Plasma membrane rupture (PMR), the ultimate event during lytic cell death, releases damage-associated molecular patterns (DAMPs) that trigger inflammation and immune responses in the development of various diseases. Recent years have witnessed significant advances in understanding the PMR mediated by ninjurin1 (NINJ1) in different lytic cell death processes. NINJ1 oligomerizes and ruptures the membrane in pyroptosis and other lytic cell death, participating in the pathogenesis of multiple diseases. Although the membrane-permeabilizing function of NINJ1 is well recognized, the role of NINJ1 in different types of lytic cell death and its impact on multiple disease processes have yet to be fully elucidated. This review summarizes the latest advances in the mechanisms of NINJ1-mediated PMR, discusses the membrane-inducing activity of NINJ1 in different lytic cell death, explains the implications of NINJ1 in lytic cell death-related diseases, and lists the inhibitory strategies for NINJ1. We expect to provide new insights into targeting NINJ1 to suppress lytic cell death for therapeutic benefit, which may become a new strategy to control inflammatory cell lysis-related diseases.

Sepsis is one of the most prevalent conditions in critical care medicine and is characterized by a high incidence, mortality, and poor prognosis, with no specific treatment currently available. The pathogenesis of sepsis is complex with a dysregulated inflammatory response at its core. If the initial inflammatory response is not promptly controlled, patients often develop multiple organ dysfunction syndrome or die, whereas survivors may experience post-sepsis syndrome. Regulation by the central and autonomic nervous systems is essential for maintaining inflammatory homeostasis. Among these, the cholinergic anti-inflammatory pathway (CAP) has been extensively studied in sepsis owing to its significant role in modulating inflammatory responses. Recent advancements in CAP-related interventions include minimally invasive vagus nerve stimulation, novel α7nAchR-targeting drugs, serum choline acetyltransferase and cholinesterase, acupuncture, and focused ultrasound stimulation therapy. This review primarily discusses the advantages, limitations, and therapeutic prospects of these approaches. Additionally, heart rate variability, which reflects changes in autonomic nervous system function, can serve as an indicator for assessing the functional status of the vagus nerve. In summary, modulation of inflammatory responses through the vagus nerve-mediated CAP represents a potential strategy for achieving precision medicine for sepsis. Future research should focus on conducting high-quality clinical studies on CAP-based therapies in the context of sepsis-induced inflammatory dysregulation. Incorporating indicators to evaluate the autonomic nervous system function may further elucidate the impact of inflammatory dysregulation in the body.

This study investigated the relationship between the neutrophil-to-lymphocyte ratio (N/LPR) and its variability ratio (N/LPRR) with 30-day and 1-year mortality outcomes.

A total of 7,443 patients from the MIMIC-IV 2.2 database were included, with 1,765 having multiple N/LPR measurements. Mortality at 1 year and within 30 days served as the primary endpoints. Patients were stratified into four groups according to baseline N/LPRR quartiles. Receiver operating characteristic (ROC) curves assessed the predictive value of N/LPR and N/LPRR for mortality. Kaplan-Meier analysis estimated the risk of mortality events, while restricted cubic spline (RCS) analysis explored the non-linear associations between N/LPR, N/LPRR, and mortality. Cox proportional hazards regression identified the relationship between N/LPRR and all-cause mortality.

A total of 792 cases of 1-year mortality (44.9%) were recorded, with 437 deaths (24.8%) occurring within 30 days. ROC analysis revealed that N/LPRR outperformed N/LPR in predicting adverse outcomes. Higher N/LPR and N/LPRR were associated with increased mortality rates. RCS analysis indicated significant non-linear relationships between N/LPR, N/LPRR, and mortality risk (both p-values for nonlinearity < 0.001). Subgroup analyses confirmed the robustness of these findings.

In conclusion, elevated N/LPR and N/LPRR are linked to 30-day and 1-year mortality in patients with sepsis. N/LPRR, with its heightened sensitivity, offers clinicians valuable prognostic information on sepsis severity and progression.

Until recently, severe fever with thrombocytopenia syndrome (SFTS)-related disseminated intravascular coagulation (DIC) had not been elucidated. This study aimed to explore the clinical characteristics and outcomes of DIC in patients with SFTS.

Patients diagnosed with SFTS who were admitted to Zhongnan Hospital of Wuhan University from August 2016 to October 2023 were included. Patients' demographics and clinical data were collected. According to the presence of DIC, they were assigned into the DIC and non-DIC groups. Independent risk factors for prognosis were identified by univariate and multivariate logistic regression analyses.

A total of 246 consecutive patients diagnosed with SFTS were enrolled, including 216 (87.8%) patients in the non-DIC group and 30 (12.2%) patients in the DIC group. ALT, AST, ALP, GGT, LDH, creatinine, cystatin-C, amylase, lipase, CK, CK-MB, troponin I, BNP, PT, PTA, APTT, TT, FDP, D-dimer, CRP, procalcitonin, IL-6, SAA, ESR, ferritin levels, and viral load were significantly higher in patients with DIC. The cumulative survival rate of patients with DIC was significantly lower than that of patients without DIC. Furthermore, it is demonstrated that the presence of DIC was an independent risk factor for in-hospital mortality of patients with SFTS.

DIC is a potential complication and is associated with high mortality in patients with SFTS. Early recognition and timely management of this serious complication are important for patients with SFTS.

Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such as acute respiratory distress syndrome, sepsis, trauma and ischemia lead to the aberrant cytosolic accumulation and massive release of nucleic acids that are detected by antiviral innate immune receptors in the endosome or cytosol. Activation of receptors for deoxyribonucleic acids and ribonucleic acids triggers inflammation, a major contributor to morbidity and mortality in critically ill patients. In the past decade, there has been growing recognition of the therapeutic potential of targeting nucleic acid sensing in critical care. This review summarizes current knowledge of nucleic acid sensing in acute respiratory distress syndrome, sepsis, trauma and ischemia. Given the extensive research on nucleic acid sensing in common pathological conditions like cancer, autoimmune disorders, metabolic disorders and aging, we provide a comprehensive summary of nucleic acid sensing beyond critical illness to offer insights that may inform its role in critical conditions. Additionally, we discuss potential therapeutic strategies that specifically target nucleic acid sensing. By examining nucleic acid sources, sensor activation and function, as well as the impact of regulating these pathways across various acute diseases, we highlight the driving role of nucleic acid sensing in critical illness.

Sepsis, a systemic inflammation that occurs in response to a bacterial infection, is a significant medical challenge. Research conducted over the past decade has indicated strong associations among a patient's nutritional status, the composition of their gut microbiome, and the risk, severity, and prognosis of sepsis. Octanoic acid (OA) plays a vital role in combating sepsis and has a protective effect on both animal models and human patients. In this discussion, the potential protective mechanisms of OA in sepsis, focusing on its regulation of the inflammatory response, immune system, oxidative stress, gastrointestinal microbiome and barrier function, metabolic disorders and malnutrition, as well as organ dysfunction are explored. A comprehensive understanding of the mechanisms by which OA act may pave the way for new preventive and therapeutic approaches to sepsis.

Limited data are available on the use, duration, and dosage of anticoagulant therapy in patients with pneumonia-induced sepsis, and the survival benefits of heparin remain uncertain. This study aimed to assess whether heparin administration improves near-term survival in critically ill patients with pneumonia-induced sepsis and identify the optimal dosage and treatment duration.

This study utilized the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The variance inflation factor was employed to exclude highly collinear variables. Propensity score matching (PSM), the Cox proportional hazards model, and Cox regression subgroup analysis were used to evaluate the outcomes of subcutaneous heparin prophylactic anticoagulation after intensive care unit (ICU) admission. The primary outcomes were 30-, 45-, and 60-d mortality rates. Secondary outcomes included ICU length of stay (LOS_ICU), hospital length of stay (LOS_Hospital), in-hospital mortality, and the incidence of gastrointestinal bleeding.

We enrolled 1,586 adult patients with pneumonia-induced sepsis. After PSM, 1,176 patients remained (588 in the heparin group and 588 in the non-heparin group). The 45-d survival rate was significantly higher in the heparin-treated group than that in the non-heparin group (84.4% vs. 79.4%; HR: 0.75; 95% CI: 0.572-0.83; adjusted HR: 0.73, 95% CI: 0.563-0.964; P < 0.05). LOS_ICU and LOS_Hospital were significantly shorter in the heparin group (P < 0.001), with no significant difference in gastrointestinal bleeding incidence between the two groups. Cox proportional hazards models demonstrated that heparin dose and duration were strongly associated with 45-d survival. Subgroup analysis indicated a significant survival advantage in patients aged 18-60 years, without diabetes, chronic obstructive pulmonary disease, or stage 1 acute kidney injury, who received a daily heparin dose of 3 mL for more than 7 d.

Our study found that early administration of heparin, particularly in sufficient doses (Heparin Sodium 5,000 units/mL, 1 mL per dose, three times daily (TID)) for more than 7 d, was associated with reduced near-term mortality in critically ill patients with pneumonia-induced sepsis. These findings underscore the potential benefits of anticoagulant therapy in this high-risk patient population.

Cardiorenal syndrome (CRS) is a common and critical complication of sepsis, with high morbidity and mortality rates. Studies on biomarkers for the early prediction of septic CRS are sporadic. Classic and novel potential biomarkers were identified to explore their diagnostic performance of in patients with septic CRS.

A total of 138 patients with sepsis from Peking University People's Hospital were enrolled in this prospective observational study, which was conducted between May 2019 and June 2022. The patients were divided into non-CRS (n = 106) and CRS (n = 32) groups. Serum levels of cystatin C, KIM-1, neutrophil gelatinase-associated lipocalin (NGAL), and α-Klotho were detected at admission using enzyme-linked immunosorbent assay. The relationship between the biomarker levels and risk factors of CRS were analyzed, as well as discrimination accuracy comparisons were performed.

The incidence of CRS in patients with sepsis was 23.2% (32/138) during hospitalization, with an obvious mortality. Compared with the non-CRS group, serum cystatin C, brain natriuretic peptide (BNP), troponin-I (TNI), KIM-1, and NGAL levels were both significantly elevated at admission in patients with sepsis complicated with CRS. Logistic regression analysis revealed that BNP, TNI, cystatin C, albumin, Lac, D-dimer were risk factors for CRS in sepsis patients. Compared with other biomarkers, serum cystatin C had moderate discriminative power for predicting septic CRS (area under a receiver operating characteristic curve, 0.746; sensitivity, 0.719; specificity, 0.783). BNP combined with cystatin C and D-dimer demonstrated an excellent discrimination performance, for its AUROC was up to 0.878 (sensitivity, 0.844; specificity, 0.759).

Serum cystatin C, BNP, TNI, KIM-1, and NGAL levels are elevated in patients with septic CRS. Our study provides reliable evidence that cystatin C in combination with BNP and D-dimer might better predict septic CRS upon admission. Further research on sensitive biomarkers is needed.

Sepsis, as a clinically critical disease, usually induces coagulation disorders. It has been reported that ERBB2 Interacting Protein (Erbin) is involved in the development of various inflammatory diseases, and macrophages are involved in the regulation of coagulation disorders in sepsis. However, the role of Erbin in coagulation disorders in sepsis and the relationship between Erbin and macrophage regulation of coagulation function are still unclear.

At the cellular level, macrophages were treated with lipopolysaccharide (LPS) or MEK inhibitor (PD98059), protein expression levels were detected by Western blot, co-immunoprecipitation (Co-IP), and immunofluorescence, mRNA expression levels were detected by quantitative real-time polymerase chain reaction (qPCR), and the concentration of tissue factor (TF) in cell supernatant was detected by enzyme linked immunosorbent assay (ELISA). At the animal level, the cecal ligation and perforation (CLP) model was constructed in mice, and the inflammatory response and coagulation disorder of mice were observed by hematoxylin-eosin (HE) staining, immunohistochemistry, ELISA, and automatic hemagglutination analyzer. The protein and mRNA expression level were detected by Western blot and qPCR. Pearson linear correlation analysis was used to analyze the correlation between the inflammation index and the coagulation function index.

We confirmed that the Erbin is involved in the regulation of coagulation function by macrophages and plays a role in the coagulation disorder of sepsis. In vivo studies have shown that mice with Erbin deletion have more obvious enhanced coagulation function, and in vitro studies have shown that Erbin knockout mediated macrophage secretion of TF by activating the Ras/Raf pathway.

Erbin reduces the coagulation activation by inhibiting TF release from macrophages.

Pediatric patients with sepsis are frequently subjected to red blood cell (RBC) transfusions but yet its association with mortality is still controversial.

We consecutively selected 125 patients with sepsis, severe sepsis, and septic shock admitted to intensive care unit (ICU) in our center from January 2022 to January 2023, and finally 100 patients were included in this retrospective cohort study. The patients were divided into two groups: group I who received RBC transfusion and group II who did not receive RBC transfusion. Logistic regression analysis was used to determine the demographic and clinical factors related to receiving RBC transfusion. The association of RBC transfusion with mortality was determined by the Cox regression model, and the mechanical ventilation rate and length of stay by the logistic regression model.

Among the 100 patients, 67 and 33 cases belonged to the RBC-transfused and not-transfused groups, respectively. Lower hemoglobin level (OR = 0.918, 95%CI: 0.881-0.957, p < 0.001), increased c-reactive protein level (OR = 1.022, 95%CI: 1.002-1.043, p = 0.034), and lower platelets count (OR = 0.994, 95%CI: 0.988-0.999, p = 0.023) were associated with RBC transfusions. While the associations of RBC transfusion with mortality and mechanical ventilation were not shown to be statistically significant (HR = 3.926, 95%CI: 0.952-16.186, p = 0.058 and OR = 2.588, 95%CI: 0.832-8.046, p = 0.1), RBC transfusion might be associated with increased ICU length of stay (OR = 16.477, 95%CI: 3.86-70.342, p < 0.001). In the overall survival analysis, younger age (HR = 0.093, 95%CI: 0.027-0.320, p < 0.001), the use of mechanical ventilation (HR = 8.893, 95%CI: 1.483-53.336, p = 0.017), and more severe disease (severe sepsis vs. sepsis, HR = 24.531, 95%CI: 1.923-321.914, p = 0.014; septic shock vs. sepsis, HR = 32.187, 95%CI: 2.977-347.949, p = 0.004) were related to increased mortality.

RBC transfusions are significantly associated with increased ICU length of stay and not associated with 28-day mortality and mechanical ventilation rate. Other factors affecting mortality in pediatric patients with sepsis, severe sepsis, and septic shock are younger age, use of mechanical ventilation, and more severe disease.

To assess antithrombin and activated protein C (aPC) levels in relation to disseminated intravascular coagulation (DIC) and severe outcomes in pediatric sepsis.

Prospective, observational study conducted between April 2023 and October 2024. Coagulation profiles including conventional coagulation, antithrombin activity, and aPC were obtained at PICU admission.

PICU in the Vietnam National Children's Hospital, Hanoi, Vietnam.

PICU admissions, 1 month to 18 years old, with sepsis.

None.

One hundred thirty children (78 males; median age 7.5 mo) with mortality 23/130 (17.7%). The prevalence of overt DIC was 37 of 130 (28.5%). Nonsurvival at 28 days, compared with survival, was associated with hemorrhage and/or thrombosis at presentation, and higher number of dysfunctional organs, and overt DIC. Those with overt DIC, compared with not, had longer activated partial thromboplastin time, higher international normalized ratio and d -dimer, and lower antithrombin, and aPC. Activity of antithrombin and aPC correlated inversely with the Vasoactive-Inotropic Score in survivors ( p = 0.002 and 0.009, respectively). Patients with a cutoff value for antithrombin less than 63.5% had a mortality risk with area under the receiver operating characteristic (AUROC) curve 0.64, with sensitivity 0.51 and specificity 0.74, and positive predictive value 0.30. Regarding overt DIC, a cutoff value for antithrombin less than 55.5% had an AUROC 0.78, sensitivity 0.72 and specificity of 0.73, and positive predictive value 0.52.

In this observational study of pediatric sepsis patients, first 24-hour coagulation data in those who did not-survive to 28 days, vs. survivors showed an associated prior lower level of antithrombin in nonsurvivors. Furthermore, using the outcome of overt DIC and nonovert DIC in the first 72 hours, we found that lower levels of antithrombin or aPC are each associated with overt DIC and nonovert DIC in pediatric sepsis. Further validation work is needed in larger case series of pediatric sepsis.

Dahuang Mudan decoction (DMD) is a traditional Chinese prescription from Zhang Zhongjing's Synopsis of the Golden Chamber. In clinical practice, it is often used in the treatment of infectious diseases.

To assess the therapeutic effect of DMD and its disassembled prescriptions on septic mice, and explore its potential mechanism.

Cecal ligation and puncture (CLP) sepsis and endotoxemia mice models were established. The effects of DMD, its disassembled prescriptions and active compounds were studied. Xuebijing injection (XBJ) was used as positive drug. Mice 7-day survival rates, blood biochemical markers, hematoxylin and eosin (HE) staining and immune cell infiltration were used to evaluate the overall protective effect of the drugs on mice. Inflammatory cytokines and coagulation activation indicators were detected by enzyme-linked immunosorbent assay (ELISA).

DMD, its Huoxue prescription, constituent drugs Mudanpi (MDP) and Taoren (TR) significantly protected mice with sepsis, improved the survival rate, reduced the degree of organ damage, and reduced the infiltration of immune cells in the lung tissues. The protective effect is comparable to that of XBJ. MDP and TR inhibited the levels of inflammatory factors and coagulation activation in septic mice. Paeonol and paeoniflorin in MDP showed significant protective effects on septic mice, and inhibited inflammatory cytokines level and coagulation activation.

These results confirm that DMD and its disassembled prescriptions have good therapeutic effect on septic mice, and the mechanism may be related to inhibition of the inflammatory response and coagulation activation.

Heparin-binding protein (HBP) levels have been linked to organ failure and may represent an inflammatory biomarker of sepsis. We found disseminated intravascular coagulation (DIC) is associated with higher HBP levels in patients and in in vivo and in vitro models. This prospective, single-center observational study investigated the effects and underlying mechanisms of HBP on the coagulation cascade in sepsis.

538 patients with sepsis from June 2016 to December 2019 were enrolled. Mechanisms underlying HBP and the coagulation system were investigated in human umbilical vein endothelial cells (HUVEC) and C57 mice.

Increased HBP was associated with sepsis-induced DIC. The optimal cutoff value was 37.5 ng/mL (sensitivity: 56 %, specificity: 65 %). Antithrombin-III (AT-III) activity, plasmin-a2 plasmin inhibitor complex (PIC), procalcitonin (PCT), hemoglobin, and HBP ≥37.5 ng/mL were associated with of DIC occurrence. In HUVECs &C57 mice models, Western blotting, qPCR, and immunohistochemistry analysis showed that the binding between HBP and TGF-β receptor 2 (TGFBR2) caused elevation of plasminogen activator inhibitor-1 (PAI-1) levels. Furthermore, we found that mice stimulated with HBP had higher levels of fibrinogen and D-dimer in the blood. HBP treatment caused the accumulation of fibrinogen in mice lung tissue. Treatment with TGFBR2-small interfering RNAs inhibited the effects.

Patients with sepsis having HBP ≥37.5 ng/mL at admission were more likely to develop DIC. HBP upregulates the expression of fibrinogen and PAI-1 via TGFBR2 and the TGF-β signalling pathway.

The complement system, comprising over 30 proteins, is integral to the immune system, and the coagulation system is critical for vascular homeostasis. The activation of the complement and coagulation systems involves an organized proteolytic cascade, and the overactivation of these systems is a central pathogenic mechanism in several diseases. This review describes the role of complement and coagulation system activation in critical illness, particularly sepsis. The complexities of sepsis reveal significant knowledge gaps that can be compared to a profound abyss, highlighting the urgent need for further investigation and exploration. It is well recognized that the inflammatory network, coagulation, and complement systems are integral mechanisms through which multiple factors contribute to increased susceptibility to infection and may result in a disordered immune response during septic events in patients. Given the overlapping pathogenic mechanisms in sepsis, immunomodulatory therapies currently under development may be particularly beneficial for patients with sepsis who have concurrent infections. Herein, we present recent findings regarding the molecular relationships between the coagulation and complement pathways in the advancement of sepsis, and propose potential intervention targets related to the crosstalk between coagulation and complement, aiming to provide more valuable treatment of sepsis.

Coagulopathy is a critical pathophysiological mechanism of acute pancreatitis (AP), arising from the complex interplay between innate immune, endothelial cells and platelets. Although initially beneficial for the host, uncontrolled and systemic activation of coagulation cascade in AP can lead to thrombotic and hemorrhagic complications, ranging from subclinical abnormalities in coagulation tests to severe clinical manifestations, such as disseminated intravascular coagulation. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1. Finally, increased fibrin generation and impaired break down lead to deposition of (micro) vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. Despite the high burden of coagulopathy that have a negative impact on AP patients' prognosis, there is no effective treatment yet. Although a variety of anticoagulants drugs have been evaluated in clinical trials, their beneficial effects are inconsistent, and they are also characterized by hemorrhagic complications. Future studies are called to unravel the pathophysiologic mechanisms involved in coagulopathy in AP, and to test novel therapeutics block coagulopathy in AP.

This research investigated the intricate relationship between ferroptosis and sepsis by utilizing advanced genomic and pharmacological methodologies. Specifically, we obtained expression quantitative trait loci (eQTLs) for 435 genes associated with ferroptosis from the eQTLGen Consortium and detected notable cis-eQTLs for 281 of these genes. Next, we conducted a detailed analysis to assess the impact of these eQTLs on susceptibility to sepsis using Mendelian randomization (MR) with data from a cohort of 10,154 sepsis patients and 452,764 controls sourced from the UK Biobank. MR analysis revealed 16 ferroptosis-related genes that exhibited significant associations with sepsis outcomes. To bolster the robustness of these findings, sensitivity analyses were performed to assess pleiotropy and heterogeneity, thus confirming the reliability of the causal inferences. Furthermore, single-cell RNA sequencing data from sepsis patients offered a detailed examination of gene expression profiles, demonstrating varying levels of ferroptosis marker expression across different cell types. Pathway enrichment analysis utilizing gene set enrichment analysis (GSEA) further revealed the key biological pathways involved in the progression of sepsis. Additionally, the use of computational molecular docking facilitated the prediction of interactions between identified genes and potential therapeutic compounds, highlighting novel drug targets. In conclusion, our integrated approach combining genomics and pharmacology offers valuable insights into the involvement of ferroptosis in sepsis, laying the groundwork for potential therapeutic strategies targeting this cell death pathway to enhance sepsis management.

Bilateral adrenal hemorrhage is a rare but often a fatal cause of primary adrenal insufficiency that can result in adrenal crisis if not identified and managed appropriately.

We present a case of a 27-year-old Caucasian female who was admitted to the hospital 17 days postpartum with pleuritic chest and flank pain, shortness of breath and nausea. Computed tomography imaging confirmed multiple thromboemboli including pulmonary emboli and noted bilateral bulky adrenal glands. She was managed for infection and pulmonary emboli; however, she complained of persistent headaches, nausea, and vomiting despite appropriate management. Radiology re-review found the computed tomography imaging was consistent with bilateral adrenal hemorrhage in hindsight. Subsequent endocrine evaluation with hypothalamic-pituitary-adrenal axis interrogation and adrenocorticotropic hormone (Synacthen) stimulation testing confirmed resultant primary adrenal insufficiency. She required urgent intravenous hydrocortisone and was subsequently discharged on oral adrenal replacement therapy and anticoagulation.

Delay in identification and treatment of adrenal insufficiency can lead to catastrophic outcomes. This case highlights the challenge of diagnosing bilateral adrenal hemorrhage and resultant adrenal insufficiency as patients may not present with the classic risk factors, signs, symptoms, and electrolyte derangements.

Sepsis, characterized by a widespread and dysregulated immune response to infection leading to organ dysfunction, presents significant challenges in diagnosis and treatment. In this study, we investigated 203 coagulation-related genes in sepsis patients to explore their roles in the disease. Through differential gene expression analysis, we identified 20 genes with altered expression patterns. Subsequent correlation analysis, visualized through circos plots and heatmaps, revealed significant relationships among these genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that these genes are involved in immune response activation, coagulation, and immune receptor activity. Disease Ontology (DO) enrichment analysis further linked these genes to autoimmune hemolytic anemia and tumor-related signaling pathways. Additionally, the CIBERSORT analysis highlighted differences in immune cell composition in sepsis patients, revealing an increase in neutrophils and monocytes and a decrease in inactive NK cells, CD8 T cells, and B cells. We employed machine learning techniques, including random forest and SVM, to construct a diagnostic model, identifying FCER1G and FYN as key biomarkers. These biomarkers were validated through their expression levels and ROC curve analysis in an independent validation cohort, demonstrating strong diagnostic potential. Single-cell analysis from the GSE167363 dataset further confirmed the distinct expression profiles of these genes across various cell types, with FCER1G predominantly expressed in monocytes, NK cells, and platelets, and FYN in CD4+ T cells and NK cells. Enrichment analysis via GSEA and ssGSEA revealed that these genes are involved in critical pathways, including intestinal immune networks, fatty acid synthesis, and antigen processing. In conclusion, our comprehensive analysis identifies FCER1G and FYN as promising biomarkers for sepsis, providing valuable insights into the molecular mechanisms of this complex condition. These findings offer new avenues for the development of targeted diagnostic and therapeutic strategies in sepsis management.

Background: Disseminated intravascular coagulation (DIC) is a severe condition affecting the coagulation system. However, current knowledge regarding its incidence and mortality remains limited. In this study, we examined the incidence and mortality of DIC, including time trends, in Denmark. Methods: In this population-based cohort study, potential DIC cases were identified through the hospital laboratory database in the Central Denmark Region which has a population of approximately 1.3 million residents. Eligibility criteria were age above 18 years, a positive DIC score, and a disease associated with DIC. All eligible patients underwent a review of their medical records. Follow-up started on the date of a patient's first positive DIC score. Age- and sex-standardized incidence rates were calculated using year-specific DIC events as the numerator and the adult population of the Central Denmark Region as the denominator. All-cause 30-day mortality in the DIC cohort was computed based on Kaplan-Meier estimates and the mortality rates between subgroups were examined using logistic regression. Results: Among the 40,534 patients for whom all DIC biomarkers were measured on the same date, 6748 had a positive DIC score. Of these, 2565 were included in the cohort. The median age was 64 years, and 56.1% were men. The overall incidence rate per 100,000 person years declined during the study period, from 33.1 in 2013 to 24.0 in 2020. Thirty-day all-cause mortality was 35% in 2013 and 41.3% in 2020. Conclusions: The overall incidence rate of DIC declined between 2013 and 2020, mainly reflecting a declining incidence among patients with infection-associated DIC. Mortality did not improve.

This prospective study investigated the relationship between inflammation, damage-associated molecular patterns (DAMPs), and thrombus formation on dialyzer membranes in critically ill patients undergoing renal replacement therapy (RRT) from July 2020 to August 2022, identifying mechanisms and interventions to prevent clotting. The patients were divided into two groups: inflammatory (n = 56, serum C-reactive protein >10 mg/dl) and noninflammatory control (n = 45, serum C-reactive protein <5 mg/dl). Cell-free deoxyribonucleic acid (DNA) levels, high mobility group box 1 protein (HMGB1), histone H3, and myeloperoxidase (MPO) in the lumen of the hollow fiber membrane of the dialyzer were quantified. Immunostaining assessed leukocytes, fibrin fibers, and platelet thrombi on the luminal surface of the hollow fiber membrane. The inflammatory group, compared to controls, exhibited elevated cell-free DNA, HMGB1, and MPO levels, although histone H3 remained unchanged. Damage-associated molecular patterns increased with disseminated intravascular coagulation (DIC) severity. Immunostaining in the inflammatory group revealed leukocytes, amorphous nuclei, neutrophil extracellular trap-like structures, fibrin fibers, and platelet thrombi on the hollow fiber membrane's luminal surface. Elevated DAMP levels in severely inflamed patients' dialyzer membranes, correlating with DIC severity, indicate a link between inflammation, coagulation activation, and dialyzer clotting. Research into thrombus prevention in RRT for DIC-affected critically ill patients is warranted.

Sepsis is a life-threatening condition that affects 49 million people annually. Managing sepsis-associated coagulopathy poses a significant challenge due to its high mortality rates in intensive care. Recent reports suggest that administering heparin may offer potential survival benefits in sepsis and coronavirus disease cases. However, there is currently no established evidence supporting the use of heparin for sepsis. Thus, in this study, we aimed to assess the efficacy of heparin administration in patients with sepsis.

A systematic review was conducted following the PRISMA guidelines. The searches included MEDLINE, Cochrane, and Japanese databases up to January 2023. The inclusion criteria consisted of randomized control trials (RCTs) involving adult sepsis patients receiving heparin. The risk of bias was assessed using RoB2, and the data extraction included 28-day mortality and bleeding complications.

Out of 1733 initial articles, only three studies met the inclusion criteria. The analysis, which included 426 patients, showed no significant difference in 28-day and in-hospital mortality between the heparin and control groups (risk ratio [RR] = 0.86, 95% confidence interval [CI]: 0.60-1.24). Subgroup analysis of sepsis-associated disseminated intravascular coagulation (DIC) patients (n = 109) also did not show a significant reduction in mortality (RR = 0.84, 95% CI: 0.51-1.38). Heterogeneity was zero, and no publication bias was observed. Additionally, there was significant difference in bleeding complications (RR = 0.49, 95% CI: 0.24-0.99, p = 0.047).

This meta-analysis did not demonstrate a survival benefit of heparin administration in patients with sepsis and sepsis-associated DIC. Further investigation into the potential benefits of heparin is warranted. Moreover, the analysis revealed no increase in bleeding risks with heparin administration; instead, a significant reduction in the risk of bleeding was noted.

This review was preregistered with PROSPERO (registration: CRD42023385091).

Background/Objectives: Neutrophils, as the first line of defense in the immune response, produce neutrophil extracellular traps (NETs) upon activation, which are significant in the pathogenesis and organ damage in sepsis. This study aims to explore the clinical value of myeloperoxidase-DNA (MPO-DNA) and cell-free DNA (cf-DNA) in sepsis patients. Methods: Clinical data were collected from 106 sepsis patients, 25 non-sepsis patients, and 51 healthy controls. Sequential Organ Failure Assessment (SOFA) scores were calculated, and levels of MPO-DNA) complexes and cf-DNA were measured using specific kits. Correlation analyses assessed relationships between indicators, while logistic regression identified independent risk factors. Receiver operating characteristic (ROC) curves calculated the area under the curve (AUC) to evaluate the diagnostic value of the biomarkers. Results: Sepsis patients exhibited significantly elevated levels of MPO-DNA and cf-DNA compared to non-sepsis patients and healthy controls. In sepsis patients, MPO-DNA and cf-DNA levels correlated with inflammation, coagulation, and organ damage indicators, as well as procalcitonin (PCT) levels and SOFA scores. Both C-reactive protein (CRP) and cf-DNA were identified as independent risk factors for sepsis, demonstrating moderate diagnostic value. ROC analysis showed that the combination of MPO-DNA and CRP (AUC: 0.837) enhances the AUC value of CRP (0.777). Conclusions: In summary, elevated serum levels of MPO-DNA and cf-DNA in sepsis patients correlate with SOFA scores and PCT levels, providing reference value for sepsis diagnosis in clinical settings.

Sepsis is a severe inflammatory disease characterized by cytokine storm, often accompanied by disseminated intravascular coagulation (DIC). PANoptosis is a novel form of cell death triggered by cytokine storms, characterized by a cascade reaction of pyroptosis, apoptosis, and necroptosis. It exists in septic platelets and is closely associated with the onset and progression of DIC. However, there remains an unmet need for drugs targeting PANoptosis. The anti-PANoptosis effect of myricetin was predicted using network pharmacology and confirmed through molecular docking. In vitro platelet activation models demonstrated that myricetin significantly attenuated platelet particle release, integrin activation, adhesion, spreading, clot retraction, and aggregation. Moreover, in a sepsis model, myricetin reduced inflammatory infiltration in lung tissue and platelet activation while improving DIC. Additionally, whole blood sequencing samples from sepsis patients and healthy individuals were analyzed to elucidate the up-regulation of the PANoptosis targets. Our findings demonstrate the inhibitory effect of myricetin on septic platelet PANoptosis, indicating its potential as a novel anti-cellular PANoptosis candidate and therapeutic agent for septic DIC. Furthermore, our study establishes a foundation for utilizing network pharmacology in the discovery of new drugs to treat various diseases.

Dysregulated host response to infection causes life-threatening organ dysfunction. Excessive inflammation and abnormal blood coagulation can lead to disseminated intravascular coagulation (DIC) and multiple-organ failure in the late sepsis stages. Platelet function impairment in sepsis contributes to bleeding, secondary infection, and tissue injury. Platelet transfusion is considered in patients with sepsis with DIC and bleeding; however, its benefits are limited and of low quality. Fibrinogen plays a crucial role in platelet function, and establishing a fibrin network binds to activated integrin αIIbβ3 and promotes outside-in signaling that amplifies platelet functions. However, the role of fibrinogen in sepsis-induced platelet dysfunction remains unclear.

We evaluated the effects of fibrinogen on platelet hyporeactivity during septic shock in adult male Wistar rats using lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP) surgery. Changes in the hemodynamic, biochemical, and coagulation parameters were examined. Platelet activation and aggregation were measured using whole-blood assay, 96-well plate-based aggregometry, and light-transmission aggregometry. Additionally, platelet adhesion, spreading, and fibrin clot retraction were evaluated.

Rats with LPS- and CLP-induced sepsis displayed considerable decreases in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and clot retraction. The aggregation of platelets obtained from rats with sepsis was markedly augmented by fibrinogen supplementation. Additionally, fibrinogen administration improved platelet adhesion, spreading, and clot retraction in rats with sepsis.

Fibrinogen supplementation could serve as a potential therapeutic intervention for alleviating platelet hyporeactivity in patients with sepsis and bleeding.

Sepsis is a life-threatening organ dysfunction caused by an abnormal host response to microbial infections. During its pathogenesis, vascular endothelial cells (ECs) play a pivotal role as essential components in maintaining microcirculatory homeostasis. This article aims to comprehensively review the multifaceted physiological functions of vascular ECs, elucidate the alterations in their functionality throughout the course of sepsis, and explore recent advancements in research concerning sepsis-related therapeutic drugs targeting ECs.

Vitamin K is essential for numerous physiological processes, including coagulation, bone metabolism, tissue calcification, and antioxidant activity. Deficiency, prevalent in critically ill ICU patients, impacts coagulation and increases the risk of bleeding and other complications. This review aims to elucidate the metabolism of vitamin K in the context of critical illness and identify a potential therapeutic approach.

In December 2023, a scoping review was conducted using the PRISMA Extension for Scoping Reviews. Literature was searched in PubMed, Embase, and Cochrane databases without restrictions. Inclusion criteria were studies on adult ICU patients discussing vitamin K deficiency and/or supplementation.

A total of 1712 articles were screened, and 13 met the inclusion criteria. Vitamin K deficiency in ICU patients is linked to malnutrition, impaired absorption, antibiotic use, increased turnover, and genetic factors. Observational studies show higher PIVKA-II levels in ICU patients, indicating reduced vitamin K status. Risk factors include inadequate intake, disrupted absorption, and increased physiological demands. Supplementation studies suggest vitamin K can improve status but not normalize it completely. Vitamin K deficiency may correlate with prolonged ICU stays, mechanical ventilation, and increased mortality. Factors such as genetic polymorphisms and disrupted microbiomes also contribute to deficiency, underscoring the need for individualized nutritional strategies and further research on optimal supplementation dosages and administration routes.

Addressing vitamin K deficiency in ICU patients is crucial for mitigating risks associated with critical illness, yet optimal management strategies require further investigation.

To the best of our knowledge, this review is the first to address the prevalence and progression of vitamin K deficiency in critically ill patients. It guides clinicians in diagnosing and managing vitamin K deficiency in intensive care and suggests practical strategies for supplementing vitamin K in critically ill patients. This review provides a comprehensive overview of the existing literature, and serves as a valuable resource for clinicians, researchers, and policymakers in critical care medicine.

Severe inflammation and oxidative stress are characteristics of sepsis-associated kidney injury with high morbidity and mortality. Eriocitrin (ERI) has shown promise in suppressing sepsis-associated kidney injury and LPS-induced periodontal disease, however, its efficacy in alleviating SAKI remains unexplored. This study aimed to investigate the therapeutic potential of ERI on SAKI through in vivo and in vitro experiments, elucidating its underlying mechanism.

The therapeutic effects of ERI against SAKI were evaluated by survival rate, changes of serum creatinine (Scr) and blood urea nitrogen (BUN) and statistic of renal histological score in a Cecal ligation and puncture (CLP)-induced septic mice. Impactions about anti-coagulation, anti-inflammation, anti-oxidative stress and improvement of mitochondrial damage and mitochondrial morphology were further assayed. In vitro, HUVECs upon stimulation of LPS with or without different dosage of ERI, followed by evaluating changes in inflammation, mitochondrial dynamic equilibrium and signaling pathways.

ERI demonstrated ameliorative effects on SAKI by attenuating inflammation, oxidative stress and coagulation evidenced by the improved survival rate, alleviated kidney histological injury, declined BUN and Scr in serum and diminished levels of inflammation cytokines, and coagulation factors. Mechanistically, ERI suppressed DRP1-regulated mitochondrial fission and promoted OPA1-modulated mitochondrial fusion by activating Nrf2 in septic mice and LPS-stimulated HUVECs, which maintained mitochondrial dynamic equilibrium, improved mitochondrial morphology, assured integrity of mitochondrial function, decreased oxidative stress, impeded overwhelming inflammation, and thus, played a pivotal role in ERI's protection against SAKI.

Our data confirmed the therapeutic potential of ERI in mitigating SAKI，suggesting its viability as a pharmacological agent in clinic settings.

Acute lung injury (ALI) linked to sepsis has a high mortality rate, with limited treatment options available. In recent studies, medical ozone has shown promising results in alleviating inflammation and infection. Here, we aimed to evaluate the therapeutic potential of medical ozone in sepsis-induced ALI using a mouse model, measuring behavioral assessments, lung function, and blood flow. Western blot was used to quantify the levels of protein. In vitro, experiments on BMDM cells examine the impact of AMPK inhibitors and agonists on phagocytic activity. Results indicate that medical ozone can enhance the survival rate, ameliorate lung injury, and improve lung function and limb microcirculation in mice with ALI. Notably, it inhibits NETs formation, a crucial player in ALI development. Medical ozone also counteracts elevated TF, MMP-9, and IL-1β levels. In ALI mice, the effects of ozone are nullified and BMDMs exhibit impaired engulfment of NETs following Sr-a1 knockout. Under normal physiological conditions, the use of an AMPK antagonist produces similar effects to Sr-a1 knockout, significantly inhibiting the phagocytosis of NETs by BMDMs. On the contrary, AMPK agonists enhance this phagocytic process. In conclusion, medical ozone can alleviate sepsis-induced lung injury via the AMPK/SR-A1 pathway, thereby enhancing phagocytosis of NETs by macrophages.

Sepsis is a common and critical condition encountered in clinical practice that can lead to multi-organ dysfunction. Sepsis-induced coagulopathy (SIC) significantly affects patient outcomes. However, the precise mechanisms remain unclear, making the identification of effective prognostic and therapeutic targets imperative.

The analysis of transcriptome data from the whole blood of sepsis patients, facilitated the identification of key genes implicated in coagulation. Then we developed a prognostic model and a nomogram to predict patient survival. Consensus clustering classified sepsis patients into three subgroups for comparative analysis of immune function and immune cell infiltration. Single-cell sequencing elucidated alterations in intercellular communication between platelets and immune cells in sepsis, as well as the role of the coagulation-related gene FYN. Real-time quantitative PCR determined the mRNA levels of critical coagulation genes in septic rats' blood. Finally, administration of a FYN agonist to septic rats was observed for its effects on coagulation functions and survival.

This study identified four pivotal genes-CFD, FYN, ITGAM, and VSIG4-as significant predictors of survival in patients with sepsis. Among them, CFD, FYN, and ITGAM were underexpressed, while VSIG4 was upregulated in patients with sepsis. Moreover, a nomogram that incorporates the coagulation-related genes (CoRGs) risk score with clinical features of patients accurately predicted survival probabilities. Subgroup analysis of CoRGs expression delineated three molecular sepsis subtypes, each with distinct prognoses and immune profiles. Single-cell sequencing shed light on heightened communication between platelets and monocytes, T cells, and plasmacytoid dendritic cells, alongside reduced interactions with neutrophils in sepsis. The collagen signaling pathway was found to be essential in this dynamic. FYN may affect platelet function by modulating factors such as ELF1, PTCRA, and RASGRP2. The administration of the FYN agonist can effectively improve coagulation dysfunction and survival in septic rats.

The research identifies CoRGs as crucial prognostic markers for sepsis, highlighting the FYN gene's central role in coagulation disorders associated with the condition and suggesting novel therapeutic intervention strategies.

Hypercoagulability and reduced fibrinolysis are well-established complications associated with COVID-19. However, the timelines for the onset and resolution of these complications remain unclear. The aim of this study was to evaluate, in a cohort of COVID-19 patients, changes in coagulation and fibrinolytic activity through ROTEM assay at different time points during the initial 30 days following the onset of symptoms in both mild and severe cases. Blood samples were collected at five intervals after symptoms onset: 6-10 days, 11-15 days, 16-20 days, 21-25 days, and 26-30 days. In addition, fibrinogen, plasminogen, PAI-1, and alpha 2-antiplasmin activities were determined. Out of 85 participants, 71% had mild COVID-19. Twenty uninfected individuals were evaluated as controls. ROTEM parameters showed a hypercoagulable state among mild COVID-19 patients beginning in the second week of symptoms onset, with a trend towards reversal after the third week of symptoms. In severe COVID-19 cases, hypercoagulability was observed since the first few days of symptoms, with a tendency towards reversal after the fourth week of symptoms onset. A hypofibrinolytic state was identified in severe COVID-19 patients from early stages and persisted even after 30 days of symptoms. Elevated activity of PAI-1 and alpha 2-antiplasmin was also detected in severe COVID-19 patients. In conclusion, both mild and severe cases of COVID-19 exhibited transient hypercoagulability, reverted by the end of the first month. However, severe COVID-19 cases sustain hypofibrinolysis throughout the course of the disease, which is associated with elevated activity of fibrinolysis inhibitors. Persistent hypofibrinolysis could contribute to long COVID-19 manifestations.

Sepsis is accompanied by a less-known mismatch between hemodynamics and mitochondrial respiration. We aimed to characterize the relationship and time dependency of microcirculatory and mitochondrial functions in a rodent model of intraabdominal sepsis. Fecal peritonitis was induced in rats, and multi-organ failure (MOF) was evaluated 12, 16, 20, 24 or 28 h later (n = 8/group, each) using rat-specific organ failure assessment (ROFA) scores. Ileal microcirculation (proportion of perfused microvessels (PPV), microvascular flow index (MFI) and heterogeneity index (HI)) was monitored by intravital video microscopy, and mitochondrial respiration (OxPhos) and outer membrane (mtOM) damage were measured with high-resolution respirometry. MOF progression was evidenced by increased ROFA scores; microcirculatory parameters followed a parallel time course from the 16th to 28th h. Mitochondrial dysfunction commenced with a 4-h time lag with signs of mtOM damage, which correlated significantly with PPV, while no correlation was found between HI and OxPhos. High diagnostic value was demonstrated for PPV, mtOM damage and lactate levels for predicting MOF. Our findings indicate insufficient splanchnic microcirculation to be a possible predictor for MOF that develops before the start of mitochondrial dysfunction. The adequate subcellular compensatory capacity suggests the presence of mitochondrial subpopulations with differing sensitivity to septic insults.

Sepsis in pediatric patients can progress to severe sepsis, and identifying biomarkers of this progression may permit timely intervention to prevent it. This study aimed to investigate the ability of thrombin-antithrombin complex (TAT), α2-plasmininhibitor-plasmin complex (PIC) and tissue-type plasminogen activator-inhibitor complex (t-PAIC) to predict severe sepsis in pediatrics early.

148 eligible pediatric sepsis patients were enrolled in this study, and were then divided into those who progressed to severe sepsis (n = 50) or not (n = 98). Serum levels of TAT, PIC, and t-PAIC were analysed, and simplified pediatric critical illness score (PCIS) and DIC score were calculated on the day of pediatric sepsis diagnosis.

Compared with sepsis patients, severe sepsis patients had higher levels of TAT, PIC and t-PAIC. Correlation analysis revealed that TAT, PIC and t-PAIC were significantly correlated with simplified PCIS and DIC score. ROC curve analysis suggested that TAT, PIC and t-PAIC could serve as biomarkers for predicting severe sepsis with the AUC up to 0.862, 0.759 and 0.851, respectively. Stratified analysis demonstrated that the patients with increased levels of TAT, PIC and t-PAIC had worse illness severity and clinical outcome. Univariate logistic regression analysis revealed that TAT, PIC and t-PAIC were all risk factors for severe sepsis, yet only TAT and t-PAIC were independent risk factors in multivariate model.

TAT, PIC and t-PAIC could serve as biomarkers for predicting severe sepsis, and correlated with illness severity in pediatrics, what's more, serum levels of TAT and t-PAIC may be independent risk factors for pediatric severe sepsis.

The performance of the sepsis-induced coagulopathy (SIC) and sequential organ failure assessment (SOFA) scores in predicting the prognoses of patients with sepsis has been validated. This study aimed to investigate the time course of SIC and SOFA scores and their association with outcomes in patients with sepsis.

This prospective study enrolled 209 patients with sepsis admitted to the emergency department. The SIC and SOFA scores of the patients were assessed on days 1, 2, and 4. Patients were categorized into survivor or non-survivor groups based on their 28-day survival. We conducted a generalized estimating equation analysis to evaluate the time course of SIC and SOFA scores and the corresponding differences between the two groups. The predictive value of SIC and SOFA scores at different time points for sepsis prognosis was evaluated.

In the non-survivor group, SIC and SOFA scores gradually increased during the first 4 days (P < 0.05). In the survivor group, the SIC and SOFA scores on day 2 were significantly higher than those on day 1 (P < 0.05); however, they decreased on day 4, dropping below the levels observed on day 1 (P < 0.05). The non-survivors showed higher SIC scores on days 2 (P < 0.05) and 4 (P < 0.001) than the survivors, whereas no significant differences were found between the two groups on day 1 (P > 0.05). The performance of SIC scores on day 4 for predicting mortality was more accurate than that on day 2, with areas under the curve of 0.749 (95% confidence interval [CI]: 0.674-0.823), and 0.601 (95% CI: 0.524-0.679), respectively. The SIC scores demonstrated comparable predictive accuracy for 28-day mortality to the SOFA scores on days 2 and 4. Cox proportional hazards models indicated that SIC on day 4 (hazard ratio [HR] = 3.736; 95% CI: 2.025-6.891) was an independent risk factor for 28-day mortality.

The time course of SIC and SOFA scores differed between surviving and non-surviving patients with sepsis, and persistent high SIC and SOFA scores can predict 28-day mortality.

Sepsis is defined as a life-threatening organ dysfunction caused by excessive host response to infection, and represents the most common cause of in-hospital deaths. Sepsis accounts for 30% of all critically ill patients in the intensive care unit (ICU), and has a global mortality rate of 20%. Activation of blood coagulation during sepsis and septic shock can lead to disseminated intravascular coagulation, which is characterized by microvascular thrombosis. Von Willebrand factor (VWF) and ADAMTS13 are two important regulators of blood coagulation that may be important links between sepsis and mortality in the ICU. Herein we review our current understanding of VWF and ADAMTS13 in sepsis and other critical illnesses and discuss their contribution to disease pathophysiology, their use as markers of severe illness, and potential targets for new therapeutic development.

Sepsis is a disorder of host response caused by severe infection that can lead to life-threatening organ dysfunction. There is no specific treatment for sepsis. Although there are many different pathogens that can cause sepsis, endothelial dysfunction is a frequent mechanism resulting in vascular leakage and coagulation problem. Recent studies on the regulatory pathways of vascular endothelium have shown that the disturbance of angiopoietin (Ang) /Tie2 axis can induce endothelial cell activation, which is the core pathogenesis of sepsis. In this review, we aim to discuss the regulation of Ang/Tie2 axis and the biomarkers involved in the context of sepsis. Also, we attempt to explore the prospective and feasibility of Ang/Tie2 axis as a potential target for sepsis intervention to improve clinical outcomes.

A stroke, also known as a cerebral hemorrhage, occurs when there is an interruption in the blood supply to a part of the brain, resulting in damage to brain cells. This issue is one of the leading causes of death in developed countries, currently killing about 5 million people annually. Individuals who survive ischemic stroke often face serious vision problems, paralysis, dementia, and other sequelae. The numerous efforts to prevent and/or treat stroke sequelae seem insufficient, which is concerning given the increasing global elderly population and the well-known association between aging and stroke risk. In this review, we aim to present and discuss the importance of vitamins in stroke prevention and/or incidence. Vitamins from diet or dietary supplements influence the body at various levels; they are a relevant factor but are reported only in isolated articles. This review reports and updates the multitarget role of vitamins involved in reducing stroke risk.

To investigate the clinical value of complement-3a receptor 1 (C3aR1) and neutrophil extracellular traps (NETs) in predicting sepsis-induced coagulopathy (SIC).

A prospective study was conducted among 78 children with sepsis who attended Xuzhou Children's Hospital Affiliated to Xuzhou Medical University from June 2022 to June 2023. According to the presence or absence of SIC, they were divided into two groups: SIC (n=36) and non-SIC (n=42) . The two groups were compared in terms of clinical data and the levels of C3aR1 and NETs. The factors associated with the occurrence of SIC were analyzed. The receiver operating characteristic (ROC) curve was used to evaluate the performance of C3aR1 and NETs in predicting SIC.

Compared with the non-SIC group, the SIC group had significantly higher levels of C-reactive protein, interleukin-6 (IL-6), interleukin-10, C3aR1, and NETs (P<0.05). The multivaiate logistic regression analysis showed that the increases in C3aR1, NETs, and IL-6 were closely associated with the occurrence of SIC (P<0.05). The ROC curve analysis showed that C3aR1 combined with NETs had an area under the curve (AUC) of 0.913 in predicting SIC (P<0.05), which was significantly higher than the AUC of C3aR1 or IL-6 (P<0.05), while there was no significant difference in AUC between C3aR1 combined with NETs and NETs alone (P>0.05).

There are significant increases in the expression levels of C3aR1 and NETs in the peripheral blood of children with SIC, and the expression levels of C3aR1 and NETs have a high clinical value in predicting SIC.

Sepsis is defined as "a life-threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection." At present, sepsis continues to pose a grave healthcare concern worldwide. Despite the use of supportive measures in treating traditional sepsis, such as intravenous fluids, vasoactive substances, and oxygen plus antibiotics to eradicate harmful pathogens, there is an ongoing increase in both the morbidity and mortality associated with sepsis during clinical interventions. Therefore, it is urgent to design specific pharmacologic agents for the treatment of sepsis and convert them into a novel targeted treatment strategy. Herein, we provide an overview of the molecular mechanisms that may be involved in sepsis, such as the inflammatory response, immune dysfunction, complement deactivation, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we highlight important targets involved in sepsis-related regulatory mechanisms, including GSDMD, HMGB1, STING, and SQSTM1, among others. We summarize the latest advancements in potential therapeutic drugs that specifically target these signaling pathways and paramount targets, covering both preclinical studies and clinical trials. In addition, this review provides a detailed description of the crosstalk and function between signaling pathways and vital targets, which provides more opportunities for the clinical development of new treatments for sepsis.

Pyroptosis is a form of programmed cell death mediated by gasdermins, particularly gasdermin D (GSDMD), which is widely expressed in tissues throughout the body. GSDMD belongs to the gasdermin family, which is expressed in a variety of cell types including epithelial cells and immune cells. It is involved in the regulation of anti-inflammatory responses, leading to its differential expression in a wide range of diseases. In this review, we provide an overview of the current understanding of the major activation mechanisms and effector pathways of GSDMD. Subsequently, we examine the importance and role of GSDMD in different diseases, highlighting its potential as a pan-biomarker. We specifically focus on the biological characteristics of GSDMD in several diseases and its promising role in diagnosis, early detection, and differential diagnosis. Furthermore, we discuss the application of GSDMD in predicting prognosis and monitoring treatment efficacy in cancer. This review proposes a new strategy to guide therapeutic decision-making and suggests potential directions for further research into GSDMD.