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OBJECTIVES:. To develop and validate machine learning (ML) models to predict high-flow nasal cannula (HFNC) failure in COVID-19, compare their performance to the respiratory rate-oxygenation (ROX) index, and evaluate model accuracy by self-reported race. DESIGN:. Retrospective cohort study. SETTING:. Four Emory University Hospitals in Atlanta, GA. PATIENTS:. Adult patients hospitalized with COVID-19 between March 2020 and April 2022 who received HFNC therapy within 24 hours of ICU admission were included. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Four types of supervised ML models were developed for predicting HFNC failure (defined as intubation or death within 7 d of HFNC initiation), using routine clinical variables from the first 24 hours of ICU admission. Models were trained on the first 60% (n = 594) of admissions and validated on the latter 40% (n = 390) of admissions to simulate prospective implementation. Among 984 patients included, 317 patients (32.2%) developed HFNC failure. eXtreme Gradient Boosting (XGB) model had the highest area under the receiver-operator characteristic curve (AUROC) for predicting HFNC failure (0.707), and was the only model with significantly better performance than the ROX index (AUROC 0.616). XGB model had significantly worse performance in Black patients compared with White patients (AUROC 0.663 vs. 0.808, p = 0.02). Racial differences in the XGB model were reduced and no longer statistically significant when restricted to patients with nonmissing arterial blood gas data, and when XGB model was developed to predict mortality (rather than the composite outcome of failure, which could be influenced by biased clinical decisions for intubation). CONCLUSIONS:. Our XGB model had better discrimination for predicting HFNC failure in COVID-19 than the ROX index, but had racial differences in accuracy of predictions. Further studies are needed to understand and mitigate potential sources of biases in clinical ML models and to improve their equitability.

Limited data highlight the need to understand differences in SARS-CoV-2 omicron (B.1.1.529) variant viral load between the gold standard nasopharyngeal (NP) swab, mid-turbinate (MT)/anterior nasal swabs, oropharyngeal (OP) swabs, and saliva. MT, OP, and saliva samples from symptomatic individuals in Atlanta, GA, in January 2022 and longitudinal samples from a small familial cohort were tested by both RT-PCR and ultrasensitive antigen assays. Higher concentrations in the nares were observed in the familial cohort, but a dominant sample type was not found among 39 cases in the cross-sectional cohort. The composite of positive MT or OP assay for both RT-PCR and antigen assay trended toward higher diagnostic yield but did not achieve significant difference. Our data did not identify a singular preferred sample type for SARS-CoV-2 testing, but higher levels of saliva nucleocapsid, a trend toward higher yield of composite OP/MT result, and association of apparent MT or OP predominance with symptoms warrant further study.

Abstract This report identifies, for the first time, a phytochelatin compound, phytochelatin 2 [γ‐E‐C‐γ‐E‐C‐G], and related metabolites in human urine. Phytochelatins are metal‐binding peptides produced by plants. They are present in nearly all human diets, due to their ubiquity in plants. The urinary concentration of phytochelatin 2 among 143 adults was in the low micromolar range, and phytochelatin 2 and its metabolites had differential correlations with urinary selenium and toxic metals. Activities of ingested phytochelatins are largely undescribed. Observed urinary metal interactions were investigated further in cell and animal models. Selenite reacted with phytochelatin to form a phytochelatin selenotrisulfide, and the preformed selenotrisulfide showed increased selenium uptake by renal proximal tubule cells. In vivo studies further showed that oral phytochelatin increased renal selenium content and decreased lung cadmium in mice. Presence of phytochelatin in human urine combined with its function in selenium and heavy metal distribution present a new route by which diet may influence metal disposition and bioavailability.

Abstract Background Sepsis and associated organ failures confer substantial morbidity and mortality. Xanthine oxidoreductase (XOR) is implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders including sepsis and sepsis-associated acute respiratory distress syndrome (ARDS). We examined whether single nucleotide polymorphisms (SNPs) in the XDH gene (encoding XOR) might influence susceptibility to and outcome in patients with sepsis. Methods We genotyped 28 tag SNPs in XDH gene in the CELEG cohort, including 621 European American (EA) and 353 African American (AA) sepsis patients. Serum XOR activity was measured in a subset of CELEG subjects. Additionally, we assessed the functional effects of XDH variants utilizing empirical data from different integrated software tools and datasets. Results Among AA patients, six intronic variants (rs206805, rs513311, rs185925, rs561525, rs2163059, rs13387204), in a region enriched with regulatory elements, were associated with risk of sepsis (P

OBJECTIVES:. Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies—lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes. DESIGN:. Genetic and clinical epidemiology, and experimental models. SETTING:. Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis. PATIENTS OR SUBJECTS:. Nine human cohorts with sepsis (total n = 12,514) were assessed for an association between sepsis mortality and PCSK9 loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in Pseudomonas aeruginosa and Staphylococcus aureus bacteremia sepsis models, and in lipopolysaccharide-induced animal models. INTERVENTIONS:. Observational human cohort studies used genetic PCSK9 LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis. MEASUREMENTS AND MAIN RESULTS:. Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic PCSK9 LOF was odds ratio = 0.86 (95% CI, 0.67–1.10; p = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32–1.20; p = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival. CONCLUSIONS:. PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.

Abstract The Sequential Organ Failure Assessment (SOFA) score was developed more than 25 years ago to provide a simple method of assessing and monitoring organ dysfunction in critically ill patients. Changes in clinical practice over the last few decades, with new interventions and a greater focus on non-invasive monitoring systems, mean it is time to update the SOFA score. As a first step in this process, we propose some possible new variables that could be included in a SOFA 2.0. By so doing, we hope to stimulate debate and discussion to move toward a new, properly validated score that will be fit for modern practice.

Background and Aims: Patients admitted with decompensated cirrhosis who develop acute kidney injury (AKI) tend to experience poor outcomes, even if provided with increased organ support such as renal replacement therapies. We assessed the association of albumin administered ≤24 hours of admission with hospital length of stay (LOS) and in-hospital mortality. Methods: The Cerner Health Facts Database was queried for hospitalized patients with cirrhosis who had >0.3 mg/dL increase in serum creatinine within 48 hours and received diuretics following admission between January 2009 and April 2018. This study received institutional review board exemption through federal regulation 45CFR46. Albumin infusion was “timely” if administered ≤24 hours after admission and “nontimely” if administered >24 hours after admission or not at all. Two subgroups were assessed: the AKILOS subgroup (patients who survived to discharge) and the AKIMORTALITY RISK subgroup (patients with the highest risk of mortality, ie, AKI stage 3). Results: A total of 4135 hospitalizations with cirrhosis and AKI were grouped into AKILOS (n = 3321) and AKIMORTALITY RISK (n = 609) subgroups. Albumin administration occurred in 59.7% of the AKILOS subgroup and 77.8% of the AKIMORTALITY RISK subgroup, but timely treatment only occurred in 25.9% and 35.8% of encounters within these subgroups, respectively. Risk-adjusted analysis showed timely albumin administration to be associated with a 15.5% reduction (P < .01) in LOS in the AKILOS subgroup and a 49% reduction in the odds of death (adjusted odds ratio: 0.51; P < .01) in the AKIMORTALITY RISK subgroup, when compared to the nontimely group. Conclusion: Among patients with cirrhosis and AKI, treatment with albumin ≤24 hours after admission was associated with a shorter LOS and lower risk of death in patients with stage 3 AKI.

Abstract Since the advent of critical care in the twentieth century, the core elements that are the foundation for critical care systems, namely to care for critically ill and injured patients and to save lives, have evolved enormously. The past half-century has seen dramatic advancements in diagnostic, organ support, and treatment modalities in critical care, with further improvements now needed to achieve personalized critical care of the highest quality. For critical care to be even higher quality in the future, advancements in the following areas are key: the physical ICU space; the people that care for critically ill patients; the equipment and technologies; the information systems and data; and the research systems that impact critically ill patients and families. With acutely and critically ill patients and their families as the absolute focal point, advancements across these areas will hopefully transform care and outcomes over the coming years.

IMPORTANCE:. Initial Society of Critical Care Medicine Discovery Viral Infection and Respiratory illness Universal Study (VIRUS) Registry analysis suggested that improvements in critical care processes offered the greatest modifiable opportunity to improve critically ill COVID-19 patient outcomes. OBJECTIVES:. The Structured Team-based Optimal Patient-Centered Care for Virus COVID-19 ICU Collaborative was created to identify and speed implementation of best evidence based COVID-19 practices. DESIGN, SETTING, AND PARTICIPANTS:. This 6-month project included volunteer interprofessional teams from VIRUS Registry sites, who received online training on the Checklist for Early Recognition and Treatment of Acute Illness and iNjury approach, a structured and systematic method for delivering evidence based critical care. Collaborators participated in weekly 1-hour videoconference sessions on high impact topics, monthly quality improvement (QI) coaching sessions, and received extensive additional resources for asynchronous learning. MAIN OUTCOMES AND MEASURES:. Outcomes included learner engagement, satisfaction, and number of QI projects initiated by participating teams. RESULTS:. Eleven of 13 initial sites participated in the Collaborative from March 2, 2021, to September 29, 2021. A total of 67 learners participated in the Collaborative, including 23 nurses, 22 physicians, 10 pharmacists, nine respiratory therapists, and three nonclinicians. Site attendance among the 11 sites in the 25 videoconference sessions ranged between 82% and 100%, with three sites providing at least one team member for 100% of sessions. The majority reported that topics matched their scope of practice (69%) and would highly recommend the program to colleagues (77%). A total of nine QI projects were initiated across three clinical domains and focused on improving adherence to established critical care practice bundles, reducing nosocomial complications, and strengthening patient- and family-centered care in the ICU. Major factors impacting successful Collaborative engagement included an engaged interprofessional team; an established culture of engagement; opportunities to benchmark performance and accelerate institutional innovation, networking, and acclaim; and ready access to data that could be leveraged for QI purposes. CONCLUSIONS AND RELEVANCE:. Use of a virtual platform to establish a learning collaborative to accelerate the identification, dissemination, and implementation of critical care best practices for COVID-19 is feasible. Our experience offers important lessons for future collaborative efforts focused on improving ICU processes of care.

Among symptomatic outpatients, subgenomic RNA of severe acute respiratory syndrome coronavirus 2 in nasal midturbinate swab specimens was concordant with antigen detection but remained detectable in 13 (82.1%) of 16 nasopharyngeal swab specimens from antigen-negative persons. Subgenomic RNA in midturbinate swab specimens might be useful for routine diagnostics to identify active virus replication.

Importance:. Adults hospitalized with sepsis/septic shock commonly develop acute kidney injury (AKI) which imposes a significant burden on the healthcare system. The administration of early human albumin in this patient population may yield more efficient healthcare resource utilization. Objectives:. To examine the association between early use of albumin and time to discharge in adults who develop severe AKI while hospitalized with sepsis/septic shock. Design:. Retrospective cohort study using de-identified electronic health records from a national database (Cerner Health Facts; Cerner Corp., Kansas City, MO). Setting and Participants:. Patients (n = 2,829) hospitalized between January 2013 and April 2018 with a diagnosis of sepsis/septic shock (identified using International Classification of Diseases, 9th Revision and 10th Revision codes) who developed severe AKI (stage 3 according to Kidney Disease Improving Global Outcomes criteria) during hospitalization (n = 2,845 unique encounters). Main Outcomes and Measures:. Patients were grouped according to timing of albumin exposure: within less than or equal to 24 hours of admission (“early albumin”) or unexposed/exposed late (“nonearly albumin”). A cause-specific hazard model, censoring for death/discharge to hospice, was used to examine the association between “early albumin” and the rate of hospital discharge with clinical stability. Results:. Albumin was administered early in 8.6% of cases. Cases with early albumin administration had a median time to discharge of 13.2 days compared with 17.0 in the nonearly group (Log-rank p < 0.0001). An adjusted analysis showed that the rate of hospital discharge with clinical stability increased by 83% in the early albumin group compared with the nonearly group (hazard ratio, 1.832; 95% CI, 1.564–2.146; p < 0.001 nonearly group. Conclusions and Relevance:. The use of albumin within 24 hours of hospital admission was associated with a shorter time to discharge and a higher rate of discharge with clinical stability, suggesting an improvement in healthcare resource utilization among patients with sepsis/septic shock who developed stage 3 AKI during hospitalization.

Humans are exposed to millions of chemicals but mass spectrometry (MS)-based targeted biomonitoring assays are usually limited to a few hundred known hazards. Here, the authors develop a workflow for MS-based untargeted exposome profiling of known and unidentified environmental chemicals.

IMPORTANCE:. The role of early, serial measurements of protein biomarkers in sepsis-induced acute respiratory distress syndrome (ARDS) is not clear. OBJECTIVES:. To determine the differences in soluble receptor for advanced glycation end-products (sRAGEs), angiopoietin-2, and surfactant protein-D (SP-D) levels and their changes over time between sepsis patients with and without ARDS. DESIGN, SETTING, AND PARTICIPANTS:. Prospective observational cohort study of adult patients admitted to the medical ICU at Grady Memorial Hospital within 72 hours of sepsis diagnosis. MAIN OUTCOMES AND MEASURES:. Plasma sRAGE, angiopoietin-2, and SP-D levels were measured for 3 consecutive days after enrollment. The primary outcome was ARDS development, and the secondary outcome of 28-day mortality. The biomarker levels and their changes over time were compared between ARDS and non-ARDS patients and between nonsurvivors and survivors. RESULTS:. We enrolled 111 patients, and 21 patients (18.9%) developed ARDS. The three biomarker levels were not significantly different between ARDS and non-ARDS patients on all 3 days of measurement. Nonsurvivors had higher levels of all three biomarkers than did survivors on multiple days. The changes of the biomarker levels over time were not different between the outcome groups. Logistic regression analyses showed association between day 1 SP-D level and mortality (odds ratio, 1.52; 95% CI, 1.03–2.24; p = 0.03), and generalized estimating equation analyses showed association between angiopoietin-2 levels and mortality (estimate 0.0002; se 0.0001; p = 0.04). CONCLUSIONS AND RELEVANCE:. Among critically ill patients with sepsis, sRAGE, angiopoietin-2, and SP-D levels were not significantly different between ARDS and non-ARDS patients but were higher in nonsurvivors compared with survivors. The trend toward higher levels of sRAGE and SP-D, but not of angiopoietin-2, in ARDS patients may indicate the importance of epithelial injury in sepsis-induced ARDS. Changes of the biomarker levels over time were not different between the outcome groups.

Abstract Objective To identify priorities for administrative, epidemiologic and diagnostic research in sepsis. Design As a follow-up to a previous consensus statement about sepsis research, members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis. Methods Six questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified through a consensus process. Results The document provides a framework for priorities in research to address the following questions: (1) What is the optimal model of delivering sepsis care?; (2) What is the epidemiology of sepsis susceptibility and response to treatment?; (3) What information identifies organ dysfunction?; (4) How can we screen for sepsis in various settings?; (5) How do we identify septic shock?; and (6) What in-hospital clinical information is associated with important outcomes in patients with sepsis? Conclusions There is substantial knowledge of sepsis epidemiology and ways to identify and treat sepsis patients, but many gaps remain. Areas of uncertainty identified in this manuscript can help prioritize initiatives to improve an understanding of individual patient and demographic heterogeneity with sepsis and septic shock, biomarkers and accurate patient identification, organ dysfunction, and ways to improve sepsis care.

Abstract While there has been significant progress in the development of rapid COVID-19 diagnostics, as the pandemic unfolds, new challenges have emerged, including whether these technologies can reliably detect the more infectious variants of concern and be viably deployed in non-clinical settings as “self-tests”. Multidisciplinary evaluation of the Abbott BinaxNOW COVID-19 Ag Card (BinaxNOW, a widely used rapid antigen test, included limit of detection, variant detection, test performance across different age-groups, and usability with self/caregiver-administration. While BinaxNOW detected the highly infectious variants, B.1.1.7 (Alpha) first identified in the UK, B.1.351 (Beta) first identified in South Africa, P.1 (Gamma) first identified in Brazil, B.1.617.2 (Delta) first identified in India and B.1.2, a non-VOC, test sensitivity decreased with decreasing viral loads. Moreover, BinaxNOW sensitivity trended lower when devices were performed by patients/caregivers themselves compared to trained clinical staff, despite universally high usability assessments following self/caregiver-administration among different age groups. Overall, these data indicate that while BinaxNOW accurately detects the new viral variants, as rapid COVID-19 tests enter the home, their already lower sensitivities compared to RT-PCR may decrease even more due to user error.

Abstract The impact of repeated sample collection on COVID-19 test performance is unknown. The FDA and CDC currently recommend the primary collection of diagnostic samples to minimize the perceived risk of false-negative findings. We therefore evaluated the association between repeated sample collection and test performance among 325 symptomatic patients undergoing COVID-19 testing in Atlanta, GA. High concordance was found between consecutively collected mid-turbinate samples with both molecular (n = 74, 100% concordance) and antigen-based (n = 147, 97% concordance, kappa = 0.95, CI = 0.88–1.00) diagnostic assays. Repeated sample collection does not decrease COVID-19 test performance, demonstrating that multiple samples can be collected for assay validation and clinical diagnosis.

Abstract The current coronavirus pandemic has impacted heavily on ICUs worldwide. Although many hospitals and healthcare systems had plans in place to manage multiple casualties as a result of major natural disasters or accidents, there was insufficient preparation for the sudden, massive influx of severely ill patients with COVID-19. As a result, systems and staff were placed under immense pressure as everyone tried to optimize patient management. As the pandemic continues, we must apply what we have learned about our response, both good and bad, to improve organization and thus patient care in the future.

Summary: As the emergence of SARS-CoV-2 variants brings the global pandemic to new levels, the performance of current rapid antigen tests against variants of concern and interest (VOC/I) is of significant public health concern. Here, we report assessment of the Abbot BinaxNOW COVID-19 Antigen Self-Test. Using genetically sequenced remnant clinical samples collected from individuals positive for SARS-CoV-2, we assessed the performance of BinaxNOW against the variants that currently pose public health threats. We measured the limit of detection of BinaxNOW against various VOC/I in a blinded manner. BinaxNOW successfully detected the Omicron (B.1.1.529), Mu (B.1.621), Delta (B.1.617.2), Lambda (C.37), Gamma (P.1), Alpha (B.1.1.7), Beta (B.1.351), Eta (B.1.525), and P.2 variants and at low viral concentrations. BinaxNOW also detected the Omicron variant in individual remnant clinical samples. Overall, these data indicate that this inexpensive and simple-to-use, FDA-authorized and broadly distributed rapid test can reliably detect Omicron, Delta, and other VOC/I.

Abstract The gut microbiome regulates a number of homeostatic mechanisms in the healthy host including immune function and gut barrier protection. Loss of normal gut microbial structure and function has been associated with diseases as diverse as Clostridioides difficile infection, asthma, and epilepsy. Recent evidence has also demonstrated a link between the gut microbiome and sepsis. In this review, we focus on three key areas of the interaction between the gut microbiome and sepsis. First, prior to sepsis onset, gut microbiome alteration increases sepsis susceptibility through several mechanisms, including (a) allowing for expansion of pathogenic intestinal bacteria, (b) priming the immune system for a robust pro-inflammatory response, and (c) decreasing production of beneficial microbial products such as short-chain fatty acids. Second, once sepsis is established, gut microbiome disruption worsens and increases susceptibility to end-organ dysfunction. Third, there is limited evidence that microbiome-based therapeutics, including probiotics and selective digestive decontamination, may decrease sepsis risk and improve sepsis outcomes in select patient populations, but concerns about safety have limited uptake. Case reports of a different microbiome-based therapy, fecal microbiota transplantation, have shown correlation with gut microbial structure restoration and decreased inflammatory response, but these results require further validation. While much of the evidence linking the gut microbiome and sepsis has been established in pre-clinical studies, clinical evidence is lacking in many areas. To address this, we outline a potential research agenda for further investigating the interaction between the gut microbiome and sepsis.

Abstract Background The initial presentation of sepsis in the emergency department (ED) is difficult to distinguish from other acute illnesses based upon similar clinical presentations. A new blood parameter, a measurement of increased monocyte volume distribution width (MDW), may be used in combination with other clinical parameters to improve early sepsis detection. We sought to determine if MDW, when combined with other available clinical parameters at the time of ED presentation, improves the early detection of sepsis. Methods A retrospective analysis of prospectively collected clinical data available during the initial ED encounter of 2158 adult patients who were enrolled from emergency departments of three major academic centers, of which 385 fulfilled Sepsis-2 criteria, and 243 fulfilled Sepsis-3 criteria within 12 h of admission. Sepsis probabilities were determined based on MDW values, alone or in combination with components of systemic inflammatory response syndrome (SIRS) or quick sepsis-related organ failure assessment (qSOFA) score obtained during the initial patient presentation (i.e., within 2 h of ED admission). Results Abnormal MDW (> 20.0) consistently increased sepsis probability, and normal MDW consistently reduced sepsis probability when used in combination with SIRS criteria (tachycardia, tachypnea, abnormal white blood count, or body temperature) or qSOFA criteria (tachypnea, altered mental status, but not hypotension). Overall, and regardless of other SIRS or qSOFA variables, MDW > 20.0 (vs. MDW ≤ 20.0) at the time of the initial ED encounter was associated with an approximately 6-fold increase in the odds of Sepsis-2, and an approximately 4-fold increase in the odds of Sepsis-3. Conclusions MDW improves the early detection of sepsis during the initial ED encounter and is complementary to SIRS and qSOFA parameters that are currently used for this purpose. This study supports the incorporation of MDW with other readily available clinical parameters during the initial ED encounter for the early detection of sepsis. Trial registration ClinicalTrials.gov, NCT03145428 . First posted May 9, 2017. The first subjects were enrolled June 19, 2017, and the study completion date was January 26, 2018.

Abstract Background Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state. Methods The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting. Discussion We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties.

OBJECTIVES:. Analyze a unique clinical and genealogical resource for evidence of familial clustering of sepsis to test for an inherited contribution to sepsis predisposition. DESIGN:. Observational study. SETTING:. Veteran’s Health Affairs (VHA) Genealogy/Phenotype resource, a U.S. genealogy database with veterans individually linked to VHA electronic health records. PATIENTS:. Sepsis was identified using International Classification of Disease, 9th Edition and 10th Edition codes. There were two comparison groups: one composed of the all veterans with linked data and deep genealogy and the other included 1,000 sets of controls, each set randomly sampled from the entire cohort after matching on sex and 10-year birth year range on a 1:1 ratio with cases. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. There were 4,666 cases of sepsis from 2001 to 2018, of which 96% were male and 80% greater than or equal to 65 years old. Utilizing the Genealogical Index of Familiality, there was a significant excess of pairwise relatedness among sepsis cases over that in the control sets sampled from VHA population (p = 0.03). The relative risk (RR) of sepsis among identified relatives compared with the larger linked VHA cohort demonstrated an excess of sepsis cases in the first-degree (RR, 1.39; 95% CI, 1.03–1.92; p = 0.05) and second-degree (RR, 1.50; 95% CI, 1.07–2.17; p = 0.04) relatives that were not demonstrated in higher degree relatives. The sepsis cases clustered into 1,876 pedigrees of which 628 had a significant excess of sepsis cases among the descendants (p < 0.05). CONCLUSIONS:. The data from this cohort of nearly all male U.S. veterans demonstrate evidence for contribution of an inherited predisposition to sepsis and the existence of pedigrees with a significant excess of diagnoses that provide a valuable resource for identification of the predisposition genes and variants responsible. This complements studies on individual genetic variants toward estimating the heritability patterns and clinical relevance of genetic sepsis predisposition.

Background An ideal test for COVID-19 would combine the sensitivity of laboratory-based PCR with the speed and ease of use of point-of-care (POC) or home-based rapid antigen testing. We evaluated clinical performance of the Diagnostic Analyzer for Selective Hybridization (DASH) SARS-CoV-2 POC rapid PCR test. Methods We conducted a cross-sectional study of adults with and without symptoms of COVID-19 at four clinical sites where we collected two bilateral anterior nasal swabs and information on COVID-19 symptoms, vaccination, and exposure. One swab was tested with the DASH SARS-CoV-2 POC PCR and the second in a central laboratory using Cepheid Xpert Xpress SARS-CoV-2 PCR. We assessed test concordance and calculated sensitivity, specificity, negative and positive predictive values using Xpert as the “gold standard”. Results We enrolled 315 and analyzed 313 participants with median age 42 years; 65% were female, 62% symptomatic, 75% had received ≥2 doses of mRNA COVID-19 vaccine, and 16% currently SARS-CoV-2 positive. There were concordant results for 307 tests indicating an overall agreement for DASH of 0.98 [95% CI 0.96, 0.99] compared to Xpert. DASH performed at 0.96 [95% CI 0.86, 1.00] sensitivity and 0.98 [95% CI 0.96, 1.00] specificity, with a positive predictive value of 0.85 [95% CI 0.73, 0.96] and negative predictive value of 0.996 [95% CI 0.99, 1.00]. The six discordant tests between DASH and Xpert all had high Ct values (>30) on the respective positive assay. DASH and Xpert Ct values were highly correlated (R = 0.89 [95% CI 0.81, 0.94]). Conclusions DASH POC SARS-CoV-2 PCR was accurate, easy to use, and provided fast results (approximately 15 minutes) in real-life clinical settings with an overall performance similar to an EUA-approved laboratory-based PCR.

Abstract Background Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. Methods and design The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. Trial registration ClinicalTrials.gov, NCT03509350 . Registered on 26 April 2018.

Abstract Background Higher inspiratory airway pressures are associated with worse outcomes in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). This relationship, however, has not been well investigated in patients without ARDS. We hypothesized that higher driving pressures (ΔP) and plateau pressures (Pplat) are associated with worse patient-centered outcomes in mechanically ventilated patients without ARDS as well as those with ARDS. Methods Using data collected during a prospective, observational cohort study of 6179 critically ill participants enrolled in 59 ICUs across the USA, we used multivariable logistic regression to determine whether ΔP and Pplat at enrollment were associated with hospital mortality among 1132 mechanically ventilated participants. We stratified analyses by ARDS status. Results Participants without ARDS (n = 822) had lower average severity of illness scores and lower hospital mortality (27.3% vs. 38.7%; p

The electronic health records (EHR) infrastructure offers a tremendous resource for identifying controls who match the characteristics of study participants in a single-arm trial. The objectives are to (1) demonstrate the feasibility of curating a synthetic control group for an existing study cohort through EHR data extraction and (2) evaluate the effect of a lifestyle intervention on selected cardiovascular health metrics. A total of 711 university employees were recruited between 2008 and 2012 to participate in a health partner intervention to improve cardiovascular health and were followed for five years. Data of nearly 8000 eligible subjects were extracted from the EHR to create a synthetic control cohort during the same study period. To minimize confounding, crude comparison, exact matching, propensity score matching, and doubly robust estimation were used to compare the selected cardiovascular health metrics at 1 and 5 years of follow-up. Blood pressure and body mass index improved in the intervention group compared to the EHR synthetic controls. The findings of changes in lipid measurements were somewhat unexpected. When analyzing the subgroup without lipid-lowering medications, the intervention group exhibited better control of cholesterol levels over time than did our synthetic controls. Some measurements in the EHR system may be more robust for synthetic selection than others. EHR synthetic controls can provide an alternative to estimate intervention effects appropriately in single-arm studies for these measurements.

Introduction Current medications for idiopathic pulmonary fibrosis (IPF) have not been shown to impact patient-reported outcome measures (PROMs), highlighting the need for accurate minimal clinically important difference (MCID) values. Recently published consensus standards for MCID studies support using anchor-based over distribution-based methods. The aim of this study was to estimate MCID values for worsening in IPF using only an anchor-based approach. Methods We conducted secondary analyses of three randomised controlled trials with different inclusion criteria and follow-up intervals. The health transition question in the 36-Item Short-Form Health Survey (SF-36) questionnaire was used as the anchor. We used receiver operating curves to assess responsiveness between the anchor and 10 variables (four physiological measures and six PROMs). We used an anchor-based method to determine the MCID values of variables that met the responsiveness criteria (area under the curve ≥0.70). Results 6-min walk distance (6MWD), the St George's Respiratory Questionnaire (SGRQ), physical component score (PCS) of SF-36 and University of California, San Diego, Shortness of Breath Questionnaire (UCSD SOBQ) met the responsiveness criteria. The MCID value for 6MWD was −75 m; the MCID value for SF-36 PCS was −7 points; the MCID value for SGRQ was 11 points; and the MCID value for the UCSD SOBQ was 11 points. Conclusions The MCID estimates of 6MWD, SGRQ, SF-36 and UCSD SOBQ using only anchor-based methods were considerably higher compared to previously proposed values. A single MCID value may not be applicable across all classes of disease severity or durations of follow-up time.

Objectives:. Describe the longitudinal national epidemiology of tracheostomies performed in acute care hospitals and describe the annual rate of tracheostomy performed for patients with respiratory failure with invasive mechanical ventilation. DESIGN:. Serial cross-sectional study. Setting:. The 2002–2014 and 2016–2017 Healthcare Utilization Project’s National Inpatient Sample datasets. Patients:. Discharges greater than or equal to 18 years old, excluding those with head and neck cancer or transferred from another hospital. We used diagnostic and procedure codes from the International Classification of Diseases, 9th and 10th revisions to define cases of respiratory failure, invasive mechanical ventilation, and tracheostomy. Interventions:. None. Measurements and Main Results:. There were an estimated 80,612 tracheostomies performed in 2002, a peak of 89,545 tracheostomies in 2008, and a nadir of 58,840 tracheostomies in 2017. The annual occurrence rate was 37.5 (95% CI, 34.7–40.4) tracheostomies per 100,000 U.S. adults in 2002, with a peak of 39.7 (95% CI, 36.5–42.9) in 2003, and with a nadir of 28.4 (95% CI, 27.2–29.6) in 2017. Specifically, among the subgroup of hospital discharges with respiratory failure with invasive mechanical ventilation, an annual average of 9.6% received tracheostomy in the hospital. This changed over the study period from 10.4% in 2002, with a peak of 10.9% in 2004, and with a nadir of 7.4% in 2017. Among respiratory failure with invasive mechanical ventilation discharges with tracheostomy, the annual proportion of patients 50–59 and 60–69 years old increased, whereas patients from 70 to 79 and greater than or equal to 80 years old decreased. The mean hospital length of stay decreased, and in-hospital mortality decreased, whereas discharge to intermediate care facilities increased. Conclusions:. Over the study period, there were decreases in the annual total case volume and adult occurrence rate of tracheostomy as well as decreases in the rate of tracheostomy among the subgroup with respiratory failure with invasive mechanical ventilation. There is some evidence of changing patterns of patient selection for in-hospital tracheostomy among those with respiratory failure with invasive mechanical ventilation with decreasing proportions of patients with advanced age.

OBJECTIVES:. Patients with infection can develop sepsis, and their mortality can be high. An important aspect in the treatment of sepsis is adequate management of the infection. DATA SOURCES:. Using a modified Delphi approach, the Surviving Sepsis Campaign research committee recently published a series of 26 priorities for sepsis and septic shock. STUDY SELECTION:. Task force members with specific expertise were tasked with generating expanded reviews for all infection questions and a subset of adjunctive therapy questions from the larger list of sepsis priorities. Each question was addressed by one of the six task force members. DATA EXTRACTION:. In-depth reviews were then edited by the group as a whole, with added input from the committee cochairs. DATA SYNTHESIS:. Six questions were addressed: 1) should empiric antibiotic combination therapy be used in sepsis or septic shock? 2) does optimization of antimicrobial pharmacokinetics and pharmacodynamics impact patient outcomes in sepsis? 3) should viral reactivation resulting from sepsis-induced immunosuppression be treated with antiviral therapy in critically ill septic patients? 4) should rapid diagnostic tests be implemented in clinical practice? 5) what is the role of lung-protective ventilation in sepsis patients without acute respiratory distress syndrome? and 6) how do we determine the efficacy of “blood purification” therapies such as endotoxin absorbers, cytokine absorbers, and plasmapheresis. CONCLUSIONS:. The research committee members for the Surviving Sepsis Campaign aimed to explore research questions in order to provide existing evidence and highlight areas of uncertainty and future directions.

(1) Background: The disease-modifying mechanisms of high-dose intravenous vitamin C (HDIVC) in sepsis induced acute respiratory distress syndrome (ARDS) is unclear. (2) Methods: We performed a post hoc study of plasma biomarkers from subjects enrolled in the randomized placebo-controlled trial CITRIS-ALI. We explored the effects of HDIVC on cell-free DNA (cfDNA) and syndecan-1, surrogates for neutrophil extracellular trap (NET) formation and degradation of the endothelial glycocalyx, respectively. (3) Results: In 167 study subjects, baseline cfDNA levels in HDIVC (84 subjects) and placebo (83 subjects) were 2.18 ng/µL (SD 4.20 ng/µL) and 2.65 ng/µL (SD 3.87 ng/µL), respectively, p = 0.45. At 48-h, the cfDNA reduction was 1.02 ng/µL greater in HDIVC than placebo, p = 0.05. Mean baseline syndecan-1 levels in HDIVC and placebo were 9.49 ng/mL (SD 5.57 ng/mL) and 10.83 ng/mL (SD 5.95 ng/mL), respectively, p = 0.14. At 48 h, placebo subjects exhibited a 1.53 ng/mL (95% CI, 0.96 to 2.11) increase in syndecan-1 vs. 0.75 ng/mL (95% CI, 0.21 to 1.29, p = 0.05), in HDIVC subjects. (4) Conclusions: HDIVC infusion attenuated cell-free DNA and syndecan-1, biomarkers associated with sepsis-induced ARDS. Improvement of these biomarkers suggests amelioration of NETosis and shedding of the vascular endothelial glycocalyx, respectively.

Abstract Background Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed. Methods The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30 days following randomization. The key secondary outcome is mortality at 30 days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed. Discussion VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide. Trial registration ClinicalTrials.gov Identifier: NCT03509350. First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019

Abstract Background Differentiating sepsis from the systemic inflammatory response syndrome (SIRS) in critical care patients is challenging, especially before serious organ damage is evident, and with variable clinical presentations of patients and variable training and experience of attending physicians. Our objective was to describe and quantify physician agreement in diagnosing SIRS or sepsis in critical care patients as a function of available clinical information, infection site, and hospital setting. Methods We conducted a post hoc analysis of previously collected data from a prospective, observational trial (N = 249 subjects) in intensive care units at seven US hospitals, in which physicians at different stages of patient care were asked to make diagnostic calls of either SIRS, sepsis, or indeterminate, based on varying amounts of available clinical information (clinicaltrials.gov identifier: NCT02127502). The overall percent agreement and the free-marginal, inter-observer agreement statistic kappa (κ free) were used to quantify agreement between evaluators (attending physicians, site investigators, external expert panelists). Logistic regression and machine learning techniques were used to search for significant variables that could explain heterogeneity within the indeterminate and SIRS patient subgroups. Results Free-marginal kappa decreased between the initial impression of the attending physician and (1) the initial impression of the site investigator (κ free 0.68), (2) the consensus discharge diagnosis of the site investigators (κ free 0.62), and (3) the consensus diagnosis of the external expert panel (κ free 0.58). In contrast, agreement was greatest between the consensus discharge impression of site investigators and the consensus diagnosis of the external expert panel (κ free 0.79). When stratified by infection site, κ free for agreement between initial and later diagnoses had a mean value + 0.24 (range − 0.29 to + 0.39) for respiratory infections, compared to + 0.70 (range + 0.42 to + 0.88) for abdominal + urinary + other infections. Bioinformatics analysis failed to clearly resolve the indeterminate diagnoses and also failed to explain why 60% of SIRS patients were treated with antibiotics. Conclusions Considerable uncertainty surrounds the differential clinical diagnosis of sepsis vs. SIRS, especially before organ damage has become highly evident, and for patients presenting with respiratory clinical signs. Our findings underscore the need to provide physicians with accurate, timely diagnostic information in evaluating possible sepsis.

Background: A significant proportion of adults have normal weight obesity (NWO), defined as a normal body mass index (BMI) but disproportionately high body fat percentage. Individuals with NWO may have increased risk of cardiometabolic disorders and lower exercise tolerance, but it is unclear if this obesity phenotype is linked with dysregulated production of adipokines or myokines such as adiponectin and apelin, respectively. Methods: This cross-sectional, secondary analysis included 177 working adults (mean age 49.6 ± 9.9 yrs, 64% female). Plasma high-molecular weight adiponectin and apelin levels were measured by ELISA. Body composition and fat distribution were assessed using dual energy X-ray absorptiometry. Exercise tolerance (VO2 maximum) was determined by treadmill testing. NWO was defined as a BMI 30% for women or >23% for men. Participants were categorized as lean, NWO, or overweight-obese. Results: A total of 14.7% of subjects were categorized as lean, 23.7% as having NWO, and 61.6% as having overweight-obesity. Plasma adiponectin levels were elevated in the overweight-obesity group (P 0.05). Adiponectin concentrations were inversely associated with BMI, fat mass, fat mass percent, visceral fat, and trunk to leg fat ratio and positively associated with leg fat mass (all P

Objectives:. Coronavirus disease 2019 is associated with high mortality rates and multiple organ damage. There is increasing evidence that these patients are at risk for various cardiovascular insults; however, there are currently no guidelines for the diagnosis and management of such cardiovascular complications in patients with coronavirus disease 2019. We share data and recommendations from a multidisciplinary team to highlight our institution’s clinical experiences and guidelines for managing cardiovascular complications of coronavirus disease 2019. Design, Setting, and Patients:. This was a retrospective cohort study of patients admitted to one of six ICUs dedicated to the care of patients with coronavirus disease 2019 located in three hospitals within one academic medical center in Atlanta, Georgia. Measurements/Interventions:. Chart review was conducted for sociodemographic, laboratory, and clinical data. Rates of specific cardiovascular complications were assessed, and data were analyzed using a chi-square or Wilcoxon rank-sum test for categorical and continuous variables. Additionally, certain cases are presented to demonstrate the sub committee’s recommendations. Main Results:. Two-hundred eighty-eight patients were admitted to the ICU with coronavirus disease 2019. Of these, 86 died (29.9%), 242 (84.03%) had troponin elevation, 70 (24.31%) had dysrhythmias, four (1.39%) had ST-elevation myocardial infarction, eight (2.78%) developed cor pulmonale, and 190 (65.97%) with shock. There was increased mortality risk in patients with greater degrees of troponin elevation (p < 0.001) and with the development of arrhythmias (p < 0.001), cor pulmonale (p < 0.001), and shock (p < 0.001). Conclusions:. While there are guidelines for the diagnosis and management of pulmonary complications of coronavirus disease 2019, there needs to be more information regarding the management of cardiovascular complications as well. These recommendations garnered from the coronavirus disease 2019 cardiology subcommittee from our institution will add to the existing knowledge of these potential cardiovascular insults as well as highlight suggestions for the diagnosis and management of the range of cardiovascular complications of coronavirus disease 2019. Additionally, with the spread of coronavirus disease 2019, our case-based recommendations provide a bedside resource for providers newly caring for patients with coronavirus disease 2019.

Acute respiratory failure (ARF) is a common problem in medicine that utilizes significant healthcare resources and is associated with high morbidity and mortality. Classification of acute respiratory failure is complicated, and it is often determined by the level of mechanical support that is required, or the discrepancy between oxygen supply and uptake. These phenotypes make acute respiratory failure a continuum of syndromes, rather than one homogenous disease process. Early recognition of the risk factors for new or worsening acute respiratory failure may prevent that process from occurring. Predictive analytical methods using machine learning leverage clinical data to provide an early warning for impending acute respiratory failure or its sequelae. The aims of this review are to summarize the current literature on ARF prediction, to describe accepted procedures and common machine learning tools for predictive tasks through the lens of ARF prediction, and to demonstrate the challenges and potential solutions for ARF prediction that can improve patient outcomes.

Background: South Asians are a high-risk ethnic group for cardiovascular disease despite having lower levels of conventional cardiovascular risk factors such as obesity and smoking. Ethnic differences in pulse wave reflections, arterial stiffness, and subclinical atherosclerosis as measured using augmentation index (AIX), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT) may reflect some of this excess risk. Methods: We conducted a cross-sectional analysis of pooled data from three community-based sources in Atlanta, Georgia, USA. Data on 530 South Asians collected from local health fairs was compared with data on 507 White and 192 African Americans from the Emory Predictive Health Initiative and 351 White and 382 African Americans from the Morehouse and Emory Team up to Eliminate Health Disparities Study. Results: Linear regression models adjusted for age, sex, smoking, MAP, fasting glucose, TC, HDL-C, creatinine, and body mass index were used to assess the relationship between ethnicity and vascular function measures. In fully adjusted models, South Asians had higher heart rate corrected AIX as compared with Whites and African Americans (by 5.47%, p

Trial registration ClinicalTrials.gov : NCT03509350 . Registered on 26 April 2018.

Abstract There is a paradigm shift happening for sepsis. Sepsis is no longer solely conceptualized as problem of individual patients treated in emergency departments and intensive care units but also as one that is addressed as public health issue with population- and systems-based solutions. We offer a conceptual framework for sepsis as a public health problem by adapting the traditional model of primary, secondary, and tertiary prevention.

Background: There is a high prevalence of vitamin D deficiency in the critically ill patient population. Several intensive care unit studies have demonstrated an association between vitamin D deficiency [25-hydroxyvitamin D (25(OH)D)

BackgroundLower levels of circulating progenitor cells (PCs) reflect impaired endogenous regenerative capacity and are associated with aging, vascular disease, and poor outcomes. Whether biologic sex and sex hormones influence PC numbers remains a subject of controversy. We sought to determine sex differences in circulating PCs in both healthy persons and patients with coronary artery disease, and to determine their association with sex hormone levels. Methods and ResultsIn 642 participants (mean age 48 years, 69% women, 23% black) free from cardiovascular disease, we measured circulating PC counts as CD45med+ mononuclear cells coexpressing CD34 and its subsets expressing CD133, chemokine (C‐X‐C motif) receptor 4, and vascular endothelial growth factor receptor 2 epitopes using flow cytometry. Testosterone and estradiol levels were measured. After adjustment for age, cardiovascular risk factors, and body mass, CD34+ (β=−23%, P

BackgroundLifestyle modifications are first‐line measures for cardiovascular disease prevention. Whether lifestyle intervention also preserves cardiovascular health is less clear. Our study examined the role of a Health Partner–administered lifestyle intervention on metrics of ideal cardiovascular health. Methods and ResultsA total of 711 university employees (48±11 years; 66% women, 72% Caucasian/22.5% African Americans) enrolled in a program that promoted healthier lifestyles at Emory University (Atlanta, GA). Anthropometric, laboratory, and physical activity measurements were performed at baseline and at 6 months, 1 year, and 2 years of follow‐up. Results were utilized by the Health Partner to generate a personalized plan aimed at meeting ideal health metrics. Compared to baseline, at each of the 6‐month, 1‐year, and 2‐year follow‐up visits, systolic blood pressure was lower by 3.6, 4.6, and 3.3 mm Hg (P