less air pollution exposure.

Dr. Thomas Flaig:

Let me build on one thing you said there. You talked about those green days where the air quality is good. And we're going to talk about different groups, perhaps to higher risk groups, those with cardiovascular disease or asthma. But what about a healthy person who wants to go out and run on a particular day, and it's a yellow or other day, right? Someone that's not at risk with these comorbid diseases. How do you think about advising people in that situation – healthy people on a less than optimal day?

Dr. Fernando Holguin:

It's a very, very interesting question. And I think that’s a question for which the public health systems don't have a great explanation in how to best protect people, because it's a complicated question. If you look at whether people get sick or not from air pollution, there's a lot of variable responses. There's people that are more sensitive to it and people that are not, and I'm talking people without lung diseases, who for example have a cough, they sneeze, their eyes get irritated. And in the same exposure or situation, somebody else may have no symptoms. So I think it's important for people to think whether or not when the air pollution is elevated, whether or not they experience any type of symptoms. If they do, that means that they're more susceptible to it. By that I mean like a little bit of cough or throat discomfort, or difficulty breathing. Those people should probably avoid exercising on high air pollution days.

Now, if we get in situations like we did a few years ago where the sky was orange, and we had massive air pollution coming from California, and the mountains. When we get to those high degrees, Tom, it's probably advisable for everyone not to be exercising outdoors. So you have to use some degree of rationale in evaluating what the situation is on a day-to-day basis, which is not a perfect public health message, it's not a white and black phenomenon. You have to just see how bad it is and how you feel in relation to those exposure days.

Dr. Thomas Flaig:

I'm glad you mentioned the wildfires, which are certainly a phenomenon in the West, but I've had some colleagues the last few years on the East Coast, for example. They've experienced some of those similar high forest fire (pollution) sort of days.

Dr. Fernando Holguin:

And one of the things that pollution (discussion) misses, Tom, that's important is a lot of the pollutants that we measure are called background air pollutants. So they're in the atmosphere more diffusely across a large geographical area. But there are other sources of exposure that are also very important that are perhaps more dangerous – proximity to the source. So for example, people that are right next to where the trees are burning, or they're exposed to different kinds of particulate matter, and high concentration of carbon monoxide, it could be more dangerous. Or people, for example, that live near freeways and thoroughfares where there's a lot of traffic, there's very good literature about cancer, cardiovascular disease, and respiratory disease in relation to proximity to traffic. So these things: one pollutant is not the same across the board; it depends on how you are in relation to where it is being emitted.

Dr. Thomas Flaig:

Very interesting. Go back for a second to the healthy individual – no lung disease, no cardiovascular disease. I think the message there is you have to individualize it how you respond to the conditions at the time.

Dr. Fernando Holguin:

You do.

Dr. Thomas Flaig:

One question I've heard or thought about is, so it's a medium day, it's not a perfect day, it's not dreadful. Is it better to go for a jog, better to walk? Can the healthy person moderate their exercise intensity to help with some of the potential symptomology?

Dr. Fernando Holguin:

I don't think we really know, Tom. The more you exercise, for example, a normal person like you and I talking in this room, we're breathing in and out six to eight to 10 liters per minute of air. When you go and exercise and run, depending on how fit you are as well, you could be breathing in 30, 40 liters per minute. So that by itself means that you're getting exposed to a much, much larger concentration of pollutants just by how much air you're breathing in and out of your lungs. So it would be advisable not to be engaging in very heavy exercises when the air pollution is bad. There is data, there are studies coming out, for example, from California, the 12 community studies where they showed that particularly in younger kids, that high intensity exercise during high ozone days was associated with increased risk for developing asthma, for example. So these things, they play along with each other. Now, for a particular person, what that particular person's risk are is hard to tell.

Chris Casey:

And when people are out there and exposed to particulate matter, Fernando, and you mentioned some of the symptoms, they'll be coughing, or maybe they just notice it's a little harder to breathe. Can you explain a bit deeper as to physiologically what's happening? Is it an inflammation response that's occurring in the lungs?

Dr. Fernando Holguin:

It's a great question, Chris, it's a complex phenomenon. So it depends on the pollutant, but for example, ozone, it's a very powerful oxidant. When it gets into your lungs, it's buffered by some of the pulmonary antioxidants, but it can cause damage and that could lead to acute inflammation, and changes in airway caliber, which could cause feeling a little bit wheezy or chest tightness, particularly people with sensitive disease. But they're also more of, after a high air pollution day, if you look at the epidemiology, the number of emergency room visits related to that event can occur on the day, but also days later.

Which means that you go and you exercise, and you start to build some degree of inflammation that can lead to disease manifestation even a few days later. And so it's a complex phenomenon of inflammation and oxidation, and how much air pollution mixture you’re inhaling may depend on the type of symptoms you eventually develop.

Chris Casey:

And you touched on people living near very busy highways, their exposure levels are higher. Could you touch on perhaps the issue of lung health, how it appears in health disparity situations? Perhaps people who are living in more congested areas, maybe this is a social determinant of health issue? Is there research that elaborates on any of that?

Dr. Fernando Holguin:

Absolutely Chris, there are a number of recent publications that involve redlining districts. So in the 1930s part of the new initiative, some areas across the cities were deemed less desirable in terms of the government wanting to insure those homes. And so the people that were living there were predominantly minority groups.

Unfortunately, that has not changed over the years. Many of those red zones continue to show a lot of disparities, minority groups that are economically disadvantaged. And the reason shows that those areas are exposed to higher levels of pollutants, higher levels of average temperatures. So a lot of adverse environmental conditions that lead to more disease. Studies coming out of California have shown, for example, that exposures to pollution in these areas lead to much higher rates of emergency visits for asthma and COPD, for example. And people that live, for example, next to a highway have different socioeconomical situations, for example, than people that live farther away and therefore are less exposed. So these things are intertwined unfortunately at many different levels.

Dr. Thomas Flaig:

We've talked a bit about people who have certain medical conditions, cardiovascular disease, asthma. Are there other populations of people – old, young and so forth – that are more at risk, or who have to take more precautions around air quality concerns?

Dr. Fernando Holguin:

Absolutely. As you mentioned, Tom, anybody with lung disease, with cardiovascular disease, but also people at the extremes of ages are people that are more susceptible to air pollution. But even some things that you wouldn't necessarily off the top would consider as risk factors that put you on a different level of being more susceptible to air pollution. Things for example, like diabetes, like obesity, are things that have been looked at as potential comorbidities that could put people at higher risk of being exposed to particles, for example. So the more comorbidities you have in terms of number of diseases that you have, the more you could be affected by air pollution. And some of them may not be necessarily obvious.

Dr. Thomas Flaig:

And you spoke a bit about the process of the lung damage or injury that can occur here, so it can take several days to sort of manifest clinically. How about the other side of that, the healing process for those people that have undergone lung damage, maybe they're in a smoky area for a prolonged period, and have some inflammation or more chronic issues. Can that revert back to a more normal state, or how does that healing process occur?

Dr. Fernando Holguin:

It's a very good question. So there's data both from lung growth in children, lung function decline in adults. So for lung function, for both of those situations, the slopes of either growth or decline may be affected by air pollution if you are living in an area where air pollution is just a phenomenon that happens on a regular basis. However, if you move away from that city and evidence is showing that if you relocate, for example, your rate of lung growth or lung function decline can become that of a person that's not exposed to a high level of pollution. Unfortunately, that's not the case for most people, they cannot afford to relocate. It's not like a one day off thing, you would have to move away for a long period of time to get the benefits of not being exposed.

Dr. Thomas Flaig:

Just as an aside, I enjoy history, I think about the history of our medical center and so forth. 100 years ago people came to the Rocky Mountains for lung health. This place was founded here after World War I because of two things: tuberculosis in the soldiers was thought to be better at a higher elevation, but also the chemical lung injury that occurred in the trench warfare. It was also thought as understand it, they would get to the Rocky Mountains in the clear air up here, it would clear and heal their lungs. Whether that's true or not true, that's part of our history of our medical center in this part of the country.

Dr. Fernando Holguin:

What's ironic about it, Tom, now that I'm hearing you talking about it, is that the higher altitude you go, you breathe faster because there's less oxygen. And so if you're breathing faster – to the analogy of exercising – and there's more air pollution, you're getting more exposure.

Chris Casey:

Because we're at a higher altitude, as I understand it, combustion engines have to work harder and therefore they're emitting more pollutants – is that the case?

Dr. Fernando Holguin:

It could be the case for sure.

Chris Casey:

I wonder, Fernando, so the cumulative effects, we talk about these bad air days that people encounter during the summer, and they might try to hedge and avoid exposure. Is there compounding risk there that they're going to do great damage to themselves just by the cumulative effect? And are we entering a period maybe where communities are just chronically at risk?

Dr. Fernando Holguin:

I think over the years, and again, it's hard to be very specific about it because I think there's a lot of variability in the degree of susceptibility that people have to these exposures. But studies have shown that, for example, years of exposure to these particles are associated with a small percentual risk in increase of lung cancer. But again, the exposure is more broadly, so it becomes a really large public health (concern). Because it's not like smoking where it's much of a greater risk, but less people are smoking. Here, everybody's breathing the same air. So even though it's much smaller in proportion, it's a major public health issue. There's very good data on the development of chronic obstructive lung disease over time. So all these things eventually, for some people, will accumulate and lead to chronic lung diseases.

Chris Casey:

Is there any data out there about how climate change is, we touched on things, but climate change could be contributing – like through these ozone days that we have frequently in the Denver area?

Dr. Fernando Holguin:

So a lot of the ozone is generated both through primarily emission particle, but also through chemical reactions of particles in the air when they get exposed to sunlight. So it's primary and secondary generation of ozone. And so that's why we tend to have very high ozone days through nitrogen dioxide, eventually ozone production. So that always is going to be great in the summer when there's heat and there's sunlight, and ozone will lead to all kinds of lung diseases and problems down the road. But also heat itself, independent of air pollution, is associated with increased risk for COPD, chronic obstructive lung disease exacerbation and asthma problems. And so global warming is a major problem for cardiovascular and respiratory diseases over time.

Dr. Thomas Flaig:

What can we do? What can people do? What can we do more broadly to try to curb some of the air quality issues we're talking about, any sense of that aspect?

Dr. Fernando Holguin:

We can try to be more environmentally conscious and use our car less, commute together, use public transportation, ride a bike, use an electric vehicle. There's ways that we can try to reduce our carbon footprint, I think that's important. From a protection perspective, it's complicated because we don't have great ways, from a medicine perspective, like take this pill, or take this vitamin, or take this inhaler, it's going to protect you. The level of data and science is not there yet. So aside from being indoors and getting protected, that's really the only thing we can do for people that are very vulnerable. And that has issues that relate Chris to your question, because poor housing, for example, has very high coefficient of filtration of particles. We recently completed a study here on Colfax (Avenue) with Children's (Hospital Colorado) where we measured air pollutants on Colfax.

Both in many of the motels that are used as housing units on Colfax and single unit facilities, and found that very high levels of carbon-related particles get inside that are being emitted from just Colfax traffic. So if you're in a poor housing condition and you're telling a patient stay indoors, that may not be as great as somebody who's living in a more affluent place where the houses are newer, well-sealed, air-conditioned, where the levels of ozone and particles are really lower inside. So a lot of things, and certainly things that we can all do is don't smoke, don't vape, don't generate other things that are known sources of pollution directly to your lungs, or to other people that are being exposed passively.

Dr. Thomas Flaig:

On those really smoky days we have sometimes, we haven't had too many this year, I'm tempted to put a mask on or just wonder if wearing something on my face would help if I'm out going for a walk or something. On the individual level, do any of those things help at all, do you recommend them, not useful?

Dr. Fernando Holguin:

It would help, depending on type of mask, but if you think about it, the particles, the fine particulate matter that causes harm, is 2-1/2 microns in diameter. So for example, a regular surgical mask is not going to protect you. You would have to have one of those K99 masks that are below 2-1/2 micron protection, which is very uncomfortable to be using outdoors. So for the most part, you go to a place where some people are using the typical surgical masks, those will only protect you to like large dust, pollen type of things, but not for these select particles, or fine particles, or ozone for that matter.

Dr. Thomas Flaig:

It's really helpful to hear that. That makes sense, certainly.

Chris Casey:

With the advent of machine learning and AI that's having sweeping effects on healthcare and research these days, from what you've observed Fernando, is there any way that machine learning or AI could be applied to the study of air pollution, and it's threat to public health, and perhaps yield some sort of solutions down the road?

Dr. Fernando Holguin:

My short answer would be, I sure hope so. I'm not aware of any literature, but I think it may be useful when it comes to a point of trying to understand from a larger perspective, how do we reduce what people call the air pollution emission inventory, which is how much millions of gallons of pollutants and pounds of pollutants, are produced per unit of time. And I think that at the end of the day, the only way to successfully improve health is by reducing emissions. But unfortunately, you get to a point, this is a struggle, right? In order for industry and commerce to move, you generate pollution. So that means that in order for you for us to come to work and do work, we are generating some level of pollution. At some point, for example, the EPA levels that are assumed to be safe for human health – the relationship between exposure and disease is linear – so that means that there's events that are happening below those thresholds, but you have to keep the economies moving. So the point is to the AI is how little, in essence with protecting the economy, can we or should we tolerate for human health? It's a very difficult question.

Dr. Thomas Flaig:

So you are a very active investigator, and researcher, and do a lot of work in this area. What do you think are some of the most pressing research questions that you're pursuing or the broader field is looking at right now?

Dr. Fernando Holguin:

Yeah, thanks Tom. To me, I think a little bit about air pollution from a clinical researcher perspective. We should be doing more research trying to understand what level of interventions that are safe and affordable, protect people directly. I've been involved in studies where we gave people supplementation – antioxidants or omega-three fatty acids – and published those results and show some level of benefit to reducing cardiovascular effects, pollutants or respiratory effects of pollutants. But many of those studies have been small and not replicated at a much broader scale. So it would be really nice to know, let’s say on higher pollution days, if you take X, your level of risk goes down. We need to understand even basic things, Tom, for example, I'm an asthma doctor, and my patients ask me questions like, "Well, when there's air pollution days, should I be inhaling more of my medications?" And it makes sense, but the data is very unconvincing that that's an adequate protection strategy. So it may not be the best thing for people to take more inhaled steroids, for example, during high ozone days. We just don't know. It does not appear to be that that's very protective as we thought it would be, based on some of our literature that we're producing. So it's a complicated question. I would love to see more individual risk assessment – outside the obvious trends – for people that are otherwise healthy. Some of the studies that are being done by Dr. (Anthony) Gerber at National Jewish are trying to identify common polymorphisms or changes in your DNA that could potentially put you at risk for different types of pollutants. Because then you can identify people much more broadly that are on a higher risk category and they don't know it. And then maybe that's the kind of people you want to develop some interventions to protect them, but we're not there yet.

Dr. Thomas Flaig:

Has there been a lot of investigation into some of these home air filtration devices? Do any of those individual home filtration devices provide any benefit in the research?

Dr. Fernando Holguin:

They do, but it has to be the correct one. So there's a lot of air purifiers that work through electrostatic chargers that you have to plug them in. Those typically are not preferred because they can produce ozone, secondary ozone generation.

Dr. Thomas Flaig:

Oh, interesting.

Dr. Fernando Holguin:

But if you take a HEPA filter, which is what's in some certified vacuums, for example, that filter traps all the particles. So if you take a HEPA filter and you put it on a fan, and the fan sucks air from your room and makes it go through the filter, it reduces overall the burden of particle exposure, especially in the room where you're sleeping. And data from our colleagues at (Johns) Hopkins, Nadia Hansel, who's now the chair of medicine there, has published results that, in people with chronic lung diseases, that it improves health. And those are actually fairly inexpensive to do.

Dr. Thomas Flaig:

Yeah, right.

Dr. Fernando Holguin:

They actually just took a large fan and put a cardboard box, and attached a filter behind it, and then turned it on, and that was sufficient to reduce burden of particle exposure. So it doesn't have to be something very expensive.

Chris Casey:

And you I know you've done a fair amount of research into looking at the relationship of the microbiome, nutrition and asthma, or lung function. Could you talk about any particular highlights of the research you've done into that area, and just how gut microbiome could play into lung function?

Dr. Fernando Holguin:

It's a good question, Chris. The microbiome is obviously very complicated and involves understanding of not the actual particular bacteria, but the group of taxa, the different bacteria. And we have thought for the longest time that the lungs, particularly lower airways, were sterile. But they in fact are not. There's actually colonies, there's microbiome in there – although to a much lesser extent than other parts of the bodies. And we've published results in the past showing that, for example, chronic allergy or certain types of asthma associated with lack of diversity of those microbiome, those taxa. So it could be associated with changes in lung function and outcomes, but we don't know how to necessarily manipulate it. So we know it happens, but it's a hard relationship to understand.

What we do know is that changes in nutrition by way of people gaining weight or becoming obese is associated with worse asthma outcomes, less response to therapy, and also increased susceptibility to air pollution. There's very good data showing that obese subjects are more susceptible to ozone, for example, and that may be because they have more propensity to suffer from oxidant damage. So all these things are all linked together, (including) diet. People say that you are what you eat, but (also) you are what you breathe at some point. It's all combined.

Dr. Thomas Flaig:

It's interesting to hear about the microbiome, we think so much about that in the GI tract, but less about the pulmonary system. But I guess it's an important component there as well.

Dr. Fernando Holguin:

It's an important component, and there's actually research going into what people call the gut-lung axis. So there's changes in the microbiome of the gut that can affect lung function, and that comes up, not going into details, and we've put out research that shows that different types of microbiome produces different types of changes in your bile acid composition. And bile acid composition, per se, can affect the lung function. There are just all kinds of ramifications. So now there's undergoing manipulation, so whether or not if you change your gut microbiome, you could improve lung health. I think that's not really known … but an interesting question, per se.

Dr. Thomas Flaig:

Yeah, the microbiome, when it first emerged a number of years ago and became more of a research topic, you sort of wonder where it was going to go. And it just continues to be relevant to what we're doing. As an oncologist, I think about checkpoint inhibitors, like the microbiome, how that could affect some of these immune agents we're giving patients, and now you're talking about the connection with the lungs. So there's just a lot to that story.

Dr. Fernando Holguin:

Don't they say that we have more cells that are in our microbiome than our own cells? It's just that we depend on this colonies for health.

Chris Casey:

Fascinating information. Thank you for the education on the pulmonary effects of air pollution, Fernando, I appreciate it, and I've learned a lot. Thank you for sharing your expertise.

Dr. Fernando Holguin:

Thanks for the invitation.

Dr. Thomas Flaig:

Wonder if I could just state one thing at the end here. So we've talked about kind of like the take-home message. Let's think about the healthy (people) without any lung disease who are active, what's the take-home message as they think about air pollution and activity outside and exercising?

Dr. Fernando Holguin:

If you really want to minimize your exposure, try to exercise (indoors). If you look at the trends or air quality index in your city, depending on where you are and which season you are in, you can probably target your exercise in areas where there's less air pollution.

So for example, if you're in an area where there's a lot of ozone, typically the ozone peaks occur early in the afternoon for different cities. So you may want to run early in the mornings, but if you're an area in which it's in the winter and there's inversion, you're going to have high particulates early in the morning, and you may want to run later in the day. There's a lot of apps where you can actually look at the trends over time, so you want to target doing exercise in a time in which you're exposed less.

Dr. Thomas Flaig:

Guess the take home there is to be engaged, right? Think about the conditions, when's the optimal time and just be thoughtful about it.

Dr. Fernando Holguin:

It's the reality of our time.

Dr. Thomas Flaig:

And the take home message for those that are at risk – how would you have them think about air pollution, for those with asthma or other risk factors?

Dr. Fernando Holguin:

Many of my patients have lung disease. If you're sensitive, most people know it. Most people sort of figure out that you pay attention to the news and when the fires are coming, or when the pollution is happening, and stay indoors. Stay indoors and stay properly medicated. I think another point, too, is to be well vaccinated, because the combination of pollution and – having at the same time – a viral infection can be a really bad combo for lung disease. So you want to minimize how those exposures work together.

Dr. Thomas Flaig:

Great conversation today.

Chris Casey:

Yes. Thank you very much, Fernando. We appreciate it.

Dr. Fernando Holguin:

Thanks for the invitation. Enjoyed it.