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Early-onset sepsis (EOS) is a global health issue, considered one of the primary causes of neonatal mortality. Diagnosis of EOS is challenging because its clinical signs are nonspecific, and blood culture, which is the current gold-standard diagnostic tool, has low sensitivity. Commonly used biomarkers for sepsis diagnosis, including C-reactive protein, procalcitonin, and interleukin-6, lack specificity for infection. Due to the disadvantages of blood culture and other common biomarkers, ongoing efforts are directed towards identifying innovative molecular approaches to diagnose neonates at risk of sepsis. This review aims to gather knowledge and recent research on these emerging molecular methods. PCR-based techniques and unrestricted techniques based on 16S rRNA sequencing and 16S–23S rRNA gene interspace region sequencing offer several advantages. Despite their potential, these approaches are not able to replace blood cultures due to several limitations; however, they may prove valuable as complementary tests in neonatal sepsis diagnosis. Several microRNAs have been evaluated and have been proposed as diagnostic biomarkers in EOS. T2 magnetic resonance and bioinformatic analysis have proposed potential biomarkers of neonatal sepsis, though further studies are essential to validate these findings.

Background Late-Onset Neonatal Sepsis (LOS) is a rare condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not completely preventable, identifying susceptibility factors is critical to characterizing the pathophysiology and developing interventions. Prior studies demonstrated both genetics and infant sex influence susceptibility. Our study was designed to identify LOS associated genetic variants. Methods We performed an exploratory genome wide association study (GWAS) with 224 LOS cases and 273 controls from six European countries. LOS was defined as sepsis presenting from 3 to 90 days of age; diagnosis was established by clinical criteria consensus guidelines. We tested for association with both autosomal and X-chromosome variants in the total sample and in sex-stratified analyses. Results In total, 71 SNPs associated with neonatal sepsis at p  < 1 × 10 −4 in at least one analysis. Most importantly, sex-stratified analyses revealed associations with multiple SNPs (28 in males and 16 in females), but no variants from single-sex analyses associated with sepsis in the other sex. Pathway analyses showed NOTCH signaling is over-represented among genes linked to these SNPS. Conclusion Our results indicate genetic susceptibility to LOS is sexually dimorphic and corroborate that NOTCH signaling plays a role in determining risk. Impact Genes associate with late onset neonatal sepsis. Notch pathway genes are overrepresented in associations with sepsis. Genes associating with sepsis do not overlap between males and females. Sexual dimorphism can lead to sex specific treatment of sepsis.

Neonatal early-onset sepsis (EOS) has unfortunately been the third leading cause of neonatal death worldwide. The current study is aimed at discovering reliable biomarkers for the diagnosis of neonatal EOS through transcriptomic analysis of publicly available datasets. Whole blood mRNA expression profiling of neonatal EOS patients in the GSE25504 dataset was downloaded and analyzed. The binomial LASSO model was constructed to select genes that most accurately predicted neonatal EOS. Then, ROC curves were generated to assess the performance of the predictive features in differentiating between neonatal EOS and normal infants. Finally, the miRNA-mRNA network was established to explore the potential biological mechanisms of genes within the model. Four genes (CST7, CD3G, CD247, and ANKRD22) were identified that most accurately predicted neonatal EOS and were subsequently used to construct a diagnostic model. ROC analysis revealed that this diagnostic model performed well in differentiating between neonatal EOS and normal infants in both the GSE25504 dataset and our clinical cohort. Finally, the miRNA-mRNA network consisting of the four genes and potential target miRNAs was constructed. Through bioinformatics analysis, a diagnostic four-gene model that can accurately distinguish neonatal EOS in newborns with bacterial infection was constructed, which can be used as an auxiliary test for diagnosing neonatal EOS with bacterial infection in the future. Conclusion : In the current study, we analyzed gene expression profiles of neonatal EOS patients from public databases to develop a genetic model for predicting sepsis, which could provide insight into early molecular changes and biological mechanisms of neonatal EOS. What is Known: • Infants with suspected EOS usually receive empiric antibiotic therapy directly after birth. • When blood cultures are negative after 48 to 72 hours, empirical antibiotic treatment is often halted. Needless to say, this is not a short time. Additionally, because of the concern for inadequate clinical sepsis production and the limited sensitivity of blood cultures, the duration of antibiotic therapy for the kid is typically extended. What is New: • We established a 4-gene diagnostic model of neonatal EOS with bacterial infection by bioinformatics analysis method. The model has better diagnostic performance compared with conventional inflammatory indicators such as CRP, Hb, NEU%, and PCT.

Background & objectives: Zinc alters gene expression mainly by binding to a site on the transcription factor. Genome-wide expression studies have shown early repression of genes related to zinc and immunity in adult patients with sepsis. The present study was conducted to evaluate the role of zinc supplementation on relative expression of immune response genes in neonatal sepsis. Methods: In the present study, a sample of convenience of 22 neonates each was selected from the zinc supplemented and control groups using random numbers for expression of immune-related genes by zinc supplementation. These neonates with sepsis were earlier randomized into two groups: with and without zinc supplementation in addition to standard antibiotics and supportive care. Relative expression of immune response genes were analyzed for 22 neonates in each group using quantitative real-time PCR for calprotectin (S100A8/A9), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), toll-like receptor-4 (TLR-4), cluster of differentiation 14 (CD14) and lipopolysaccharide-binding protein (LBP) genes. Results: An increase in serum zinc levels was observed in zinc-supplemented group compared to controls. S100A8 gene showed downregulation by three-fold (P <0.001) and S100A9 gene showed upregulation by two-fold (P <0.05) in zinc group compared to controls. CD14 gene showed upregulation by one-fold in zinc-supplemented group compared to controls (P <0.05). No significant fold changes were observed with respect to TNF-α, IL-6, LBP and TLR-4 genes between the two groups. Interpretation & conclusions: The results of our preliminary study showed that the zinc supplementation might modulates the relative expression of immune-related genes involved in sepsis pathway among neonates. However, studies with larger sample size are needed to be done to provide a better picture on the outcome by gene expression in neonatal sepsis by zinc supplementation.

To determine if miRNA (miR) expression in umbilical cord blood and umbilical cord tissue differs between neonates with early onset sepsis (EOS) versus neonates without true infection. Retrospective case-control study design of human patients with EOS (n = 8), presumed sepsis (N = 12) and non-infected control patients (N = 21). Differential expression of >300 miRs was examined using the MIHS-3001ZE-miScript miRNA PCR Array Human miFinder 384HC. Expression levels of miRs were normalized using the global Ct mean of expressed miR and compared between groups. Data analysis was performed using GeneGlobe data analysis software. Ratios of over and under-expressed miRs were calculated and compared between groups using receiver operating characteristic (ROC) curves. Both umbilical cord plasma and umbilical cord tissue revealed several miRs with differential expression with little overlap between the two specimen types. The most overexpressed miR in plasma of EOS patients was miR-211-5p and the most overexpressed in EOS cord tissue was miR-223-5p. ROC curves comparing the ratios of over and under-expressed miRs for EOS patients and controls resulted in an area under the curve of 0.787 for cord plasma (miR-211-5p/miR-142-3p) and 0.988 for umbilical cord tissue (miR-223-5p/miR-22-3p), indicating good discrimination. miRs show differential expression in EOS versus non-infected controls and presumed sepsis. A ratio of over and under-expressed miRs can provide a potentially sensitive and specific diagnostic test for EOS.

Sepsis-associated encephalopathy (SAE), as shown as acute and long-term cognitive impairment, is associated with increased mortality of sepsis. The causative factors of SAE are diverse and the underlying pathological mechanisms of SAE remain to be fully elucidated. Multiple studies have demonstrated a crucial role of microglia in the development of SAE, but the role of neutrophils and neutrophil extracellular traps (NETs) in SAE is still unclear. Here, we firstly show that in murine sepsis model, neutrophils and NETs promote blood-brain barrier (BBB) disruption, neuronal apoptosis and microglia activation in hippocampus and induce hippocampus-dependent memory impairment. Anti-Gr-1 antibody or DNase I treatment attenuates these sepsis-induced changes. Then, we find that genetic deletion of neutrophil GSDMD or PD-L1 reduces NET release and improves SAE in murine sepsis model. Finally, in human septic neutrophils, p-Y705-Stat3 binds to PD-L1, promotes PD-L1 nuclear translocation and enhances transcription of the gasdermin D (GSDMD) gene. In summary, our findings firstly identify a novel function of PD-L1 in maintaining transcriptional activity of p-Y705-Stat3 to promote GSDMD-dependent NET release in septic neutrophils, which plays a critical role in the development of SAE.

Sepsis-associated encephalopathy (SAE) is common in septic patients, characterized by acute and long-term cognitive impairment, and is associated with higher mortality. This study aimed to identify SAE-related biomarkers and evaluate their diagnostic potential. We analyzed three SAE-related sequencing datasets, using two as training sets and one as a validation set. Weighted Gene Co-expression Network Analysis and four machine learning methods—Elastic Net regression, LASSO, random forest, and XGBoost—were employed, dentifying 18 biomarkers with significant expression changes. External validation and in vitro experiments confirmed the differential expression of these biomarkers. These findings provide insights into SAE pathogenesis and suggest potential therapeutic targets.

Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.

Cellular lipid metabolism has been linked to immune responses; however, the precise mechanisms by which de novo fatty acid synthesis can regulate inflammatory responses remain unclear. The NLRP3 inflammasome serves as a platform for caspase-1-dependent maturation and secretion of proinflammatory cytokines. Here, we demonstrated that the mitochondrial uncoupling protein-2 (UCP2) regulates NLRP3-mediated caspase-1 activation through the stimulation of lipid synthesis in macrophages. UCP2-deficient mice displayed improved survival in a mouse model of polymicrobial sepsis. Moreover, UCP2 expression was increased in human sepsis. Consistently, UCP2-deficient mice displayed impaired lipid synthesis and decreased production of IL-1β and IL-18 in response to LPS challenge. In macrophages, UCP2 deficiency suppressed NLRP3-mediated caspase-1 activation and NLRP3 expression associated with inhibition of lipid synthesis. In UCP2-deficient macrophages, inhibition of lipid synthesis resulted from the downregulation of fatty acid synthase (FASN), a key regulator of fatty acid synthesis. FASN inhibition by shRNA and treatment with the chemical inhibitors C75 and cerulenin suppressed NLRP3-mediated caspase-1 activation and inhibited NLRP3 and pro-IL-1β gene expression in macrophages. In conclusion, our results suggest that UCP2 regulates the NLRP3 inflammasome by inducing the lipid synthesis pathway in macrophages. These results identify UCP2 as a potential therapeutic target in inflammatory diseases such as sepsis.

MiRNAs in mesenchymal stem cells (MSCs)-derived exosome (MSCs-exo) play an important role in the treatment of sepsis. We explored the mechanism through which MSCs-exo influences cognitive impairment in sepsis-associated encephalopathy (SAE). Here, we show that miR-140-3p targeted Hmgb1 . MSCs-exo plus miR-140-3p mimic (Exo) and antibiotic imipenem/cilastatin (ABX) improve survival, weight, and cognitive impairment in cecal ligation and puncture (CLP) mice. Exo and ABX inhibit high mobility group box 1 (HMGB1), IBA-1, interleukin (IL)-1β, IL-6, iNOS, TNF-α, p65/p-p65, NLRP3, Caspase 1, and GSDMD-N levels. In addition, Exo upregulates S-lactoylglutathione levels in the hippocampus of CLP mice. Our data further demonstrates that Exo and S-lactoylglutathione increase GSH levels in LPS-induced HMC3 cells and decrease LD and GLO2 levels, inhibiting inflammatory responses and pyroptosis. These findings suggest that MSCs-exo-mediated delivery of miR-140-3p ameliorates cognitive impairment in mice with SAE by HMGB1 and S-lactoylglutathione metabolism, providing potential therapeutic targets for the clinical treatment of SAE. MSCs-exo-mediated delivery of miR-1403p ameliorates cognitive impairment in mice with SAE by HMGB1-related microglial pyroptosis and S-lactoylglutathione metabolism.