Jessica N. Lancaster, Ph.D., an assistant professor of immunology at Mayo Clinic in Arizona, discusses the effects of aging on the immune system, and the correlation between biological aging and COVID-19.
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Welcome to Mayo Clinic Cove in 19 expert insights and strategies. The following activity is supported in part by an independent medical education grant from Pfizer Inc and is in accordance with a C. CMI Guidelines Co. Vid 19 Expert Insights and Strategies is a comprehensive curriculum from the Mayo Clinic for healthcare personnel worldwide. This presentation covers aging, the impact on immunity during a pandemic. Our expert for this course is Doctor Jessica Lancaster, a senior associate consultant, one who focuses on immunology research and an assistant professor of immunology at Mayo Clinic. This course is accredited by the A M A. For 0.5 contact hours. It's important to note that there are no relevant disclosures for all those involved in this presentation. Now I'll turn things over to Dr Lancaster. Yes, as mentioned, I am Doctor Jessica Lancaster, a senior researcher for immunology at Mayo Clinic. I'd like to begin by saying thank you for joining us in this course today. We have the following learning objectives. We will identify the relationship between biological aging and disease, explain the physiology and function of the immune system, apply knowledge of biological aging and the immune system to determine age associated alterations to the immune system. We will analyze the correlation between biological aging and co vid 19 infection and lastly identify potential perspectives for immune aging research. With improvements in medicine and public infrastructure, the average life expectancy in the developed world has increased, with human population aged 65 years and older increasing dramatically in the past century. Unfortunately, the extension of our healthy years, or health Spahn has not kept pace with lifespan. The elderly are often sick for longer periods of time and may cope with multiple chronic diseases. In fact, two thirds of the elderly take five or more medications to regulate various conditions. Thus, the aged are both a growing and a vulnerable segment of society, and their health care is a matter of great public importance. The SARS cov to pandemic has had a profound impact worldwide, and its ideology, treatment and prevention are still active areas of research. While most cases have mild to moderate symptoms, about 20% of patients experience severe symptoms that require physician guided care. This includes progression to severe pneumonia and further the development of acute respiratory distress syndrome or arts septic shock and also multi organ failure. It has become apparent early in the SARS cov to pandemic that the elderly comprised the most vulnerable population to severe infection. This trend is in line with what is seen with other infectious diseases, such as the previous SARS cov, a pandemic in which 50% of patients over the age of 50 died. In addition, 14,000 patients over the age of 65 die each year from respiratory syncytial virus RSV and one quarter to half a million in elderly individuals worldwide each year by seasonal influenza. From a population level, it is well supported that the elderly a more susceptible to poor outcomes against infectious disease. But what does this mean On the level of the individual? For example, a 65 year old patient may ask her health care provider, I am fit and healthy. Um, I still at greater risk. Unfortunately, the answer is yes. As we age, intrinsic molecular and cellular changes occur in our bodies and our immune system that decrease our ability to fight infectious disease as compared to a young, healthy adult. Fortunately, there are some caveats. Our individual genetic makeup can greatly influenced the impact of aging on our immune system. Further healthy lifestyle habits also mitigate risk, since they can decrease the chance for co morbidity. Is that negatively impact disease outcomes? The impact of aging on our health and vitality can be obvious to us, even from childhood. Unfortunately, it is difficult to study why aging impacts our health because there are currently no ways to directly measure biological age in research, a variety of parameters have been measured as proxies for biological age. These include the chronological age of the individual. For example, the W H O uses 60 plus years to define aging and their programs, though there is no biological basis for this demarcation lifespan, which is a collection of molecular parameters that describe various cellular processes such as energy metabolism, proliferate of capacity and stress response. Frailty, divine increased clinical vulnerability of the individual and senescent cell burden. The accumulation of quiet isn't or metabolically inactive cells. While medicine has generally focused on the treatment of one disease at a time, the integrative nature of aging pathology has become increasingly more appreciated. Recent efforts in the basic science of aging have identified roughly seven aspects of biology that are altered with age and promote the development of chronic age associated diseases. Thes pillars of aging encompass changes at the molecular, cellular and systems level of biology. Adult stem cells, with the capacity to regenerate all body tissues, had declining function with age. Metabolic pathways by which cells use energy are increasingly dis regulated with age. Macro molecular damage, such as oxidation of lipoproteins, accumulates with age and contributes to chronic disease. Epigenetic regulation determines which genes are active or inactive, and aging can change epigenetic patterns. Inflammation describes an increased baseline of pro inflammatory factors in the body, which can dis regulate many cellular functions and lead to disease. Stress adaptation relates mental health and psychological stress to very really alterations inflicted on molecular processes. Rodeo Stasis involves the handling of proteins, but the machinery for generating and breaking down proteins can get overwhelmed with aging. By studying aging and simple invertebrate models such as worms and flies, researchers have been able to identify conserved molecular pathways that impact aging. Mutants of the simple life forms have even demonstrated resistance to the effects of aging by studying mammals such as the mouse, more detail has been gained regarding these age associated changes. Thes ongoing studies continue to outline biological aging and the applicability of these findings to humans. Thus, the goals of gero science or the science of aging are to understand how aging enables chronic disease at these fundamental levels, and how to use this knowledge to inform the development of preventive and therapeutic approaches as previously eluded, we have greatly increased human lifespan but not health Spahn. Thus we have a growing aged population which is at greater risk of illness. Aged patients have poor outcomes to infectious disease, which makes it the fourth most common cause of elderly death in the developed world. Now on Lee, do they have a decreased magnitude of immune response to pathogens. They also respond poorly to vaccines with at least a two fold diminished response to immunization. On the other hand, elderly also have reduced tolerance to self antigens, causing increased prevalence of autoimmune pathology. Aged immune response is also impaired in its ability to detect and eliminate tumor cells, which leads to an increased incidence of cancer with age. Furthermore, aging appears to impact the sexes unequally. The regulation of FINA tip ICS sex differences, it determined by genetic mechanisms such as the sex chromosomes X, X and X Y, and also hormonal mechanisms, which include androgen signaling and male testes and estrogen signaling and female ovaries. The reason for aging sex disparities. Still poorly understood in general, it is widely recognized across many geographical locations worldwide that female life expectancy exceeds that of males. More centenarians are female, and a later age at menopause is a strong predictor of increased longevity. This may be linked to the greater self renewal and regenerative capacity of adult stem cells and females, as well as greater wound healing ability and liver regeneration. Shifting sex hormone levels with advanced age leads to a net positive energy balance, and this contributes to accumulation of fat tissues. This increase in adipose tissue then leads to increase susceptibility to age related diseases as adipose cells engage in chronic, low level inflammatory signaling. Now on Lee do fatty tissues increase, but they are redistributed. This is especially significant in males who have increased visceral adipose tissue with declining testosterone levels. Among the other, sex disparities and disease include cardiovascular conditions, which are more common in men. Women have better odds of survival after heart failure, which may be linked to their differing lipid profile and possibly a protective benefit from estrogen. Neurological disorders of age also impact the sexes differently, with women more susceptible to Alzheimer's disease and males more susceptible to Parkinson's disease. Lastly, we should mention that the impact of the bacteria that live in symbiosis with our body interfaces, known as commence aled microbiota on the immune response, has become an area of immense interest within the past several years. The MICROBIOTA is fairly similar among males and females before puberty, after which circulating sex hormones may be driving altered composition and adults has been been noted that males are more susceptible to severe outcomes to Cove in 19. And it does appear that sex differences play a significant role in the study of the aged immune response. However, besides the general trends noted above, the definitive mechanisms that drive this sex disparity to Cove in 19 are still unclear. The fundamental question is, why does the immune system weakened with age? We now appreciate that the immune system is not static. It is immature at birth and then evolves during the lifetime of foreign antigen exposures. Once established, our immune systems are at their optimum capacity roughly around our reproductive prime. Perhaps once reproduction has been completed, the energy needed to ensure survival is no longer expended. This is one hypothesis. Thus, the answer to this complicated question may lie in our evolutionary need to continue our species. While it is easy to accept that aging decline is simply due to wear and tear on our bodies over time, there are mammals that exhibit negligible effects of aging. This includes the naked mole rat, which can live much longer than other rodents. End is seemingly cancer free as well. A submarine mammal species. Thus, our response to aging may not be destiny, but a process that could be studied and even treated. Before we discuss how the immune system is altered with age, let us go through a basic review of the immune system. In the context of a young adult, there are essentially two layers of the immune response which fall along a continuum. It is either rapidly responding and generalized in what is termed the innate immune system or delayed but targeted. Called the adaptive immune system, the Nate immune system maintains surveillance against generic but obvious signals of invading microbes and are triggered by the antigens that are unique to foreign organisms. Among the in a immune cells are neutrophils, macrophages and dendritic cells, as well as many other subsets of these. They are generally capable of Fargo cytosine or engulfing microbes, as well as releasing site a kinds or chemical signals. Also to clarify Auntie Jen is any substance that can elicit and immune response. Antigens can come from foreign pathogens such as bacteria or virus, harmless foreign substances like food or even the host itself, which is recognized as a self antigen. The next layer of the immune defense is the adoptive immune system. It is primarily composed of specialized white blood cells known as T cells and B cells, though there are other specialized groups which will we will set aside for the sake of simplicity. Um, Angola B cells is to produce antibodies directed against the antigens of a particular invader. A main goal of T cells is to clear infections, particularly viral infections, by triggering the death of infected cells, thus halting the viral replication cycle and allowing for cellular restoration to follow. Each component of the immune system is functionally specialized. Immune cells are blood cells and are all derived from stem cells that are made continuously in the bone marrow even into adulthood. The stem cells are influenced by signaling factors in the bone marrow environment to become either myeloid or lymphoid progenitors. The myeloid progenitors go onto for many cells of the innate immune system, such as the previously mentioned neutrophils, macrophages and dendritic cells. On the other hand, the lymphoid progenitors go on to form B cells, which complete their maturation in the bone marrow, or T cells that traveled to the thymus to finish their development. Not only are the immune cells evolved towards their purpose, but they're also specialized to the environments that they protect. The innate immune cells patrol the tissue surfaces. They are able to engulf microbes and can often stop many infections from ever being detected by the host. Once they have encountered foreign antigens. They also send outside a kind signals to send the nearby tissues into an inflammatory state and to call the adaptive immune cells toe action. Beyond the superficial tissue surfaces, T and B cells of the adaptive response circulate through the blood. When traveling through different regions in the body, they await inflammatory signals from innate immune cells. Individual T cells and B cells each bear a unique receptor that allows them to respond on Lee to antigens that have the right fit, so to speak and can bind to the receptor. The expression of a broad range of unique receptors allows for the T and B cells to be Onley activated when facing their specific antigen. Innate immune cells, such as dendritic cells engulf pathogens found in the tissues and break them down into small protein pieces. The dendritic cells then travel to the nearest lymph node, which are akin toa local staging areas for organizing the immune response here. T cells passed through lymph nodes via the blood vasculature and make contact with danger excels the dendritic cells air, presenting the protein antigens they acquired from the pathogen Onley. Those T cells with a receptor that combined the presented antigens are activated. Once activated, they're able to travel to the site of inflammation and initiate the adaptive stage of the immune response. We have seen that the immune system is comprised of both the generalized innate response and an antigen specific adaptive response with aging. Both layers air dramatically affected. The primary lymphoid organs, which are bone marrow and the thymus, are the sites where B cells and T cells respectively, are matured. The bone marrow and famous undergo profound changes that result in decreased output of new T and B cells. In addition to decreased output, the maintenance of antigen inexperienced or naive T and B cells is further inhibited. The ability of cells to faggots atos particles and to chemo tax or migrate and respond to stimulus is reduced in aged immune cells. The generation of antibodies, which bind to their specific antigen and prevent pathogen invasion, is also reduced with age. At the same time, other features air amplified in the aged immune system. The generation of Saida kinds, in particular the ones associated with inflammation, is increased so that there's a higher baseline level of inflammation. In the innate compartment, we see the increased representation of my Lloyd cells, such as macrophages. While we saw a decrease in naive T and B cells, we see a rise in the memory cell subset. While this is likely a result of the lifetime of antigen exposure, we now see that many memory cells exhibit the exhausted or dysfunctional phenotype. Changes to the function of the adaptive immune system have been well characterized, so the mechanisms driving these changes air still poorly understood. One significant change is the diminished activation of aged T cells. As we previously reviewed, dendritic cells will interact with T cells that have a T cell receptor, recognizing the antigen presented by the dendritic cell. The recognition of antigen and further stimulation by the dendritic cell will drive the T cell from a naive state toe inactivated one. Once activated, the T cell will undergo rapid proliferation, producing an army of identical T cells that each bear the same antigen. Recognizing T cell receptor, some of the T cells Theophile actors will immediately traveled to the inflamed site in order to resolve the infection. Once their job is complete, most will quickly die off. Others will be long lived and maintained in the bloodstream. They become part of the T cell memory pool, and they will be ready to respond to the same Auntie Jen when it is experienced again by the host. Interestingly, age T cells seem to have the same capacity to be stimulated when cultured in vitro. However, there activation appears to be blunted when it occurs in the context of the aged tissue micro environment. Furthermore, the magnitude of their activation against their specific antigen appears to be dampened. This has consequences for the aged T cell response. Without full activation, the age T cells do not produce as many effective T cells as their young counterparts. Thes effect er T cells can also have reduced function, which has been demonstrated by measuring either the concentration of cytokines released by age T cells or by measuring their ability to kill infected targets. Furthermore, there are less memory T cells being produced. Not only are there less of them produced, but their ability to rapidly mobilize upon reinfection is limited. Thus, pathogens first encountered an advanced age are less likely to be recalled by the immune system when re encountered. These defects in the activation of T cells is part of a phenomenon known as T cell exhaustion, and it is most apparent and chronic inflammatory conditions such as seen in the aged and in metabolic disease. While much research has focused on intrinsic changes to the immune cells, it also appears that the tissue micro environment that they reside in has a tremendous impact on their potential with age. Many of the structural cells of the body undergo profound changes. While we can readily appreciate the physical change in the integrity of the cells of the body with age, they're undergoing genetic changes as well. The immune organs, which include the bone marrow, famous lymph nodes and spleen, are not exempt from such changes. For example, we can compare the lymph nodes, the staging ground of the immune response with age and young adult mammals. The lymph nodes are compartmentalize so that different immune cells confined each other and orchestrate the appropriate immune response. The danger Excel bearing pathogenic material enters through the lymphatic vessels and searches for the antigen specific T cell, which are all contained in the T cell zone. T cells and B cells must also find each other in order to promote antibody formation. Once activated, the B cell, situated and follicles around the perimeter of the lymph node, will travel to the boundary of the T cell zone in order to interact with its activated T cell partner. With age, the structure of the lymph node changes and becomes disorganized in such an environment. It could take longer for the immune cells to find each other and engage in their immune interactions. In addition, the structural cells of the lymph node also participate inside a kind signaling and promote these interactions. But with age, these chemical messages are being altered or lost. Thus changes to immune cells and tissue with age has profound consequences on their ability to carry out the immune response. The elderly can be at greater risk of cove in 19 illness, even from the first exposure to the virus. Estimates have placed the transmission variable are not of SARS cov to anywhere from 1 to 3, meaning that for every infected person they can transmit the virus to 1 to 3 other individuals. The stars. Kobe to virus has been especially threatening when compared to other highly infectious diseases. Because it will be transmitted from asymptomatic, carriers will likely not know to take precautions, thus unknowingly pass along the virus to the community. For the approximately one million senior citizens in the US that live in assisted living communities, they could be especially at increased risk due to living in close proximity to others. Like all pathogens, SARS cov too must penetrate through a highly protected barrier surface in order to infect its host SARS. Cov, too, has been primarily characterized as a pathogen that invades to the upper respiratory tract, having been inhaled through the mouth or nose like all body to environment surfaces. The lining of the respiratory track has evolved a sophisticated set of defenses to protect this vulnerable region. Specialized cells generate mucus tow line the respiratory tract, which encapsulate particles to prevent their adherence to cells. The cellular lighting facing the environment have many extending hair like cilia that beat and regular Paras Tallec tempo in order to drive particles down the track towards the highly his it'd environment of the gut. In the age, thes defenses are compromised as mucus formation is diminished and the parasol tick action of cilia is weaker. Beyond the respiratory micro structure, the chests muscles of the elderly are weaker, making it difficult to effectively cough and keep the airway clear. Thus, the virus could be more successful in its initial invasion of the respiratory tract and penetration into the vulnerable host. It has now been determined that stars Kobe to engages the angiotensin two receptor, or ace two receptor found on epithelial cells of the lung using prominent spike proteins. Currently, reports based on patients in China, such as by Lee at all, have not found any obvious difference in ACE's to expression with age. On the other hand, Chan and colleagues have found that expression could decrease with age and that expression was lower in males, the population more susceptible to severe illness. Similarly, Xudong and colleagues for the first Stars pandemic found that ace to expression levels in rat lung were slightly decreased in age and further found that there was no sex difference in expression at any age. Thus, it cannot be concluded that differences in illness severity could be tied to obvious differences in Ace's two receptor expression. Once the virus has entered the interstitial space, it will be encountered by the innate immune cells in eight cells that detected the foreign invader will engulf the virus, such as shown with this neutral Phil macrophages secrete inflammatory cytokines. In order, thio signal other cells. Dendritic cells migrate to the lymph node near the lung in order to present antigen toe activate T cells in the aged immune system. The numbers of innate immune cells are greatly increased. However, it appears that their function is either limited or altered so that they do not lead to a productive immune response. Molecules that correlate to the ability of neutrophils being able to destroy pathogens are now decreased macrophages air skewed towards, ah, hyper inflammatory state, which actually serves to dampen rather than promote, the adaptive immune response. Dendritic cells are found to be decreased in numbers, and the ones remaining have poor antigen presentation capacity, further limiting adaptive immune cell recruitment. The value of the immune response largely comes from the sophistication of the adaptive immune system. As we previously reviewed, T cells and B cells bear unique receptors that allow them to identify their cognitive Auntie Jen with a high degree of specificity as a whole, the adaptive immune cell populations, comprised of hundreds of millions of cells, are diverse enough to recognize the broad range of antigens that an organism will encounter throughout its lifetime. Thus, once the danger Excel has brought viral pieces to the lymph nodes for presentation to T cells, it is likely that a T cell bearing a receptor recognizing the viral antigen can quickly make contact and initiate the T cell response, the number of T cells maintained in the body remained fairly constant throughout life. Unfortunately, over a lifetime of antigen exposure, the diversity of the T cell pool becomes restricted as some clones become overrepresented thes clones that were selected based on previous exposure to infectious agents. But they're expanded at the expense of clones that can recognize hitherto un encountered pathogens. Thus, when the dendritic cell in the aged immune system presents antigens from a novel pathogen such as SARS cov too, it will take a longer time for a T cell with some reactivity to this new antigen to be selected for activation. The function of B cells is very important to the adaptive immune response, since they're responsible for generating protective antibodies against the virus. Naive B cells that bear receptors recognizing the viral antigens are activated. However, before they can fully reach their potential, they must receive additional stimulation from helper T cells. The helper T cell itself has been activated by the Danger Excel bearing the viral antigen. Once the B cell has received signals from the helper T cell, it can complete its differentiation. The B cell gives rise to a type of cell, known as the plasma Blast, which is essentially a factory for antibody production. The antibodies produced are finally tuned to be highly specific to the viral antigen. A cohort of memory B cells are also produced, which are ready to respond when the virus is encountered again. The full expression of the B cell responses limited with age, in part because of inadequate help from the T cells. Since the B cells are not being fully activated by helper T cell signaling the B cells produce reduced immune outputs, fewer plasma blasts were formed, and the ones that are form do not generate the highly specific antibodies against the virus. Instead, they produce antibodies of lower affinity, which may not be as affected at neutralizing the virus. Limited memory B cells are formed, which results in a reduced ability to fight the same virus. Again, it has become more apparent that severe cases of Cove in 19 can lead to the development of acute respiratory distress syndrome, ARDS, septic shock or multi organ failure. Ours is the main cause of death for Kobe in 19. There is currently a need for prognostic markers that can identify high ARDS risk patients. It is unclear how much of the damages due to direct action of the virus. Research suggests that what separates the severe cases is an uncontrolled inflammatory response, a phenomenon known as Saida kind storm. The aged and those with chronic disease such as hypertension and diabetes, are at increased risk for side a kind storm. Severe patients have elevated levels of the site of kinds interleukin six interleukin one B and indifferent Alfa in their blood. Once released by innate immune cells, thes cited kinds trigger inflammation, which causes leaky nissen, the blood vessels and fluid buildup. Increased levels of chemo tactic factors. CCL. Five c x e, l eight and see X E l 10. Also recruit Maurin eight cells to the damage site, further compounding inflammatory damage, thus damage inflicted by viral invasion, a dampened adaptive response and an over exuberant innate response all contribute to co vid 19 Pathology. Frailty is a physical state, have increased susceptibility to injury and illness and could be determined based on clinical assessment. Physical frailty such as patient co morbidity, is like diabetes and chronic inflammatory conditions correlate highly with severe outcomes to Kobe 19, much more so than simply chronological age. Though frailty is associated with severe illness, frail patients have been able to recover from Cove in 19. Thus, some research authors have explicitly cautioned against triaging care away from frail patients has had been sometimes suggested during pandemic peaks. Rather, patient frailty must be taken into account for long term care plans. In addition, social distancing measures intended to reduce viral transmission can exacerbate frailty, as patients with chronic conditions may have limited contact with case managers and the elderly may feel discouraged against exercise. There have been tremendous public interest in the development of a SARS cov to vaccine, which be intended for prevention of disease. The goal is to prevent the virus from attaching to and invading cells by generating antibodies specific for the spike protein on the viral surface. However, the efficacy of a given vaccine is often evaluated in young lab animals and young adult patients. As we have learned, the aged immune system responds to an antigen with decreased intensity and is often delayed when compared to that in a young individual, as had been seen in other vaccines, such as for seasonal influenza. The elderly are given less protection against disease and tend to have shorter lived protective responses until an effective vaccine is available. Pharmaceutical methods to improve outcomes for those already infected have been explored. A one group are antiviral drugs intended to inhibit the replication of the virus. This includes drugs such as Romney Severe, which has been shown to be effective in shortening disease. Durations. Convalescent serum, obtained from patients who have recovered from the disease, is also a prophylactic therapy that introduces antibodies that bind the virus. In the other group are therapies intended to mitigate damage caused by the hyperactive immune system. These include both non steroidal and steroid based anti inflammatory agents Clara Quinn and its derivatives and Antagonists Against Side a Kind Signaling thes treatments have had varying degrees of success in improving patient outcomes. The challenge has been to determine the timing of effective anti inflammatory treatment. These agents worked to non specifically damp in both the innate and adaptive arms of the immune response. Thus, while reducing inflammatory damage, the ability to clear the virus is also reduced and can potentially cause further harm to the patient. Experiments and lab models have demonstrated that aging can be induced by systemic factors. It has been found in many different contexts that transplanting tissues derived from age specimens can induce aging characteristics and otherwise young and healthy organisms. For example, para bio sis experiments use surgical techniques to join the blood circulation of two specimens. It was determined that when a young mouse was joined to an aged mouse, the young mouse developed immune cell characteristics similar to that of the aged mouse. Interestingly, when the circulation of the mice was separated, the young mouse was able to recover its young phenotype. These experiments suggest that some factors of aging are powerful soluble components, and perhaps that inhibiting these factors can lead to therapies to treat aging. Despite provocative results in experimental models, the translation of anti aging therapies to humans is still limited. Currently, the best proven practices for curtailing aging decline are also the most mundane. Chronic inflammation is heavily influenced by nutrition, especially the variety seen by the high fat, high sugar western diet. Modulation of food and take such has been observed with calorie restriction or intermittent fasting has been demonstrated to reduce markers of inflammation and aging. Consistent exercise is also recommended for reducing frailty and also mitigating chronic inflammation. Mental and cognitive health are also important as stress and hormones play instructive roles in immune function by means still being defined. We will end by summarizing the main areas of research interest in the aged immune response. It is important to understand how changes in the genetic level an epigenetic regulation are altered in immune cells, subsets with age, the influence of the age tissue micro environment plays a significant role in the delayed communication and compartmentalization of immune cells, and the means for this change are still unclear. Adult stem cells have reduced to regenerative capacity with age and as immune cells differentiate, their skewed towards myeloid lineage is which may contribute to increased inflammation and reduced lymphoid diversity. Along these lines, T and B cell repertoires shrink with age, reducing the diversity of antigens that can be recognized by the aged immune response experiments, such as by mouse para bios, ISS demonstrate that systemic factors can be transferred in the blood to cause aging. Identification of these factors may shed further light on the mechanisms that accelerate aging and possible therapeutic targets. Finally, I'd like to say thank you for joining me today If you would like to claim CMI credit and view additional existing and upcoming cove it 19 related topics, please be sure to visit. See ee dot mayo dot e d u slash Kobe expert. You'll need to log into the site. If it's your first time visiting, you may need to create an account. This will allow you to access the course, complete a short evaluation and then you'll be given access to your CMB certificate. Thank you.