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Objectives: The relationship between adiposity and sepsis has received increasing attention. This study aims to explore the causal relationship between life course adiposity and the sepsis incidence., Methods: Mendelian randomization (MR) method was employed in this study. Instrumental variants were obtained from genome-wide association studies for life course adiposity, including birth weight, childhood body mass index (BMI), childhood obesity, adult BMI, waist circumference, visceral adiposity, and body fat percentage. A meta-analysis of genome-wide association studies for sepsis including 10,154 cases and 454,764 controls was used in this study. MR analyses were performed using inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. Instrumental variables were identified as significant single nucleotide polymorphisms at the genome-wide significance level ( P < 5×10 -8 ). The sensitivity analysis was conducted to assess the reliability of the MR estimates., Results: Analysis using the MR analysis of inverse variance weighted method revealed that genetic predisposition to increased childhood BMI ( OR = 1.29, P = 0.003), childhood obesity ( OR = 1.07, P = 0.034), adult BMI ( OR = 1.38, P < 0.001), adult waist circumference ( OR = 1.01, P = 0.028), and adult visceral adiposity ( OR = 1.53, P < 0.001) predicted a higher risk of sepsis. Sensitivity analysis did not identify any bias in the MR results., Conclusion: The results demonstrated that adiposity in childhood and adults had causal effects on sepsis incidence. However, more well-designed studies are still needed to validate their association., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cheng, Li, Tong, Liu, Zhang, Ma and Lu.)

Myeloid-derived suppressor cells (MDSCs) expand during sepsis and contribute to the development of persistent inflammation-immunosuppression-catabolism syndrome. However, the underlying mechanism remains unclear. Exploring the mechanisms of MDSCs generation may provide therapeutic targets for improving immune status in sepsis. Here, a sepsis mouse model is established by cecal ligation and perforation. Bone marrow cells at different sepsis time points are harvested to detect the proportion of MDSCs and search for differentially expressed genes by RNA-sequence. In lethal models of sepsis, polymorphonuclear-MDSCs (PMN-MDSCs) decrease in early but increase and become activated in late sepsis, which is contrary to the expression of metastasis-associated lung adenocarcinoma transcript 1 (Malat1). In vivo , Malat1 inhibitor significantly increases the mortality in mice with late sepsis. And in vitro , Malat1 down-regulation increases the proportion of PMN-MDSCs and enhanced its immunosuppressive ability. Mechanistically, Malat1 limits the differentiation of PMN-MDSCs by accelerating the degradation of phosphorylated STAT3. Furthermore, Stattic, an inhibitor of STAT3 phosphorylation, improves the survival of septic mice by inhibiting PMN-MDSCs. Overall, the study identifies a novel insight into the mechanism of sepsis-induced MDSCs and provides more evidence for targeting MDSCs in the treatment of sepsis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cytokine storms are crucial in the development of various inflammatory diseases, including sepsis and autoimmune disorders. The immunosuppressive cytokine INTERLEUKIN (IL)-37 consists of five isoforms (IL-37a-e). We identified IL-37a as a nuclear cytokine for the first time. Compared to IL-37b, IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock. The full-length (FL) form of IL-37a and the N-terminal fragment, which is processed by elastase, could translocate into cell nuclei through a distinctive nuclear localization sequence (NLS)/importin nuclear transport pathway. These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor (PPARγ). This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβ and H3K4me1/2 to the enhancer/promoter of Pparg. The receptor-independent regulatory pathway of the nuclear IL-37a-PPARγ axis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases, including sepsis., (© 2023. The Author(s), under exclusive licence to CSI and USTC.)

Background: Degradation of the endothelial glycocalyx is critical for sepsis-associated lung injury and pulmonary vascular permeability. We investigated whether sulodexide, a precursor for the synthesis of glycosaminoglycans, plays a biological role in glycocalyx remodeling and improves endothelial barrier dysfunction in sepsis., Methods: The number of children with septic shock that were admitted to the PICU at Children's Hospital of Fudan University who enrolled in the study was 28. On days one and three after enrollment, venous blood samples were collected, and heparan sulfate, and syndecan-1 (SDC1) were assayed in the plasma. We established a cell model of glycocalyx shedding by heparinase III and induced sepsis in a mouse model via lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Sulodexide was administrated to prevent endothelial glycocalyx damage. Endothelial barrier function and expression of endothelial-related proteins were determined using permeability, western blot and immunofluorescent staining. The survival rate, histopathology evaluation of lungs and wet-to-dry lung weight ratio were also evaluated., Results: We found that circulating SDC1 levels were persistently upregulated in the non-alive group on days 1 and 3 and were positively correlated with IL-6 levels. Receiver operating characteristic curve analysis showed that SDC1 could distinguish patients with mortality. We showed that SDC1-shedding caused endothelial permeability in the presence of heparinase III and sepsis conditions. Mechanistically, sulodexide (30 LSU/mL) administration markedly inhibited SDC1 shedding and prevented endothelial permeability with zonula occludens-1 (ZO-1) upregulation via NF-κB/ZO-1 pathway. In mice with LPS and CLP-induced sepsis, sulodexide (40 mg/kg) administration decreased the plasma levels of SDC1 and increased survival rate. Additionally, sulodexide alleviated lung injury and restored endothelial glycocalyx damage., Conlusions: In conclusion, our data suggest that SDC1 predicts prognosis in children with septic shock and sulodexide may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ying, Zhang, Wang, Liu, Yu, Wang, Chen, Zhou and Lu.)

Background: Notch signaling is critical for regulating the function of vascular endothelial cells (ECs). However, the effect of the intracellular domain of Notch1 (NICD) on EC injury in sepsis remains unclear., Methods: We established a cell model of vascular endothelial dysfunction and induced sepsis in a mouse model via lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Endothelial barrier function and expression of endothelial-related proteins were determined using CCK-8, permeability, flow cytometry, immunoblot, and immunoprecipitation assays. The effect of NICD inhibition or activation on endothelial barrier function was evaluated in vitro . Melatonin was used for NICD activation in sepsis mice. The survival rate, Evans blue dye of organs, vessel relaxation assay, immunohistochemistry, ELISA, immunoblot were used to explore the specific role of melatonin for sepsis induced vascular dysfunction in vivo ., Results: We found that LPS, interleukin 6, and serum collected from septic children could inhibit the expression of NICD and its downstream regulator Hes1, which impaired endothelial barrier function and led to EC apoptosis through the AKT pathway. Mechanistically, LPS decreased the stability of NICD by inhibiting the expression of a deubiquitylating enzyme, ubiquitin-specific proteases 8 (USP8). Melatonin, however, upregulated USP8 expression, thus maintaining the stability of NICD and Notch signaling, which ultimately reduced EC injury in our sepsis model and elevated the survival rate of septic mice., Conclusions: We found a previously uncharacterized role of Notch1 in mediating vascular permeability during sepsis, and we showed that inhibition of NICD resulted in vascular EC dysfunction in sepsis, which was reversed by melatonin. Thus, the Notch1 signaling pathway is a potential target for the treatment of sepsis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Zhang, Ying, Wang, Yan, Zhou and Lu.)

Bloodstream infection is a life-threatening complication in critically ill patients. Multi-drug resistant bacteria or fungi may increase the risk of invasive infections in hospitalized children and are difficult to treat in intensive care units. The purpose of this study was to use metagenomic next-generation sequencing (mNGS) to understand the bloodstream microbiomes of children with suspected sepsis in a pediatric intensive care unit (PICU). mNGS were performed on microbial cell-free nucleic acid from 34 children admitted to PICU, and potentially pathogenic microbes were identified. The associations of serological inflammation indicators, lymphocyte subpopulations, and other clinical phenotypes were also examined. mNGS of blood samples from children in PICU revealed potential eukaryotic microbial pathogens. The abundance of Pneumocystis jirovecii was positively correlated with a decrease in total white blood cell count and immunodeficiency. Hospital-acquired pneumonia patients showed a significant increase in blood bacterial species richness compared with community-acquired pneumonia children. The abundance of bloodstream bacteria was positively correlated with serum procalcitonin level. Microbial genome sequences from potential pathogens were detected in the bloodstream of children with suspected sepsis in PICU, suggesting the presence of bloodstream infections in these children., Competing Interests: Author YZ was employed by company BGI PathoGenesis Pharmaceutical Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yan, Liu, Chen, Chen, Cheng, Tao, Cai, Zhou, Wang, Wang and Lu.)

What Is Known and Objective: Meropenem, a broad-spectrum carbapenem, is frequently used to treat severe bacterial infections in critically ill children. Recommendations for meropenem doses in adult infections are available; however, few studies have been published regarding the use of meropenem in children with sepsis, especially in those receiving continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO). We aimed to investigate the pharmacokinetic (PK) parameters of meropenem in children with sepsis receiving extracorporeal life support (ECLS)., Methods: This was a prospective observational clinical study of children with sepsis receiving ECMO or CRRT in the paediatric intensive care unit (PICU) of a children's hospital. The enrolled children received 20 mg/kg meropenem infusion over 1 hour, every 8 hours, and were grouped into children receiving ECMO, children receiving CRRT and children receiving neither ECMO nor CRRT. Plasma meropenem concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The key PK parameters were determined using the non-compartmental approach., Results and Discussion: Twenty-seven patients were finally enrolled. The eCLCR of the CRRT group was lower than that of the ECMO group. The values of elimination half-life (t 1/2 ), area under the plasma concentration-time curve (AUC tau ), area under the plasma concentration-time curve from time zero to infinity (AUC 0-∞ ), and total clearance (CL) in the ECMO group were not different from those of the other groups (all p > 0.05). However, the AUC tau (p = 0.0137) and AUC 0-∞ (p = 0.0234) significantly decreased after filtration through a hemofiltration membrane in patients receiving CRRT., What Is New and Conclusion: No significant alterations in the PK parameters of meropenem occurred in children with sepsis administered ECMO and/or CRRT. Further investigations including PK modelling could provide evidence for appropriate meropenem dosing regimens during ECLS administration., (© 2021 The Authors. Journal of Clinical Pharmacy and Therapeutics published by John Wiley & Sons Ltd.)

Objectives: Continuous renal replacement therapy becomes available utilization for pediatric critically ill, but the impact of mortality rate in severe sepsis remains no consistent conclusion. The aim of the study is to assess the effect of continuous renal replacement therapy in pediatric patients with severe sepsis and the impact this therapy may have on their mortality., Design: Propensity score-matched cohort study analyzing data prospectively collected by the PICUs over 2 years (2016-2018)., Setting: Four PICUs of tertiary university children's hospital in China., Patients: The consecutive patients with severe sepsis admitted to study PICUs were enrolled from July 2016 to June 2018., Interventions: The patients were divided into the continuous renal replacement therapy group and the conventional (noncontinuous renal replacement therapy) group., Measurements and Main Results: A total of 324 patients with severe sepsis were enrolled. The hospital mortality rate was 35.6% (64/180) in the continuous renal replacement therapy group and 47.9% (69/144) in the noncontinuous renal replacement therapy group. After propensity score adjustment, the hospital mortality rate was 21.3% (29/136) in the continuous renal replacement therapy group and 32.4% (44/136) in the noncontinuous renal replacement therapy group. In subgroup analysis, the relative risk of dying was 0.447 (95% CI, 0.208-0.961) only in patients complicated by acute respiratory distress syndrome (p = 0.037), but not in patients with shock, acute kidney injury, acute liver dysfunction, encephalopathy, and fluid overload greater than 10%. The mean duration of continuous renal replacement therapy was 45 hours (26-83 hr) with an ultrafiltration rate of 50 mL/kg/hr. The level of interleukin-6 was decreased, and the percent of natural killer cells (%) was improved in the continuous renal replacement therapy group compared with the noncontinuous renal replacement therapy group. Furthermore, continuous renal replacement therapy was an independently significant risk factor for hospital mortality in pediatric patients with severe sepsis, and the interval between continuous renal replacement therapy initiation and PICU admission was an independent risk factor for hospital mortality in patients receiving continuous renal replacement therapy., Conclusions: Continuous renal replacement therapy with an ultrafiltration rate of 50 mL/kg/hr decreases hospital mortality rate in pediatric severe sepsis, especially in patients with acute respiratory distress syndrome.

Objective: To evaluate efficacy of continuous blood purification (CBP) in childhood severe sepsis through the analysis of organ function, inflammatory mediators and prognosis., Method: Forty-seven children with severe sepsis aged 29 days -16 years who were treated in PICU of Shanghai and Zhejiang five hospitals during October 1, 2011 and September 30, 2012 were enrolled; 30 cases treated with CBP were recorded as logged group , 17 cases without CBP as unlogged group. Changes in the cardiovascular, respiratory function, renal function, inflammatory markers, PRISM score III, PCIS and survival were observed and compared between the two groups at baseline (d0), first days (d1), second days (d2), third days (d3), fifth days (d5)., Result: (1) Cardiovascular function: In d3 and d5, heart rate (HR) and mean arterial pressure (MAP) were improved as compared to unlogged group (121, 119 vs. 138, 137; 71, 80 mmHg vs. 63, 62 mmHg, P < 0.05), with no statistical significance in arterial blood lactate concentration. (2) Oxygenation index (PaO₂/FiO₂) and arterial oxygen saturation (SaO₂) increased as compared to unlogged group, but did not reach statistical significance. (3) Blood urea nitrogen (BUN) and creatinine (Cr) were improved as compared with unlogged group from d1 (P < 0.05). (4) Inflammatory mediators did not show significant differences. (5) Twenty-eight days survival rate: logged group was 70.0%, unlogged group was 52.9%, but the difference was not statistically significant (P = 0.242)., Conclusion: CBP can improve circulatory function, oxygenation, and renal function in children with severe sepsis. No evidence was found that CBP could decrease the level of inflammatory mediators, improve critical score and 28 days survival rate.

Objective: To learn application status of continuous blood purification (CBP) in pediatric intensive care unit (PICU), to provide reference to promote the development of CBP technology., Method: The survey of CBP application was conducted using questionnaire in 40 hospitals providing intensive care, which included children's hospitals and the pediatric sections of general hospitals from 28 provinces/municipalities/autonomous regions in China during March to July of 2012., Result: Totally 38 hospital replied, 25 hospitals carried out CBP technology, first carried out in 1997, the median year was 2008, 21 hospitals' PICU could independently carry out CBP device, 18 hospitals had the nurses who could professionally operate, routinely maintain the device. Continuous veno-venous hemodiafiltration was the largest implementation mode of CBP, accounting for 51.9%. Twenty-three hospitals used ordinary heparin, and 2 hospitals used low molecular weight heparin; 21 hospitals chose activated partial thromboplastin time as the coagulation testing, due to lack of equipment, only four hospitals chose activated clotting time as coagulation testing. Only 3 hospitals could apply before and after dilution joint technology. Kidney failure is still the disease accounting for the highest proportion of diseases requiring CBP application, accounting for 38.1%, followed by sepsis, 19.1%, drug poisoning 16.7%., Conclusion: CBP started 10 years ago, and got attention and promotion nearly five years ago in China, but the associated personnel, equipment were inadequate, anticoagulation, before and after dilution and other technical applications were not complete enough, high volume hemofiltration mode was seldom used.

Two independent experiments were performed with three groups each (sepsis control, sepsis, and sepsis with apoE23 treatment) to investigate the anti-inflammatory effect of apolipoprotein 23 (apoE23) in a mouse model of sepsis induced by S. typhimurium. Survival rates; plasma level variations in tumor necrosis factor (TNF)-α, interleukin (IL)-6, and lipopolysaccharide (LPS); S. typhimurium colony-forming units in the spleen tissue; and mRNA and protein expression levels of low-density lipoprotein receptor (LDLR), LDLR-related protein (LRP), syndecan-1, and scavenger receptor B1 were evaluated in the livers of mice from the three groups. Results found that the survival rate of septic mice treated with apoE23 was 100% within 48 h, while it was only 40% in septic mice without apoE23 treatment (P < 0.001). The plasma LPS, TNF-α, and IL-6 levels and the S. typhimurium load in mice in the apoE23-treated group were significantly lower than those in septic mice (P < 0.05). Moreover, apoE23 restored the downregulated expression of LDLR and LRP in the liver tissue of septic mice. So apoE23 exhibits an anti-inflammatory effect in the mouse model of S. typhimurium-induced sepsis. Further studies are required to understand the mechanisms underlying the anti-inflammatory effects of apoE23.

Sepsis is a critical condition affecting patients worldwide. Systemic inflammatory response syndrome in sepsis contributes to organ dysfunction and mortality. The oXiris is a recently developed continuous renal replacement therapy (CRRT) hemofilter indicated for the adsorption of cytokines from the bloodstream. In our study, in a septic child, CRRT with three filters, including the oXiris hemofilter, resulted in a downregulation of inflammatory biomarkers and a reduction of vasopressors. Herein, we described the first report of such usage in septic children. [ABSTRACT FROM AUTHOR]

Objectives: To develop a population pharmacokinetic model of meropenem in children with sepsis receiving extracorporeal life support (ECLS) and optimize the dosage regimen based on investigating the probability of target attainment (PTA). Methods: The children with sepsis were prospectively enrolled in a pediatric intensive care unit from January 2018 to December 2019. The concentration-time data were fitted using nonlinear mixed effect model approach by NONMEM program. The stochastic simulation considering various scenarios based on proposed population pharmacokinetics model were conducted, and the PTAs were calculated to optimize the dosage regimens. Results: A total of 25 children with sepsis were enrolled, of whom13 received ECMO, 9 received CRRT, and 4 received ECMO combined with CRRT. 12 children received a two-step 3-h infusion and 13 children received 1-h infusion. Bodyweight and creatinine clearance had significant impacts on the PK parameters. ECMO intervention was not related to the PK properties. If 100%T > MIC was chosen as target, children receiving 40 mg/kg q8h over a 3 h-infusion only reached the PTA up to 77.4%. If bacteria with MIC 2 mg/L were to be treated with meropenem and the PTA target was 50%T > MIC, a dose of 40 mg/kg q8h for 1 h infusion would be necessary. Conclusions: The PK properties of meropenem in septic children receiving extracorporeal life support were best described. We recommended the opitimized dosing regimens for septic children receiving ECLS depending on the PTA of PK target 50%T > MIC and 100%T > MIC, for children with sepsis during ECLS with different body weight, estimated creatinine clearance (eCRCL) and MIC of bacteria. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: Definitions for pediatric sepsis were established in 2005 without data-driven criteria. It is unknown whether the more recent adult Sepsis-3 definitions meet the needs of providers caring for children. We aimed to explore the use and applicability of criteria to diagnose sepsis and septic shock in children across the world. METHODS: This is an international electronic survey of clinicians distributed across international and national societies representing pediatric intensive care, emergency medicine, pediatrics, and pediatric infectious diseases. Respondents stated their preferences on a 5-point Likert scale. RESULTS: There were 2835 survey responses analyzed, of which 48% originated from upper-middle income countries, followed by high income countries (38%) and low or lower-middle income countries (14%). Abnormal vital signs, laboratory evidence of inflammation, and microbiologic diagnoses were the criteria most used for the diagnosis of "sepsis." The 2005 consensus definitions were perceived to be the most useful for sepsis recognition, while Sepsis-3 definitions were stated as more useful for benchmarking, disease classification, enrollment into trials, and prognostication. The World Health Organization definitions were perceived as least useful across all domains. Seventy one percent of respondents agreed that the term sepsis should be restricted to children with infection-associated organ dysfunction. CONCLUSIONS: Clinicians around the world apply a myriad of signs, symptoms, laboratory studies, and treatment factors when diagnosing sepsis. The concept of sepsis as infection with associated organ dysfunction is broadly supported. Currently available sepsis definitions fall short of the perceived needs. Future diagnostic algorithms should be pragmatic and sensitive to the clinical settings. [ABSTRACT FROM AUTHOR]