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As the mortality of severe acute pancreatitis (SAP) is significantly higher than those with mild or moderate severity, it is of clinical significance to identify patients most likely to develop SAP at the time of emergency department (ED) presentation. The aim of this study was to compare the performance of the Bedside Index for Severity in Acute Pancreatitis (BISAP) and the Emergency Department SpO 2 , Age and SIRS (ED-SAS) scoring systems as early risk assessment tools for identifying patients at high-risk of developing SAP. We retrospectively reviewed adult patients with AP presented to ED between January 2019–September 2022. We calculated the scores of each patient with the parameters of the initial data. The primary outcome was SAP. The secondary outcomes were 30-day mortality, intensive care admission, and identifying low-risk patients without complications. Of 415 patients, 34 (8.2%) developed SAP and 15 (3.6%) died. With regard to predicting SAP, BISAP and ED-SAS scores had similar discriminative ability with area under the curves (AUCs) of 0.84 (95% confidence interval [CI]:0.80–0.88) and 0.83 (95% CI:0.79–0.86), respectively (p = 0.642). At a cut-off score of ≥2 for SAP, sensitivity/specificity values were 73.5%/82.4% for BISAP, 76.5%/83.2% for ED-SAS. BISAP and ED-SAS scores of ≥3, yielded sensitivity/specificity values of 50%/95.8% and 35.3%/95.5%, respectively. BISAP and ED-SAS were also similar in predicting mortality (AUCs of 0.92 vs. 0.90, respectively) and intensive care unit admission (AUCs 0.91 vs. 0.91). The BISAP and ED-SAS scores performed similarly in predicting SAP, mortality, and intensive care unit admission. As an easily calculated tool early in the ED, ED-SAS may be helpful in disposition decisions for emergency physicians. [ABSTRACT FROM AUTHOR]

Sepsis is a systemic inflammatory response syndrome caused by trauma or infection, which can lead to multiple organ dysfunction. In severe cases, sepsis can also progress to septic shock and even death. Effective treatments for sepsis are still under development. This study aimed to determine if targeting the PI3K/Akt signaling with CAL-101, a PI3K p110δ inhibitor, could alleviate lipopolysaccharide (LPS)-induced sepsis and contribute to immune tolerance. Our findings indicated that CAL-101 treatment improved survival rates and alleviated the progression of LPS-induced sepsis. Compared to antibiotics, CAL-101 not only restored the Th17/regulatory T cells (Treg) balance but also enhanced Treg cell function. Additionally, CAL-101 promoted type 2 macrophage (M2) polarization, inhibited TNF-α secretion, and increased IL-10 secretion. Moreover, CAL-101 treatment reduced pyroptosis in peritoneal macrophages by inhibiting caspase-1/gasdermin D (GSDMD) activation. This study provides a mechanistic basis for future clinical exploration of targeted therapeutics and immunomodulatory strategies in the treatment of sepsis. • CAL-101 improved the survival rate and alleviated the progression in LPS-induced sepsis compared to antibiotic therapy. • CAL-101 not only rebalanced proportion of Th17/Treg, but also restored the function of Treg cells in LPS-induced sepsis. • CAL-101 promoted the M2 macrophages polarization and reduced pyroptosis by inhibiting the activation of Caspase 1/GSDMD. [ABSTRACT FROM AUTHOR]

Burn wound conversion is the observed process where superficial partial thickness burns convert into deep partial or full thickness burn injuries. This conversion process often involves surgical excision to achieve timely wound healing. Unfortunately, the pathophysiology of this phenomenon is multifactorial and poorly understood. Thus, a therapeutic intervention that may prevent secondary progression and cell death in burn-injured tissue is desirable. Recent work by our group and others has established that tranexamic acid (TXA) has significant anti-inflammatory properties in addition to its well-known anti-fibrinolytic effects. This study investigates TXA as a novel therapeutic treatment to mitigate burn wound conversion and reduce systemic inflammation. Sprague-Dawley rats were subjected to a hot comb burn contact injury. A subset of animals underwent a similar comb burn with an adjacent 30%TBSA contact injury. The interspaces represent the ischemic zones simulating the zone of stasis. The treatment group received injections of TXA (100 mg/kg) immediately after injury and once daily until euthanasia. Animals were harvested for analyses at 6 h and 7 days after injury. Full-thickness biopsies from the ischemic zones and lung tissue were assessed with established histological techniques. Plasma was collected for measurement of damage associated molecular patterns (DAMPs), and liver samples were used to study inflammatory cytokines expression. Treatment with TXA was associated with reduced burn wound conversion and decreased burn-induced systemic inflammatory response syndrome (SIRS). Lung inflammation and capillary leak were also significantly reduced in TXA treated animals. Future research will elucidate the underlying anti-inflammatory properties of TXA responsible for these findings. • Burn wound conversion is the observed process where partial thickness burns convert into full thickness burn injuries. • Burn wound conversion has been attributed to a combination of prolonged inflammation, ischemia, ROS, and autophagy. • Animals treated with systemic tranexamic acid had reduced burn wound conversion and decreased burn-induced SIRS. • Future research will elucidate the underlying anti-inflammatory properties of TXA responsible for these findings. [ABSTRACT FROM AUTHOR]

Data on systemic inflammatory response syndrome (SIRS) after transcatheter aortic valve implantation (TAVI) are scarce and limited to small cohorts. We aimed to investigate its incidence and mid-term impact in a large cohort of TAVI patients. From January 2018 to December 2020, 717 patients with severe aortic valve stenosis undergoing TAVI were included. SIRS was defined as fulfilling at least two of the following criteria within 48 h from the procedure: leucocyte count >12.0 or <4.0 × 109/l, respiratory rate > 20 breaths per minute or PaCO 2 ≤ 4.3 kPa/32 mmHg, heart rate > 90 beats per minute and temperature > 38.0 °C or <36.0 °C. Clinical endpoints were 1-year rehospitalization for chronic heart failure (CHF) and 2-years all-cause mortality. Event rates during follow-up were calculated as Kaplan-Meier estimates. SIRS developed in 56.3 % (404/717) of patients after TAVI. SIRS occurred more frequently in patients with post-dilatation (SIRS 34.7 % (140/404) vs. no SIRS 23.3 % (73/313); p < 0.001) and major vascular complications (SIRS 16.1 % (65/404) vs. no SIRS 8.6 % (27/313); p = 0.004). Further, ICU days were more in patients who developed SIRS (SIRS 1.56 ± 1.50 days vs. no SIRS 1.22 ± 1.02 days; p = 0.001). At 2-years, all-cause mortality in the entire population was 23.9 %. However, there was no difference in CHF at 1-year (5.9 % vs. 4.1 %; log-rank = 0.347) nor in all-cause mortality at 2-years (22.0 % vs. 26.2 %; log-rank = 0.690) between the groups. SIRS is a common finding after TAVI, which may prolong hospital stay but is without effect on mortality during 2-years follow-up. • SIRS is a common finding after TAVI, occurring in more than half of patients. • SIRS occurs more often in patients with post-dilatation and major vascular complications. • Inflammatory markers after TAVI increase, irrespective of SIRS development. • The occurrence of SIRS after TAVI is without effect on 2-years mortality. [ABSTRACT FROM AUTHOR]

Sepsis is a systemic inflammatory response syndrome caused by the invasion of pathogenic microorganisms. Despite major advances in diagnosis and technology, morbidity and mortality remain high. The level of neutrophil extracellular traps (NETs) is closely associated with the progression and prognosis of sepsis, suggesting the regulation of NET formation as a new strategy in sepsis treatment. Owing to its pleiotropic effects, atorvastatin, a clinical lipid-lowering drug, affects various aspects of sepsis-related inflammation and immune responses. To align closely with clinical practice, we combined it with imipenem for the treatment of sepsis. In this study, we used a cecum ligation and puncture-induced lung injury mouse model and employed techniques including western blot, immunofluorescence, and enzyme-linked immunosorbent assay to measure the levels of NETs and other sepsis-related lung injury indicators. Our findings indicate that atorvastatin effectively inhibited the formation of NETs. When combined with imipenem, it significantly alleviated lung injury, reduced systemic inflammation, and improved the 7-day survival rate of septic mice. Additionally, we explored the inhibitory mechanism of atorvastatin on NET formation in vitro , revealing its potential action through the ERK/NOX2 pathway. Therefore, atorvastatin is a potential immunomodulatory agent that may offer new treatment strategies for patients with sepsis in clinical settings. [Display omitted] • Atorvastatin regulates the formation of neutrophil extracellular traps (NETs). • Atorvastatin inhibits NETs through the ERK/NOX2 signaling pathway. • Atorvastatin combined with imipenem alleviates sepsis-induced lung injury by inhibiting NETs. [ABSTRACT FROM AUTHOR]

Bacteremia is a major cause of morbidity. Blood cultures are the gold standard for diagnosing bacteremia. To compare previously published clinical decision rules for predicting a true positive blood culture (bacteremia) in the emergency department. Retrospective analysis of medical records of patients who had a blood culture performed in a tertiary hospital emergency department in 2020 (12 months). Positive blood cultures were compared with randomly selected negative blood cultures (1:4 ratio). Blood cultures were analyzed per patient presentation. Clinical data from patient presentations were extracted and appraised against the modified-Shapiro (mShapiro) rule and systemic inflammatory response syndrome (SIRS) criteria to calculate diagnostic accuracy to detect bacteremia. During the study period, 3870 blood cultures were taken from 2921 patients: 476 (12.3%) cultures were positive for bacterial growth, from 421 individual patient presentations (10 excluded as incomplete data). Of included patients, 338 were true positives and 73 contaminates, these were compared with 1446 patients with negative blood culture presentations. Evaluating mShapiro's rule and SIRS criteria to detect bacteremia vs. no bacteremia (negative + contaminated cultures) had a sensitivity of 94.4% (95% confidence interval [CI] 91.4–96.4%) and 84.9% (95% CI 80.7–88.3%), respectively, and a specificity of 37.9% (95% CI 35.5–40.1%) and 33.8% (95% CI 31.5–36.3%), respectively. Both had a high negative predictive value for bacteremia of 96.8% (95% CI 95.1–98.0) and 91.0% (95% CI 88.3–93.1) for mShapiro's rule and SIRS criteria, respectively. In this cohort, mShapiro's rule performed better than the SIRS criteria at predicting bacteremia. [ABSTRACT FROM AUTHOR]

• Infection is very common in alcoholic hepatitis. • Both infection and alcoholic hepatitis are causes of SIRS. • IL-6 may be able to differentiate when infection is present. Severe alcoholic hepatitis is the most lethal complication in alcohol dependent patients. The concurrence of infections in these patients is very frequent. Both produce a systemic inflammatory response syndrome (SIRS), secondary to intense release of inflammatory cytokines, which can complicate the diagnosis. In our study, Interleukin (IL)-6 and IL-10 levels are higher in patients with SIRS (p <0.001 and p = 0.033, respectively). IL-4, IL-6, Interferon‐gamma (IFNγ), Tumor necrosis factor alpha (TNFα) and IL-17 levels correlate with liver function, as estimated by MELD-Na (p = 0.018, p = 0.008, p = 0.009, p = 0.016 and p = 0.006, respectively). Malondialdehyde (MDA), a product of lipid peroxidation and marker of cell damage, also correlates with liver function (p = 0.002), but not with SIRS or infections. Only elevated IL-6 correlates independently with the presence of infections (RR=1.023 IC 95% 1.000–1.047), so it may be useful for the correct diagnosis in these patients. Values greater than 30 pg/mL have a sensitivity: 86.7% and specificity: 94.7% for the diagnosis of infections. [ABSTRACT FROM AUTHOR]

The development of systemic inflammatory response syndrome (SIRS) criteria leads to increased mortality. Little is known about development of SIRS in patients who have prosthetic joint infection (PJI). We aimed to determine the incidence, risk factors, clinical outcomes, and causative organisms in patients who develop SIRS with PJI. We retrospectively identified 655 patients (321 men, 334 women; 382 total hip, 273 total knee) who have hip or knee PJI at 1 institution between July 1, 2015 and December 31, 2020. We formed 2 groups: patients who have SIRS alert (PJI + SIRS) and patients who do not have SIRS alert (PJI). We analyzed clinical outcomes, comorbidities, and operating room culture results. Of 655 patients, 63 developed SIRS with PJI (9.6%). Intensive care unit (ICU) admission rates (27.0 versus. 6.9%, P <. 001) and length of stay (7.7 versus. 5.6 days, P =. 003) were greater in PJI + SIRS. At 2 years, reoperation (36.5 versus. 22.3%, P =. 01) and mortality rates (17.5 versus. 8.8%, P =. 03) were greater in PJI + SIRS. Risk factors included deficiency anemia (P =.001), blood loss anemia (P =. 013), uncomplicated diabetes (P =. 006), diabetes with complication (P =. 001), electrolyte disorder (P <. 00001), neurological disorder (P =. 0001), paralysis (P =. 026), renal failure (P =. 005), and peptic ulcer disease (P =. 004). Staphylococcus aureus more commonly speciated on tissue cultures in PJI + SIRS (P =. 002). The incidence of SIRS is 10% among patients who have PJI. Development of PJI + SIRS is associated with increased lengths of stay, ICU admissions, and 2-year reoperation and mortality rates. Identifying certain comorbidities can stratify patients' risk of developing PJI + SIRS. [ABSTRACT FROM AUTHOR]

Derangements in the innate and adaptive immune responses observed in systemic inflammatory syndromes contributes to unique elevated atherosclerotic risk and incident cardiovascular disease. Novel multimodality imaging techniques may improve diagnostic precision for the screening and monitoring of disease activity. The integrated application of these technologies lead to earlier diagnosis and noninvasive monitoring of cardiac involvement in systemic inflammatory diseases that will aid in preclinical studies, enhance patient selection, and provide surrogate endpoints in clinical trials, thereby improving clinical outcomes. We review the common cardiovascular manifestations of immune-mediated systemic inflammatory diseases and address the clinical and investigational role of advanced multimodality cardiac imaging. [Display omitted] • Immune-mediated systemic inflammatory diseases are commonly associated with adverse CV manifestations. • Integrated multimodality imaging can improve screening, detection, and serial monitoring of cardiac function in patients with SIDs. • An evaluation and management approach that incorporates multimodality imaging is integral to improving clinical outcomes. [ABSTRACT FROM AUTHOR]

Hypertriglyceridemia (HTG) is a major cause of acute pancreatitis (AP). We aimed to determine whether HTG is an independent risk factor for AP complications and construct a prediction model for non-mild AP. We conducted a multi-center cohort study including 872 patients with AP and divided them into HTG-AP and non-HTG-AP groups. Multivariate logistic regression was performed, and a prediction model for non-mild HTG-AP was developed. HTG-AP patients had a higher risk of systemic complications, including systemic inflammatory response syndrome [odds ratio (OR): 1.718; 95% confidence interval (CI): 1.286–2.295], shock (OR: 2.103; 95%CI: 1.236–3.578), acute respiratory distress syndrome (OR: 2.231; 95%CI: 1.555–3.200), acute renal failure (OR: 1.593; 95%CI: 1.036–2.450), and local complications such as acute peripancreatic fluid collection (OR: 2.072; 95%CI: 1.550–2.771), acute necrotic collection (OR: 1.996; 95%CI: 1.394–2.856), and walled-off necrosis (OR: 2.157; 95%CI: 1.202–3.870). The area under curve of our prediction model was 0.898 (95%CI: 0.857–0.940) and 0.875 (95%CI: 0.804–0.946) in the derivation and validation datasets respectively. HTG is an independent risk factor for AP complications. We constructed a simple and accurate prediction model for progression of non-mild AP. [ABSTRACT FROM AUTHOR]

• We explored absolute and relative PHE measurements using brain CT scans of patients with primary ICH. • NLR and SIRS do not predict absolute or relative PHE measurements in ICH. • NLR, but not SIRS, is associated with unfavorable functional outcomes at 90 days following ICH onset. Perihematomal edema (PHE) is a marker of secondary brain injury in patients with intracerebral hemorrhage (ICH) and is associated with increased inflammatory markers and neurological disability. This study aims to assess the effect of the neutrophile-to-lymphocyte ratio (NLR) and systemic inflammatory response syndrome (SIRS) on PHE measurements and functional status in patients with ICH. We included 215 patients with primary ICH and the primary outcomes were absolute and relative PHE, and edema extension distance (EED). A favorable functional outcome was defined as a modified Rankin Scale (mRS) score 0–2 measured 3 months after ICH. Median age was 73.0 years (interquartile range 66–80) and 54.4% patients were males. Fifty-nine patients were functionally independent at 90 days (mRS 0 to 2). NLR and SIRS were not predictors of absolute, relative PHE, and EED when adjusted for multiple confounders. However, admission NLR was independently associated with an unfavorable functional outcome at 90 days (aOR = 0.38; 95% CI 0.17–0.87; p = 0.021). NLR and SIRS are not independent predictors of absolute and relative PHE measurements following ICH. Nevertheless, NLR predicts long-term disability in ICH patients. Further research is needed to understand the mechanisms by which inflammation causes neurological injury in ICH. [ABSTRACT FROM AUTHOR]

Bacterial infections (BIs) are well-recognized precipitants of hepatic encephalopathy (HE). Nevertheless, there is a paucity of data in patients with HE associated with BI. Our aim was to describe clinical characteristics, recurrence, and prognosis of HE in patients with BI. A prospective study with inclusion of hospitalized cirrhotic patients with BI, followed until discharge, death, or liver transplantation. 172 patients (age 57 ± 13, model of end-stage liver disease [MELD]-sodium 22 ± 8) were included. Infections were more commonly due to spontaneous bacterial peritonitis and cellulitis (22% and 23%), non-nosocomial (70%), and associated with systemic inflammatory response syndrome and septic shock in 40% and 9%, respectively. HE was diagnosed in 66 patients (grade ≥2 in 58%). In multivariate analysis, MELD-sodium, albumin, and prior HE were associated with HE at diagnosis of BI. Recurrence of HE was diagnosed in 30 patients (median 13 [interquartile range 5–22] days), more commonly manifested as overt HE (90% vs. 60% at first episode, P = 0.012) and more frequently in patients with hyponatremia (54% vs. 27% for patients without, P < 0.001). In-hospital mortality was 34% and was more common for patients with HE (51% vs. 22%, P < 0.001), irrespective of grade, and for those with recurrence (63% vs. 42%, P < 0.001). In multivariate analysis, HE at diagnosis of infection and MELD-sodium were predictors of mortality. HE is frequent in cirrhotic patients with BI and is associated with severity of liver disease, but not with infection. These patients are at increased risk of short-term HE recurrence, especially those with hyponatremia. The presence and recurrence of HE, independent of severity, are associated with in-hospital mortality. [ABSTRACT FROM AUTHOR]

The Epic Sepsis Prediction Model (SPM) is a proprietary sepsis prediction algorithm that calculates a score correlating with the likelihood of an International Classification of Diseases, Ninth Revision code for sepsis. This study aimed to assess the clinical impact of an electronic sepsis alert and navigator using the Epic SPM on time to initial antimicrobial delivery. We performed a retrospective review of a nonrandomized intervention of an electronic sepsis alert system and navigator using the Epic SPM. Data from the SPM site (site A) was compared with contemporaneous data from hospitals within the same health care system (sites B–D) and historical data from site A. Nonintervention sites used a systemic inflammatory response syndrome (SIRS)–based alert without a sepsis navigator. A total of 5368 admissions met inclusion criteria. Time to initial antimicrobial delivery from emergency department arrival was 3.33 h (interquartile range [IQR] 2.10–5.37 h) at site A, 3.22 h (IQR 1.97–5.60; p = 0.437, reference site A) at sites B–D, and 6.20 h (IQR 3.49–11.61 h; p < 0.001, reference site A) at site A historical. After adjustment using matching weights, there was no difference in time from threshold SPM score to initial antimicrobial between contemporaneous sites. Adjusted time to initial antimicrobial improved by 2.87 h (p < 0.001) at site A compared with site A historical. Implementation of an electronic sepsis alert system plus navigator using the Epic SPM showed no difference in time to initial antimicrobial delivery between the contemporaneous SPM alert plus sepsis navigator site and the SIRS-based electronic alert sites within the same health care system. [ABSTRACT FROM AUTHOR]

Approximately half of patients who undergo cardiac surgery develop systemic inflammatory response syndrome. Extracorporeal circulation and intestinal injury may play a role in this inflammatory response, although their relative contributions remain elusive. Moreover, it is largely unknown to what extent these factors contribute to cardiac surgery-induced postoperative organ dysfunction. In this secondary analysis, we measured circulating levels of the intestinal damage marker intestinal fatty acid binding protein (I-FABP) and of the inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-10, IL-1RA, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and MIP-1β in 180 patients undergoing on-pump cardiac surgery. The average Z-score of levels of the different cytokines was used as an integral measure of the cytokine response. Relationships between duration of extracorporeal circulation, extent of intestinal injury, inflammation, and postoperative organ dysfunction were explored. Plasma I-FABP levels increased during surgery, with peak levels observed at the end of cardiopulmonary bypass (CPB). Except for TNF-α, the levels of all cytokines increased during surgery, with peak levels observed either 2 (MCP-1, MIP-1α, and MIP-1β), 4 (IL-6, IL-8, and IL-1RA) or 6 (IL-10) hours after the end of CPB. While the duration of CPB significantly correlated with cytokine Z-score (r=0.544, p<0.05), no relationship with I-FABP levels was found. Furthermore, no significant correlations between I-FABP and cytokine levels were observed. The duration of CPB correlated with a deterioration in postoperative kidney function (estimated glomerular filtration rate [eGFR]) and troponin levels. Cytokine Z-score was associated with postoperative troponin levels, fluid administration, inotropic score, pulmonary alveolar–arterial gradient on the first postoperative morning, and deterioration of kidney function (eGFR). I-FABP levels did not correlate with any of the cardiovascular, pulmonary, or renal parameters. In patients undergoing low-risk cardiac surgery, the duration of CPB represents an important determinant of the systemic cytokine response, whereas both the CPB duration and the systemic inflammatory response contribute to subsequent organ dysfunction. Intestinal damage does not appear to play a relevant role in the postoperative inflammatory response and development of postoperative organ dysfunction in these patients. [ABSTRACT FROM AUTHOR]

• Inflammatory markers could be helpful in defining the severity of status epilepticus. • Neutrophil-to-Lymphocyte ratio predicts ICU admission in patients with SE. • Biomarkers should be implemented in the management of SE. Status epilepticus (SE) is a time-dependent neurological emergency. The current study evaluated the prognostic value of admission neutrophil-to-lymphocyte ratio (NLR) in patients with status epilepticus. In this retrospective observational cohort study we included all consecutive patients discharged from our neurology unit with the clinical or EEG diagnosis of SE from 2012 to 2022. Stepwise multivariate analysis was conducted to test the association of NLR with length of hospitalization, need for Intensive Care Unit (ICU) admission and 30 days mortality. Receiver operating characteristic (ROC) analysis was performed to identify the best cutoff for NLR to identify patients who will need ICU admission. A total of 116 patients were enrolled in our study. NLR was correlated with length of hospitalization (p = 0.020) and need for ICU admission (p = 0.046). In addition, the risk of ICU admission increased in patients with intracranial hemorrhage and length of hospitalization was correlated with C-reactive protein-to-albumin ratio (CRP/ALB). ROC analysis identified a NLR of 3.6 as best cutoff value to discriminate need of ICU admission (area under the curve [AUC]=0.678; p = 0.011; Youden's index=0.358; sensitivity, 90.5%, specificity, 45.3%). In patients with SE admission NLR could be a predictor of length of hospitalization and need for ICU admission. [ABSTRACT FROM AUTHOR]

Intestinal ischemia reperfusion (I/R) is a common clinical pathological process. We previously reported that pharmacological inhibition of protein kinase C (PKC) βII with a specific inhibitor attenuated gut I/R injury. However, the endogenous regulatory mechanism of PKCβII inactivation is still unclear. Here, we explored the critical role of caveolin-1 (Cav1) in protecting against intestinal I/R injury by regulating PKCβII inactivation. PKCβII translocated to caveolae and bound with Cav1 after intestinal I/R. Cav1 was highly expressed in the intestine of mice with I/R and IEC-6 cells stimulated with hypoxia/reoxygenation (H/R). Cav1-knockout (KO) mice suffered from worse intestinal injury after I/R than wild-type (WT) mice and showed extremely low survival due to exacerbated systemic inflammatory response syndrome (SIRS) and remote organ (lung and liver) injury. Cav1 deficiency resulted in excessive PKCβII activation and increased oxidative stress and apoptosis after intestinal I/R. Full-length Cav1 scaffolding domain peptide (CSP) suppressed excessive PKCβII activation and protected the gut against oxidative stress and apoptosis due to I/R injury. In summary, Cav1 could regulate PKCβII endogenous inactivation to alleviate intestinal I/R injury. This finding may represent a novel therapeutic strategy for the prevention and treatment of intestinal I/R injury. Schema of critical role of Cav1 in intestinal I/R by inhibiting PKCβII/p66shc signaling pathway. Intestinal ischemia reperfusion induces up-regulation of Cav1. Increased level of Cav1 suppresses PKCβII activation via its scaffolding domain, subsequently inhibiting downstream p66shc associated oxidative stress and apoptosis in intestinal I/R. [Display omitted] • Cav1 protects against mice intestinal ischemia and reperfusion (I/R) injury. • Cav1-KO mice suffer from extremely low survival during early reperfusion after intestinal ischemia. • Cav1 restrains excessive PKCβII phosphorylation at ser-660 via its scaffolding domain. • Cav1 inhibts PKCβII's downstream p66shc associated oxidative stress and apoptosis in intestinal I/R injury. [ABSTRACT FROM AUTHOR]

Clinically relevant postoperative pancreatic fistula (CR-POPF) is the most feared complication following pancreaticoduodenectomy (PD). There is increasing evidence that very early postoperative factors can be helpful to identify high-risk patients. The aim of this study is to analyze whether postoperative day one (POD1) systemic inflammatory response can be used as an early biomarker of CR-POPF development. All patients undergoing PD from 2014 to 2020 were considered. Variables were extracted from a prospectively held database. Clinical and perioperative variables, including POD1 systemic inflammatory response syndrome (SIRS) and C-reactive protein level were collected. To elucidate the independent role of early CR-POPF biomarkers, multivariate hierarchical logistic regression analyses were planned. Out of 243, 213 patients were included in this analysis. CR-POPF occurred in 49 (23.0%) patients and 90-day mortality was 1.4%. POD1 SIRS was reported in 65 (30.5%) patients. Following hierarchical logistic regression analyses, CR-POPF was independently associated with body mass index (OR = 2.787, p = 0.003), soft pancreatic texture (OR = 4.258, p = 0.002) and POD1 SIRS (OR = 50.067, p = 0.001). POD1 SIRS is powerfully associated with CR-POPF and therefore it could be used as a tool to optimize postoperative care of PD patients. Further prospective studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Cervicofacial infections carry significant morbidity. Patients present on a broad spectrum of severity, with some requiring outpatient management and others admission to higher level care. Recognition of risk factors is helpful in decision making regarding the need for admission to higher level care. Prospective data were captured on 1002 patients in 25 centres across 17 regions of the United Kingdom (UK) by the Maxillofacial Trainee Research Collaborative (MTReC). Patients admitted to critical care were compared with those who received ward-level care. Multivariate and receiver operating characteristic curve analyses were used to identify predictors for critical care admission. Our results show that the best predictor for critical care admission is the presence of three or more features of airway compromise (AUC 0.779), followed by C-reactive protein (CRP) >100 mg/L (OR 2.70; 95% CI 1.59 to 4.58; p < 0.005), submandibular space involvement (OR 3.82; 95% CI 1.870 to 7.81; p = 0.003), white cell count (WCC) >12 × 109/ dl (1.05; 95% CI 1.01 to 1.10; p = 0.03), and positive systemic inflammatory response syndrome criteria (OR 2.78; CI 1.35 to 5.80; p = 0.006). Admission to critical care is multifactorial, however, the presence of three or more features of airway compromise is the best predictor. Awareness of this alongside other key clinical findings in cervicofacial infections may allow for the early recognition of patients who may require escalation to critical care. [ABSTRACT FROM AUTHOR]

This prospective study compared scoring systems in predicting adverse outcomes in HIV associated acute pancreatitis (HIV+ve AP) Systemic inflammatory response syndrome (SIRS), Glasgow criteria, C-reactive protein (CRP), bedside index of severity in acute pancreatitis (BISAP) and APACHE II scores using standard cut-off values were used to predict the endpoint of moderate and severe disease in HIV−ve and HIV+ve patients and in CD4 counts above and below 200 cells/mm3. Ninety (38%) of 238 patients with AP were HIV+ve. Fifteen had organ failure, 33 local complications and 12 patients died. Advanced age was not associated with severe disease. The APACHE II was the best predictor of severe disease in HIV+ve (AUC 0.88) and HIV−ve patients (AUC 0.81) and CRP was the poorest predictor (AUC 0.59) in HIV+ve patients. In HIV+ve patients with CD4 counts greater and less than 200 cells/mm3 the Glasgow and APACHE II scores were the best prognosticators (AUC > 0.8) and BISAP in patients with CD4 > 200 cells/mm3 (AUC 0.90). The APACHE II score was most effective irrespective of HIV status whereas the BISAP scores was better in CD4 > 200 cells/mm3. [ABSTRACT FROM AUTHOR]

To compare dexmedetomidine and fentanyl constant rate infusions in anesthetic protocols for septic dogs with pyometra, using microcirculatory, hemodynamic and metabolic variables. Randomized clinical study. A total of 33 dogs with pyometra with two or more systemic inflammatory response syndrome variables undergoing ovariohysterectomy. Dogs were randomized into two groups: group DG, dexmedetomidine (3 μg kg–1 hour–1; 17 dogs) and group FG, fentanyl (5 μg kg–1 hour–1; 16 dogs) infused during isoflurane anesthesia and mechanical ventilation. Microcirculation flow index (MFI), total vessel density and De Backer score were assessed using orthogonal polarization spectral imaging at the sublingual site. Heart rate, invasive blood pressure, temperature, arterial blood gas analysis and lactate concentration were obtained at various time points. Variables were recorded at baseline (BL), immediately before (T0), 30 (T30) and 60 (T60) minutes after infusion, and 60 minutes after surgery. Data were analyzed using the Shapiro-Wilk test. To compare variables between groups, the unpaired Student t test was used. Comparison between evaluation time points was performed with two-way anova for repeated measures. Where statistical significance was detected, the Bonferroni post hoc test was used. MFI was significantly higher in group FG at T30. Mean arterial pressure at T30 was higher in group DG (89 ± 15 mmHg) than in group FG (72 ± 13 mmHg). Lactate concentrations were not significantly different between groups at each time point. Both groups had similar clinical outcomes (mortality, extubation time and occurrence of hypotension and bradyarrhythmias). Dexmedetomidine (3 μg kg–1 hour–1) without a loading dose can be included in the maintenance of anesthesia in dogs with pyometra and sepsis without compromising microcirculation and hemodynamic values when compared with fentanyl (5 μg kg–1 hour–1). [ABSTRACT FROM AUTHOR]

In previous studies, propofol has shown immunomodulatory abilities on various in vitro models. As this anesthetic molecule is extensively used in intensive care units, its anti-inflammatory properties present a great interest for the treatment of inflammatory disorders like the systemic inflammatory response syndrome. In addition to its inhibition abilities on important neutrophils mechanisms (chemotaxis, reactive oxygen species (ROS) production, Neutrophil Extracellular Traps (NETs) formation, ...), our group has shown that propofol is also a reversible inhibitor of the oxidant myeloperoxidase (MPO) activity. Propofol being subject to rapid metabolism, its derivatives could contribute to its anti-inflammatory action. First, propofol-β-glucuronide (PPFG), 2,6-diisopropyl-1,4- p -benzoquinone (PPFQ) and 3,5,3′,5′-tetraisopropyl-(4,4′)-diphenoquinone (PPFDQ) were compared on their superoxide (O 2 .- ) scavenging properties and more importantly on their inhibitory action on the O 2 .- release by activated neutrophils using EPR spectroscopy and chemiluminescence assays. PPFQ and PPFDQ are potent superoxide scavengers and also inhibit the release of ROS by neutrophils. An Enzyme-Linked Immunosorbent Assay (ELISA) has also highlighted the ability of both molecules to significantly decrease the MPO degranulation process of neutrophils. Fluorescence enzymatic assays helped to investigate the action of the propofol derivatives on the peroxidase and chlorination activities of MPO. In addition, using SIEFED (Specific Immunological Extraction Followed by Enzyme Detection) assays and docking, we demonstrated the concentration-dependent inhibitory action of PPFQ and its ability to bind to the enzyme active site while PPFG presented a much weaker inhibitory action. Overall, the oxidation derivatives and metabolites PPFQ and PPFDQ can, at physiological concentrations, perpetuate the immunomodulatory action of propofol by acting on the oxidant response of PMN and MPO. [Display omitted] • Investigation of the inhibitory action of three propofol derivatives on the myeloperoxidase (MPO) activity. • Study of the inhibitory action of the propofol derivatives on the neutrophils respiratory burst and degranulation processes. • The quinone propofol metabolite (PPFQ) and the diquinone derivative (PPFDQ) act as potent superoxide scavengers. • PPFQ and PPFDQ significantly decrease the MPO release by activated neutrophils. • PPFQ inhibits in a concentration-dependent way the peroxidase and chlorination activities of MPO. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is thought to be associated with poor outcomes in cervicofacial infections (CFI), yet little is known about the prevalence of DM in these cases. Stress hyperglycaemia (SHG), a normal physiological response to inflammation, is distinct from DM, though they overlap and may be conflated. We aimed to establish the prevalence of DM and SHG in CFI, and to determine the effect of each on severity of disease and outcome measures. The Maxillofacial Surgery Trainee Research Collaborative (MTReC) carried out an audit of all patients with CFI admitted to 25 hospitals between May and October 2017. To the best of our knowledge this created the largest prospective database on CFI, with information collected on presentation, source of infection, biological data, and outcomes. We recorded 1002 admissions, of which 78 (7.8%) had DM. Random blood glucose was measured on admission in 401 patients (40%), of which 45 (11%) displayed SHG. Patients diagnosed with DM were more likely to have infections arising from a salivary source (13% vs 4%, p < 0.00), more returns to theatre (9% vs 2%, p < 0.00), and a longer hospital stay (median (range) 2 (0-34) vs 1 (0-139) day, p = 0.01) than non-DM patients. In contrast, patients with SHG had more severe disease (multiple fascial spaces involved in 59% vs 19%, p = 0.01, and systemic inflammatory response syndrome present in 66% vs 45% p = 0.03), but did not have significantly more returns to theatre (2% vs 3%, p = 0.91) or longer stays in hospital (median (range) 1 (0-63) vs 1 (0-6), p = 0.55) than normoglycaemic patients. The prevalence of DM in our cohort was only marginally higher than in the general population, despite previous retrospective case reviews suggesting a significantly higher prevalence. SHG was not associated with poor outcomes in our cohort, but is likely to be associated with a small increased risk of subsequent diagnosis of DM, which can be quantified using a calculator tool. On discharge, it is important to give appropriate advice about diet, lifestyle, exercise, and weight loss to all patients with CFI. [ABSTRACT FROM AUTHOR]

Objective: This study compared the modulatory effect of two intravenous magnesium sulfate (MgSO4) regimens on the systemic inflammatory response in pregnant women diagnosed with imminent eclampsia.Study Design: In a single-blind cross-sectional study, 33 women were allocated according to the Zuspan (n = 16) and Sibai (n = 17) MgSO4 regimens, and treated for 24 h. Blood samples were collected pre-administration of the loading dose, at 24 h of the maintenance dose of MgSO4, and at 48 h, when patients were without treatment. Plasma was used to determine interleukin (IL)-1 beta (IL-1β), IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), heat shock protein (Hsp70), and heme oxygenase-1 (HO-1) by ELISA.Results: The treatment with the Zuspan's regimen didn't change plasma concentrations of TNF-α, IL-10, and Hsp70 in the three-time points studied. However, it decreased IL-1β at 24 h and 48 h and IL-6 at 48 h, and increased HO-1 concentration at 48 h. On the other hand, compared to the pre-treatment period, Sibai's regimen induced a significant decrease in TNF-α, IL-1β, IL-6, and Hsp70, while increased HO-1 levels both at 24 h and 48 h and, IL-10 concentration at 48 h.Conclusions: Sibai's regimen determined an early and efficient immunoregulatory effect on systemic inflammatory response in preeclampsia, suggesting that the maintenance dose of two grams of MgSO4 was better than one gram in the treatment of imminent eclampsia. [ABSTRACT FROM AUTHOR]

Patients with endocarditis requiring urgent valvular surgery with cardiopulmonary bypass are at a high risk of developing systemic inflammatory response syndrome and septic shock, necessitating intensive use of vasopressors after surgery. The use of a cytokine hemoadsorber (CytoSorb, CytoSorbents Europe GmbH, Germany) during cardiac surgery has been suggested to reduce the risk of inflammatory activation. The study authors hypothesized that adding a cytokine adsorber would reduce cytokine burden, which would translate into improved hemodynamic stability. A randomized, controlled, nonblinded clinical trial. At a university hospital, tertiary referral center. Nineteen patients with endocarditis undergoing valve surgery. A cytokine hemoadsorber integrated into the cardiopulmonary bypass circuit. The accumulated norepinephrine dose in the intervention group was half or less at all postoperative time points compared to the control group, although it did not reach statistical significance; at 24 and 48 hours (median 36 [25-75 percentiles; 12-57] μg v 114 [25-559] μg, p = 0.11 and 36 [12-99] μg v 261 [25-689] μg, p = 0.09). There was no significant difference in chest tube output, but there was a significantly lower need for the transfusion of red blood cells (285 [0-657] mL v 1,940 [883-2,148] mL, p = 0.03). There was no statistically significant difference between the groups with regard to vasopressor use after surgery for endocarditis with the use of a cytokine hemoadsorber during cardiopulmonary bypass. Additional, larger randomized controlled trials are needed to definitely assess the potential effect. [ABSTRACT FROM AUTHOR]

Mortality rates following pediatric cardiac surgery with cardiopulmonary bypass have declined over decades, but have plateaued in recent years. This is in part attributable to persistent issues with postoperative global inflammation and myocardial dysfunction, commonly manifested by systemic inflammatory response syndrome and low cardiac output syndrome, respectively. Quantified cell-free DNA (cfDNA), of nuclear or mitochondrial origin, has emerged as a biomarker for both inflammation and myocardial injury. Recent data suggest that nuclear cfDNA (ncfDNA) may quantify inflammation, whereas mitochondrial cfDNA (mcfDNA) may correlate with the degree of myocardial injury. We hypothesize that threshold levels of ncfDNA and mcfDNA can be established that are sensitive and specific for postoperative mortality mediated through independent pathways, and that association will be enhanced with combined analysis. Prospective observational study of infants younger than age 1 year undergoing planned surgery with cardiopulmonary bypass. The study received institutional review board approval. Samples were drawn before skin incision, immediately after completion of cardiopulmonary bypass, and subsequently at predetermined intervals postoperatively. Association of early postoperative ncfDNA and mcfDNA levels with mortality were assessed by logistic regression with cut-points chosen by receiving operating characteristic curve exploration. Data were available in 59 patients. Median age and weight were 122 days (interquartile range, 63-154 days) and 4.9 kg (interquartile range, 3.9-6.2 kg). Median STAT category was 3 (interquartile range, 1-4). The primary outcome of death was met in 3 out of 59 (5%). Combined analysis of ncfDNA and mcfDNA levels at 12 hours after the initiation of cardiopulmonary bypass with death at a threshold of 50 ng/mL ncfDNA and 17 copies/μL mcfDNA yielded 100% sensitivity and negative predictive value. The specificity (91%) and positive predictive value (38%) increased through combined analysis compared with univariate analysis. Combined analysis exhibited high specificity (93%) and negative predictive value (78%) for prolonged (>30 postoperative days) hospitalization. Combined analysis of early postoperative ncfDNA and mcfDNA can stratify risk of mortality and prolonged hospitalization following infant cardiac surgery. Evaluation of both ncfDNA and mcfDNA to identify states of generalized inflammation and myocardial injury may allow for targeted interventions and improved outcomes. Summary slide of the methods, results, and implications of this study. Combined analysis of early postoperative nuclear cell-free DNA concentration and mitochondrial cell-free DNA concentration can stratify risk of mortality and prolonged hospitalization following infant cardiac surgery. Evaluation of both nuclear cell-free DNA concentration and mitochondrial cell-free DNA concentration to identify states of generalized inflammation and myocardial injury may allow for targeted interventions and improved outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

• Intraoperative fluid type does not increase risk of postoperative SIRS. • Female sex, body mass index, operative length increase risk of postoperative SIRS. • Intraoperative fluid type is associated with increased acute kidney injury postoperatively. To evaluate the effect of intraoperative fluid type [half normal saline (0.45NS) or lactated Ringer's solution (LR)] on the risk of systemic inflammatory response syndrome (SIRS) and acute kidney injury after total pancreatectomy with islet autotransplantation in children. Retrospective review where demographics, operative details, systemic inflammatory response, and evaluation for end organ dysfunction over the first 5 postoperative days was obtained. Mixed effects Poisson regression compared risk of SIRS and acute kidney injury by intraoperative fluid type. Forty three patients were included with no difference in demographic characteristics between groups. SIRS was observed in 95, 77, and 71% over post operative days 1, 3, and 5. Intraoperative fluid type was found to not be associated with postoperative SIRS (RR: 0.91, p = 0.23). However, female sex (RR: 1.30, p < 0.01), increased BMI (RR: 1.08, p < 0.01), and longer operative time (RR: 1.07, p < 0.01) were found to be factors that are associated with increased risk of postoperative SIRS. Intraoperative 0.45NS use was associated with increased acute kidney injury compared to LR on postoperative day 1 (52% vs 0%, p < 0.01), but not on postoperative days 3 or 5. Intraoperative fluid type (0.45NS vs LR) does not increase the risk of postoperative SIRS in children after TPIAT. Predictive factors that are associated with an increased risk of eliciting postoperative SIRS includes female sex, increased BMI, and longer operative times. III [ABSTRACT FROM AUTHOR]

• The Au 10 exhibit the antioxidant capacity 5.7 times higher than Trolox. • The Au 10 achieve effects in septic lung, brain, liver, kidney and spleen. • The Au 10 can clear reactive ROS, effectively harnessed inflammation in sepsis. Sepsis is a systemic inflammatory response syndrome, and severe cases often present with inadequate organ perfusion and multiple organ failure. The interplay of inflammation and infection can lead to vascular dilation and disruptions in microcirculation, consequently causing damage and hypoxia to multiple organs. Thus, suppressing inflammation and alleviating multi-organ damage, especially lung injury, are crucial for the treatment of sepsis. We employ atomically precise Au 10 clusters protected by 6-Aza-2-thiothymine (ATT) ligand, which possess remarkable antioxidant capabilities, 5.7 times higher than natural antioxidant Trolox. Au 10 clusters also exhibit excellent catalase-like (CAT-like) activity, effectively eliminating excessive hydrogen peroxide and generating oxygen. Therefore, in cases of sepsis, Au 10 clusters can effectively clear inflammatory factors, ensuring the proper functioning of vital organs in the body. This functionality underscores the potential of the Au 10 clusters as an intervention in the treatment of sepsis, providing a unique combination of antioxidant and anti-inflammatory properties for multiple anoxic organs protection. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS), a lipid-induced inflammatory condition of the arteries, is a primary contributor to atherosclerotic cardiovascular diseases including stroke. Arctium lappa L. leaf (ALL), an edible and medicinal herb in China, has been documented and commonly used for treating stroke since the ancient times. However, the elucidations on its anti-AS effects and molecular mechanism remain insufficient. To investigate the AS-ameliorating effects and the underlying mechanism of action of an ethanolic extract of leaves of Arctium lappa L. (ALLE). ALLE was reflux extracted using with 70% ethanol. An HPLC method was established to monitor the quality of ALLE. High fat diet (HFD) and vitamin D3-induced experimental AS in rats were used to determine the in vivo effects; and oxidized low-density lipoprotein-induced RAW264.7 macrophage foam cells were used for in vitro assays. Simvatatin was used as positive control. Biochemical assays were implemented to ascertain the secretions of lipids and pro-inflammatory mediators. Haematoxylin-eosin (H&E) and Oil red O stains were employed to assess histopathological alterations and lipid accumulation conditions, respectively. CCK-8 assays were used to measure cytotoxicity. Immunoblotting assay was conducted to measure protein levels. ALLE treatment significantly ameliorated lipid deposition and histological abnormalities of aortas and livers in AS rats; improved the imbalances of serum lipids including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C); notably attenuated serum concentrations of inflammation-associated cytokines/molecules including TNF-α, IL-6, IL-1β, VCAM-1, ICAM-1and MMP-9. Mechanistic studies demonstrated that ALLE suppressed the phosphorylation/activation of PI3K, Akt and NF-κB in AS rat aortas and in cultured foam cells. Additionally, the PI3K agonist 740Y–P notably reversed the in vitro inhibitory effects of ALLE on lipid deposition, productions of TC, TNF-α and IL-6, and protein levels of molecules of PI3K/Akt and NF-κB singnaling pathways. ALLE ameliorates HFD- and vitamin D3-induced experimental AS by modulating lipid metabolism and inflammatory responses, and underlying mechanisms involves inhibition of the PI3K/Akt and NF-κB singnaling pathways. The findings of this study provide scientific justifications for the traditional application of ALL in managing atherosclerotic diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Hypertrophic burn scars contribute to morbidity through secondary symptoms of pain, pruritus, and scar contracture. Traditional treatment methods are now augmented by the use of monochromatic light therapies, which are generally accepted as safe and effective. However, little literature is available regarding the complications of laser treatments of hypertrophic burn scars and even less regarding inflammatory and infectious complications.Methods: A literature search using PubMed was performed to identify literature pertaining to infectious and inflammatory complications of cutaneous laser treatments. Additionally, we reviewed cases of inflammatory and infectious complications occurring at our institution after laser treatment of hypertrophic burn scars.Results: We identified 1 publication related to complications of laser therapy in the treatment of burn scars. In this series of 163 laser sessions, the reported incidence of adverse events was 25.1%, of which 6 cases 3.7% were related to inflammatory and infectious processes. In the 391 laser sessions performed at our institution (December, 2015 and July, 2016) 9 cases of inflammatory and infectious complications were noted yielding an incidence of 2.3%. Cases included 3 each of cellulitis, Systemic Inflammatory Response Syndrome (SIRS), and complicated SIRS.Conclusion: We found the most common inflammatory complication was SIRS with MSSA positive wound cultures. Three cases underwent hospitalization along with fluids and vasopressors, despite negative blood cultures. In light of the high prevalence of MSSA in the natural skin flora and negative blood cultures, the inability to establish a true source of infection lead to declaring these cases "complicated SIRS" and not sepsis. Correlative factors that may have led to complications reported in our cases were: preoperative evidence of infection, no preoperative antibiotics administered, no postoperative antibiotic dressings, combined procedures, and large treatment areas. The true mechanism of inflammatory and infectious complication is yet to be determined, but we postulate that these factors place a greater challenge on an already burdened immune system. Determining whether this is a true causal mechanism, leading to an aggravated inflammatory response, benefits from further investigation.Applicability Of Research To Practice: We urge institutions preforming such procedures to advise patients on preoperative wound preparation. We recommend that each individual with a preexisting history of infection and/or preoperative culture evidence of infection receive antibiotics, particularly when undergoing combined procedures or procedures involving higher surface areas. Although complications are rare, the benefits of these precautionary measures outweigh the risks when it comes to prevention and management. [ABSTRACT FROM AUTHOR]

In recent years, there have been important advances in our understanding of alcohol-associated hepatitis (AH), which have occurred in parallel with a surge in clinical trial activity. Meanwhile, the broader medical field has seen a transformation in care paradigms based on emerging digital technologies. This review focuses on breakthroughs in our understanding of AH and how these breakthroughs are leading to new paradigms for biomarker discovery, clinical trial activity, and care models for patients. It portends a future in which multimodal data from genetic, radiomic, histologic, and environmental sources can be integrated and synthesised to generate personalised biomarkers and therapies for patients with AH. [ABSTRACT FROM AUTHOR]

Heat stress (HS) reduces production and efficiency in almost every metric of the dairy operation, and it thus compromises profitability and sustainability. If the magnitude of HS progresses, it can become lethal. Death can occur acutely or days following the heat load, even if environmental conditions have become nonstressful. Consequently, lethal heat stress (LHS) is often difficult to identify and almost always misdiagnosed. The precise mechanisms of death when dairy cows succumb to LHS has not been fully elucidated or documented, but the pathophysiology of LHS appears to be conserved among several species. The unique digestive physiology of ruminants adds additional layers of complexity that contribute to failure of multiple systems involved with LHS. Consequently, the ostensible etiology and pathogenesis of LHS described herein is extended from the physiological adaptations cows use to survive HS and pertinent pathology extrapolated from other species. The multifactorial causes of death likely involve dysfunction and imbalance of several interdependent systems as follows: (1) electrolyte dyshomeostasis, (2) unstable blood pH, (3) gastrointestinal tract hyperpermeability, (4) sepsis, (5) severe immune activation-induced inflammation, (6) disseminated intravascular hypercoagulation, (7) systemic endothelial permeability, (8) multiple organ failure, and (9) circulatory failure. Having a better understanding of the mechanisms of LHS will improve diagnosis, enable a more accurate prognosis, and provide insight into strategies aimed at preventing dairy cow mortality and morbidity. [ABSTRACT FROM AUTHOR]

Sepsis is involved in ~ 20% of annual global deaths. Despite decades of research, the current management of sepsis remains supportive rather than curative. Clinical trials in sepsis have mainly been focused on targeting the inflammatory pathway, but without success. Recent data indicate that metabolic dysregulation takes place in sepsis, and targeting metabolic pathways might hold much promise for the management of sepsis. Sepsis yields a strong starvation response, including the release of high-energy metabolites such as lactate and free fatty acids. However, the activity of two major transcription factors, GR and PPARα, is downregulated in hepatocytes, leading to the accumulation and toxicity of metabolites that, moreover, fail to be transformed into useful molecules such as glucose and ketones. We review the literature and suggest mechanisms and potential therapeutic targets that might prevent or revert the fatal metabolic dysregulation in sepsis. Sepsis is associated with severe metabolic dysregulation. Two key metabolic transcription factors, GR and PPARα, are dysfunctional in sepsis, leading to failure of the starvation response. Metabolites such as lactate and free fatty acids accumulate and contribute to disease progression in sepsis. Further characterization of metabolic dysregulation might uncover novel therapeutic targets for treating sepsis patients. [ABSTRACT FROM AUTHOR]

• The study used the WIND classification to categorize patients with myasthenic crisis. • The weaning process is significantly associated with clinical outcome in myasthenic crisis patients. • Predictors for difficult-/prolonged-weaning include pneumonia and SIRS presence. Weaning from invasive mechanical ventilation (MV) represents a pivotal step for myasthenic crisis (MC) patients. The aim was to evaluate the association between the weaning process and clinical outcomes, as well as to determine the independent predictors for difficult-/prolonged-weaning in MC. MC patients requiring invasive MV were recruited from Jan 2014 through Sep 2020. Among 124 consecutive MC patients, we finally included 66 patients (age 48.4 ± 18.7 years, female 45.5%). According to the WIND (Weaning according to a New Definition) classification, these patients were classified into no-weaning (n = 5, 7.6%), short-weaning (n = 13, 19.7%), difficult-weaning (n = 26, 39.4%), and prolonged-weaning group (n = 22, 33.3%). Four-week functional assessment in short-weaning group was more favorable than that in difficult-/prolonged-weaning group (p <0.001). Length of hospital stay (23.0 (15.0–28.0) vs. 37.5 (27.0–54.8), p <0.001), length of ICU stay (17.0 (8.5–22.5) vs. 34.0 (20.3–45.0), p <0.001), duration on ventilation (6.0 (6.0–8.5) vs. 18.0 (13.3–30.0), p <0.001), and time interval from MV to first weaning (6.0 (6.0–8.0) vs. 11.0 (8.0–20.8), p <0.001) in short-weaning group were significantly shorter than those in difficult-/prolonged-weaning group. Short-weaning group had a lower prevalence of pneumonia (23.1% vs. 75.0%) and systemic inflammatory response syndrome (SIRS) (38.5% vs. 85.4%), and a higher value in the lowest hemoglobin level (123.0 ± 12.9 g/L vs. 108.3 ± 18.1 g/L) and the lowest serum albumin level (33.2 ± 3.4 g/L vs. 29.9 ± 4.2 g/L) than difficult-/prolonged-weaning group. Multivariate logistic regression analysis identified pneumonia and the presence of SIRS within one week of MC as independent predictors for difficult-/prolonged-weaning. The weaning process is associated with clinical outcomes in MC patients requiring ventilation. Pneumonia concurrence and the presence of SIRS within one week of MC were identified as independent predictors for difficult-/prolonged-weaning after invasive MV. [ABSTRACT FROM AUTHOR]

[Display omitted] • We identified zinc finger protein 91 (ZFP91) as a novel therapeutic target for necroptosis-associated diseases. • ZFP91 promoted necrotic cell death induced by TNF-α, Z-VAD-FMK and SM-164. • ZFP91enhanced necrosome formation by inducing the phosphorylation or oligomerization of RIPK1/RIPK3/MLKL. • ZFP91 leads to a further reduction of RIPK1 K63 ubiquitination and substantially enhances necrosome formation in TNFα-induced cells. • ZFP91-knockdown impairs the inflammatory response in TNFα-induced SIRS. Necroptosis is a form of regulated programmed cell death that is mediated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting serine/threonine protein kinase-3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL); however, it is not known whether zinc finger protein 91 (ZFP91) is involved in this process. Here, we investigated ZFP91 as a potential mediator of necroptosis. Our mechanistic study demonstrates that ZFP91 promotes RIPK1-RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. ZFP91 stabilized RIPK1 to promote cell death by inducing RIPK1 de-ubiquitination. ZFP91 also significantly increased production of mitochondrial reactive oxygen species (ROS). Accumulation of ROS promoted RIPK3-independent necroptosis triggered by tumor necrosis factor (TNF). in vivo , ZFP91 knockdown alleviated TNFα-induced systemic inflammatory response syndrome (SIRS). These results provide direct evidence that ZFP91 plays an important role in the initiation of RIPK1/RIPK3-dependent necroptosis in vitro and in vivo. We discussed the potential of ZFP91 as a novel therapeutic target for necroptosis-associated diseases. [ABSTRACT FROM AUTHOR]

• Multisystem inflammatory syndrome in adults (MIS-A) is a rare, life-threatening hyperinflammatory complication of COVID-19. • MIS-A may rarely occur if messenger RNA vaccination follows natural infection in young adults. • MIS-A is associated with high morbidity and mortality, often requiring intensive care unit support. • The optimal timing of vaccination after natural infection in young adults is unknown. Multisystem inflammatory syndrome in adults is a rare and life-threatening complication that follows natural COVID-19 infection and primarily affects young unvaccinated adults. This complication is seldom described following vaccination, which would have important implications for the vaccination timing and platform in this population. COVID-19 vaccines are extremely effective; however, the risk of rare adverse events needs to be balanced with the vaccination benefits. [ABSTRACT FROM AUTHOR]

[Display omitted] • Oxidative stress is critical for SAP-induced spleen injury pathogenesis upon activation of TLR4. • Autopahgy and mitophagy were impaired by ROS in spleen stimulated by SAP through PI3K/AKT/mTOR pathway. • Mitochondrial dysfunction contributes to SAP-induced spleen injury by accumulating oxidant species and damaged mitophagy. • SAP-induced spleen injury with the decreased serum tuftsin, while tuftsin administration was protective in spleen injury. Severe acute pancreatitis (SAP) is complicated by systemic inflammatory response syndrome and multiple organ dysfunction, the disease will eventually result in death in almost half of the case. The spleen, as the largest immune organ adjacent to the pancreas, is prone to damage in SAP, thereby aggravating the damage of other organs and increasing mortality. However, to date, the research on the mechanism and treatment of spleen injury caused by SAP is still in its infancy. Herein, we investigated the mechanism of spleen injury, and explored the application potential of tuftsin for relieving spleen damage in SAP mice. Firstly, SAP mice model was constructed via the retrograde infusion of 3.5 % sodium taurocholate into the biliopancreatic duct. Then, we proved that the up-regulation of Toll-like receptor 4 (TLR4) in spleen would lead to the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction under SAP conditions. The splenic ROS and mitochondrial dysfunction could be improved by N-acetylcysteine (NAC) treatment or knocking out TLR4 in SAP mice. Meanwhile, we found that NAC treatment could also improve the autophagy of spleen tissue, suggesting that splenic ROS may affect impaired autophagy, causing the accumulation of damaged mitochondria, aggravating spleen damage. Furthermore, we verified the mechanism of spleen injury is caused by splenic ROS affecting PI3K/p-AKT/mTOR pathway-mediated autophagy. In addition, we detected the spleen injury caused by SAP could decrease the concentration of tuftsin in the serum of mice. Whereas, exogenous supplementation of tuftsin ameliorated the pathological damage, ROS accumulation, impaired autophagy, inflammation expression and apoptosis in damaged spleen. In summary, we verified the new mechanism of SAP-caused spleen damage that TLR4-induced ROS provoked mitophagy impairment and mitochondrial dysfunction in spleen via PI3K/p-AKT mTOR signaling, and the application potential of tuftsin in treating spleen injury, which might expand novel ideas and methods for the treatment of pancreatitis. [ABSTRACT FROM AUTHOR]

To identify predictors of poor prognosis in previously healthy young individuals admitted to hospital with coronavirus disease 2019 (COVID-19). We studied a cohort of patients hospitalized with COVID-19. All patients without co-morbidities, without usual treatments and ≤65 years old were selected from an international registry (HOPE-COVID-19, NCT04334291). We focused on baseline variables—symptoms and signs at admission—to analyse risk factors for poor prognosis. The primary end point was a composite of major adverse clinical events during hospitalization including mortality, mechanical ventilation, high-flow nasal oxygen therapy, prone, sepsis, systemic inflammatory response syndrome and embolic events. Overall, 773 healthy young patients were included. The primary composite end point was observed in 29% (225/773) and the overall mortality rate was 3.6% (28/773). In the combined event group, 75% (168/225) of patients were men and the mean age was 49 (±11) years, whereas in the non-combined event group, the prevalence of male gender was 43% (238/548) and the mean age was 42 (±13) years (p < 0.001 for both). On admission, respiratory insufficiency and cough were described in 51.4% (114/222) and 76% (170/223) of patients, respectively, in the combined event group, versus 7.9% (42/533) and 56% (302/543) of patients in the other group (p < 0.001 for both). The strongest independent predictor for the combined end point was desaturation (Sp o 2 <92%) (OR 5.40; 95% CI 3.34–8.75; p < 0.001), followed by tachypnoea (OR 3.17; 95% CI 1.93–5.21; p < 0.001), male gender (OR 3.01; 95% CI 1.96–4.61; p < 0.001) and pulmonary infiltrates on chest X-ray at admission (OR 2.21; 95% CI 1.18–4.16; p 0.014). Major adverse clinical events were unexpectedly high considering the baseline characteristics of the cohort. Signs of respiratory compromise at admission and male gender, were predictive for poor prognosis among young healthy patients hospitalized with COVID-19. [ABSTRACT FROM AUTHOR]

Background: Collecting blood cultures from patients admitted from the emergency department (ED) with acute respiratory infection (ARI) is common, but the rate of secondary bacteremia in adult patients admitted from the ED with ARI associated with respiratory syncytial virus (RSV) is unknown. Indiscriminate collection of blood cultures can be associated with contaminated blood cultures and increased inappropriate antimicrobial use and health care costs.Objective: This study sought to determine the rate and etiology of secondary bacteremia, factors associated with secondary bacteremia, and factors associated with collecting blood cultures in the ED, in adults hospitalized with RSV.Methods: We performed a retrospective substudy using data from a prospective study of adults admitted with RSV infections during two respiratory seasons (October 2017 to April 2018 and October 2018 to April 2019). Blood cultures were collected at the discretion of ED providers. We compared demographic and clinical characteristics among those with and without secondary bacteremia and among those with and without blood cultures collected using multivariate logistic regression models.Results: Of the 365 hospitalized RSV-positive patients (mean age 68.8 years), 269 (73.7%) had blood cultures collected in the ED and 18 (6.7%) patients had secondary bacteremia, most commonly from a nonrespiratory source (n = 13). Patients with asthma and chronic obstructive pulmonary disease were significantly less likely to have secondary bacteremia. Patients who were immunocompromised, met systemic inflammatory response syndrome criteria, or had pneumonia described on chest x-ray reports were more likely to have blood cultures collected.Conclusions: Overall, 6.7% of adults hospitalized with RSV infections had secondary bacteremia, more commonly from nonrespiratory sources. [ABSTRACT FROM AUTHOR]

Necroptosis is a type of regulated cell death known for its pro-inflammatory nature due to the substantial release of cellular contents. The phosphorylation of key proteins, namely RIP1, RIP3, and mixed lineage kinase domain-like protein (MLKL), plays a pivotal role in the processes associated with necroptosis. Consequently, inhibiting the phosphorylation of any of these three key protein kinases could effectively block necroptosis. Utilizing a scaffold hopping strategy, we have successfully designed and synthesized a series of novel RIP1 inhibitors with selective and anti-necrotic properties, using compound o1 as the lead compound. In comparison to o1 , SY1 has demonstrated heightened antinecroptosis activity and binding affinity in vitro studies. Moreover, SY1 has exhibited superior efficacy in both in vivo studies, specifically in the context of SIRS, and pharmacokinetic assessments. Furthermore, SY1 has proven effective in significantly suppressing the central inflammatory response induced by epilepsy. [Display omitted] • We used compound o1 as the lead compound to discover the novel necroptosis inhibitor SY1 through the scaffold hopping strat. • SY1 specifically binds to RIPK1, and it is effective in animal models of SIRS and epilepsy. • After structure optimization, the oral bioavailability of SY1 had significantly increased. [ABSTRACT FROM AUTHOR]

Sepsis is a systemic inflammatory response syndrome caused by an infection. Toll-like receptor 4 (TLR4) is activated by endogenous molecules released by injured or necrotic tissues. Additionally, TLR4 is remarkably sensitive to infection of various bacteria and can rapidly stimulate host defense responses. The TLR4 signaling pathway plays an important role in sepsis by activating the inflammatory response. Accordingly, as part of efforts to improve the inflammatory response and survival rate of patients with sepsis, several drugs have been developed to regulate the inflammatory signaling pathways mediated by TLR4. Inhibition of TLR4 signal transduction can be directed toward either TLR4 directly or other proteins in the TLR4 signaling pathway. Here, we review the advances in the development of small-molecule agents and peptides targeting regulation of the TLR4 signaling pathway, which are characterized according to their structural characteristics as polyphenols, terpenoids, steroids, antibiotics, anthraquinones, inorganic compounds, and others. Therefore, regulating the expression of the TLR4 signaling pathway and modulating its effects has broad prospects as a target for the treatment of lung, liver, kidneys, and other important organs injury in sepsis. [Display omitted] • TLR4 signaling pathway activates the inflammatory response, contributing to sepsis. • Advances on the impacts of small-molecule drugs and peptides on TLR4 signaling are reviewed. • Targeting intracellular LPS and its receptors in TLR4 interactions can attenuate sepsis. • Drugs targeting multiple TLR4 signaling components will likely have the best therapeutic effects. [ABSTRACT FROM AUTHOR]

• IL-35 ameliorates lipopolysaccharide-induced endothelial dysfunction by inhibiting Endothelial-to-mesenchymal transition. • Endothelial-to-mesenchymal transition is a important part of LPS-induced endothelial dysfunction. • IL-35 may exert it's protective effect through the NF-κB pathway. • IL-35 plays an important biological function and can provide a new rationale for sepsis prevention and treatment. Sepsis is a systemic inflammatory response syndrome (SIRS) caused mainly by bacterial infection. The morbidity and mortality rates of sepsis are extremely high. About 18 million people worldwide suffer from severe sepsis each year, and about 14,000 people die from it every day. Previous studies have revealed that endothelial dysfunction plays a vital role in the pathological change of sepsis. Furthermore, endothelial-mesenchymal transition (EndMT, EndoMT) is capable of triggering endothelial dysfunction. And yet, it remains obscure whether interleukin-35 (IL-35) can alleviate endothelial dysfunction by attenuating LPS-induced EndMT. Here, through in vivo and in vitro experiments, we revealed that IL-35 has a previously unknown function to attenuate LPS-induced endothelial dysfunction by inhibiting LPS-induced EndMT. Mechanistically, IL-35 acts by regulating the NFκB signaling pathway. [ABSTRACT FROM AUTHOR]

Aortic valve stenosis is the most common type of heart valve disease in the United States and Europe and calcific aortic stenosis (AS) affects 2–7% of people aged 65 years and older. Aortic valve replacement (AVR) is the only effective treatment for individuals with this condition. Transcatheter Aortic Valve Replacement (TAVR) has been widely accepted as a minimally invasive therapeutic approach for addressing symptomatic AS in patients who are considered to have a high risk for traditional surgical intervention. TAVR procedure may have a paradoxical effect on the immune system and inflammatory status. A major portion of these immune responses is regulated by activating or inhibiting inflammatory monocytes and the complement system with subsequent changes in inflammatory cytokines. TAVR has the potential to induce various concurrent exposures, including disruption of the native valve, hemodynamic changes, antigenicity of the bioprosthesis, and vascular damage, which finally lead to the development of inflammation. On the other hand, it is important to acknowledge that TAVR may also have anti-inflammatory effects by helping in the resolution of stenosis.The inflammation and immune response following TAVR are complex processes that significantly impact procedural outcomes and patient well-being. Understanding the underlying mechanisms, identifying biomarkers of inflammation, and exploring therapeutic interventions to modulate these responses are crucial for optimizing TAVR outcomes. Further research is warranted to elucidate the precise immunological dynamics and develop tailored strategies to attenuate inflammation and enhance post-TAVR healing while minimizing complications. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series of biaryl benzoxazepinone RIPK1 inhibitors were designed and synthesized. • Analog 19 with p -cyanophenyl showed the best anti-necroptotic effect in HT-29 cells (EC 50 = 1.7 nM). • Analog 19 showed superior anti-necroptotic and anti-inflammatory activities than GSK'772 in mice. Systemic inflammatory response syndrome (SIRS), an exaggerated defense response of the organism to a noxious stressor, involves a massive inflammatory cascade that ultimately leads to reversible or irreversible end-organ dysfunction and even death. Suppressing RIPK1, a key protein in necroptosis pathway, has been proven to be an effective therapeutic strategy for inflammation and SIRS. In this study, a series of novel biaryl benzoxazepinone RIPK1 inhibitors were designed and synthesized by introducing different aryl substituents at the C7 position of benzoxazepinone. As a result, p -cyanophenyl substituted analog 19 exhibited the most potent in vitro anti-necroptotic effect in HT-29 cells (EC 50 = 1.7 nM) and superior protection against temperature loss and death in mice in the TZ-induced SIRS model compared to GSK'772. What's more, in vivo analysis of the levels of inflammatory factors in mice also revealed that compound 19 had better anti-inflammatory activity than GSK'772. [ABSTRACT FROM AUTHOR]

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulatory factor in the necroptosis signaling pathway, and is considered an attractive therapeutic target for treating multiple inflammatory diseases. Herein, we describe the design, synthesis, and structure–activity relationships of 4-amino-1,6-dihydro-7 H -pyrrolo [2,3- d ]pyridazin-7-one derivatives as RIPK1 inhibitors. Among them, 13c showed favorable RIPK1 kinase inhibition activity with an IC 50 value of 59.8 nM, and high RIPK1 binding affinity compared with other regulatory kinases of necroptosis (RIPK1 K d = 3.5 nM, RIPK3 K d = 1700 nM, and MLKL K d > 30,000 nM). 13c efficiently blocked TNFα-induced necroptosis in both human and murine cells (EC 50 = 1.06–4.58 nM), and inhibited TSZ-induced phosphorylation of the RIPK1/RIPK3/MLKL pathway. In liver microsomal assay studies, the clearance rate and half-life of 13c were 18.40 mL/min/g and 75.33 min, respectively. 13c displayed acceptable pharmacokinetic characteristics, with oral bioavailability of 59.55%. In TNFα-induced systemic inflammatory response syndrome, pretreatment with 13c could effectively protect mice from loss of body temperature and death. Overall, these compounds are promising candidates for future optimization studies. [Display omitted] • Pyrrolo [2,3- d ] pyridazinone derivatives were synthesized as RIPK1 inhibitors. • 13c showed high RIPK1 binding affinity and anti-necrosis cell activity. • 13c could effectively protect mice from hypothermia and death in the SIRS model. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the mRNA expression of insulin-like growth factor-1 (IGF-1), pro-inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α), serum immunoglobulin profiles (IgG and IgM), and lipid peroxidation status (MDA) in relation to pro-inflammatory cytokines. A case-controlled, prospective, and observational investigation was completed on 85 calves. Total RNA was isolated from whole blood samples of both the SIRS and healthy calves, followed by reverse transcription into cDNA. The resulting cDNAs were mixed with iTaq Universal SYBR Green Supermix and primers specific to the relevant genes using the Rotor-Gene Q instrument. After the reaction was completed, gene expressions were normalised against β-actin using the 2-ΔΔCT method. The mRNA levels of pro-inflammatory cytokines namely (IL-1β [SIRS: 2.15 ± 0.55, Control: 1.13 ± 0.62; P = 0.001], IL-6 [SIRS: 2.82 ± 0.52, Control: 0.91 ± 0.11; P < 0.001], IL-18 [SIRS: 1.92 ± 0.41, Control: 0.99 ± 0.13; P < 0.001], and TNF-α [SIRS: 2.59 ± 0.28, Control: 0.93 ± 0.09; P < 0.001]) and IGF-1 (SIRS: 3.55 ± 0.55, Control: 0.91 ± 0.15; P < 0.001) were up-regulated in calves with SIRS, while serum IgG (SIRS: 4.16 ± 0.26, Control: 1.73 ± 0.17; P < 0.001), IgM (SIRS: 1.55 ± 0.11, Control: 1.09 ± 0.13; P < 0.001), and MDA levels (SIRS: 41.12 ± 3.48, Control: 3.76 ± 0.81; P < 0.001) increased significantly in these calves. Furthermore, significant (P < 0.01) positive correlations were found in calves with SIRS in relation to the expression levels of IL-1β, IL-6, IL-18, TNF-α, IGF-1, serum immunoglobulins, and MDA levels. These results suggest that IGF-1 could be a valuable pro-inflammatory marker, considering its high positive correlation with the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) and markers (MDA, IgG, and IgM) in calves with SIRS. [ABSTRACT FROM AUTHOR]

Electrochemical analysis of total phospholipids was performed for the diagnosis of sepsis. The influence of electrode materials on the analysis of the chromogenic substrate was analyzed using Au, graphite, and pyrolyzed carbon electrodes. The total phospholipid analysis based on electrochemical analysis with pyrolyzed carbon was used for diagnosis of sepsis using sera from healthy volunteers, systemic inflammatory response syndrome (SIRS), and severe sepsis patients. The analysis results using the optical measurement and the electrochemical analysis were compared for the serum samples from sepsis patients and healthy controls. Additionally, the interference of human serum on the optical measurement and electrochemical analysis was estimated by signal-to-noise (S/N) calculation. The assay results of the levels of other biomarkers for sepsis (C-reactive protein and procalcitonin) and the total phospholipid levels obtained using the optical measurement and electrochemical analysis methods were statistically similar. Finally, the mortality of patients, indicated by the results of the total phospholipid assay performed using the electrochemical analysis of the patient samples collected daily (1, 3, and 7 day(s) after admission to hospital), was compared with the patient mortality assessed via conventional severity indexes, such as the SOFA and APACHE Ⅱ scores. The 28-day survival rate was estimated by Kaplan–Meier survival analysis based on the total phospholipid level of patient samples that were obtained after 1, 3, and 7 day(s) from hospital admission. [Display omitted] • Electrochemical analysis of total phospholipids performed for diagnosing sepsis. • The performance of Au, graphite, and pyrolyzed carbon electrodes was assessed. • Optical density and electrochemical analyses data compared for patients and controls. • Correlation of total phospholipids with other sepsis biomarkers (CRP, PCT) assessed. • Mortality prediction of severe sepsis performed using electrochemical analysis. [ABSTRACT FROM AUTHOR]

• The performance of predictive models should be reevaluated periodically. • A large-scale investigation was performed using the MIMIC IV database. • The Youden index of the SAPS III model was the highest among the models. • SAPS III is superior to the SOFA score for predicting 28-day mortality in Sepsis 3.0 patients. The discrimination and calibration accuracy of prediction models tends to become poor over time. The performance of predictive models should be reevaluated periodically. The aim of this study was to reassess the discrimination of the six commonly used models for predicting 28-day mortality in patients with sepsis based on the Sepsis 3.0 criteria. Patient data were extracted from the fourth edition of the Medical Information Mart for Critical Care (MIMIC IV) database. The systemic inflammatory response syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), Oxford Acute Severity of Illness Score (OASIS), Logistic Organ Dysfunction System (LODS), and Simplified Acute Physiology Score II (SAPS II) and III (SAPS III) scores were calculated and collected. The area under the receiver operating characteristic curve (AUROC) was used to compare the discrimination abilities of the models using non-parametric Wilcoxon statistics. The Delong method was used to perform pairwise comparisons of the AUROCs of the models. Multiple subgroup analyses for age, body mass index, and sex were performed with regard to the 28-day mortality prediction of the models. A total of 12 691 patients were included. The mean age of the patients was 65.97 ± 15.77 years; 7673 patients (60.50%) were male. The mean SIRS, SOFA, OASIS, SAPS II, LODS, and SAPS III scores were higher in the non-survivor group than in the survivor group. The discrimination for 28-day mortality with the SAPS III (AUROC 0.812, 95% confidence interval (CI) 0.802–0.822) and LODS (AUROC 0.804, 95% CI 0.743–0.765) models was superior to that of the SIRS (AUROC 0.575, 95% CI 0.562–0.589), SOFA (AUROC 0.612, 95% CI 0.598–0.626), OASIS (AUROC 0.753, 95% CI 0.742–0.764), and SAPS II (AUROC 0.754, 95% CI 0.743–0.765) models. The Youden index of the SAPS III model was 0.484, which was the highest among the models. Subgroup analyses showed similar results to the overall results. The discrimination for 28-day mortality with the SAPS III and LODS models was superior to that of the SIRS, SOFA, OASIS, and SAPS II models. The SAPS III model showed the best discrimination capacity for 28-day mortality compared with the other models. [ABSTRACT FROM AUTHOR]