 Thank you all for having me to speak with you today, like he mentioned, I'm a gastroenterologist at the downtown campus, specifically, I'm an esophagologist. That's my topic today about GERD. I chose this topic and this title because it was something that's been very controversial during the COVID-19 pandemic. My hope is that it will spark discussion amongst us today when we're dealing with this talk and also redirect attention to prescribing patterns, personal use of medications directed at treating GERD. So I'll go through several studies in detail, but this is going to add more attention to the bad press surrounding anti-secretary therapies for GERD. Okay, so let's talk about GERD and disease. I imagine I actually don't know all the specialties represented, but at some point we've either managed GERD for a patient, had some reflux ourselves, have a family member who wanted to talk to us about GERD. So data shows that about 10 to 20% of adults in Western countries experience GERD symptoms at least once a week, if not. Okay, so GERD, very prevalent in Western countries outside of the West as well, but today we'll talk about the U.S. There's also data showing that the prevalence of GERD is increasing by about 4% per year and it's done that steadily over the past several decades. Part of that is thought to be due to the increased obesity that we've been seeing in the last few decades. It accounts for over 5.6 million physicians each year, and as of 2015, the total direct economic impact of GERD and its complications were thought to be over $18 billion. And the indirect cost with loss of labor was as much as $75 million. So GERD is everywhere, and it also has a huge impact on our health care and our health care expenditure in this country. So what exactly is GERD? Just as a very quick reminder, it is a disease where you have symptoms or mucosal damage that are produced by the abnormally flux of gastric contents into the esophagus. Now to briefly go over the physiology because it's relevant for the rest of the talk, the main concepts historically, I don't know if you can see my arrow here, but focused around this area where you have either a hiatal, something that makes your GERD junction incompetent. That can be a hiatalemia where you have loss of some of the effects of the diaphragmatic cura against where your GERD junction is, and that predisposes to reflux or an incompetent lower esophageal sphincter. The traditional teaching is that reflux of X in patients with GERD largely were happening during lower esophageal sphincter relaxations, and that's when you're seeing this. I'm not sure if this phone is ringing, but you might have heard it. Dr. Akrasov, could you please mute your line? So this is the main issue when it comes to gastroesophageal reflux disease. However, there are several other contributing factors to physiology. One is that in patients with GERD, you have impaired mucosal defensive factors. You also can see patients with abnormal abdominal thoracic pressure gradients, i.e. our patients with obesity, they have a change in their pressure gradients, and that leads to reflux. Esophageal dysmotility, especially when it leads to poor clearance of reflexant, leads to worsened symptoms of reflux, and then delayed gastric emptying also leads to reflux. It's a common disease. It's made by diagnosis of classic symptoms or mucosal damage, secondary reflux of gastric contents, and there are several factors that play a role. Most of these areas, actually, if they're mild symptoms, we can target them just with lifestyle changes alone. However, when we get to the point where there are complications of reflux, then we have to do more aggressive management and lifestyle coaching is inadequate. Complications of GERD that I'm referring to will be erosive, anaphygitis, baritsosophagus, peptic strictures, and extra esophageal complications like pulmonary complications. So in these patients in particular, you are forced to do something a bit more aggressive, i.e. pharmacotherapy, surgical or endoscopic intentions. So what are the major players when you have someone who has not straightforward GERD or complicated GERD or just severe GERD, and we have to turn to pharmacotherapy. I broke it into two areas. One is going to be our anti-secretary therapy, which is all of our acid suppressants. PPIs, H2 blockers and antacids, that's listed in a biological gradient for what is most effective at acid suppression to weakest acid suppressive effects. And then outside of acid suppression, we also see various drugs that are working on the physiology that I mentioned before. So prokinetics can be used for patients who have GERD, especially if they're patients who have delayed gastric emptying that's contributing to their GERD. Backliphon, we know decreases the transient lower esophageal sphincter relaxations that are part of the pathophysiology of GERD. And then there are agents that don't fall into any of these categories and are just cytoprotective slash barrier therapies like caraphate or alginates that we prescribe for our patients. Many options exist on the market. At the end of the day, what matters is still proton pump inhibitors. Time and time again, we keep going back to the therapy. Our data keeps showing that proton pump inhibitors are most effective, especially with patients who have more complicated GERD. So GPIs, we know are super clear. They have a strong inhibitory effect. Acid secretion much longer than histamine receptor agonist. I quickly here just mentioned one of many studies that were showing the superiority of PPIs back in 2002. They looked at patients with erosive esophageitis. They specifically studied omeprazole versus femuridine, which will be relevant because those are the meds that were also studied during the COVID period. And controlled for various factors. And they saw that healing in the omeprazole group was greater than the femuridine group. So omeprazole, they saw that 72% had healing versus 32% at four weeks. And at eight weeks, that difference was even greater with 95% having healing with omeprazole, but only 53% with femuridine. Again, why we go back to PPIs all the time is for patients. So PPIs are everywhere now. There were great, there's great data to support it. They've been on the market for a long time. Omeprazole was the first of its class to be released on the market back in 1989. Subsequently, over the decades, we saw additional proton-pump inhibitors hit the market. Most recently, most recently, dexlan-soprazole hit the market in 2009. That's, to me, it doesn't seem like too long ago. But shortly after, from the time the last PPI hit the market, go to 2015. And then now PPIs are really everywhere in their rank, the top 10 national health-related drug expenditure. I think few medications have had that kind of success, whether it's because of aggressive marketing or just because it's not effective. Now, the drugs with the blue stars next to them are the ones that are available over the counter. So PPIs are effectively like the statins of gastroenterology where they're literally everywhere. But the difference is now you have increased public access because they're over the counter. And just going hand-in-hand with that, the use of PPIs accounted for 12.4 billion of that initial quote of 18 billion total direct economic impact of goods. So they're everywhere. We use a lot of our health care dollars with them. So it is important to know we were giving them out like candy and then things changed. So bad press started coming out a lot for anti-secretary therapy. I kind of jokingly refer to it as a war on GERD treatment because it's all of our go-to medications started having issues. So I have 2016 as the start on my timeline, but this really goes back further than 2016 when studies started coming out about the potential adverse effects of PPIs and acid suppression in general. I highlight 2016 because that's when I was in my Motility Fellowship at Hopkins and a lot of patients started coming in with concerns about being on PPI therapy long-term. This is when the New York Times and major news outlets like it started to report about the growing adverse effects of PPI. So patients were concerned. They weren't necessarily comfortable with being on PPI's anyway. Most providers continue to provide them whether or not they were indicated. Fast forward then to 2019. Fine. PPI's patients don't want to use. Everyone ran to Zantac. I think all of my patients who were not on PPI's that I saw were on Zantac. October 2019, we all saw that they were at recall of renitting products because of concerns of unacceptable levels of NDMA, which was a probable human carcinogen. So, renitidine was pulled off the market. And now, you know, people are getting concerned. What can I do about this? Literally the question I got from my patients, what can I do about my GERD? These drugs are bad. This drug is no longer available. What is left to mean? So that's where we were back in 2019. And then coronavirus enters the picture in China in later 2019. And then the U.S. in 2020 is when we really started picking it up. And again, that redirected some of the spots towards PPI therapy. And are they the enemies? Are they causing a lot of issues? And most of the talk will go into why there was concern. I wanted to point out one other thing because I think it was not on most people's radar. In April 2020, Acid was actually also recalled for the same issues as renitidine. So another drug that was taken away as an option for managing GERD. So we're really running, I'm exaggerating, but running thinner on our options for GERD management. 2020, say spring, early summer, a slew of articles came out that were concerned about PPI use and increased risk of COVID-19 slash worsened COVID-19 outcomes, which is what we're going to spend much of the rest of our time talking about. So again, another reason to be worried about PPI's. You want to revert back to the H2 blockers that you know, maybe a different one like Femodity. Lo and behold, May 2020, the FDA announces there's a COVID, there's a Femodity inshorted. And if you go on to the FDA website, even today, there's an ongoing Femodity inshorted. So really what's left is the question. So let's talk a little bit about where all this concern is stemming from. So just a really quick overview for COVID-19, which is the disease caused by SARS-CoV-2. The virus in and of itself is a positive single stranded RNA virus. That positive sense genome can act as messenger RNA and be directly translated into proteins by the host cell ribosomes. We have a framework to work with in our studies of this virus because it's the successor for SARS-CoV-1. A little bit about the virus structurally, it has four structural proteins. Three of those structural proteins make up the envelope. The main structural protein that we'll be mentioning today are the spike proteins. And spike proteins allow the virus to attach to and fuse to the membrane of a host cell. And that's where a lot of the impact we think potentially of acid suppression is. So going into that, this diagram here is just to quickly talk about how SARS is infecting the respiratory tract, which is what we tend to think about, but also affecting the gut. So SARS-CoV-2 enters the alveolar type cells of the lungs by binding to the acetylcholine, ACE2 receptors. And then with the help of the serine protease, then it can enter cells. Now, these ACE2 receptors are found in the lung abundantly on alveolar type cells. But previous work also showed that it is actually more highly expressed in small intestine and enterocytes than anywhere else in the body. So you have a highly expressed ACE2 receptors on differentiated enterocytes, which act as an entry point for SARS-CoV-2 in the GI tract. We know that this virus in particular has a higher affinity for this receptor than its predecessor. And we know also that in patients with COVID-19, we are seeing viral shedding in the stool, and we're also seeing active GI symptoms. So there was a study done that was published, it was quite nice in science in 2020, that basically just demonstrated that not only do these, does the virus attach to these receptors, the enterocytes also increase the replication of the virus, and that's thought to contribute to the disease process. So all of that is to say that SARS isn't just a pulmonary infection, it is truly an enteric infection as well. Why does that matter? Because we know historically that PPIs increase the odds of enteric infections. It's one of the things that we counsel patients about when we're talking about long-term PPI use. A quick study here showed that PPI use increased the odds of enteric infections by 33%. In this particular study, they were looking at various complications of PPI use that we typically think of, pneumonia, C. diff, fractures, kidney disease, etc., and included enteric infections for a medium of three years of PPI use. And what they saw was that there was the only thing that was statistically significant between the pantopazole group and the placebo group was enteric infections. Consistent with many studies that came before that, that PPIs have increased risk of enteric infections, both bacterial and potentially viral. Again, we just established that SARS-CoV-2 is an enteric infection. Then that leads us to the next point about how does that happen? What is the role of PPI use and increase SARS-CoV-2? We'll backtrack to some of the studies that were done in 2004 during the SARS epidemic. They really set out to find what methods could inactivate the virus. They looked at many things, including UV light, but ultimately find that a pH less than or equal to three inactivates the virus. It impairs the infectivity of SARS-CoV-1. This graph just shows where you have the minimal level of detection at this line. Between one to three is not detectable, and you're fully suppressing the infectivity greater than three. It's detectable until you get to 12 or so. Our physiologic gastric pH is going to be less than three. We're typically in about the two range if we're not suppressed. The thought behind that is that that naturally low pH is protecting us against enteric infections like COVID. Then the paper started coming out. The hypothesis here was that inhibiting gastric acid might allow a larger inoculum of SARS-CoV-2 to gain entry into the GI tract, replicate, lead to GI symptoms, and potentially even spread beyond the GI tract. There is also a thought that, and it's not quite proven yet, but when there is an infection of the GI epithelium of SARS-CoV-2, you get a disruption of that epithelium, and that disruption subsequently leads to like an increased cytokine response in even other organs. So potentially like a long cytokine response just from having an enteric infection is a theory. So, July 2020, a study came out in the American Journal of Gastroenterology that kind of really shook things up about PPI use and the risk of COVID-19. This was done by several big names in gastroenterology, Bill Shea, Brennan Spiegel, and their aim was to test their a priori hypothesis and see if PPI use increases the odds of requiring COVID-19. The way they did this was by pairing with a research forum called SINT and did an online, just they called it a National Health Survey from May 3rd to June 24th. They had many respondents, but really they wanted to see respondents with specific GI symptoms. If you have those GI symptoms, then they went on to ask if the patients use PPI or H2 blockers and if they had ever tested positive for COVID. So, 53,000 respondents fell into that category. They performed multivariate logistic regressions on those reporting a positive COVID test to calculate an adjusted odds ratio and adjust for other confounders. 6.4% of the patients of those respondents tested positive for COVID, which might be a little bit higher than the population, the rate in the general population. So, this was the result of the study. And you see for patients with PPI use, what stands out the most is that, well, once daily PPI, you've actually had an adjusted odds ratio of 2.15, which is increased, but twice daily PPI use had an even higher adjusted odds ratio of 3.67 for a positive COVID test, which for them was concerning. They also looked at H2 blockers and noted that odds ratios were quite low, 0.85% and 0.8, sorry, 0.85 and 0.86 for once versus twice daily H2 blocker use. From this, they concluded that PPI use was associated with an increased risk of COVID-19 positivity in a dose dependent fashion, but that H2 blocker use was not. They did apply the criteria to assess the causality and focus on twice daily PPI use mostly because that adjusted odds ratio is greater than 3. So, for adjusted odd ratios, if we're trying to determine likelihood of causality, 0 to 0.33, if it fell into that range, very strong chance that it is protective. If it's greater than 3, very strong chance that that's increased risk and not necessarily due to biases, if it's falling within that range, there's a potential for bias. So really their outcome was concerning for twice daily PPI use being associated with increased risk for positive COVID test. Now, this paper had a lot of support and received a lot of flak from the GI community, partly because of abnormal demographics that were reported. This table, I won't really go into detail. It's reporting the same thing except with various subgroup analyses because their demographics were a bit odd between the first half of the study. So, a very notable finding, but a limited study, one, they only evaluated patients with GI symptoms as you can imagine might be a confounder. They might have a higher than expected positivity rate because we know that COVID can lead to some GI symptoms in the first place. They subsequently tried to adjust for that and do additional subgroup analyses and still found the exact same finding. The other areas that were concerning for critics of the article was that there was potentially a lot of confounding recall bias. Again, the demographic data was low and unusual. It had a higher percentage of Latin American people, lower levels of education, much higher levels of household income than the general US population. Okay, but this is something that came out. It was a big study, big names supporting it, lots of respondents involved. So it just looked like more bad news for PPIs and this is potentially public enemy number one. It's a drug that's everywhere and now this drug seems to be increasing the rate of COVID positivity. So, because of this study, the American College of Gastroenterology came out with a fact sheet specifically for this addressing the findings and how that should affect kind of what we're doing in clinical practice. And this is just a direct statement from their fact sheet, which says that the study extends upon previously public research that PPIs increase the risk of GI infection, although the absolute risk of any PPI induced infection is low. There's a clear link between PPI use and then increase odds of GI infections. And that this study, the novelty of it lies in the extension of this knowledge to COVID-19. Okay. Then they also go on to say, and just to summarize this part, that the study does not definitively prove that PPIs increase the risk of COVID-19, which I think we would all also conclude based on the quick review I did of the paper. So, we're neither here nor there, but is it something to entirely ignore? No. Their main recommendation that was that as with any medication, the lowest effective dose should be used when clinically indicated and when appropriate, H2 blockers should also be an alternative. They went on to list several recommendations for how we should practice in light of these of this particular study findings. One was that we shouldn't emphasize adherence and CDC guidelines just to prevent COVID transmission, wash hands, social distancing, wearing a mask, etc. They also recommended that whenever we interact with patients on PPIs, we should consider whether twice daily PPI dosing is necessary for our patients, especially if they're vulnerable for severe COVID-19. They thought it was reasonable to make sure that there's clear indication of all patients taking a PPI. And when a PPI is indicated, patients should be informed about an association between PPIs and enteric infections included COVID-19. Again, reevaluate the need for twice daily dosing. Now, that was the kind of first study to set things off. Subsequently, there were several studies and I'll just go over the main ones that looked at not the rate of PPI of COVID positivity, but what PPI, what effect PPIs have on outcomes with COVID. And I think these, there were far more studies looking at outcomes than the rate of positivity. The first one we'll look at was all that was published in GUT in 2020. Large study is a Korean nationwide study with 132,000 COVID tested patients. And in this study, they looked at the adjusted odds ratio as well to see for patients who tested COVID positive to see what their outcomes were. Their primary endpoint was to see susceptibility, whether or not susceptibility to COVID infection was increased with PPI usage. Secondary endpoint was to see the admission to ICUs or invasive and ventilation or death. So looking through this, we can see that for patients who tested, who were, I'm sorry, I don't know if you can see my arrow here or not. But for patients who are current PPI users and for patients, particularly in patients who would use PPI's within the last 30 days. There was an increased risk of the endpoint one, which is admission to the ICU ventilation or death. The ratios here were 1.63 and 1.77. You don't see an increased risk of death or intubation or ICU admission if they were past PPI users who were not currently using it. The other thing that they saw was here, sorry. It's actually, it's not on this graph, but it's not on this chart, I don't think. But they didn't see an increased risk of positivity like the previous study did. Two other studies came out looking at the exact same outcomes to see if there was increased risk of ICU admissions, ventilation and death with PPI use. One very quickly was by Raman Shadron at all in European Journal of Gastroenterology and Hepatology November 2020. They looked at 295 hospitalized COVID-19 positive patients, 15.6% of them were on PPI's at home. They found that the mortality amongst PPI users was 2.3 times higher than non-users along with 2.3 times higher risk of acute respiratory distress syndrome after adjusting for confounding variables. Part of the thought behind that, again, was that the theory that if you have infection of COVID-19 that disrupts the epithelium and can lead to a cytokine response, even in other organs like the lungs. Luxemburger at all, Journal of Internal Medicine October 2020, they published an article where 152 PPI users were identified. First of all, 48.4% of them had no clear indications for being on PPI, which is a problem for our prescribing patterns. But they saw that PPI users had higher rates of poor COVID-19 outcomes, including secondary infection, ARDS, and mortality compared to non-users. They also saw that GERD was a significant independent predictive factor for secondary infection. Part of the theory there is that with the reflux, potentially those patients are having regurgitation all the way through the proximal esophagus and having microaspiration, increasing their risk of secondary infection. So all these studies so far, again, showing poor outcomes or increased risk of infection. There was one study who did not quite show that, and that study was published a little later than the rest in September 2020. And that was published in gastroenterology, showing that there wasn't really a significant increased risk of poor outcomes or infection with the acid suppressing therapy. So in this study, they looked at 9,469 patients who were tested for COVID in the UK. And they were looking at, they grouped PPI use and H2 blocker use as acid suppressive therapy, and then subsequently did additional analysis to look at PPI use and H2 blockers secondarily or independently. They also did a subgroup analysis of patients with upper GI symptoms alone to compare their results to that first study I mentioned by Spiegel's group. Their outcomes, they saw that no single type of acid suppression was associated with the risk of infection, unlike what the Spiegel group saw. But when they looked individually at PPI's or H2 blockers, neither was associated with the risk of infection. One thing that they did see when they did their subgroup analysis for patients with upper GI disease, again making it more similar to that initial study by Spiegel's group, was that omeprazole only. They saw other PPI, but only omeprazole was significantly related to an increased risk of infection in patients with upper GI disease. So that finding in a group that mirrors the group studied in the original study is similar where there was increased risk with PPI's. The last thing that they saw was that they had 19% death rate in their patients with COVID-19 and neither PPI's or H2 blockers were associated with risk of death in their patients. Again, very different than the last three or four studies that we just looked at. So what to make of all of that? Because there was a lot of buzz. Many articles were published. Ultimately, these articles start making it to some news outlets and patients started coming to my office because they were worried that their PPI's were going to make them get COVID or that their PPI's would make them die if they did get COVID. At the end of the day reviewing the data for PPI's and COVID, I felt that the data was insufficient to really make large leaps in how we, or large changes in how we practice GERD management. I felt that the studies that were performed, kind of similar to what ACG fact sheet was saying, the studies that were performed had their limitations, whether or not bias was introduced or there are confounders there. There are largely retrospective studies. And then obviously whenever you have an online survey, there are biases that can be introduced there. So what I do is kind of in line with what ACG recommended doing. I discussed with my patients, particularly those who are on high dose therapy. And I mentioned the risk of increased possibility of enteric infections. I talk about COVID-19 being an enteric infection as well. And that there's a potential of increased risk with that, but that it's always the balance of risk benefits. And then we just, we decide together whether or not it's appropriate. I always revisit my patients who are long standing PPI therapy with the goal of reaching the lowest dose, lowest effective dose, and then assessing for patients to switch over to an H2 blocker as recommended. And this fact sheet as well. So H2 blockers seem to have been a great alternative, like running off the market. So it was really pepsid because pepsid is over the counter and easy access for people. Then all of a sudden, all the news outlets started reporting what seemed like great news. So Fox had it, CNN had it, New York Times had it. It seemed like it might be this miracle drug. Heartburn medications might be this miracle drug to improve how you do with COVID-19. And then it started flying off the shelf and my patients who needed it could not get it. So a quick look into why this buzz came to be and where to go from there. So there was this Friedberg study was the main study that was done looking at Femotidine and COVID-19 and the study that the Infectious Disease Society of America used to make the recommendations. So this was a propensity score matched retrospective cohort study. They looked at admitted patients who tested positive for COVID-19 within 72 hours of admission. And those patients, they looked at patients who were given Femotidine within 24 hours of admission. Their primary outcome was death or intubation between day two and day 30 of admission. And they saw that Femotidine was associated with reduced risk of intubation or death. And here I just have the Kaplan-Meier curves, which are illustrating the same thing. We can see the bad line here represents patients who are on Femotidine have a better intubation-free survival compared to patients who are not on Femotidine. And then that is largely driven by death, decreased rates of death in patients as opposed to just decreased rates of intubation. This is a second study that was published later in 2020. Similar outcomes, retrospective propensity matched 878 patients, 9.5% of them received Femotidine. The patients on Femotidine were slightly younger, you know, might be a confounder, but matched for comorbidities. The use of Femotidine in this study also was associated with a decreased risk of inhospital mortality and combined death or intubation. When they propensity, when they did propensity score matching for age differences, it didn't change the outcomes. Femotidine still seemed to be protective. So why is it working in that way? Because if we think about acidity, it doesn't quite make sense from an acid suppression standpoint based on what we reviewed previously. Well, it turns out that there were some computational models that were made before. That's what people were initially conducting some of their experiments based on. But a computational model predicted the structures of the proteins encoded by SARS-CoV-2. And they saw that Femotidine was one of the drugs based on that structure that was most likely to inhibit a specific protease that was necessary for viral replication. It was thought to be the not acid suppression that was the factor here, but the drug itself inhibiting a protease. A preprint study followed that up with an in vitro study to see whether or not Femotidine actually binds to anything or inhibits any of these proteases, and it didn't. It had zero direct antiviral activity. So that theory was kind of effectively debunked. The other thought was that the effect isn't from acidity, but rather the actual effect of histamine blockade and its effects on cytokine release and dysfunctional mass cell activity when you have infection and then when you give an H2 blocker. So that created a lot of buzz. Femotidine was flying off the shelves. There was a clinical trial that was started to see the symptoms of patients who self-treated with Femotidine at home and outpatient setting. And it became, again, there was a shortage. There was even a shortage of injection Femotidine in hospitals. So the Infectious Disease Society of America evaluated the data, which is the table I have down here from that initial Friedberg study, and suggest against using Femotidine for the sole purpose of treating COVID-19 and hospitalized patients with severe code of a 19. Outside of the context of a clinical trial, they felt that the data was not robust enough. There were significant confoundings and limitations to study design, so it is not currently recommended. Yet the shortage continues and people are still concerned in coming to my office with questions. So what I've done now because of all of this is that I effectively do the same thing I've been doing. The blood circulation is the same. We have to keep going back to make sure that our PPIs are only used as indicated. It was very concerning that that one study showed that 48% of patients had no indication for being on their PPIs. I get referrals for patients with various symptoms who've been on PPIs for 20 years and have never tried to taper off of it or doing a step-down therapy to an H2 blocker. So if anything, the data might be flawed. It might show a very concerning trend. There are all things that we should consider, but if anything, it says to us that at the end of the day, we have to be very mindful about how we're prescribing these medications or for those of us personally with GERD, how we're using these medications because they're not 100% safe. There are risks and additional risks might continue to come out with time. We've drawn attention to one of those possibilities, which is poor outcomes or increased infection. So I counsel patients extensively, like I said, the ones who are on higher doses, that this is the data that's out there. We don't know 100%. More studies are needed, but these are the risks. Then I go into extensive lifestyle coaching if I can. So lifestyle coaching is going to be most effective in patients who have clear dietary triggers, who are obese or who are smoking. It's also going to be more effective in patients with very mild symptoms as opposed to patients with frequent symptoms or complications. So I take advantage of this when I can, and that's going to be reducing silent aspiration. Who knows if that microaspiration theory of why you get secondary infection is true, but if it is true, having your head elevated and staying upright two hours after a meal would help to decrease that. Weight loss has been shown to decrease gastric acid exposure or esophageal acid exposure and symptoms, as well as tobacco smoking cessation and eating early evening meals. Now, I have a very mixed population of patients, but some of them are young and are very into wellness and yoga and didn't like medications in the first place, and now they're seeing even more bad press about these medications and then you want something that they can potentially try for their milder symptoms. I will take time and go into some maybe integrative medicine or I'll just call him integrative medicine approaches for managing their GERD, which might include some mind body techniques or mindfulness apps that are out there now. We'll talk about physical activity, acupuncture can actually be have been effective for a few of my patients and then other herbal or naturopathic therapies that are out there that I won't go in today. This is just a list of the full spectrum of therapies that are available for patients with reflux disease. If the meds aren't are ineffective, then obviously they're surgical and laparoscopic options. But if anything, I'll conclude again by saying these medications are ubiquitous. They're the statins of GI except they're even more readily available. We have to be mindful about how we're prescribing it. We should be willing to have open conversations with our patients about potential risks. We know without doubt that they are that PPIs in particular are associated with increased risk of enteric infections. COVID is an enteric infection. There's some data pointing pointing to the fact that it might affect COVID outcomes. It's not as strong as we'd like it to be. It's not strong enough to make formal recommendations saying don't give it to patients. We just need to be mindful about how we're giving it to patients.