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.

Sepsis is a leading cause of death among patients with HIV, but early diagnosis remains a challenge. This study evaluates the diagnostic performance of monocyte distribution width (MDW) in detecting sepsis in patients with HIV. A prospective observational study was conducted at Shanghai Public Health Center, involving 488 hospitalized patients with HIV aged 18-65 between December 2022 and August 2023. MDW was measured at admission, and its diagnostic accuracy was compared with Sepsis-3 criteria. Survival rates on day 28 and 90 were also recorded. Additionally, five machine learning (ML) models were tested to enhance diagnostic efficacy. Of 488 subjects, 90 were in the sepsis group and 398 in the control group. MDW showed a diagnostic area under the curve (AUC) of 0.82, comparable to C-reactive protein (CRP) and Procalcitonin (PCT) with AUCs of 0.78 and 0.82, respectively. With a cut-off value of 25.25, MDW had a sensitivity of 0.83 and specificity of 0.76. The positive and negative predictive values were 44% and 95%, respectively. When MDW was combined with platelet count, serum albumin, and hemoglobin in a random forest model, the AUC improved to 0.931. The model achieved a sensitivity of 1.00 and specificity of 0.732. MDW is a useful diagnostic marker for sepsis in patients with HIV, with strong sensitivity and specificity. Combining MDW with other lab markers can further enhance diagnostic accuracy.Trial registration: ClinicalTrials.gov identifier: NCT05036928..

Sepsis and septic shock are associated with microcirculatory dysfunction, significantly impacting patient outcomes. This study aimed to evaluate the effects of a 20 % albumin bolus on microcirculation compared to crystalloid resuscitation in fluid-responsive patients (ClinicalTrials.govID:NCT05357339).

We conducted a single-centre randomised controlled trial, enrolling 103 patients (Albumin n = 52, Control n = 51). Fluid responsiveness was assessed, and fluid was administered in boluses of 100 ml to clinical effect. Microcirculation was measured using the Side stream Dark Field camera and AVA 4.3 software. Baseline characteristics, macrohaemodynamics, and microcirculation parameters were recorded. Three patients were excluded from analysis.

The final cohort comprised 100 patients, 35 (35 %) females with a mean age of 58 years (range: 18-86). The mean APACHE score was 28 (range: 7-45), and the mean SOFA score was 9.4 (range: 1-17). No significant differences in APACHE (26.24 vs. 29.4, p = 0.069) or SOFA (9.08 vs. 9.78, p = 0.32) scores were found for albumin and control group respectively. The albumin group had worse microcirculation at baseline but demonstrated significant improvements in microvascular density and activity at 15 min and 60 min (p < 0.005), while the control group exhibited no significant changes. Additionally, both groups were fluid responsive, with a mean pulse pressure variability of 17 % at admission. There were no significant differences in overall fluid balances, vasopressor days, length of ICU stay, or mortality between groups.

This study demonstrates that a 20 % albumin bolus significantly enhances microcirculation in fluid-responsive patients with septic shock. These findings underscore the potential benefits of targeted microcirculation therapy in critically ill patients.

Sepsis, a condition of significant clinical concern, is characterized by life-threatening organ dysfunction that arises from an infection and is exacerbated by a dysregulated host response. Targeting immune modulation, particularly against tumor necrosis factor-alpha (TNF-α), has emerged as a promising anti-inflammatory therapeutic strategy. However, approaches such as blood purification to eliminate inflammatory mediators or the use of anti-TNF-α therapies have shown limited efficacy in clinical practice. This literature review aims to elucidate the pathogenesis of sepsis and dissect the factors contributing to unfavorable outcomes in TNF-α-targeted treatments. Our analysis highlights several potential reasons for therapeutic failure. Complete blockade of TNF-α may adversely affect both TNFR1 and TNFR2 signaling, thereby reducing the efficacy of TNF-α inhibitors. Additionally, the complex heterogeneity of sepsis, including the etiology of infection, patient-specific factors (e.g., immune responsiveness, body mass index, and obesity), the development of anti-drug antibodies, and treatment duration, significantly influences therapeutic outcomes. Based on these insights, we emphasize the need for precision medicine in sepsis management. This includes stratifying patients into subgroups, using TNFR2 agonists or TNFR1-specific antagonists, refining drug design, implementing multi-target combination therapies, and considering the patient's physiological state at the time of treatment. Collectively, these strategies could enhance the efficacy of sepsis management. This review underscores the multifaceted nature of sepsis treatment and highlights the imperative for personalized, multimodal therapeutic approaches to improve clinical outcomes.

Sepsis is characterized by multiple organ dysfunction, dysregulation of the response to the infection process, and a high mortality rate in intensive care units. In addition, individuals who overcome sepsis often manifest cognitive deficits associated with neuroinflammation resulting from the entry of pro-inflammatory cytokines into the brain. Post-translational protein modifications, such as SUMOylation, can regulate the expression of pro-inflammatory genes during sepsis. Since SUMO-2/3 can play a role in pathological conditions, our aim was to investigate a potential link between sepsis-induced cognitive decline and SUMOylation by this isoform. Firstly, the cecal slurry model was induced by intraperitoneally injecting male Swiss mice with different volumes of a cecal solution. Following assessment of body temperature, mass and septic scores, the groups that received 300 μL and 350 μL of the cecal solution were selected for the behavioural tests, as they presented signs of sepsis without excessive mortality. Surviving animals were evaluated for cognition/memory and anxious/depressive-like behaviours through the open-field, object recognition, Y-maze, and tail suspension tests. Subsequently, SUMO-2/3 conjugation was determined in samples from the hippocampus and prefrontal cortex by Western blotting. Mice in the septic groups showed decreased locomotor activity, anxious-and depressive-like behaviours, as well as impaired memory. These deficits were accompanied by a decrease in SUMO-2/3 conjugation in the hippocampus and prefrontal cortex at 24 h and 10 days after the induction of the cecal slurry model. Taken together, our findings suggest that SUMOylation is impaired in septic animals and this could be related to the behavioural deficits seen in the surviving mice.

Mitochondria‑derived peptides (MDPs) are a unique class of peptides encoded by short open reading frames in mitochondrial DNA, including the mitochondrial open reading frame of the 12S ribosomal RNA type‑c (MOTS‑c). Recent studies suggest that MDPs offer therapeutic benefits in various diseases, including neurodegenerative disorders and types of cancer, due to their ability to increase cellular resilience. Mitochondrial dysfunction is a key factor in the onset and progression of cardiovascular diseases (CVDs), such as atherosclerosis and heart failure, as it disrupts energy metabolism, increases oxidative stress and promotes inflammation. MDPs such as humanin and MOTS‑c have emerged as important regulators of mitochondrial health, as they show protective effects against these processes. Recent studies have shown that MDPs can restore mitochondrial function, reduce oxidative damage and alleviate inflammation, thus counteracting the pathological mechanisms that drive CVDs. Therefore, MDPs hold promise as therapeutic agents that are capable of slowing, stopping, or even reversing CVD progression and their use presents a promising strategy for future treatments. However, the clinical application of MDPs remains challenging due to their low bioavailability, poor stability and high synthesis costs. Thus, it is necessary to improve drug delivery systems to enhance the bioavailability of MDPs. Moreover, integrating basic research with clinical trials is essential to bridge the gap between experimental findings and clinical applications.

Sepsis is a global health challenge with high mortality rates. It demands timely risk identification and biomarker-based strategies to optimize ICU management and outcomes.

To explore the prognostic value of cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP) in predicting 28-day mortality in septic patients.

We analyzed clinical data of septic ICU patients at Shanghai General Hospital. We used Cox models and ROC curves to assess the association between cTnI and BNP levels and 28-day mortality, and their prognostic accuracy.

A total of 333 septic patients were included in this study (mean age [SD], 64.7 [15.2] years; 65.8 % male), of whom 63 (18.9 %) patients died during 28 days. Elevated peak cTnI levels, identified in 233 patients (70.0 %), were independently associated with higher 28-day mortality in septic patients, even after adjusting for SOFA scores, BNP, and other confounding variables. (adjusted HR 2.33, 95 % CI 1.08-5.04, P = 0.03). However, neither first-day cTnI nor BNP levels remained independent predictors of 28-day mortality. Sensitivity analyses for the magnitude of cTnI elevation as a predictive variable also yielded similar results. Compared to first-day cTnI, first-day BNP, and peak BNP, the peak cTnI had the most significant and modest area under the ROC curve (AUC: 0.64 [0.57-0.71]).

Elevated peak cTnI or the magnitude of cTnI, rather than first-day, could independently predict the risk of 28-day mortality in septic patients. This finding highlighted the importance of dynamic monitoring cTnI levels for risk stratification identification and management in septic patients.

Partially hydrolyzed guar gum (PHGG) protects against intestinal barrier dysfunction and can ameliorate some intestinal diseases. However, whether PHGG has a role in protecting intestinal barrier function (IBF) during sepsis remains unclear. This study aimed to investigate the role and probable mechanism of PHGG in the intestinal mucosa in sepsis. A rat sepsis model was constructed using cecal ligation and puncture (CLP). FITC-dextran 4 (FD-4) flux, serum inflammatory mediator levels, tight junction (TJ) levels, jejunum mucosa pathology, and epithelial intercellular junction ultrastructure were monitored to evaluate the effect of PHGG on IBF. Caco-2 monolayers were used to study the impact and mechanism of PHGG on lipopolysaccharide (LPS)-induced barrier dysfunction in vitro. The expression of zonula occludens protein-1 and occludin and the location of P65 were studied by immunofluorescence. Nuclear factor kappa B (NF-κB) and myosin light chain kinase 3 (MLCK) pathway-related protein expression was verified by quantitative reverse transcriptase polymerase chain reaction or western blotting. The results indicated that the jejunal mucosa structure was destroyed, the villi were disrupted and shortened, and neutrophil infiltration was evident in the septic rats. Compared to Sham group, spetic rats had increased Chiu's score, serum inflammatory mediator levels, and FD-4 flux but decreased TJ and gap junction density. In addition, the expression of MLCK, p-MLC, and TJ proteins and the expression of P65 in the nucleus were increased in septic rats. Furthermore, compared to those in the Control group, LPS-treated Caco-2 cells showed lower cell viability and transepithelial electrical resistance, while had higher FD-4 flux and the expression of MLCK, p-MLC, TJ proteins and P65 in the nucleus. PHGG pretreatment reversed the above effects induced by CLP or LPS treatment. Moreover, SN50, an NF-κB inhibitor, attenuated the above effects of LPS on Caco-2 cells. Overall, PHGG reduced inflammation, increased TJ protein expression and localization, and relieved damage to the TJ structure and intestinal permeability through suppression of the NF-κB/MLCK pathway. This study provides new insights into the role of PHGG in sepsis therapy.

Sepsis, a life-threatening condition marked by organ dysfunction due to a dysregulated host response to infection, involves complex physiological and biochemical abnormalities.

To develop a multivariate model to predict 4-, 6-, and 8-week mortality risks in intensive care units (ICUs).

A retrospective cohort of 2389 sepsis patients was analysed using data captured by a clinical decision support system. Patients were randomly allocated into training (n = 1673) and validation (n = 716) sets at a 7:3 ratio. Least Absolute Shrinkage and Selection Operator (LASSO) regression identified variables incorporated into a multivariate Cox proportional hazards regression model to construct a prognostic nomogram. The area under the receiver operating characteristic curve (AUROC) assessed model accuracy, while performance was evaluated for discrimination, calibration and clinical utility.

A risk score was developed based on 11 independent predictors from 35 initial factors. Key predictors included minimum Acute Physiology and Chronic Health Evaluation II (APACHE II) score as having the greatest impact on prognosis, followed by days of mechanical ventilation, number of vasopressors, maximum and minimum Sequential Organ Failure Assessment (SOFA) scores, infection sources, Gram-positive or Gram-negative bacteria and malignancy. The nomogram demonstrated superior discriminative ability, with AUROC values of 0.882 (95% confidence interval [CI], 0.855-0.909) and 0.851 (95% CI, 0.804-0.899) at 4 weeks; 0.836 (95% CI, 0.798-0.874) and 0.820 (95% CI, 0.761-0.878) at 6 weeks; and 0.843 (95% CI, 0.800-0.887) and 0.794 (95% CI, 0.720-0.867) at 8 weeks for training and validation sets, respectively.

A validated nomogram and web-based calculator were developed to predict in-hospital mortality in ICU sepsis patients. Targeting identified risk factors may improve outcomes for critically ill patients.

The developed prediction model and nomogram offer a tool for assessing in-hospital mortality risk in ICU patients with sepsis, potentially aiding in nursing decisions and resource allocation.

Sepsis is a life‑threatening organ dysfunction disorder caused by dysfunctional host response to infection. Sepsis‑induced cardiomyopathy (SIC) is a common and serious complication of sepsis, and it is associated with increased mortality rates; however, its specific pathogenesis is still unclear. Ferroptosis, which is an iron‑dependent form of programmed cell death, is involved in the pathophysiology of SIC. Further study on the mechanism and therapeutic targets of ferroptosis in SIC may provide new strategies for clinical diagnosis and treatment of this condition. The present article reviews the mechanisms between SIC and ferroptosis, summarizes the progress in research of the involvement of ferroptosis in SIC and provides new potential strategies for further research and treatment in the future.

Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using 18F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.

Glucagon-like peptide-1 (GLP-1) has been widely studied in the context of treating obesity and various forms of metabolic disease. Sepsis is a life-threatening medical emergency characterized by the widespread dysregulation of energy metabolism within cells. The potential for GLP-1 to improve sepsis patient outcomes through improvements in energy metabolism and inflammation has been a focus of growing research interest, with many studies of GLP-1 itself and related compounds, including GLP-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 (DPP-4) inhibitors, having explored the impact on sepsis in cells and organs. Such studies require that attention be paid to both the physiological and potential pathological effects of GLP-1 in sepsis. In many reports, researchers have demonstrated that endogenous GLP-1, GLP-1RAs, or DPP-4 inhibitors (a GLP-1 depressant) can modulate glucose homeostasis, inflammatory activity, immune function, and organ dysfunction in studies of sepsis model systems in vitro and in vivo. To date, GLP-1-based treatments have yet to be specifically used to manage sepsis, but its pleiotropic effects suggest its significant potential in sepsis treatment. This review provides an overview of the relationship between GLP-1 and its related compounds with sepsis, aiming to offer novel perspectives for the diagnosis and treatment of this condition. It highlights that GLP-1 may serve as a new biomarker for assessing the severity and prognosis of sepsis, and potentially contribute to improving clinical outcomes in septic patients. Meanwhile, GLP-1 may function as a messenger of metabolic reprogramming, shifting cellular energy production from oxidative phosphorylation to glycolysis, thereby modulating immune responses and influencing inflammatory reactions to enhance the clearance of pathogens. However, GLP-1 may act as a double-edged sword, the enhanced inflammatory response can potentially induce cytotoxic and organ-damaging effects while exerting beneficial actions.

Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS/MS) is a valuable alternative to ligand-binding assay, enabling specific and accurate quantification of protein biomarkers. We developed a robust antibody-free LC-HRMS/MS method for the multiplex quantification of three sepsis biomarkers in serum: NGAL, CRP and SAA. The method was thoroughly optimized from sample preparation to LC-HRMS/MS analysis, alongside the calibration. Specifically, a modified trichloroacetic acid/isopropanol protein precipitation procedure combined with an optimized Parallel Reaction Monitoring acquisition allowed the quantification of the low abundant NGAL at ng/mL levels. While reference material and reference measurement procedure were available for CRP, no such standards existed for NGAL and SAA. Well-characterized peptide calibrators traceable to the international system of units were developed for NGAL and SAA. The method demonstrated suitable trueness and precision for the quantification of NGAL, CRP, and SAA with coefficients of variation (CV%) ranging from 1.6 % to 22.4 % and bias between -12.6 % and +18.0 %. Successful application to pooled serum samples illustrated the method's effectiveness. Our results pave the way toward the development of reference systems for additional sepsis biomarkers.

Traditional biomarkers used for sepsis diagnosis have limited sensitivity and specificity and, so far, are not recommended for sepsis diagnosis. We aimed to evaluate diagnostic accuracy of XN-9000® hematology analyzer derived cell population data (CPD) for sepsis.

We conducted a cross-sectional cohort study on patients admitted to an emergency department (ED) with a suspicion of infection, having a complete blood count with differential (CBC-Diff). CBC-Diff were performed on XN-9000® analyzer (Sysmex, Kobe, Japan). CPD were measured routinely for each CBC-Diff ordered by ED physician. They include: neutrophils-related - Neut-GI and Neut-RI; monocytes-related - Mono-X, Mono-Z, Re-Mono and Mono-Y; IG referring to immature granulocytes; and lymphocytes-related - As-lymp and Re-lymp. Intensive care infection (ICIS) and neutrophile and monocyte (NEMO) scores were calculated using several CPD parameters. Diagnostic performance of each biomarker was computed together with receiver operating characteristic curves for sepsis diagnosis (according to Sepsis-3 definition).

A total of 1,155 patients with a suspicion of infection were included and 230 had sepsis. Median age was 64 years and 49 % were female. Except for lymphocyte count with an area under the receiver operating characteristic (AUROC) of 0.67 (95 % confidential interval 0.63-0.70), the other CPD exhibited modest performances with AUROC under 0.65. The ICIS and NEMO scores had a modest performance with AUROC of 0.56 (0.52-0.61) and 0.55 (0.51-0.59) respectively.

None of the biomarkers and scores tested demonstrated sufficient diagnostic accuracy to be recommended for routine sepsis screening in the ED.

The present study estimated lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-α) levels and its association with health care associated infection (HAI) and duration of multi-organ dysfunction syndrome (MODS). LPS-induced TNF-α levels were estimated in 67 children on day 3 of MODS. Variables recorded were Pediatric Index of Mortality (PIM-3), cultures, diagnosis, HAI, days of MODS, survivors and non-survivors. Of 67 children, 37 (52.2%) were male and 27 (40.2%) expired. Sixty-three (94%) children had reduced TNF-α levels (<200 pg/ml); 23.11 (10.38, 40.59). The median number of days in MODS was 7 (5, 12) and prolonged MODS (≥7 d) was observed in 49/67 (73.1%) children. Forty-five (67.1%) children had HAI, among these 33/45 (73.3%) had ventilator associated pneumonia (VAP). TNF-α levels were significantly lower in children with MODS, prolonged MODS, children who developed HAI and non-survivors as compared to healthy children (p <0.0001), children with MODS <7 d (p=0.01), children without HAI (p=0.009) and survivors (p=0.04), respectively. HAI was independently associated with reduced levels of TNF-α (p=0.01).

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host immune response to pathogenic infection. Due to its high mortality rate, it has been a major global public health problem. Recent studies have shown that the formation of immunothrombosis plays as a "double-edged sword" in the pathogenesis of sepsis, and how to properly regulate immunothrombosis to avoid organ damage and end the high-inflammation state as early as possible are the key steps for sepsis therapy. Considering the complexity of sepsis therapy, the development of an effective combined therapeutic strategy is the goal of this study. First, the insoluble Panexin1 (Panx1) channel inhibitor probenecid (Prob) was prepared as nanocrystals and administered via intramuscular injection. At the same time, septic mice were intravenously injected with cefotaxime sodium through the tail vein for combination therapy. After treatment, the number of infection foci and the level of serum inflammatory factors in septic mice were significantly reduced, and also neutrophil NETosis was significantly inhibited; thus, the survival rate of septic mice was dramatically increased. Pathological analysis revealed that the combination treatment was safe and effective and could significantly reduce the formation of immunothrombosis in septic mice.

Sepsis is a major cause of mortality in low-resource settings. Effective microbiological culture services are a bottleneck in diagnosis and surveillance.

We aimed to evaluate the performance of the BIOFIRE FILMARRAY Blood Culture Identification 2 (BCID2, bioMérieux) assay in a low-resource setting laboratory in comparison to standard practice.

This five month prospective validation study included all positive blood cultures collected at Sally Mugabe Central Hospital, Harare, Zimbabwe. BCID2 testing was done in parallel to standard phenotypic procedures and resistance testing. Reference identification was performed using mass spectrometry or whole genome sequencing. Only samples with available reference standard results were included in the analysis. Data captured on paper-based forms was entered into electronic case report forms (ODK Collect). Specificity and sensitivity for BCID2 were calculated in comparison to the reference standards, with performance measures calculated using the Wilson score. Biomedical scientists using BCID2 completed a system usability survey (SUS).

Positive results were recorded in 780/2,023 (38.5%) blood cultures, within which 377 (48.3%) had reference results and so were included in analysis. Neonatal samples were most frequent (182, 48.3%), then paediatric (150, 39.8%), then adults (18, 4.8%) and unknown (27, 7.2%). Specificity exceeded 95% throughout. Sensitivity ranged from 50% (A. calcoaceticus-baumanii complex, Proteus spp.) to 100% (S. pneumoniae, Salmonella spp). Using BCID2, CTX-M was detected in 111/175 (74.5%) Enterobacterales, from which 5/111 also had NDM and VIM detected. NDM-5 was detected in 2/5 NDM samples using sequencing. In total 3/23 S. aureus isolates were methicillin resistant, from which one was confirmed using phenotypic antimicrobial susceptibility testing. Usability was good (SUS score = 79.5).

Rapid molecular tests have potential to improve turn-around time and quality of sepsis diagnostics. However, specific work-flows are critical to supplement molecular tests with minimal phenotypic tests for optimal clinical decision-making.

Bacterial infections in the blood (sepsis) have been recognized as a leading cause of mortality in the clinical field due to limitations in the detection of bacteria at low concentration and their resistance to antibiotics by excessive misuse. Some of the common symptoms are fever, chills, rapid heartbeat, difficulty breathing, confusion, and changes in mental status with occasionally pale, clammy, and mottled skin. Early diagnosis and identification are the keys to a successful treatment for sepsis patients. Researchers have developed nanoparticles to enrich bacterial populations followed by detection and applied them to conventional methods such as phenotypic and molecular diagnostics to enhance different detectors' responses toward pathogens. This short review systematically overviews steps that are followed in clinical labs for bacterial detection, identification, and their drawbacks. In this context, we discuss the role that nanoparticles can play in overcoming the limits of traditional microbiology methods in terms of turnaround times (TATs) and accuracy. We believe that this short review will provide up-to-date information about the applications of nanoparticles in the enrichment, separation, and identification of bacterial infection in the clinical field and, therefore, a way of rapid treatment.

Sedatives are often used to facilitate mechanical ventilation in patients with sepsis. Ciprofol is a new promising sedated candidate with a higher binding activity to the gamma-aminobutyric acid-A receptor than propofol. This study aimed to compare the efficacy and safety of ciprofol and propofol for long-term sedation in mechanically ventilated patients with sepsis.

In this single-center randomized clinical trial, mechanically ventilated adults with sepsis in the intensive care unit (ICU) who anticipated to require long-term sedation ≥ 24 h were randomly assigned to receive intravenous ciprofol or propofol. The target sedation goal was - 3 to 0 according to the Richmond Agitation-Sedation Scale. The primary outcome was weaning time. Secondary outcomes included the percentage of time within the target sedation range, successful sedation (the percentage of time within the target sedation range ≥ 70% without rescue sedation), ICU and in-hospital mortality, length of ICU and hospital stay, hypotension, and bradycardia.

A total of 60 patients were randomized, 4 were excluded because of withdrawing treatment, 28 were assigned to ciprofol group and 28 to propofol group. Weaning time in ciprofol group was shorter than propofol group (median [interquartile range (IQR)], 104.0 [40.8-147.3] hours vs 132.5 [69.8-207.8] hours), but not reached significant difference between groups (P = 0.123). Ciprofol had significantly higher percentage of time within the target sedation range (median [IQR], 72.2% [14.3-92.7%] vs 22.6% [0.0-45.4%]) and successful sedation (53.6% [15/28] vs 14.3% [4/28]) than propofol. No significant differences were observed in ICU mortality, in-hospital mortality, length of ICU stay, length of hospital stay, hypotension, and bradycardia between groups.

Ciprofol is an effective and safe agent among mechanically ventilated patients with sepsis who anticipated to require long-term sedation.

The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200066835) on December 19, 2022.

Sepsis is a life-threatening condition with a high mortality rate in intensive care unit (ICU). However, rapid and accurate diagnostic criteria are still lacking. This pilot study explored the role of METRNL as a novel biomarker for sepsis by focusing on its diagnostic potential and rapid secretion mechanism.

METRNL levels were measured in cell and animal models of sepsis. Serum samples from 107 sepsis patients and 95 non-septic controls in ICU were collected. Diagnostic performance of METRNL, Procalcitonin (PCT) and C-reactive protein (CRP) were assessed using ROC analysis. Endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl-/- mice) were used to identify the source of METRNL secretion. Chemical inhibitors and RNA interference were used to explore the secretion pathways.

In lipopolysaccharide (LPS)-induced cell and mouse models of sepsis, METRNL levels significantly increased in a dose- and time-dependent manner. Similarly, in the cecal ligation and puncture mouse models, serum METRNL levels were elevated over time and correlated with sepsis severity. In animals, serum METRNL increased within 1 h post-modeling, preceding PCT and CRP. Clinically, sepsis patients had significantly higher serum METRNL levels. ROC analysis showed area under the curves [95% confidence intervals] of 0.943 [0.91-0.975] for METRNL, 0.955 [0.929-0.981] for PCT and 0.873 [0.825-0.921] for CRP. At the optimal cutoff value, METRNL (91.6%) exhibited relatively greater diagnostic specificity than PCT (88.4%) and CRP (69.5%). EC-Metrnl-/- reduced majority of serum Metrnl levels in sepsis mouse models. Inhibition of the endoplasmic reticulum-Golgi (ER-Golgi) pathway through chemical inhibitors or RNA interference significantly reduced METRNL levels in the supernatant of sepsis cell models compared to control groups. Similar results were obtained with Toll-like receptor 4 (TLR4) and ERK inhibitors.

This pilot study demonstrates that METRNL is a novel potential biomarker for sepsis with diagnostic capability comparable to that of PCT. Serum METRNL rapidly increased during the early phase of sepsis. Mechanistically, it mainly originates from the endothelium during sepsis, and TLR4-ERK signaling mediates the rapid secretion of METRNL via the classical ER-Golgi pathway in response to LPS stimulation.

Neonatal sepsis causes significant morbidity and mortality worldwide but is difficult to diagnose clinically. Clinical prediction models (CPMs) could improve diagnostic accuracy, facilitating earlier treatment for cases and avoiding antibiotic overuse. Neonates in low-income and middle-income countries (LMICs) are disproportionately affected by sepsis, yet no review has comprehensively synthesised evidence for CPMs validated in this setting.

We performed a scoping review of CPMs to diagnose neonatal sepsis using Ovid MEDLINE, Ovid Embase, Scopus, Web of Science, Global Index Medicus and the Cochrane Library. The most recent searches were performed on 16 June 2024. We included studies published in English or Spanish that validated a new or existing CPM for neonatal sepsis in any healthcare setting in an LMIC. Studies were excluded if they validated a prognostic model or where data for neonates could not be separated from a larger paediatric population. Studies were selected by two independent reviewers and summarised by narrative synthesis.

From 4598 unique records, we included 82 studies validating 44 distinct models in 24 252 neonates. Most studies were set in neonatal intensive or special care units (n=64, 78%) in middle-income countries (n=81, 99%) and included neonates already suspected of sepsis (n=58, 71%). Only four studies (5%) were set in the WHO African region, and only one study included data from a low-income country. Two-thirds of CPMs (n=30) required laboratory parameters, and three-quarters (n=34) were only validated in one study.

Our review highlights several literature gaps, particularly a paucity of studies validating models in the lowest-income countries where neonatal sepsis is most prevalent, and models for the undifferentiated neonatal population that do not rely on laboratory tests. Furthermore, heterogeneity in study populations, definitions of sepsis and reporting of models inhibits meaningful comparison between studies and may hinder progress towards useful diagnostic tools.

Sepsis remains a significant global health threat with a disproportionate burden in low-income countries including those in sub-Saharan Africa where case fatality rates are as high as 30% to 50%. Defined as a severe systemic response to infection, sepsis leads to widespread immune dysregulation and organ dysfunction, including adrenal insufficiency. Critical illness-related corticosteroid insufficiency (CIRCI) arises from dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids, all of which can occur during sepsis. Clinical trials of corticosteroids for the treatment of patients with sepsis and septic shock have shown improvements in shock reversal, and in some studies, patient survival; however, their role in the treatment of sepsis in sub-Saharan Africa is unknown. The incidence of sepsis in sub-Saharan Africa is compounded by high rates of human immunodeficiency virus (HIV) and co-infections, including tuberculosis (TB), which is the leading cause of sepsis. Both HIV and TB can cause immune dysregulation and adrenal insufficiency, which may exacerbate CIRCI and prolong shock. Existing sepsis research has been predominantly conducted in high-income countries and has largely excluded people living with HIV or TB. Therefore, there is a need to better understand sepsis and CIRCI pathophysiology in the context of specific regional host and pathogen characteristics. In this narrative review, we explored the pathophysiology of sepsis in sub-Saharan Africa including the existing literature on the immune response to sepsis and the prevalence of adrenal insufficiency in patients with HIV and TB, with a focus on the implications for corticosteroid management. We found a compelling need to further evaluate corticosteroids for the treatment of sepsis in Africa.

Systemic inflammatory response syndrome (SIRS) and organ dysfunction make it challenging to predict which major trauma patients are at risk of developing sepsis. Additionally, the unclear pathogenesis of sepsis after trauma contributes to its high morbidity and mortality. Identifying early predictive and diagnostic biomarkers, as well as exploring related metabolic pathways, is crucial for improving early prevention, diagnosis, and treatment. This study prospectively analyzed plasma samples from patients with severe trauma collected between March 2022 and November 2023. Trauma patients were divided into two groups based on whether they developed sepsis within two weeks: the TDDS group (trauma patients who did not develop sepsis) and the TDS group (trauma patients who did develop sepsis). Plasma samples from the TDS group were collected at the time of sepsis diagnosis (Sepsis group). Metabolite concentrations were measured using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) through untargeted metabolomics. From the differential metabolites between the TDS and TDDS groups, we identified five significant metabolites (all area under the curve (AUC) ≥ 0.94) as early predictive biomarkers for sepsis after trauma: (1) docosatrienoic acid, (2) 7-alpha-carboxy-17-alpha-carboxyethylandrostan lactone phenyl ester, (3) sphingomyelin (SM) 8:1;2O/26:1, (4) N1-[1-(3-isopropenylphenyl)-1-methylethyl]-3-oxobutanamide, and (5) SM 34:2;2O. Furthermore, five significant metabolites (all AUC ≥ 0.85) were identified as early diagnostic biomarkers from the comparison between the TDS and TDDS groups: (1) lysophosphatidylcholine (LPC) O-22:1, (2) LPC O-22:0, (3) uric acid, (4) LPC O-24:2, and (5) LPC 22:0-SN1. 26 metabolites shared between two comparisons (TDS vs. TDDS and sepsis vs. TDS) were identified. Of which, 19 metabolites belong to lipid metabolism. The top three metabolic pathways related to sepsis after trauma under the impact of severe trauma were: (1) glycerophospholipid metabolism, (2) porphyrin metabolism, and (3) sphingolipid metabolism. The top three metabolic pathways related to sepsis after trauma under the impact of infection were: (1) caffeine metabolism, (2) biosynthesis of unsaturated fatty acids, and (3) steroid hormone biosynthesis. Our study identified early predictive and diagnostic biomarkers and explored metabolic pathways related to sepsis after trauma. These findings provide a foundation for future research on the onset and development of sepsis, facilitating its early prevention, diagnosis, and treatment based on specific metabolites and metabolic pathways.

Neonatal sepsis is a major cause of mortality in low-resource settings. We assessed how neonatal sepsis guidelines were used in 2 Zimbabwean hospitals and 1 Malawian hospital.

Using routine data collected with the digital health intervention, Neotree, we retrospectively reviewed doctors' and nurses' agreement with national and World Health Organization (WHO) guideline recommendations for antibiotic prescription for sepsis. We compared clinical features and outcomes of neonates who should have received antibiotics as per guideline with those who actually received them and fitted a logistic regression model to identify features associated with prescription.

Data were collected between January 2021 and June 2022 from 10 868 neonates: 6045 admitted to Sally Mugabe Central Hospital (SMCH), 1094 to Chinhoyi Provincial Hospital (CPH) and 3729 to Kamuzu Central Hospital (KCH). Complete implementation of national guidelines would increase antibiotics at admission: from 2188 (38%) to 3745 (64%) at SMCH, 472 (44%) to 852 (79%) at CPH, and 1519 (41%) to 3043 (82%) at KCH. Clinical features of sepsis were frequently not acted on, but the case fatality rate was lower in those not prescribed antibiotics despite guideline recommendation. Application of WHO guidelines would increase antibiotic prescription to 91% at SMCH, 88% at CPH, and 77% in KCH. Maternal risk factors for sepsis, male gender, low birth weight, older age at admission, and spontaneous vaginal delivery were associated with higher rate of antibiotic prescription.

Guideline-recommended clinical signs for sepsis are inconsistently used, with clinicians using other features for antibiotic decision-making. Work is needed to revise clinical diagnostic algorithms in low-resource settings to ensure they are useful, usable and contextually appropriate.

Sepsis is the 10th leading cause of death globally and the most common cause of death in patients with infections. Ubiquitination plays a key role in regulating immune responses during sepsis. This study combined bioinformatics and Mendelian randomization (MR) analyses to identify ubiquitin-related genes (UbRGs) with unique roles in sepsis.

Relevant genes were obtained from the GSE28750 dataset and GSE95233, weighted gene co-expression network analyses were performed to identify gene modules, and differentially expressed UBRGs (DE-UBRGs) were generated by differentially expressed genes (DEGs) crossover with key modular genes and UBRGs in sepsis and normal samples. Causal relationships between sepsis and UbRGs were analysed using MR, performance diagnostics were performed using subject work characteristics (ROC) curves, and an artificial neural network (ANN) model was developed. On this basis, immune infiltration was performed and the expression of key genes was verified in animal models.

3022 DEGs were found between sepsis and normal. A total of 2620 genes were obtained as key modular genes. Crossing DEGs, key modular genes and UBRGs yielded 93 DE-UBRGs. MR results showed WDR26 as a risk factor for sepsis (OR>1) and UBE2D1 as a protective factor for sepsis (OR<1), which was reinforced by scatterplot and forest plot. ROC curves showed that WDR26 and UBE2D1 could accurately differentiate between sepsis and normal samples. Confusion matrix and ROC curve results indicate that the artificial neural network model has strong diagnostic ability. The results of immune infiltration showed that.WDR26 was negatively correlated with plasma cells, while UBE2D1 was positively correlated with CD4 naïve T cells. Significant differences between sepsis and normal were obtained between UBE2D1 and WDR26 in the animal model.

There appeared to be a causal relationship between sepsis, WDR26 and UBE2D1. The insights were of value for effective clinical diagnosis and treatment in sepsis.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. However, how this dysregulation occurs remains to be elucidated. In this study, we use single-cell RNA sequencing (scRNA-seq) and conventional RNA-seq to analyze the immune landscape of sepsis and observe that adaptive immunity is acutely and strongly suppressed. This systemic immunosuppression occurs not only in the peripheral blood but also in all other immune compartments, including the spleen, lymph nodes, and bone marrow. Clinical data show that these adaptive immunity-related genes may have the potential to be used to distinguish patients with sepsis from those with common infections. CD47 is found to play a pivotal role in this immunosuppression by inducing the production of amyloid-β (Aβ), which interacts with CD74 on B cells, leading to B-cell suppression and subsequent adaptive immunosuppression. Blocking CD47-Aβ signaling significantly reduces organ injury and improves the survival rate of septic mice by restoring phagocytic cell functions and alleviating B-cell suppression and adaptive immunosuppression.

Sepsis, a lethal organ dysfunction caused by a dysregulated host response to infection, is the leading cause of worldwide in-hospital mortality. However, the early diagnostic methods for sepsis are still urgent for guiding accurate antibiotic usage and improving the survival rate of the patients. Herein, we constructed a PD-L1 antibody affinity microfluidic (PAAM) chip for early sepsis diagnosis and severity assessment. The chip was used to capture PD-L1-expressing leukocytes from whole blood samples obtained from healthy control (HC) volunteers (n = 15) and sepsis patients on day 1 (D1) and day 7 (D7) (n = 20), and there was a statistically significant difference between HC and sepsis patients (p < 0.0001), and the AUC was 0.96. However, there was no significant difference in the number of cells captured on-chip between sepsis patients on D1 and D7 (p = 0.16). Therefore, we performed immunofluorescence staining of PD-L1, CD64, and CD123 on the chip. The results showed that the combination of PD-L1, CD64, and CD123 for sepsis diagnosis had an AUC of 0.98, and there was a significant difference in PD-L1+/CD64+/CD123+ leukocytes between sepsis patients on D1 and on D7 (p < 0.0001). In conclusion, we found that the combination of multiple biomarkers was more precise and dependable for sepsis diagnosis and severity assessment.

Clinical implications of metagenomics next-generation sequencing (mNGS) in sepsis have not been fully evaluated. This study aimed to determine the diagnostic, therapeutic, and prognostic impacts of mNGS in sepsis.

This multicenter prospective study was conducted at 19 sites in China from 2020 to 2021, and 859 adult patients hospitalized with sepsis were enrolled. The advantages, challenges, knowledge gaps and privacy risks of mNGS were carefully introduced to all participants, and participants chose on their own to either receive conventional microbiological test (CMT) alone (conventional-test-only group, n = 394) or receive mNGS test along with CMT (combined test group, n = 465). For prognostic analysis, the primary endpoint was 28-day mortality. Secondary endpoints included 7-day mortality and average per-day hospital cost. Inverse probability of treatment weighting was used to balance covariates between groups. Concurrent CMT and mNGS results from patients in the combined test group were used for diagnostic analyses. Therapeutic impact of mNGS was evaluated based on subsequent antibiotic adjustment.

Compared with composite reference standard, the positive percent agreement of mNGS among infected site samples was significantly higher than that of CMT (92.0% [95% CI, 88.7 to 94.5] vs. 51.1% [95% CI, 45.9 to 56.2], p < 0.001), while the negative percent agreement of mNGS was inferior to that of CMT (39.6% [95% CI, 29.5 to 50.4] vs. 69.2% [95% CI, 58.7 to 78.5], p < 0.001). The mNGS test identified causal microbes in 344 (74.0%) patients, and concomitant antibiotic changes occurred in 136 patients (29.2%). Death by day 7 occurred in 24 of 465 (5.2%) patients in the combined test group and in 34 of 394 (8.6%) patients in the conventional-test-only group (hazard ratio, 0.44 [95% CI, 0.26 to 0.77], p = 0.004). However, no significant difference in 28-day mortality was observed between two study groups (hazard ratio, 0.82 [0.56 to 1.20], p = 0.300).

The mNGS test of infected site samples exhibited 40% higher pathogen detection rate than CMT in patients with sepsis, which led to improved etiological diagnosis and tailored antibiotic therapy. Additional use of mNGS halved the risk of early death in 7 days, but did not improve 28-day survival in patients with sepsis.

chictr.org.cn Identifier: ChiCTR2000031113. Registered 22 March 2020.

Sepsis is a prevalent and severe condition. However, research investigating the relationship between the immune microenvironment in sepsis-associated acute kidney injury (SA-AKI) through diagnostic models using RNA biomarkers remains limited. Therefore, this study developed a diagnostic model using gene expression data from the Gene Expression Omnibus (GEO) database, leveraging a sufficient sample size.

We proposed a computational method to identify RNAs Rela and Stat3 constructing a diagnostic model using Least Absolute Shrinkage and Selection Operator regression algorithms. Gene expression data from the GEO, comprising five samples each of SA-AKI and sepsis, were analyzed.

Diagnostic models were developed for the datasets, followed by immune cell infiltration and correlation analyses. Experiments were conducted to test and confirm the high expression of Stat3 via Rela in AKI cells post-sepsis, leading to a worse prognosis.

This study identified the significant roles of RNAs Rela and Stat3 in SA-AKI. The developed diagnostic model demonstrated improved accuracy in identifying SA-AKI, suggesting that these RNA markers may provide valuable insights into the pathophysiology of SA-AKI and enhance early diagnosis. These findings contribute to a better understanding of immune-related mechanisms underlying SA-AKI and may inform future therapeutic strategies.

Amoxicillin plus gentamicin is the recommended first-line empiric therapy for neonates with infection. Guidelines vary widely in dose (mg/kg), dose frequency, and adjustments according to post-menstrual age (PMA) and post-natal age (PNA). We aimed to develop a population pharmacokinetic (PK) model for amoxicillin in neonates with clinical evidence of sepsis and design optimal dosing regimens. One hundred seventy-seven neonates receiving intravenous amoxicillin for infection were enrolled in a prospective, observational PK study in Papua New Guinea (PNG). The probability of PK-pharmacodynamic target attainment (PK-PD PTA) was determined based on minimum inhibitory concentrations (MIC) and the proportion of time concentrations that remained above these values (%T > MIC). Neonates with concentrations > 140 mg/L were considered to be at increased risk of amoxicillin neurotoxicity. A population PK model was developed. Simulations tested existing guidelines and proposed simplified regimens. The median PMA and PNA were 38 (37-40) weeks and 0 (0-2) days, respectively. From simulations, existing regimens with 50 or 100 mg/kg doses were associated with higher potential neurotoxic concentrations (24.9% and 84.5%, respectively). With the existing 30 mg/kg PNG regimen, neonates receiving twice-daily dosing between 3 and 7 days were systematically underdosed. A proposed 30 mg/kg regimen, with twice-daily dosing for the first 2 days PNA and three times daily from day 3, provides an optimal balance between the probability of PK-PD target attainment while minimizing toxicity. For fixed volume dosing, using 52 mg (0.25 mL of 250 mg in 1.2 mL) for those <3 kg and 104 mg (0.5 mL) for those ≥3 kg is proposed.

Aims: Sepsis progression is marked by a complex immune response, where the involvement of hypoxia-inducible factors (HIFs) plays an uncertain role. The study aims to elucidate the involvement of HIF-1α in monocyte function during sepsis and its potential as a prognostic indicator. Methods and Results: Transcriptomic data from healthy individuals and septic patients in datasets GSE54514, GSE167363, and GSE46955 were analyzed. Additionally, human monocytes were employed to elucidate how HIF regulates immune responses in the context of sepsis. Septic nonsurvivors exhibited sustained upregulation of HIF-1α expression alongside compromised inflammatory response and antigen presentation, with downregulation of NF-κB and HLADRB1 genes associated with poor sepsis prognosis. Conversely, septic survivors displayed an increased proportion of classical monocytes and enhanced inflammation and expression of antigen presentation-related genes. During the recovery phase of sepsis, monocytes continued to demonstrate elevated HIF-1α expression. In cultured THP1 cells and septic CD14 + monocytes, HIF hindered inflammatory responses and antigen presentation, while also suppressing the proportion of classical monocytes after LPS stimulation. Mechanistically, HIF significantly attenuated LPS-induced immune responses in monocytes by inhibiting the phosphorylation of IKK. Conclusions: HIF in monocytes acts as a suppressor of immune-inflammatory responses and antigen presentation, and may serve as a negative molecular marker for sepsis development.

In this study, we aimed to explore the association between the choice of empirical antibiotic therapy and outcomes in ED patients with sepsis.

Patients admitted to ED with sepsis were identified from a single center in the United States, and the data is stored in the MIMIC-IV-ED database. Propensity score matched model was used to match patients receiving empirical mono or combination antibiotic therapy. Logistic regression model was used to assess the associations between empirical antibiotic therapy and in-hospital mortality.

A total of 11,380 ED patients with sepsis were included in the data analysis. After PSM, 3920 pairs of patients were matched between the empirical mono-antibiotic therapy group and combination antibiotic therapy group. No significant benefit was observed among the empirical combination antibiotic therapy patients compared with the mono-antibiotic therapy in in-hospital mortality (OR, 0.96; 95 % CI, 0.81-1.15; P: 0.684). Empirical quinolones mono-therapy was associated with significantly lower mortality compared to cephalosporins (OR, 2.12; 95 % CI, 1.35-3.50; P:0.002), penicillins (OR, 1.87; 95 % CI, 1.08-3.34; P:0.029) and vancomycin mono-therapy (OR, 2.15; 95 % CI, 1.19-3.97; P:0.012).

Empirical combination antibiotic therapy was not associated with reduced mortality in ED patients with sepsis. Compared with cephalosporins, penicillins and vancomycin, quinolone mono-antibiotic therapy was significantly associated with a decreased risk of in-hospital mortality, especially in patients with respiratory tract infections.

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.