Prescribing Exercise in the 2020s: Novel Strategies for the Musculoskeletal Physiatrist-Session Presentation

Session Presentation

Video Transcription

Thank you. Thank you everyone for joining our session today on prescribing exercise in the 2020s novel strategies for the musculoskeletal physiatrist.  I'm Prakash Jayabalan, I'm the session director, and I'd like to thank you all so much for joining us just after lunch today.  And today's session, we would love it to have been in person to get even more feedback from you all, but I'm going to go through the structure of the session today.  Firstly, if you go to the next slide, we have no disclosures. And the next slide I'd like to introduce my faculty, and I'm very fortunate to have fantastic  faculty as part of this session today and I know that you're going to all learn so much from them.  Firstly, I want to introduce Dr. Alexandria Hazelhorst, who goes by Ali Hazelhorst. She's an attending physician at Ascension Sports Medicine in Austin, and she's an assistant  professor at UT Austin Dell Medical School. Next I want to introduce Melissa Kolsky. She's an assistant professor at Northwestern University in the PT school and is a senior  education manager at the Shirley Ryan Ability Lab. And myself, I'm an attending physician scientist at the Shirley Ryan Ability Lab and an assistant  professor at Northwestern University. Next slide. The objectives of the session today is to really provide you food for thought as what  we think may be the future of the prescription of exercise going forward in our specialty.  So the goal is, overall, is to present novel strategies for developing individualized exercise  prescriptions that are potentially efficacious for the patient with musculoskeletal disease. And we're really going to use a case-based approach and outline three novel perspectives  in prescribing exercise, and really in three different domains. So the first is going to be looking at metabolic evaluation for sports performance, using physical  examination to prescribe exercise for the evaluation of a chronic musculoskeletal issue, and finally looking at biological evaluation of a patient pertaining to a musculoskeletal  pathology. Next slide. And really what we decided on these pathologies when we thought that they really cover the  spectrum of ages of the type of patients that a musculoskeletal physiatrist sees. So when we're talking about metabolic evaluation, Dr. Hazel Horst is going to be talking about  as it alludes to sports performance. In middle age, most patients start developing low back pain, and that is what Melissa Kolsky will be focusing on.  And I'll be focusing on sort of older age individuals with knee osteoarthritis. And so we really think, we really hope that with this broad cases that we provide today,  it gives you a lot of food for thought. Before I turn it over to Dr. Hazel Horst, we're going to hold all questions until the end.  We're going to give plenty of time for questions and sort of feedback and perspectives that you have in your own practices that may pertain to these cases.  So with that, I pass it over to Dr. Hazel Horst. All right. Thank you so much, Prakash, and thank you, everyone, for joining us today.  I'm going to get started talking about metabolic profiling and exercise. So to begin, we have a case of a 21-year-old male soccer player in his first season as  a professional athlete. On pre-participation physical exam, he gives you a history of overtraining syndrome, which  is characterized by decline in sports performance when performance, when stress chronically over exceeds recovery capacity.  He had a negative prior workup in college and his symptoms resolved with two weeks of rest. He asks you if there's anything you can do to improve his overall sports performance,  prevent overtraining, or know when he might possibly be at risk. This is not a simple question with a simple answer.  Many factors play a role in the performance of an athlete, including genetics, age, environment, medication, lifestyle, and training.  But what if we could study and predict factors that influence the athlete at a personalized biological level? That brings us to the idea of metabolomics.  Metabolomics is the global assessment and validation of endogenous small molecule metabolites within a biological system. This is just a brief overview of how we study metabolomics.  To start, you start with a biological sample and a variety of samples can be used. However, urine is the preferred sample for analysis given it is noninvasive.  Other examples include serum, cerebrospinal fluid, synovial fluid, and tissue. These samples are then run through mass spectrometry or nuclear magnetic resonance spectroscopy  in order to identify low molecular weight structures such as lipids, amino acids, nucleic acids, vitamins, and carbohydrates.  We then run this through multivariate data analysis in order to find statistical significance in the data.  And we end up with a small concentration of molecules to construct a fingerprint, which can be unique to an individual and the environmental influences.  Metabolite changes are highly sensitive and specific biomarkers can be used for non-biopsy tests for early detection of disease.  Hence the measurement of metabolites to become an important clinical, important part of clinical practice on the development of diagnostics, therapeutics, and drug development.  Some examples include urine metabolites to detect renal cell carcinoma, blood markers for early detection of ovarian cancer, or even markers for ALS and cerebrospinal fluid.  So back to our athlete with concerns of overtraining in his professional career. We will review the current research for the potential detecting metabolic changes in response  to types of training, sports, and diet. The ultimate goal would be to develop metabolic profiles associated with performance and fatigue and health issues in athletes.  This would allow the health care team and coaches to predict potential problems and make changes to training and attempts to prevent overtraining in our athletes.  Our first study compared 1,200 males who filled out a questionnaire on their average daily activity quantified by metabolic equivalent scores, or METs, over 12 months.  They were then classified into levels by metabolic equivalent scores and sedentary behavior.  Higher concentrations of branched-chain amino acids have been correlated with future type 2 diabetes risk and insulin resistance.  In this study, the concentrations of isoleucine were higher in the lower daily activity group, while leucine and valine were decreased in the groups with less sitting time.  Alanine and proline are amino acids that are involved in glycogenesis, which is the synthesis of glucose from glucogenic amino acids.  Leucine and proline were both increased in the lower daily activity group, which can lead to uninhibited gluconeogenesis in an insulin-resistant state.  These findings were all unchanged after adjustment for BMI, smoking, alcohol, and energy intakes in the subjects.  Another study compared high-versus-low fitness participants based on their VO2 max, which is the maximum amount of oxygen an individual can utilize during maximal exercise.  There is lower levels of amino acids in the groups of higher fitness, which could result from a more efficient utilization of fat stores.  And exercise greatly increases energy expenditure and promotes oxidation of branched-chain amino acids, which also play an important role of substrates in gluconeogenesis.  In the low fitness group, there was an increase in branched-chain amino acids, which in prior studies have been elevated up to 12 years prior to the onset of diabetes in high-risk  subjects. It's also been associated with insulin resistance. The low fitness group also showed higher levels of cholesterol, fat percentage, and BMI.  And these findings were all more pronounced in females when compared to the male subjects. Another study in 2010 compared acute exercise testing on either a treadmill or stationary  bike in 302 subjects. Niacinamide is a form of vitamin B3, which helps to enhance insulin release and improve glycemic control, and it was increased by 79% after exercise.  Subjects who were leaner with a BMI index less than 28 had more than double the increase of niacinamide that was seen in the subjects with a BMI greater than 28.  In a 2020 study, there was 23 healthy young soccer players who were analyzed with metabolomics before and after high-intensity interval training, or HIT.  HIT consists of alternating periods of intense aerobic activity with periods of passive rest or active mild-intensity activity.  This type of exercise is able to elicit a greater training stimulus and improve maximal aerobic capacity, which allows athletes to exercise for longer periods than with continuous  exercise. Argine and proline are associated with carbohydrate metabolism for energy utilization, and both  were increased in the post-exercise, and in the recovery sample, they were decreased to pre-exercise levels.  Glutamate is used as a raw material for synthesis of the glutathione and oxy of stress, and glutathione is a major non-enzymatic endogenous antioxidant.  According to recent literature, upregulation of glutamate after head exercise may be a response to oxy of stress and lead to overall improvement in the immune system of athletes.  Androsinidine, a precursor of testosterone, was decreased post-exercise and elevated in recovery.  Testosterone is a major promoter of muscle growth and increase in muscle strength in response to resistance training in men.  Another study of junior and elite male rowers who underwent two weeks of strength and endurance  training were compared to sex- and age-matched healthy male controls who did not undergo this training.  Hemoglobin was increased in the rowers at one and two weeks post-training, which authors suggested was indicative of a well-balanced training program.  There was also higher serum lactate levels in the rowers compared to the control subjects, suggesting that the process of glycolysis was altered by exercise, and glycolysis is  a breakdown of glucose to generate energy. There was also an elevation of free serum fatty acids after two weeks of training in  the rowers, indicating enhanced lipolysis, and lipolysis is a process of breaking down triglycerides into free fatty acids for energy utilization during exercise and fasting states.  Another study evaluated metabolic alterations in female adolescent volleyball athletes after two weeks of strength and endurance training.  There was decrease in testosterone, which is an anabolic hormone, and increase in cortisol, which is a catabolic hormone, after the two weeks of training.  Theories are important markers to assess endocrine homeostasis and evaluate for athletic performance.  Serum MDA was increased, which is one of the byproducts of lipid perioxidation, and has been used as a marker of oxidative stress.  There was also a reduction of the antioxidant glutathione and an increase of the oxidized  glutathione ratio, indicating a shift in the redox balance towards a more oxidizing environment.  Free radicals, when maintained at low to moderate levels, are of crucial importance to human health for immunity, blood flow, and neural activity.  However, when there is an imbalance to a more oxidizing environment, cellular and molecular  changes can occur, leading to development of cancer, metabolic disorders, and even cardiovascular disease.  A 2018 study compared 191 elite athletes from different sports disciplines classified by their endurance and power.  And in this study, endurance was classified by maximal oxygen uptake, or VO2 max, and power is defined by a maximal voluntary contraction percentage.  Some examples included a moderate power in a moderate endurance sport as baseball, a high endurance and high power sport was cycling, and a high endurance moderate power sport  was basketball. And in this study, for the high endurance sports, there was an increase in sex steroid  hormones, which have stimulatory effects on muscle mass energy generation through glucose metabolism and protein synthesis in muscle.  There is also a reduction in free fatty acids and lipids, which are the preferred substrates for energy utilization in exercising muscle.  Emerging data and other research suggests that a greater beta oxidation of fatty acids in athletes belong to higher endurance sports.  In the high power group, creatine was increased, and a more adaptable muscular storage of creatine  phosphate during exercise can provide the essential source of high energy needed to replenish ATP in the first few seconds of intense activity.  Lastly, N-acetylkerosine was reduced, which acts as an oxidative scavenger in muscle against lipid perioxidation.  And these findings, again, were similar between males and females, but more pronounced in the female group.  Another 2020 study evaluated metabolic profiles by sport by analyzing 88 elite male athletes from different sports, such as cycling, aquatics, and weightlifting.  Then comparisons were then made to compare the different levels of power endurance in order to study immune, inflammatory, and oxidative stress profiles of these elite athletes.  The anti-inflammatory interleukin IL-10 was higher in the moderate power group compared to the higher power group.  And in previous studies, it's been indicated that short bouts of exercise can induce an anti-inflammatory environment for several hours.  There was also an increase in the oxidative stress marker NDA and an increase in the activity of the anti-oxidative stress enzyme, SOD, in the higher power groups compared to the  lower power groups. Data may suggest that high power groups exhibit a greater overall oxidative stress profile,  less anti-inflammatory profile, and lower tissue healing compared to the moderate to low power groups.  In IL-10 and macrophage inflammatory protein MIP-1 beta were also increased in the low to moderate endurance compared to the high endurance group.  MIP-1 beta is produced by macrophages to stimulate oxidative stress system in response to infection or inflammation.  An interesting study in 2021 utilized metabolites in order to predict the success rate of finishing  the Trans-Europe Foot Race, which is one of the most extreme multi-stage competitions worldwide. It's an ultra-marathon distance of 4,487 kilometers, and it goes from Bari, Italy,  all the way to North Cape, Norway in 64 days. And the participating ultra-long distance runners essentially had to complete almost two marathons a day for 64 days.  The finishers and the non-finishers were well-separated based on 223 signal differences.  The main finding was the thiamine triphosphate, which is the triphosphate ester of the water-soluble  essential vitamin, vitamin D1, or thiamine, which has antioxidant, erythropoietic, and mood-modulating and glucose-regulating functions.  Exercise has been suggested to affect thiamine status by increasing thiamine-dependent mitochondrial enzymes in order for tissue repair.  And finally, a 2020 study looked at how adherence to WHO healthy eating guidelines and exercise can impact urinary metabolites and microbial gut flora diversity.  In this study, adherence to the healthy diet was associated with higher levels of urinary markers of fruit and vegetables.  It was also characterized by lower urinary levels of laxate and 2-hydroxybutyrate, which are markers of anaerobic respiration and oxytocin stress, respectively.  Diet alone was not enough to affect microbial gut flora diversity, however, participants  that had diet plus exercise were able to increase their microbial gut diversity in this study.  So the research we discussed today are only preliminary studies of metabolic changes in response to various exercise, training, and diet.  The ultimate clinical goal would be to distinguish a unique metabolic profile to an athlete that would take into account different training and environmental factors.  This could be used in consideration for athletes from different levels of performance from novice to elite levels.  And further research would need to be done to identify specific biomarkers associated with performance, fatigue, and overtraining syndrome in our athletes.  The studies today are just the beginning of a promising path to the role of metabolics and exercise performance and guiding clinicians on prescribing exercise in the 2020s.  Thank you everyone. I'll just stop now for Melissa to take over.  Great. Can everyone hear me? Yeah? Okay. It says unmute myself. Okay. If you can't hear me, let me know. You're good. We can hear you. Okay, great. So today, as  Prakash and Ali discussed, I'm a practicing physical therapist for the last 21 years in orthopedics, and today I'd like to discuss how a clinical  assessment can guide specific exercise prescription in the case of low back pain. Ideally, I want to cover a case, I'm just gonna get this out of the way, a  case of low back pain and discuss essential elements based on the evidence for prescription of exercise and education. Again, I have no relevant  disclosures. So we know that patients are coming to us for two reasons, a loss of function and pain that limits them from that function, and we know that a good  clinical examination can help us to determine not only what the patient is describing, but also the course of their condition and any red or yellow  flags that may delay the course of care. So I'm going to discuss the story of two backs. Both of these individuals have two laterally shifted spines, and the spine  on the left is laterally shifted left, and the spine on the right is laterally shifted right. But the spine on the right has all the characteristics of a  relevant right lateral shift, however a lot more to the story than meets the eye. A relevant lateral shift is being defined by the direction of the  shoulders relative to the pelvis, and the fact that the patient is visibly and unmistakably shifted, that the shift came on with this episode, and that frontal  plane movements cause peripheralization or centralization of symptoms. We know that the outcome the patient expects to achieve after receiving a treatment is a  significant factor. We know that patients with greater expectations generally have better outcomes after treatment, and when treatment expectations are fulfilled  that patient is more satisfied. This relationship has been shown for a variety of orthopedic conditions. Patient satisfaction is becoming increasingly  important in determining successful outcomes. If a patient's treatment expectations are related to patient outcomes and satisfaction, then a big  question is, are patient expectations modifiable? This tool is the modems, and it covers expectations regarding sleep, job tasks, hobbies, everyday tasks, and  pain relief. In our clinic we are looking into researching patient expectations and finding that therapists are tending to be able to determine that not only  can they predict the patient expectations, but also change those expectations based on a good therapeutic alliance. So the first step is really  creating that therapeutic alliance and determining what expectations the patient has in the situation. In this example you see patient R and patient L's  modems. You see that patient R is in yellow and patient L is in red. Both generally have low expectations about work and recreational tasks. So one of  our hypotheses is that in the form of physical therapy treatment and outcomes, are they modifiable based on a standard of care initial evaluation?  Changes in patient expectations for recovery with physical therapy treatment were observed in patients following an initial evaluation, and the change in  expectations was greater in patients whose therapists believed that the patient should increase their expectations for recovery based on their  perceived prognosis. This is particularly valuable in patients who perceive their functional outcome to be lower than their evaluating  therapist. So next we look at the patient's outcome measures, and we see that both have generally low expectations and the high end of severe  disability based on their ODI or their oswestry. Looking at their outcome measure of the patient-specific functional scale, we see relatively low  functioning, with patient L wanting to return to work and return to running, and patient R wanting to return to running and returning to child care tasks. We  also see relatively high pain ratings for both and a high level of irritability. So again, looking at these two patients, we see that they both have high  irritability and high disability, and low expectations and low function. So we know that both patients are 35 years old, male and a female, who were referred to  physical therapy prior to neurosurgery. Both present with a herniated disc at L5 S1, and both present with distal symptoms to the calf. Both of these  individuals presented with pain with dynamic and range motions initially, and we also know that manipulation would generally be off the table based on  their symptoms. So we have to determine what is our treatment outcome or intervention going to be. Additionally, both presented with  significant mechanosensitivity. Neurologically, on their neuro exam, we saw diminished right heel sensation to light touch. Patient R had weak right  knee extension, and both had absent S1 reflexes. Both presented with significant dural tension with knee extension at the first 20 degrees, producing an increase  in low back pain. So if we look at this image described in the 2015 updated treatment-based classification system by Alarwali, and most recent clinical  practice guidelines by Delito, we want to consider both of these patient scenarios. So looking at patient L, we see that determining whether or not  their medical management is appropriate for rehabilitation, and we see that patient L has leg pains, but does not, and some neurologic deficits, but not  progressive yet. We also see that he presents with somewhat low psychosocial risk factors with predominantly leg pain, thereby fitting him into, based on  this category, more of a symptom modulation or high disability, high volatility, and a high pain rating. Thereby, his treatment should be fitting  in a directional preference exercise, ruling out traction, active rest, or manipulation. So what is directional preference exercise? It's the generic  word for MDT, which is mechanical diagnosis and therapy. Additionally, when we look at patient R, we see that she also has a laterally shifted spine.  However, she presents with medium to high psychosocial risk status. Based on her medium to high psychosocial risk status, we would like to figure out what  treatment-based classification she fits in, but again, she'll fit into our symptom modulation category, being both of her high ratings, but also the potential to  do a good mechanical exam and attempt to figure out if she also has a directional preference and would respond to frontal plane movements. So in this  next scenario, we also want to consider her, their pain mechanisms. There has been much debate about pain mechanisms because we still have not reached expert  consensus about what meets each category. I use the classification system listed here, but also understand the IASP definitions of nociceptive, neuropathic,  nociplastic mechanisms. The greatest consensus for nociceptive pain is that they are generally responsive to anti-inflammatory drugs, that they have  signs of inflammation, such as redness or heat and warmth, and that their pain recovery is based on predictable or expected tissue recovery guidelines.  These findings are unsurprising based on the fact that they're typically with an acute injury or a clear nociceptive mechanism. Next, you see  the peripheral neurogenic listed here, but also referred to as neuropathic pain, whereas most features are reaching high agreement as  being unique to those related to nerve damage, such as neurologically plausible distribution of pain, characteristic signs and symptoms, such as hypoesthesia,  numbness, or electrical shock type symptoms, and also confirmation of nerve damage via tests. These findings were unsurprising and consistent with the  definition of neuropathic pain. And then, lastly, considering nociplastic pain and the most agreed upon with this category being diffuse or widespread and poorly  localized distribution of pain, general hypersensitivity, and multiple somatic symptoms, such as fatigue, memory difficulties, mood disturbances, sleep  disturbances. And these features align with the presentation that could be explained by things like central sensitization and or abnormal processing  in the central nervous system. Now, consider patient R and patient L and understand how are we going to figure out how to move somebody who may be more  nociceptive or somebody who may have more central acting mechanisms. We want to create a great therapeutic alliance and try to assess the ability to reduce  fear and threat, while also assessing mechanical movements at the same time. We also know that in the presence of centralization, these psychosocial  variables may be less important, and we may still be able to change those psychosocial variables based on a good movement exam. We also see the things  that objectively we can assess, such as things like the pain detect questionnaire, which can differentiate neuropathic from nociceptive, allodynia or widespread pain  and disproportionately pain related to the injury, and or using a central sensitization inventory. So, considering both of these patients, patient L sits  more on the on the peripheral or the mechanical influence side, whereas patient R is sitting more on the nervous system influence side. We know that both  of these individuals have two classification systems. One is peripheral or centrally mediated, and both having either mechanical or chemical pain. So, we  want to try to determine their prognosis based again on our mechanical exam. When considering the intervention spectrum in the treatment-based classification  approach, we know that mobility interventions can bridge symptom modulation and movement control, and we know that endurance interventions can  bridge movement control and functional functional optimization approaches. So, these approaches are again, just like the last slide, are nonlinear or hierarchical.  Patients can enter and come in at any point in the spectrum. So, both of our patients again are fitting in this symptom modulation category. Again, it's  time to consider all factors. So, considering the ICF framework and the pain and disability drivers module by Toussaint Laflamme and Chad Cook, we want  to consider what are the nervous system, how is the nervous system in both of these patients? Are there signs of central sensitization? Are there signs of  myelopathy and radiculopathy? Are there comorbidities and sleep disturbances or mental health issues? What are their cognitive and emotional factors? Is there  pain avoidance, illness perception, or coping and self-efficacy in these individuals? We also want to consider the contextual drivers. What's the access to  care like for them? Are there poor attitudes from their family or work? And we want to consider several implications for rehabilitation for painful and highly  prevalent musculoskeletal disorders. Knowing that many maladaptive cognitive and emotional factors are also known to influence pain, perception, and disability,  and we know that physical comorbidities can tend to worsen the severity of symptoms of low back pain. So, based on our research and the research of  SMART, we see that there is a benefit to subgrouping individuals with pain and using a classification system to identify pain mechanisms. We also found a  fair amount of patients that were able to identify with chronic conditions in our sample. And the last bullet, you can see that our sample is based on a year's  worth of patients at the Shirley Reinability Lab, or at the time Rehabilitation Institute of Chicago, and we see that at least 35% had some form  of central dominating or nociplastic mechanisms in our outpatient neurologic and orthopedic practice. We also can see that there is empirical support for  findings that the peripheral components of a pain classification system can be implemented consistently in outpatient clinical practice, but we had much worse,  lower sensitivity in central mechanisms rather than the peripheral mechanisms, and the specificity in both was high. So, we see that there is good  agreement when considered to a gold standard between a therapist trained in a classification system versus a computer-generated model. So, overall,  when we see that trained therapists can effectively classify patients based on an introduction to an educational program, we see that those  therapists trained in classification systems were better in decreasing patients' pain, improving patient-specific functional goals, and you saw earlier  the patient-specific functional scale, that they took less visits to achieve their goals and had more statistically significant outcomes. And for our  hospital, that amounted to a change that was about a million dollars of savings for those individuals. So, again, if we go back to the two  individuals, it is crucial to recognize that they are that, they are individuals, but also to recognize what are the drivers and what is the exercise  prescription going to look like. So, we see that L responded well to a lateral shift correction. His trajectory was somewhat easy, somewhat linear, and  somewhat responsive to just straight shift correction, which is a technique to correct a frontal plane motion in a mechanical problem, whereas the same  patient, patient R, needed movement-safe communication. She needed a safe walking program, despite the fact that initial walking wasn't tolerated, and that she  was able to progress into end ranges and successfully use the same shift correction to correct her patho-anatomic lesion, but both had the same amount of  treatment. However, the trajectory looked and timeline was somewhat different. So, overall, the same curative exercise was performed. They fit into the same  category, but, however, they need, they looked much more, much different. R needed much more support in changing her expectations, whereas L's expectations  were tied to his pain, and so we want to consider this as mechanical movements, classification systems, and what are the drivers of pain and disability in our  patients, and using these, we can create an effective exercise program, and so, overall, I'm going to now turn this over to Dr. Prakash Jayabalan, and I'm going to stop sharing now.  Hopefully everyone can see my screen there. Great. So today I'm going to thank you so much for the fantastic talks by Dr. Hazel Horse and  Dr. Kolsky, and now I'm going to take it forward and talk about my real specialty, which is knee osteoarthritis. I'm just going to make sure I'm not muted. Oh, sorry.  Not in the presentation mode. Thanks, Ali. So I'm going to take it forward and we'll just wait for this to come on in a second.  Okay, hopefully that's good. Thank you, Ali. So we're going to be talking about knee osteoarthritis.  And as many of you know, I'm British and whenever I give a presentation, I always like to feature  a cricket player at some point. So I want to imagine my case is going to be a 68 year old, 67 year old former cricket player who presents with a seven to eight month history  of medial sided knee pain. And our classic evaluation of this patient will be to examine  perform radiographs potentially in a clinic and diagnose them with osteoarthritis of their knee.  Now, as a musculoskeletal physiatrist, one of my, and a researcher as well, what I've, my, my career passion is really to look at what is the optimal level of physical activity for  an individual with knee osteoarthritis to prevent progression down the line of their disease.  And also what sort of rehab regimen or tailored exercise program should we prescribe for their disease as well? And many of the studies have not really shown that there's  one specific exercise that's potentially beneficial. Before I go further, I want to talk about osteoarthritis, and I think it's important to understand the pathological basis  of osteoarthritis. When we think about osteoarthritis, there's this complex interplay between abnormal biomechanics, which feeds into abnormal biology. And this leads to a cycle of  inflammation and degradation that potentiates that joint damage further. Now, classically,  with our treatments, whether they're injectable or oral medications, we're targeting some of  these inflammatory and potentially degradative processes that are going on inside the joints.  But we also advocate for weight loss and activity modification in our patients as well. And these have both a biological basis, as well as a biomechanical basis to improving  our patient's symptoms as well. Then it's also important to remember that when we think about the joint and the knee joint itself is an organ, that means it's a complex structure,  and it consists of cells with different functions, which are encapsulated within a membrane.  And the knee joint, often in osteoarthritis, and we focus on one particular aspect of the joint,  particularly articular cartilage, but there are many different aspects of the knee joint,  which haven't been well studied. So we think about the synovium, which produces hyaluronic acid,  which sits on the layer, on the cartilage layer of the knee joint, which is healthy towards cartilage.  We have subchondral bone, which has this crosstalk with the cartilage above it,  which studies have shown if the subchondral bone is diseased, that can lead to potentiation of the  cartilage disease. We have the synovial fluid, which bathes the cartilage, which is known,  which in individuals with knee osteoarthritis has been shown to be more acidic and have different  components, which may potentiate that cartilage disease. But then obviously that leads to  articular cartilage, which is avascular, alymphatic, and aneural. That means when it's initially  damaged, patients don't know about it unless there's concomitant bone injury. It's avascular  and alymphatic, which means it has a very limited healing potential. But we know in the native healthy joint, there's this optimal balance between catabolic and anabolic processes.  What happens in osteoarthritis, as we all know, is that there's damage to articular cartilage,  such as as the patient bears weight over time. There's different parts of the joint that are  impacted, which is the disease process. And there's a release of these inflammatory mediators  and cartilage degradative enzymes into the joint. And eventually that leads to bone-on-bone motion,  which leads to joint pain. So, and that balance gets tipped more towards catabolic processes, as opposed to anabolic processes. So going back to our patients, can we tell,  find a methodology in the future that will tell us how loading will impact that patient's joint  in the long term? And I don't want to get too deep into the science behind this, but what is  important to remember is that cartilage consists of a chondrocyte surrounded by an extracellular  matrix. And that extracellular matrix has two major components, proteoglycans, which is cartilage's  compressive strength, and collagen, mainly collagen type two, which gives cartilage's tensile strength. And we know in osteoarthritis, there's damage to that extracellular matrix.  And as the release of these cartilage degradative enzymes cause MMPs from macrophages, which are  attracted to this area, which leads to the release of those breakdown products into the bloodstream  or in the synovial fluid, which we can measure. So taking all this knowledge and this background  I've given you, now I want to present some data of what exercise prescriptions in the further  2020s could look like. So firstly, any talk about exercise can't really be a complete talk about  exercise without talking about weight loss. And so we know that individuals with osteoarthritis  generally have higher weights or are overweight. And in the old days, we used to talk about weight  loss as being taking more stress off your joints. But what we know more and more is that there's  this systemic inflammation in individuals with osteoarthritis as seen by individuals with hand  OA in individuals who are obese who have hand OA, there's more likelihood of them being obese with  hand OA than those who are not obese. So that's important to remember is that osteoarthritis is  not just a wear and tear or biomechanical disease process. But as I go back to the beginning of my  presentation, it also has a biological basis. There's also studies that suggest that white  adipose tissue, which is in belly fat, essentially releases these adipokines into the bloodstream of  our patients, which potentiates inflammation. We know that inflammation is highly associated with  osteoarthritis. So that can worsen their disease process. So when even now, when I'm counseling my  patients, I'm often talking about osteoarthritis, weight loss associated with that could be  anti-inflammatory and impact their disease, not just biomechanically, but biologically also.  Then when we think about our exercise prescription, the most common prescription for individuals with OA is greater than 30 minutes per day of moderate intensity activity,  five times per week. Now I'll challenge that prescription is that that really is based on cardiac health. We don't know how that impacts someone's knee joint, and it may not impact  someone's knee joint beneficially always. So the first thing to say is that loading the joints  does have a biological effect. There are studies have shown that diet and exercise intervention,  where you decrease some of the joint forces at the joint can impact someone's,  and decrease the inflammation and decrease the potentiation of someone's joint disease.  And aquatic resistance programs have actually shown that they can improve the biochemical content  of someone's cartilage. And physical activity programs, where someone's in the highest level  of physical activity, or highest total of physical activity, have shown reasonable increases in  extracellular matrix constituents. So exercise can be beneficial to someone's joints in the long-term,  particularly their cartilage. But what about our patients? So when I think about the future and  what it could hold for our patients, this is what my career goal, I would say, has been. And it's  to take that patient that we saw at the beginning of this presentation, and potentially take some  sort of biological sample from them, create a unique biomarker profile for that patient,  review that biological profile in the context of their function, and to prescribe an individualized  type, intensity, and duration of physical activity. And obviously, this is, we're talking  about a career goal here. So this is all the work that I'm going to present is with that in mind of  potentially being the future of exercise prescription. And then we can measure some of these biological markers in response to exercise to see if there's a pathological  progression of a patient's disease. So the first thing to say is, how do we develop that? So  my lab is developing something like a cartilage stress test, where we take a biomechanical  stimulus. So we get someone to, we load their joints, get someone to walk in our laboratory,  and we measure certain biological markers of cartilage stress while someone's walking  in our laboratory. And studies have shown that this has potential diagnostic or prognostic value.  The unique capacity of this methodology is that I measure some of these markers while someone's walking. So it allows a dynamic assessment of those biological markers in  response to loading. And we can also outline potentially individuals with compromised cartilage earlier on in the disease process. So studies have shown that if you get someone  to walk on a treadmill for 30 minutes, and you measure this biological response, you can predict potentially cartilage thickness of five years down the line on an MRI.  So we did a study looking at walking for 45 minutes on a treadmill continuously, and we take the same patients and we get them to walk in an interval type approach,  where they walk 45 minutes with two breast breaks of an hour. And what we did was we measured a  biomarker of cartilage stress, which is COMP. And essentially what COMP does is it transduces  that mechanical signal when you put load on your cartilage, and it transduces that signal from the  extracellular matrix to the chondrocyte. So we measure high amounts of COMP in response to exercise in our patients. It's analogous to cartilage stress. So what we found was that  at 45 minutes of this type of walking, there was a significant increase in that biological  marker of cartilage stress in our patients, which is the red line here, compared to interval walking  regimen, which is the blue line. So walking continuously led to more cartilage stress in  these individuals, at least biologically. Then we wanted to look at exercise prescription in a  specific sport. So when we're thinking about golf as being a sport, which is a moderate intensity  activity, and potentially whether it's a sport that could be used as part of an exercise prescription,  there are different types of golfing. So there's golfing that you can do with a golf cart, or golfing that you could do where you are walking the course. So we say that  for the purpose of the study, it's sort of lower dose walking versus higher dose walking.  And we recently published this data where essentially we got patients to walk the course  for one round, and then the same patients came back in, and they would use the golf cart for that  round. And we randomized which one they did first, and we measured some of these biological markers  in these patients. So the first thing to say is that when they walk the course, there's a significant increase in this biomarker of cartilage stress. And there's a significant  increase in inflammation at all time points at the baseline, sorry, at ninth hole, and then  the end completion of the round. Whereas there was actually a slight reduction in inflammation  when they did that sort of stratified approach with the golf carts. And there was overall no  significant increase in pain, which matched some of those changes in some of those inflammatory  mediators that we measured in these subjects. The other thing is when we looked at cartilage  stress, when they walked continuously, there was a significant increase in this marker of cartilage  stress. And we only saw that increase at the last time points when they used the golf carts,  as opposed to walking the golf course. And the other thing is to say that exercise also has  a systemic hormonal effect. And then we found in these patients, when they walk the course, there was a significant increase in beta endorphins, as opposed to when they use the  golf carts. And what's important to these players is that their golf scores were improved as well,  which is not probably, when you think about exercise prescription, that's probably important  to people playing golf. So finally, what I want to talk is about stressing the system. And this  is some of the work that we're doing right now, which is trying to early diagnose osteoarthritis  and then prognosticate how someone's going to respond to a particular exercise program. So what we're trying to look at is developing a cartilage stress test, where we can look at  the biological state of the joint and then be able to decipher how that joint will respond to loading.  So we've developed a treadmill. And so the middle on the left here is this subject, basically walking on a treadmill at a flat treadmill, which you see in regular gyms.  And on the middle and on the right here, we have our subjects essentially on a tilted treadmill.  So this tilted treadmill has a medial lateral tilt, and we're able to vary the amount of force  that's placed on an individualized knee joint, as opposed to both knee joints. So each knee joint  gets a differential loading paradigm. So what we found was that using this type of approach,  we can see that in the knee joint that is lower actually gets a significant increase in the amount  of stress that is placed on it. What that means is that now we can say that there's a specific stress that's placed on a  knee joint and now potentially can we look at that biological marker response that's individualized to  that particular knee joint, which is the weakness when we look at walking on a flat treadmill because we're not able to vary the amount of stress that's placed on each knee joint.  So what we found is that with this specific approach, we were able to differentiate individuals with knee osteoarthritis from healthy controls, but also that biological  marker response, stress response, was higher whether an individual was from an OA cohort as opposed to a normal healthy control cohort. And also what we found was that a significant  marker of cartilage, that a cartilage degradative enzyme, MMP13, was significantly increased in  individuals with osteoarthritis as opposed to healthy controls with this type of paradigm.  We were also able to look at risk factors for osteoarthritis. So individuals are older,  female, higher BMI, had a higher stress response. And also we were able to differentiate grading of  osteoarthritis based on radiographs. Finally, we also looked at now an exercise prescription for  our patients with knee osteoarthritis. And one thing that's commonly used is an anti-gravity  treadmill. And what we wanted to look at was how did this type of treadmill change these biological  markers of cartilage stress and how potentially could it impact our patients with knee osteoarthritis?  And these treadmills are available in many rehab institutes across the country. And essentially it works on a positive pressure to raise the low extremities. And you can vary the  amount of body weight that's placed on someone's low extremities. So what we did was compare 100%  body weight versus 50% body weight for the same subject. And we did the same tool, a biomarker  approach that we did previously. So what we found was when someone walked at 50% body weight, there was a significant reduction in this cartilage biomarker of cartilage stress.  And there was a significant increase in pain when they walked at 100% body weight as opposed to 50% body weight. So here we see that significant increase at 100% body weight  compared to 50% body weight when they walk on this treadmill. And on the right here, what you'll see is that the individual walking at 50% body weight has a wider base of  support and less of a pathologic gait based on a biomechanical measures compared to when they  walk at 100% body weight. So what it shows here is that the biomechanics match some of the biological  improvements that we see in our patients when they use this type of treadmill as part of their  rehabilitation process. Finally, we wanted to talk about targeting the right interventions to the patients at the right time. And it's important to say that when we're prescribing  exercises, Dr. Kolsky mentioned, taking into account some of the psychosocial expectations of our patients going forward. And what's important to say is that we know that knee pain,  for example, and the likelihood of response to an intervention has many psychosocial factors  that are associated with that. And we've looked at that in terms of psychosocial factors. That  could be socioeconomic status. That could be marital status. That could be employment status.  And all of those have been associated with incident knee pain in a convenience cycle that we had at  our hospital. But also then we looked at expectations. And so how does expectations of a procedure tie into those outcomes? And though this isn't specifically looking at exercise  prescriptions, what we looked at was in our patients who had an injection, does their expectations of an injection tie into their outcomes at four weeks? And what we found was  that pain and disability did improve with an injection, a knee steroid injection, but it  did have some correlations to the expectations of a procedure in these patients. So taking all that  forward, what's the future for our patients in terms of developing an exercise prescriptions?  Certainly our imaging studies, our examinations and understanding of the expectations of the  patient, as well as some of these biomarkers and psychosocial factors, I hope will allow us to  develop individualized exercise prescriptions for our patients going forward. I'd like to thank my  lab. And with that, we will take any questions in the chat. Thank you so much. So it looks like  we, and Melissa, if you want to turn on your video as well. So we have some questions. So  Dr. Kroll asked, when we see elevated inflammatory markers, how do we know whether this is good or  bad? Dr. Hazelhurst, do you have any thoughts on that? Because I know you talked about inflammation  as well. Yeah. So it's kind of about the overall oxidizing environment. So some level of oxidation  is okay. And it's kind of starts to stimulate the immune system. But it's when you start to  kind of go into more of a redox bounce of the overall oxidizing environment, that's when the  inflammatory markers start to become a little bit more bad. So it's kind of a balance system between  the two. And I agree with that. I mean, from the NEOA perspective, some level of inflammation is  probably healthy for individuals from a, now we're talking about a reparative level. And so rather than of sports performance level. So inflammation, I don't think, I think there's  a lot of debates that could be had of when is inflammation good or bad. And I think that that's  a challenging question, but definitely in my studies, inflammation overall has been tied to worse outcomes, but that's probably these individuals who are at very high baseline  levels of inflammation. It's a question for me from Michael Danto about, in these studies, when you measured comp, did all the subjects have a way, sorry to clarify. Yes. I've only,  these studies are only in individuals with osteoarthritis. However, the stress test, we compare individuals with osteoarthritis to healthy controls in this population.  Neil Mesnick asks, am I wrong after many years of clinical practice? Actually, I'm going to read  through that while Dr. Corderbine, we're going to deal with Dr. Corderbine's questions. Would be  interested to hear Ms. Kolsky's thoughts on the work of Vandila Natal as their research indicates  that movement classification specific treatment for low back pain is done better than nonspecific therapy. Any thoughts on that, Melissa? I'd have to go back and read this specific  article, but that I believe that had to deal with movement systems impairments,  model of classification, which is a little different. And I think it was specifically related to flexion of sagittal plane corrective exercise, as opposed to like different  classifications, like treatment-based, treatment-based classification and or others. So although this specific example showed that movement classification, MSI in that population  was no better than nonspecific therapy. I don't think that's generalizable to all movement  system classification in general, because we can see that there are some examples, especially with  acute low back pain. In my example, it was acute low back pain where directional specific  classification has highly effective evidence as evidence with Audrey Long's study showing that  the direction that you do give a patient does matter. But I know that also like looking at the  work of Vandila and the WashU group, there's a lot of value to, although that study may not have  showed it, there is a lot of value to looking at kind of remodeling a movement pattern to  have a corrective exercise where the patient is essentially moving better,  can have value, especially when it's tied to function. So that's... And Melissa, Dr. Corderbine just says, yours is radicular pain, correct? And not axial low back pain?  Is that? Yeah, correct. Okay. Neil Mesnick, I think really great, really great comments overall.  And I'm, I don't think you're wrong at all. I think that's really important. So your comment is  basically saying about generalized strength training as being really important in these patients. And only part of it is performed in a gym. I think that's the challenge we all have  clinically is that what our patients do in their everyday lives is really important. And I'm sure  Melissa faces this too of like patients just do their exercise. Some people come to physical  therapy and they believe their exercise regimen is just while those 30 to 45 minutes in physical  therapy, but it's much more what they're going to do at home. I will say we are doing typically  with some sensor technology studies recently of trying to monitor patients remotely while they're  in the community. And I think that's really, I think that's really important. I think Dr. Hazelhorst, are there any biomarkers that can provide real-time nitrogen negative states to  better direct diet? Yeah. Thank you for the question. I didn't come across anything when  I was looking through the research studies when I'm really to exercise in specific relation to  nitrogen negative states. I will say of all the studies I spoke about today, they actually found  hundreds of metabolite differences in each of the studies. I kind of just narrowed it down to some more kind of clinically relevant ones that to kind of go over the discussion, but  I didn't find anything specifically about the nitrogen state.  Thanks, Ali. And then Dr. Kolsky, were you discussing also classifying patients in terms  of nervous system issues, central versus peripheral and taking into account the psychosocial issues?  Yes, Dr. Krols, in response to that, we did in our, in that study, we looked at sub classifying  not based on movement, but based on strictly signs and symptoms of pain alone. And there's a lot of  good work coming out now with a systematic review, looking at pain mechanism classification  and trying to kind of ours was, was an old study, but it's still a system that we use throughout.  But yes, we looked at that and multiple failed therapy attempts and things like that as well,  going into the classification. That's great. And then Neil, I just want to go back to your comment. I think also there's a second part to your comment, which is about  how patients must recover properly by getting enough protein and rest. And I think that's  very important, a sort of holistic approach, which is what we aim to do in physiatry as trying to  optimize a patient's outcome is really, really important. I say to all my patients that you're  an athlete, whether if you want to move, you're an athlete and it doesn't matter. So I think  treating them that way is really, really important. And talking about diet and nutrition is extremely  important as well. Okay. Just last question. Melissa Tinney, does J-Bar often we see patients  to modify exercise, but do we see correlation of symptom increase with comp increase? You know,  and we have done some specific studies looking at between this correlation between symptoms and comp, we have done it with inflammation and function. So we have seen that if someone  has very high inflammatory mediators, they're potentially less able to do an exercise. We  haven't looked at symptom changes and correlated with comp. And then thank you for that question. And then Dr. Ruth Thornton, do you advise supplements such as glucosamine? There's  very mild evidence for glucosamine. I definitely never talk about it as being a magic bullet for  someone's osteoarthritis, but it's low risk and it might help people with very, very early disease.  So someone with bone on bone osteoarthritis, I don't, I really do. I do talk about turmeric a lot  nowadays, particularly the medication turmeric where you have a strength rather than specifically  in their food because it has some anti-inflammatory properties as well as fish oil. I also talk about  as well because it has anti-inflammatory properties as well. And both of those are sort of low risk  and ginger too. Agree with you, Jose. Okay. I think that's it. We're over time by one minute.  Thank you so much to this wonderful panel and thank you for so much for your thought-provoking  and engaging questions. It was a huge audience, so it was great to have you all and thank you so much  for being here and hope you enjoy the rest of the virtual meeting. Thank you. Thank you. Ali and Melissa, you want to stay on?

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