---
title: 'Targeted Nutrition in Orthopedic Surgery - A Missed Opportunity to Enhance Outcomes'
type: 'lecture'
url: 'https://doc.social/lectures/targeted-nutrition-in-orthopedic-surgery-a-missed-opportunity-to-enhance-outcomes'
published: '2023-09-15'
author: 'Eziah Syed'
transcript: 'yes'
---

# Targeted Nutrition in Orthopedic Surgery - A Missed Opportunity to Enhance Outcomes

## Summary

Surgery triggers a series of inflammatory, immune, and metabolic responses. The stress response leads to an increase in protein breakdown that outpaces protein synthesis. The body's natural store of essential amino acids exit skeletal muscle tissue to aid in recovery; prioritizing glycemic control, immune support, and surgical site repair. This leads to muscle tissue damage, and when accompanied by periods of immobilization, significant skeletal muscle loss occurs. In older adults undergoing orthopedic surgery, postoperative changes in skeletal muscle size and function have long-lasting, and potentially irreversible, consequences to muscle strength and function. Targeted perioperative nutrition interventions address nutritional deficiencies that cannot be overcome by whole food intake alone. The purpose of this webinar is to introduce evidence-based approaches to perioperative nutrition in orthopedics.

Supplemental Materials: [OVBC Nutrition Panel Follow Up (PDF Document)](https://media.doc.social/wp-content/uploads/2023/09/23102926/OVBC-Nutrition-Panel-Follow-Up.pdf)

## Transcript

14,282 words · 86 min · 7 speakers · automatically transcribed (aws-transcribe) and not checked by a person; it may contain errors, particularly in names, drugs and dosages. The recording is the source.

[1:11] Speaker 1: Thank you for joining us today to discuss targeted nutritional interventions in Orthopedic Surgery. My name is Arin Owen. I'm the vice president of Clinical Research at Men Labs. We are excited to welcome everyone today, including nearly every sub-specialty in Orthopedics is represented, as well as athletic trainers, medical teams, dietitians from professional sports teams, and the United States Military Force Special Forces.
[1:45] Speaker 1: Um, I am pausing because I can't see any slides. My apologies.
[1:53] Speaker 1: Thank you.
[1:55] Speaker 1: I'm gathered here, I'm here today with some great panelists. I'm excited to introduce, including Doctor Paul Wismeyer, professor of anesthesiology and Surgery with tenure at Duke University. Doctor Wismeyer Practices at the intersection of perioperative Medicine, critical care, and nutrition. He has well over 200 peer-reviewed publications.
[2:16] Speaker 1: With more than 16,000 citations, including 50 high-impact articles with more than 100 citations in this space. He's the recipient of multiple awards, including the John M. Kinney Award and the Lifetime Achievement Award of the International Parental Nutrition Society for significant contributions to the field of nutrition.
[2:37] Speaker 1: Also welcoming Doctor Hans Dreyer, associate professor of human Physiology from the University of Oregon.
[2:44] Speaker 1: Doctor Dreyer is a muscle physiologist with expertise in muscle metabolism and physical Rehabilitation. He's credited with originating then defining the perioperative protocol for administering Essential amino acids to older adults undergoing Total joint arthroplasty, which has been replicated in the United States and Other countries. And also Doctor Mike Willy, clinical assistant professor of Orthopedics at the University of.
[3:10] Speaker 1: Of Iowa. Dr. Willie is a fellowship trained orthopedic trauma surgeon. His Research is focused on understanding and improving nutritional status and related outcomes in orthopedic trauma populations. He recently published a 400 patient randomized controlled trial on the use of targeted nutrition following extremity and pelvic fractures. We have a lot of content to cover, so without further delay, I'll pass it to Doctor Wismeyer.
[3:39] Speaker 2: Thank you, I'll share my slides.
[3:45] Speaker 2: OK.
[3:46] Speaker 2: Pull this down and.
[3:52] Speaker 2: Everybody see that, Aaron, can they see the slides?
[3:56] Speaker 2: Looks great. OK, thanks. So, it's great to be with all of you here tonight and to talk to you about a subject I'm truly passionate about, Perioperative nutrition, and
[4:06] Speaker 2: The reality being that we really can and must do better for our patients. I think it's an area that doesn't nearly get the attention it deserves, as it's one of the few things we can actually do for our patients prior to Surgery that makes a big difference in outcome, is cost-effective, and, and is something that can change their outcome with even a week or two of therapy. Encourage all of you to share anything you see interesting on Twitter and Instagram and to follow. We share lots of things and nutrition on this.
[4:32] Speaker 2: On these platforms and share anything you can so others can learn as well. So briefly, my alignments of interest, uh, I, I would like to say I'm not in conflict with the NIH or the Department of Defense or the industry sponsors I work with, um, but in alignment, um, hopefully improving patient outcomes, uh, through the Research that we do.
[4:51] Speaker 2: So I think this is the key message I would like to leave everyone with. If you remember one thing I said tonight, it is no malnourished patient should ever have Elective Surgery without nutrition screening and optimization. And sadly, this is something that happens in the US and around the world routinely, and it's something we can change and you can change by being here tonight. And that's the reality, we need to do better, because I'll show you the data says this is something we're not routinely doing.
[5:17] Speaker 2: Um, but we easily can, and, and we'll talk about tonight things you can do. So how can we do this? How can we be better? Well, how common is malnutrition in our surgical patients? Well, we know in any hospital, on any ward, in any kind of diagnosis group, uh, on average, 1 in 3 to 1 in 2 patients that any of you care for are malnourished with admission to the hospital.
[5:41] Speaker 2: And of course, the hospital food's not that great, so the patients don't get better nourished while they're with us. And so the malnutrition rate often goes up quite significantly during hospitalization.
[5:51] Speaker 2: And we also know that although albumin is not the perfect nutritional marker, when inflammation is not significantly present, it is a good marker and it's a very good marker for risk. And so a low albumin predicts mortality in Surgery. This, I'm gonna show you some data from the NSO database. It's a 2 million patient database that covers all different sorts of surgeries across the US.
[6:11] Speaker 2: And if you look, malnutrition or a low albumin is the #4 cause of death or predictor of death within 30 days of any operation in anyone, healthy, well, young, old, anyone. And if you look at this list, it's the only thing, nutritional status is the only thing of this list that we can change in the few weeks before Surgery. It's the only modifiable risk factor for death we have.
[6:36] Speaker 2: And so again, specific to Orthopedic Surgery, I was um honored to write a, uh, an invited review on the peroper nutrition care of the Orthopedic Surgery patient, and we found there's uh just a few publications specific to Orthopedic Surgery. And so in a Hip and Knee replacement,
[6:50] Speaker 2: A low albumin led to significantly higher hospital costs and a significantly longer length of stay.
[6:56] Speaker 2: In Shoulder arthroplasty, and this is from the NICO database, a, a low albumin was associated with increased morbidity and death, um, and increased risk. malnutrition was significantly associated with blood transfusion risk, length of stay risk, and death within 30 days. And then in Hip and Knee arthroplasty, a low albumin again, 7-fold increase in major wound complications. So significant risks, and this is truly an emergency malnutrition is, malnutrition is truly an emergency for the Orthopedic Surgery patient.
[7:25] Speaker 2: So we need to be better. And, and again, how can we do that? Well, I think one way that is starting to lead to improvements is ERRAS. And of course, any of you who have done ERAS or know what ERARAS is, it's a bundle of different interventions for Surgery um that are set up to improve outcomes, and it's really awesome. But I'm gonna let someone tell you about it briefly, um, who does awesome, much better than I do. Listen closely.
[8:04] Speaker 3: I
[8:06] Speaker 3: 121, go. Have you all the news. Everyone's talking of good because everyone's walking 10 operation recovery is faster and limited products like a master. I realize he reps are passing gas. I'm eating all the food and I easily pass. Two days later, beating the forecast, feeling like a boss. He rep is awesome. Stepped on my bed, grabbing my skateboard, toss in the m, awesome, awesome, awesome food.
[8:29] Speaker 2: So, without doubt, ERAS is awesome. And again, nutrition plays a key role in every part of ERRASAS. And I was also honored to be able to chair the guidelines for nutrition in Surgery in the US and within an ERAS pathway for patients anticipating Surgery a few years ago, working with surgeons, anesthesiologists, and Other multidisciplinary providers from around the world.
[8:53] Speaker 2: And these are some of the key messages that came out of the guidelines about peroper nutrition. First, we know that 1 out of every 3 patients at a minimum, coming for Elective Surgery are malnourished at the time of Surgery. And we know that your risk of death is 5-fold greater if you go into Surgery malnourished without having that being treated.
[9:11] Speaker 2: Unfortunately, we screen big academic programs who are supposed to be the best perhaps at screening for things like malnutrition, only 1 in 5 hospitals have any formal nutrition screening processes. Even though the surgeons we surveyed universally said they knew nutrition was critical to their patients, and it would improve outcome if we could improve patients' nutritional status.
[9:32] Speaker 2: And I'll show you some data that shows that every $1 you spend on this high protein drinks that cost just a few cents in many cases, you save $52 in hospital costs. So they're quite cost-effective. But only 1 in 5 patients who are malnourished ever received any nutrition intervention.
[9:48] Speaker 2: And so we tried to make it simple, and so, these are the key messages we wanted to have people take away as they think about surgical nutrition. One, you have to screen for malnutrition to find it. So, nutrition screening is critical. Protein is more important than calories. We wanna get protein in, caloric delivery is less important.
[10:06] Speaker 2: We wanna stop feeding late pre-op. We don't want people NPO overnight. We don't want people NPO from midnight, and we want them eating the morning of Surgery after they leave the OR. Oral nutrition supplements, these high protein drinks, and high protein delivery is essential for everyone. People are not going to eat enough food, or before injury before parent control, and this is a team game. We need our nurses, our, our dietitians, we need everyone to be part of this process.
[10:30] Speaker 2: To briefly talk about the guidelines we suggest, I'm gonna tell you about a patient I cared for not long ago. Her name was Michelle, and she was 63 years old, coming for a Hip Replacement.
[10:40] Speaker 2: Her BMI was low. She'd lost some weight due to poor appetite, due to Pain and inflammation from her Hip, and her albumin was quite low. And so we tried to develop for this new guideline process, a, a screening score specific for Surgery that uses validated questions that could be put into an electronic medical record. And so we developed the PON score. All 60,000 patients at Duke are phone screened by our phone screeners. These aren't nurses, these are technic.
[11:05] Speaker 2: Um, and the rest of the data is extracted from the chart and we screen all 60,000 patients and it's simple low BMI, have you lost weight without trying? Are you eating less than half of what you usually do, or is your albumin less than 3.5? And we've published validation data. This is an excellent risk predictor. If you have any one of those.
[11:23] Speaker 2: Positive answers. If you have a yes to any one of those, we consider you to be malnourished and we refer you to, we have a pre-op nutrition clinic for Surgery that's staffed by a dietitian that the hospital pays for.
[11:35] Speaker 2: If you don't reach criteria for malnutrition, we still encourage immun nutrition, which I'll tell you about for 7 days before Surgery. Everyone needs that malnourished or not, and a car loading 2 hours before Surgery, and then immuno nutrition after Surgery, and a high protein supplement with an H&B supplement, and, a specific nutrient that's anabolic for 4 weeks after Surgery.
[11:56] Speaker 2: If you are malnourished, we have you see our dietitian. We try to do 1 to 4 weeks of a high protein supplement with HMB, immune nutrition for 7 days, and a carb load before Surgery, and then the immun nutrition for 7 days and high protein H&B for 1 month after Surgery, and then our dietitian follows you up. So, this particular patient, Michelle's very high risk. She's got a positive answer for all the questions.
[12:19] Speaker 2: And so, these questions, as you noticed, are fairly subjective and the albumin has its limitations. So, we think the future is the use of CT scans and ultrasounds to measure lean body mass. It's very hard to look at, say, someone who's obese and look at who's really at risk with low muscle mass cause we know that's a predictor of outcome. And so, for instance, in trauma patients, we looked at CT scans and
[12:42] Speaker 2: Of all the patients that came in with trauma, and looked at how many were sarcopenic, and these were free-living elderly folks with an average age of almost 80, 71% met criteria for sarcopenia at the L3 cut of a CT scan.
[12:54] Speaker 2: The challenge was you couldn't look at them and tell it was sarcopenic. There was no correlation with being underweight, a normal weight, or obese and overweight with who was sarcopenic. So you can't eyeball test these patients. But what we did see was there was a doubling of mortality in these healthy elderly trauma patients who were, had low muscle mass, who we otherwise might not have ever thought were malnourished because they were otherwise healthy at the time of admission in most cases.
[13:20] Speaker 2: This has been looked at specifically in Orthopedic Surgery, and again, sarcopenia is associated with at least one adverse outcome in many studies of thousands of patients and it's associated with mortality and poor survival in most of the studies that have been done. And so, again, this is a significant risk factor, and we think this is really the future of how
[13:37] Speaker 2: We'll diagnose nutrition risk. We have muscle-specific ultrasounds now called muscle sound devices that the professional soccer teams like Real Madrid and the Dallas Cowboys use. We're using them in patients, and you can it's a probe about this big that plugs into your iPad and you can measure muscle in minutes really quickly.
[13:54] Speaker 2: And all of our new global malnutrition criteria now depend on muscle mass as part of the malnutrition diagnosis. In fact, insurers are starting to ask for muscle mass when I diagnosed malnutrition in the hospital. So, they're catching on and so we need to incorporate this into our care. How to treat your pre-op nutrition? Again, we, we want protein to be critical. We have to reach greater than 1.2 g per kilo per day of protein. Um, we wanna use this in the seven days before Surgery, the immun nutrition or a high protein oral nutrition supplement.
[14:23] Speaker 2: We know that in many kinds of Surgery, this is just one particular study, giving these drinks for even just 7 to 10 days reduces the risk of surgical site infection 2.5-fold. If you can't get oral nutrition in or internal nutrition in, then we strongly recommend TPN or parenteral nutrition.
[14:40] Speaker 2: And of course, we don't want anyone to think that what they were taught in medical school is still true. It's just TPN has no risk of increased infection. It's just as safe to put saline through our TPN through a central line as it is saline through a central line. So, if you were taught TPN has an infection risk, that's not true. Many studies and journals you've heard of show this.
[14:57] Speaker 2: We also recommend immune nutrition, which is a combination of arginine and fish oil. And the reason we do this is we have as humans have evolved a process where our depleted neutrophils deplete arginine in our spleen and lymph nodes, and ultimately then impair our immune system about 3 days after any major Surgery and trauma. This was to turn off our immune system when the tiger bit us because there wasn't a surgeon coming to save us.
[15:19] Speaker 2: Now we don't want our patient's immune system to become impaired at 3 days. And so giving arginine back in many, many studies of many, many patients leads to significant reductions in infectious complications and reduces length of stay by 2 days. Again, this is 5 to 7 days of therapy before, after or during Surgery. And again, there's many studies have gone into this, and it's a significant consistent reduction in infection.
[15:41] Speaker 2: And we understand the scientific mechanism well, and this works pre-op, post-op, or if you give it before and after Surgery. So again, this is critical, and this is not related to malnutrition. This is true in all patients. If I was having Surgery tomorrow, if my son at 18 or 19 was having Surgery tomorrow, I would give him this, and I think that's critical. Anyone having Surgery needs this. So she's malnourished. Should we cancel her Surgery and give 1 to 4 weeks of nutrition?
[16:05] Speaker 2: Unfortunately, as is common, this patient didn't get that even though she was malnourished. So, in the morning of Surgery, she would give her a carbo drink, and we suggest a complex carbohydrate be given to everybody 2 hours or more before they come in for their Surgery. There's great data for this. It reduces length of stay by 1 day and a half in many studies, and including Cochrane meta-analysis. And again, we want this to be a complex carbohydrate, not juice or not Gatorade. It needs to be low in osmoality.
[16:32] Speaker 2: Sports drinks are not useful here because they're simple sugars and they have the wrong osmality. They don't empty the stomach well, and they could lead to aspiration. You wanna tell your patients to drink these over about 5 minutes, not over 2 hours, because that's where you get the best insulin response that leads to the clinical benefits that we see. So again, we want them to drink them quickly. And then the Other thing is, again, simple sugars are not ideal because it's the maltodextrin that produces the faster gastric emptying and all the studies have been done with this complex carbohydrate.
[17:02] Speaker 2: We don't want to give amino acids with this. Amino acids actually delay gastric emptying, especially arginine and citrulline, and they can lead to risk for aspiration as well. So you just want the complex carbohydrate.
[17:13] Speaker 2: This seems like a simple thing that we can do for our patients, but unfortunately, many of our patients are not getting it. And so this sad, sadly, this patient didn't either. So, she goes to Surgery, and then after Surgery, we recommend a high protein diet, not clear liquids, or some sort of um juice or broth be started, but a protein containing high protein drink be started on the day of Surgery. And we looked at this, we looked at patients who got clear liquids versus those that got a protein drink.
[17:40] Speaker 2: And in multiple studies, we saw significant reductions in mortality and Other meta-analyses have shown a similar effect, reductions in all the Other complications, including nausea and vomiting, that our patients see, and there was no risk associated with it.
[17:53] Speaker 2: So I think this is something that we really need to be better at doing. We need to feed our patients early, because we know they won't eat enough. We know our patients average about 700 calories a day, which is not enough to recover from a major Surgery. So, we recommend high protein drinks in all patients, and this was the strongest recommendation of the committee besides nutrition screening.
[18:12] Speaker 2: And again, there's lots of data for this oral nutrition supplements and many trials have been shown to reduce mortality, reduce complications, and over a 1 million patient premier database analysis, every $1 spent on these drinks saves $52 in hospital costs and shortened lengths of stay by 21%. This was over a million patients studied.
[18:31] Speaker 2: So again, we've looked at specifically Orthopedic Surgery outcomes, and these supplements lead to improvements in infections and in various orthopedic surgeries, complication and death have also been significantly reduced. So, again, these are key interventions for our patients. Um, we looked at the premium database for Hip fracture patients. We looked at 160,000 patients and we found malnutrition is poorly diagnosed in these patients. We only saw about 8% of them as codVID. We should be seeing like 30 or 40%.
[18:59] Speaker 2: And only about 4.9% of the malnourished patients got any high protein oral nutrition drinks during their hospital stay.
[19:07] Speaker 2: And so we compared outcomes and we found that patients that did receive them had a significantly shorter length of stay in practice, real-world practice. We like the HMB containing or HMB added oral nutrition drinks because there's a large randomized trial that shows it can reduce death at 90 days after hospitalization by 50%. So, significant reductions every 20 patients, you have a high protein drink with HMB as an addition to, you save.
[19:32] Speaker 2: Life every 20 patients. So again, this is critical to improving outcome. So as we finish key points, Sur creates a really unique teachable moment where patients will stop smoking, treat their diabetes, and improve their nutrition. And a lot of them will continue to do that throughout their stay. In fact, some of them we've even got exercise before Surgery repair, and they'll keep doing it. So this is a chance to really change a patient's life. Behavioral change needs to start with us.
[19:56] Speaker 2: And we need to be better. Again, these key things, we have to screen to find it, we have to deliver protein, and these drinks are critical. This is, if you wanna learn about starting a nutrition, surgical nutrition clinic in your center, this is a free paper if you wanna take a picture of this or you can download this article for free. We have all our posters, our screening tools, and we describe how we started our surgical nutrition clinic in this tutorial paper.
[20:19] Speaker 2: Um, if you wanna really learn a lot more about nutrition, we have a Duke Online clinical nutrition fellowship we've started that you can sign up for, and we'll teach you with experts from around the world to be able to learn more about clinical nutrition. So, with that, I wanna conclude and again remind everyone, no patient should ever have an Elective Surgery without nutrition optimization. And I dream of a day when our patients have a chance to be best prepared. And with that, I'll let the people who do awesome best take us out.
[20:57] Speaker 4: Yep, that just happened. What just happened? Nothing, OK.
[21:04] Speaker 4: Well then,
[21:05] Speaker 5: next time I'll have Surgery, I'm having it done EAS style. I'll have my skateboard ready.
[21:13] Speaker 5: All right, back to
[21:13] Speaker 2: work.
[21:16] Speaker 2: And with that, I encourage again, follow on Social Media, learn more. I'm happy to share these slides or the papers I shared with anybody. Feel free to email me at any time and I look forward to hearing the rest of the lectures and hearing the data to come. Thank you.
[21:34] Speaker 1: Thanks, Paul.
[21:38] Speaker 2: Just
[21:40] Speaker 1: OK, we're back on. So, patients need our help because they are just not getting enough on their own plates, uh, before they get to us.
[21:53] Speaker 1: Nutrition status is really complicated. We have 13 to 50% of all US adults suffering from a dual burden of obesity and disease, while 1/8 of households are food insecure, and malnutrition and nutrient deficiency are common, with 3/4 of US adults being energy rich and nutrient poor.
[22:17] Speaker 1: This is in large part because what they don't have on their plates at baseline. So the percent of adults who report consuming fruit less than 1 time per day ranges from 33% to 50%, depending on jurisdiction.
[22:33] Speaker 1: And some states report almost up to 47% of adults do not report consuming vegetables less than one time daily, and in the best case scenario, it ranges from 13 to 18%.
[22:47] Speaker 1: We just heard that protein consumption needs to be at 1.5 to 2 g per day during Surgery, Fracture, injury.
[22:56] Speaker 1: This is because we need Essential amino acids to stimulate muscle protein synthesis and trigger response of the release of anabolic hormones. We also need Essential amino acids to enhance sensitivity of muscle cells to the effects of resistance exercise, and tracer studies completed in older adults demonstrate that there's anabolic resistance to that protein absorption, that um makes it harder to stimulate muscle protein synthesis if you're not getting enough protein.
[23:26] Speaker 1: And then what protein we're actually the older adults are intaking through their diet, only about 70% of that, or 30% less than the intake is absorbed and available for metabolic processes.
[23:43] Speaker 1: The protein deficiency after Surgery means that preserving muscle takes a backseat to the body's need for Glycemic control and inflammatory response, and this can last 2 to 4 weeks depending on the severity of the Surgery or the injury, or the invasiveness of the Surgery. That translates into loss of loss of muscle volume estimated at 1% per day, which leads to loss of muscle strength.
[24:09] Speaker 1: So in elective Joint replacement, for example, you have patients being offered self-selected meals that are approximately 0.8 per grams per kilogram per day in the Inpatient setting. This is well below the needed 1.5 to 2.0 g per kilogram per day. What they're actually consuming is even less. On average, 0.6 g per kilogram per day postoperatively.
[24:34] Speaker 1: And 3/4 of joint patients experience appetite suppression that lasts a median of 4 weeks. When you look at orthopedic trauma populations, at least 60% of Hip fracture patients have protein, energy, malnutrition, and admission.
[24:50] Speaker 1: Their protein energy malnutrition in all orthopedic trauma populations was sometimes compounded by more than 1/8 of orthopedic trauma patients that experienced food insecurity at baseline before they were injured.
[25:06] Speaker 1: So you take an example of how the protein need and energy deficit can impact patients. Here's an example in Joint replacement. So we know in Joint replacement we've seen improvement in surgical techniques and early mobilization, reduced Inpatient stays that have reduced overall complication rates and improved the Patient experience. However, patients having Knee Replacement, for example, experience chronic muscle activation failures that that lead to persistent strength impairments that can last for years.
[25:37] Speaker 1: Total total Knee patients have 30 to 48% less quadriceps strength compared to healthy age match controls. The implications for functional independence in an older adult population are significant.
[25:49] Speaker 1: We know that quadriceps strength predicts functional independence in nursing home residents, and the greater the leg strength, the lower the degree of disability in community dwelling adults. So what we need to do is increase efforts to preserve muscle volume and perioperative care. We need to increase muscle protein synthesis, and so we can mitigate type 2 muscle fiber atrophy.
[26:12] Speaker 1: And that which leads to a persistent loss of muscle contractile force. So in short, we need strategies that synthesize more protein, so to support healing and preserve muscle volume at a time that it's really critical, and that we know patients are unlikely to be getting enough protein to meet metabolic demands.
[26:36] Speaker 1: So what we need to do is focus through our diet on improved nutrition status and really sure up what is on the plate. But we have to pair that with a targeted nutrition Approach that closes the gap between dietary intake and what the body actually needs to heal. To do that, we have to supplement with the missing micronutrients that are insufficient through dietary intake alone.
[27:05] Speaker 1: And that's exactly what my friend and colleague, Hans Dreyer did, when he started the journey of supplementing older adults undergoing Total joint arthroplasty with Essential amino acids before and after Surgery. And that work, he's grown and expanded to Other indications, including starting trials on mitigating muscle atrophy and ACL um reconstruction. I'll let Hans talk about his essential amino acid work.
[27:36] Speaker 6: Yeah. Thank you, Doctor Owen. That was awesome. Uh, the next slide, please.
[27:44] Speaker 6: Yeah, so here is um a title of a paper that we published back in 2013. This is a double-blind placebo controlled trial uh where we gave Essential amino acids to older total Knee patients uh um before and after Surgery.
[27:58] Speaker 6: On the lower left there, you can see the uh the composition of the supplement at that time. The percentages basically come from what you'd find in raw meat, for example, histidine, isoleucine, but leucine, in particular, there's highlighted in blue because we doubled the amount of leucine. So, these are, are, are ingredients that were started by Bob Wolf's Group back in Galveston a long, long time ago.
[28:20] Speaker 6: And we use them to our advantage to try to see if we can increase synthesis rates before and after different types of resistance exercise. It was during that post-doctoral experience that I had where I thought that this could be great for individuals uh before and after Surgery. And you can see there, we gave this supplement 2 times a day, uh, starting 1 week before Surgery, and then we concluded 2 weeks post-op, and then there's just a little sample of the characteristics of the patients.
[28:44] Speaker 6: Uh, between the placebo and the essential amino acid group. Here is a slide on our study design. So, so you can go back one slide, please. There you go. Thank you. Uh, so -2 weeks, we had MRI back one slide, please.
[28:57] Speaker 6: So we had MRI strength and function, uh, 3-day dialogues, um, and then 1 week before we started the twice daily supplementation of Essential amino acids. So this is 20 g of Essential amino acids that was given between meals. So our goal was truly a supplement, not a meal replacement. So between breakfast and lunch, we had them, uh, ideally take the first supplement and then between lunch and dinner, we had the same thing. And that was twice a day for the 7 days leading up to Surgery, in this case, total nearthroplasty.
[29:26] Speaker 6: And then for 2 weeks after Surgery. And after Surgery when they had Physical therapy, our goal was for them to ingest the Essential amino acids within 30 minutes to 1 hour after that, uh, Physical therapy session to maximize the anabolic response. Um, and then we, uh, also did, uh, um, follow-up, uh, MRIs and strength, etc. at 2 weeks post when the treatment stopped and also at 6 weeks to see how things, uh, uh, were preserved, uh, by that time. Next slide, please.
[29:56] Speaker 6: So here is some data for the uh for the functional test that we did, some of the functional tests that we did. You can see here in the open bars, the placebo group had an increase in the percent of time it took for them to accomplish each of these tasks. So, the higher up it goes, ostensibly it's worse, taking longer time to get up and go. The time up and go is basically getting out of a chair, walking a few meters, turning around and coming back and sitting down. So you can see in the open bars for the placebo group, again at 6 weeks post this.
[30:24] Speaker 6: was, uh, there's a significant increase in the time it took for them to accomplish this task, and you can see the same kind of trend for stair climb going up and stair climb going down. The difference between those two really is the stair climb down targets the quadricep, which is the, the muscle that we are most interested in here, but, um, we're also interested in Other muscles too, so, uh, next slide, please.
[30:46] Speaker 6: Yeah, so here is the MRI data for 2 weeks post. So again, the open bars is the placebo group, the dark bars is the essential amino acid group, and you can see here that 2 weeks post there's a significant atrophy in the placebo group, atrophy occurring in both groups, but much
[31:02] Speaker 6: More so in the those receiving placebo. The placebo here was alanine and that was also 20 g uh at the same time as the essential amino acid group. So we have on the top there we have quadriceps volume and we have the bottom, we have hamstrings and ADductors. We just kind of group those together. Next slide, please.
[31:21] Speaker 6: So here is the 6-week data and you can see the transition from 2 to 6 weeks is not a very, uh, not, not very different really at all. Uh, there was some catchup atrophy, if you will, in, uh, in both groups, it looked like. Um, but, uh, overall, the, the majority of the atrophy seemed to occur within the 1st 2 weeks. I'll get to that, uh, in just a few seconds here. Next slide, please.
[31:46] Speaker 6: So this is a follow-up study. So the first one was, was funded by startup funds here at the University of Oregon as well as some uh funding that I got through a CAMM mechanism. This was actually funded through an RO1 mechanism. Uh, this is our second double-blind placebo controlled trial.
[32:00] Speaker 6: Uh, where we gave Essential amino acids to the same cohort of individuals. There you can see the, the cocktail, didn't change. Uh, the only difference here is that we gave for an additional 4 weeks. So instead of ending at 2 weeks post-op, we did end at 6 weeks post-op, seeing if we can address some of that little kind of additional atrophy that occurred once we, uh, ended the treatment in that, that prior study. Here you can see a breakdown of the, of the subject characteristics at baseline. You see, there's
[32:25] Speaker 6: Number of different things on there, but I will also just highlight that tourniquet time didn't change between the two different studies, but I will just say that there's a difference between tourniquet times from teaching hospitals, which can go up to closer to 2 hours versus um individuals who are doing, uh, you know, 8 to 10 total knees in a day, for example. So there's also some physical activity data there, and it was not different necessarily between groups. Next slide, please.
[32:54] Speaker 6: Yeah, so here is a sneak peek at this study design. No real difference Other than the blue arrow basically is a little bit longer since we went for 4 additional weeks. Next slide, please.
[33:06] Speaker 6: OK, so here is um the uh the uh replicate data. So, on the left, we have the six-week data for the JCI paper on the right, the 2018, we have the, the paper, the, the MRI data that was published in 2018, JBGIS and you can see that the two Clinical trials are fairly similar in terms of their MRI data. Uh, it was unfortunate we did do strength and function and we didn't see the, the differences between groups that we saw in the 2013 paper.
[33:35] Speaker 6: Um, that could have something to do with patient activation measures which Doctor Owen can speak more to. Um, there are different, there's lots of things that are contributing to these, these, um, uh, why the, the patients may or may not be having a catabolic response that's more or less than Other individuals, but, um, I will just say that the, the two studies were fun to do, but there was a difference in how the patients kind of looked in the 2013 versus the 2018, uh, cohort. And so I think there's a lot more, um.
[34:03] Speaker 6: Area for study that's, that we need to, to, to figure out. Um, next slide, please.
[34:11] Speaker 6: So, one of the things that we did also include in that second follow-up trial was uh biopsies. And the next slide, please.
[34:20] Speaker 6: So our, our rationale for the biopsies was that uh as I spoke to for the 2013 paper, we noticed that uh if you look at the total amount of muscle loss at six weeks post-surgery, you would expect not much more loss after that. And, in fact, it should start to return a little bit. Um, but the majority, 80% of that muscle that was lost by 6 weeks had all occurred already by 22 weeks. So it's a very rapid process.
[34:45] Speaker 6: And muscle nerves like myself have been debating whether or not the atrophy that occurs with uh bed rest or uh putting a boot on or unloading with crutches, etc. etc. is typically the result of a decrease in protein synthesis. Now, this could be
[35:00] Speaker 6: Synthesis that's occurring after a meal, as long as it has protein, it would be an anabolic, uh, but also between meals. So synthesis rates was reduced by 50 to 60% in both those scenarios, post meals as well as between meals. But this at 14%.
[35:16] Speaker 6: Uh, 14% at 2 weeks, which is about, you know, percent of muscle mass loss per day, that's above and beyond what you'd expect as a result of just a reduction in protein synthesis rates. So I do think that this is actually an active catabolic pathway that we're trying to mitigate and we're having some success with success with, with the Essential amino acids. I'll just put this out there that everyone, when they wake up in the morning, that all of your muscles are in a catabolic state.
[35:44] Speaker 6: So we are metabolizing skeletal muscles so we could have uh non-essential amino acids, alanine and glutamine in particular, leave and then go off to the, to the liver, have the nitrogen removed, and how we have glucose. So that's brain fuel, that's our default uh evolutionary kind of constrained, um, part of our, our biology. So, next slide.
[36:07] Speaker 6: Thank you. So the biopsies, uh, we had uh bilateral biopsies, uh, take place in the OR. This is before the tourniquet was, uh, inflated. So again, on the operative and non-operative side in the OR and then we had, uh, the, the subjects randomized to either have bilateral biopsies at 1 or 2 weeks post. You can see the end there, which is slightly bigger than the or larger than the, the prior study, but uh, not significantly so. We really need this to be like in the 100s, etc. Um, so, next slide, please.
[36:40] Speaker 6: So here is the uh some surprising data that we found. So these are, these are muscle satellite cells, and you can see here on the top A, B, and C, this is the essential amino acid group. This is a merged image of both PAC 7 of the A slide is PC 7 demise and heavy chain 1, basically just fiber types, and then dappy stain for nuclei, I'm sorry, laminin.
[37:02] Speaker 6: And we also have the placebo group that's just below that and uh and below that we have a bar graph that indicates the levels of satellite cells per fiber and the um in the uh preoperative part for both the um the uh the uh the treatment group and the the placebo group, you can see there's grossly different.
[37:24] Speaker 6: So, um,
[37:27] Speaker 6: This was quite surprising for us. So we were expecting actually satellite cells to be elevated postoperatively because ostensibly they should be induced by damage. So this figure to the right, which is a reproduction of what Hawke and Gary published back in 2001.
[37:43] Speaker 6: Shows the ideology of satellite cell recruitment. It goes to the zone of injury. They increase in numbers. They proliferate. They donate DNA ostensibly to the to the damaged muscle fiber in order to promote the regrowth, and then they kind of have a centrally located nuclei which was from the satellite cells. Now it's a myonuclei, and then it comes back towards baseline.
[38:05] Speaker 6: And what we see here in that figure on the lower left is that satellite cell numbers were elevated in response to 7 days of twice daily ingestion of Essential amino acids. This is relative to the Other group, the placebo group, which received alanine, so still nitrogen coming into the body necessarily, but just in a non-essential form, so.
[38:24] Speaker 6: Um, this is very, uh, very interesting results. Again, I was expecting damage to occur postoperatively since we're having a major Surgery and a tourniquet on for some period of time. And, and again, there's also massive, uh, muscle loss. So why is that loss occurring? Well, it seems like it's a number of different things. OK. Next slide, please.
[38:45] Speaker 6: Yeah, so here's just a little bit more data. This is central nuclei again, we're expecting these numbers to be elevated postoperatively, and they all seem to be elevated preoperatively. So, again, these centrally located nuclei ostensibly, presumably would be coming from satellite cells, and the fact that we saw so many more of them preoperative.
[39:01] Speaker 6: Versus postoperative will suggest that preoperatively something is going on with the muscle cells, um, that this, the, the Essential amino acids may be having a favorable response. In Other words, promoting the satellite cell numbers, and that may or may not be connected to what we're seeing here with these central nuclei.
[39:18] Speaker 6: But these are very interesting results suggesting that there's some level of damage signal that's causing the central nuclei, ostensibly from satellite cells to be recruited and uh be prominent before uh Surgery is even occurring. So I'm not sure if this is related to the changes in medications that are occurring before Surgery or um uh I'm not really sure. So, next slide, please.
[39:46] Speaker 6: There is another marker of, of damage. This is the stained for NCCAM. These are proteins that are increased in expression inside muscle cells. You can see that those kind of uh asterisks with the green, light green in the background. Uh, that's an increase in expression of this protein, uh, and it presumably occurs ostensibly because of denervation. And again, we saw this up regulated preoperatively and not necessarily postoperatively. So, um, again, just another indication that there's a lot of interesting things that are occurring preoperatively that we should probably get a better handle on.
[40:16] Speaker 6: Uh, in addition to the nutrition status, um, in all these patients. Next slide, please.
[40:27] Speaker 6: So, this is a very preliminary data. This is not published. This is from young individuals, uh, also, um, I'll say that it's placebo controlled. So we had 2 in the placebo group, those are the open bars down there in the, uh, the bottom right. And we had 4 subjects. These again, healthy college-aged individuals.
[40:44] Speaker 6: Uh, we had 4 of those subjects. And what we gave them was, uh, a little bit of a, of a different, uh, cocktail. This time we had quite a bit more of the leucine, so 5.8 g per dose and fairly similar proportions of all the Other Essential amino acids. Um.
[41:02] Speaker 6: And we gave this to them for 7 days. That's what you can see here at the 7-day mark. This day 8 and day 14 are after an eccentric exercise damage protocol. But what we have here is identified as type 1 fibers and type 2 fibers, and you can see that those, again, young college aged individuals who are on Essential amino acids, and this is actually 3 times a day, not twice a day, but 3 times a day.
[41:26] Speaker 6: For 7 days and it had an impact on their satellite cells. Again, this is also very surprising. These are muscle stem cells, resident stem cells that are impacted by amino acids. So this was also very, very surprising and very preliminary, and we're pursuing this heavily to see if we could take advantage of this increase in satellite cells in young and old and anyone essentially to possibly increase muscle resilience.
[41:54] Speaker 6: Some of that resilience seems to be accounted for or attributed to the increase in nuclei. One of the main ways to get new nuclei in skeletal muscle is through satellite cell activation. So this might be a very promising avenue for uh for the Research. I will just close by saying that there was some published data from Tom Rando's group down, down at Stanford where they did the opposite. Instead of increasing the amount of amino acids that were going into their animal models in this case.
[42:22] Speaker 6: Uh, they decreased it and they saw that the satellite cells in that case were refractory. They went into deeper acquiescence and ours seems to be the opposite. So if you think of it was a ketogenic diet or a starvation diet on these animals, the satellite cells are attenuated in my studies so far. We give them extra Essential amino acids, ostensibly more food, energy, and there was a positive impact on, on satellite cells.
[42:49] Speaker 6: This slide here just is in general for all orthopedic surgeons, all medical doctors in general, to show you the kind of ideology of sarcopenia. So, down on the lower left, you can see that's Mike Schultz. He's actually a, a recent uh uh victim. He survived, but he lost a significant amount of muscle mass because of COVID, because he has a port in, so there was nutrition being pushed into him, but there's still a significant
[43:13] Speaker 6: Amount of, of muscle loss and I believe it was about 30 or so kilograms or about 50 pounds of weight loss. This was 6 weeks, I think he was on an event, um, and also was having a food supplement. So this would be an example of rapid muscle wasting and a healthy individual. Uh, on the right, you can see here, this is actually Doctor John Turner. This is a book that was published a while ago.
[43:35] Speaker 6: And he at 67 on the left and then I believe at 79 on the right was an active resistance trainer, but he still lost skeletal muscle. So this will be indicative of the age-related loss of muscle that is occurring in all of us and much more prominent in older individuals. And this is despite the fact that he continues to do resistance type training. It's not well controlled. It's just, you know, pictures, but they exemplify what we're trying to talk about here, so.
[44:01] Speaker 6: Uh, these are examples of, of, of muscle loss. If you look in the middle two sections there where it's kind of a stepwise reduction in muscle loss, that can happen in any older adult, younger adult, etc. etc. with uh just a limited amount of immobilization. So, our muscles.
[44:17] Speaker 6: Very difficult and it takes a lot of time to gain that muscle mass, but it takes almost no time whatsoever to begin to lose that muscle mass. You can just go back to the two week post total Knee data, so that was 14%, 1% per day. That's pretty significant, so.
[44:32] Speaker 6: Uh, with that, I'll, uh, turn it over to Doctor Wiley. Thank you.
[44:42] Speaker 7: Thanks, Hans. That was a great talk. It's uh really cool to see you summarize all that data uh you've put together and a lot of our work has been based on that. So it's uh really cool to see that.
[44:53] Speaker 7: Um, go ahead to next slide, Catherine.
[45:01] Speaker 7: So I'm a uh orthopedic trauma and Hip surgeon at the University of Iowa. Um, you can progress to the next slide. Uh, we have a specific interest in uh nutrition interventions to improve outcomes.
[45:13] Speaker 7: These are my disclosures.
[45:16] Speaker 7: Thanks for the opportunity to present this work.
[45:20] Speaker 7: Uh, so I'm gonna focus on two patient populations. Uh, number one, older adults with Hip fractures, uh, as well as our younger adults, uh, that we treat with high energy trauma. And in both of these groups, we see a major problem with loss of function and independence after these injuries. Um, we note that these patients have significant loss of muscle mass. And we see, uh, nutrition interventions, uh, uh, and their potential to prevent, uh, these losses after trauma.
[45:50] Speaker 7: Next slide.
[45:58] Speaker 7: So, these two, patients specifically, as we've shown in these Other, um, talks, uh, Hip fractures, very commonly required discharge to a skilled facility. Uh,
[46:10] Speaker 7: You know 1 in 5 individuals will require a long-term stay in a nursing home after injury. And when we looked at our patients, we had about a 10% incidence of mortality at 6 months.
[46:22] Speaker 7: This is also reflected in younger adults who have high energy trauma. We know that in service members, over 1/3 do not Return to work, school, or active duty by 2 years after high energy trauma. And this is definitely reflected in our civilian patients.
[46:39] Speaker 7: Next.
[46:44] Speaker 7: So the goal of our group uh is to develop interventions to prevent complications and loss of function independence after trauma.
[46:52] Speaker 7: Next.
[46:56] Speaker 7: So we know that malnutrition is common, as we've seen in these Other talks. It varies widely depending on how you define uh malnutrition.
[47:05] Speaker 7: Uh, we, uh, did a study in the Pearl Diver database, specifically in patients with Hip fracture. And documentation is very infrequent. Uh, only 13% of patients where it's actually recognized while they're in the hospital. But we did find in this study in patients where malnutrition is recognized, they have increased risk of mortality, wound infection, and also difficulty healing the Fracture.
[47:30] Speaker 7: Next.
[47:34] Speaker 7: And this is a, a slide demonstrating recognition over time of uh malnutrition in older adults with Hip fracture. You can see it was very uncommonly recognized in 2010. But as we progressed to 2019, uh, malnutrition is a much more recognized risk factor in these older adults.
[47:54] Speaker 7: Next,
[47:57] Speaker 7: And when we reviewed all of our patients uh that had trauma, uh, we did find that low albumin, uh, as Paul presented in his talk, was predictive of complications. But also the malnutrition diagnosis was the best predictor, um, of complications after trauma, indicating that it's really important to include a dietitian on your team, uh, when treating these patients.
[48:22] Speaker 7: Next,
[48:26] Speaker 7: So we did uh nutrition, food frequencies, screening questionnaires, and all of our trauma patients, uh, who we treated with Fracture fixation. And we documented significant macro and micronnutrition, uh, uh, nutrient deficiencies after injury. In Hip fractures, 78% of our patients had less than 1 g per kilogram per day of protein.
[48:49] Speaker 7: And actually, the mean um protein intake was um less than that 1 g per kilogram per day in almost all of our patients uh who are young after trauma. So most of these patients are not meeting their needs after injury.
[49:07] Speaker 7: Next.
[49:11] Speaker 7: So I like this slide, because this really demonstrates how um both poor intake, poor absorption, as well as the inflammatory and catabolic response after injury both lead to malnutrition, which leads to the complications that we see, including altered healing, infection, and then the loss of muscle function.
[49:34] Speaker 7: Next.
[49:39] Speaker 7: So, uh, we've designed a series of studies, uh, working with Doctor Owen, uh, also, uh, where we quantified changes in muscle mass after trauma. We looked at Risk factors for loss of muscle mass. And we're also interested in the relationship between muscle loss, malnutrition, and loss of function after injury.
[50:03] Speaker 7: So, we took a large group of our trauma patients, which included both Hip fracture, uh, older adults, as well as uh younger people who had high energy trauma. And we measured, uh, body composition using BIA. Um, one of the previous talks, uh, did mention some alternative methods for measuring body composition, but this is what we chose for this study.
[50:26] Speaker 7: Next slide.
[50:28] Speaker 7: We evaluated a pre-injury malnutrition uh using the mini nutritional assessment.
[50:34] Speaker 7: And we also screened for um protein deficiency um prior to injury using the uh protein screener uh 55.
[50:44] Speaker 7: Next slide.
[50:47] Speaker 7: And advance again.
[50:50] Speaker 7: So this is our Hip fracture patients, uh, first. Uh, so you can see on the Y axis is skeletal muscle mass, and on the X axis is time of injury up to 6 months. And what we saw in our Hip fracture patients is that there was a significant loss of skeletal muscle mass, specifically in the 1st 6 weeks after trauma.
[51:11] Speaker 7: It's interesting that it was actually the patients with a normal nutrition status that lost more skeletal muscle mass uh early after injury.
[51:21] Speaker 7: As we looked further out through time, uh, the patients had a persistent decrease in the skeletal muscle mass that did not recover back to their baseline, even to 6 months.
[51:33] Speaker 7: Next slide.
[51:37] Speaker 7: And we quantified physical function, uh, using the promised physical function score. And you can see the drastic decrease, uh, from baseline to 3 months, uh after a Hip fracture, and then only slight recovery that doesn't come near that, uh, baseline function that these patients had prior to injury.
[51:57] Speaker 7: And we were able to find that there was a correlation between loss of muscle and that loss of uh physical function. So then, we also graph in our young high-energy trauma patients, uh, looking at changes in skeletal muscle mass after time.
[52:13] Speaker 7: As you'd expect, uh, our younger patients had a higher starting, uh, skeletal muscle mass. But these patients saw a similar loss of skeletal muscle mass in the 1st 6 weeks after trauma.
[52:26] Speaker 7: One point that I think is an interesting distinction in our young patients is that loss of skeletal mass continued between 6 weeks and 3 months after trauma, indicating that these patients were more severely injured, likely leading to more loss of skeletal muscle mass, but also that these patients had a higher baseline and more baseline function or muscle mass to lose after injury.
[52:55] Speaker 7: Next.
[53:00] Speaker 7: So, currently in, uh, orthopedic practice, we don't have a lot of guidance on how to screen or treat malnutrition. Basically, our academy recommends screening, but there's really no guidance for the screening method, when to use a supplement or that supplement's composition. So, that leads to the next step in our work.
[53:20] Speaker 7: Next slide.
[53:23] Speaker 7: So we performed a randomized Clinical Trial of all of our patients who are indicated for Fracture fixation over 18 years old. Next slide.
[53:36] Speaker 7: So we stratified these patients to older adults with fragility fractures, our multiply injured patients, uh, including open fractures, and also isolated fractures and randomized these three groups to nutritional supplementation. Next slide.
[53:54] Speaker 7: So our intervention was a conditionally essential amino acid, uh, that included 7 g of arginine, 7 g of glutamine, and 1.5 g of HMB. And this was dosed twice daily for 14 days.
[54:09] Speaker 7: Next slide.
[54:14] Speaker 7: And we found some really interesting results. Uh, we enrolled 400 patients. Uh, and in our intervention group, we found a significant reduction in overall complications, a reduction in non-healing or, uh, non-union or difficulty healing fractures, as well as a reduction in mortality in patients that received, uh, the, uh, nutrition supplementation. Next slide.
[54:43] Speaker 7: Additionally, uh, we found that a loss of a, uh, lean body mass, uh, using Ultrasound, uh, was seen in our control groups, our patients that did not receive supplementation, um, where we did not see that loss of skeletal muscle mass in patients that did receive supplementation.
[55:02] Speaker 7: Next slide.
[55:07] Speaker 7: So, uh, in summary, a substantial loss of skeletal muscle mass occurs after trauma. And that's all the way through the age spectrum. Uh, we see that in young patients, uh, with high energy trauma and also older adults with Hip fracture.
[55:21] Speaker 7: Uh, the loss of function and independence in both of these groups is unacceptably high. I, I really liked how Paul highlighted that in his talk. Um, we need to be doing better for these patients after trauma.
[55:33] Speaker 7: Uh, we found in our, uh, preliminary Clinical Trial that, uh, 2 weeks of twice daily, uh, amino acid supplementation can reduce overall complications and also present the early loss of skeletal muscle mass.
[55:48] Speaker 7: Uh, so we recommend protein and amino acid supplementation, uh, after undergoing Fracture fixation Surgery.
[55:57] Speaker 7: Next slide.
[56:02] Speaker 7: So, just to acknowledge our funding sources for this work, the academy, uh, as well as the OTA.
[56:09] Speaker 7: Next slide.
[56:13] Speaker 7: And I also acknowledge our Research team, and specifically uh Doctor Aaron Owen, who's been an excellent collaborator with all this work. So, I really appreciate all your effort into it.
[56:25] Speaker 7: Thanks.
[56:34] Speaker 1: Well, as everyone is joining, I see there's um quite a few questions, and so I'm gonna consolidate a couple of them and ask you to all identify what the placebo was you used, um, for your trials, um, and that shows up a couple of times in the questions, um, when you're studying nutritional interventions.
[56:55] Speaker 1: So which placebo did you use and what do you think is a good idea? Let's do both at the same time.
[57:03] Speaker 7: I can go first with our Clinical Trial, probably cause ours was the most simple. So, we maintained our patients on a standard diet. So, we did not provide a controlled placebo, uh, supplement for the patients in our RCT. I think the advantage of that is we are not altering their diet at all. So, you can look at exactly how these patients will behave, um,
[57:30] Speaker 7: Without additional supplementation.
[57:33] Speaker 7: Anything that you give them additional, I think could affect uh the outcomes that we looked at. So I think.
[57:40] Speaker 7: There is a disadvantage in that.
[57:43] Speaker 7: You know, those patients probably feel let down because they don't receive a supplement, may go out and seek a supplement. But um I felt like it was a clean study that we did because we didn't change at all what the patients were doing for nutrition.
[58:02] Speaker 6: I'll just add that we chose uh alanine because it was a non-essential amino acid. And I am not, uh, I don't have, I have a suspicion that alanine actually could be beneficial in this regard because it is contributing nitrogen necessarily, which I think is probably one of the things that's necessary for any kind of trauma or immune response. You need more of those nitrogens. I mean, amino acids, be them essential or non-essential, are much different than fats and carbohydrates. They should be considered almost independently on their own.
[58:30] Speaker 6: Um, as their own category as nitrogen can be very valuable. I mean, as we mount an immune response, we are also synthesizing new DNA and new RNA, mostly through salvage pathways.
[58:42] Speaker 6: Because the immune response needs to up-regulate all the white blood cells, etc. So that's, that's a rapid increase in cell mass for those different immune, uh, uh, pathways, so.
[58:53] Speaker 1: Doctor Wichmere, do you have any placebos of choice?
[58:57] Speaker 2: Yeah, you know, we often have used maltodextrin, um, as, as a placebo because we don't want to deliver any protein content because we're often studying the effect of specifically an amino acid or protein. Uh, so we've used maltodextrin in the past for some of the NIH studies that we've done. Um, that big, uh, oral nutrition supplement study that reduced hospital mortality by 50%.
[59:20] Speaker 2: Um, used a low calorie non-protein containing control nutrition supplement that was boxed and made to or or put in a container looked the same. And so that when you get into sort of more elaborate studies of particular drinks, right, you can use even similar appearing low calorie, uh, usually not with protein of any sort in them containing.
[59:43] Speaker 2: Uh, supplements. We have also used alanine, Hans, in, in some of our studies at times, um, in the laboratory and outside the laboratory. But I agree with you. I mean, any amino acid potentially could provide some benefit. Allanine is very nicely turned into glucose, which could be a benefit in as much as like a carb load is. And so, um, which maltodextrin supposedly could as well, I suppose, um, because it's what's contains in the carb load. So.
[1:00:08] Speaker 2: I, I think what Mike did is actually the best of all things because I think what we wanna compare to is what patients are doing now, which is their standard diet. And so I think the most robust for the place we're at now we clearly have this wealth of data that nutrition helps it, it is comparing what we can do in addition to what patients are doing now and have them comply with um above and beyond their standard diet, which I think that's the most robust.
[1:00:42] Speaker 6: I'm not, I, maybe that's directed towards me. We actually haven't done any studies in ACL patients, but we would like to. We have tried to get funding for it, but we were unsuccessful many times.
[1:00:56] Speaker 7: And quad atrophy is a real problem with ACL reconstruction. So I think there's a, you know, that's a patient population that would benefit from something to preserve muscle.
[1:01:06] Speaker 6: 100%. I agree. 100%. Absolutely.
[1:01:14] Speaker 6: Mm,
[1:01:16] Speaker 2: so, I mean I can touch on this. I might be curious what you think too, but um.
[1:01:21] Speaker 2: You know, there are a range that exist, um.
[1:01:25] Speaker 2: When people are in the hospital, obviously, um, most hospitals have contracts with certain suppliers. Well, and I'm gonna list some product names now because that's the ones that are typically occur in our hospitals, either Abbott or Nestle. Um, at Duke, we're an Abbott Hospital. Um, we have like their HMB containing Instru Li product, although that's hard to get right now, I will tell you.
[1:01:50] Speaker 2: But I can tell you when patients go home, I actually send them advice to, sadly, because there isn't the perfect supplement for patients to take it home to supplement their diet beyond sort of the Ensures and, and some of the Other drinks, um, I'll have them get HMB and, and some of the Other supplements right from Amazon. I think the perfect product doesn't yet exist that I think is simple and combines.
[1:02:15] Speaker 2: The and I'll have them get branchin's amino acids by themselves, but I think what we want is a product that combines branch chain amino acids, whey protein, HMB, and some of the nutrients that have a lot of robust data to them that makes it simple for the average patient to take. And I think, um, you know, that product.
[1:02:34] Speaker 2: Needs to be developed and I think needs to be there because it's complicated for patients to try to take them individually. So I, I've had a lot of surgeries in my life, 27 big abdominal surgeries and 5 or 8678 orthopedic surgeries. Um, and, and so I take mine individually, but my life is nutrition and, and because of my surgeries and always being at risk for them, um, that's something I have to obsess about and take separate luggage with me when I travel to take all the supplements I take, and most people are not gonna do that.
[1:03:00] Speaker 2: So I think there's a real need for the ideal products to be made. If I had to say, I don't know, Mike, what do you think?
[1:03:07] Speaker 7: Yeah, it's a, it's a good question. Um, I would say that the two main issues for my patients are cost and also portability. Um,
[1:03:18] Speaker 7: You know, we do have a contract at our hospital and do provide supplements while they're Inpatient, but it's a different thing when they go home. Um, so I've had the best luck with, um, powder supplements and containers that are, you know, easily mobile, and they can fill it with a scoop that's easy for them to use. Um, also, the packets, I think work really well. I've had not good success with the liquid supplements that come in a bottle because they're
[1:03:46] Speaker 7: A lot, it's a lot for patients to transport home.
[1:03:51] Speaker 7: Is my very simple answer logistic issues,
[1:03:55] Speaker 2: yeah, we use the insulin lives, but and insure max proteins, but they are, they're all liquid and that you need a bunch of them to, to, to get anywhere.
[1:04:03] Speaker 1: And um, although we're keeping this, uh, you know, kind of entirely, um, you know, on the scientific side, um, the panel, uh, was put together by Ms Labs, so, um, you're definitely you could check out, check out some of the nutritional offerings that we have, um, as well.
[1:04:24] Speaker 2: I, I'll just say, I think one of the exciting things just from a person who's just started looking at the men products and looking at what they make, some of the things that they're creating really, I think are gonna fill these holes, um, uh, and are really gonna be unique products that I, I think have been needed to be made for a long time. And
[1:04:41] Speaker 2: I, I think it really shows a lot on their part that they are going for medical food indications and they're going to NIH and Other sort of academic researchers like 33 of us you see here to help them think about and talk about the best ways to do this, um, and, and I think that, that, that's bodes well for the future.
[1:05:01] Speaker 1: And on the, you know, on the supplement cost side, um, it is definitely a problem, and we all on this panel believe that this type of, um, supplement access should be available to all patients. Um, one of the strategies for that is to get the, um, supplements actually manufactured, um, and recognized as medical foods instead, and the Joint replacement formula, um, that, that we, uh, currently offer at ME, um, that was developed by Doctor Dreyer, um.
[1:05:31] Speaker 1: I actually was just approved by Medicare and assigned a code that's a non-reimbursed code in Medicare but is a reimbursed code right now in many commercial insurance plans and many states that recognize medi you know, food as Medicine um and uh for their Medicaid programs. So this is expanding. We do expect that um kind of these medical foods will gain traction over time and costs will become less of a barrier.
[1:06:02] Speaker 2: That's huge. Yeah, it is a challenge. There are about 200 insurers that we know about there that do cover some of these protein supplements and some of these protein drinks. Um, but, you know, it's, you have to kind of really help patients navigate that and in order to get them reimbursed, and I, we hope this is the future, honestly, those of us who do nutritionist.
[1:06:23] Speaker 2: You need to write a prescription for these nutrition supplements for your patients, and we actually do that sometimes in our clinics. They can take it to an Outpatient pharmacy and then their insurance will cover it.
[1:06:33] Speaker 2: Um, and so I, I think that's part of the future, right? I think in order for patients to value nutrition, A, they need to hear from their surgeon, as someone who lives and dies by the surgeons that operate on me, what they say is the word of God. And I think we as physicians need to be writing prescriptions that make this look equally as important as the antibiotics they take and the Other medications that, they take that they would never not think of taking.
[1:06:55] Speaker 2: But they see nutrition as optional. And so I think the future for nutrition really being taken up by patients and complied with is we need to write prescriptions for these supplements in the same way that we'd write a prescription for an antibiotic or another medication because then patients realize this is essential to my outcome and to my care, like the drugs I take. And, and I think then actually there are some insurers that are beginning to cover like you're experiencing, Erin, and.
[1:07:20] Speaker 2: And I think it's really actually outstanding that that Medicare has stepped in and decided that this is a really valuable asset.
[1:07:26] Speaker 7: Yeah. Paul, I think that's a really good point about prescribing. Um, I, I hope that someday this is really similar to how we give DVT prophylaxis and Pain medications when patients discharged from the hospital. It would make sense that a nutrition intervention could be provided in the same way. We've gone to doing vitamin D prescriptions for patients when they leave the hospital, but there's definitely a lot of improvement we could do.
[1:07:53] Speaker 2: And there are lots of hospitals that pay for these supplements. They've realized, so the University of Indiana and the University of Pittsburgh are two examples. They found, they've realized they're so cost effective in improving outcomes for patients and reducing the stay. We're all trying to get our beds, you know, available. There are hospital systems that actually pay for these and give them to their patients, and I think that is a major part of the future as well. These are so cost effective to give.
[1:08:20] Speaker 2: That there's lots of CMOs that are realizing and hospital residents are realizing, gosh, we should just give them to the patients for free, and that is happening in big hospital systems and we hope that happens and more.
[1:08:38] Speaker 7: This one's probably a good question for Hans.
[1:08:40] Speaker 6: Uh, I didn't really want to chime in on this one. I mean, when you talk about intact protein versus, uh, non-intact or just raw amino acids. I say that the raw supplement version of amino acids is easier to absorb, so the absorption kinetics are much, much faster. So there might be some benefits there on the anabolic side.
[1:08:59] Speaker 6: Uh, when we talk about protein, I kind of sometimes think about uh intact protein versus a vendor to purchase from that's already been kind of covered. Uh, so, with regards to those two things, um, you could say that you might be able to recoup or not make it so much more expensive by just asking them to eat more protein, for example.
[1:09:17] Speaker 6: Chicken or beef, but besides the cost of that, um, there is some digestion there, some mechanical and chemical, etc. that's occurring within our systems that just slows down that process. And so some of the data would suggest at least the kinetics of the, um, the entrance of, of the amino acids into the body. So again, mouth to anus is outside the body. The bacteria, the microbiome is taking their fair share. That's probably upwards of about 30, maybe even more% of whatever we eat, they're taking that.
[1:09:46] Speaker 6: And then the remainder just gets absorbed into the body. So with that, the work is less if it's already just kind of digested for you. It's free, uh, floating, if you will, uh, amino acids.
[1:09:56] Speaker 1: Yeah, Hans, do you remember, um, off the top of your head, and I, I think I might if you don't, the number of chicken breasts you would have to eat to get equivalent amount of amino acids of one day of EAA supplementation.
[1:10:10] Speaker 6: With one of our supplementations, yeah, I don't know. I don't remember the number.
[1:10:14] Speaker 6: No, go ahead and just,
[1:10:15] Speaker 1: I have a, I have a, it's, it's 9.3, 9.3 additional chicken breasts per day. Um, you would have to eat to get the same amount of Essential amino acids as the 20 g twice daily in the supplement,
[1:10:26] Speaker 2: yeah.
[1:10:28] Speaker 2: Yeah, we really advocate that patients, and I, I tell this to all the patients before and after Surgery, really think about using whey protein, right? We know there's robust data that shows that whey protein is much more efficient at being absorbed and utilized into muscle in both young athletes, young.
[1:10:46] Speaker 2: Healthy people and elderly people, it's much more efficient to being absorbed and making muscle than egg protein or eating foods protein, or case or Other forms of protein, and it's markedly better to say than a vegetable protein. I have a lot of patients that tell me, oh, I, I wanna take in a soy or a vegetable protein, and I'm like,
[1:11:04] Speaker 2: Please, please don't do that. That's not nearly as efficient in helping you recover from Surgery or helping you repair or for the athletes that I work with, um, in helping them build muscle. And so whey protein, I think is critical. And then Essential amino acids at night have a robust set of data to show that that's when you should take them and.
[1:11:22] Speaker 2: If you take branch chains at night, there's data that shows you can add 15 to 20% more muscle mass even in elderly folks, but especially in athletes. I grew up as a personal trainer in a professional bodybuilding gym, and everybody took their branch chains at night before they went to bed. I've been doing it ever since for 2030 years now. Um, that is a critical time for branch chains to be taken in because there's some unique benefits of the branch and amino acids and the leuccine that, that they contain. And so, and especially taken at night or after exercise.
[1:11:51] Speaker 2: And so, you know, there's really a strategy to this where there's a lot of data that exists for the benefits of whey protein and branch chains, and the timing of them as well that we are trying to now impart to patients um as they recover.
[1:12:06] Speaker 6: If I could just add to that timing component, I think, uh, besides, before they go to bed necessarily, especially for older individuals, but as soon as you wake up in the morning when you're in that catabolic state, those are the two prime times when a massive amount of amino acid should be ingested. And ostensibly, everyone, everyone should be getting at least 100 to, you know, maybe 150 or more grams of protein per day.
[1:12:29] Speaker 6: So, uh, the majority of that should be equally distributed between the morning and the pre-sleep meal, if you will. That could even be, uh, pre-sleep could be something like caseian as opposed to whey where it's kind of slowly digested so that the amino acids, the branch chains, etc. can get into the, um, into the body, um, a little bit more, more slowly. So, to offset some of the metabolism, that is a default parameter of us as we all go to sleep, uh, to basically maintain, uh, blood sugar levels.
[1:12:59] Speaker 2: And of course, your growth hormone and your, your anabolic hormones are released overnight. So if you wanna gain muscle optimally, you've got to provide that fuel and that building block of the amino acids and the branch chains and things overnight while you're
[1:13:11] Speaker 2: sleeping.
[1:13:13] Speaker 1: Doctor Wichmere, I think this question is well teed up for you and your perioperative Medicine expertise across all different types of surgeries.
[1:13:21] Speaker 2: Yeah, yeah.
[1:13:23] Speaker 2: Yeah, I mean, for sure. So, and, and, you know, tonight I, I, I, I didn't show a lot of the data, of course, that exists for many of the Other kinds of surgeries. The, actually, the bulk of the nutrition intervention data, a lot, a lot of it exists in GI Surgery, colorectal Surgery, GI Cancer Surgery in particular has robust data, um.
[1:13:44] Speaker 2: There's a study of 900 Cancer patients where they looked at people who got 70% or more of the ERAS components and they looked at their 5 year survival 5 years after the Surgery. If you got 70% or more of the ERAS components, your 5 year survival was 40% higher. Of the factors of ERAS that predicted that survival, the number one factor along with fluid management in the OR was nutrition delivery on day one after Surgery.
[1:14:11] Speaker 2: And so feeding people the day after Surgery appears to have significant effects even 5 years later, um, in, in patients. And so there is robust data and if, if any of you want that data or want some slides around that data or some papers on that data, I'm happy to share those if you guys wanna email me and, and we share them a lot on our Social Media and Instagram and Twitter. But, um, but there is robust data in those Other surgical areas. I think Orthopedic Surgery is where we need to Research the most. It's one of the most common and fastest growing surgeries we're seeing in the country as the population ages.
[1:14:41] Speaker 2: And honestly, when we review the data, it's one of the areas aside from Mike and Han's data that has some of the least amount of outcome data. So I think it's an area of great need. Um, you, you never think of Orthopedic Surgery as an orphan indication, but in the nutrition field, it kind of is, where a lot of the Research is focused in colorectal and GI Cancer surgeries. But I think Orthopedics because of the physical recovery required is, is really an area that we're gonna see grow quickly.
[1:15:07] Speaker 7: I would also like to echo that it's important for young patients also. I think the question was focused on older patients. But, uh, you know, in our studies, we've shown that younger patients lose at least as much, if not more, uh, than our older adults, um, both with their muscle mass and their function. So I think there's
[1:15:29] Speaker 7: You know, need to improve across the age spectrum.
[1:15:33] Speaker 2: So.
[1:15:36] Speaker 2: I lost, I had one of my big surgeries in 2014. I lost 20 kg in 17 days and I was in the best shape of my life. I was 105 kg, running 5 miles a day, you know, could bench 305 and squat 500, but it didn't matter.
[1:15:51] Speaker 2: It didn't matter. Within a week, I was short of breath walking down the hallway and within, I mean, 20 days, I was down 17 kg. It took me a year to recover that.
[1:16:01] Speaker 2: So no one's immune, even the fittest people.
[1:16:06] Speaker 2: We think we are, but we're
[1:16:08] Speaker 1: not.
[1:16:10] Speaker 1: Doctor Dreyer, I'm gonna let you take that question. I think we, we've kind of talked about it already, but we could just briefly reiterate.
[1:16:17] Speaker 6: Yeah, this was just basically the absorption kinetics. So we are hoping for more to be absorbed and faster, uh, with, when it's free versus intact protein. So in Other words, you don't have to chew it necessarily, just swallow it or, or whatever.
[1:16:39] Speaker 2: Hm.
[1:16:40] Speaker 2: So, uh, we do do some of this, but as you saw, we have a nutrition clinic. Mike, I don't know if you guys do so much as you probably do for vitamin D. I think if you're gonna test for something preoperatively, and I was glad Mike said it before, vitamin D is one of the key things to test for. There was a nice JAMA Surgery paper that showed that if you went into, let's, I'm gonna use bariatric Surgery because that's what the paper was on.
[1:17:01] Speaker 2: With a deficient vitamin D level, your complication rate was 2 to 3-fold higher, and this is kind of bearing out for a lot of different parts of Medicine. You don't wanna go into a major stress vitamin D deficient, and anywhere from 1 in 3 to 2 in 3 of the population, which depends on ethnicity, race, and Other factors, and sex actually, um.
[1:17:21] Speaker 2: Significant amounts of the population are vitamin D deficient, and that is not the way vitamin, there's a vitamin D receptor in every cell in your body and it's critical to immune function. It's critical to preventing infection in the lung and how macrophages function. You can't rebuild muscle without vitamin D being present and normal, so it impairs muscle building. Um, we check for Other things too. We check, um, selenium and copper and zinc in people that are more malnourished, but Orthopedic Surgery patients.
[1:17:49] Speaker 2: tend to eat reasonable amounts to where those kind of nutrients aren't deficient Other than D. It's more that they're muscle deficient, right? It's your muscle mass that really is the key deficiency you come in with at your metabolic reserve and to recover, and I think a lot of people come in obese and they think they're not malnourished, but their muscle mass would say they are. And I think that's one of the big features of diagnosis is, is looking at muscle mass. But we do check nutrient levels. I don't know, Mike, if you do much of that besides vitamin D,
[1:18:16] Speaker 7: but we, we do
[1:18:17] Speaker 2: sometimes.
[1:18:18] Speaker 7: Yeah,
[1:18:20] Speaker 7: So our protocol right now is, uh, any, uh, older adults, so patients over 50 is how we define it, um, who are treated for a Fracture, uh, have a vitamin D lab drawn. Um, and you'd be surprised, even the patients that are on supplements, um, it's often not enough, um, what they're taking because they're still low, even if they're taking a vitamin D supplement, um, prior to the injury. Um.
[1:18:46] Speaker 7: All of our Fracture patients, so including older and younger patients, um, all go home with a prescription for a vitamin D supplement. Um, we probably could check it also in our younger patients to give them more motivation, um, to follow up on that recommendation. Um, but all of our young Fracture patients, as well as our patients who have an osteotomy or a bone realignment procedure, uh, to get vitamin D supplement post-op.
[1:19:15] Speaker 2: It's great.
[1:19:24] Speaker 2: So, uh, this is a great question and, and, and one that has baffled me for 30 years in Medicine. So, there's been robust data for the benefits of arginine and immuno nutrition delivery. You know, typically, these immuno nutrition supplements contain arginine, a small amount of fish oil, like 1.5 g, cause, uh, fish oil impairs the arginase enzyme that depletes arginine in our immune system. Um,
[1:19:50] Speaker 2: And so there's all these trials and all these meta-analysis we've all published that showed dramatic reductions in infections. We understand the scientific mechanism for the myeloid drive suppressor cell that creates this arginase deficient state in surgical and trauma patients. It actually was discovered by the Cancer doctors. That's how.
[1:20:05] Speaker 2: Cancers like glioblastomas evade the immune system. They induce the production of this arginase as well. And so we found it in Surgery and trauma consistently. So we even know why it happens, and it has nothing to do with malnutrition. Everybody has this conserved evolutionary pathway in our bodies. Um, and when we give it, even very well-nourished patients have significant reductions in infections and shorter lengths of stay, but we can't get more than 1% of the US surgical population to do it.
[1:20:33] Speaker 2: And we went to the NIH and we said we need a large definitive trial of this, and they said, you've got to be kidding me. There's 35, 7000 patients' worth of data on this. Why aren't you guys just doing it? Why aren't, we, we aren't gonna fund any more trials of this. This is common knowledge. This is obvious data. Why aren't physicians doing this? And so I think that has been something we really wish was more commonly practiced. I think we need better, um.
[1:21:01] Speaker 2: Delivery agents for it. I, I think, you know, most of them have been that the drinks like you described, Mike, that I think some patients either maybe don't love the taste of or or because of the cost or the volume of them is difficult for patients. So I think us developing powder forms are easier to take forms, I think could be helpful here, um.
[1:21:20] Speaker 2: But, but yeah, if you have a patient having Surgery or if your mom is having Surgery or if your child's having Surgery, you should give them some sort of origin and nutrition for at least 5 days before and at least 5 to 7 days after. I mean, just hands down, everybody we've ever studied benefits basically, even in ERAAS pathways. It's been studied specifically in ERS pathways. Some people said once ERASTS has come, we don't need anymore. That's not true. There's studies in ERASTS that shows it reduces infection even versus Other protein supplements.
[1:21:47] Speaker 2: So the data is, is, is robust and, and so, and we're not gonna get any more studies and IH won't fund it. It's too, it's too proven if that's possible.
[1:21:59] Speaker 2: Happy to share those meta-analysis if you want them as well.
[1:22:13] Speaker 2: We have used microcrystalline cellulose um in a placebo. We did a COVID study where we're using a probiotic and we use microcrystalline cellulose as our placebo. So that's an interesting question. It's, it's an inert filler substance.
[1:22:25] Speaker 2: We have done that
[1:22:29] Speaker 2: It actually caused more side effects than the probiotics did though, by the way, I will tell you in a large, reasonably large randomized trial. So it's not without um some GI side effects, even the inert fillers.
[1:22:41] Speaker 6: Mm
[1:22:47] Speaker 7: Yes. Did you have a, did you have an I&D exemption, Hans, for your studies,
[1:22:52] Speaker 6: or no, we ran our trials, uh, with an I&D, so we treated these amino acids as, as if they were a drug.
[1:23:01] Speaker 7: Yeah, I I, I bet that added a substantial amount of preliminary work for that
[1:23:06] Speaker 7: study.
[1:23:07] Speaker 6: And cost, yeah, at least, yeah.
[1:23:11] Speaker 6: I will say though that uh we did publish some of the, the data in our JBDS paper that showed that uh placebo versus Essential amino acids, there was no difference in markers of liver function or kidney function, which would be the reason why we were asked to do it. They were thinking that amino acids, too much of them would be uh overburdensome to the, to the, to the kidneys.
[1:23:31] Speaker 6: So
[1:23:32] Speaker 7: that would probably be good data to use for someone who is interested in getting an IND exemption.
[1:23:38] Speaker 6: Uh, so,
[1:23:41] Speaker 1: for sure,
[1:23:42] Speaker 2: we, we've got 90s for glutamine studies before, um, there are some FDA approved glutamine formulations for sickle cell, and so we use them in a study that we've done.
[1:23:51] Speaker 2: Um, and we got an IND, for instance, for the probiotic COVID study we did that we're gonna submit for publication here soon. Um, that actually wasn't very hard to get surprisingly, it cost us almost nothing and we got it in a week. Um, maybe that was the COVID effect, I don't know, but, but, um, we were surprised. So we haven't had to get them though for any Other oral or internal supplements, um, that weren't probiotic or specific amino acid in nature.
[1:24:17] Speaker 1: Do you still have to write the uh the exemption request though, to get it approved as exempted?
[1:24:24] Speaker 1: Work.
[1:24:26] Speaker 1: Do you recall?
[1:24:27] Speaker 2: We haven't for oral nutrition supplement studies, um,
[1:24:34] Speaker 2: Only for probiotics and individual amino acids.
[1:24:39] Speaker 2: So we've studied individual amino acids.
[1:24:43] Speaker 2: We did it because there were some FDA approved examples of that that existed. Again, the sickle cell glutamine improved sickle cell outcomes and so there's some FDA approved examples of that.
[1:24:56] Speaker 2: So
[1:24:57] Speaker 2: Yeah, it's, it's a, it's an interesting question. Sometimes people ask for them and sometimes they don't.
[1:25:04] Speaker 1: Alright.
[1:25:08] Speaker 1: OK, I feel like the question boxes have slowed down. So I think we made it through all the questions. Thanks to everyone who stayed um a little bit over um with us and um we hope that uh we brought you some great information today, um, that you can take back to your patients or at least gives you some ideas of where to start.
[1:25:32] Speaker 2: Thanks everybody.
[1:25:34] Speaker 6: Thank you everyone. That was wonderful. Thanks.
[1:25:38] Speaker 2: Great night.
[1:25:40] Speaker 6: Yeah, thanks.