Good morning, and welcome to the federal government's sepsis priorities, working together to educate, innovate, and optimize patient outcomes. I am Sarah Dunsmore, and I am here from the National Institutes of Health, and I'm pleased to have my other federal government partners and colleagues, Runa Gokhale from the Centers for Disease Control, and Kim Scioretta from the DRIVE Division of BARDA. And Runa is going to start off first today and tell you what about what is going on with sepsis at the Centers for Disease Control. Good morning. If some of you with your eagle eyes notice in the posted slides that my first slide is incorrectly titled, I was prepping for two presentations while responding to COVID-19. So this is not in fact the CMS Quality Conference, although that's what you'll see on my slides. So my objectives today are to briefly discuss the complexities of defining sepsis, followed by a review of sepsis epidemiology, and finally I'll quickly summarize CDC's sepsis activities. So most of you do not need this definition, but sepsis is thought to be a life-threatening organ dysfunction caused by a dysregulated host response to infection, and septic shock, a common pathway to death characterized by complex hemodynamic and metabolic derangements. Defining sepsis can be challenging. Multiple definitions and terminologies can lead to discrepancies in reported incidents and observed mortality. There's no gold standard approach to identifying cases and no definitive diagnostic test. What these figures show are trends in sepsis incidence and mortality as assessed by EHR clinical data, the solid lines, and administrative codes, the dashed and dotted lines. Trends towards increasing incidence and decreasing mortality are clearly steeper when assessed by administrative codes. This raises the question as to whether hospitals using administrative codes to track sepsis are seeing higher sepsis case counts and lower sepsis mortality rates, and if this may at least in part be due to ascertainment rather than true representation of disease incidence and outcome. This figure shows differences in mortality estimates obtained via death certificates in blue versus administrative codes in red, highlighting again the need for reliable objective methods for measuring sepsis incidence and mortality. Given challenges with defining sepsis, demonstrated in part by varying trend estimates depending on surveillance method, an effort was undertaken in 2014 to develop a surveillance definition for sepsis informed by clinical data alone. This effort, undertaken with the Harvard Prevention EpiCenters, a CDC-funded research network, collected and estimated 1.7 million cases of sepsis among adults, adult patients, and nearly 270,000 deaths. It found that 22% of patients with sepsis did not survive their hospitalization or went to hospice. It found that sepsis was present in nearly one-third of all hospitalizations that culminated in death. We're working with partners currently to determine how to reliably assess pediatric sepsis burden. You'll notice that these estimates are for adults alone. Around the same time that this work was being undertaken, a pilot investigation was conducted assessing characteristics of 246 adults and 79 children admitted to the hospital with severe sepsis or septic shock. They found that sepsis begins outside of the hospital for nearly 80% of patients. That seven in 10 patients with sepsis had recently interacted with healthcare providers or had chronic diseases requiring frequent medical care. And found that four types of infections were most often associated with sepsis, and these were lung, urinary tract, skin, and gut. A CDC vital signs report was published that demonstrated life-saving prevention opportunities. This pilot project was followed up by a larger project that involved reviewing medical records of 1,000 adults and over 800 children hospitalized with severe sepsis or septic shock. The preliminary results of this project are presented in the next few slides. Similar to the pilot assessment, the larger project found that 75% of adult sepsis patients were admitted from a private residence. 90% had sepsis onset in the community. 93% had an underlying medical condition. 24% had an outpatient medical encounter seven days before sepsis diagnosis. 65% were discharged to a private residence or skilled nursing facility. And 34% died within 90 days of diagnosis. We found that in 57% of cases, a true pathogen was identified. And the top three pathogens identified were E. coli, staph species, and strep species. For pediatric cases, the findings were similar. 92% admitted from a private residence, 86% with sepsis onset in the community, 54% with an underlying medical condition, 38% with an outpatient medical encounter seven days before sepsis diagnosis, 81% discharged to a private residence or skilled nursing facility, and 11% died within 90 days of diagnosis, far fewer than the adult sepsis patients. In cases of pediatric sepsis, in 48% of cases, a true pathogen was identified. And the top three pathogens identified were staph species, strep species, and E. coli. So same pathogens, different order. I want to talk a little bit about the surveillance platform that we used to conduct this work. The Emerging Infections Program is a CDC-supported network in 10 states that funds personnel at each site to carry out a variety of studies. The backbone is active surveillance for all selected lab-confirmed infections in defined areas. For most pathogens under surveillance, this ends up being around 20 million persons in the catchment areas. One important characteristic is that we get all infections in both community and health care settings, so we can better understand the interactions and potential intervention points. DHQP leads surveillance for health care-associated infections, staph aureus, CRE, ESBL, and C. diff, among others. When you see estimates of the number of cases of C. diff in the U.S., for example, those numbers come from this system. In addition to surveillance, EIP can do specific studies on conditions such as sepsis, and that's how this sepsis study was undertaken. So that takes me to my next section, which is a little bit more on the sepsis work currently conducted at CDC. So I want to show this figure taken from a viewpoint published a couple of years ago by key members of our sepsis team at CDC. The figure illustrates a need for public health to adopt a sepsis prevention framework that recognizes patient risk factors and prevention opportunities before the onset of sepsis and before the patient presents to the hospital. In the center, the emphasis is that infection precedes sepsis, and infection prevention is the key to sepsis prevention. There are many opportunities to prevent infection or exposure to pathogens, but these are not currently thought of as sepsis prevention necessarily. Vaccination, appropriate antibiotic use that preserves activity of key antibiotics used to treat sepsis, tracking of pathogens so clinicians know the sorts of pathogens their septic patients are most likely to have, responding to outbreaks to reduce exposures to vulnerable patients, reducing healthcare-associated infections, and supporting implementation of diagnostics. On the right, the focus is on host susceptibility. Who is at most risk, and where do they receive care where education can be best addressed? What health behaviors can reduce the risk of infection? One example being smoking. Preserving the microbiome, that is the natural flora in our gut, skin, and other surfaces, reducing and identifying comorbidity risk factors like diabetes, and identifying ways to only use when absolutely essential, those factors such as indwelling devices, catheters, and IVs that bypass natural defenses and allow pathogens access. Our strategic goals for reducing the impact of sepsis reside largely in four buckets. The first bucket, data, is where the bulk of the work that I have presented to you thus far resides. I will give some examples of work we are doing in the other three buckets, innovation, education, and collaboration in the next few slides. So I presented the Emerging Infections Program earlier. Another program that is run by DHQP is the Prevention EpiCenters Program, and it is through these two platforms that much of the innovative work to reduce the burden and severity of sepsis is conducted. The Prevention EpiCenters Program, started in 1997, is focused on translational research that helps move enhanced interventions into clinical practice, with the focus on interventions that are aligned with public health goals. This has expanded to 11 academic centers that have access to data for over 250 hospitals. Emphasis on multi-center studies include pathogen transmission, antimicrobial resistance and stewardship, healthcare environment, and sepsis, with sepsis work including appropriate use of antibiotics during sepsis care, microbiome disruption as a risk for infection in sepsis, and biomarkers research. Some of the innovations taking place include the Hospital Toolkit for Adult Sepsis Surveillance, which was created to guide healthcare facilities through the process of implementing the clinically-based adult sepsis event definition presented earlier. This toolkit is publicly available for download on the CDC sepsis website, and several EIP sites have partnered with institutions in their jurisdictions to implicate the toolkit. Our communications activities are included here with Vital Signs and Get Ahead of Sepsis. We have made major investments in creating messaging that is based on science and resonates with patients, families, and clinicians. We have tried to pull in prevention messaging and provide additional amplification of early recognition messaging based on screening and treatment recommendations from critical care experts, with whom we have worked closely in the past several years. The impact of our Get Ahead of Sepsis campaign, a national campaign launched in 2017, has been sizable, with several public service announcements, 5.4 million people reached by a blog tour, almost 200,000 social media engagements, more than 125,000 materials downloaded, and with CDC sepsis web traffic increasing by over 100% after implementation of this campaign. Over 950 partners have received CDC partner toolkits through the Get Ahead of Sepsis campaign. Finally, our collaborative efforts include integration of sepsis into ongoing agency priorities, and this has been something that has been very important to us, particularly as we tackle sepsis from a prevention angle. We have tried to integrate our sepsis messaging into other agency priorities, such as antimicrobial resistance, antibiotic use in C. diff, flu, hand hygiene, quality chronic conditions, and vaccines. We have extended partnership with broader efforts, such as the Global AMR Challenge, a year-long U.S. government initiative to bolster global efforts across sectors to fight antimicrobial resistance, and have integrated sepsis messaging with the efforts of global partners such as WHO. Federal government partners such as NIH and BARDA, as well as patient advocate partners such as Rory Staunton Foundation and Sepsis Alliance, who have been huge instigators to us to get moving in the area of sepsis, and have been very valuable partners in continuing and amplifying the work that we're doing around sepsis. In summary, we see that sepsis incidence and mortality in the United States are not decreasing. Efforts are underway to better track sepsis, as well as to educate the public and health care workers to improve prevention and treatment, and collaboration across federal agencies and with state and local health departments, academic researchers, and patient advocates are a crucial component of our efforts to reduce sepsis morbidity and mortality. I wanted to end with some images from our Get Ahead of Sepsis campaign, which are, as I mentioned, available for download on the CDC sepsis website. Thank you. Thank you, Runa. So the plan for this session is you're going to hear three talks, and then we'll do a panel questions for everyone at the end. Our next speaker is Kim Sciretta from BARDA, and she's going to tell you about solving sepsis. So thank you to the organizers and the society for allowing us to have this opportunity to present on our BARDA sepsis program. I'm Kim Sciretta. I'm the BARDA DRY Solving Sepsis Program Manager. I am a federal employee, if that wasn't clear, I have no disclosures relevant to this presentation. So BARDA is the Biomedical Advanced Research and Development Authority. We sit within the ASPR, which is the Assistant Secretary of Preparedness and Response, part of the Department of Health and Human Services with my colleagues here. ASPR's mission is to save lives and protect Americans from 21st century health security threats. And that can be any of a number of known threats, chemical, biological, radiological, or nuclear threats, or it could be unknown threats, or it could be an emerging infectious disease like COVID-19. One of the priorities for ASPR is to establish a medical countermeasure enterprise, and that aligns with BARDA's mission. We develop and we procure medical countermeasures to counter these health security threats. And we do this through forming unique public-private partnerships, and we've been very successful in doing so. Since we were established in 2006, we've brought forward 54 products to the FDA for approvals, features, and clearances. There are several funding divisions and research divisions within BARDA, but DRIVE was launched in June of 2018 to support the innovation with the rest of BARDA's mission. We're the Division of Research, Innovation, and Ventures, and this is where the Solving Sepsis Program is housed. We are formed in part due to authorities that were granted under the 21st Century Cures Act. This also allowed us to work side-by-side with our contracting division to improve efficiencies in our business practices, and we also were given the authority to engage in venture practices through MCIP. The DRIVEx component is where the R&D research is housed. We make non-equity investments in our research and development, but we also innovate on our business practices, too. It's not just technology innovation. On the business side, we launched an EZBAA. This allows us to award contracts in as early as 30 days. We also established an accelerator network, currently composed of 13 accelerators spread uniquely throughout the United States. They can provide wraparound support to our funded partners, as well as be eyes and ears on the ground and seek the innovation that we're looking for within BARDA. Once Ventures is launched, we'll be able to take equity position in our investments through a third party. So currently within DRIVE, we have several major investment areas. One is ENACT, Early Notification to Act, Control, and Treat, and this is the ability to detect infection early in the post-exposure pre-symptomatic phase. Solving Sepsis is the program that I'm going to be speaking about today, and I'm the program manager for that. And then there's ODI, Other Disruptive Innovations, which is a catch-all for other innovative ideas that are relevant to BARDA. These are all topics within our EZBAA solicitation. I should also mention that within the last couple weeks, we launched a fourth topic related to in vitro diagnostics for COVID-19. So because we are a response organization and preparedness organization, we can't be fully prepared against any of these threats unless we consider sepsis as part of that threat, since sepsis can arise as a secondary confounder. So we say within our organization that all roads can lead to sepsis. And we do think of sepsis along this patient continuum. We take a little bit of a different approach with this. So we're thinking about the patient from prevention side, once they acquire the infection, when it progresses to sepsis, how you identify sepsis at that stage. How do you prevent or identify progression to severe states, organ dysfunction and shock? And even if the patient survives sepsis, we still need to monitor these patients and look for deterioration in health. We map this out on this continuum with every red node as an opportunity we seek for intervention, mitigation or intervention of sepsis. So our goal is to reduce the incidence, morbidity and mortality and economic burden of sepsis. And we're taking a systems approach in doing this, starting with education awareness to empower the health care provider and the patient in recognition of sepsis. And then the development of innovative diagnostics focused on the host response. This is to predict, identify or prognosticate the severity of sepsis. We're also interested in improving the clinical management of these patients or exploring novel host-based therapies. And again, following the patient's post-discharge from the hospital to ensure that we can detect those early signs of health deterioration. The slide got warped a little bit. For education awareness, we've made significant progress to date. We've worked with two groups in developing training and education modules for health care providers along that continuum of care. And we're also focusing on some special populations. In the diagnostic space, we're developing innovative diagnostics that can distinguish sepsis from infection alone or from other systemic inflammatory responses where infection is not present. These diagnostics are based on host biomarker panels or data from EHR, like vital sign data or other clinical data. They can be used in a variety of health care settings in the hospital, the emergency department, the ICU, or the general wards. Many of them are dependent on machine learning or artificial intelligence to be able to predict a risk of sepsis or identify sepsis. And we envision that these will be able to be launched as digital health tools or as in vitro diagnostics. In the future, we want to expand upon these investments to date, so expand our diagnostic portfolio more into the pre-hospital space, as this is where a majority of the sepsis cases arise. Greater than 85% of cases start in the community. So we need tools for early recognition. We also want to focus on special populations, such as neonates and pediatrics. And we're interested in developing those diagnostics that can monitor the health of the survivors once they leave the hospital. We're also interested in methods to stratify or endotype these patients that can improve clinical management strategies and improve health outcomes, as well as novel host-based therapies. We continue to work closely across the government and with you all as our partners. We're interested in supporting our BARDA-funded sponsors of sepsis products through that regulatory approval path. We're still interested in developing a data enclave to store and interrogate health data for specific sepsis use cases. Once these products are approved and begin to get marketed, we want to ensure that we have strategies in place to improve the implementation and utilities of these products in the clinical settings. And we're also interested in expanding these products into other settings, low-resource settings, and to these special populations. We don't just work within HHS. We're also working across all of government, DOD, and other departments as well. We held the first sepsis interagency meeting about a year ago, last March, to align on sepsis and some of our focus areas. Within HHS, we've been partnering closely with the CDC in development of some of these sepsis training modules and educational tools. And we've also partnered with CMS to explore Medicare data to look at the burden and health outcomes of sepsis, as well as the economic burden. And that has culminated in the publication of three manuscripts that were released in critical care medicine this past Friday. We will be presenting on these manuscripts in the late-breaking abstract sessions here at this meeting. One is this afternoon, and one is tomorrow. As I mentioned, the main funding mechanism within DRIVE currently is our EZBAA solicitation. This is a unique mechanism of awarding, since we can make awards within 30 days. There is a cap on funding at $750,000. And we also encourage proposers to propose a cost share of 30 to 50 percent. These are supposed to be innovative, sepsis-relevant pilot projects to demonstrate potential for future investment. We're interested in projects that focus on sepsis of any etiology that are considering these implementation or adoption strategies for their product. There must be some efficacy to support, or preliminary data to support, the product to date in a sepsis-relevant model. And if regulatory path with the FDA is appropriate, an explanation of that pathway. And also some consideration of the commercialization strategy. Not of interest right now are approaches that are focused just on the pathogen. And that's because we have other programs within BARDA funding those activities. Infection alone is not of interest, or we're interested in infection as it progresses to sepsis. Exploratory or fundamental research is not of interest, or diagnostics that are just limited in the ICU, since we've had significant investment in that space to date. So I'm lucky and honored to be working with a very talented group within BARDA DRIVE. This is the team here. You can reach us at solvingsepsis at hhs.gov. We also have a website, drive.hhs.gov slash solvingsepsis. And we launched the Solving Sepsis Together hashtag during Sepsis Awareness Month last September because we know it's very important to continue to partner within government, with industry, academia, not-for-profits, all of you, in addressing this problem. Some information on BARDA. Thank you. Thank you, Kim, for all of that great information. So I'm the final speaker for this session. I'm Sarah Dunsmore. I'm here representing the National Institutes of Health, and specifically my home institute, the National Institute of General Medical Sciences. And I'm going to tell you more about what's happening in the realm of gathering new knowledge to provide new treatments, potentially new treatments for sepsis. I'm going to start out with giving you just some orientation and remind everyone that all of us here on the stage, we're part of the Department of Health and Human Services. And we in government like to have mission statements. And the Health and Human Services Department is the department that has as its mission to foster sound, sustained advances in the sciences, underlying medicine, public health, and social services. So within that, we have CDC with their role in public health surveillance. And we have ASPR and BARDA with their role in emergency preparedness. And we have NIH. And we play the biomedical research role. And NIH is the largest source of funding for medical research in the world, not just in the U.S. And our mission has two prongs to it. One is to seek fundamental knowledge, and the other is to kind of form the research that's the foundation for the application of that knowledge. And this is our home campus here in Bethesda, Maryland. NIH funding is divided into three major buckets, a clinical research bucket, a more basic research bucket, and a training bucket. And this is data from 2018, and that's the year that the most recent public data is available. And in 2018, NIH devoted about $12 billion to clinical research. And of that, about 1% was specifically devoted to sepsis research. I'll give you the caveat that a lot of the research in infectious disease and other areas is applicable or translatable to sepsis research. And this data is obtained by using NIH Reporter and specific what we call RCDC categories. Those are research disease and categorization categories that are used to report spending out to Congress and to you, the taxpayer. One more point before I move on. The primary funding for sepsis research at the NIH is divided between three major institutes, the NIH Institute, NIGMS, the Allergy and Infectious Disease Institute, or NIAID, and the Heart, Lung, and Blood Institute, or NHLBI, with a smaller portion going to pediatric sepsis research at the Eunice Kennedy Shriver Institute of Child Health and Human Development. To kind of drill down a bit and tell you what these dollars go for, what's going on in the world of NIH-funded sepsis research, in the fiscal year 2018, we funded 337 unique projects. They went to 299 different organizations and 142 different principal investigators. So we're spreading out the funding fairly well, not concentrating in any one organization or investigator. Overwhelmingly, the funding is investigator-initiated and using our bread-and-butter research project grant mechanism called an R01. And those of you in the audience who've ever applied to NIH funding, I'm sure you're familiar with the R01 mechanism. We have some other kind of concentration of funding in training and career development and also small business. Most of this research is on the translational sphere. There were 12 clinical studies registered in clinicaltrials.gov that were recruiting or enrolling patients in fiscal year 2018. And the primary purpose of this research is to provide new knowledge and disseminate it via publication. So you can see NIH-funded sepsis researchers are very prolific in their publications. So they're doing their role to publish new knowledge, get it out in the public domain for industry or other people who are more in the product development sphere to act upon that knowledge. There were nine patents reported, and funding's almost always domestic for sepsis, and 37 states received funding in fiscal year 2018. This part of the talk is going to kind of tell you about what is currently going on. And part of the purpose is if you are sitting in the audience and you'd like to approach NIH with an idea and get some funding for your sepsis research, we're going to try to give you some idea of who you might approach and where you might go with that idea. So you're going to need a little background on how NIH is structured, and we have different institutes. Each institute's established by a congressional mandate, and each institute has a distinct mission and leadership. We have many common funding mechanisms and policies, but most institutes have separate budgets, and in the case of sepsis research, you generally will be funded by a single institute. We do not do much co-funding at the present time. And I'm going to give you snapshots of the four institutes today. NIAID, or the National Institute of Allergy and Infectious Disease, the National Heart, Lung, and Blood Institute, or NHLBI, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD, and the National Institute of General Medical Sciences, NIGMS. So at NICHD, as you may infer from the title, this is where the pediatric sepsis research is funded, and the mission of NICHD is to fund studies that focus on sepsis from the perspective of infants, children, adolescents, and pregnant and lactating women. The program contact there is Bob Taboro, and he will be very glad to talk to you if you approach him with an idea, and he knows his email address is being projected at this meeting. And currently in Bob's portfolio at NICHD, he has studies that focus on the molecular and pathophysiologic basis of sepsis, novel diagnostic tools, epidemiology and screening, and clinical interventions that include pharmacokinetic and safety studies of anti-infective agents. He's certainly interested in receiving inquiries on topics outside that area that is just the major topics that he has right now. The next institute that I'd like to tell you about today is the National Heart, Lung, and Blood Institute, or NHLBI, and they are divided into three divisions, and they are entitled the Heart, Lung, and Blood Division. And you have Laura Reinick and Neil Agarwal who are from the Lung Division, and Rita Sarkar who's from the Blood Division. And they will get you a contact in the Heart Division if you need one. But as you may infer again from the title of the institute, studies that are funded at NHLBI focus on blood and vascular systems response to sepsis, sepsis-associated lung injury, and cardiovascular complications of sepsis. The next institute to be aware of that's a primary funder of sepsis research at the NIH is NIAID, or the National Institutes of Allergy and Infectious Disease. We actually have a NIAID representative in the audience, Nancy Lewis Ernst is attending the meeting. And if you have any questions for her, I will be glad to call on her during the panel discussion part of this session. There's some other contacts at NIAID too who will be more than willing to accept your inquiries who are listed on this slide. Studies funded by NIAID focus on diagnosis, treatment, and prevention of sepsis as a result of bacterial, fungal, parasitic, and viral infections. And you can see that some of their current research is trying to identify the pathogens that cause sepsis, the pathogen virulence mechanisms and host response. NIAID plays a strong role in funding research about effective therapeutics development. And also research that is more focused on pathogenic and protective host immune responses. So this is my institute and I am the NIGMS Sepsis Research Portfolio Program Director and I've had that title for 13 years now. And at NIGMS we kind of define the sepsis research that we fund is from the perspective of the host response. So generally the infectious part would go to NIAID and we take over once you're looking at how the host is responding to that infection. And typically at NIGMS we are looking for studies that are doing systemic or whole body assessments or multi-organ assessments. Because if you're more appropriate for what we call categorical institutes, you're focused on lung, you'll go to NHLBI. If you're focused on kidney, there's another institute that funds kidney research. So we're looking at sepsis from the perspective of the whole body, the whole patient. And currently what is in the NIGMS Sepsis Research Portfolio are studies on early identification of sepsis patients. Some of these are data driven, some of these are more biomarker driven. Mechanisms of immune dysfunction, we would like to see studies that focus on mechanisms of immune resolution, but I can't say we have a lot of those in the portfolio right now. And also different ways to phenotype sepsis patients. I'm going to shift gears a bit, so this is kind of the second part of the talk, and we're going to focus on what NIGMS is doing to rebalance our sepsis research portfolio to better utilize the taxpayer dollars and also be in a better position to partner with the other agencies in the Department of Health and Human Services and really help get the knowledge that will lead to new therapeutics. And these are two titles from two different parts of an article that were on, they actually happened to be from two NIGMS funded sepsis researchers. They were on the same page of Nature Medicine back in 2012. And one quote was, rodent models of sepsis found shockingly lacking. And the other was, execution of sepsis trials needs an overhaul. So kind of both ends of the spectrum, it was like, well it's not working, what do you do? And here we are at NIGMS trying to make the best decisions about how to leverage our dollars, what to fund, and we were faced with the facts that for many years, and even today, 80% of our NIGMS sepsis research portfolio goes to rodent model research. And on the other side of the spectrum, we have funded some very successful large-scale clinical trials at NIGMS. We were the funders for PROCESS, we funded another trial called PROACT, but that ties up a lot of our dollars. We decided to fund one of those, we're not funding 8 to 10 of what we call our basic research project grants, so that's a big decision for us to devote that amount of money. These trials take a long time, and they also tie up a lot of investigator bandwidth within the sepsis research community. So we were faced with some very hard decisions about what's the best way, where do we guide our researchers to go? And we turned to the experts in the field and formed what we call these council working groups on sepsis. And they were convened a little over a year and a half ago, in September of 2018, NIGMS convened a working group on sepsis to advise its council on the extramural portfolio of research grants that study both fundamental and clinical aspects of sepsis. And it was co-chaired by John Younger and Monica Kraft, I'll show you all the members in the next slide. And there are links here, if they don't come through, I'd be happy to send them to you, but we have information in the public domain that will let you know the final report of this working group. You can actually watch the video cast of Dr. Younger's and Kraft's presentation. And our main means of communicating in NIGMS is what we call a feedback loop blog, so if you ever want to know what's going on, please subscribe to our feedback loop, because we do our best to get the information out into the public domain. So this is our council working group on sepsis members. At least one of them I know is in the audience, and that's Dr. Cooper-Smith. Several others are likely at this meeting. Please feel free to talk to them about the recommendations of the NIGMS sepsis council working group. I'll point out, we tried to get a diverse group. We have animal model researchers, we have more clinical researchers, we have industry representation, we have small business representation, we have government representation. And only less than half, only about 40% of these people were funded by NIGMS, so we were advised by people who were not dependent upon us for their funding. The NIGMS working group on sepsis gave four recommendations that are kind of directly applicable to the NIGMS sepsis research portfolio, and those are that NIGMS should significantly expand its support of clinical research related to sepsis, NIGMS should broaden its collaborations with other institutes to support ... oh, sorry, this slide got kind of garbled, too. But the second recommendation is NIGMS should broaden its collaborations with other institutes, and the third is NIGMS should not support what we call large-scale or multi-site independent clinical trials. We should only do that in partnership, and the fourth one is NIGMS should work with the Center for Scientific Review to assure appropriate peer review or expertise. And NIGMS has accepted these recommendations, we've immediately responded to these recommendations. You can go on our intranet, there's a talk at our September Council by Dr. Rocha Long kind of outlining what the NIGMS response will be. In kind of broad strokes, our goal will be to invest in sepsis research in more targeted strategic ways and place greater emphasis on studies that utilize patient-derived materials, that is a bedside-to-bench approach. Studies that provide mechanistic understanding of sepsis endotypes, and studies that use new approaches and models for sepsis research, such as machine learning, artificial intelligence, and new models such as organoids and kind of bioengineering the organs-on-a-chip type of models. We have published our NIGMS sepsis research priorities in a notice, so for those of you who are kind of plugged into the NIH system and want to look it up, it is NOTGM19-054. The important things to know about this notice are that it applies to all NIGMS funding opportunity announcements, so those are funding that we provide for research grants, for training and career development awards, and for small business opportunities. We are also looking at ways to enable access for our NIGMS-funded sepsis researchers to clinical data and biospecimens, and we're also kind of actively engaged both internally at NIH, talking to program directors at other institutes, particularly the institutes I mentioned previously in my talk today, and also kind of at the department level, talking to people like Rubina and Kim, we've had this series of monthly phone calls that we get on to talk about sepsis. So we're very much engaged in communication about how best to leverage and invest your tax dollars. Going back to NIGMS specifically in our notice, we outline 15 examples of specific topics of research interest, and these are things such as molecular discovery approaches, omics, many people call them, data science, assay and technology development, predictive modeling, endotyping strategies, clinical trajectories that would include resolution and long-term outcomes. There are two low-priority areas, and those are rodent models and clinical trials. If you're in that bucket as an investigator, I strongly encourage you to schedule a telephone call with me so I can explain it to you. But I will let the audience know we are already acting upon our low-priority areas and not funding quite a few grants that are exclusively utilizing rodent models. I'll close today and move into our panel discussion, our Q&A period, by really emphasizing the point of this session, is that there are many stages of sepsis research processes to get a concept all the way into the level of public health awareness and adoption. In government, we're trying to work together. Here at NIH, we're kind of at the bottom of the pyramid of providing the knowledge that will drive a concept to an early-stage product or treatment. We have an agency now to hand it off to who can take that product and treatment a bit further, and we have a very good agency here at the top providing 24-7 public health surveillance for sepsis. I appreciate everyone who's come to this session, and I'm going to open it up now for questions from the audience. If you could go to the mics, and also if you could identify yourself. Hi. Good morning. My name is Dr. Faisal Masood. I'm from Houston Methodist in Texas. First of all, thank you for sharing this information. Just to give you our institution is number one in the lowest mortality in vision. My two big questions is that we diagnose sepsis, we treat sepsis, but if you ask patients, they don't get to be told that they have sepsis or septal shock. If they have a heart attack, they get told they have heart attacks. If they've got kidney failure, they get told they've got kidney failure, but people don't get to know. One of the most common DRG sepsis, that's one part. The second part is that the public awareness and health policy decision-maker and state level and everything, they're not engaged in sepsis, and they're more engaged in other diseases. If one-third of people in the U.S. would be dying from heart attacks, there would be a lot more uproar. I feel that how you all can make a difference in that. Thank you for that question. I think we have been going through the process with our Get Ahead of Sepsis campaign in targeting the campaign towards new groups of healthcare providers and patients, including sepsis survivors, EMS technicians, professionals. It's been illuminating for us to have a view into the focus groups that have been a part of developing messaging for this campaign, to hear exactly what you said, that many people who we're talking to, even if they are people who we would consider to be at high risk for sepsis, are not familiar with the term sepsis and don't know what sepsis looks like, and don't know that sepsis could be the end result of an infection that has not been treated adequately. So that's been one of our big focuses with our Get Ahead of Sepsis campaign, is targeting those individuals both inside the healthcare community and outside of it, because I think this is not a problem that's unique to folks outside of the healthcare community, to make sure that people are aware of sepsis and why we partner with organizations such as the Rory Staunton Foundation and Sepsis Alliance to help amplify the amazing work that they're doing to make sepsis a more widely known term amongst healthcare providers and the public outside of healthcare. I think that's one of the states. The rest of the country, there's not much. The whole state of Texas, they didn't have sepsis. That's the right of the state to support that. The rest of the country, it is not being done. And I'm really excited to hear that the state representatives and state leaders are going to help with that, because they do a lot of work. Thank you for that. Oh, the remark was encouraging us as federal government. We work for the whole U.S. to engage with state leadership, and I think it was heard. We appreciate that feedback. Did you want to comment any on that, Kim? No? Okay. That's very apropos to my comment or question. I'm Craig Weiner from the University of Minnesota. There's no CMS representative here, but maybe people don't know that CMS funds something called the Health Improvement Network, which gives large grants to, last count, 16 statewide organizations or regional organizations to improve not just sepsis, but pressure ulcer prevention, hospital-acquired infections, these kinds of things. And the Minnesota Hospital Association is one of the recipients of that grant. And so I encourage any people in the community, especially from academics, to work with their state healthcare organizations. This is not the health departments. This is the hospital associations, if they are funded by these health improvement networks, because they will fund sepsis campaigns. I do outreach visits to many small rural hospitals to implement and talk about their sepsis prevention programs from a hospital basis. So it's the federal government, but the federal government is supporting state-level initiatives to improve sepsis. I'll make two comments in response to that, and then I'll pass it on if my colleagues have further comments. I apologize. There was a CMS representative scheduled to be in the session, and he had to pull out about two weeks ago due to some complications. So we tried to get CMS here, but it was unfortunately not possible. And the second, at NIH we're very much aware of differences in rural and urban treatment of sepsis, and we're very open to receiving applications to further define those differences and ways to intervene in making treatment better in both. There are issues in both settings, so we're very open to research that would better define those settings and give information that would help the doctors and the nurses, the caregivers. Anything? No, I'll just reiterate, too, that we also are interested in expanding into all settings, especially in the pre-hospital setting, and it doesn't matter if that's a low-resource setting, that you could find in a disaster scenario where ASPR responds, or if it's a low-resource setting just based on what's available in that hospital. Although it may not be targeted specifically to a state, it's targeted to activities that may be going on or clinical settings going on in that state. Yeah, no, I appreciate that comment. We are always working to learn what states are doing to implement policies that impact sepsis outcomes, both for our education to inform our efforts and to target our prevention activities. And we also work with CMS closely, both in developing quality measures as well as with the HINs. One of our key staff, Ray Dantes, recently presented on a HIN call on implementing the hospital toolkit for adult sepsis surveillance. So we are keen to take advantage of those opportunities to work with states as well as more closely with CMS. Let's go to the far left, and then we'll come back to you, Wendy. Hi, Rishi Kemal Soren from Emory University. I think it was a wonderful presentation. You outlined some of the key interests and focus on sepsis. As a researcher that focuses on data science and machine learning, I find it very awkward that data is not available. There's a lot of studies, research. There's CMS. There's federal funded agencies that are just hoarding data and not making it available for real innovation and real data science to be performed at large. NIH has several funded grants, but many of that data is inaccessible or products of them are proprietary and not available for the community. Is there a focus on the funding agency's point of view to ensure that whatever data that is used for any product creation is available for the community at large to perform holistic, reproducible assessments of whatever those results are? Yes, at NIH we take data very seriously. We actually have a strategic plan for data science that was published about a year ago, and that came down to us as a request from Congress that we had to develop a strategic plan for data science. The caveat to that is that we've had data sharing policies at NIH for some time, but the caveat is those apply to basic research too. There's a lot of legal issues when you get into HIPAA and clinical research that NIH is working on. We're one partner, but we don't totally control. NIH is totally devoted to data sharing for research purposes, but we have to partner with some other people. We had an RFI this summer on FHIR, the interoperability of clinical data. So there's still, I think, a few challenges that NIH is a partner in, but we're not the only partner in. For instance, we have no say over how CMS shares their data. We can say we'd like you to, but they're another federal agency. I think there is more and more data becoming shareable. Certainly, if you gather data with an NIH-funded grant, we will ask you to adhere to NIH data sharing policies. So our NIH-funded investigators who are working with clinical data are going to be expected to share that data, but that's not all the data that may be useful to you about sepsis or useful that you need as a sepsis clinical researcher. Yes, we at BARDA know that data is critical, and it's a priority for us to think about how we can encourage access to it and also start interrogating the data. We've been talking about this since the start of our program. As Dr. Dunsmore mentioned, there are several challenges with acquiring and housing all the data together, data use agreements that need to be in place. Under specific contracts, there are clauses for access to data, so the government has access to data. It's that next step of figuring out the strategy of how to ensure that we can share it appropriately or how you house all that data. But these are conversations that are occurring across government. We're trying not to silo ourselves and have these conversations with all of the agencies together because we all know we are sitting on a wealth of data that could be leveraged. Specifically with CMS, the papers that I mentioned were part of us breaking down those barriers and working across government to gain access to data. And you'll see in our talks at 2 o'clock today and tomorrow that we, a little teaser, but the papers already came out so I don't feel like I'm revealing anything, but we were able to look at approximately 9.6 million Medicare inpatient sepsis records, and that's an incredibly large data set, kind of unprecedented really. And so we're hoping to engage in further types of collaboration like this for analysis of data and develop those larger strategies of how we can do this. It's not just sepsis data. It's all of health data and then thinking about sepsis as a use case to interrogate. I hear your frustration and echo my colleagues in that CDC recognizes the importance of sharing the data that we collect and have access to and has made significant strides in making those data available to the public in a more timely manner. I think the surveillance system that I work with, the Healthcare Associated Infections, Community Interface Surveillance Program through the Emerging Infections Program, we recently launched, if not will launch soon, HAIC-VIS, which is access to our surveillance data as most recently as we have it available for sharing. We do not currently have ongoing sepsis surveillance. One little known fact is that we don't receive funding for sepsis, so our sepsis work is mostly carved out of where we can take it from other programs. But we certainly are positioned to perform sepsis surveillance, and the sharing of those data are an important component to our future plans for sepsis surveillance. That's great because, I mean, CDC mortality data sets are things that I think the entire community would really benefit from, but you have to pay quite a bit to get access to that. So democratizing that data I think would be an invaluable tool for moving the needle in the entire industry. Understood. Thank you. Well, it's Wendy Walker from TTUHSC El Paso. First, I wanted to thank all the three speakers for sharing this information with us on how the federal government is supporting sepsis research. And so my question is for Sarah Dunsmore. With the NIGMS Working Group on Sepsis and the shift in the priorities of what GMS is going to fund, are these same criteria being adopted by the other institutes that support sepsis research, such as NHLBI? Or do they have their own criteria? The short answer is no. Each institute determines its own funding priorities. I work closely with the other program directors that I show on the slides, so they're aware of what we're funding and our priorities. And I think in many ways they support them, but they will have to translate them to their own institute. I don't know of them, any of the other institutes, kind of immediately working to get out their sepsis research priorities in the same sort of format that we publish, such as a guide notice. So they're going to share those with you if you contact them one-on-one. But I think they'll all be able to articulate their sepsis research priorities if you contact them one-on-one. But if you're specifically asking about rodent models, the other institutes will continue to fund rodent models of sepsis if it's within their mission. Okay, thank you. I'm Lawrence Lynn from Columbus, Ohio. I have a quick question about the NIH. Presently the application process is not really very well suited to show complex software. And it's very hard to put, for instance, we do imaging software where we image all the data and generate dynamic images, motion images of lab data and those sorts of things. It's almost impossible to show that in the present application. And reviewers then have no idea what we're doing. Is there a mechanism for any kind of process to advance? Is there an interview process or anything like that with the NIH to make that work? There are a few very limited mechanisms where we would do what we call reverse site visit or interview. You pretty much need to be able to negotiate the grants.gov interface for most of our applications. I know we've recently allowed some videos. There's still a lot of limitations on the size of the video you can upload. My best advice for how to attack that right now, there's actually an Institute of Biomedical Imaging, NIBIB. And I think an NIBIB program director may be your best advocate. If they can't get the information they need and the applications they would like to fund, then they can work with the Center for Scientific Review. But changing an application package is a difficult thing. It goes to something we call OMB. And that takes a long time for any of us to negotiate those sorts of standards that we use. These are laws that regulate how we receive applications and how we review them. And that's hard for us to change. Okay, thanks. I'm Nathan Brummel from Ohio State. I wanted to ask about how aging is being integrated into sepsis research. We have NIA and other institutes, and how well those play together in the sepsis sandbox. We've reached out to the Aging Institute, and I think they're interested in the cognitive impairment that may occur not just after sepsis, but after any intensive care unit stay. We see this loss of executive function, diminished multitasking ability. So they have an interest in that. We will take some of that on at NIGMS. So if that's a component of a larger grant that's overall focused on mechanisms that may be applicable to the disease as a whole, we're certainly open to receiving some of that as a bridge to maybe moving on to the Aging Institute. And the Heart, Lung, and Blood Institute, too, I know, is very interested in incorporating long-term outcomes into the research that they're funding. So I think most of the program directors that fund sepsis research are aware of that need, and we're trying to find ways to work together to meet that need. In my opinion, it's an emerging area. It may not be sepsis-specific. It may be more of this critical care, post-critical care recovery type of issue. We've been working closely with our long-term care colleagues to address issues of sepsis in long-term care facilities. One of the things that's been brought to our attention is that sepsis assessment tools validated within long-term care facility settings are few and far between, and there's not much data out there assessing the accuracy of those tools. So we've been working with them to figure out how we can learn more about sepsis in nursing homes. A sizable percentage of our inpatient sepsis population comes from nursing homes. A sizable percentage go to nursing homes. So it's certainly relevant to the sepsis conversation and something we're trying to learn more about. Hi, Jason Springs with Endpoint Health. I was just curious a little bit about linking up things like sepsis endotypes in clinical trials, at least from the NIH perspective, if there's a reduced appetite for clinical trials, which makes sense. Thousands of patients cost quite a bit of money, which could go to other research. But there is a focus on using machine learning, advanced biomarkers, endotypes. There's a point at which those two kind of clash because you have to ask, well, you can do very quick, smaller trials with picking the right patients out, whether you're diagnosing or subtyping. And then there's that next step. So what does it actually mean in an interventional trial? And I'm just curious, has that conversation come up? It makes sense not to fund giant trials if they've never worked, but there's a point at which we have to kind of prove out some of the more novel things that are a research focus. So you should kind of read the NIGMSC Council Working Group on Sepsis report. I would say the appetite is not just at NIH, and it's in industry, too. And it's been in industry for a long time, because there were no industry-developed therapeutics that came onto the market after Zygos was taken off. But the sentiment that was expressed, I think, very clearly by the NIGMSS sepsis working group was that we don't understand enough right now about the disease to adequately design the clinical trials. And I think if you talk to industry, they will kind of echo that, that it's hard for them to invest in therapeutic and product development because we don't know about the patients to adequately test them in a clinical trial setting. And more so than the understanding, too, there's not been a product pipeline. There are really not any new therapeutics to test in sepsis patients unless you start bringing over immunoecology drugs from cancer or drugs that were first developed in another context. But, again, it's hard to get what you call an appetite or enthusiasm for doing that right now because it's really hard to design a feasible, efficient clinical trial. I'll just add to that that BARDA, for our next year or this year in FY20, that is one of our interest areas to start looking at ways to endotype or stratify patients and tying that to the novel therapeutic or a different approach to a clinical management strategy. The one caveat to that is that our EZBA only does fund up to $750,000 plus that cost share, and so it's hard to do a large-scale clinical trial with that funding amount. We understand that. But if there are ways that you think there could be an opportunity to partner with other divisions within BARDA that may have different budgets or focus on different threat areas, then we can have that conversation about what you're envisioning as far as that approach. Are there any other questions or comments from the audience? If not, I think we're about at our designated time. Again, I thank everyone for your attendance and your interest. And I thank my co-speakers, too.

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