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Xiuwen Ling,1,* Jun Shen,2,* Junqing Liang,2 Kai Yang,1 Jianzhong Yang1 1Emergency & Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, People’s Republic of China; 2Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianzhong Yang, Emergency & Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830011, People’s Republic of China, Tel/Fax +86 18040399020, Email 18040399020@163.comBackground: New-onset atrial fibrillation (AF) in sepsis significantly impacted patient morbidity and mortality, yet the optimal animal model for studying this condition remains undetermined. This study aimed to establish a stable animal model for new-onset AF in sepsis and to explore the molecular mechanisms involved.Methods: Forty-seven Sprague-Dawley rats were utilized, with the cecal ligation and puncture (CLP) group divided into 0.6 mm and 1.0 mm needle outer diameter subgroups, and the lipopolysaccharide (LPS) group into 5 mg/kg, 10 mg/kg, 15 mg/kg, and 20 mg/kg dosage subgroups. The incidence of new-onset AF and five-day mortality rates were compared to identify the most stable modeling conditions. Selected subgroups underwent further analysis, including cardiac ultrasound, electrophysiology, and pathological examinations. Inflammation-related molecular levels in the atrium were assessed using ELISA and Western blotting (WB).Results: The intraperitoneal injection of 10 mg/kg LPS was identified as the most stable model for new-onset AF in sepsis, with significant findings including increased left atrial area and fibrosis, left ventricular pump dysfunction, uncoordinated ventricular wall motion, and impaired electrical impulse conduction. The effective atrial refractory period was markedly shorter, and susceptibility to AF was higher in the LPS group compared to the CLP group. Molecular analysis revealed elevated levels of NOD-like receptor protein 3(NLRP3) inflammasomes, apoptosis-associated speck-like protein containing a CARD(ASC), Caspase-1 p20 Elevated levels of three inflammation-related proteins and increased activity of the Sphingosine 1-phosphate/Sphingosine 1-phosphate Receptor 2(S1P/S1P2) signaling axis.Conclusion: Intraperitoneal injection of 10 mg/kg of LPS can successfully construct a new-onset AF model in sepsis, and NLRP3 inflammatory vesicles mediated by the S1P/S1P2 signaling axis may promote new-onset AF in sepsis.Keywords: sepsis, atrial fibrillation, rat model, lipopolysaccharide, NLRP3 inflammasome, S1P/S1P2 signaling axis

Xiao-ling Wu, Ya-nan Guo Intensive Care Unit, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Ya-nan Guo, Intensive Care Unit, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 26 Shengli Street, Wuhan, 430014, People’s Republic of China, Tel +86-18186120762, Fax +86-27-82811446, Email guoyanan1104@sina.comIntroduction: Sepsis is the leading cause of death in critically ill patients; it results in multiorgan dysfunction, including acute respiratory distress syndrome (ARDS). Our study was conducted to determine the role of cellular senescence genes and immune infiltration in sepsis and sepsis-induced ARDS via bioinformatic analyses.Experimental Procedures: Datasets GSE66890 and GSE145227 were obtained from the Gene Expression Omnibus (GEO) database and utilized for bioinformatics analyses. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the differentially expressed genes (DEGs) were performed to identify the key functional modules. Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE), were used to screen for characteristic genes in sepsis and sepsis-induced ARDS. ROC curves were generated to evaluate the predictive ability of gene hubs. Differences in immune infiltration levels between the disease and control groups were compared via ssGSEA. The diagnostic value of the hub genes was verified via quantitative PCR (qPCR) in hospitalized patients.Results: Four characteristic genes (ATM, CCNB1, CCNA1, and E2F2) were identified as biomarkers for the progression of sepsis-induced ARDS. E2F2 showed the highest predictive ability for the occurrence of ARDS in patients with sepsis. CD56bright and plasmacytoid dendritic cells exhibited high infiltration in the sepsis-induced ARDS group, whereas eosinophils, MDSCs, macrophages, and neutrophils exhibited low infiltration. In addition, ATM expression was lower in patients with sepsis than in those without sepsis (n = 6).Conclusion: Sepsis-induced ARDS is correlated with circulating immune responses, and the expression of ATM, CCNB1, CCNA1, and E2F2 may serve as potential diagnostic biomarkers and therapeutic targets in sepsis-induced ARDS.Keywords: sepsis, cellular senescence genes, immune infiltration, acute respiratory distress syndrome, bioinformatics analysis

Abstract Isolation of adult mouse cardiomyocytes is an essential technique for advancing our understanding of cardiac physiology and pathology, and for developing therapeutic strategies to improve cardiac health. Traditionally, cardiomyocytes are isolated from adult mouse hearts using the Langendorff perfusion method in which the heart is excised, cannulated, and retrogradely perfused through the aorta. While this method is highly effective for isolating cardiomyocytes, it requires specialized equipment and technical expertise. To address the challenges of the Langendorff perfusion method, researchers have developed a Langendorff-free technique for isolating cardiomyocytes. This Langendorff-free technique involves anterograde perfusion through the coronary vasculature by clamping the aorta and intraventricular injection. This method simplifies the experimental setup by decreasing the need for specialized equipment and eliminating the need for cannulation of the heart. Here, we introduce an updated Langendorff-free method for isolating adult mice cardiomyocytes that builds on the Langendorff-free protocols developed previously. In this method, the aorta is clamped in situ, and the heart is perfused using a peristaltic pump, water bath, and an injection needle. This simplicity makes cardiomyocyte isolation more accessible for researchers who are new to cardiomyocyte isolation or are working with limited resources. In this report, we provide a step-by-step description of our optimized protocol. In addition, we present example studies of analyzing mitochondrial structural and functional characteristics in untreated isolated cardiomyocytes and cardiomyocytes treated with the acute inflammatory stimulus lipopolysaccharide (LPS).

Abstract Background Sepsis is a potentially fatal systemic inflammatory response syndrome (SIRS) that threatens millions of lives worldwide. Echinococcus granulosus antigen B (EgAgB) is a protein released by the larvae of the tapeworm. This protein has been shown to play an important role in modulating host immune response. In this study we expressed EgAgB as soluble recombinant protein in E. coli (rEgAgB) and explored its protective effect on sepsis. Methods The sepsis model was established by cecal ligation and puncture (CLP) procedure in BALB/c mice. The therapeutic effect of rEgAgB on sepsis was performed by interperitoneally injecting 5 µg rEgAgB in mice with CLP-induced sepsis and observing the 72 h survival rate after onset of sepsis. The proinflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-6] and regulatory cytokines [IL-10, transforming growth factor beta (TGF-β)] were measured in sera, and the histopathological change was observed in livers, kidneys, and lungs of septic mice treated with rEgAgB compared with untreated mice. The effect of rEgAgB on the macrophage polarization was performed in vitro by incubating rEgAgB with peritoneal macrophages. The levels of TLR2 and MyD88 were measured in these tissues to determine the involvement of TLR-2/MyD88 in the sepsis-induced inflammatory signaling pathway. Results In vivo, we observed that treatment with rEgAgB significantly increased the survival rate of mice with CLP-induced sepsis up to 72 h while all mice without treatment died within the same period. The increased survival was associated with reduced pathological damage in key organs such as liver, lung, and kidneys. It was supported by the reduced proinflammatory cytokine levels and increased regulatory cytokine expression in peripheral blood and key organ tissues. Further study identified that treatment with rEgAgB promoted macrophage polarization from classically activated macrophage (M1) to regulatory M2-like macrophage via inhibiting TLR2/MyD88 signal pathway. Conclusions The therapeutic effects of rEgAgB on mice with sepsis was observed in a mice model that was associated with reduced inflammatory responses and increased regulatory responses, possibly through inducing polarization of macrophages from proinflammatory M1 to regulatory M2 phenotype through inhibiting TLR2/MyD88 inflammatory pathway. Graphical Abstract

Abstract Objective: The objective was to establish a machine learning-based model for predicting the occurrence and mortality of nonpulmonary sepsis-associated ARDS. Methods: 80% of sepsis patients selected randomly from the MIMIC-IV database, without prior pulmonary conditions and with nonpulmonary infection sites, were used to construct prediction models through machine learning techniques (including K-nearest neighbour, extreme gradient boosting, support vector machine, deep neural network, and decision tree methods). The remaining 20% of patients were utilized to validate the model’s accuracy. Additionally, local data were employed for further model validation. Results: A total of 11,409 patients were included, with the most common type of infection being bloodstream infection. A total of 7,632 (66.9%) patients developed nonpulmonary sepsis-associated ARDS (NPS-ARDS). Patients with NPS-ARDS had significantly longer ICU stays (6.2 ± 5.2 days vs. 4.4 ± 3.7 days, p

Abstract We aimed to investigate the correlation between the serum D-dimer (D-D) to albumin (ALB) ratio (DAR) and 28-day all-cause mortality in patients with sepsis. Data from sepsis patients admitted to the intensive care unit (ICU) of Wuhan Fourth Hospital from October 2021 to January 2024 were collected. Univariate cox analysis was performed for mortality factors in sepsis patients, and multiple cox regression models were used to analyze independent mortality risk factors. The receiver operating characteristics (ROC) curve was used to analyze the value of DAR in predicting sepsis mortality, and the Kaplan–Meier method was used to plot the survival curve. A total of 833 patients with sepsis in the ICU of our hospital were selected and divided into alive group (n = 574) and death group (n = 171) according to their 28-day survival. In the death group, D-D and DAR levels were higher, while ALB levels was lower than in the alive group. Spearman analysis found that DAR level were positively correlated with APACHE II and SOFA scores. Multivariate cox regression analysis showed that DAR was an independent predictor of all-cause mortality within 28 days of admission for sepsis patients (HR = 17.956, 95% CI 3.435–93.851, p

Abstract In the intensive care unit (ICU), acute kidney injury (AKI) is the most common cause of morbidity and mortality. Hospital-acquired acute kidney injury (HAAKI) is AKI developing after 48 h. We aimed to study the development of AKI and its associated risk factors. We conducted a longitudinal observational study. Inclusion criteria were patients > 18 years of age admitted to ICU. The primary outcome was the development of AKI as defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria. A total of 273 patients were included in the study. Out of 273, 44(16.11%) patients developed AKI. The mean age was 45.80(17.39) years, and 60.81% were males. The median acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores were 12(8–18) and 5(3–7), respectively. Diabetes mellitus (23.44%) and hypertension (23.81%) were predominant comorbidities. The risk factors associated with AKI were serum chloride level, colistin, invasive ventilation, positive end-expiratory pressure (PEEP), and fluid balance. The hospital mortality was significantly higher in patients with AKI (43.18%) as compared with no AKI (14.41%). Among the secondary outcomes, 7 (15.90%) patients required renal replacement therapy (RRT) during hospitalisation. The length of ICU stay was higher in patients with AKI 8(5–13) compared to no AKI 5(3–8). A total of 16.11% developed HAAKI, and mortality was 43.18%. Post 6 months follow-up of AKI patients, mortality was 23%. Among survivors none of the patients were on RRT.Patients admitted with normal kidney function can develop AKI. Hence, careful monitoring of ICU patients is necessary.

Abstract Acinetobacter baumannii, a common nosocomial pathogen, is known for its rapid acquisition of antimicrobial resistance, underscoring the urgent need to develop an effective vaccine against this pathogen. Outer membrane protein 22 (Omp22) regulates the biogenesis of outer membrane vesicles to transport virulence-promoting factors into the host cells and facilitates the progression of A. baumannii infection. In this study, we used a mouse model to assess a vaccine’s immunogenicity and protective efficacy using recombinant Omp22 protein within the hypervariable region of flagellin (FliC-Omp22). FliC-Omp22 demonstrated superior protection following challenge with a lethal dose of multidrug-resistant (MDR) A. baumannii strain 58ST compared to Omp22 alone. In addition, it elicited increased IgG1/IgG2a and IL-4/IFN-γ ratios, indicating a predominant Th2 immune response. Furthermore, the FliC-Omp22 vaccination elicited strong specific antibodies that inhibited the adhesion and invasion of A. baumannii 58ST and enhanced the opsonic killing activity against the pathogen. FliC-Omp22 immunization significantly reduced bacterial loads in infected mice’s spleen, lungs, and liver, thereby improving their survival against the lethal infection caused by MDR A. baumannii 58ST. This study suggests that integrating Omp22 into the hypervariable domain of flagellin holds promise for developing an effective vaccine against A. baumannii infections.

Abstract Background Sepsis-induced organ failure and high mortality are largely ascribed to the failure of bacterial clearance from the infected tissues. Recently, probiotic bacteria-released extracellular vesicles (BEVs) have been implicated as critical mediators of intercellular communication which are widely involved in the regulation of the inflammatory response. However, their functional role in macrophage phagocytosis during sepsis has never been explored. Methods BEVs were collected from three different strains of probiotics including Lactiplantibacillus plantarum WCFS1 (LP WCFS1), Lactobacillus rhamnosus Gorbach-Goldin (LGG), and Escherichia coli Nissle 1917 (EcN), or from LGG cultured under three pH conditions (pH5-acid, pH6.5-standard, pH8-akaline) through differential centrifugation, filtration, and ultracentrifugation of their culture supernatants. In vitro phagocytosis was measured in Raw264.7 cells and bone marrow-derived macrophages using pHrodo red E. coli BioParticles. The in vivo therapeutic effects of BEVs were tested using a feces-injection-in-peritoneum (FIP) model of polymicrobial sepsis. Results LGG-derived EVs (BEVLGG) were the best among these three probiotics BEVs in stimulating macrophages to take up bacteria. Furthermore, BEVLGG collected from pH8 culture condition (BEVpH8) exhibited the strongest capacity of phagocytosis, compared with BEVpH5 and BEVpH6.5. Treatment of septic mice with BEVpH8 significantly prolonged animal survival; increased bacterial clearance from the blood, peritoneal lavage fluid, and multiple organs; and decreased serum levels of pro-inflammatory cytokines/chemokines, as well as reduced multiple organ injuries, in comparison with control-treated septic mice. Mechanistically, RNA-seq and bioinformatic analysis identified that the FPR1/2 signaling was remarkably activated, along with its downstream pathways (PI3K-Akt-MARCO and NADPH-ROS) in BEVpH8-treated macrophages, compared with control cells. Accordingly, pre-addition of Boc2, a specific antagonist of FPR1/FPR2, to macrophages significantly attenuated BEVpH8-mediated phagocytosis, compared to controls. Conclusions This study demonstrates that LGG-derived BEVs may have therapeutic effects against sepsis-induced organ injury and mortality through enhancing FPR1/2-mediated macrophage phagocytosis.

Abstract Septic shock (SS) is a potential life-threatening condition in which an early identification and immediate therapy stand out as the main cornerstones to improve survival chance; in this context, emergency medical services (EMS) become key to reduce the time between diagnosis and management in the ICU or emergency department. However, guidelines for the prehospital management of SS patients remains unclear, and literature around this topic is scant. Our scoping review was conducted following the PICO framework and a search strategy related to septic shock management and diagnosis in prehospital settings was executed in PubMed, Scopus and Virtual Health Library; articles in English and Spanish from 2015, onwards, were screened by the authors and selected by mutual consensus. Our aim is to analyze the prehospital management strategies of SS reported in the literature, and to showcase and summarize the screening tools, demographic factors, clinical manifestations and prognostic factors of SS in the prehospital setting.

Abstract Background The impairment of endothelial function represents a key pathophysiological mechanism in the development of sepsis. This research aimed to evaluate the prognostic significance of angiopoietin-2 (Ang-2), an endothelial biomarker, in predicting mortality in sepsis patients. Methods Chinese and English studies were systematically retrieved in PubMed, Cochrane Library, Embase, WanFang, CNKI, CQVIP, and CBM databases up to July 16, 2023. We conducted a study selection established upon predefined inclusion and exclusion criteria and used the Newcastle-Ottawa scale (NOS) to assess its quality. We extracted available data from the included studies for data analysis. Results The final inclusion comprised 33 studies with 4703 participants. According to the NOS, one study was of medium quality, while the rest were of high quality. In comparison to survivors, the levels of Ang-2 in non-survivors were markedly elevated [standardized mean difference (SMD) = 1.08, 95% confidence intervals (CI) 0.68–1.49, P

Liyan Wu,1 Zhenyan Yuan,1 Min Wang,1 Xiaomeng Fu,1 Xiaohui Liu,1 Bing Wei,2 Yugeng Liu1 1Department of Infectious Diseases and Clinical Microbiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100043, People’s Republic of China; 2Emergency Medicine Clinical Research Center, Beijing Chaoyang Hospital, Capital Medical University, & Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Clinical Center for Medicine in Acute Infection, Capital Medical University, Beijing, 100043, People’s Republic of ChinaCorrespondence: Bing Wei; Yugeng Liu, Email dr_weibing@126.com; yugeng_liu@126.comPurpose: Sepsis is a life-threatening condition associated with acute organ dysfunction. Iron is an essential trace element for multicellular organisms and almost all microorganisms, and its role in sepsis has been increasingly recognized. The aim of this study was to investigate the changes in iron metabolism in caecal ligation and puncture solution (CLP) -induced septic mice and the effects of hepcidin pretreatment on serum inflammatory marker levels and liver iron metabolism in CLP-induced septic mice.Methods: C57BL/6 mice were given normal saline, CLP (peritonitis model) or 100 μg of hepcidin via intraperitoneal injection. The experimental animals were divided into 4 groups: the control group, model group (CLP), hepcidin pretreatment Groups CLP+hepcidin-2h and CLP+hepcidin-24 h. Blood samples were collected at 6, 12 and 24 hours after CLP surgery, and the mice were euthanized and livers were obtained.Results: ELISA revealed that hepcidin pretreatment, especially 2 hours in advance (p< 0.01), increased the serum hepcidin, TNF-a and IL-6 in CLP-induced septic mice; the serum iron content of CLP-related septic mice decreased (P< 0.01), while the liver iron content increased (P< 0.01); Hepcidin pretreatment reduced the serum iron (P< 0.05) at 6 h and 12 h and liver iron concentrations (P< 0.01) at 6 h, 12 h and 24 h in CLP-related septic mice. Western blotting revealed that the hepatic iron absorption-related proteins transferrin receptor-2 (TFR2), ZRT/IRT-like protein 14 (ZIP14) and divalent meta lion transporter-1 (DMT1) were elevated (P< 0.01); The iron-exporting protein ferroportin (SLC40A1) was decreased (P< 0.01) throughout CLP and CLP+hepcidin sepsis. Compared with CLP group, the protein expressions in the CLP+ hepcidin-2 h group were more obvious than that in the CLP+ hepcidin-24 h group.Conclusion: Hepcidin has proinflammatory effect. Hepcidin exacerbates iron metabolism imbalances in sepsis by influencing the expression of iron absorption-related proteins and iron export-related proteins.Keywords: hepcidin, sepsis, iron metabolism, SLC40A1, liver

Abstract Background Coagulase-negative staphylococci (CoNS) have been linked to severe conditions such as bloodstream infection, with biofilm formation regarded as the major virulence mechanism. This study determined virulence genes (VGs) (icaA, icaB, icaC, and icaD) responsible for biofilm formation and antibiotic resistance genes (ARGs) (blaZ, mecA, and aac(6’)-Ie-aph(2’’)-Ia) in CoNS isolated from blood samples of 70 neonates with sepsis in Dar es Salaam, Tanzania. We used VITEK®MS (BioMérieux, France) for speciation and phenotypically detected biofilm production using the Congo red agar. Polymerase chain reaction was performed for ARGs and VGs detection; principal component analysis was used to ascertain their relationship. Results Out of 70 CoNS, Staphylococcus epidermidis, 27 (36.8%) was the most commonly isolate, subsequently to Staphylococcus haemolyticus, 24 (34.3%). The intercellular adhesion genes (ica) were detected in all isolates, with IcaD found in 70 (100.0%), followed by icaB 69 (98.6%), icaC 69 (98.6%), and icaA 65 (92.9%). Four virulence gene combinations (icaADBC, icaBCD, icaACD, and icaABD) were detected, predominantly icaADBC 63 (90.0%). Sixty-one (87.1%) isolates harbored three ARGs, mostly the mecA gene 69 (98.6%), followed by blaZ 67 (95.7%) and aac (6’)-Ie-aph (2’’)-Ia, 65 (92.7%). We observed a moderate positive correlation between mecA and icaA genes (r = 0.4341). Sixty-five (97.0%) isolates resistant to penicillin harbored blaZ genes, and all 62 (100%) resistant to oxacillin harbored mecA genes. Of the 66 isolates resistant to gentamycin, 62 (93.9%) harbored the aac (6’)-Ie-aph (2’’)-Ia gene. The mecA gene contributed most of the resistance, followed by aac(6’)-Ie-aph(2’’)-Ia genes. However, the icaA and icaD genes significantly influenced the virulence of CoNS. Conclusions Most CoNS isolated from blood samples of neonates with sepsis harbor a variety of clinically relevant virulence and resistance genes, indicating their ability to cause severe infections that are difficult to treat. Significantly, 59 (84.3%) isolates were phenotypically penicillin, gentamycin, and oxacillin resistant; the antibiotics recommended in the national guidelines for empiric treatment of neonatal sepsis.

Abstract Background The stress hyperglycemia ratio (SHR) is associated with poor outcomes in critically ill patients. However, the relationship between SHR and mortality in patients with sepsis-associated acute kidney injury (SA-AKI) remains unclear. Methods The data of patients with SA-AKI, identified based on the KDIGO criteria, were retrospectively collected from the Beth Israel Deaconess Medical Center between 2008 and 2019. SHR was calculated as follows: (glycemia [mmol/L]) / (1.59 × HbA1c [%] – 2.59). Primary outcomes were 30-day and 1-year mortality. The cumulative incidence of all-cause mortality was assessed using Kaplan–Meier survival analysis. Multivariable-adjusted logistic and Cox models and restricted cubic spline curves were used to analyze the correlation between SHR and all-cause mortality. Post-hoc subgroup analysis was performed to compare the effects of SHR across different subgroups. Results 1161 patients with SA-AKI were identified and categorized into four SHR quartiles as follows: Q1 (0.26, 0.90), Q2 (0.91, 1.08), Q3 (1.09, 1.30), and Q4 (1.31, 5.42). The median age of patients was 69 years, with 42.7% of the patients being women and 20.2% of the patients having chronic kidney disease. The 30-day and 1-year mortality were 22.1% and 35.0% respectively. Kaplan–Meier survival analysis indicated a gradual decrease in survival probability with increasing SHR quartiles. An increased SHR exhibited a strong correlation with 30-day mortality (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.18–1.90; P

Abstract Sepsis continues to be a major cause of death and illness globally, posing significant challenges for healthcare professionals. In the pursuit of more accurate and timely monitoring tools, the concept of capnodynamically derived mixed venous oxygen saturation (Capno-SvO2) has emerged as a promising method. Capno-SvO2 provides a non-invasive way to assess and track SvO2 and could serve as an additional tool alongside more invasive methods like the pulmonary artery catheter. This could potentially be of great value in the care of critically ill patients with sepsis, where alternative minimal invasive monitoring methods may vary in reliability. The aim of the current study was to compare capno-SvO2 against values obtained through pulmonary artery blood sample CO-oximetry and continuous fiberoptic SvO2 monitoring, using a well-established porcine experimental sepsis model. Anesthetized pigs were exposed to a standardized endotoxin infusion sepsis protocol, followed by a series of maneuvers typically applied in sepsis care. Simultaneous recordings were done throughout the experiment for all three monitoring methods. Bland–Altman analysis corrected for repeated measurements was used to assess the agreement of absolute values between the paired recording of CO-oximetry and Capno-SvO2 as well as between CO-oximetry and fiberoptic SvO2. The ability of Capno-SvO2 and fiberoptic SvO2 to track changes was assessed by concordance rate. A total of 10 animals and 275 paired datapoints were included in the study. The majority of the animals displayed pronounced hemodynamical instability in response to endotoxin exposure and subsequent treatment interventions. Analysis of all paired data points showed a bias between Capno-SvO2 and CO-oximetry SvO2 of + 1% with 95% limits of agreement of -14% to + 17%. The corresponding numbers for fiberoptic SvO2 and CO-oximetry SvO2 were -4% and -15% to + 8%. The concordance rate as compared to CO-oximetry, were 97% and 93% for Capno-SvO2 and fiberoptic SvO2, respectively. In this experimental sepsis model, continuous, non-invasive Capno-SvO2 generates average absolute values comparable to the gold standard CO-oximetry albeit with relatively wide limits of agreement. Capno-SvO2 displayed a concordance rate of 97% against CO-oximetry and exhibits better trending ability compared to invasive fiberoptic SvO2.

Abstract Sepsis is a clinical syndrome caused by infection, leading to organ dysfunction due to a dysregulated host response. In recent years, its high mortality rate has made it a significant cause of death and disability worldwide. The pathophysiological process of sepsis is related to the body’s dysregulated response to infection, with microcirculatory changes serving as early warning signals that guide clinical treatment. The Peripheral Perfusion Index (PI), as an indicator of peripheral microcirculation, can effectively evaluate patient prognosis. This study aims to develop two new prediction models using PI and other common clinical indicators to assess the mortality risk of sepsis patients during hospitalization and within 28 days post-ICU admission. This retrospective study analyzed data from sepsis patients treated in the Intensive Care Unit of Peking Union Medical College Hospital between December 2019 and June 2023, ultimately including 645 patients. LASSO regression and logistic regression analyses were used to select predictive factors from 35 clinical indicators, and two clinical prediction models were constructed to predict in-hospital mortality and 28-day mortality. The models’ performance was then evaluated using ROC curve, calibration curve, and decision curve analyses. The two prediction models performed excellently in distinguishing patient mortality risk. The AUC for the in-hospital mortality prediction model was 0.82 in the training set and 0.73 in the validation set; for the 28-day mortality prediction model, the AUC was 0.79 in the training set and 0.73 in the validation set. The calibration curves closely aligned with the ideal line, indicating consistency between predicted and actual outcomes. Decision curve analysis also demonstrated high net benefits for the clinical utility of both models. The study shows that these two prediction models not only perform excellently statistically but also hold high practical value in clinical applications. The models can help physicians accurately assess the mortality risk of sepsis patients, providing a scientific basis for personalized treatment.

Abstract In this study, peripheral whole blood samples from 22 hospitalized patients and 10 healthy individuals were analyzed using a combination of Data Independent Acquisition (DIA) and Enzyme-Linked Immunosorbent Assay (ELISA) techniques to identify differentially expressed proteins (DEPs) in sepsis patients’ plasma. The aim was to provide accurate and detailed biomarkers, such as SPP1, for determining the pathological stages of sepsis. SPP1, known as osteopontin1 is a pleiotropic protein with a wide distribution and multifunctional effects. Its protein expression is associated with inflammatory changes, including variations in expression levels in infectious diseases, allergic diseases, and situations involving tissue damage. The registration number was ChiCTR1900021261.The full date of first registration year is 2018. In the affiliated hospital of southwest medical university, 22 sepsis patients were hospitalized from January 2019 to September 2020 and 10 normal healthy individuals were selected for DIA-based quantitative proteomics analysis. In addition to gene ontology analysis and Kyoto Encyclopedia of genes and genomes analysis, enrichment analysis of data was performed and target protein network was screened through joint protein–protein interaction and visualization techniques. The selected protein targets were then validated by Elisa kit. The software was used to analyze the differences comparing the control group to the sepsis group and the sepsis group, as well as between sepsis survivals and non-survivals, and a ROC curve was drawn to evaluate the diagnostic value and prognostic effect of the method of the corresponding target proteins. A total of 174 DEPs were screened by bioinformatics analysis. An analysis of go pathway enrichment revealed the following: These proteins were mainly involved in biological processes among them are the inflammation response, the metabolism of extracellular matrix, the secretion of cell secretions, the activation of cells, and the immune response. According to the Kegg pathway analysis, they were mainly involved in complement cascade polymerization, extracellular protease and glycosylase activation, protein synthesis process, biotin metabolism, leukocyte transmembrane migration, bacterial infection and phagosome formation. SPP1 was identified as a possible plasma biomarker and was therefore further validated using Elisa. As a result of experiments, it has been demonstrated that level in sepsis patients is significantly compared to the normal control group and the level is also higher in non-survivals of sepsis. The ROC curve can be used to see that it can diagnose sepsis more accurately and improve prognostic ability prediction. Cell experiments confirm that SPP1 is highly expressed in sepsis. There is a significant difference in the levels of SPP1 protein between the normal group and the sepsis group; it not only has good diagnostic significance for sepsis, but also provides corresponding reference value for patient prognosis; Therefore, it is more likely to become a biological marker of sepsis over time.

Abstract Background Synchronous abscesses of the prostate and seminal vesicles represent a rare but clinically significant form of purulent retention. They pose diagnostic and therapeutic challenges and are associated with considerable morbidity and a high risk of sepsis. Case presentation We present the case of a 60-year-old Caucasian man with a history of insulin-dependent diabetes mellitus, who had a voluminous prostatic abscess associated with a right seminal vesicle abscess due to compression of the right ejaculatory duct, and who presented to our department with sepsis. He had clinical and radiological confirmation with computed tomography scan and magnetic resonance imaging. The patient underwent percutaneous drainage of the prostatic abscess resulting in the subsidence of the seminal vesicle abscess. The treatment also consisted on prolonged antibiotic therapy. The clinical evolution was favorable. Conclusion We conclude that prostatic abscesses can lead to synchronous seminal vesicle abscesses due to ejaculatory duct compression. Percutaneous drainage of the prostatic abscess by transrectal ultrasound-guided drainage, combined with prolonged antibiotic therapy, can effectively treat both abscesses.

Abstract Background Sepsis survivors exhibit immune dysregulation that contributes to poor long-term outcomes. Phenotypic and functional alterations within the myeloid compartment are believed to be a contributing factor. Here we dissect the cellular and transcriptional heterogeneity of splenic CD11b+Ly6Chigh myeloid cells that are expanded in mice that survive the cecal ligation and puncture (CLP) murine model of polymicrobial sepsis to better understand the basis of immune dysregulation in sepsis survivors. Methods Sham or CLP surgeries were performed on C57BL/6J and BALB/c mice. Four weeks later splenic CD11b+Ly6Chigh cells from both groups were isolated for phenotypic (flow cytometry) and functional (phagocytosis and glycolysis) characterization and RNA was obtained for single-cell RNA-seq (scRNA-seq) and subsequent analysis. Results CD11b+Ly6Chigh cells from sham and CLP surviving mice exhibit phenotypic and functional differences that relate to immune function, some of which are observed in both C57BL/6J and BALB/c strains and others that are not. To dissect disease-specific and strain-specific distinctions within the myeloid compartment, scRNA-seq analysis was performed on CD11b+Ly6Chigh cells from C57BL/6J and BALB/c sham and CLP mice. Uniform Manifold Approximation and Projection from both strains identified 13 distinct clusters of sorted CD11b+Ly6Chigh cells demonstrating significant transcriptional heterogeneity and expressing gene signatures corresponding to classical-monocytes, non-classical monocytes, M1- or M2-like macrophages, dendritic-like cells, monocyte-derived dendritic-like cells, and proliferating monocytic myeloid-derived suppressor cells (M-MDSCs). Frequency plots showed that the percentages of proliferating M-MDSCs (clusters 8, 11 and 12) were increased in CLP mice compared to sham mice in both strains. Pathway and UCell score analysis in CLP mice revealed that cell cycle and glycolytic pathways were upregulated in proliferating M-MDSCs in both strains. Notably, granule protease genes were upregulated in M-MDSCs from CLP mice. ScRNA-seq analyses also showed that phagocytic pathways were upregulated in multiple clusters including the classical monocyte cluster, confirming the increased phagocytic capacity in CD11b+Ly6Chigh cells from CLP mice observed in ex vivo functional assays in C57BL/6J mice. Conclusion The splenic CD11b+Ly6Chigh myeloid populations expanded in survivors of CLP sepsis correspond to proliferating cells that have an increased metabolic demand and gene signatures consistent with M-MDSCs, a population known to have immunosuppressive capacity.

Abstract Objective This study aimed to investigate the relationship between serum lactate levels at admission to the intensive care unit (ICU) and the clinical outcomes of children with sepsis. Methods We used the Pediatric Intensive Care (PIC) database to identify 288 pediatric patients with sepsis. We analyzed the relationship between lactate levels and hospital and ICU mortality in sepsis by establishing a segmented multivariable Cox regression model. We also conducted subgroup analysis as well as analyzed the restricted cubic spline curves. Results After adjusting for all potential confounding factors, an increase of 1 mmol/L in lactate levels was found to be associated with an 17% rise in the 28-day hospital mortality risk among sepsis patients (HR: 1.17, 95% CI: 1.08–1.27, P = 0.0002). When considering lactate as a categorical variable, the mortality risk of patients with lactate levels ≥ 2.2 mmol/L was significantly increased (HR: 3.61, 95% CI: 1.24–10.54, P = 0.0189). The restricted cubic spline curve analysis revealed a nonlinear correlation between lactate and 28-day mortality, with an inflection point at 2.2 mmol/L. Similar findings were also observed in the assessment of secondary outcomes. Conclusions Our study demonstrates a non-linear correlation between lactate levels and 28-day mortality in pediatric sepsis, with a critical threshold of 2.2mmol/l for lactate levels in septic patients. Early assessment of lactate levels is recommended for children with sepsis to facilitate prompt intervention and mitigate the risk of fatality.

Abstract Berberine (BBR), a widely recognized traditional Chinese medicine, has attracted considerable attention for its promising anti‐inflammatory effects. The activation of nuclear factor erythroid 2‐related factor 2 (Nrf2) effectively safeguards against organ damage stemming from sepsis‐induced oxidative stress and inflammatory responses. This study examined the potential of BBR in alleviating sepsis‐induced acute gastric injury, with a particular focus on elucidating whether its mechanism of action involves the activation of the Nrf2 signaling pathway. Following intraperitoneal injection of BBR, mice were subjected to the cecal ligation and puncture (CLP) method to induce sepsis. In vitro experiments involved pre‐treating the normal gastric epithelial cells (GES‐1) with BBR, followed by treatment with lipopolysaccharide (LPS). Functional assays were then performed to assess cell proliferation and apoptosis. To validate the role of Nrf2 in pyroptosis and inflammation, siRNA targeting Nrf2 (si‐Nrf2) was transfected into LPS‐treated GES‐1 cells. Additionally, mice were administered the Nrf2 inhibitor ML385 to confirm the protective effects of BBR in vivo. BBR displayed a dose‐dependent effect in mitigating gastric tissue damage, suppressing the release of inflammatory cytokines, and reducing the expression of NLRP3, ASC, and GSDMD‐N. In vitro, BBR fostered GES‐1 cell proliferation, hindered apoptosis, and suppressed the levels of TNF‐α, IL‐18, IL‐1β, NLRP3, ASC, and GSDMD‐N. Further analysis revealed that knocking down Nrf2 reversed BBR's inhibitory effect on pyroptosis in LPS‐treated GES‐1 cells. Through binding to Keap1, BBR efficiently prevented the ubiquitination and degradation of Nrf2, ultimately promoting its nuclear translocation. In vivo experiments confirmed that ML385 reversed the protective effect of BBR on pyroptosis and inflammation. Our research reveals that BBR interacts with Keap1 to activate the Keap1/Nrf2 signaling pathway in gastric epithelial cells, thereby suppressing pyroptosis and inflammation in sepsis‐induced acute gastric injury.

Background: Shock index is the ratio of heart rate to the systolic blood pressure. The use of shock index for risk stratification or as an indicator of clinical improvement is helpful in early recognition of shock and optimizing treatment in sepsis and septic shock. Aims and Objectives: The objective of the study was to assess the shock index and associated outcome in children with sepsis/septic shock at the tertiary care hospital. Materials and Methods: A cross-sectional study was conducted among 95 patients admitted with sepsis or septic shock to the pediatric intensive care unit and pediatric wards of a tertiary center in Surat. The study was done over a period of 2 years from January 2020 to December 2021. The study was carried out after obtaining ethical approval from the Human Research Ethics Committee, GMC Surat. Through-out the study privacy and confidentiality was maintained at all cost for each participant by coding of patients data. Results: The mean age of the study population was 3.12±2.40 years, with age range from 1 month to 12 years. The gender distribution of the study population had 51.6% male and 48.4% female. On analysis of the shock index to the mortality of the patients at 0, 1, 2, 4, and 6 h after admission, the cutoff value of shock index at 1.6, 1.7, 1.7, 1.4, and 1.3 had a sensitivity of 89.4%, 84.8%, 78.8%, 82.3%, and 86.4%, with a specificity of 62.4%, 69%, 75.9%, 72.4%, and 75.9%, respectively. The cutoff values of the various age groups decrease as the ages of the patients increase. The overall survival rate in the study was 30.5% and mortality rate at 69.5%. Conclusion: The study concluded that shock index can be used in emergency for triage of critically ill patients. Shock index and mortality were higher compared to other studies as majority of the study participants were referred cases and were in critical stages of shock on admission to the tertiary care center.

Background: Sepsis is a potentially life-threatening condition with significant mortality and morbidity. An estimated 48.9 million cases and 11 million deaths occur due to sepsis worldwide. The gold standard for the diagnosis of suspected sepsis patients is blood culture. Aims and Objectives: The aims and objectives of the study are to evaluate the growth of rare microorganisms in blood cultures of intensive care unit (ICU) patients, to determine their antimicrobial susceptibility patterns, and also to assess the associated risk factors in those patients. Materials and Methods: This study was conducted for 1 year (August 2023–July 2024) in our department including blood culture samples from ICU patients and relatively rare microorganisms isolated were included in the study accounting for 40 cases. Blood specimens were cultured in automated BD BACTECTM Fx40 blood culture system and identification of microorganisms and their antimicrobial susceptibility pattern were detected by Vitek2 system. Results: Female patients were more in number than male patients and patients of 0–20 years’ age group were most commonly affected. Staphylococcus hominis was most commonly isolated out of all rarely isolated microorganisms. The different parameters for the assessment of sepsis severity in our study were C-reactive protein (CRP), Neutrophil count, D-dimer, Procalcitonin, and quick sequential organ failure assessment (qSOFA) score. Out of all, CRP was most commonly raised among sepsis patients. The most common risk factor involved was prolonged ICU stay. Conclusion: Appropriate collection and processing of blood culture samples can reduce sepsis-related morbidity and mortality manifold. Combination of biomarkers study and qSOFA scoring system can improve diagnosis and monitoring of sepsis patients.

Abstract Background Sepsis-induced myocardial injury (SIMI) is a severe complication of sepsis, contributing significantly to mortality. Mitochondrial dysfunction and dysregulated autophagy are implicated in SIMI pathogenesis. Long non-coding RNA MALAT1 has been associated with various diseases, including sepsis, but its role in SIMI remains unclear. Objective This study aimed to investigate the role of lncRNA MALAT1 in SIMI, specifically in the regulation of mitochondrial autophagy. Methods A sepsis-induced cardiomyopathy model was established in mice, and the cardiac tissues were analyzed. The expression of lncRNA MALAT1 was modulated and its effects on mitochondrial autophagy, myocardial injury, inflammation, and apoptosis were assessed. Furthermore, the interaction between MALAT1 and miR-146a was explored, as well as the involvement of the TLR4/NF-kB/MAPK signaling pathway. Results Activation of mitochondrial autophagy by urolithin A (UA) alleviated SIMI, inflammation, and cardiac dysfunction. Downregulation of MALAT1 enhanced mitochondrial autophagy, stabilized the mitochondrial membrane potential, and inhibited mitochondrial reactive oxygen species (ROS) production, leading to improved cell viability and reduced myocardial injury. Furthermore, MALAT1 interacted with miR-146a, and their modulation influenced mitochondrial autophagy, myocardial injury, and inflammation. The TLR4/NF-kB/MAPK signaling pathway was implicated in these processes. Conclusion Our findings suggest that lncRNA MALAT1 plays a crucial role in SIMI by modulating miR-146a-mediated mitochondrial autophagy and the TLR4/NF-kB/MAPK signaling pathway. These results provide new insights into the pathogenesis of SIMI and potential therapeutic targets.

Abstract Background Sepsis presents a significant healthcare challenge, characterized by high morbidity and mortality rates. There is a scarcity of relevant studies investigating the association between serum lactate dehydrogenase level and the prognosis of sepsis in patients from intensive care unit, with smaller sample sizes compared to other studies. Methods A retrospective analysis was conducted utilizing data from the Second Affiliated Hospital of Guangzhou Medical University and the Medical Information Mart for Intensive Care IV (MIMIC-IV). The primary outcome was the in-hospital mortality. Multivariate Cox proportional hazards regression was adopted to assess the independent association. Receiver operator characteristic (ROC) curve was used to evaluate the predictive value. Results We included a total of 2148 patients in the Guangzhou Sepsis Cohort (GZSC) database and 5830 patients in the MIMIC-IV database. In multivariate Cox proportional hazards regression, high levels of LDH are significantly associated with higher mortality (HR = 1.21, 95% CI 1.13–1.30, p

Abstract Sepsis is a heterogeneous syndrome resulting from a dysregulated host response to infection. It is considered as a global major health priority. Sepsis is characterized by significant metabolic perturbations, leading to increased circulating metabolites such as lactate. In mammals, pyruvate is the primary substrate for lactate production. It plays a critical role in metabolism by linking glycolysis, where it is produced, with the mitochondrial oxidative phosphorylation pathway, where it is oxidized. Here, we provide an overview of all cytosolic and mitochondrial enzymes involved in pyruvate metabolism and how their activities are disrupted in sepsis. Based on the available data, we also discuss potential therapeutic strategies targeting these pyruvate-related enzymes leading to enhanced survival.

Sepsis is a global health challenge that causes more than 11 million deaths annually and represents a substantial medical and economic burden. With rising treatment costs and significant mortality rates associated with organ dysfunction and septic shock, research efforts have focused on investigating the mechanism of glycocalyx (GCX) degradation as well as its regenerative capacity. Therefore, GCX has become a target in therapeutic strategies.

Aim Injudicious usage of antibiotics has led to the emergence of antibiotic resistance which is a major health-care problem in developing countries such as India. Our aim was to show how antibiotic therapy based on serial procalcitonin (PCT) assay can help in antibiotic de-escalation in septic patients. Materials and Methods A pre–post interventional study was conducted among 300 septic patients admitted to an intensive care unit (ICU). All septic patients admitted 2 months before and 2 months after the introduction of monitoring of PCT were included and they were divided into Group P (with PCT monitoring) and Group C (without PCT monitoring). The proportion of patients for whom antimicrobials were de-escalated, the average time taken to de-escalate antimicrobials, and the average duration of ICU stay were compared. Proportions and averages with standard deviations were calculated to describe the data. A test of proportions was done to compare the proportion de-escalated and a Student’s t-test was done to compare the average duration of antibiotic therapy. Results The proportion of patients in whom de-escalation of antimicrobials was done was 125 (83.33%) in Group P as compared to 92 (61.33%) in Group C. The time taken to de-escalate was 3.04 ± 0.83 days (95% confidence interval [CI] 2.89–3.18) in Group P compared to 4.7 ± 1.4 days (CI 4.41–4.98) in Group C. The duration of ICU stay was also less in Group P - 3.08 ± 0.91 days (CI 3.08–3.38) as compared to Group C - 5.16 ± 2.17 days (4.80–5.51). Conclusion Serial PCT assay-based antimicrobial therapy helped to wean patients with sepsis off antimicrobials earlier thus reducing the duration of ICU stay.

Abstract Background Sepsis is a common cause of death in patients with pulmonary arterial hypertension (PAH). Treatment requires careful fluid management and hemodynamic support. This study compares patients with or without PAH presenting with sepsis with a focus on initial fluid resuscitation. Methods This retrospective analysis compared adults with and without PAH admitted for sepsis at two academic hospitals between 2013 and 2022. Prior PAH diagnosis was verified by review of right heart catheterization data and sepsis present on admission was verified by chart review. Demographics, vital signs, laboratory values, imaging results, treatment approaches, and all-cause mortality data were obtained. Controls were propensity score weighted by age, sex, and Charlson Comorbidity index. Logistic regression models controlling for age and Charlson comorbidity indices were used to examine factors associated with survival. Results Thirty patients admitted for sepsis with pre-existing PAH were compared to 96 matched controls. Controls received significantly more fluids at 24 h compared to PAH patients (median 0 mL v. 1216 mL, p

Abstract Background Early diagnosis and antibiotic therapy in patients with sepsis reduce morbidity and mortality, thus pre-hospital management is likely to affect patient outcomes. Pre-hospital administration may increase the risk of unnecessary use of broad-spectrum antibiotics, but identification of an infectious focus enables more targeted antibiotic therapy. The aim of this study was to investigate how paramedics, with or without the assistance of general practitioners, can administer empiric intravenous antibiotic treatment against sepsis in a timely manner. Methods Cohort study of patients with suspected sepsis that received pre-hospital intravenous antibiotics and were transported to hospital. The setting was mainly rural with long average distance to hospital. Patients received targeted antibiotic treatment after an assessment based on clinical work-up supported by scoring systems. Patients were prospectively included from May 2018 to August 2022. Results are presented as median or absolute values, and chi-square tests were used to compare categorical data. Results We included 328 patients. Median age was 76 years (IQR 64, 83) and 48.5% of patients were female. 30-days all-cause mortality was 10.4%. In cases where a suspected infectious focus was determined, the hospital discharge papers confirmed the pre-hospital diagnosis focus in 195 cases (79.3%). The presence of a general practitioner during the pre-hospital assessment increased the rate of correctly identified infectious focus from 72.6% to 86.1% (p = 0.009). Concordance between pre-hospital identification of a tentative focus and discharge diagnosis was highest for lower respiratory tract (p = 0.02) and urinary tract infections (p = 0.03). Antibiotic treatment was initiated 44 min (median) after arrival of ambulance, and median transportation time to hospital was 69 min. Antibiotic therapy was started 76 min (median) before arrival at hospital. Conclusions Pre-hospital identification of infectious focus in suspected sepsis was feasible, and collaboration with primary care physicians increased level of diagnostic accuracy. This allowed initiation of intravenous focus-directed antibiotics more than one hour before arrival in hospital in a rural setting. The effect of pre-hospital therapy on timing was much stronger than in previous studies from more urban areas.

Abstract Background Neonatal sepsis represents a significant cause of morbidity and mortality among infants in healthcare settings. This study explored nurses’ experiences in preventing and managing neonatal sepsis in the Tamale metropolis. Methods An exploratory, descriptive qualitative cross-sectional study design was used, and data was collected using semi-structured interviews. The sample size was determined at the point of data saturation of fifteen participants. Thematic analysis was employed to identify codes, subthemes, and themes within the interview transcripts. Results Three major challenges nurses face in preventing and managing neonatal sepsis, including (1) the absence of a protocol for handling newborns upon admission, (2) an excessive workload that made it difficult for staff to follow infection prevention protocols, and (3) inadequate, obsolete and/or lack of equipment that caused devices to be overused. The nurses also identified critical psychological and emotional difficulties they encounter as a result of working within such a stressful environment. Other activities nurses conducted were handwashing before and after every procedure, infection prevention, and separating the babies in the incubator. In managing babies with neonatal sepsis, nurses provided daily treatment, hygiene care, and supported activities of living. The nurses also assert that the availability of resources, appropriate staff, and critical skills are important for preventing and managing neonatal sepsis. Conclusion The lack of basic working consumables like gloves, syringes, and needles, inadequate staff, and lack of defined protocol of care were identified as critical challenges that hamper the care provided in neonatal care units. Hospital authorities must focus attention on addressing the critical challenges faced by neonatal care units. Also, measures should be instituted to address the emotional and psychological concerns associated with nursing care. Future research must consider the level of influence of each of the challenges enumerated on nurses’ overall health.

Abstract To compare the efficacy and advantages of mini percutaneous nephrostomy (MPCN), micropercutaneous nephrostomy (MicroPCN), and retrograde ureteric stenting (RUS) in the treatment of acute upper urinary tract calculi (UUTC) obstruction with hydronephrosis and infection, and verify the safety and indications of clinical application of micropercutaneous nephrostomy. Clinical-epidemiological data of patients with acute upper urinary tract calculi obstruction and infection treated in Ningbo No.2 hospital were retrospectively collected from May 2019 to May 2023. 64 patients (20 patients in MPCN group, 13 patients in MicroPCN group, and 31 patients in RUS group) were eligible for analysis based on inclusion and exclusion criteria. P value

Abstract Acute lung injury (ALI) is a serious acute respiratory disease that can cause alveolar-capillary barrier disruption and pulmonary edema, respiratory failure and multiple organ dysfunction syndrome. However, there is no effective drugs in clinic until now. GSK3179106 has been reported can alleviate intestinal stress syndrome, but the protective effect of GSK3179106 on ALI has not been elucidated. The present study will evaluate the pharmacological activity of GSK3179106 on lipopolysaccharide (LPS)-induced inflammation and lung injury and clarify its underlying mechanism. We found that GSK3179106 significantly attenuated LPS-induced lung injury in vivo, accompanied by inhibited infiltration of inflammatory cells and reduced expression of inflammatory cytokines. Meanwhile, GSK3179106 dose-dependently reduced the LPS-induced IL-6 expression both in protein and gene levels in macrophages. Mechanistically, GSK3179106 could inhibited the phosphorylation of P38 MAPK induced by LPS. Importantly, results showed that there is a direct combination between GSK3179106 and P38 MAPK. Together, our findings not only clarified the anti-inflammatory activity of GSK3179106 but also discovered its new clinical indications. Therefore, compound GSK3179106 may be a potential candidate for the treatment of acute inflammatory diseases.

Canine parvoviral enteritis (CPE) has a high mortality rate in untreated dogs due to systemic inflammation and multi-organ dysfunction. The inflammatory process can lead to coagulation abnormalities. This study aimed to evaluate the coagulation status using thromboelastography (TEG) and assess the thrombin generation (TG) and clot dissolution using TEG-derived velocity curve (v-curve) parameters in dogs with CPE. It included 21 dogs with CPE and five healthy dogs. In addition to the clinico-haemato-biochemical examinations, the coagulation status was analysed using citrated venous blood samples with TEG. All the dogs with CPE met at least two criteria for systemic inflammatory response syndrome (SIRS). The comparison to healthy controls showed a statistically significant prolongation of reaction times (R time; P = 0.005) and times to the maximum rate of thrombus generation (TMRTG; P = 0.003). However, the times to the maximum rate of lysis (TMRL; P = 0.041) and total lysis (L; P = 0.024) decreased significantly. The TEG tracings showed coagulation states varying from hypocoagulation to hypercoagulation in dogs with CPE. These results showed that the v-curve derivate can be used to evaluate the coagulation in dogs with CPE, and it could be superior to the standard TEG variables for determining the low fibrinolytic activity. Thus, the v-curve parameters may provide a novel insight into the underlying mechanism and clinical treatment strategy of CPE-induced inflammation.

Chaoping Ma,1,&ast; Weisong Jiang,2,&ast; Juan Li,1,&ast; Wenwu Sun,2,&ast; Jiyuan Zhang,1 Peixian Xu,1 Yiran Guo,1 Ning Ning,2 Jiaoyan Li,2 Bing Zhao,2 Enqiang Mao,2 Chengjin Gao1 1Departments of Emergency, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, People’s Republic of China; 2Departments of Emergency, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengjin Gao; Enqiang Mao, Email gaochengjin@xinhuamed.com.cn; maoeq@yeah.netIntroduction: In critically ill patients, the stress hyperglycemia ratio (SHR) was significantly associated with mortality. However, the relationship between SHR and mortality in septic patients is still unclear.In this study, patients with sepsis from two Chinese academic centers were identified and divided into quartiles based on SHR levels.Methods: Multivariable regression analysis will be used to determine associations between SHR and clinical outcomes in sepsis patients.The Kaplan-Meier curve was used to predict mortality in various groups of septic patients.Results: A total of 1835 septic patients were included in the study.The in-hospital, 30-day, and 60-day mortality rates for all septic patients were 22.8%, 18.7%, and 21.7%, respectively. Increased SHR was significantly associated with hospital mortality in multivariate regression analysis.These results were further confirmed in the adjusted analysis, where the hospital mortality and the 60-day mortality of the highest SHR quartile were significantly increased compared to the lowest SHR quartile. However, the highest SHR quartile was not associated with 30-day mortality.In addition, the risk of in-hospital mortality, 30-day mortality and 60-day mortality showed a consistent upward trend with increasing SHR quartile. The survival curve showed that the worst prognosis was in the fourth SHR quartile.Discussion: In conclusion, SHR was significantly associated with hospital mortality in patients with sepsis. This finding indicates that the SHR may be useful in identifying septic patients at higher risk of hospital mortality.Keywords: sepsis, stress hyperglycemia ratio, mortality, Hyperglycemia

Yongru Chen,1 Chongyue Chen,1 Wei Chen,2,3 Wei Gai,4 Yafeng Zheng,4 Yuxin Guo,4 Zhaoning Wang,1 Yongsong Chen,1 Zhiming Cai1,5,6 1The First Affiliated Hospital of Shantou University, Shantou, Guangdong, People’s Republic of China; 2Department of Urology, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, International Cancer Center, Shenzhen University School of Medicine, Shenzhen, People’s Republic of China; 3Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, People’s Republic of China; 4WillingMed Technology (Beijing) Co., Ltd, Beijing, People’s Republic of China; 5BGI Genomics, BGI Shenzhen, Shenzhen, People’s Republic of China; 6Carson International Cancer Center, Shenzhen University, Shenzhen, People’s Republic of ChinaCorrespondence: Zhiming Cai, Carson International Cancer Center of Shenzhen University, No. 1066, Xueyuan Road, Shenzhen, Guangdong Province, People’s Republic of China, Tel +86 136 0253 0322, Email caizhiming2000@163.com Yongsong Chen, The First Affiliated Hospital of Shantou University, No. 57, Changping Road, Shantou, Guangdong Province, People’s Republic of China, Tel +86 0754-88905000, Email yongsongchen@126.comPurpose: This study aimed to evaluate the clinical utility of metagenomic next-generation sequencing (mNGS) in sepsis patients who received early empirical antibiotic treatment.Patients and Methods: A retrospective analysis was conducted on clinical data from sepsis patients diagnosed in the Emergency Intensive Care Unit (EICU) between April 2019 and May 2023. All patients underwent standard conventional microbiological testing. Patients were categorized into either the mNGS group or the control group based on whether they underwent mNGS tests. Baseline variables were matched using propensity scores.Results: Out of 461 sepsis patients screened, 130 were included after propensity matching, with 65 patients in each group. Despite prior antibiotic treatment, 57 cases (87.69%) in the mNGS group had positive mNGS results, exceeding the culture detection rate (52.31%). Besides, a higher proportion of patients in the mNGS group experienced antibiotic adjustments compared to the control group (72.31% vs 53.85%). Mortality rates were also compared based on the duration of antibiotic exposure before mNGS sampling. Patients exposed to antibiotics for less than 24 hours had a lower mortality rate compared to those exposed for over 8 days (22.22% vs 42.86%). COX multivariate analysis identified mNGS testing, underlying diseases, lymphocyte percentage, infection site (respiratory and bloodstream) as independent risk factors for mortality in sepsis patients.Conclusion: With increased antibiotic exposure time, the positive rate of culture testing significantly decreased (44.44% vs 59.52% vs 35.71%, P = 0.031), whereas the positive rate of mNGS remained stable (77.78% vs 88.10% vs 92.86%, P = 0.557). mNGS demonstrated less susceptibility to antibiotic exposure. Early mNGS detection positively impacted the prognosis of sepsis patients.Keywords: metagenomic next-generation sequencing, sepsis, antibiotic management, clinical value, prognosis

Huixin Cheng,1 Xuehan Wang,1 Juyi Yao,2 Chunbo Yang,3 Jian Liu1,4 1The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China; 2Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China; 3Department of Critical Medicine Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 4Department of Intensive Care Unit, Gansu Provincial Maternity and Child Health Hospital/Gansu Provincial General Hospital, Lan Zhou, Gansu Province, People’s Republic of ChinaCorrespondence: Jian Liu, The First Clinical Medical College of Lanzhou University, No. 222 Tianshui South Road, Lanzhou, Gansu Province, 730013, People’s Republic of China, Email medecinliujian@163.comAbstract: Sepsis is a common critical illness characterized by high mortality rates and a significant disease burden. In the context of sepsis-induced organ dysfunction, the lungs are among the initial organs affected, which may progress to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Recent studies have highlighted the crucial roles of mitophagy and ferroptosis in the development and progression of sepsis-induced ALI/ARDS. Identifying key convergence points in these processes may provide valuable insights for the treatment of this condition. In recent years, certain herbs and their bioactive compounds have demonstrated unique benefits in managing sepsis-induced ALI/ARDS by modulating mitophagy or ferroptosis. This review summary the mechanisms of mitophagy and ferroptosis, explores their interactions, and emphasizes their regulatory roles in the progression of sepsis-induced ALI/ARDS. Additionally, it offers a novel perspective on treatment strategies by summarizing various herbs and their bioactive compounds relevant to this condition.Keywords: sepsis, acute lung injury, acute respiratory distress syndrome, mitophagy, ferroptosis

Jie Xu,1,2 Liujun Tao,1 Liangyan Jiang,1 Jie Lai,1 Juntao Hu,1 Zhanhong Tang1 1Department of Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 2Department of Critical Care Medicine, Suining Central Hospital, Suining, Sichuan, 629000, People’s Republic of ChinaCorrespondence: Zhanhong Tang; Juntao Hu, Department of Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi, 530021, Tel +86 13978816316 ; +86 18978866565, People’s Republic of China, Email tangzhanhong139@sina.com; hujuntao80@126.comPurpose: Sepsis-associated acute lung injury (SA-ALI) is a common complication in patients with sepsis, contributing to high morbidity and mortality. Excessive inflammation and oxidative stress are crucial contributors to lung injury in sepsis. This study aims to examine the protective effects of moderate hypothermia on SA-ALI and explore the underlying mechanisms.Methods: Sepsis was induced in rats through cecal ligation and puncture followed by intervention with moderate hypothermia (32– 33.9°C). Blood, bronchoalveolar lavage fluid, and lung tissues were collected 12 hours post-surgery. Inflammatory responses, oxidative injury, SA-ALI-related pathophysiological processes, and Keap1/GSK3β/Nrf2/GPX4 signaling in septic rats were observed by ELISA, lung W/D ratio, immunohistochemistry, immunofluorescence, histological staining, Western blotting, RT-qPCR, and TEM assays.Results: Moderate hypothermia treatment alleviated lung injury in septic rats, reflected in amelioration of pathological changes in lung structure and improved pulmonary function. Further, moderate hypothermia reduced arterial blood lactate production and suppressed the expression of inflammatory factors IL-1β, IL-6, and TNF-α; downregulated ROS, MDA, and redox-active iron levels; and restored GSH and SOD content. TEM results demonstrated that moderate hypothermia could mitigate ferroptosis in PMVECs within lung tissue. The underlying mechanism may involve regulation of the Keap1/Nrf2/SLC7A11/GPX4 signaling pathway, with the insulin pathway PI3K/Akt/GSK3β also playing a partial role.Conclusion: Collectively, we illustrated a novel potential therapeutic mechanism in which moderate hypothermia could alleviate ferroptosis induced by excessive inflammation and oxidative stress via the regulation of Keap1/GSK3β/Nrf2/GPX4 expression, hence ameliorating acute lung injury in sepsis.Keywords: moderate hypothermia, sepsis, acute lung injury, ferroptosis, Nrf2, inflammation

Jiamin Yu,1 Yongxia Chen,1 Xiaoyan Pan,1 Ji Chen,1 Zhenhua Mai,1 Yuanli Zhang,1 Xiaoyan Wang,2– 4 Gaosheng Zhou,5 Sayed Adam Bukhari,6 Daqing Ma,6,7 Liehua Deng1 1Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, People’s Republic of China; 2Doctoral Scientific Research Center, Lianjiang People’s Hospital, Zhanjiang, 524400, People’s Republic of China; 3Affiliated Lianjiang People’s Hospital, Guangdong Medical University, Zhanjiang, 524400, People’s Republic of China; 4Laboratory of Southern Marine Science and Engineering, Zhanjiang, 524023, People’s Republic of China; 5Department of Critical Care Medicine, The First College of Clinical Medical Science, China Three Gorges University, Yichang Central People’s Hospital, Yichang, Hubei, 443003, People’s Republic of China; 6Division of Anaesthetics, Pain Medicine & Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK; 7Perioperative and Systems Medicine Laboratory, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of ChinaCorrespondence: Liehua Deng, Email glinson@126.comPurpose: The early diagnosis of septic cardiomyopathy remains a challenge. The present work aims to evaluate the diagnostic and prognostic value of plasma soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) levels in septic cardiomyopathy when compared with traditional myocardial biomarkers.Methods: In the 143 sepsis enrolled patients, 67 and 76 patients were classified as non-septic cardiomyopathy and septic cardiomyopathy, respectively. Their blood samples were harvested up to 14th day after hospital admission for measurements of sTREM-1 and other biomarkers, such as N-terminal pronatriuretic peptide (NT-proBNP), highly sensitive troponin (TNT-HS), myoglobin (MYO), creatine kinase isoenzyme (CK-MB), etc. All the data were collected at 8:00 a.m. The area under the receiver operating characteristic curve was obtained to assess the diagnostic accuracy of those biomarkers. The Log rank test was utilized to evaluate the prognostic value of sTREM-1 on septic cardiomyopathy.Results: Circulating sTREM-1 showed a high specificity (88.1%) and moderate sensitivity (64.5%) to distinguish patients with septic cardiomyopathy in the 143 septic patients. The diagnostic efficiency of sTREM-1 was higher than inflammatory biomarkers and traditional myocardial markers. Logistic regression revealed that plasma sTREM-1 was an independent predictor of septic cardiomyopathy. Furthermore, in the whole septic cardiomyopathy cohorts, the sTREM-1 levels in the non-survivors were significantly higher than those of survivors during ICU stay. In addition, the left ventricular systolic dysfunction had a high odds ratio (3.968) to predict 90-day mortality in septic patients with cardiomyopathy.Conclusion: High plasma sTREM-1 level may be a diagnostic marker in predicting ICU poor outcome of patients with septic cardiomyopathy.Keywords: sepsis, septic cardiomyopathy, diagnosis, sTREM-1

Abstract Sepsis-induced myopathy is one of the serious complications of sepsis, which severely affects the respiratory and peripheral motor systems of patients, reduces their quality of life, and jeopardizes their lives, as evidenced by muscle atrophy, loss of strength, and impaired regeneration after injury. The pathogenesis of sepsis-induced myopathy is complex, mainly including cytokine action, enhances free radical production in muscle, increases muscle protein hydrolysis, and decreases skeletal muscle protein synthesis, etc. The above mechanisms have been demonstrated in existing studies. However, it is still unclear how the overall pattern of gene co-expression affects the pathological process of sepsis-induced myopathy. Therefore, we intend to identify hub genes and signaling pathways. Weighted gene co-expression network analysis was our main approach to study gene expression profiles: skeletal muscle transcriptome in ICU patients with sepsis-induced multi-organ failure (GSE13205). After data pre-processing, about 15,181 genes were used to identify 13 co-expression modules. Then, 16 genes (FEM1B, KLHDC3, GPX3, NIFK, GNL2, EBNA1BP2, PES1, FBP2, PFKP, BYSL, HEATR1, WDR75, TBL3, and WDR43) were selected as the hub genes including 3 up-regulated genes and 13 down-regulated genes. Then, Gene Set Enrichment Analysis was performed to show that the hub genes were closely associated with skeletal muscle dysfunction, necrotic and apoptotic skeletal myoblasts, and apoptosis in sepsis-induced myopathy. Overall, 16 candidate biomarkers were certified as reliable features for more in-depth exploration of sepsis-induced myopathy in basic and clinical studies.

Abstract Septic lung injury is strongly associated with polarization of M1 macrophages and excessive cytokine release. Fibroblast growth factor (FGF) signaling plays a role in both processes. However, the impact of FGF2 deficiency on macrophage polarization and septic acute lung injury remains unclear. To investigate this, we obtained macrophages from FGF2 knockout mice and examined their polarization and inflammatory cytokine expression. We also eliminated endogenous macrophages using clodronate liposomes and administered FGF2 knockout or WT macrophages intravenously in conjunction with cecal ligation and puncture (CLP) surgery to induce sepsis. In vitro analysis by flow cytometry and real-time PCR analysis demonstrated that FGF2 deficiency resulted in increased expression of M1 markers (iNOS and CD86) and inflammatory cytokines (CXCL1, IL1β, and IL6), especially after LPS stimulation. Additionally, immunofluorescence demonstrated increased nuclear translocation of p65 NF-κB in FGF2 knockout macrophages and RNA-seq analysis showed enrichment of differentially expressed genes in the IL17 and TNFα inflammatory signaling pathways. Furthermore, in vivo experiments revealed that depletion of FGF2 in macrophages worsened sepsis-induced lung inflammation, lung vascular leak, and lung histological injury, accompanied by an increase in CD86-positive cells and apoptosis. Our study suggests that FGF2 deficiency in macrophages plays a critical role in the pathogenesis of septic ALI, possibly because of the enhanced M1 macrophage polarization and production of proinflammatory cytokines. These findings provide empirical evidence for potential therapeutic interventions targeting FGF2 signaling to modulate the polarization of M1 and M2 macrophages in the management of sepsis-induced acute lung injury.

Abstract Background Metoprolol is commonly administered to critically ill patients; however, its effect on mortality in patients with sepsis-induced cardiomyopathy (SICM) remains uncertain. This study aimed to investigate the relationship between metoprolol use and mortality in patients with SICM. Methods Adults with SICM were identified from the MIMIC-IV database. The exposure of interest was metoprolol treatment. The outcomes assessed were 30-day mortality, 1-year mortality, and in-hospital mortality. Kaplan–Meier survival analysis evaluated the effect of metoprolol on these outcomes. Multivariable Cox proportional hazards and logistic regression analyses were performed to determine the correlation between metoprolol treatment and mortality in patients with SICM. Results 1163 patients with SICM were identified, with 882 receiving metoprolol treatment (MET group) and 281 not receiving metoprolol treatment (NOMET group). Overall, the 30-day, 1-year, and in-hospital mortality rates were 10.2%, 18.2%, and 8.9%, respectively. Significant differences in mortality existed between the groups. Multivariable Cox analysis revealed that patients in the NOMET group had a higher risk of 1-year mortality (adjusted hazard ratio [HR] 2.493; 95% confidence interval [CI] 1.800–3.451; P

Abstract Background Trauma and infection induce emergency granulopoiesis. Counts of immature granulocytes and transcriptional pathways of terminal granulocytic differentiation in blood are elevated in sepsis but correlate with disease severity. This limits their performance as sepsis biomarkers in critically ill patients. We hypothesized that activation of these pathways in sepsis is attributable to immature low-density (LD) rather than mature high-density (HD) granulocytes. Methods We included patients with sepsis and systemic inflammatory response syndrome (SIRS) of comparable disease severity, and additionally septic shock, on intensive or intermediate care unit admission. Blood granulocyte isolation by CD15 MicroBeads was followed by density-gradient centrifugation. Flow cytometry was used to determine counts of developmental stages (precursors) and their relative abundancies in total, HD, and LD granulocytes. Five degranulation markers were quantified in plasma by multiplex immunoassays. A set of 135 genes mapping granulocyte differentiation was assayed by QuantiGene™ Plex. CEACAM4, PLAC8, and CD63 were analyzed by qRT-PCR. Nonparametric statistical tests were applied. Results Precursor counts appeared higher in sepsis than SIRS but did not correlate with disease severity for early immature and mature granulocytes. Precursor subpopulations were enriched at least ten-fold in LD over HD granulocytes without sepsis-SIRS differences. Degranulation markers in blood were comparable in sepsis and SIRS. Higher expression of early developmental genes in sepsis than SIRS was more pronounced in LD and less in HD than total granulocytes. Only the cell membrane protein encoding genes CXCR2 and CEACAM4 were more highly expressed in SIRS than sepsis. By qRT-PCR, the azurophilic granule genes CD63 and PLAC8 showed higher sepsis than SIRS levels in LD granulocytes and PLAC8 also in total granulocytes where its discriminatory performance resembled C-reactive protein (CRP). Conclusions Transcriptional programs of early terminal granulocytic differentiation distinguish sepsis from SIRS due to both higher counts of immature granulocytes and elevated expression of early developmental genes in sepsis. The sustained expression of PLAC8 in mature granulocytes likely accounts for its selection in the whole blood SeptiCyte™ LAB test. Total granulocyte PLAC8 rivals CRP as sepsis biomarker. However, infection-specific transcriptional pathways, that differentiate sepsis from sterile stress-induced granulocytosis more reliably than CRP, remain to be identified.

Abstract In sepsis, inflammation, and nutrient deficiencies endanger cellular homeostasis and survival. Autophagy is primarily a mechanism of cellular survival under fasting conditions. However, autophagy-dependent cell death, known as autophagic cell death, is proinflammatory and can exacerbate sepsis. Autophagy also regulates various types of non-inflammatory and inflammatory cell deaths. Non-inflammatory apoptosis tends to suppress inflammation, however, inflammatory necroptosis, pyroptosis, ferroptosis, and autophagic cell death lead to the release of inflammatory cytokines and damage-associated molecular patterns (DAMPs) and amplify inflammation. The selection of cell death mechanisms is complex and often involves a mixture of various styles. Similarly, protective autophagy and lethal autophagy may be triggered simultaneously in cells. How cells balance the regulatory mechanisms of these processes is an area of interest that is still under investigation. Therapies aimed at modulating autophagy are considered promising. Enhancing autophagy helps clear and recycle damaged organelles and reduce the burden of inflammatory processes while inhibiting excessive autophagy, which could prevent autophagic cell death. In this review, we introduce recent advances in research and the complex regulatory system of autophagy in sepsis.

Abstract Group 2 innate lymphocytes (ILC2) have an important role in orchestrating sepsis-induced immune response. However, the impact of LC2 on sepsis-induced cardiac injury is still not fully understood. This study investigated the mechanisms governing ILC2 activation within the cardiac tissue after sepsis. In vivo experiments using wild-type and IL-33 deficient mice indicated that the presence of interleukin (IL)-33, which participates in expanding and activating ILC2 cells, was correlated with higher ILC2 levels (246 ± 34 vs. 66 ± 18, p

Abstract Background To determine the optimal fluid resuscitation volume in septic patients with acutely decompensated heart failure (ADHF). Methods Septic patients with ADHF were identified from a tertiary urban medical center. The generalized additive models were used to explore the association between fluid resuscitation volume and endpoints, and the initial 3 h fluid resuscitation volume was divided into four groups according to this model: 15 to ≤ 20 mL/kg group, and > 20 mL/kg group. Logistic and Cox regression models were employed to explore the association between resuscitation volume and primary endpoint, in-hospital mortality, as well as secondary endpoints including 30-day mortality, 1-year mortality, invasive ventilation, and ICU admission. Results A total of 598 septic patients with a well-documented history of HF were enrolled in the study; 405 patients (68.8%) had sepsis-induced hypoperfusion. Patients with NYHA functional class III and IV were 494 (83.9%) and 22 (3.74%), respectively. Resuscitation volumes above 20 mL/kg (OR 3.19, 95% CI 1.31–8.15) or below 10 mL/kg (OR 2.33, 95% CI 1.14–5.20) significantly increased the risk of in-hospital mortality in septic patients, while resuscitation volumes between 15 and 20 mL/kg were not associated with the risk of in-hospital death in septic patients (OR 1.79, 95% CI 0.68–4.81). In the multivariable Cox models, the effect of resuscitation volume on 30-day and 1-year mortality in septic patients was similar to the effect on in-hospital mortality. Resuscitation volume exceeds 15 mL/kg significantly increased the risk of tracheal intubation, while fluid resuscitation volume was not associated with ICU admission in the septic patients. In septic patients with hypoperfusion, these fluid resuscitation volumes have similar effects on patient outcomes. This association was consistent across the three subgroups with worsened cardiac function, as well as in sensitivity analyses. Conclusions Our study observed that an initial fluid resuscitation volume of 10–15 mL/kg in the first 3 h was optimal for early resuscitation in septic patients with ADHF, particularly those with worsened cardiac function. These results need to be confirmed in randomized controlled trials with larger sample sizes.

Abstract Background Senescent immune cells exhibit altered gene expression and resistance to apoptosis. The prevalence of these cells increases with age and emerging data implicate senescence-associated maladaptive signaling as a potential contributor to sepsis and septic shock. The senolytic drug fisetin promotes clearance of senescent cells and is hypothesized to mitigate septic responses to infection. Methods We are conducting a multi-center, randomized, double-blinded, adaptive allocation phase 2 clinical trial to assess the efficacy of the senolytic drug fisetin in preventing clinical deterioration of elderly patients diagnosed with sepsis. We intend to enroll and randomize 220 elderly patients (age > 65) with the clinical diagnosis of sepsis to receive either fisetin as a single oral dose of 20 mg/kg, fisetin in two oral doses of 20 mg/kg each spaced 1 day apart, or placebo. The primary outcome will be changed in the composite of cardiovascular, respiratory, and renal sequential organ failure assessment scores at 7 days from enrollment. Secondary outcomes include quantification of senescent CD3 + cells at 7 days, and 28-day assessments of organ failure-free days, days in an intensive care unit, and all-cause mortality. Discussion This multi-center, randomized, double-blinded trial will assess the efficacy of fisetin in preventing clinical deterioration in elderly patients with sepsis and measure the effects of this drug on the prevalence of senescent immune cells. We intend that the results of this phase 2 trial will inform the design of a larger phase 3 study. Trial registration This trial is registered to ClinicalTrials.gov under identifier NCT05758246, first posted on March 7, 2023.

Abstract Background Sepsis, a severe inflammatory response to infection, is a global health priority due to its high mortality and long-term disability rates. Its pathophysiology involves both inflammation and immune suppression. Managing sepsis requires significant healthcare resources and expenditure, with sepsis being a leading cause of hospital costs. Gut microbiotas play a crucial role in sepsis, and probiotics show promise in managing it by restoring microbial balance. Despite advances, targeted therapies for sepsis remain elusive, necessitating innovative approaches such as probiotic therapy. Method Fifty-four eligible patients with sepsis will be randomly assigned to either the synbiotic or placebo group. The synbiotic supplement, KidiLact, comprises ten probiotic strains and prebiotic fructooligosaccharides. Participants will receive two sachets daily for 7 days, mixed with sterile water and administered orally or via gavage. Inflammatory factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) will be evaluated. Anthropometric measurements, nutritional assessment, biochemical analysis, and clinical evaluation will be conducted to assess treatment outcomes. Statistical analysis will be performed to compare results between the two groups, employing SPSS version 19 with a significance level of P

Abstract Introduction Sepsis, a life-threatening syndrome, is often accompanied by tachycardia in spite of hypovolemia and hypotension have been corrected. Recently, relevant studies have shown that sustained tachycardia in sepsis was related to high mortality, and appropriate control of heart rate (HR) could improve prognosis. Ivabradine reduces HR directly without a negative inotropic effect through inhibition of the If ionic current, which is different from the traditional rate control drug (beta-blockers). Methods and analysis This is a prospective, multicenter, randomized, open label study designed to investigate the effect of heart rate control with ivabradine on hemodynamic in patients with sepsis. Our study will enroll 172 patients with sepsis as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria with sinus rate of 95 bpm or higher despite a hemodynamic optimization. Patients will be randomly assigned to standard treatment group (GS) or ivabradine group (GI, standard treatment for sepsis plus enteral ivabradine). Patients in GI will receive ivabradine to maintain HR between 70 and 94 bpm. The primary outcome is the difference of a reduction in HR below 95 bpm and the effect of ivabradine on hemodynamics between GI and GS group within the first 96 h after randomization. The secondary outcomes include organ function measures, the difference in SOFA score, incidence of adverse events, need for organ support, length of ICU stay, and 28-day overall mortality. Discussion There are limited studies on ivabradine to control heart rate in patients with sepsis. Our study aims to evaluate whether direct sinus node inhibition can improve hemodynamics, as well as its impact on organ function and prognosis in patients with sepsis, so as to provide evidence for the safe usage in clinical practice. Trial registration ClinicalTrials.gov NCT05882708. Registered on May 11, 2023, https://clinicaltrials.gov/ct2/show/NCT05882708 .

Latar belakang. Insiden sepsis pada negara berkembang sampai saat ini masih tinggi. Banyaknya faktor risiko yang memengaruhi, menjadikan sepsis sebagai penyumbang tingginya angka kematian pada bayi. Diagnosis yang seringkali terlambat ditegakkan karena pemeriksaan kultur darah sebagai Gold Standard baru bisa didapatkan hasilnya setelah beberapa hari. Deteksi dini sepsis neonatorum dapat diltegakkan salah satunya dengan pemeriksaan rasio neutrofil limfosit dan red cell distribution width. Tujuan. Menilai rasio neutrofil limfosit, red cell distribution width, dan faktor risiko pada neonatus dengan diagnosis sepsis di neonatal intensive care unit - NICU Rumah Sakit Zainoel Abidin Banda Aceh dengan luaran kematian. Metode. Penelitian desain kohort retrospektif dengan data rekam medis neonatus di NICU Rumah Sakit Umum Daerah Dr. Zainoel Abidin, Banda Aceh, dari Februari hingga Oktober 2023. Sebanyak 43 neonatus dengan diagnosis sepsis yang memenuhi kriteria inklusi dianalisis. Data yang dikumpulkan meliputi karakteristik demografis, hasil laboratorium, serta luaran klinis. Analisis dilakukan menggunakan uji Chi-square dan analisis multivariat dengan SPSS versi 20.0. Hasil. Diperoleh 88,3% neonatus menunjukkan peningkatan NLR, dan 86,05% mengalami peningkatan RDW. Terdapat hubungan signifikan antara metode persalinan sectio caesaria (p