 We're going to talk about sun. Exposures impact on health and go through this in an evidence-based fashion. One of the things that I find constantly challenging with information, which is plentiful, is it's hard to get a non-bias view. You've probably heard people say, there's never been one study that showed that sunscreen protects against cancer. Or you've probably heard people make the opposite, where cancer clearly causes cancer. You hear all these extreme positions and it's hard to know where the truth actually lies. I'm hoping to uncover some of that today by navigating some of the nuance of this topic. So the outline, we'll cover the health benefits, the risks. Briefly I'll touch on vitamin D not being a substitute for sun exposure. We'll lay out some guidelines for safe sun exposure and briefly we'll touch on tanning beds. The brief part is because there's time limitations today and while I wish I could go into everything in a detail, we have to pick our battles here. So first paper, I should show you the abstract first. Great paper by Michael Holick's group, Michael Holwick and Marianne Berwick, both who have been on the podcast, both who I felt did a fantastic interview. This is their paper, The Risks and Benefits of Sun Exposure and there are several main points I want to highlight for you. To quote, studies that have shown a wide range of health benefits from sun slash UV exposure. These benefits include, among others, various types of cancer, cardiovascular disease, Alzheimer's disease dementia, myopia, macular degeneration, diabetes and multiple sclerosis. So we see there's a number of conditions that can be protected from sun exposure, from obtaining sun exposure. Now in terms of ideal levels, they recommend 4 to 60 in this paper. And they also, to quote, it is apparent that vitamin D supplements are not an effective substitute for adequate sun exposure and we'll fill some of the justification for that statement in a little later in the presentation. Now here's where we start seeing a hint at some of the guidelines. White people type 2 skin, type 2 means you almost always burn and rarely tan. So this would be the lowest dose of sun exposure. At 40 degrees latitude, approximately US-ish range, mid-north US can obtain their annual requirements of vitamin D by spending about 15 minutes in the sun with face, arms and legs exposed, half that time if you're in a bathing suit, two to three times a week between 11 and three. So this seems reasonable, right? Is this an hour a day? No. But is this complete avoidance? No. Now remember that this is for the most sensitive skin type. So for the non-sensitive skin types, it will be slightly more than this. People with darker skin require more time in the sun. So let's go through some of their additional results. Melanoma, the most dangerous form of skin cancer. Non-burning sun exposure reduces risk while burning increases risk. This is where some of the nuance comes in. This shouldn't really be too counter-intuitive. Burning increases risk of skin cancer. What's left out of this often is that the non-burning exposure actually seems to decrease the risk of at least some skin cancers. Sun exposure is associated with a reduced risk of melanoma, while sun burns are associated with a doubling of the risk of melanoma. It has long been observed that outdoor workers have a lower incidence of melanoma than indoor workers, according to a 1997 MET analysis. Sun exposure may protect the skin from cancer because sun exposure leads to the formation of active vitamin D in the skin, which may locally help with DNA repair. The rise in melanoma incidence is likely due to a combination of two factors. Again, this is according to the Burwick-Hollick paper, so I'm just kind of paraphrasing for you. One, less chronic non-burning exposure to the sun, plus increased bouts of high exposure and burning as in non-vacations. So we no longer condition our skin with chronic non-burning exposure, but rather overexposed non-conditioned skin episodically. Does that make sense? Yeah. Almost like your weekend warrior injury mentality, you don't stay fit, you go and you go nuts once in a great while, you blow out your knee, you pull your hamstring. Okay, what about non-melanoma skin cancer? This is a critical distinction. While non-burning sun exposure is associated with a decreased risk of melanoma, it appears it may increase the risk of squamous cell and basal cell carcinoma. However, not all the data here agree, some studies show no association, and the relationship between sun exposure and non-melanoma skin cancer is not entirely clear. So this is where some of the anti-sun camp will pull their supports from, and they're not wrong, but they're also not right, so there's a nuance here, and we'll develop some of that nuance here in a moment. In the same Hollick-Burwick paper, this was the only factor, non-melanoma skin cancer, that showed an increased risk associated with sun exposure. All other measured parameters actually decreased in incidence upon sun exposure. And there's the quote supporting that for you. Okay, so we're going to circle back to skin cancers a bit more in a moment, but just kind of starting off with this broad overview laid out by the Hollick and Burwick paper, let's talk about all-cause mortality. A 20-year follow-up study found avoiding the sun increased all-cause mortality, those avoiding the sun had nearly a two-fold increase in mortality. And then there's the reference, and there's the quote. Another study found that sudden avoidance also increased all-cause mortality to a degree similar to smoking, hence the title of today's talk. And that, I believe, Burwick was one of the main authors on that paper also. Colorectal cancer, there's no consistent effect between sun exposure, nor vitamin D supplementation, and colorectal cancer. Breast cancer, one meta-analysis showed that a higher blood level of vitamin D was associated with decreased mortality. Two studies have shown that increased sun exposure reduces breast cancer risk. And in some cases, I'll read the quote for you guys, and in other cases, I'll just leave it up there for your own notification. Non-Hodgkin's lymphoma, colorectal cancer, prostate cancer, breast cancer, and multiple sclerosis. There's a lot here, and I'll just summarize this for you. A systematic review concluded the following in short. Sun exposure seems generally protective, and the protective effects are sometimes independent of vitamin D levels or intake. Meaning sun exposure exclusively appears to be responsible for the effect. Cardiovascular disease, two studies have shown sun exposure helps to lower blood pressure independent of vitamin D. And not listed in this same study that I'm outlining for you by Burwick and Hollick, another prospective European cohort study found that latitude was the strongest predictor of carotid artery intima media thickness, which is an independent risk factor for heart disease. Obesity and type 2 diabetes. Sun exposure, not vitamin D levels or supplementation, reduced risk. Again, there's a reference. Multiple sclerosis, again, sun exposure but not vitamin D levels nor supplementation reduced risk. Again, there's your reference supporting that, actually two references. Type 1 diabetes, sun exposure reduces risk, according to a Jacobson study. And liver disease, again, sun exposure but not vitamin D levels or supplementation reduced risk. So this is a great paper by Burwick and Hollick outlining the health benefits of sun exposure that may in part be independent of vitamin D levels. So their conclusion. Insufficient sun exposure has become a major public health problem demanding an immediate change in the current sun avoidance public health advice. The degree of change needed is small but critically important. The public must be advised to obtain enough sun exposure and vitamin D supplementation to maintain a serum 25 hydroxy vitamin D level of at least 30 nanograms. Some clinical takeaways, obtain chronic, non-burning sun exposure as a key practice for optimum health. A vitamin D supplementation may not be an acceptable substitute. It's not to say you can't supplement with vitamin D but you shouldn't only supplement with vitamin D. It should be a union of the two. Obtain at least 15 minutes or more for dark skin types of direct unprotected sun exposure two to three days per week midday during the sunny months. Some caveats apply will develop these momentarily. OK, another paper. Can UV exposure reduce mortality? This was a somewhat infamous now Swedish cohort study following a group of women for 15 years. Their main results, a significant reduction in all-cause mortality and in cardiovascular mortality were associated with several measures of sun exposure. In addition, ultraviolet exposure from tanning beds is associated with a significant increase in all-cause mortality and cancer mortality. Some additional results. Sun exposure, overall mortality was reduced amongst those who had been sunburned two or more times a year as a teenager compared with those who had been sunburned once a year or fewer times. That's a proxy. Sometimes the researchers will use amount of sunburns as a proxy for sun exposure. Overall mortality and cardiovascular disease mortality was reduced among those who had taken sunbathing vacations more than once a year during three decades. Tanning beds, conversely, use once or more per month for at least a decade increased the risk of all-cause mortality compared with those who never used tanning beds. Now, there's also some nuance here that's important, which is unhealthy lifestyle behaviors may accompany tanning bed use, and that may confound the association. And we'll come back to that in a little bit. This is your Jersey Shore, folks. You smoke and drink and party and tan. I'm Italian, so I can say that. It is well established that chronic sun exposure does not increase the risk of developing melanoma, although the mechanisms for that are unclear. So we're starting to see this picture emerge that melanoma seems to be protected. But non-melanoma, there may actually be an increased risk from sun exposure, but it's a little bit less clear. Now, here's another interesting point. The authors make the note that intermittent sun exposure was associated with a 1.6 increased risk of melanoma, while chronic sun exposure is protective. Do you follow that? Now, sometimes the term intermittently is meant to describe people who get somewhat regular sun exposure. And then sometimes, alternatively, it's used to denote someone who only gets sun once in a great while. So we have to be careful with the term intermittent. I'll contextualize it for you as we navigate here through the talk, but I don't want to be overly literal with the use of the term intermittent. So clinical takeaways, sun exposure is protected against death from any cause. Tanning bed use increases the risk of death from any cause. Chronic sun exposure protects from melanoma, intermittent, or not very often, sun exposure increases the risk of melanoma. And then one more study here tying some of the health benefits home. Essentially, this was a North American database looking at the level of UV radiation in certain regions of North America and correlating that with health outcomes. What they found in areas with increasing daily average sunlight. So this is not people reporting their exposure to sun, but this is just looking at different areas of the US that have a higher or lower, I guess you could say, natural levels of sun exposure. Most cancer types see a decreased incidence, and most cancer types show no change in mortality. And here's the data that support that. I'm going to just leave that for if you want to read through it so as not to put anyone to sleep. So let's go through some of the risks. Melanoma is the less common but more dangerous form. The point here, sunburn increases melanoma risk. Here's a systematic review of meta-analysis and the results I'm giving you in the summary. Light complexion equaled increase risk. The following risk factors were identified. Fareskin color, light eye color, propensity towards sunburn. So this suggests that there may be an inverted dose regarding sun exposure and melanoma. Some exposure protective, excessive exposure detrimental. Now what this does is this is a very typical problem you see with arguments in health care, which is there may be a inverted u-distribution of the dose. And so people pick data points from different dosing positions. And then they say, well, look, lots of sun equaled increased melanoma. And then other people who are pro-sun pick studies from the lower end of the dose curve that show protection and say, no, they don't. The sun protects against melanoma. And they argue back and forth. And if we could just step back and approach us with some equanimity, we could see that it's a matter of dose. It's not a matter of absolutes. So seem to suggest that well-conducted studies support the intermittent sun exposure hypothesis. A positive association for intermittent sun exposure, sunburns, and an inverse association with high continuous pattern of sun exposure. So this is where the terminology is a little bit confusing. Essentially what they're saying is if you get a lot of sun, you have protection. If you don't get much sun, you have an increased risk, if that makes sense. You guys following with me? OK, hands up if you're confused. OK, so essentially, the way that researchers are using the term intermittent and chronic isn't always consistent, so it's challenging. But the general theme seems to be showing this inverted u-dose response, where some exposure to the sun, as long as you're having regular exposure to the sun, then that seems to be protective. If you become only occasional with your sun exposure or you start burning often, you see an increased risk of melanoma. Does that make sense? So too much not enough a problem, so the sweet spot, the Goldilocks dose, seems to be protective. And that's kind of the general theme that most of these cancer types seem to follow. Another study here, our results suggest that melanoma development in younger patients is a result of more so genetic factors, whereas in older patients, environmental factors such as severe chronic sun exposure play a major role. Do you see that delineation now? Severe exposure. So you have to really read these studies carefully. This is probably where some of the contention comes from, is if you're just pulling abstracts quickly, it's easy to get misstudied. You really have to slow down and read these things carefully and try to figure out what the dose is meant based upon the language being used. OK, so another point. Sun exposure trends toward protecting against melanoma, whereas data for non-malignant melanoma are a little bit mixed. So remember our simple concept here to summarize this. It seems that as a general rule, the appropriate dose of sun exposure protects against melanoma that likely also holds true for non-malignant melanoma, but the data there are a little bit less clear. There's a little bit more data supporting that the sun may be a detriment toward the progression of non-malignant melanoma. So to summarize again, one more time so we're all on the same page, there's more data showing that sun exposure is protective for melanoma. There's less data showing that sun exposure is protective for non-malignant melanoma. Does that make sense? OK. Now part of the reason why there may be this inconsistent association to non-malignant melanoma might be confounding variables like alcohol consumption and drinking. So this is another challenge, because many of the studies looking at sun exposure are just observational. And we don't know if people who are more prone to drinking and smoking are also more prone to being in the sun. So this has to be included in a regression analysis so that we don't see a false observation coming back to the whole Jersey Shore tanning bed association. So again, coming back to malignant melanoma, lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma. And non-malignant melanoma, lifetime sun exposure was predominantly associated with an increased risk of squamous cell and to a lesser extent, basal cell carcinoma. So again, I'm showing you the nuance here because you need to understand this to be able to navigate this conversation responsibly. There are data showing that sun exposure may be problematic in provocating non-malignant melanoma. That is the thorn in the side of someone who's trying to argue the position that sun is good for you across the board. So hang with me because I want to arm you with the knowledge to be able to have a constructive argument about this. So with melanoma, it's fairly clear the sun protects from melanoma. With non-malignant melanoma, the data are more mixed. So keep those two pillars in your head and we'll keep developing those. So here's the kicker. Statistical significance was not always reached after adjustments in this case for age. So some of this association, so if you're trying to persuade your friend that sun exposure is healthy and they say, well, there's a study that showed that sun exposure increases non-malignant melanoma. One of the things that you can come back with is did they control for the impacts of smoking, age, and alcohol consumption? In this case, age, when that was controlled for, weakened the association, there was no longer that association, all right? Okay, hang with me. I know this is a little bit complicated. So more on non-malignant melanoma. Remember, this is kind of the thorn in the side of the sun advocates. So it's important that we understand this. Point, non-malignant melanoma may also follow this inverted you-dose relationship. Intermittent or weekly sun exposure may protect, burning appears to increase risk. So an intermittent pattern of weekly sun exposure was not associated with squamous cell carcinoma. Three plus blistering sunburns to the site was positively associated, all right? So even though some of the details here are confusing and I wanna provide you those nuances so that you can really have a granular conversation about this, when we zoom way out, that inverted-dose curve seems to also apply for non-malignant melanoma. And interestingly, the use of sunscreens and hats has shown an inconsistent effect. Okay, now to build this inverted you-more, the skin type seems to matter. The darker the skin, the less risk is associated with exposure to the sun. That makes sense, right? I'm sure we all know someone who is very fair-skinned, who's had many things they needed to have burnt off or cut out, right? Because your skin tone dictates how much exposure to sun you need, the darker you are, the more you need. If you're lighter-skinned and you're getting the amount of sun a darker-skinned person should have, you may have gone over the line for that optimum dose. Subjects with pale skin and red hair had an elevated risk of squamous cell carcinoma. Subjects whose mothers were of Southern European ancestry had a reduced risk of squamous cell carcinoma. Are you starting to see some of the nuance here? All right, so the individual matters in this argument, the individual dictates where they should be on the dose curve. After accounting for pigmenting factors, no association was seen between squamous cell carcinoma and cumulative lifetime exposure. Does that make sense? So what they're saying here is once you factor in for someone's skin type, the association is attenuated. Meaning what we were probably seeing was this artifact projected into the data, which is we see this association between sun exposure and skin cancer, but when we parse that out by skin type, that association fades away because it was the highly sensitive people that were skewing the data set, right? It's almost like maybe you could say people who are very much so carbohydrate intolerant would make it look like everyone has to be in a low carbohydrate diet, but when you parse out the people by insulin sensitivity, you can see that insulin sensitive individuals could thrive on a higher carbohydrate diet, whereas insulin resistant people couldn't. So same kind of concept that we're probably used to grappling with in other areas. Another point, exposure in adulthood carries more risk for non-melanoma compared to children. So the age matters, right? And this is true even after adjusting for confounding lifestyle factors. And why might this be? Well, when you're older, your cells are less able to repair. So you can get away with more when you're younger, and this may be comforting to parents. You don't have to chase your kids around with sunblock all the time. I mean, don't be irresponsible either, but the dermis in children may be more protected against just naturally due to age the potential delterious effects of excessive time in the sun. So this study reveals an increase in non-malignant skin cancer risk associated with adult UV exposure with no effect for childhood UV exposure. So I think the implications of this are somewhat important where we don't have to be as concerned with children. Okay. Occupational sun exposure is associated with an increased risk of non-malignant melanoma. So remember, there are data, that's the thorn in the side again, there are these data showing that non-malignant melanoma risk may increase with exposure to the sun, right? But as I mentioned earlier, adjusting for confounding variables may attenuate or make that relationship disappear. And if we focus on, and we look at just those who have fair skin, that may make the association look more severe. Does that make sense? So I'm just kind of, it's the same concept I'm just trying to repeat this because I know it's a little bit hairy, but once you kind of get it, hopefully you won't forget it. Okay. And I'll turn to, like I said a moment ago, when they adjust for smoking, that may seem to attenuate the relationship and there's the references for that. Okay. And here's one more example of adjusting for the confounders. And this was actually in a fairly well-performed meta-analysis. They actually found, and so this is a good counterpoint if you want to argue the other side that sun exposure protects against non-malignant melanoma. When they put this meta-analysis through what's known as a meta-regression, so you take data and if you do a regression, you're controlling for the variables, right? When you do a meta-analysis, analyzing all the data, you do a meta-regression, right? So when they did a meta-regression, when they tried to control for all these factors that may skew the data, they actually found an inverse relationship between sun exposure and non-malignant melanoma. Does that make sense? So the sun protected when there was appropriate adjustment for the confounders. But the reason why I'm giving you kind of both sides of the argument here, and if you're having a little bit of trouble following the argument, I apologize, but I'm trying to articulate, thank you, that there are data on both sides of this argument. So we shouldn't bull into this conversation thinking because you saw one reference supporting what you think that you're completely supported in your position. There are really data on both sides. The most contestable point is with non-malignant melanoma. We've covered data showing that sun exposure increases the risk of non-malignant melanoma, but we've also covered other data that shows that that association may be an artifact of confounding variables like age, smoking, and skin type, all right? So here's kind of what this sums out to. You have your health benefit or your health detriment, and you have increasing sun exposure. Light people will go up and down on the inverted U at an earlier level of sun exposure than medium-skinned people compared to dark-skinned people. Does that make sense? So this is a major reason how we can account for some of these contradictory data. Also, if we spackle in their smoking status and alcohol consumption, perhaps BMI, although I haven't really seen much that associates BMI to sun exposure, although I guess it logically would make sense that the higher BMI, probably the less you'd want to be in the bathing suit, but maybe not, but I've never seen it. I haven't seen that written anywhere. Maybe nobody wants to jump on that grenade, I suppose. But anyway, we see this association where the darker-skinned people may need more time in the sun. They may be able to take more liberties, but they also may need more time in the sun to experience the health benefits. This may be why we see Hispanic and African-American populations having a harder time, at least according to some of the preliminary data associated with vitamin D deficiency and sunlight insufficiency. Okay, okay. So vitamin D is not a substitute, but it can help. I just want to mention that. There's no case I'm going to bill. I think we already made that case earlier in the presentation. So some guidelines for safe sun exposure. Chronic, non-protected, bounce of exposure are important. 15 minutes up to X for darker-skinned types, two or three times per week. X is really going to be the X factor you're going to have to determine. Back to the Burwick-Hollick paper, they were suggesting part of the reason that underlies increased skin cancer is people are not getting chronic exposure to the sun, and thus learning their skin, and rather they're going out once in a while and getting a ton of exposure, and, oh, I got burned. Well, yeah, because you don't know, you don't have that sense about how much you can tolerate and how much is too much. So chronic exposure, nothing crazy. You have to make sure you stay underneath that threshold where you burn or even feel like you're close to burning. Sunblock or cover the face and the back of the hands most of the time. These are the two most common sites for skin cancers. Cover or use block during longer-term exposure, right? So, again, we want to be careful not to exceed the positive position in the inverted U. So if you're going to be in the sun for a long period of time, block or cover. And condition and get to know your skin. The lighter your complexion, the less time in the sun you should obtain. In healthy, good health of you, I detail some inferential sun exposure dosing goals, and these are based upon the 2011 Innocent Society position paper. I'm not going to read through these. You can, you know, they're up there. You can read through them at your leisure. But essentially, I lay out some guidelines for how to dose your sun exposure either as a maintenance dose or a treatment dose if you're low in vitamin D, and also kind of stratifying that dose based upon if you're in a bathing suit or if you're just exposing your arms and your legs. Okay, sunblock. Sunblock can reduce UV damage and prevent burns, but the data supporting this are weak and somewhat contradictory. So the people who say there's never been one study showing that sunblock helps, they're not wrong, but they're not right. And they're actually more wrong than they are right because there are some data that support that. But the data are weak and the data are contestable. Okay, to quote here, there is no consistent evidence that interventions are associated with improved sunburn frequency in children or adults, and this is just a study in sunblock. But all the studies in sunblock report markedly reduced UV induced damage. So there is a protective effect, whether that protective effect translates to less burns and its effect on outcomes is a bit unclear. Some data show no protection from sunscreen. And this is actually a Cochrane database systematic review, so this is very high level science. We were unable to demonstrate from the available evidence whether sunscreen was effective for the prevention of basal cell carcinoma or cutaneous squamous cell carcinoma. So there are that data there. But I'm gonna skip forward here. Part of the reason that the sunblocks were not able to show positive effect was they may not have accounted for misuse, formulation type or the total UV dose. So this study did not address four important concepts, sunscreen abuse, meaning you're over the exposure yourself to the sun and thinking you're spending five hours out in the sun and using sunblock and thinking that's your ghetto jail free card. Misuse of sunscreen, not using the appropriate SPF, not reapplying at the appropriate intervals as examples, and cumulative exposure. So that's important to keep in mind. There's also this other theory that the people who are at most risk for skin cancer are most prone to use sunblock. So perhaps it's hardest to show benefit because just like certain diets, right? Sometimes they say, well, maybe the reason why diet sodas don't show any weight loss benefit is because everyone who's drinking diet sodas is already overweight to begin with and they're working against an unfavorable genetic hand. That's not actually true, that example, but it just gives you an example. So it's important to factor that into the conversation. Now, there's this pivotal study by Green at all in 1999. Some cite this study as showing protective effect, others report it did not demonstrate protection. So the Cochrane Database Systematic Review found no protective effect. And a Cochrane Database Systematic Review is very high level scientific evidence. However, part of this appears influenced by the follow up window when Green's study window was extended and effect was shown. This is one of the challenges with skin cancer research is that it's not like a weight loss trial where you track people for eight weeks, right? The cancers don't form for a latency period until after the exposure, right? So you may not have caught the preventive effect if your follow up window was not long enough. So in another follow up analysis of Green's data or Green's cohort, 10 years after trial cessation, melanoma, the conclusion here, melanoma may be preventable by regular sunscreen use in adults. And another analysis, after eight years of cessation, regular application of sunscreen has prolonged preventive effects on squamous cell but no clear benefit in reducing basal cell carcinoma. So this is why I say that people, they're not wrong, but they're not right and they're probably more wrong than they are right. Tanning bed use. There are clear data suggesting the risk associated with tanning beds. Due to limitations, I'm not gonna detail these. I'm just gonna kind of give you the summary, which is we have to factor in for confounding associations and the inverted U. This is a great paper on the issue. Sun exposure is self-promoting. You know that tanning bed use may or may not pose a health risk. The data up here are mixed. This might be confounded by unhealthy lifestyle factors, accompanying tanning bed use, the Jersey Shore example from earlier. Dose may also be an important variable. Light use of tanning beds, less than 12 times per year, may pose minimal risk and even be associated with benefits. Use of 12 times per year or more or use once per month or more may pose health detriment. Tanning bed use should be discouraged, and this is my opinion on my summary. Tanning bed use should be discouraged or use cautiously slash minimally, focusing on sun exposure instead until more complete data are available, using them only in non-sunny months and not exceeding 12 sessions per year. I think that's a pretty reasonable conclusion. That's the maximally progressive conclusion. I shouldn't say it reasonable because this is not conserved. This is the maximally progressive conclusion. I think we can come to you based upon the data. Here's a few resources. A lot of this comes from our clinicians newsletter which summarizes this data, but there's a number of links there for you. And I think we have a few minutes for questions. Okay, all right. So we have about six minutes for questions if there are any questions. But thank you guys, hopefully. I know this is detailed, but this is a contentious issue and I hope you can see that the contention comes from the fact that the data here are not clear in one way or the other. There are some important nuances and if we factor those into our conversations, our arguments or our guidelines, I think we can really help people navigate this effectively. So thank you. You've seen the proposed like model that was explained, I think it's partially explained a lot of these correlational data put out by Gorham and Garland from the UC San Diego I think. They've seen it low by midi in least regards to cancer that the low by midi weakens the tie junctions between cells. And when the tie junctions are released, therefore a somatic mutation doesn't alert its neighbors that it's becoming pre-canturous. And so the neighboring cells can't call in the police force to attack them. Actually, it's very interesting model, but I don't know if you can see. No, I really had to keep my focus kind of at the outcome level on this. Because as you can see, it's even challenging to get a read on the outcome data. If you start peppering in mechanism and conjecturing for mechanism, it's probably close to impossible. That makes, I think there's a number of mechanisms that make sense. But for me, again, what I wanted to do was try to see what the outcome data shows. I think a mechanism like that is absolutely plausible looking at the fact that we see the protective effect. And perhaps there's a certain saturation point where sun exposure can help enhance tide junction function, but too much sun exposure, perhaps through oxidation, then leads to a diminishment of tide junction function. And maybe that is part of the reason why we see the inverted U.