Hi, my name is Krista Schor and I'm pleased to present to you today in this PROCON debate about are sepsis outcomes really modifiable and I'm going to be taking the PRO approach and trying to convince you that we can move the needle on sepsis outcomes. So my objectives for this talk are to provide an introduction with some discussion about morbidity and mortality of sepsis as well as discussing how research design and data usage can help us identify patients and potentially phenotypes using electronic medical record, artificial intelligence, as well as some big data and machine learning. And then I'm going to close with a talk about patients who survive sepsis and considering their long-term outcomes and goals of care. So here we have some sepsis facts that are provided in a nice graphic from World Sepsis Day recently and they have a great toolkit if you need to educate your staff or your patients regarding sepsis or your community. So you can see here that there's about 51 million cases per year of sepsis with about 11 million deaths worldwide. One in five deaths are associated with sepsis and again when we think about what's happening in the U.S., sepsis is the number one cause of death in hospitals, the number one cause for readmissions and it is extremely expensive to care for patients with sepsis. So we want to consider what we can do to actually move the needle and sepsis is not only common to adults, it's also common in children and 40% of sepsis cases are in children under five. So this is a really important disease process and again it's something that we need to consider in improving outcomes for this population. So what about outcomes of sepsis care? What matters? What matters to the clinicians? What matters to the hospital administration and what matters to patients? For this talk, sepsis is defined as an infection-induced organ dysfunction. So in this schematic, we can see the process from initial infection to an outcome of death. We know that death is one of the primary outcomes in most research studies, but are there other important outcomes that we should be thinking about as well? And has the discharge disposition for patients changed in how we measure mortality and perhaps it's not as accurate as it once was? So in thinking about sepsis mortality and mortality from many disease processes, it appeared that mortality was decreasing for several high-frequency diagnoses including septic shock. So as more hospitals incorporated hospice care into their practice, which is good for the patient and family to receive the resources that they need, I personally was curious how patient discharges reflected mortality recordings in hospitals. So here in this study published in 2020 in the Journal of Healthcare Management, the purpose of this study was to determine if the decline in in-hospital mortality is at least partly due to the change in end-of-life care with an increased discharge to hospice setting in six common high-volume acute and chronic hospital and ICU admission diagnoses. Here we can see for all six diagnoses combined, as hospice use increased, mortality decreased. So what does it look like for each of the six diagnoses? Here we have each diagnosis. Hospitalizations for lung cancer saw a 1.82% rise in hospice and a 1.2% decline in mortality. In HMI with cardiogenic shock, the mortality flattened from 2008 to 2011 with a 1.6% rise in hospice use from 2007 to 2010. Mortality for patients with septic shock decreased by 6% while hospice use increased from 3.5% to 5.4% during this study period. This information is important as we consider resources in U.S. hospitals and how in-hospital mortality is reported. Although we consider mortality to be an important outcome, there may be other outcomes that are important. For instance, what is important to sepsis survivors? In this qualitative study, the investigators aim to identify important health-related quality of life domains for sepsis survivors. Interestingly, this study shows that 7 of the 11 domains are not addressed by the widely used SF36, which is a quality of life short form, and EQ5D, which is the European quality of life five-dimension, which are widely used in ICU study survivorship. The authors concluded that future studies should consider using traditional instruments as well as another one that is a little bit more holistic, the World Health Organization quality of life questionnaire, which is 26 questions, and it really focuses on the individual's perceptions of their health and well-being over the previous two weeks. So, given this information, I believe we can move the needle on outcomes, however, we may want to consider outcomes that are not frequently included in sepsis studies. For instance, if researchers include mortality, how far should we follow patients out? Is in-hospital mortality enough or should we follow patients every few months? And is in-hospital mortality a measure enough to say that we made a difference, or is there more, such as what's important to patients and families? If we decrease organ dysfunction or reduce the time on the ventilator, will that translate to better outcomes? What about the quality of life, shouldn't that matter too? And here I'm thinking about discharge disposition, should that be considered an outcome where patients able to go home may have a better outcome than a patient who needs to be discharged to a long-term ventilator facility? And what about functional status? If a patient comes to the hospital and is fully independent and leaves the hospital completely dependent, that's an outcome that is not as good as we would want. So again, thinking about other outcomes other than mortality, I think is something you want to consider as we move through this presentation. So now we move on to methods that may contribute to our ability to move the needle in sepsis care. Continue to improve capability of identifying sepsis earlier. First we wanted to seek out methods to identify patients with sepsis so we can deliver timely treatment and decrease the severity of organ dysfunction and improve overall outcomes. Some of the methods include utilization of the electronic health record, biomarker profiles, and rapid microbial identification. For this talk, we're talking about moving the needle to the right. However, we must not forget that it is possible to move the needle to the left in sepsis if we do not continue to educate health care providers, screen to achieve early diagnosis, and provide feedback on performance. The electronic medical record alerts have been incorporated into clinical practice either through proprietary systems or homegrown best practice alerts. However, in order to improve care, these systems need to balance a balance of sensitivity where we identify patients that most likely have sepsis and specificity avoiding alert fatigue. In a study by Wang, I was looking at a proprietary sepsis prediction model that was implemented in hundreds of hospitals and found that their extended validation cohort study suggested that the early sepsis alert had poor discrimination and calibration in predicting the onset of sepsis. In an editorial, there was focus on helping doctors and these alerts should have a high sensitivity and specificity and it should facilitate safe and efficient handling of alerts and it shouldn't disrupt workflow. Again, the alerts really should do what they were intended to do as far as urgency and grabbing the attention of the provider. In 2021, Dr. Nomadi and colleagues incorporated clinical notes into their machine learning to improve prediction of sepsis and their findings indicated that incorporation of clinical text features, the pre-trained language, was able to actually improve early prediction of sepsis and reduce false alarms. What about biomarkers? A biomarker is a characteristic by which a pathophysiologic process can be identified. In the clinical setting, a biomarker needs to quickly assist physicians confronted with a critically ill patient in their decision to make the best possible treatment. Biomarker profiles can identify patients with an infectious versus a non-infectious disease or determine the causative agent and that's considered a diagnostic biomarker. Biomarkers can also be a prognostic value in assigning risk profiles and predict the outcomes and then finally, the future may be the use of theranostics in aiding the selection of patients for a particular treatment or monitoring their response to treatment, again looking at the future of personalized medicine and clinical management of patients with sepsis. Biomarkers also need to be obtainable samples and they have limited hands-on time as well as not have specialized laboratories for this, so they need to be tests that can be done in most institutions targeted to the treatment in the future of clinical management of sepsis. What about rapid microbial identification? Antimicrobial susceptibility testing results are crucial for timely administration and appropriate antimicrobial treatment and should be available to clinicians in a timely fashion. Phenotype RAST is a universal mechanism and is independent and allows exact categorization but it demands time for the microorganism to start growth and express the response to antibiotics. Detection of selected resistance mechanisms is more rapid, but the interpretation of its clinical impact is limited. Ease of use is a concern, random access, capacity for simultaneous testing of multiple specimens and affordability are all things that we are concerned about. Efforts really should be made by industry and authorities who have control over these tests and academia to enable wide dissemination of the rapid antimicrobial susceptibility testing in clinical diagnostics. We want to continue to do research with well-thought-out questions. The answers which will inform the bedside healthcare providers on important treatment decisions. For example, there was a question about administering fluids, whether we should give liparal fluids or restrictive fluids and we can reference the Clover study to further understand how a well-thought-out study flows here. You can see this study included all patients with sepsis-induced hypotension, received one to three liters of crystalloid and they had persistent hypotension and they were randomized. They followed the treatment regimen and returned to usual care after 24 hours. I also wanted to highlight some of the outcomes. The outcome assessment they included was mortality, ventilator-free days and organ failure-free days. When we think about outcomes, we need to think about things that potentially would affect long-term outcomes in addition to mortality. What about big data? Would it be helpful to clinicians and research to identify phenotypes? Perhaps some phenotypes have worse outcomes than others and some may respond to treatment where others may not. In a recent study, you can see information that was used to assess phenotypes. They used clinical biomarker, laboratory and outcomes data. Here are the authors' claims aimed to derive sepsis phenotypes from clinical data, determining their reproducibility in correlation with host response biomarkers and clinical outcomes and evaluate the potential causal relationship with results from randomized clinical trials. In a derivation cohort, they had over 20,000 patients with sepsis. In the validation cohort, they had 43,000 patients. They had four clinical phenotypes that were identified and they correlated with the host response patterns and clinical outcomes and simulations suggested that these phenotypes may help to understand heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care but they may help inform trial design and interpretation. In this particular study by Seymour and colleagues, again looking at outcomes, some of the outcomes that they looked at were mechanical ventilation days, administration of vasopressors and days on vasopressors, admission to the ICU as well as in-hospital mortality. In this particular systematic review, it's the first systematic review to look at machine learning to predict sepsis in the intensive care unit, hospital wards and emergency department. There were 28 papers that were used in this particular study looking at 130 machine learning models, each showing excellent performance on retrospective data. I just want to have you think about this, that we can leverage advancements in machine learning to identify patients and phenotypes from real electronic medical records. It's also important to know how are we going to use it. You can see here that the most common variables that went into these models were vital signs in the dark blue. What about artificial intelligence? In this particular study by Nomadi and colleagues, artificial intelligence, sepsis prediction algorithm learns how to say, I don't know. Here this study was specifically designed to reduce false alarms by detecting unfamiliar patients or situations arising from erroneous data or missingness or distribution shifts or drifts. Out of over 6 million prediction windows, they were able to determine that there were patients that did not appear to have sepsis or were non-septic patients. They used what they're calling a composer, which provided early warning within the clinically actionable timeframe across six cohorts and allowed for identification and prioritization of patients at risk for sepsis. Again, this was a methodology so we can identify sepsis, but then we have some patients who we really don't know. This model incorporated that into the program. What about patients who survive sepsis? What about the outcomes in those patients? I think it's important that we consider implementing a plan to address long-term outcomes and goals of care early in the patient's hospitalization. We should anticipate that early on that if patients do survive, we need to plan for long-term outcomes. One way we can address it is the same way we're addressing patients that are critically ill in our ICUs by implementing the ABCDEF bundle. We want to make sure we're controlling their pain, try to get these patients off the ventilator, decrease delirium, get the patients up and moving as early as possible with exercise, and then again, engaging the family and empowering patients and families in their treatment plan. Something that's also important is that we've seen more patients surviving sepsis, but it may leave some patients with long or short-term disabilities. Often, sepsis survivors do have some sequelae. Patients that are on long-term mechanical ventilation may be discharged with a ventilator to a vent facility. Patients who acquire acute kidney injury may require short or long-term dialysis. Some individuals are isolated in such a degree where they have cognitive or psychosocial challenges. And then we have some patients who have disabilities with digit loss or limb loss. It's important to know, too, that the severity of illness and comorbidities and length of stay are risk factors for readmission, but readmissions are common with sepsis, and often the readmission results in death or hospice care. Follow-up after discharge is important, and we need to coordinate care between the hospital, patients, and providers, and this is key to the patient's recovery and also trying to limit readmissions for these patients. So in the 2021 guidelines, the Surviving Sepsis Campaign guidelines, there is a new section with 13 recommendations focused on long-term outcomes and goals of care, again, focused on patients that are surviving and their recovery. And here you can see a schematic looking at some of the, you know, briefly some of the recommendations for long-term outcomes and goals of care. And if you're a researcher, I think this is an area that's ripe for research. As you look through the guidelines, you'll see that there's limited literature on this particular area, so this space is just ready for individuals to continue to do research in this area so we can improve the recommendations. First, you can see that goals of care, discussing the prognosis with the family is important, preferably within the first 72 hours. We want to provide verbal and written education about the patient's diagnosis, some of the treatments that they receive, and also inform them about the potential for post-intensive care syndrome or sepsis syndrome. We want to provide an opportunity for patients and families to participate in decision-making if they feel that they want to engage in those decisions. Discharge follow-up is key. We want to screen for economic and social support. Medication reconciliation should be part of the discharge planning. We want to make sure that they follow up with a physician, refer patients to support groups as appropriate, and again, evaluate patients for post-intensive care syndrome in the follow-up setting. And we think about transitions of care that occurs through the continuum, from the emergency department through the wards. We want to make sure that we have a good handoff process where we describe the severity of illness that the patient has undergone and some of the challenges, like maybe the days on the ventilator, how many days on dialysis, because that all comes into play in their recovery process. So we don't have a specific recommendation for a type of handoff process, but do recommend that a handoff process is used with transitions of care. And last but not least, palliative care. You want to integrate principles of palliative care in the treatment plan when appropriate to decrease the pain and suffering patients and families experience. So in closing, we discussed sepsis facts and outcomes. Hopefully I made you think a little bit more about potential outcomes other than hospital mortality. We also discussed the importance of research study design and how we can leverage data for early identification of sepsis. And you want to consider outcomes beyond mortality and in those patients that survive, we want to think about long-term outcomes and ensure that we are following the goals of care that the patient and the family have aligned. So with that, I thank you so much for your time and I hope you enjoy the rest of the Congress. Hello, my name is Emily Brandt. I'm an assistant professor of emergency and critical care medicine at the University of Pittsburgh School of Medicine. It is my pleasure to welcome you to this session. In the next few minutes, I hope to convince you that indeed, focusing on sepsis outcomes is problematic. I have no pertinent financial or personal conflicts of interest to relay. The year was 1976. The mighty Pittsburgh Steelers defeated the Dallas Cowboys 21-17 in Super Bowl X. NASA celebrated the landing of the Vikings I and II landers on the surface of Mars. Democrat Jimmy Carter narrowly defeated incumbent Republican President Gerald Ford. Our fearless moderator, Dr. Mitchell Levy, was in his third year of medical school at the University of Buffalo. The man never ages. And the first sepsis clinical trial was published in the annals of surgery. It was the first trial to test the sepsis hypothesis. That is that the tissue and organ damage observed among sepsis patients is due to the endogenous inflammatory response of the host, ultimately determining the outcome of life-threatening infection. The paper and sole author, Dr. William Schumer, sought to quell the controversy of the role of steroids in sepsis. He was responding to criticisms such as the one here by Weitzman and Berger, stating, only future studies with sufficient adherence to sound principles of clinical trial design can resolve the controversy surrounding the use of corticosteroids as adjunctive therapy in bacterial infection. This study reported on 172 patients with septic shock. Dr. Schumer reported that among those patients who received large dose methylprednisolone, a bolus of 30 milligrams per kilogram at the time of septic shock diagnosis, could reduce sepsis mortality from 39 to 11%. Fast forward 46 years, the role of steroids in septic shock, including the timing, the dosage, the duration remains unclear. Though clinicians do certainly have more guidance today than those folks who were working at the bedside in 1976. This is thanks in part to the efforts by the Surviving Sepsis Campaign, who do indeed recommend administration of IV corticosteroid therapy for patients with septic shock, a weak recommendation based on moderate quality of evidence. The debate, the equipoise, and at times the disappointment about what treatments we should be giving to patients with sepsis does not stop, however, with corticosteroids. Since 1976, brilliant researchers have reported on thousands of clinical trials in sepsis. This figure illustrates some of those efforts, including more than 100 phase two and phase three clinical trials of strategies to modify the systemic inflammatory response in sepsis. And yet, healthy patients continue to die from sepsis. Patients like Mr. Tom Wilson, a systems analyst at Westinghouse, who was memorialized in this New York Times piece by Jane Brody written in 2002. And though it was written two decades ago now, many of us could write a similar story today. Mr. Wilson's story is not unique. I could write a similar story of a patient I cared for in Pittsburgh, whose life and the life of his family was forever changed by the devastating impact of sepsis. A patient in Pittsburgh whose story is similar to the story of millions of patients across the globe. A recent investigation by Rugg and colleagues estimated that 2017 sepsis occurred in 48.9 million people worldwide, ending in the deaths of 11 million patients. These estimates are nearly double what we had previously thought. Sepsis is a significant public health crisis with high mortality and morbidity and a major impact on resource utilization. Even among those patients who do survive, survivors often suffer post-sepsis symptoms that impair their ability to ever return home, their ability to return to independence and return to self-sustaining gainful employment. So why is it that despite decades of the most brilliant minds dedicating their professional lives to understanding and taming this public health crisis, why haven't we moved the needle on sepsis? Over the next few minutes, I hope to inspire you to challenge conventional wisdom on sepsis. In particular, I invite you to consider these three key prillers to contemporary thinking. That we do indeed have strong evidence-based guidelines, but perhaps they're just not adhered to at the bedside. Second, that we do indeed have positive trials of sepsis. And finally, that mortality is indeed the worst possible outcome in sepsis. Instead, I inspire you to consider these counterfactuals. First, perhaps we have not moved this needle on sepsis because though we do have evidence-based guidance for the treatment of sepsis, sepsis is a heterogeneous syndrome and perhaps a one-size-fits-all approach is not ideal. Second, though there are indeed positive sepsis trials, these trials target a marginal patient population. And finally, maybe death is not the worst possible outcome. Let's consider each of these in turn. We know that sepsis is a very heterogeneous syndrome. To illustrate this point, consider two patients in your intensive care unit. One is a 40-year-old man with no previous medical history who was admitted through the emergency department and diagnosed with influenza. Since admission, his case has been complicated by the development of a staphylococcal pneumonia and clinical decompensation requiring endotracheal intubation and also mechanical ventilation for the previous 24 hours. In contrast, consider another patient, an 85-year-old man who was admitted from the post-procedural area in the setting of a percutaneous cholecystostomy tube placement. This man has a history of end-stage renal disease and a history of heart disease. He presents with ascending cholangitis and is now treated in your intensive care unit with norepinephrine and vasopressin. These patients are not the same. They have significant differences in demographics, post-response, site of infection, likely pathogen, organ injury, and even tolerance. Yet, current clinical guidance recommends that treating these two patients should be done the same. But is a one-size-fits-all approach really the best approach? Thanks to the brilliant work of colleagues across the globe, we have gained substantial information and knowledge about the host immune response in sepsis. Evidence confirms that our bedside suspicions are correct. The host immune response in these patients is unique. We know that a sepsis patient's immune response is a choreographed interplay of intercellular signaling that is dependent on a number of factors. These factors range from patient factors such as demographics, but also genetic and epigenetic factors, also the differences in the gut microbiome, to just name a few. This discussion of heterogeneity doesn't even scratch the surface of the evolution of an individual's heart. We know that a sepsis patient's immune response is dependent on a number of factors, such as genetic and epigenetic factors, and how the timing of therapy may impact a drug's effectiveness. Yet, our understanding of the immune response in sepsis has not translated into individualized therapies for use at the bedside. In large clinical trials, studying heterogeneous patient populations may provide opportunities to individualized treatments. For example, sepsis trials could study treatments that are targeted to an individual's clinical phenotype. For example, a clinical phenotype that could be derived using factors that you and I routinely measure in the early hours of sepsis treatments. Consider next that perhaps a sepsis patient's treatment could be determined using even machine learning models that derive therapy based on the clinical directory of millions of patients who have come before. The heterogeneity of sepsis syndrome has stymied progress, yet our greater understanding of the host immune response yields substantial opportunities to individualized sepsis treatments. Second, I invite you to consider this point. We have made strides in sepsis. These strides have been accomplished through landmark clinical trials that have positively impacted clinical care, through demonstration of either benefit or even treatment failures. However, these trials target a marginal population. I'd like to consider this point from two perspectives. First, through the perspective of trial recruitment and considering those patients who we enroll in our studies. Second, I'd like to consider differences in the trial design themselves. Let's first consider study recruitment in the patients who are enrolled in sepsis clinical trials. There is a critical mismatch between sepsis burden and the high mortality burden of sepsis patients in the countries in which these high mortalities occur and the countries in which sepsis trials are performed. Sepsis trials are predominantly performed in high-income countries. Consider this, in 2018, among the 62 countries that were actively involved in an open clinical trial, 34 or 55% of those countries are considered high-income countries by the World Bank. Yet the mismatch between sepsis burden and sepsis trial participation persists even in these high-income countries. For example, in the United States, despite evidence of disparities in sepsis incidence and worse outcomes among folks with a history of socioeconomic distress or those folks who are ethnic minorities, the patients who actually participate in clinical trials skew very heavily white, with Black patients only participating in about 5% of trials. Further, even if an interventional trial is conducted among low and middle-income populations, recent evidence suggests that the limited availability of study medications occur even if a drug is shown to be effective. For non-interventional trials or even observational studies, publication costs and the price of obtaining data that is not open access significantly limits the widespread dissemination of knowledge that could impact clinical care. Second, the challenging interface between clinical research and clinical care simply transcends the dissemination of knowledge and medicines among disadvantaged populations. Consider the gap between research and clinical care that is occurring at the bedside of even large academic medical centers in the U.S. today. It is true that no single person, agency, or entity ensures the integrated coordination of research and clinical care. Throughout the U.S., local investigators that are simply armed with an idea and a study protocol must try to persuade their clinical colleagues to either refer or help enroll patients in their trial. The clinical care may see the logistical challenges associated with the execution of the study as distracting, and maybe even counter to the priorities and tasks that clinical care requires. Although researchers might argue that clinicians faced with therapeutic uncertainty should be motivated to facilitate patient enrollment in a randomized trial, such an argument can simply be oversimplistic. A clinician may wish that there was less uncertainty, but nonetheless feel the choice of research or care as binary, with the duty to care often prevailing. The impetus to just do it is not to do it, the impetus to just do it in the face of uncertainty, despite a lack of evidence and a time pressured environment, such as a pandemic, for example, may prevail over one's duty to advancing scientific understanding. Many of these challenges have been simply exacerbated by contemporary staffing challenges. As bedside staff are asked to do more than ever before, the additional challenges prescribed by a study protocol, no matter how mundane, may be too arduous for an overworked bedside nurse. These challenges inspire and beget opportunities though. First, there is an urgent need for trial designs that are able to be implemented the world over. These trials must only not include the study of what interventions are important, but how these interventions should be delivered, particularly among countries with fewer resources. Second, funders and drug companies must provide incentives to cast a wide net, including opportunities to support and conduct trials in countries with fewer resources. Third, there must be the development of a streamlined interface between clinical care and research that lessens the burden on frontline workers. For example, there is a significant opportunity to provide improved data flow and interoperability across research and clinical care that allows for real-time implementation of research protocols that are embedded in the electronic health record platforms that are in typical use today. Finally, design and implementation of adaptive trials that test multiple interventions at once and provide study treatments to those patients who are most likely to benefit could likely lessen the discomfort that clinical partners feel when it comes to randomization. Studying sepsis, especially outcomes among the limited marginal population has also likely stymied progress in sepsis. Work to enhance diversity and trial enrollment and approaches that can be broadly implemented is very much needed. Consider this final point. Much time, energy, and resources have been invested in studying sepsis outcomes. However, I inspire you to consider this. Perhaps we are studying the wrong thing. In this piece, Washington Post writers Bernstein and Keating write, a lot of people think after the ICU, if you make it, you come home and your life's going to be better. Your life is going to be normal again. Because that's what I thought, said the daughter of an ICU survivor. She wrote, I thought, oh my God, we're going to have her back home with us. We're going to have the same life that we had before. The reality is, however, that life after sepsis is never the same, even among those patients who survive. Within days to weeks, patients can be healed. On the other hand, some will succumb to their multi-system organ failure. However, a high frequency of patients develop chronic critical illness. This condition is mechanistically caused by persistent inflammation, immunosuppression, and a catabolic syndrome that is typical of sepsis. During this phase, some patients die due to their organ dysfunctions. Some might even develop a secondary infection. Though some patients with chronic critical illness can still fully recover, some patients, however, will experience worsening of their chronic conditions, and some will even suffer from the onset of new ones. In practice, this chronic cycle of acute and chronic critical illness often results in long-term debility among sepsis survivors. Indeed, even among those patients who do survive, a large portion of sepsis survivors will never return home. Many of them will never return to work, and many of them will never return to self-sufficiency. These long-term challenges are not unique to sepsis survivors. Indeed, the families of sepsis patients are faced with profound financial and emotional challenges following the diagnosis of sepsis in a loved one. These challenges often extend beyond the intensive care unit, and they extend beyond the hospitalization. For example, this work, and many like it, report that long-term emotional struggles, such as depression, are common among survivors of sepsis and among the spouses of sepsis survivors, and this is independent of whether or not a patient survived. Recognizing these challenges, there is an urgent need for evidence-based strategies that incorporate the principles of palliative care in our routine clinical practice. The surviving sepsis guidelines urge clinicians to incorporate principles of palliative care, including early goals of care discussion, routine check-ins to assess family and patient symptoms and symptoms of sepsis, and the importance of a comprehensive, and patient symptoms and suffering, and routine palliative care consultation in environments where such resources exist. These recommendations, though rooted in the principles of just good medicine, are best practice statements, or even weak recommendations based on low quality of evidence. Thus, future research priorities must include continuing the incredible body of work that was started by Dr. Randy Curtis to develop a sound evidence base for implementation of palliative care strategies in sepsis. The year is now 2022. Sepsis remains one of the world's most pressing public health problems. We have made incredible strides in our understanding and treatment of sepsis, yet opportunities to develop individualized therapies to address sepsis heterogeneity, opportunities for enhanced trial approaches to touch at-risk populations around the globe, and opportunities to enhance end-of-life and post-sepsis care inspire us to learn more. I thank you, and special thank you to the patients, to the families, and the pioneers leading this work.

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