Enrolling High-Acuity Emergency General Surgery Patients in a Prospective Longitudinal Cohort Study.

Over three million patients are admitted to hospitals annually with high-acuity conditions mandating emergency abdominal or skin/soft-tissue operation. Patients with these high-acuity emergency general surgery (HA-EGS) diseases experience significant morbidity/mortality, yet the quality of life (QOL) impact on survivors is not well studied. Acuity, transfer patterns, and adverse social determinants of health (SDOH) documented in epidemiologic studies are cited reasons for inability to measure patient-reported outcomes (PROs) among HA-EGS survivors. We conducted a feasibility study to understand facilitators and barriers of conducting a prospective study of changes in QOL after surviving HA-EGS. From September 2019 to April 2021, we collected baseline (pre-admission) and 30/60-days post-surgery data on activities of daily living, depression, self-efficacy, resilience, pain, work limitations, social support, and substance use from patients who enrolled during index hospitalization. 100 patients were consented to participate in the study (71.9% enrollment rate). The retention rate was 65.9% for 30-day calls and 53.8% for 60-day calls. Median time to complete each time point remained under 25 minutes. Patients with a longer length of stay and nicotine users didn't complete their 30-day interview while those with systemic complications didn't complete their 60-day interview. These results set the foundation for future PRO studies.

Characterization of Mortality by Sepsis Source in Patients Admitted to the Surgical Intensive Care Unit.

INTRODUCTION: The impact of infectious source on sepsis outcomes for surgical patients is unclear. The objective of this study was to evaluate the association between sepsis sources and cumulative 90-d mortality in patients admitted to the surgical intensive care unit (SICU) with sepsis. METHODS: All patients admitted to the SICU at an academic institution who met sepsis criteria (2014-2019, n = 1296) were retrospectively reviewed. Classification of source was accomplished through a chart review and included respiratory (RT, n = 144), intra-abdominal (IA, n = 859), skin and soft tissue (SST, n = 215), and urologic (UR, n = 78). Demographics, comorbidities, and clinical presentation were compared. Outcomes included 90-d mortality, respiratory and renal failure, length of stay, and discharge disposition. Cox-proportional regression was used to model predictors of mortality; P < 0.05 was significant. RESULTS: Patients with SST were younger, more likely to be diabetic and obese, but had the lowest total comorbidities. Median admission sequential organ failure assessment scores were highest for IA and STT and lowest in urologic infections. Cumulative 90-d mortality was highest for IA and RT (35% and 33%, respectively) and lowest for SST (20%) and UR (8%) (P < 0.005). Compared to the other categories, UR infections had the lowest SICU length of stay and the highest discharge-to-home (57%, P < 0.0005). Urologic infections remained an independent negative predictor of 90-d mortality (odds ratio 0.14, 95% confidence interval: 0.1-0.4), after controlling for sequential organ failure assessment. CONCLUSIONS: Urologic infections remained an independent negative predictor of 90-d mortality when compared to other sources of sepsis. Characterization of sepsis source revealed distinct populations and clinical courses, highlighting the importance of understanding different sepsis phenotypes.

Microvesicle-Mediated Transfer of DNA Methyltransferase Proteins Results in Recipient Cell Immunosuppression.

INTRODUCTION: Patients with sepsis exhibit significant, persistent immunologic dysfunction. Evidence supports the hypothesis that epigenetic regulation of key cytokines plays an important role in this dysfunction. In sepsis, circulating microvesicles (MVs) containing elevated levels of DNA methyltransferase (DNMT) mRNA cause gene methylation and silencing in recipient cells. We sought to examine the functional role of MV DNMT proteins in this immunologic dysfunction. METHODS: In total, 33 patients were enrolled within 24 h of sepsis diagnosis (23 sepsis, 10 critically ill controls). Blood and MVs were collected on days 1, 3, and 5 of sepsis, and protein was isolated from the MVs. Levels of DNMT protein and activity were quantified. MVs were produced in vitro by stimulating naïve monocytes with lipopolysaccharide. Methylation was assessed using bisulfate site-specific qualitative real-time polymerase chain reaction. RESULTS: The size of MVs in the patients with sepsis decreased from days 1 to 5 compared to the control group. Circulating MVs contained significantly higher levels of DNMT 1 and 3A, protein. We recapitulated the production of these DNMT-containing MVs in vitro by treating monocytes with lipopolysaccharide. We found that exposing naïve monocytes to these MVs resulted in increased promoter methylation of tumor necrosis factor alpha. CONCLUSIONS: An analysis of the isolated MVs revealed higher levels of DNMT proteins in septic patients than those in nonseptic patients. Exposing naïve monocytes to DNMT-containing MVs produced in vitro resulted in hypermethylation of tumor necrosis factor alpha, a key cytokine implicated in postsepsis immunosuppression. These results suggest that DNMT-containing MVs cause epigenetic changes in recipient cells. This study highlights a novel role for MVs in the immune dysfunction of patients with sepsis.

Transfer Status and 90-Day Mortality in Intensive Care Unit Patients With Sepsis: A Propensity Matched Analysis.

BACKGROUND: Timely identification and management of sepsis in surgical patients is crucial, and transfer status may delay optimal treatment of these patients. The objective of this study was to compare in-house and 90-day mortality between patients primarily admitted or transferred into the surgical ICU (SICU) at a tertiary referral center. MATERIAL AND METHODS: All patients admitted to the SICU with a diagnosis of sepsis (Sepsis III) were reviewed at a single institution between 2014 to 2019 (n = 1489). Demographics, comorbidities, and sepsis presentation were compared between transferred (n = 696) and primary patients (n = 793). Primary outcomes evaluated were in-house and 90 day mortality in an unmatched and propensity score matched cohorts. A P value < 0.05 was considered statistically significant. RESULTS: Transfer patients were more likely to have obesity (60% versus 49%, P < 0.005), a higher median SOFA (6 (4-8) versus 5 (3-8), P = 0.007), and require vasopressors on admission (42% versus 35%, P = 0.004). Compared to primary patients, transfer patients exhibited higher rates of respiratory failure (76% versus 69%, P = 0.003), in-house (30% versus 17%, P < 0.005), and 90 day mortality (36% versus 24%, P < 0.005). After matching, transferred patients were associated with 75% and 83% increased odds of in-house and 90 day mortality after controlling for age, sex, race, comorbidities, BMI, and sepsis severity. CONCLUSIONS: Transfer status is associated with an over 80% increase in the odds of 90 day mortality for patients admitted to the SICU with sepsis. Aggressive patient identification and earlier transfer of those at higher risk of death may reduce this effect.

Analyzing Outcomes Among Older Adults With Necrotizing Soft-Tissue Infections in the United States.

BACKGROUND: Necrotizing soft-tissue infections (NSTIs) encompass a group of severe, life-threatening diseases with high morbidity and mortality. Evidence suggests advanced age is associated with worse outcomes. To date, no large data sets exist describing outcomes in older individuals, and risk factor identification is lacking. METHODS: Retrospective data were obtained from the 2015 Medicare 100% sample. Included in the analysis were those aged ≥65 y with a primary diagnosis of an NSTI (gas gangrene, necrotizing fasciitis, cutaneous gangrene, or Fournier's gangrene). Risk factors for in-hospital mortality and discharge disposition were examined. Continuous variables were assessed using central tendency, t-tests, and Wilcoxon rank-sum tests. Categorical variables were assessed using the chi-squared and Fisher's exact tests. Statistical significance was defined as P < 0.05. RESULTS: 1427 patient records were reviewed. 59% of patients were male, and the overall mean age was 75.4±8.6 y. 1385 (97.0%) patients required emergency surgery for their NSTI diagnosis. The overall mortality was 5.3%. Several underlying comorbidities were associated with higher rates of mortality including cancer (OR: 3.50, P = 0.0009), liver disease (OR: 2.97, P = 0.03), and kidney disease (OR: 2.15, P = 0.01). While associated with high in-hospital mortality, these diagnoses were not associated with a difference in the rate of discharge to home compared with skilled nursing or rehab. Overall, patients discharged to skilled nursing facilities or rehab had higher rates of underlying comorbidities than patients who were discharged home (3 or more comorbid illness 84.3% versus 68.6%, P < 0.0001); however, no individual comorbid illness was associated with discharge location. CONCLUSIONS: In our Medicare data set, we identified several medical comorbidities that are associated with increased rates of in-hospital mortality. Patients with underlying cancers had the highest odds of increased mortality. The effect on outcomes of the potentially immunosuppressive cancer treatments in these patients is unknown. These data suggest that patients with underlying illnesses, especially cancer, kidney disease, or liver disease have higher mortalities and are more likely to be discharged to skilled nursing facilities or rehab. It is unclear why these illnesses were associated with these worse outcomes while others including diabetes and heart disease were not. These data suggest that these particular comorbid illnesses may have special prognostic implications, although further analysis is necessary to identify the causative factors.

Macrophage microvesicles induce macrophage differentiation and miR-223 transfer.

Microvesicles are small membrane-bound particles comprised of exosomes and various-sized extracellular vesicles. These are released by several cell types. Microvesicles have a variety of cellular functions from communication to mediating growth and differentiation. Microvesicles contain proteins and nucleic acids. Previously, we showed that plasma microvesicles contain microRNAs (miRNAs). Based on our previous report, the majority of peripheral blood microvesicles are derived from platelets, while mononuclear phagocytes, including macrophages, are the second most abundant population. Here, we characterized macrophage-derived microvesicles and explored their role in the differentiation of naive monocytes. We also identified the miRNA content of the macrophage-derived microvesicles. We found that RNA molecules contained in the macrophage-derived microvesicles were transported to target cells, including mono cytes, endothelial cells, epithelial cells, and fibroblasts. Furthermore, we found that miR-223 was transported to target cells and was functionally active. Based on our observations, we hypothesize that microvesicles bind to and activate target cells. Furthermore, we find that microvesicles induce the differentiation of macrophages. Thus, defining key components of this response may identify novel targets to regulate host defense and inflammation.

Methodological challenges in utilizing miRNAs as circulating biomarkers.

MicroRNAs (miRNAs) have emerged as important regulators in the post-transcriptional control of gene expression. The discovery of their presence not only in tissues but also in extratissular fluids, including blood, urine and cerebro-spinal fluid, together with their changes in expression in various pathological conditions, has implicated these extracellular miRNAs as informative biomarkers of disease. However, exploiting miRNAs in this capacity requires methodological rigour. Here, we report several key procedural aspects of miRNA isolation from plasma and serum, as exemplified by research in cardiovascular and pulmonary diseases. We also highlight the advantages and disadvantages of various profiling methods to determine the expression levels of plasma- and serum-derived miRNAs. Attention to such methodological details is critical, as circulating miRNAs become diagnostic tools for various human diseases.

Predictors of 1-year mortality following discharge from the surgical intensive care unit after sepsis.

BACKGROUND: Postsepsis syndrome is associated with significant long-term mortality. The objective of this study was to determine predictors of mortality within 1 year of discharge from the surgical intensive care unit. METHODS: We retrospectively reviewed patients admitted to a surgical intensive care unit with sepsis (sequential organ failure assessment score ≥2, 2011-2022). Those who died within 1 year from discharge (n = 171) were compared to survivors (n = 639). Baseline characteristics, sepsis presentation, and hospitalization data were compared. A multiple logistic regression was performed to determine predictors of 1-year mortality after discharge. RESULTS: Compared with survivors, those who died were older, less likely to be transferred from another institution (35% vs 46%, P = .003), had more metastatic cancer (9% vs 1%, P < .01), or stage III + chronic kidney disease (16% vs 7%, P < .01). Admission sequential organ failure assessment score, lactate, and vasopressor use were comparable. The 1-year mortality cohort exhibited increased respiratory (15% vs 9%) and abdominal (66% vs 54%) infections (P < .01), median length of stay (29 vs 19, P < .005), renal failure (14% vs 9%, P = .048), and dependent discharge. Adjusted predictors of death included age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.02-1.05), metastatic cancer (OR 8.0, 95% CI 2.6-25), chronic kidney disease (OR 2.8, 95% CI 1.4-5.6), length of stay (OR 1.02, 95% CI 1.0-1.03), and dependent discharge. A length of stay in the top quartile (>32 days) was associated with a 3-fold increase in postdischarge mortality compared with the lowest quartile (<10 days). CONCLUSION: We identified independent predictors of postdischarge mortality following sepsis, including age, length of stay, dependent discharge, and stage III + chronic kidney disease. These data can identify at-risk patients who can be targeted for closer follow-up.

Obesity is associated with improved early survival but increased late mortality in surgical patients with Sepsis: A propensity matched analysis.

BACKGROUND: While obesity is a risk factor for postoperative complications, its impact following sepsis is unclear. The primary objective of this study was to evaluate the association between obesity and mortality following admission to the surgical intensive care unit (SICU) with sepsis. METHODS: We conducted a single center retrospective review of SICU patients grouped into obese (n = 766, body mass index ≥30 kg/m 2 ) and nonobese (n = 574; body mass index, 18-29.9 kg/m 2 ) cohorts. Applying 1:1 propensity matching for age, sex, comorbidities, sequential organ failure assessment, and transfer status, demographic data, comorbidities, and sepsis presentation were compared between groups. Primary outcomes included in-hospital and 90-day mortality, ICU length of stay, need for mechanical ventilation (IMV) and renal replacement therapy (RRT). p < 0.05 was considered significant. RESULTS: Obesity associates with higher median ICU length of stay (8.2 vs. 5.6, p < 0.001), need for IMV (76% vs. 67%, p = 0.001), ventilator days (5 vs. 4, p < 0.004), and RRT (23% vs. 12%, p < 0.001). In-hospital (29% vs. 18%, p < 0.0001) and 90-day mortality (34% vs. 24%, p = 0.0006) was higher for obese compared with nonobese groups. Obesity independently predicted need for IMV (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2-2.1), RRT (OR, 2.2; 95% CI, 1.5-3.1), in-hospital (OR, 2.1; 95% CI, 1.5-2.8), and 90-day mortality (HR, 1.4; 95% CI, 1.1-1.8), after adjusting for sequential organ failure assessment, age, sex, and comorbidities. Comparative survival analyses demonstrate a paradoxical early survival benefit for obese patients followed by a rapid decline after 7 days (logrank p = 0.0009). CONCLUSION: Obesity is an independent risk factor for 90-day mortality for surgical patients with sepsis, but its impact appeared later in hospitalization. Understanding differences in systemic responses between these cohorts may be important for optimizing critical care management. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

The calcineurin-NFATc pathway modulates the lipid mediators in BAL fluid extracellular vesicles, thereby regulating microvascular endothelial cell barrier function.

Extracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPS-treated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin-NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse bronchoalveolar lavage fluid (BALF) were analyzed for their lipid mediators by liquid chromatography in conjunction with mass spectrometry (LC-MS/MS). Our data demonstrate that EVs from LPS-treated mice contained significantly higher levels of arachidonic acid (AA) metabolites, which were found in low levels by prior treatment with CNI103. The catalytic activity of lung tissue cytoplasmic phospholipase A2 (cPLA2) increased during ALI, correlating with an increased amount of arachidonic acid (AA) in the EVs. Furthermore, ALI is associated with increased expression of cPLA2, cyclooxygenase 2 (COX2), and lipoxygenases (5-LOX, 12-LOX, and 15-LOX) in lung tissue, and pretreatment with CNI103 inhibited the catalytic activity of cPLA2 and the expression of cPLA2, COX, and LOX transcripts. Furthermore, co-culture of mouse pulmonary microvascular endothelial cell (PMVEC) monolayer and NFAT-luciferase reporter macrophages with BALF EVs from LPS-treated mice increased the pulmonary microvascular endothelial cell (PMVEC) monolayer barrier permeability and luciferase activity in macrophages. However, EVs from CNI103-treated mice had no negative impact on PMVEC monolayer barrier integrity. In summary, BALF EVs from LPS-treated mice carry biologically active NFATc-dependent, AA-derived lipids that play a role in regulating PMVEC monolayer barrier function.

Distressed Communities Index Is Not Associated with Mortality for Critically Ill Surgical Patients with Sepsis.

Background: The impact of socioeconomic metrics on outcomes after sepsis is unclear. The Distressed Communities Index (DCI) is a composite score quantifying socioeconomic well-being by zip code. The primary objective of this study was to evaluate the association between DCI and mortality in patients with sepsis admitted to the surgical intensive care unit (SICU). Patients and Methods: All patients with sepsis admitted to the SICU (Sequential Organ Failure Assessment [SOFA] score ≥2) were reviewed retrospectively. Composite DCI scores were obtained for each patient and classified into high-distress (DCI ≥75th percentile; n = 331) and control distress (DCI <50th percentile; n = 666) groups. Baseline demographic and clinical characteristics were compared between groups. The primary outcomes were in-hospital and 90-day mortality. Results: The high-distress cohort was younger and more likely to be African American (19.6% vs. 6.2%), transferred from an outside facility (52% vs. 42%), have chronic obstructive pulmonary disease (25.1% vs. 18.8%), and baseline liver disease (8.2% vs. 4.2%). Sepsis presentation was comparable between groups. Compared with the control cohort, high-distress patients had similar in-house (23% vs. 24%) and 90-day mortality (30% vs. 28%) but were associated with longer hospital stay (23 vs. 19 days). High DCI failed to predict in-hospital or 90-day mortality but was an independent risk factor for longer hospital length of stay (odds ratio [OR], 2.83 ± 1.42; p = 0.047). Conclusions: High DCI was not associated with mortality but did independently predict longer length of stay. This may reflect limitations of DCI score in evaluating mortality for patients with sepsis. Future studies should elucidate its association with length of stay, re-admissions, and follow-up.

Area Deprivation Index Predicts Mortality for Critically Ill Surgical Patients With Sepsis.

Background: The impact of socioeconomic status on outcomes after sepsis has been challenging to define, and no polysocial metric has been shown to predict mortality in sepsis. The primary objective of this study was to evaluate the association between the Area Deprivation Index (ADI) and mortality in patients admitted to the surgical intensive care unit (SICU) with sepsis. Patients and Methods: All patients admitted to the SICU with sepsis (Sequential Organ Failure Assessment [SOFA] score ≥2) were retrospectively reviewed. The ADI scores were obtained and classified as "high ADI" (≥85th percentile, n = 400, representative of high socioeconomic deprivation) and "control ADI" (ADI <85th percentile, n = 976). Baseline demographic and clinical characteristics were compared between groups. The primary outcome was 90-day mortality. Results: High ADI patients were younger (mean age 58.5 vs. 60.8; p = 0.01) and more likely to be non-white (23.7% vs. 10.0%; p < 0.0005) and to present with chronic obstructive pulmonary disease (26.5% vs. 19.0%; p = 0.002). High ADI patients had increased in-hospital (27.3% vs. 21.6%; p = 0.025) and 90-day mortality (35.0% vs. 28.9%; p = 0.03). High ADI patients also had increased rates of renal failure (20.3% vs. 15.3%; p = 0.02). Both cohorts had similar intensive care unit (ICU) lengths of stay and median hospital stay, Charlson comorbidity index, and rate of discharge to home. High ADI is an independent risk factor for 90-day mortality after admission for surgical sepsis (odds ratio [OR], 1.39 ± 0.24; p = 0.014). Conclusions: High ADI is an independent predictor of 90-day mortality in patients with surgical sepsis. Targeted community interventions are needed to reduce sepsis mortality for these at-risk patients.

Lipidomic Profiling of Bronchoalveolar Lavage Fluid Extracellular Vesicles Indicates Their Involvement in Lipopolysaccharide-Induced Acute Lung Injury.

Emerging data support the pivotal role of extracellular vesicles (EVs) in normal cellular physiology and disease conditions. However, despite their abundance, there is much less information about the lipid mediators carried in EVs, especially in the context of acute lung injury (ALI). Our data demonstrate that C57BL/6 mice subjected to intranasal Escherichia coli lipopolysaccharide (LPS)-induced ALI release, a higher number of EVs into the alveolar space, compared to saline-treated controls. EVs released during ALI originated from alveolar epithelial cells, macrophages, and neutrophils and carry a diverse array of lipid mediators derived from ω-3 and ω-6 polyunsaturated fatty acids (PUFA). The eicosanoids in EVs correlated with cellular levels of arachidonic acid, expression of cytosolic phospholipase A2, cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome epoxygenase p450 proteins in pulmonary macrophages. Furthermore, EVs from LPS-toll-like receptor 4 knockout (TLR4-/-) mice contained significantly lower amounts of COX and LOX catalyzed eicosanoids and ω-3 PUFA metabolites. More importantly, EVs from LPS-treated wild-type mice increased TNF-α release by macrophages and reduced alveolar epithelial monolayer barrier integrity compared to EVs from LPS-treated TLR4-/- mice. In summary, our study demonstrates for the first time that the EV carried PUFA metabolite profile in part depends on the inflammatory status of the lung macrophages and modulates pulmonary macrophage and alveolar epithelial cell function during LPS-induced ALI.

Exosomal Transfer of DNA Methyl-Transferase mRNA Induces an Immunosuppressive Phenotype in Human Monocytes.

INTRODUCTION: Survivors of sepsis exhibit persistent immunosuppression. Epigenetic events may be responsible for some of these immunosuppressive changes. During sepsis circulating exosomes contain large quantities of DNA methyltransferase (DNMT) mRNAs. We hypothesized that exosomes directly transfer DNMT mRNAs to recipient monocytes with resultant methylation events and immunosuppression. METHODS: Exosomes containing DNMT mRNA were generated by stimulating monocytes with LPS. Confocal microscopy was used to determine uptake kinetics in the presence of pharmacologic inhibition. Expression and packaging of specific DNMT mRNA was controlled using DNMT siRNAs. Whole genome and gene specific methylation was assessed using bisulfite sequencing. Ingenuity pathway analysis was performed to determine the biological function of significance of differentially methylated regions. RESULTS: Exosomes effectively transferred DNMT mRNA to recipient monocytes. Pharmacologic inhibition of exosome uptake prevented this increase in DNMT mRNA expression. Recipient monocytes exhibited hypermethylation changes and gene suppression. siRNAs decreased the packaging of DNMT mRNAs and prevented TNFα gene suppression, restoring immunocompetence. CONCLUSION: These data support a role for exosome-mediated transfer of DNMT mRNA with resultant methylation and gene silencing. Pharmacologic uptake inhibition or targeted siRNA mediated DNMT gene silencing prevented DNMT mRNA transfer and maintained the cell's ability to express TNFα in response to LPS. This highlights the potential therapeutic value of targeting these exosome-mediated epigenetic events to maintain the host immune response during sepsis.

Patient Factors Associated With Appendectomy Within 30 Days of Initiating Antibiotic Treatment for Appendicitis.

IMPORTANCE: Use of antibiotics for the treatment of appendicitis is safe and has been found to be noninferior to appendectomy based on self-reported health status at 30 days. Identifying patient characteristics associated with a greater likelihood of appendectomy within 30 days in those who initiate antibiotics could support more individualized decision-making. OBJECTIVE: To assess patient factors associated with undergoing appendectomy within 30 days of initiating antibiotics for appendicitis. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study using data from the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) randomized clinical trial, characteristics among patients who initiated antibiotics were compared between those who did and did not undergo appendectomy within 30 days. The study was conducted at 25 US medical centers; participants were enrolled between May 3, 2016, and February 5, 2020. A total of 1552 participants with acute appendicitis were randomized to antibiotics (776 participants) or appendectomy (776 participants). Data were analyzed from September 2020 to July 2021. EXPOSURES: Appendectomy vs antibiotics. MAIN OUTCOMES AND MEASURES: Conditional logistic regression models were fit to estimate associations between specific patient factors and the odds of undergoing appendectomy within 30 days after initiating antibiotics. A sensitivity analysis was performed excluding participants who underwent appendectomy within 30 days for nonclinical reasons. RESULTS: Of 776 participants initiating antibiotics (mean [SD] age, 38.3 [13.4] years; 286 [37%] women and 490 [63%] men), 735 participants had 30-day outcomes, including 154 participants (21%) who underwent appendectomy within 30 days. After adjustment for other factors, female sex (odds ratio [OR], 1.53; 95% CI, 1.01-2.31), radiographic finding of wider appendiceal diameter (OR per 1-mm increase, 1.09; 95% CI, 1.00-1.18), and presence of appendicolith (OR, 1.99; 95% CI, 1.28-3.10) were associated with increased odds of undergoing appendectomy within 30 days. Characteristics that are often associated with increased risk of complications (eg, advanced age, comorbid conditions) and those clinicians often use to describe appendicitis severity (eg, fever: OR, 1.28; 95% CI, 0.82-1.98) were not associated with odds of 30-day appendectomy. The sensitivity analysis limited to appendectomies performed for clinical reasons provided similar results regarding appendicolith (adjusted OR, 2.41; 95% CI, 1.49-3.91). CONCLUSIONS AND RELEVANCE: This cohort study found that presence of an appendicolith was associated with a nearly 2-fold increased risk of undergoing appendectomy within 30 days of initiating antibiotics. Clinical characteristics often used to describe severity of appendicitis were not associated with odds of 30-day appendectomy. This information may help guide more individualized decision-making for people with appendicitis.

Self-selection vs Randomized Assignment of Treatment for Appendicitis.

Importance: For adults with appendicitis, several randomized clinical trials have demonstrated that antibiotics are an effective alternative to appendectomy. However, it remains unknown how the characteristics of patients in such trials compare with those of patients who select their treatment and whether outcomes differ. Objective: To compare participants in the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) randomized clinical trial (RCT) with a parallel cohort study of participants who declined randomization and self-selected treatment. Design, Setting, and Participants: The CODA trial was conducted in 25 US medical centers. Participants were enrolled between May 3, 2016, and February 5, 2020; all participants were eligible for at least 1 year of follow-up, with all follow-up ending in 2021. The randomized cohort included 1094 adults with appendicitis; the self-selection cohort included patients who declined participation in the randomized group, of whom 253 selected appendectomy and 257 selected antibiotics. In this secondary analysis, characteristics and outcomes in both self-selection and randomized cohorts are described with an exploratory analysis of cohort status and receipt of appendectomy. Interventions: Appendectomy vs antibiotics. Main Outcomes and Measures: Characteristics among participants randomized to either appendectomy or antibiotics were compared with those of participants who selected their own treatment. Results: Clinical characteristics were similar across the self-selection cohort (510 patients; mean age, 35.8 years [95% CI, 34.5-37.1]; 218 female [43%; 95% CI, 39%-47%]) and the randomized group (1094 patients; mean age, 38.2 years [95% CI, 37.4-39.0]; 386 female [35%; 95% CI, 33%-38%]). Compared with the randomized group, those in the self-selection cohort were less often Spanish speaking (n = 99 [19%; 95% CI, 16%-23%] vs n = 336 [31%; 95% CI, 28%-34%]), reported more formal education (some college or more, n = 355 [72%; 95% CI, 68%-76%] vs n = 674 [63%; 95% CI, 60%-65%]), and more often had commercial insurance (n = 259 [53%; 95% CI, 48%-57%] vs n = 486 [45%; 95% CI, 42%-48%]). Most outcomes were similar between the self-selection and randomized cohorts. The number of patients undergoing appendectomy by 30 days was 38 (15.3%; 95% CI, 10.7%-19.7%) among those selecting antibiotics and 155 (19.2%; 95% CI, 15.9%-22.5%) in those who were randomized to antibiotics (difference, 3.9%; 95% CI, -1.7% to 9.5%). Differences in the rate of appendectomy were primarily observed in the non-appendicolith subgroup. Conclusions and Relevance: This secondary analysis of the CODA RCT found substantially similar outcomes across the randomized and self-selection cohorts, suggesting that the randomized trial results are generalizable to the community at large. Trial Registration: ClinicalTrials.gov Identifier: NCT02800785.

Analysis of Outcomes Associated With Outpatient Management of Nonoperatively Treated Patients With Appendicitis.

Importance: In the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial, which found antibiotics to be noninferior, approximately half of participants randomized to receive antibiotics had outpatient management with hospital discharge within 24 hours. If outpatient management is safe, it could increase convenience and decrease health care use and costs. Objective: To assess the use and safety of outpatient management of acute appendicitis. Design, Setting, and Participants: This cohort study, which is a secondary analysis of the CODA trial, included 776 adults with imaging-confirmed appendicitis who received antibiotics at 25 US hospitals from May 1, 2016, to February 28, 2020. Exposures: Participants randomized to antibiotics (intravenous then oral) could be discharged from the emergency department based on clinician judgment and prespecified criteria (hemodynamically stable, afebrile, oral intake tolerated, pain controlled, and follow-up confirmed). Outpatient management and hospitalization were defined as discharge within or after 24 hours, respectively. Main Outcomes and Measures: Outcomes compared among patients receiving outpatient vs inpatient care included serious adverse events (SAEs), appendectomies, health care encounters, satisfaction, missed workdays at 7 days, and EuroQol 5-dimension (EQ-5D) score at 30 days. In addition, appendectomy incidence among outpatients and inpatients, unadjusted and adjusted for illness severity, was compared. Results: Among 776 antibiotic-randomized participants, 42 (5.4%) underwent appendectomy within 24 hours and 8 (1.0%) did not receive their first antibiotic dose within 24 hours, leaving 726 (93.6%) comprising the study population (median age, 36 years; range, 18-86 years; 462 [63.6%] male; 437 [60.2%] White). Of these participants, 335 (46.1%; site range, 0-89.2%) were discharged within 24 hours, and 391 (53.9%) were discharged after 24 hours. Over 7 days, SAEs occurred in 0.9 (95% CI, 0.2-2.6) per 100 outpatients and 1.3 (95% CI, 0.4-2.9) per 100 inpatients; in the appendicolith subgroup, SAEs occurred in 2.3 (95% CI, 0.3-8.2) per 100 outpatients vs 2.8 (95% CI, 0.6-7.9) per 100 inpatients. During this period, appendectomy occurred in 9.9% (95% CI, 6.9%-13.7%) of outpatients and 14.1% (95% CI, 10.8%-18.0%) of inpatients; adjusted analysis demonstrated a similar difference in incidence (-4.0 percentage points; 95% CI, -8.7 to 0.6). At 30 days, appendectomies occurred in 12.6% (95% CI, 9.1%-16.7%) of outpatients and 19.0% (95% CI, 15.1%-23.4%) of inpatients. Outpatients missed fewer workdays (2.6 days; 95% CI, 2.3-2.9 days) than did inpatients (3.8 days; 95% CI, 3.4-4.3 days) and had similar frequency of return health care visits and high satisfaction and EQ-5D scores. Conclusions and Relevance: These findings support that outpatient antibiotic management is safe for selected adults with acute appendicitis, with no greater risk of complications or appendectomy than hospital care, and should be included in shared decision-making discussions of patient preferences for outcomes associated with nonoperative and operative care. Trial Registration: ClinicalTrials.gov Identifier: NCT02800785.

Computed Tomography-Measured Psoas Muscle Density as a Predictive Factor for Hypophosphatemia Associated With Refeeding.

BACKGROUND: Initiation of parenteral nutrition (PN) after a period of starvation can be complicated by refeeding syndrome (RFS). RFS is associated with electrolyte abnormalities including hypomagnesemia, hyponatremia, and hypophosphatemia. Risk factors include recent weight loss, low body mass index, and electrolyte deficiencies; however, these associations are not strong. We hypothesized that a validated measure of nutrition risk, computed tomography (CT)-measured psoas muscle density, can be used to predict the development of hypophosphatemia associated with RFS. METHODS: A retrospective analysis of surgical patients initiated on PN with an abdominal CT scan within the past 3 months was conducted. CT-measured psoas muscle density was assessed as a predictive variable for the development of electrolyte abnormalities. Daily electrolyte and clinical outcome measures were recorded. RESULTS: One hundred nine patients were stratified based on Hounsfield unit average calculation (HUAC). The lowest 25th percentile of patients had HUAC <25. Low HUAC was associated with a significant percent decrease in phosphate levels from baseline to PN day 3 (P < .01) and significant difference in serum phosphate value on PN day 3 (P < .01). The low muscle density quartile also experienced longer days on the mechanical ventilator (P = .01) compared with patients with a higher psoas muscle density. CONCLUSION: Psoas muscle density predicted the development of hypophosphatemia in patients initiated on PN. This measurement may aid in identifying patients at highest risk of experiencing RFS. A mean psoas HU <25 may prompt additional precautions, including additional phosphate replacement and slower initiation of PN.

Proteomic Pathway Analysis of Monocyte-Derived Exosomes during Surgical Sepsis Identifies Immunoregulatory Functions.

Background: Patients with sepsis exhibit significant long-term immunosuppressive sequelae. Monocyte dysfunction is a hallmark of this damage. Circulating exosomes are an important mediator of the systemic signaling events that occur during the septic response; thus, we sought to characterize the contribution of circulating exosomes to the inflammatory process induced during sepsis Methods: Monocyte-derived exosomes were isolated from cultured monocytes from healthy adult donors via stimulation with lipopolysaccharide (LPS) or phosphate-buffered saline (PBS). The proteome was determined by capillary-liquid chromatography-nanospray tandem mass spectrometry (capillary-LC/NT/MS). Using pathway analysis, proteomic networks of exosomes derived from LPS-stimulated monocytes were compared with those isolated from patients with surgical sepsis. Naïve monocytes were then treated with these exosomes and stimulated with LPS to determine the effects on recipient-cell immune function. Results: Proteomic analysis demonstrated 18 differentially expressed proteins (17 down-regulated, one up-regulated) in sepsis-derived exosomes, with 15 differentially expressed proteins (14 down-regulated, one up-regulated) in the LPS-stimulated exosomes. Functional enrichment analysis demonstrated several down-regulated processes, including localization, biogenesis, and metabolic and cellular processes in addition to immune system processes. In LPS-stimulated macrophages, similar down-regulated processes were seen, including metabolic and cellular processes, as well as the response to stimulus. Cells treated with sepsis-derived exosomes or exosomes from LPS-stimulated monocytes demonstrated significant reductions in tumor necrosis factor (TNF)-α generation in response to LPS stimulation. Conclusions: Proteomic analysis of sepsis-derived exosomes and LPS-stimulated, macrophage-derived exosomes exhibited down-regulation of several important protein networks, including the immune response. In addition, human monocytes treated with exosomes from patients with sepsis or LPS-stimulated monocytes demonstrated significant reductions in TNF-α generation in response to LPS stimulation. These data suggest the contribution of circulating exosomes to systemic signaling and immunomodulation during sepsis.

Circulating extracellular vesicle content reveals de novo DNA methyltransferase expression as a molecular method to predict septic shock.

Extracellular vesicles (EVs) are mRNA-containing cell fragments shed into circulation during pathophysiological events. DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) regulate gene expression by modifying DNA methylation and altering transcription. Sepsis is a systemic insult resulting in vascular dysfunction, which can lead to shock and death. We analysed plasma from ICU patients for circulating EV numbers, defined as particles isolated from 1 mL plasma at 21,000xg, and DNMTs mRNA content as prognostic markers of septic shock. Compared to plasma from critically ill patients with or without sepsis, plasma from septic shock patients contained more EVs per mL, expressed as total DNMTs mRNAs over 5 days, and more individual DNMT mRNAs at each day. A comparison of EV-DNMT1 (maintenance methylation) with EV-DNMT3A+DNMT3B (de novo methylation) expression correlated highly with severity, and EVs from septic shock patients carried more total DNMT mRNAs and more DNMT3A+DNMT3B mRNAs than control or sepsis EVs. Total plasma EVs also correlated with sepsis severity. EV-DNMT mRNAs load, when coupled with total plasma EV number, may be a novel method to diagnose septic shock upon ICU admittance and offer opportunities to more precisely intervene with standard therapy or other targeted interventions to regulate EV release and/or specific DNMT activity.