Sepsis, a dysregulated host response to infection, is a leading cause of morbidity and mortality in critically ill patients, despite advancements in antimicrobial therapies. Recent innovations in extracorporeal blood purification therapies, such as the Selective Cytopheretic Device (SCD), Polymyxin B Hemoperfusion Cartridge (PMX-HP), and Seraph 100 Microbind Affinity Blood Filter (Seraph), have demonstrated promising potential as adjuncts to conventional therapies. The SCD targets activated white blood cells, while PMX-HP binds endotoxins in Gram-negative sepsis. The Seraph targets a broad range of pathogens, including viruses, bacteria and fungi. Evidence from several clinical trials and observational studies indicate that these therapies can improve organ function, and potentially improve survival in patients with sepsis. Despite the strong pathophysiological rationale for using these devices in sepsis, conclusive evidence of their effectiveness remains limited. Multicenter randomized controlled trials are currently underway with each of these devices to establish their role in improving patient outcomes. Further research is needed to establish optimal protocols for their initiation, duration, and integration into standard sepsis management.

The TyG index serves as a valuable tool for evaluating insulin resistance. An elevated TyG has shown a strong association with the occurrence of acute kidney injury (AKI). Nevertheless, existing literature does not address the relationship between the TyG index and acute kidney injury in patients with sepsis. Sepsis patients were identified from the MIMIC-IV database and categorized into four groups according to quadrilles of their TyG index values. The primary outcome of this study was the incidence of AKI. The relationship between the TyG index and the risk of AKI in septic patients was evaluated using Cox proportional hazards and restricted cubic spline models. Subgroup analyses were conducted to investigate the prognostic value of the TyG index in different subgroups. A total of 2,616 patients with sepsis (57% of whom were male) were included in this study. The incidence of AKI was found to be 78%. Cox proportional hazards analysis revealed a significant correlation between the TyG index and the occurrence of AKI in septic patients. Furthermore, a restricted cubic spline model revealed an approximately linear relationship between a higher TyG index and an elevated risk of AKI in septic patients. The trend of the hazard ratio (HR) remained consistent across various subgroups. These findings emphasize the reliability of the TyG index as an independent predictor for the occurrence of AKI and unfavorable renal outcomes in sepsis patients. Nevertheless, establishing a causal relationship between the two requires demonstration through larger prospective studies.

Acute kidney injury (AKI) is a common complication in heart failure (HF) patients. Patients with heart failure who experience renal injury tend to have a poor prognosis. The objective of this study is to examine the correlation between the occurrence of AKI in heart failure patients and different mean arterial pressure (MAP) trajectories, with the goal of improving early identification and intervention for AKI.

A retrospective study was conducted on patients with heart failure using data from the Medical Information Mart for Intensive Care IV (MIMIC-IV). We utilized the group-based trajectory modeling (GBTM) method to classify the 24-hour MAP change trajectories in heart failure patients. The occurrence of AKI within the first 7 days of intensive care unit (ICU) admission was considered the outcome. The impact of MAP trajectories on AKI occurrence in heart failure patients was analyzed using Cox proportional hazards models, competing risk models, and doubly robust estimation methods.

A cohort of 8,502 HF patients was analyzed, with their 24-hour MAP trajectories categorized into five groups: Low MAP group (Class 1), Medium MAP group (Class 2), Low-medium MAP group (Class 3), High-to-low MAP group (Class 4), and High MAP group (Class 5). The results from the doubly robust analysis revealed that Class 4 exhibited a significantly increased AKI risk than Class 3 (HR 1.284, 95% CI 1.085-1.521, p = 0.003; HR 1.271, 95% CI 1.074-1.505, p = 0.005). Conversely, the risks of Class 2 were significantly lower than those of Class 3 (HR 0.846, 95% CI 0.745-0.960, p = 0.009; HR 0.879, 95% CI 0.774-0.998, p = 0.047).

The 24-hour MAP trajectory in HF patients influences the risk of AKI. A rapid decrease in MAP (Class 4) is associated with a higher AKI risk, while maintaining MAP at a moderate level (Class 2) significantly reduces this risk. Therefore, closely monitoring MAP changes is crucial for preventing AKI in HF.

Sepsis is the most common acute insult in patients with acute-on-chronic liver failure (ACLF), and circulatory failure portends a poor prognosis in them.

This study aimed to compare terlipressin and noradrenaline as first-line vasopressors in patients with ACLF and septic shock.

This prospective, open-label, randomized controlled study was conducted from January 2021 to June 2022 at a tertiary care center. All patients presenting with ACLF as per the chronic liver failure consortium acute on chronic liver failure in cirrhosis study and septic shock were screened. Shock was defined as a mean arterial pressure (MAP) <65 mmHg/systolic blood pressure <90 mmHg. Patients with septic shock nonresponsive to crystalloids/colloids were randomized to receive terlipressin (group I) at 2.6 μg/kg/min and noradrenaline (group II) at 0.1 μg/kg/min. The primary outcome was an MAP >65 mmHg at 6 h. The secondary outcomes were 3-, 7-, 14-, and 28-day mortality, duration of hospital stay, cumulative dose of drug, and new events such as upper gastrointestinal bleed, acute kidney injury, jaundice, and hepatic encephalopathy within 28 days.

A total of 70 patients were randomized to group I (n = 35) and group II (n = 35). According to per-protocol analysis, a higher number of patients achieved an MAP > 65 mmHg at 6 h in group II (n = 23/31, 74%) than in group I (5/34, 14%) (P < 0.001). The 3-and 7-day mortality was significantly higher in group I than in group II, with no difference at 14 and 28 days. The 28-day mortality was highest in ACLF grade-3 in both group II (22/25, 88%) and group I (15/20, 75%).

Terlipressin did not prove to be noninferior to norepinephrine, and therefore, norepinephrine should be the first-line vasopressor in ACLF patients with septic shock. The mortality rate was highest in ACLF grade-3 patients in both the groups, irrespective of the initial response to vasopressors. This indicates that holistic management of these patients is most important.

Sepsis is a common condition associated with significant morbidity and mortality. Emergency physicians play a key role in the diagnosis and management of this condition.

This paper evaluates key evidence-based updates concerning the management of sepsis and septic shock for the emergency clinician.

Sepsis is a life-threatening syndrome, and rapid diagnosis and management are essential. Antimicrobials should be administered as soon as possible, as delays are associated with increased mortality. Resuscitation targets include mean arterial pressure ≥ 65 mmHg, mental status, capillary refill time, lactate, and urine output. Intravenous fluid resuscitation plays an integral role in those who are fluid responsive. Balanced crystalloids and normal saline are both reasonable options for resuscitation. Early vasopressors should be initiated in those who are not fluid-responsive. Norepinephrine is the recommended first-line vasopressor, and if hypotension persists, vasopressin should be considered, followed by epinephrine. Administration of vasopressors through a peripheral 20-gauge or larger intravenous line is safe and effective. Steroids such as hydrocortisone and fludrocortisone should be considered in those with refractory septic shock.

An understanding of the recent updates in the literature concerning sepsis and septic shock can assist emergency clinicians and improve the care of these patients.

Background: Sepsis is a critical medical condition characterized by a dysregulated host response to infection. Platelet abnormalities frequently manifest in sepsis patients, but the causal role of platelets in sepsis remains unclear. This study employed a bidirectional two-sample Mendelian randomization (MR) approach to investigate the causal direction between platelets and sepsis. Methods: MR analysis was used to investigate the causal effect of four platelet traits-platelet count (PLT), platelet crit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW)-on sepsis risk and prognosis. Additionally, the study explored the reverse causality, assessing the impact of sepsis on these platelet traits. Genetic variants from large-scale genome-wide association studies served as instrumental variables to infer causality. Sensitivity analyses and heterogeneity tests were conducted to ensure the validity and robustness of the results. Results: Genetically predicted decreased PCT (OR = 0.938, P = 0.044) and MPV (OR = 0.410, P = 0.006) were associated with an increased risk of sepsis. In the reverse direction, 28-day sepsis mortality was significantly associated with decreased PLT (OR = 0.986, P = 0.034). No significant causal relationships were observed between sepsis and other platelet traits. Conclusions: This study suggests a causal association between low PCT and MPV levels and increased risk of sepsis. Additionally, sepsis with a poor prognosis was causally linked to decreased PLT. These findings provide novel evidence for the causal relationship between platelet traits and sepsis.

Blood cultures are critical in diagnosing bloodstream infections and guiding the treatment of sepsis, which carries a significant mortality risk. Traditional blood culture protocols often recommend a five-day incubation period to ensure the recovery of clinically significant pathogens. However, recent evidence suggests that a shorter incubation period may be sufficient, potentially reducing laboratory workload and the recovery of contaminants.

This quality improvement project was conducted to evaluate the performance of a four-day incubation protocol using the BD BACTEC automated blood culture system in a large academic center with over 1,000 beds, processing more than 70,000 blood culture requests annually. A retrospective analysis was performed on 71,862 blood cultures processed in 2022.

Results indicated that 99.2% of all positive cultures, including those in pediatric cases, were detected within four days, with a mean time to positivity of 23.97 h. Only 0.8% of blood cultures flagged positive after the four-day mark, and these were predominantly cases with previous positive cultures or repeat cultures that did not alter patient management.

We conclude that a four-day incubation period is sufficient for the detection of clinically significant pathogens using the BD BACTEC system. This change not only optimizes laboratory operations by increasing capacity and reducing waste but also supports timely clinical decision-making.

Sepsis and septic shock are common conditions evaluated and managed in the emergency department (ED), and these conditions are associated with significant morbidity and mortality. There have been several recent updates in the literature, including guidelines, on the evaluation and diagnosis of sepsis and septic shock.

This is the first paper in a two-part series that provides emergency clinicians with evidence-based updates concerning sepsis and septic shock. This first paper focuses on evaluation and diagnosis of sepsis and septic shock.

The evaluation, diagnosis, and management of sepsis have evolved since the first definition in 1991. Current guidelines emphasize rapid diagnosis to improve patient outcomes. However, scoring systems have conflicting data for diagnosis, and sepsis should be considered in any patient with infection and abnormal vital signs, evidence of systemic inflammation (e.g., elevated white blood cell count or C-reactive protein), or evidence of end-organ dysfunction. The clinician should consider septic shock in any patient with infection and hypotension despite volume resuscitation or who require vasopressors to maintain a mean arterial pressure ≥ 65 mmHg. There are a variety of sources of sepsis but the most common include pulmonary, urinary tract, abdomen, and skin/soft tissue. Examples of other less common etiologies include the central nervous system (e.g., meningitis, encephalitis), spine (e.g., spinal epidural abscess, osteomyelitis), cardiac (e.g., endocarditis), and joints (e.g., septic arthritis). Evaluation may include biomarkers such as procalcitonin, C-reactive protein, and lactate, but these should not be used in isolation to exclude sepsis. Imaging is a key component of evaluation and should be based on the suspected source.

There have been several recent updates in the literature including guidelines concerning sepsis and septic shock; an understanding of these updates can assist emergency clinicians and improve the care of these patients.

Sepsis-associated acute kidney injury (SA-AKI) is a prevalent and severe complication in critically ill patients. However, diagnostic and therapeutic advancements have been hindered by the biological heterogeneity underlying the disease. Both transcriptomic endotyping and biomarker profiling have been proposed individually to identify molecular subtypes of sepsis and may enhance risk stratification. This study aimed to evaluate the utility of combining transcriptomic endotyping with protein-based biomarkers for improving risk stratification in SA-AKI.

This secondary analysis of the PredARRT-Sep-Trial included 167 critically ill patients who met Sepsis-3 criteria. Patients were stratified into three transcriptomic endotypes-inflammopathic (IE), adaptive (AE), and coagulopathic (CE)-using a validated whole-blood gene expression classifier. Eight protein-based biomarkers encompassing kidney function, vascular integrity, and immune response were measured. Predictive performance for the primary endpoint kidney replacement therapy or death was assessed using receiver operating characteristic curve analysis and logistic regression models.

Stratification into transcriptomic endotypes assigned 33% of patients to IE, 42% to AE, and 24% to CE. Patients classified as IE exhibited the highest disease severity and were most likely to meet the primary endpoint (30%), compared to AE and CE (17% and 10%, respectively). Kidney function biomarkers showed stepwise increases with AKI severity across all endotypes, whereas non-functional biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], soluble urokinase plasminogen activator receptor [suPAR], and bioactive adrenomedullin [bio-ADM]) exhibited endotype-specific differences independent of AKI severity. NGAL and suPAR levels were disproportionately elevated in the IE group, suggesting a dominant role of innate immune dysregulation in this endotype. In contrast, bio-ADM, a marker of endothelial dysfunction, was the strongest risk-predictor of outcomes in CE. The combination of transcriptomic endotyping with protein-based biomarkers enhanced predictive accuracy for the primary endpoint and 7-day mortality, with the highest area under the receiver operating characteristic curve of 0.80 (95% CI 0.72-0.88) for endotyping + bio-ADM and 0.85 (95% CI 0.78-0.93) for endotyping and suPAR, respectively. Combinations of endotyping with functional and non-functional biomarkers particularly improved mortality-related risk stratification.

Combining transcriptomic endotyping with protein-based biomarker profiling enhances risk-stratification in SA-AKI, offering a promising strategy for personalized treatment and trial enrichment in the future. Further research should validate these findings and explore therapeutic applications.

This study aims to predict and diagnose pediatric septic shock through the screening of immune infiltration-related biomarkers. Three gene expression datasets were accessible from the Gene Expression Omnibus repository. The differentially expressed genes were identified using the R 4.3.2 ( https://www.r-project.org/ ), followed by gene set enrichment analysis. Thereafter, the genes were identified utilizing machine-learning algorithms. The receiver operating characteristic curve was employed to assess the discrimination and effectiveness of the hub genes. The inflammatory and immune status of pediatric septic shock was evaluated through cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). The correlation between diagnostic markers and infiltrating immune cells was further examined. Overall, we detected 12 differentially expressed genes. CD177, MCEMP1, MMP8, and OLAH were examined as diagnostic indicators for pediatric septic shock, revealing statistically significant differences (P < 0.01) and diagnostic efficacy in the validation cohort. The immune cell infiltration analysis suggests that various immune cells may contribute to the onset of pediatric septic shock. Furthermore, all diagnostic characteristics may exhibit varying degrees of correlation with immune cells. This study identifies four potential biomarkers-CD177, MCEMP1, MMP8, and OLAH-that provide diagnostic value and novel insights into immune dysregulation in pediatric septic shock. Through the integration of bioinformatics and machine learning methodologies, we offer a novel perspective on the immune mechanisms involved in pediatric septic shock, potentially facilitating more targeted and personalized therapies for individual patients.

Septic shock is commonly associated with reduction in vasomotor tone, mainly due to vascular hyporesponsiveness to norepinephrine (NE). Although the diastolic arterial pressure (DAP)/heart rate (HR) ratio reflects vasomotor tone, it cannot be a reliable index of vascular responsiveness to NE (VNERi). We hypothesized that adjusting DAP/HR for the NE dose could yield a VNERi value (VNERi = DAP/(NE dose x HR)), knowledge of which can help guiding therapeutic strategies in cases of persistent hypotension despite NE (e.g., increasing NE doses vs. introducing additional vasopressors). For our hypothesis be valid, at least VNERi should demonstrate a stronger association with patient outcome than DAP, DAP/HR or mean arterial pressure (MAP)/NE dose, a global marker of NE responsiveness.

We conducted a post-hoc analysis of the ANDROMEDA-SHOCK database. Hemodynamic variables and initial NE doses were recorded at the randomization time-point, within 4 h of septic shock diagnosis. NE doses were expressed in µg/kg/min (using the bitartrate NE formulation). A multivariate model was employed to compare the associations between these variables and key clinical outcomes, including in-hospital mortality, numbers of vasopressor-free days and of renal replacement therapy (RRT)-free days up to day 28.

The ANDROMEDA-SHOCK database included 424 patients with septic shock receiving NE. The median DAP was 52 mmHg [IQR: 45-50] and the median NE dose at inclusion was 0.2 µg/kg/min [IQR: 01-0.4]. In-hospital mortality was 43%. VNERi demonstrated the strongest association with in-hospital mortality compared to DAP, DAP/HR, and MAP/NE dose, emerging as the most significant covariate in the multivariate model. Similar findings were found for the associations with numbers of vasopressor-free days and RRT-free days up to day 28. The model revealed an inverted J-shaped relationship between in-hospital mortality and VNERi, with a nadir point at 6.7, below which mortality increased.

In patients receiving NE during early septic shock, VNERi demonstrated the strongest association with outcome compared to DAP, DAP/HR, and MAP/NE dose. Due to its physiological basis and robust association with outcomes, VNERi may serve as a valuable bedside marker of the vascular responsiveness to NE. This index could potentially be integrated into decision-making of early septic shock.

Fluid replacement is the primary treatment for life-threatening shock but is challenging in harsh environments. This study explores low-intensity pulsed ultrasound (LIPUS) as a resuscitation strategy. Cervical LIPUS stimulation effectively elevated blood pressure in shocked rats. It also improved cerebral and multiorgan perfusion. Mechanistically, LIPUS activated pathways related to sympathetic nerve excitation and vascular smooth muscle contraction, increasing plasma catecholamines and stimulating blood pressure-regulating neural nuclei. Partial sympathetic nerve transection reduced LIPUS efficacy, while complete inhibition of these nuclei abolished the response. Preliminary clinical trials demonstrated LIPUS's ability to raise blood pressure in shock patients. The findings suggest that LIPUS enhances sympathetic nerve activity and activates blood pressure-regulating nuclei, offering a noninvasive, neuromodulation-based approach to shock treatment. This method holds potential for improving blood pressure and organ perfusion in shock patients, especially in resource-limited environments.

Polymethyl methacrylate (PMMA) membranes are increasingly recognized for their effectiveness in treating acute kidney injury (AKI) due to their strong adsorption capabilities, particularly for inflammatory mediators like β2-microglobulin and IL-6. These membranes ensure mechanical stability and chemical inertness, minimizing adverse reactions during blood filtration.

In acute conditions such as sepsis and acute respiratory distress syndrome (ARDS), PMMA membranes show promising findings. In sepsis, they may help reduce multiorgan failure by modulating immune responses, although further research is needed to confirm their routine use. For ARDS, PMMA membranes could mitigate "cytokine storms" by adsorbing key cytokines, improving oxygenation and hemodynamic stability, which may reduce ICU stays and reliance on mechanical ventilation. Monitoring biomarkers like IL-6, TNF-α is critical for tracking efficacy and tailoring therapy to individual needs. In chronic conditions, such as hemodialysis for chronic kidney disease, PMMA membranes help lower oxidative stress and β2-microglobulin levels, reducing complications such as amyloidosis. By decreasing oxidative damage, they provide long-term protective benefits for dialysis patients.

While these advantages are notable, large-scale studies are needed to establish PMMA's efficacy, refine treatment protocols, and confirm its broader role in acute and chronic disease management. The potential of PMMA membranes highlights their value, but standardized clinical evidence is necessary for widespread adoption.

Ischemia-reperfusion injury (IRI) is a critical condition that poses a significant threat to patient safety. The production of lactate increases during the process of IRI, and lactate serves as a crucial indicator for assessing the severity of such injury. Lactylation, a newly discovered post-translational modification in 2019, is induced by lactic acid and predominantly occurs on lysine residues of histone or nonhistone proteins. Extensive studies have demonstrated the pivotal role of lactylation in the pathogenesis and progression of various diseases, including melanoma, myocardial infarction, hepatocellular carcinoma, Alzheimer's disease, and nonalcoholic fatty liver disease. Additionally, a marked correlation between lactylation and inflammation has been observed. This article provides a comprehensive review of the mechanism underlying lactylation in IRI to establish a theoretical foundation for better understanding the interplay between lactylation and IRI.

Isatidis Folium, a botanical drug widely used in traditional medicine, is known for its anti-inflammatory properties, including heat-clearing, detoxifying, and blood-cooling effects. Although its potential in sepsis treatment has been suggested, the bioactive metabolites and underlying mechanisms remain poorly understood.

Network pharmacology and molecular docking were employed to identify the therapeutic effects and mechanisms of Indirubin, the major bioactive metabolite of Isatidis Folium, in sepsis treatment. In vivo, a cecal ligation and puncture (CLP)-induced mouse sepsis model was used to evaluate the protective effects of Indirubin through histopathological analysis, ELISA, and biochemical assays. In vitro, RAW264.7 cells were stimulated with LPS and treated with varying concentrations of Indirubin. The anti-inflammatory effects of Indirubin were assessed using ELISA, apoptosis assays, and Western blotting.

Network pharmacology analysis identified Indirubin as the major bioactive metabolite of Isatidis Folium and EGFR and SRC as its key molecular targets. Experimental validation demonstrated that Indirubin significantly improved survival rates, alleviated tissue injury, and suppressed inflammatory responses in sepsis models. Mechanistically, Indirubin inhibited LPS-induced activation of the EGFR/SRC/PI3K and NF-κB/MAPK pathways in macrophages, significantly reducing cell death and inflammation in RAW264.7 cells.

Indirubin, the primary bioactive metabolite of Isatidis Folium, exerts protective effects against sepsis by targeting the EGFR/SRC/PI3K and NF-κB/MAPK signaling pathways in macrophages. These findings provide a mechanistic basis for the development of Indirubin as a multi-target therapeutic agent for sepsis treatment.

Introduction: Septic patients have low levels of high-density lipoproteins (HDLs), which is a risk factor. Replenishing HDLs with synthetic HDLs (sHDLs) has shown promise as a therapy for sepsis. This study aimed to develop a computational approach to design and test new types of sHDLs for sepsis treatment. Methods: We used a three-step computational approach to design sHDL nanoparticles based on the structure of HDLs and their binding to endotoxins. We tested the efficacy of these sHDLs in two sepsis mouse models-cecal ligation and puncture (CLP)-induced and P. aeruginosa-induced sepsis models-and assessed their impact on inflammatory signaling in cells. Results: We designed four sHDL nanoparticles: two based on the ApoA-I sequence (YGZL1 and YGZL2) and two based on the ApoE sequence (YGZL3 and YGZL4). We demonstrated that an ApoE-based sHDL nanoparticle, YGZL3, provides effective protection against CLP- and P. aeruginosa-induced sepsis. The sHDLs effectively suppressed inflammatory signaling in HEK-blue or RAW264 cells. Conclusions: Unlike earlier approaches, we developed a new approach that employs computational simulations to design a new type of sHDL based on HDL's structure and function. We found that YGZL3, an ApoE sequence-based sHDL, provides effective protection against sepsis in two mouse models.

The anti-inflammatory role of miR-23b-3p (miR-23b) is known in autoimmune diseases like multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. However, its role in sepsis-related acute lung injury (ALI) and its effect on macrophages in ALI remain unexplored. This investigation aimed to evaluate miR-23b's therapeutic potential in macrophages in the context of ALI. The study found reduced miR-23b expression in macrophages within ALI tissue. Intratracheal delivery of miR-23b mimics alleviated ALI by partially inhibiting M1 macrophage activation through the Lpar1-NF-κB pathway. Effective delivery systems are crucial for prolonging miR-23b activity in the lungs, reducing dosage, and minimizing side effects by specifically targeting macrophages. However, current vector systems for nucleic acid delivery, including viral, lipid-based, polymer-based, and peptide-based vectors, face limitations due to eliciting immune responses. Exosomes have garnered significant attention as a leading gene delivery system due to the safety, effectivity and low immunogenicity. We further isolated exosomes from bone marrow-derived mesenchymal stem cells, modified exosomes with mannosylated ligands to enhance the targeted delivery of miR-23b to macrophage. This approach represents a promising novel therapeutic strategy for treating sepsis-induced ALI.

Sepsis shock is caused by a systemic infection characterized by circulatory disorders and metabolic abnormalities. Microorganisms or their toxins enter the bloodstream, releasing inflammatory mediators and triggering systemic inflammatory reactions, leading to multiple organ dysfunction and even failure. To explore new treatment methods, we studied the improvement effect of sesamoside on the inflammatory response in septic shock. We performed in vitro experiments and animal models. We found that sesamoside reduced inflammatory cytokines such as TNF-α, IL-6, IL-1β, iNOS, and NO. Sesamoside inhibited the LPS-induced phosphorylation of ERK and JNK and downregulated the expression of NLRP3, reducing the systemic inflammatory response. In addition, sesamoside reduces multi-organ injuries in LPS-induced septic shock and restricts the nuclear localization of P65 to regulate the immune response, enhance immune function, and help restore cell metabolism and organ function. This study reveals the improved effect of sesamoside on inflammatory response in septic shock, providing new ideas and methods for treating septic shock. Future research will explore the mechanism of action of sesamoside and its clinical application value in the treatment of septic shock. Clinical trial number: Not applicable.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a simplified cardiopulmonary bypass device that provides temporary respiratory and circulatory support and adequate recovery time for the heart and lung, but the mortality rate of acute and critically ill patients undergoing VA-ECMO is still high. Progression of systemic inflammatory response is associated with mortality in ECMO patients. The objective of this study was to investigate the dynamic changes of various inflammatory markers and their relationship with 28-day mortality in patients with VA-ECMO.

A retrospective cohort analysis was conducted on 200 patients receiving VA-ECMO treatment evaluating inflammatory markers including neutrophil-to-lymphocyte ratio (NLR), systemic inflammatory response index (SIRI), procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) at various time points. A dynamic trajectory model was constructed, and survival differences between groups were assessed using Kaplan-Meier plots and log-rank tests. Multiple Cox proportional hazard models were built to analyze the relationship between dynamic trajectories and clinical outcomes. Causal mediation analysis was applied to determine whether changes in inflammatory trajectories mediated survival outcomes in patients on VA-ECMO through other variables.

Age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Lactic acid, PCO2, aspartate aminotransferase (AST) levels, diastolic blood pressure, mean arterial pressure and pH significantly impacted the 28-day survival rate (p < 0.05), with higher mortality observed in patients exhibiting poor inflammatory trajectories.Kaplan-Meier survival analysis revealed that patients in the ascending (AS) group had a significantly higher risk of death than those in the stable (ST) and descending (DS) groups (log-rank p < 0.001). Furthermore, multivariate Cox regression analysis identified IL-6 as the most strongly correlated inflammatory marker with mortality risk [Hazard ratio (HR) = 1.97, 95% confidence interval (CI) 1.35-2.87, p < 0.001].

This study highlights the importance of dynamic monitoring of inflammatory biomarkers in patients on VA-ECMO, suggesting that individualized treatment adjustments based on these markers could enhance survival rates. Future research should prioritize larger, multicenter cohort studies and clinical trials to validate these findings, aiming to optimize treatment strategies for patients on VA-ECMO.

Fluid is an essential component of initial resuscitation in sepsis or burns. Meanwhile, the optimal strategy of titrating fluids for both of the two conditions remains uncertain. In this bibliometric analysis, we compared the similarities and differences in fluid resuscitation between sepsis and burns in recent publications.

Literatures related to fluid resuscitation in either sepsis or burns were searched in the Web of Science database Core Collection from January 1, 1992, to December 31, 2022. CiteSpace and VOSviewer was used for bibliometric analysis.

A total of 1,549 and 468 publications on fluid resuscitation in sepsis and burns were retrieved from 1992 to 2022. Based on the occurrences, 341 and 86 high-frequency keywords were screened out from sepsis and burns publications, respectively, which were similarly categorized into 5 clusters [i.e. "mechanisms of hypovolemia" (cluster 1), "titration of fluid" (cluster 2), "outcomes or complications" (cluster 3), "pathophysiological alternations" (cluster 4), and "fluid types and others" (cluster 5)]. The high-frequency keywords of the top 20 were more concentrated in cluster 3 and cluster 2, with "mortality" ranked the top in both sepsis and burns literature. Significantly, 3 keywords in cluster 2 ranked in the top 5, including "goal directed resuscitation" (the 3rd), fluid responsiveness (the 4th) and fluid balance (the 5th) in sepsis literature, while the keywords of "microvascular exchange" (cluster 1) and "abdominal compartment syndrome" (ACS, cluster 3) ranked at the second and the fifth place in burns publications. Keyword burst analysis demonstrated that the keyword with the highest burst strength (BS) was "formula" (BS = 5.88, 2008-2014), followed by management (BS = 4.79, 2012-2022), ACS (BS = 4.76, 2006-2010), and fluid creep (BS = 4.74, 2011-2016) in burn publications, but they were dobutamine (BS = 12.31, 1992-2008), cardiac output (BS = 9.79, 1993-2001), catecholamine (BS = 9.54, 1993-2006), and consumption (BS = 7.52, 1992-2006) in sepsis literature. Moreover, the most frequently cited article in either sepsis or burns was categorized into cluster 2, that investigated goal-directed fluid therapy for sepsis and formula improvement for burns resuscitation.

It was demonstrated that the research priorities in titrating fluid were mainly concentrated on targeting hemodynamics in sepsis vs. improving formula (which briefly calculates the increased microvascular permeability) in burns, while concerning of "outcomes and complications" in fluid resuscitation similarly after 1992. However, hemodynamics and microvascular permeability have been simultaneously well considered in few previous studies regarding fluid resuscitation in either sepsis or burns.

Trauma remains a leading cause of morbidity and mortality in part due to secondary multi-organ injury. However, our ability to predict the downstream pathophysiology and adverse outcomes of trauma is limited. Here, we select a panel of microRNAs (miRNAs) biomarker candidates based on plasma RNA-Seq analysis of trauma patients and the unique pro-inflammatory nucleotide motif structures identified via a machine learning-guided computer exhaustive search algorithm. We test the panel of plasma miRNAs for their association with various trauma pathophysiological markers and their ability to predict organ injury and immune responses to trauma. We find a marked elevation of these plasma miRNAs as well as multiple inflammatory and organ injury factors at time of admission in a cohort of 48 blunt trauma patients. The plasma levels of these miRNA biomarkers are highly associated with multiple pathophysiological markers known for organ injury, coagulopathy, endothelial activation, and innate inflammation. AUROC analyses indicate that these miRNA biomarkers possess strong abilities to distinguish trauma severity, brain and liver injuries, metabolic acidosis, coagulopathy, and innate inflammation. These observations offer insights into potential values of the selected plasma miRNAs in prediction of trauma pathophysiological risk and clinical outcomes.

In 2020, sepsis has been defined a worldwide health major issue (World Health Organization). Lung, urinary tract and abdominal cavity are the preferred sites of sepsis-linked infection. Research has highlighted that the advancement of sepsis is not only related to the presence of inflammation or microbial or host pattern recognition. Clinicians and researchers now recognized that a severe immunosuppression is also a common feature found in patients with sepsis, increasing the susceptibility to secondary infections. Lipopolysaccharides (LPS) are expressed on the cell surface of Gram-negative, whereas Gram-positive bacteria express peptidoglycan (PGN) and lipoteichoic acid (LTA). The main mechanism by which LPS trigger host innate immune responses is binding to TLR4-MD2 (toll-like receptor4-myeloid differentiation factor 2), whereas, PGN and LTA are exogenous ligands of TLR2. Nucleotide-binding oligomerization domain (NOD)-like receptors are the most well-characterized cytosolic pattern recognition receptors, which bind microbial molecules, endogenous by-products and environmental triggers. It has been demonstrated that high-density lipoproteins (HDL), besides their major role in promoting cholesterol efflux, possess diverse pleiotropic properties, ranging from a modulation of the immune system to anti-inflammatory, anti-apoptotic, and anti-oxidant functions. In addition, HDL are able at i) binding LPS, preventing the activating of TLR4, and ii) inducing the expression of ATF3 (Activating transcription factor 3), a negative regulator of the TLR signalling pathways, contributing at justifying their capacity to hamper infection-based illnesses. Therefore, reconstituted HDL (rHDL), constituted by apolipoprotein A-I/apolipoprotein A-IMilano complexed with phospholipids, may be considered as a new therapeutic tool for the management of sepsis.

Predicting and reducing the 28-day mortality in sepsis remains a challenge in this research field.

This study aimed to explore the association between hypertension and 28-day mortality in sepsis.

This study is a cross-sectional approach with Mendelian Randomization (MR). We used GWAS data for hypertension as the exposure and 28-day mortality in sepsis as the outcome and employed the main inverse variance weighted method along with other supplementary MR techniques to verify the causal association between hypertension and 28-day mortality in sepsis. We used sensitivity analyses to ensure the robustness of the research findings. Finally, we utilized clinical data from the Medical Information Mart for Intensive Care-IV database to assess the risk association between hypertension and 28-day mortality in sepsis using difference analysis and multivariate logistic regression analysis.

According to MR, hypertension increased the 28-day mortality in sepsis in both two datasets (FinnGen: odds ratio [OR] = 1.61, 95 % confidence interval [CI] = 1.15-2.26, p = 0.006; Medical Research Council-Integrative Epidemiological Unit: OR = 160, 95 % CI = 2.76-9250, p = 0.014). In our observational study, we included a total of 2012 sepsis patients, of which 60.5 % were male, and the average age was 55.4 years. By applying univariate and multivariate logistic regression models (univariate analysis p = 0.02, multivariate analysis p = 0.02), we observed a significantly increased risk of 28-day mortality due to hypertension in sepsis patients.

This study confirmed the causal relationship between hypertension and the 28-day mortality in sepsis.

Comprehensive and in-depth research on the immunophenotype of septic patients remains limited, and effective biomarkers for the diagnosis and treatment of sepsis are urgently needed in clinical practice.

Blood samples from 31 septic patients in the Intensive Care Unit (ICU), 25 non-septic ICU patients, and 18 healthy controls were analyzed using flow cytometry for deep immunophenotyping. Metagenomic sequencing was performed in 41 fecal samples, including 13 septic patients, 10 non-septic ICU patients, and 18 healthy controls. Immunophenotype shifts were evaluated using differential expression sliding window analysis, and random forest models were developed for sepsis diagnosis or prognosis prediction.

Septic patients exhibited decreased proportions of natural killer (NK) cells and plasmacytoid dendritic cells (pDCs) in CD45+ leukocytes compared with non-septic ICU patients and healthy controls. These changes statistically mediated the association of Bacteroides salyersiae with sepsis, suggesting a potential underlying mechanism. A combined diagnostic model incorporating B.salyersia, NK cells in CD45+ leukocytes, and C-reactive protein (CRP) demonstrated high accuracy in distinguishing sepsis from non-sepsis (area under the receiver operating characteristic curve, AUC = 0.950, 95% CI: 0.811-1.000). Immunophenotyping and disease severity analysis identified an Acute Physiology and Chronic Health Evaluation (APACHE) II score threshold of 21, effectively distinguishing mild (n = 19) from severe (n = 12) sepsis. A prognostic model based on the proportion of total lymphocytes, Helper T (Th) 17 cells, CD4+ effector memory T (TEM) cells, and Th1 cells in CD45+ leukocytes achieved robust outcome prediction (AUC = 0.906, 95% CI: 0.732-1.000), with further accuracy improvement when combined with clinical scores (AUC = 0.938, 95% CI: 0.796-1.000).

NK cell subsets within innate immunity exhibit significant diagnostic value for sepsis, particularly when combined with B. salyersiae and CRP. In addition, T cell phenotypes within adaptive immunity are correlated with sepsis severity and may serve as reliable prognostic markers.

This project was supported by the National Key R&D Program of China (2023YFC2307600, 2021YFA1301000), Shanghai Municipal Science and Technology Major Project (2023SHZDZX02, 2017SHZDZX01), Shanghai Municipal Technology Standards Project (23DZ2202600).

Sepsis-associated delirium (SAD) is a common complication in intensive care unit (ICU) patients and is associated with increased mortality. Frailty, characterized by diminished physiological reserves, may influence the development of SAD, but this relationship remains poorly understood.

To comprehensively analyze the assessment of frailty as a predictive factor for sepsis-associated delirium in older adults.

A retrospective cohort analysis was performed on sepsis patients aged ≥ 65 years admitted to the ICU. Frailty was assessed using the Modified Frailty Index based on 11 items including comorbidities and functional status. Patients were categorized into non-frail (MFI: 0-2) and frail (MFI ≥ 3) groups. Delirium was assessed using the ICU Confusion Assessment Method (CAM-ICU) and retrospective nursing notes. Logistic regression analysis was used to examine the relationship between frailty in older patients and the risk of delirium, and odds ratios (OR) and their 95% confidence intervals (CI) were calculated.

Among 11,740 patients (median age approximately 76 years [interquartile range: 70.47-83.14], 44.3% female), frail patients tended to have longer ICU stays, higher severity scores, and potentially worse clinical outcomes. The study found a significant positive association between MFI and the risk of developing SAD (OR: 1.13, 95% CI: 1.09-1.17, p < 0.001). Additionally, frail patients had a higher risk of developing SAD compared to non-frail patients (OR: 1.31, 95% CI: 1.20-1.43, p < 0.001).

Frailty independently predicts SAD development in older adults with sepsis in the ICU, emphasizing the importance of early recognition and prevention.

Chronic inflammation is mainly characterized by the release of proinflammatory cytokines (cytokine storm) and reactive oxygen/nitrogen species. Sepsis is a life-threatening condition resulting from the successive chronic inflammatory responses toward infection, leading to multiple organ failure and, ultimately, death. As inflammation and oxidative stress are known to nourish each other and initiate an uncontrolled immune response, inhibiting the cross-talk between the inflammatory response using anti-inflammatory drugs and oxidative stress using antioxidants can be a promising strategy to target sepsis. Here, we present the engineering of chimeric nanomicelles (NMs) using an ester-linked polyethylene glycol-derived lithocholic acid-drug conjugate using dexamethasone (DEX), a potent glucocorticoid possessing anti-inflammatory properties, and vitamin E (VITE), an antioxidant to target oxidative stress. Interestingly, these chimeric DEX-VITE NMs show enhanced accumulation at the inflamed sites driven by enhanced permeation and retention effect and mitigate localized acute inflammation in paw, lung, and liver inflammation models. We further demonstrated the efficacy of these NMs in mitigating LPS-induced endotoxemia and CLP-induced microbial sepsis, conferring survival advantages. DEX-VITE NMs also modulate immune homeostasis by decreasing the infiltration of total immune cells, neutrophils, and overall macrophages. Finally, administration of DEX-VITE NMs also reduces the release of proinflammatory cytokines and prevents vascular damage, two critical factors of sepsis pathogenesis. Therefore, this therapeutic approach of chimeric NMs can effectively deliver steroids and antioxidants to mitigate uncontrolled localized and systemic inflammation.

Sepsis is a severe condition with high mortality, in which immune dysfunction plays a critical role. Poor oral health has been linked to frailty, but its impact on sepsis outcomes remains unclear. Therefore, we used a mouse model of malocclusion and sepsis to investigate how tooth loss affects immune responses during sepsis. Adult male C57BL/6 mice were divided into four groups: Control, Malocclusion (Mal), Sepsis (CS), and Malocclusion with Sepsis (Mal + CS). Malocclusion was induced by tooth extraction, and sepsis was induced using cecal slurry injection. We assessed survival rates, immune cell counts, and biochemical markers. The Mal + CS group exhibited significantly lower survival rates and greater weight loss compared to the CS group. The flow cytometry showed reduced neutrophils, monocytes, and T cells in the Mal + CS group. Elevated ALT and AST levels indicated liver damage. No significant differences in bacterial loads were observed, but immune suppression was exacerbated in the Mal + CS group. Malocclusion worsens sepsis outcomes by impairing both innate and adaptive immune responses. These findings emphasize the importance of oral health in improving sepsis prognosis and immune function during critical illnesses.

Early sepsis diagnosis is essential to allow timely initiation of adequate care. The TriVerity™ Test, performed on the Myrna™ Instrument, is the first rapid high-multiplex host-response mRNA diagnostic test that supports clinical decision-making by evaluating the likelihood of bacterial and/or viral infections and severity of illness. We present findings of the first, proof of concept, real-world evaluation in an emergency department (ED).

Blood was collected in PAXgene® Blood RNA tubes from adult patients visiting the ED with suspicion of infection between 4th December 2023 and 22nd January 2024. TriVerity was performed within 1 h (RNA extraction and amplification of 29 host mRNAs using LAMP technology on the Myrna Instrument within approximately 30 min). TriVerity generates three diagnostic scores (likelihood of bacterial infection, viral infection, and illness severity), each classified into five discrete interpretation bands (very low, low, moderate, high, and very high). Post hoc chart reviews were performed after hospital discharge to clinically adjudicate the infection status (consensus and forced adjudication).

Among 60 patients, there were 20 (33%) bacterial infections, 15 (25%) viral infections, 11 (18%) bacterial-viral coinfections and 14 (23%) did not have an infection under forced adjudication. Under consensus adjudication, bacterial results demonstrated 95% rule-in specificity and 95% rule-out sensitivity. Viral results demonstrated rule-in specificity 100% and 92% rule-out sensitivity. Since only three patients were admitted to the ICU or died in this cohort, we cannot draw firm conclusions about the predictive value of the test for severe endpoints.

TriVerity is a rapid whole-blood host-response test to reliably detect the presence or absence of bacterial and/or viral infections, as well as to assess illness severity in patients presenting to the ED. Its quick turnaround time aligns with the ED workflow, offering timely insights for clinical decision-making. Results from upcoming large-scale validation studies will provide more detailed results on the diagnostic and prognostic accuracy of the test.

Sepsis-associated encephalopathy (SAE) is a complication of impaired neurologic function during the development of sepsis. Its occurrence is closely related to severe systemic infection. The increase of serum Interleukin 6 kit and other inflammatory cytokines has certain clinical significance in the diagnosis of sepsis, However, there is no research at home or abroad indicating whether the high expression of related inflammatory cytokines (inflammatory cytokine storm, ICS) is valuable for the diagnosis and prognosis of SAE patients.

The aim of this study was to analyze serum inflammatory cytokines 6 kit [IL-2/4/6/10, TNF-α, and gamma interferon (IFN-γ)], heparin-binding protein (HBP), and serum cholinesterase levels and their clinical significance in septic patients. In this study, we defined the values of inflammatory storm (IL-6 > 5000 pg/ml, IL-10 > 1000 pg/ml, and HBP > 300 ng/ml) to analyze the diagnostic value and 28-day prognostic predictive ability of inflammatory cytokine storm and the severity score in SAE patients.

A total of 140 patients with sepsis in the ICU and EICU of the Lianyungang First People's Hospital were included in the present study from October 2021 to March 2023. Based on the Diagnostic criteria for SAE, the 140 cases were divided into 62 cases in the SAE group and 78 cases in the non-SAE group. On admission to the ICU/EICU, the patients gender, age, vital signs, and serum levels of various cytokines were recorded. The Glasgow Coma Scale (GCS), Sequential Organ Failure Scale (SOFA), and Acute Physiological and Chronic Health Score II (APACHE-II) scores were also assessed to analyze the risk cytokines for the occurrence of SAE.

The age, Sofa score, APACHE-II score, 28-day mortality rate, serological cellular inflammatory cytokines (IL-2/6/10, INF-α, and interferon-gamma), HBP were significantly higher in the SAE group than in the non-SAE group (P < 0.05). In addition, the GCS score and serum cholinesterase levels in the SAE group were lower than in the non-SAE group (P < 0.05). Subsequently, Multi-factor logistic regression analysis revealed that ultra-high IL-6 (> 5000 pg/ml), IL-10 (> 1000 pg/ml), and HBP (> 300 ng/ml) levels and elevated SOFA and APACHE-II scores were risk cytokines for the development of SAE (P < 0.05). 28-day mortality was significantly higher in patients in the SAE group and in the IL-6 > 5000 pg/ml group compared to patients in the USAE and IL-6 < 5000 pg/ml groups(P < 0.001).The four screened predictors of HBP > 300 ng/ml, IL-6 > 5000 pg/ml, decreased GCS score, and decreased APACHEII score were combined into a new predictive data model (risk score).In the SAE group, patients with high risk scores had a higher 28-day mortality rate compared with the low risk score group (P < 0.001).

The occurrence of SAE is closely correlated with age, concomitant diabetes, SOFA score, APACHE II score, serum cytosolic inflammatory cytokine levels (IL-2/6/10, TNF-α, and IFN-γ), HBP, and serum cholinesterase levels. In addition, inflammatory storms are associated with the mechanism of SAE, and high expression levels of the inflammatory cytokines IL-6 > 5000 pg/ml, IL-10 > 1000 pg/ml, and HBP > 300 ng/ml in patients with sepsis contribute to the early diagnosis of SAE. In addition, IL-6 > 5000 pg/ml was also associated with an increase in 28-day mortality (P < 0.05), suggesting that the level of inflammatory storms may be related to the mechanism of sepsis-related SAE and 28-day mortality. According to the LASSO results, when SAE patients admitted to the intensive care unit satisfy HBP > 300 ng/ml, IL6 > 5000 pg/ml, decreased GCS score, and increased APACHEII score, it suggests that the patient's 28-day mortality rate is higher, and it also validates that inflammatory storm can be used as a predictor of prognosis for SAE patients.

Klebsiella pneumoniae is a Gram-negative bacterium and the third most commonly isolated microorganism in blood cultures from septic patients. Despite extensive research, the mechanisms underlying K. pneumoniae-induced sepsis and its pathogenesis remain unclear. Acute respiratory failure is a leading cause of mortality in systemic K. pneumoniae infections, highlighting the need to better understand the host immune response and bacterial clearance mechanisms.

To investigate the impact of K. pneumoniae infection on organ function and immune response, we utilized a systemic infection model through intraperitoneal injection in mice. Bacterial loads in key organs were quantified, and lung injury was assessed. Survival analysis was performed in wild-type (WT) and gene deficient mice. Mitochondrial damage and reactive oxygen species (ROS) production, as well as cytokine levels were measured in macrophages isolated from these mice to evaluate their contribution to bacterial clearance capacity.

Our findings demonstrate that K. pneumoniae systemic infection results in severe lung injury and significant bacterial accumulation in multiple organs, with the highest burden in the lungs. Deficiency of caspase-11 or NLRP3 led to prolonged survival, a reduction in pulmonary bacterial load, increased blood oxygen levels, and decreased IL-6 levels in the lungs compared to WT controls. Furthermore, caspase-11- and NLRP3-deficient macrophages exhibited elevated mitochondrial ROS production in response to K. pneumoniae, which correlated with more effective bacterial clearance.

These results suggest that caspase-11 and NLRP3 contribute to K. pneumoniae-induced sepsis by impairing mitochondrial function and reducing ROS production in macrophages, thereby compromising bacterial clearance. The observed reduction in lung injury and increased survival in caspase-11- and NLRP3-deficient mice indicate that targeting these pathways may offer potential therapeutic strategies to improve host defense against systemic K. pneumoniae infection.

Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19; however, the mechanisms underlying this protection are largely unknown. Here, we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin and instead increases levels of circulating interleukin-10 (IL-10). IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia, preventing cardiac effects including impairment of glucose oxidation, ectopic lipid accumulation, ventricular stretch and possibly cardiac failure. Our work reveals a beneficial "off-target" effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential.

Platelets, traditionally known for their role in hemostasis, have emerged as key players in immune response and inflammation. Sepsis, a life-threatening condition characterized by systemic inflammation, often presents with thrombocytopenia, which at times, can be significant. Platelets contribute to the inflammatory response by interacting with leukocytes, endothelial cells, and the innate immune system. However, excessive platelet activation and consumption can lead to thrombocytopenia and exacerbate the severity of sepsis. Understanding the multifaceted roles of platelets in sepsis is crucial for developing effective therapeutic strategies. Targeting platelet-mediated inflammatory responses and promoting platelet production may offer potential avenues for improving outcomes in septic patients with thrombocytopenia. Future research should focus on elucidating the mechanisms underlying platelet dysfunction in sepsis and exploring novel therapeutic approaches to optimize platelet function and mitigate inflammation. This review explores the intricate relationship between platelets, inflammation, and thrombosis in the context of sepsis.

Sepsis, a heterogeneous illness produced by a dysregulated host response to infection, remains a severe mortality risk. Recent discoveries in sepsis research have stressed phenotyping as a feasible strategy for tackling heterogeneity and enhancing therapy precision. Sepsis phenotyping has moved from traditional stratifications based on severity and prognosis to dynamic, phenotype-driven therapeutic options. This review covers recent progress in connecting sepsis subgroups to personalized treatments, with a focus on phenotype-based therapeutic predictions and decision-support systems. Despite ongoing challenges, such as standardizing phenotyping frameworks and incorporating findings into clinical practice, this topic has enormous promise. By investigating phenotypic variation in therapy responses, we hope to uncover new biomarkers and phenotype-driven therapeutic solutions, laying the groundwork for more effective therapies and, ultimately improving patient outcomes.

Sepsis is a serious and life-threatening condition, which can lead to organ failure and death clinically. Abnormally increased cell-free DNA (cfDNA) and inflammatory cytokines are involved in the development and progression of sepsis. Thus, cfDNA clearance and down-regulation of inflammatory factors are essential for the effective treatment of sepsis. Here we designed and constructed a polydopamine-based multifunctional nanoparticle for the treatment of sepsis. These nanoparticles (NPs) are composed of polydopamine (PDA) grafted with cationic polyethyleneimine (PEI). On the one hand, the NPs can utilize the electrostatic interaction to effectively adsorb cfDNA in blood, then effectively inhibiting the activation of toll like receptors (TLRs) and nuclear factor kappa B (NF-κB) pathways induced by cfDNA. On the other hand, the NPs have an immunomodulatory function, which can effectively convert pro-inflammatory macrophage (M1) into anti-inflammatory macrophage (M2), thus reduce the release of inflammatory cytokines and slow down the inflammatory storm of sepsis. In addition, the NPs possess good reactive oxygen species (ROS) scavenging ability. Briefly, the effective treatment of sepsis can be achieved by multiple strategies of effectively capturing the inflammatory triggering factor cfDNA, modulating the polarization of M1 macrophage to M2 macrophage and scavenging ROS, which has a promising clinical application.

Early recognition of sepsis is essential for timely initiation of adequate care. However, this is challenging as signs and symptoms may be absent or nonspecific. The cascade of events leading to organ failure in sepsis is characterized by immune-metabolic alterations. Volatile organic compounds (VOCs) are metabolic byproducts released in expired air. We hypothesize that measuring the VOC profile using electronic nose technology (eNose) could improve early recognition of sepsis.

In this cohort study, bedside eNose measurements were collected prospectively from ED patients with suspected infections. Sepsis diagnosis was retrospectively defined based on Sepsis-3 criteria. eNose sensor data were used in a discriminant analysis to evaluate the predictive performance for early sepsis recognition. The dataset was randomly split into training (67 %) and validation (33 %) subsets. The derived discriminant function from the training subset was then applied to classify new observations in the validation subset. Model performance was evaluated using receiver operating characteristic (ROC) curves and predictive values.

We analyzed a total of 160 eNose measurements. The eNose measurements had an area under the ROC (AUROC) of 0.78 (95 % CI: 0.69-0.87) for diagnosing sepsis, with a sensitivity of 72 %, specificity of 73 %, and an overall accuracy of 73 %. The validation model showed an AUC of 0.83 (95 % CI: 0.71-0.94), sensitivity of 71 %, specificity of 83 %, and an accuracy of 80 %.

eNose measurements can identify sepsis among patients with a suspected infection at the ED.

The study is embedded in the Acutelines data-biobank (www.acutelines.nl), registered in Clinicaltrials.gov (NCT04615065).

Sepsis, a condition characterized by a dysregulated host response to infection, can progress to septic shock and lead to various complications. The present study aimed to identify risk factors for the early clinical identification of sepsis patients at heightened risk of complications. In the present study, a total of 383 hospitalized patients with sepsis and positive blood cultures were enrolled. Demographic characteristics, laboratory findings at admission and treatment outcomes were collected and analyzed. Among the 383 sepsis patients, 165 were diagnosed with acute kidney injury (AKI). Patients with AKI exhibited significantly lower platelet counts, elevated procalcitonin levels and higher Sequential Organ Failure Assessment (SOFA) scores. Logistic regression analysis identified the SOFA score [odds ratio (OR)=1.269, 95% confidence interval (CI): 1.067-1.510, P=0.007) as an independent predictor of AKI. Furthermore, patients with septic shock had lower platelet counts and higher white blood cell counts at admission. Multivariable analysis revealed that age (OR=1.024, 95% CI: 1.001-1.047, P=0.039), procalcitonin (OR=1.018, 95% CI: 1.003-1.032, P=0.015), SOFA score (OR=1.465, 95% CI: 1.248-1.719, P<0.001) and Pitt bacteremia score (OR=1.437, 95% CI: 1.204-1.716, P<0.001) were independently associated with septic shock. In addition, sepsis patients with acute respiratory distress syndrome (ARDS) were observed to have lower platelet counts, higher body weight and elevated alanine aminotransferase levels. Multivariable analysis identified the SOFA score (OR=1.177, 95% CI: 1.095-1.265, P<0.001) and body weight (OR=1.030, 95% CI: 1.007-1.054, P=0.010) as independent predictors of ARDS. The present study highlights the risk factors associated with AKI, ARDS and septic shock in sepsis patients with positive blood cultures. Early identification and close monitoring of these factors are crucial for improving outcomes in sepsis management.

Critically ill patients with cirrhosis and liver failure do not uncommonly have hypotension due to multifactorial reasons, which include a hyperdynamic state with increased cardiac index (CI), low systemic vascular resistance (SVR) due to portal hypertension, following the use of beta-blocker or diuretic therapy, and severe sepsis. These changes are mediated by microvascular alterations in the liver, systemic inflammation, activation of renin-angiotensin-aldosterone system, and vasodilatation due to endothelial dysfunction. Haemodynamic assessment includes measuring inferior vena cava indices, cardiac output (CO), and SVR using point-of-care ultrasound (POCUS), arterial waveform analysis, pulmonary artery pressures, and lactate clearance to guide fluid resuscitation. Fluid responsiveness reflects the ability of fluid bolus to increase the CO and is assessed effectively by POCUS, passive leg raises manoeuvre, and dynamic tests such as pulse pressure and stroke volume variation in spontaneously breathing and mechanically ventilated patients. Albumin has pleiotropic benefits through anti-inflammatory properties besides its standard action on oncotic pressure and volume expansion in patients with cirrhosis but has the potential for precipitating pulmonary oedema. In conclusion, fluid therapy in critically ill patients with liver disease is a complex and dynamic process that requires individualized management protocols to optimize patient outcomes.

KW-2449 is a novel multitargeted kinase inhibitor that has been reported to alleviate chronic inflammation and altered immunity during the treatment of autoimmune diseases. The aim of the study was to investigate the effect of KW-2449 on sepsis-induced cardiomyopathy (SIC). A rat model of moderate SIC was induced using the cecal ligation and puncture (CLP) method. KW-2449 was administered to rats at 10 mg/kg for 3 consecutive days by intraperitoneal injection. At 24 hours after CLP, echocardiography, electrocardiogram, and hemodynamic analyses were performed. Blood and cardiac tissues were collected for further analysis. RNA sequencing (RNA-seq) analyses were used to identify the key genes affected by KW-2449 treatment during SIC. KW-2449 improved the liver dysfunction in septic rats. KW-2449 significantly improved left ventricular (LV) systolic function and hemodynamics compared to the CLP group. KW-2449 suppressed the systemic inflammatory response, decreased myocardial inflammation and cell apoptosis in the CLP rats. RNA-seq analyses indicated that there were a total of 2256 differentially expressed genes in the CLP group compared to the Control group, among which 63 genes were down-regulated and 59 genes were up-regulated by KW-2449. Specifically, Pparα was identified as a key target gene of KW-2449 in the treatment of SIC by RNA-seq analysis.KW-2449 also significantly upregulated the protein expression of Pparα in the LV tissue of septic rats. KW-2449 reduced systemic inflammation, cardiac inflammation, and improved cardiac dysfunction in the CLP-induced SIC rat model. The underlying mechanism of the cardio-protective role of KW-2449 in the CLP-induced SIC might be related to Pparα.

In this study, we aimed to evaluate the role of the glucose-to-potassium ratio in predicting in-hospital mortality and prognosis of patients diagnosed with sepsis and septic shock in an emergency department and admitted to an emergency critical intensive care unit (ICU).

This study was a retrospective and observational evaluation of nontraumatic sepsis and septic shock patients > 18 years of age who were admitted to the emergency department of a tertiary training and research hospital and had available glucose and potassium values at the time of admission. The patients were evaluated over a 24-month period. The primary goal of this study was to examine the relationship between the glucose-to-potassium ratio and in-hospital mortality in sepsis patients.

Data derived from 175 patients were included in the statistical analysis. Blood urea nitrogen, creatinine, lactate dehydrogenase, direct bilirubin, C‑reactive protein, and lactate levels were found to be significantly higher in the nonsurvivor group than in the survivor group (p < 0.05). On the other hand, hemoglobin, hematocrit, albumin, pH, HCO3 and base excess levels were found to be statistically significantly higher in the survivor group than in the nonsurvivor group (p < 0.05). The glucose-to-potassium ratio was not significant in terms of predicting mortality in sepsis patients (p = 0.324). In the receiver-operating characteristic (ROC) analysis of various parameters' significance in terms of predicting mortality, APACHE 2 scores had the highest area under the curve (AUC) value (0.729).

According to the results of this study, the glucose-to-potassium ratio did not have a significant value in predicting mortality risk in sepsis and septic shock patients admitted from the emergency department to the emergency critical ICU.

Severe sepsis is cognate with life threatening multi-organ dysfunction. There is a disturbance in endocrine functions with alterations in several hormonal pathways. It has frequently been linked with dysfunction in the hypothalamic pituitary-adrenal axis (HPA). Increased cortisol or cortisolemia is evident throughout the acute phase, along with changes in the hypothalamic pituitary thyroid (HPT) axis, growth hormone-IGF-1 axis, insulin-glucose axis, leptin, catecholamines, renin angiotensin aldosterone axis, ghrelin, glucagon, hypothalamic pituitary gonadal (HGA) axis, and fibroblast growth factor-21. These changes and metabolic alterations constitute the overall response to infection in sepsis. Further research is essential to look into the hormonal changes that occur during sepsis, not only to understand their potential relevance in therapy but also because they may serve as prognostic indicators.