S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in a variety of inflammatory diseases. Although S100a8/a9 has been reported to trigger endothelial cell apoptosis, the mechanisms of S100a8/a9-induced endothelial dysfunction during sepsis require in-depth research. We demonstrate that high expression levels of S100a8/a9 suppress Ndufa3 expression in mitochondrial complex I via downregulation of Nrf1 expression. Mitochondrial complex I deficiency contributes to NAD+-dependent Sirt1 suppression, which induces mitochondrial disorders, including excessive fission and blocked mitophagy, and mtDNA released from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis in endothelial cells. Moreover, based on comprehensive scRNA-seq and bulk RNA-seq analyses, S100A8/A9hi neutrophils are closely associated with the circulating endothelial cell count (a useful marker of endothelial damage), and S100A8 is an independent risk factor for poor prognosis in sepsis patients.

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Sepsis is a major health concern globally, and identification of the causative organism usually takes several days. Furthermore, molecular amplification using whole blood from patients with sepsis remains challenging because of primer cross-reactivity with human DNA, which can delay appropriate clinical intervention. To address these concerns, we designed primers that could reduce cross-reactivity. By evaluating these primers against human DNA, we confirmed that the cross-reactivity observed with conventional primers was notably absent. In silico PCR further demonstrated the specificity and efficiency of the designed primers across 23 bacterial species that are often associated with sepsis. When tested using blood samples from sepsis patients, the designed primers showed moderate sensitivity and high specificity. Surprisingly, our method identified bacteria even in samples that were detected at other sites but tested negative using conventional blood culture methods. Although we identified some challenges, such as contamination with Acetobacter aceti due to the saponin pretreatment of samples, the developed method demonstrates remarkable potential for rapid identification of the causative organisms of sepsis and provides a new avenue for diagnosis in clinical practice.

BACKGROUND: Sepsis is considered a high risk factor for new-onset atrial fibrillation (NOAF), with neutrophil extracellular traps (NETs) being implicated in the pathogenesis of numerous diseases. However, the precise role of NETs and NETs-related genes (NRGs) in the occurrence of NOAF in sepsis remains inadequately elucidated. The objective of this study was to identify hub NRGs connecting sepsis and AF, and to investigate the potential association between NETs and NOAF in sepsis.
METHODS: The AF and sepsis microarray datasets were retrieved from the Gene Expression Omnibus (GEO) database for analysis of shared pathophysiological mechanisms and NRGs implicated in both sepsis and AF using bioinformatics techniques. The CIBERSORT algorithm was employed to assess immune cell infiltration and identify common immune characteristics in these diseases. Additionally, a rat model of lipopolysaccharide (LPS)-induced sepsis was utilized to investigate the association between NETs, NRGs, and sepsis-induced AF. Western blotting, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, immunohistochemistry, and immunofluorescence were employed to assess the expression of NRGs, the formation of NETs, and the infiltration of neutrophils. Electrophysiological analysis and multi-electrode array techniques were utilized to examine the vulnerability and conduction heterogeneity of AF in septic rats. Furthermore, intervention was conducted in LPS-induced sepsis rats using DNase I, a pharmacological agent that specifically targets NETs, in order to assess its impact on neutrophil infiltration, NETs formation, hub NRGs protein expression, and AF vulnerability.
RESULTS: A total of 61 commonly differentially expressed genes (DEGs) and four hub DE-NRGs were identified in the context of sepsis and AF. Functional enrichment analysis revealed that these DEGs were predominantly associated with processes related to inflammation and immunity. Immune infiltration analysis further demonstrated the presence of immune infiltrating cells, specifically neutrophil infiltration, in both sepsis and AF. Additionally, a positive correlation was observed between the relative expression of the four hub DE-NRGs and neutrophil infiltration. In rats with LPS-induced sepsis, we observed a notable upregulation in the expression of four DE-NRGs, the formation of NETs, and infiltration of neutrophils in atrial tissue. Through electrophysiological assessments, we identified heightened vulnerability to AF, reduced atrial surface conduction velocity, and increased conduction heterogeneity in LPS-induced sepsis rats. Notably, these detrimental effects can be partially ameliorated by treatment with DNase I.
CONCLUSIONS: Through bioinformatics analysis and experimental validation, we identified four hub NRGs in sepsis and AF. Subsequent experiments indicated that the formation of NETs in the atria may contribute to the pathogenesis of NOAF in sepsis. These discoveries offer potential novel targets and insights for the prevention and treatment of NOAF in sepsis.

BACKGROUND: The administration of colostrum through its absorption at the oropharyngeal level stimulates the mucosa-associated lymphoid tissue, providing a local immunological protection barrier. The study aimed to investigate the association of oropharyngeal colostrum administration with the reduction of inflammatory indices.
METHODS: This was an observational, ambispective, analytical study of newborns < 32 weeks of gestation at risk of sepsis. Oropharyngeal colostrum was administered at 0.2 mL every 4 h for 5 days. Inflammatory indices were analyzed. Statistical analysis included frequencies, percentages, mean and Standard deviation, contingency coefficient, and Kolmogorov-Smirnov test for the distribution curve of the numerical data.
RESULTS: There were 50 patients, 33 (66%) female and 17 (34%) male, with a median gestational age of 30-31 weeks (95% confidence interval [CI]). Nineteen patients had sepsis. A lower positivity rate in C-reactive protein was found, with a median of 0.5-0.6 (95% CI) at 5 days of colostrum administration versus 0.5-1.1 (95% CI) as the initial C-reactive protein. Analysis with χ2 yielded a p = 0.13, and the contingency coefficient showed a p = 0.196, indicating an association.
CONCLUSIONS: Oropharyngeal colostrum administration was associated with a lower C-reactive protein positivity rate and clinical improvement in premature newborns at risk of sepsis.
UNASSIGNED: La administración del calostro a través de su absorción a nivel orofaríngeo estimula el tejido linfoide asociado a mucosas, proporcionando una barrera de protección local e inmunológica. Conocer la asociación de la administración de calostro orofaríngeo con la disminución de los índices inflamatorios.
UNASSIGNED: Observacional, ambispectivo, analítico, recién nacidos < 32 semanas de gestación con riesgo de sepsis, se administró calostro orofaríngeo 0.2 ml cada 4 horas durante 5 días. se analizó índices inflamatorios, evolución clínica. Análisis estadístico: frecuencias, porcentajes, media y DS, coeficiente de contingencia y prueba de Kolmogorov Smirnov para la curva de distribución de los datos numéricos.
RESULTS: Fueron 50 pacientes, 33 (66%) femenino, 17 (34%) masculino, edad gestacional mediana 30-31 semanas (IC 95%), 19 pacientes cursaron con sepsis encontrando menor índice de positividad en la PCR, mediana de 0.5-0.6 (IC 95%) a los 5 días de administración de calostro vs 0.5-1.1 (IC 95%) como PCR inicial, analizando con Chi cuadrada con valor p = 0.13, mediante coeficiente de contingencia con p = 0.196, traduciendo asociación.
UNASSIGNED: La calostroterapia se asoció con menor índice de positividad en la PCR; clínicamente hacia la mejoría, en recién nacidos prematuros con riesgo de sepsis.

Sepsis is a life-threatening condition caused by the body\'s response to an infection. Dapsone is a sulfone with antibiotic properties, and experimental evidence suggests it has significant anti-inflammatory and anti-oxidative stress effects. The objective of this study was to investigate the efficacy of dapsone in mice after CLP (cecal ligation and puncture) surgery, which is a model for inducing sepsis. The study divided animals into five groups: CLP, sham, and three groups receiving different doses of dapsone (0.5, 1, 2 mg/kg). Sepsis was induced through CLP surgery, followed by dapsone administration. In each group, half of the mice were used to evaluate levels of various markers and pathological changes at 24 h post-CLP, while the other half was used to record the mortality rates within 96 h. The results showed that single-dose administration of dapsone at (0.5, 1, 2 mg/kg) after CLP surgery improved survival compared to the CLP group. Dapsone was also associated with a significant reduction in pro-inflammatory cytokines TNF-α, IL-1β, IL-6, NO, and MPO, as well as lactate and creatinine serum levels. However, dapsone did not have a significant effect on urea serum levels. In conclusion, the data suggest that dapsone treatment leads to increased survival in septic mice after CLP, and due to its ability to reduce TNF-α, IL-1β, IL-6, MPO, and lactate levels, it has anti-inflammatory effects in sepsis. The sepsis treatment with dapsone in mice protects against inflammation and oxidative stress.

Sepsis treatment is a challenging condition due to its complexity, which involves host inflammatory responses to a severe and potentially fatal infection, associated with organ dysfunction. The aim of this study was to analyze the scientific literature on the immunomodulatory effects of glucans in a murine model of systemic infection induced by cecal ligation and puncture. This study comprises an integrative literature review based on systematic steps, with searches carried out in the PubMed, ScienceDirect, Scopus, Web of Science, and Embase databases. In most studies, the main type of glucan investigated was β-glucan, at 50 mg/kg, and a reduction of inflammatory responses was identified, minimizing the occurrence of tissue damage leading to increased animal survival. Based on the data obtained and discussed in this review, glucans represent a promising biotechnological alternative to modulate the immune response and could potentially be used in the clinical management of septic individuals.

UNASSIGNED: The disruption of the circadian clock is associated with inflammatory and immunological disorders. BMAL2, a critical circadian protein, forms a dimer with CLOCK, activating transcription. Extracellular cold-inducible RNA-binding protein (eCIRP), released during sepsis, can induce macrophage endotoxin tolerance. We hypothesized that eCIRP induces BMAL2 expression and promotes macrophage endotoxin tolerance through triggering receptor expressed on myeloid cells-1 (TREM-1).
UNASSIGNED: C57BL/6 wild-type (WT) male mice were subjected to sepsis by cecal ligation and puncture (CLP). Serum levels of eCIRP 20 h post-CLP were assessed by ELISA. Peritoneal macrophages (PerM) were treated with recombinant mouse (rm) CIRP (eCIRP) at various doses for 24 h. The cells were then stimulated with LPS for 5 h. The levels of TNF-α and IL-6 in the culture supernatants were assessed by ELISA. PerM were treated with eCIRP for 24 h, and the expression of PD-L1, IL-10, STAT3, TREM-1 and circadian genes such as BMAL2, CRY1, and PER2 was assessed by qPCR. Effect of TREM-1 on eCIRP-induced PerM endotoxin tolerance and PD-L1, IL-10, and STAT3 expression was determined by qPCR using PerM from TREM-1-/- mice. Circadian gene expression profiles in eCIRP-treated macrophages were determined by PCR array and confirmed by qPCR. Induction of BMAL2 activation in bone marrow-derived macrophages was performed by transfection of BMAL2 CRISPR activation plasmid. The interaction of BMAL2 in the PD-L1 promoter was determined by computational modeling and confirmed by the BIAcore assay.
UNASSIGNED: Serum levels of eCIRP were increased in septic mice compared to sham mice. Macrophages pre-treated with eCIRP exhibited reduced TNFα and IL-6 release upon LPS challenge, indicating macrophage endotoxin tolerance. Additionally, eCIRP increased the expression of PD-L1, IL-10, and STAT3, markers of immune tolerance. Interestingly, TREM-1 deficiency reversed eCIRP-induced macrophage endotoxin tolerance and significantly decreased PD-L1, IL-10, and STAT3 expression. PCR array screening of circadian clock genes in peritoneal macrophages treated with eCIRP revealed the elevated expression of BMAL2, CRY1, and PER2. In eCIRP-treated macrophages, TREM-1 deficiency prevented the upregulation of these circadian genes. In macrophages, inducible BMAL2 expression correlated with increased PD-L1 expression. In septic human patients, blood monocytes exhibited increased expression of BMAL2 and PD-L1 in comparison to healthy subjects. Computational modeling and BIAcore assay identified a putative binding region of BMAL2 in the PD-L1 promoter, suggesting BMAL2 positively regulates PD-L1 expression in macrophages.
UNASSIGNED: eCIRP upregulates BMAL2 expression via TREM-1, leading to macrophage endotoxin tolerance in sepsis. Targeting eCIRP to maintain circadian rhythm may correct endotoxin tolerance and enhance host resistance to bacterial infection.

BACKGROUND: Acute brain dysfunction during sepsis, which manifests as delirium or coma, is common and is associated with multiple adverse outcomes, including longer periods of mechanical ventilation, prolonged hospital stays, and increased mortality. Delirium and coma during sepsis may be manifestations of alteration in systemic metabolism. Because access to brain mitochondria is a limiting factor, measurement of peripheral platelet bioenergetics offers a potential opportunity to understand metabolic changes associated with acute brain dysfunction during sepsis.
OBJECTIVE: Are altered platelet mitochondrial bioenergetics associated with acute brain dysfunction during sepsis?
METHODS: We assessed participants with critical illness in the ICU for the presence of delirium or coma via validated assessment measures. Blood samples were collected and processed to isolate and measure platelet mitochondrial oxygen consumption. We used Seahorse extracellular flux to measure directly baseline, proton leak, maximal oxygen consumption rate, and extracellular acidification rate. We calculated adenosine triphosphate-linked, spare respiratory capacity, and nonmitochondrial oxygen consumption rate from the measured values.
RESULTS: Maximum oxygen consumption was highest in patients with coma, as was spare respiratory capacity and extracellular acidification rate in unadjusted analysis. After adjusting for age, sedation, modified Sequential Organ Failure Assessment score without the neurologic component, and preexisting cognitive function, increased spare respiratory capacity remained associated with coma. Delirium was not associated with any platelet mitochondrial bioenergetics.
CONCLUSIONS: In this single-center exploratory prospective cohort study, we found that increased platelet mitochondrial spare respiratory capacity was associated with coma in patients with sepsis. Future studies powered to determine any relationship between delirium and mitochondrial respiration bioenergetics are needed.

BACKGROUND Sepsis-associated acute kidney injury (SA-AKI) is linked to high mortality rates and an unfavorable prognosis. Early identification of patients with poor prognosis is crucial. This study aimed to investigate the relationship between the systemic immune-inflammation index (SII) and mortality in this specific patient population. MATERIAL AND METHODS This retrospective cohort study used data from the Medical Information Mart for Intensive Care IV database. Data on patient demographics, comorbidities, vital signs, laboratory parameters, treatment usage, acute kidney injury staging, and renal replacement therapy were collected within 48 h of intensive care unit admission. Restricted cubic splines, Kaplan-Meier curves, and Cox regression models were used for analysis. Stratified analyses were performed on the basis of various factors. RESULTS In total, 7856 patients were included, with a median age of 66.9 years and a male-to-female ratio of 57.7%-42.3%. A J-shaped relationship was observed between SII and mortality risk. The lowest mortality risk occurred at an SII of 760.078×10⁹/L. Compared to the reference group (second quartile of SII), the highest and third quartiles had increased 28-day mortality risk, with adjusted hazard ratios (HRs) of 1.33 (1.16-1.52) and 1.55 (1.36-1.77), respectively. Although a trend towards higher mortality hazard was observed in the lowest SII group (Q1), it was not statistically significant, with an adjusted HR of 1.15 (1-1.32). CONCLUSIONS In patients with SA-AKI, both low and high SII were associated with increased short-term mortality risk. The lowest mortality risk was observed at an SII of 760.078×10⁹/L within a 28-day period.