Bacteria-derived extracellular vesicles: endogenous roles, therapeutic potentials and their biomimetics for the treatment and prevention of sepsis.

Sepsis is one of the medical conditions with a high mortality rate and lacks specific treatment despite several years of extensive research. Bacterial extracellular vesicles (bEVs) are emerging as a focal target in the pathophysiology and treatment of sepsis. Extracellular vesicles (EVs) derived from pathogenic microorganisms carry pathogenic factors such as carbohydrates, proteins, lipids, nucleic acids, and virulence factors and are regarded as "long-range weapons" to trigger an inflammatory response. In particular, the small size of bEVs can cross the blood-brain and placental barriers that are difficult for pathogens to cross, deliver pathogenic agents to host cells, activate the host immune system, and possibly accelerate the bacterial infection process and subsequent sepsis. Over the years, research into host-derived EVs has increased, leading to breakthroughs in cancer and sepsis treatments. However, related approaches to the role and use of bacterial-derived EVs are still rare in the treatment of sepsis. Herein, this review looked at the dual nature of bEVs in sepsis by highlighting their inherent functions and emphasizing their therapeutic characteristics and potential. Various biomimetics of bEVs for the treatment and prevention of sepsis have also been reviewed. Finally, the latest progress and various obstacles in the clinical application of bEVs have been highlighted.

Single-cell transcriptional gene signature analysis identifies IL-17 signaling pathway as the key pathway in sepsis.

Sepsis is a multiple dysregulated systemic inflammatory response with high mortality and leads to public concern. This study was designed to identify possible critical pathways associated with sepsis clinical severity and outcome, which offer potential biomarkers and therapeutic targets for sepsis diagnosis and treatment. Single-cell transcriptome profiles of human peripheral blood mononuclear (PBMC) in the healthy control population and sepsis patients were downloaded from the sepsis database GSE167363 and performed quality control before subsequent analysis. The bulk-RNA sequencing of blood samples in the sepsis-associated databases GSE100159 and GSE133822 was also used to confirm the association between critical pathways and sepsis pathology after processing raw data. We found there was a total of 18 distinct clusters in PBMC of sepsis, which was identified by the t-SNE and UMAP dimension reduction analysis. Meanwhile, the main cell types including B, NK, T, and monocyte cells were identified via the cell maker website and the "Single R" package cell-type annotation analysis. Subsequently, GO and KEGG enrichment analysis of differential expression genes in each cluster found that DEGs between healthy control and sepsis patients were significantly enriched in the IL-17 signaling pathway in monocyte, NK, and T cells. Finally, GSE100159 and GSE133822 confirmed IL-17 signaling pathway-associated genes including IL-17R, TRAF6, RELB, TRAF5, CEBPB, JUNB, CXCL1, CXCL3, CXCL8, CXCR1, and CXCR2 were significantly up-regulated in sepsis blood samples compared with the age-matched healthy control population. Taken together, we concluded that the IL-17 signaling pathway serves as a significant potential mechanism of sepsis and provides a promising therapeutic target for sepsis treatment. This research will further deepen our understanding of sepsis development.

Classification of subtypes and identification of dysregulated genes in sepsis.

Background: Sepsis is a clinical syndrome with high mortality. Subtype identification in sepsis is meaningful for improving the diagnosis and treatment of patients. The purpose of this research was to identify subtypes of sepsis using RNA-seq datasets and further explore key genes that were deregulated during the development of sepsis. Methods: The datasets GSE95233 and GSE13904 were obtained from the Gene Expression Omnibus database. Differential analysis of the gene expression matrix was performed between sepsis patients and healthy controls. Intersection analysis of differentially expressed genes was applied to identify common differentially expressed genes for enrichment analysis and gene set variation analysis. Obvious differential pathways between sepsis patients and healthy controls were identified, as were developmental stages during sepsis. Then, key dysregulated genes were revealed by short time-series analysis and the least absolute shrinkage and selection operator model. In addition, the MCPcounter package was used to assess infiltrating immunocytes. Finally, the dysregulated genes identified were verified using 69 clinical samples. Results: A total of 898 common differentially expressed genes were obtained, which were chiefly related to increased metabolic responses and decreased immune responses. The two differential pathways (angiogenesis and myc targets v2) were screened on the basis of gene set variation analysis scores. Four subgroups were identified according to median expression of angiogenesis and myc target v2 genes: normal, myc target v2, mixed-quiescent, and angiogenesis. The genes CHPT1, CPEB4, DNAJC3, MAFG, NARF, SNX3, S100A9, S100A12, and METTL9 were recognized as being progressively dysregulated in sepsis. Furthermore, most types of immune cells showed low infiltration in sepsis patients and had a significant correlation with the key genes. Importantly, all nine key genes were highly expressed in sepsis patients. Conclusion: This study revealed novel insight into sepsis subtypes and identified nine dysregulated genes associated with immune status in the development of sepsis. This study provides potential molecular targets for the diagnosis and treatment of sepsis.

[Positive effects of Xuebijing injection on intestinal microbiota and metabolite spectrum in septic rats].

OBJECTIVE: To explore the effect of Xuebijing injection on inflammation in sepsis by regulating intestinal microbiota and its metabolites. METHODS: A total of 45 male Sprague-Dawley (SD) rats were randomly divided into Sham operation group (Sham group), cecal ligation and perforation (CLP) induced sepsis group (CLP group), and Xuebijing intervention group (XBJ group, 4 mL/kg Xuebijing injection was injected intraperitoneally at 1 hour after CLP), with 15 rats in each group. The survival of rats was observed at 24 hours after operation and sacrificed. Feces were collected for 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS) analysis. RESULTS: At 24 hours after operation, all rats in the Sham group survived, the mortality of rats in the XBJ group was lower than that in the CLP group [47% (7/15) vs. 60% (9/15), P > 0.05]. Compared with the Sham group, the diversity of gut microbiota in the CLP group decreased, the dominant flora changed, and the abundance of inflammation-related flora increased. Xuebijing improved the changes in gut microbiota caused by sepsis, and α diversity showed an increasing trend (Ace index: 406.0±22.5 vs. 363.2±38.2, Chao1 index: 409.7±21.8 vs. 362.4±42.5, both P > 0.05). Restrictive constrained principal coordinate analysis (cPCoA) showed a high similarity in gut microbiota among the same group of rats. The CLP group was dominated by Bacteroidetes, while the Sham and XBJ groups were dominated by Firmicutes. In addition, compared with the CLP group, Xuebijing treatment increased the abundance of beneficial bacteria in septic rats, such as Verrucomicrobia, Akkermansia and Lactobacillus. LC-MS and orthogonal partial least squares discriminant analysis (OPLS-DA) showed that there were 12 main differential metabolites among the three groups, and there were certain correlations between these metabolites, which were related to amino acid and lipid metabolism. Correlation analysis showed a significant correlation between changes in metabolites and microbial communities. CONCLUSIONS: Xuebijing can improve the survival rate of septic rats, regulate the composition of intestinal flora and related metabolites, which provides a new pathophysiological mechanism for Xuebijing in the treatment of sepsis.

Review on Progress of Lamellar Orientation Control in Directionally Solidified TiAl Alloys.

TiAl alloys have excellent high-temperature performance and are potentially used in the aerospace industry. By controlling the lamellar orientation through directional solidification (DS) technology, the plasticity and strength of TiAl alloy at room temperature and high temperatures can be effectively improved. However, various difficulties lie in ensuring the lamellar orientation is parallel to the growth direction. This paper reviews two fundamental thoughts for lamellar orientation control: using seed crystals and controlling the solidification path. Multiple specific methods and their progress are introduced, including α seed crystal method, the self-seeding method, the double DS self-seeding method, the quasi-seeding method, the pure metal seeding method, and controlling solidification parameters. The advantages and disadvantages of different methods are analyzed. This paper also introduces novel ways of controlling the lamellar orientation and discusses future development.

A purified membrane protein from Akkermansia muciniphila blunted the sepsis-induced acute lung injury by modulation of gut microbiota in rats.

The gut microbiota has been implicated in the pathogenesis and progression of sepsis. Akkermansia muciniphila is considered to be a promising probiotic with reduced abundance in cecal ligation and puncture (CLP)-induced sepsis model, and its specific outer membrane protein (Amuc_1100) can partially recapitulate the probiotic function of Akkermansia muciniphila. However, its role in sepsis is unclear. This study aimed to investigate the effect of Amuc_1100 on the gut microbiota of septic rats, thereby improving the prognosis of septic acute lung injury (ALI). A total of 42 adult Sprague-Dawley (SD) rats were randomly divided into three groups: the sham control (SC group), the septic ALI induced by CLP method (CLP group), and administered Amuc_1100 by oral gavage (3 µg/d) for 7 d before the CLP procedure (AMUC group). The survival of the three groups was recorded and the feces and lung tissues of rats were collected 24 h after treatment for 16S rRNA sequencing and histopathological evaluation. Oral administration of Amuc_1100 improved the survival rate and alleviated lung histopathological damage induced by sepsis. Serum levels of pro-inflammatory cytokines and chemokines were substantially attenuated. Amuc_1100 significantly increased the abundance of some beneficial bacteria in septic rats. Additionally, the Firmicutes/Bacteroidetes ratio was low in septic rats, which was partially corrected by increasing Firmicutes and decreasing Bacteroidetes after oral administration of Amuc_1100 (p < 0.05). In addition, Escherichia-Shigella, Bacteroides, and Parabacteroides were relatively enriched in septic rats, while in the AMUC group, their abundance was restored to levels similar to that of the healthy group. Amuc_1100 protects against sepsis by enhancing beneficial bacteria and reducing potential pathogenic bacteria. These findings indicate that Amuc_1100 can blunt CLP-induced ALI through the modulation of gut microbiota, thereby providing a new promising therapeutic target in sepsis.

[Efficacy and safety of sivelestat sodium in patients with sepsis].

OBJECTIVE: To investigate the efficacy and safety of sivelestat sodium in patients with sepsis. METHODS: The clinical data of 141 adult patients with sepsis admitted to the intensive care unit (ICU) of the First Affiliated Hospital of Zhengzhou University from January 1, 2019 to January 1, 2022 were retrospectively analyzed. The patients were divided into the sivelestat sodium group (n = 70) and the control group (n = 71) according to whether they received sivelestat sodium or not. The efficacy indexes included oxygenation index, procalcitonin (PCT), C-reactive protein (CRP), white blood count (WBC), sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation II (APACHE II) before and after 7 days of treatment, as well as ventilator supporting time, the length of ICU stay, the length of hospital stay and ICU mortality. The safety indicators included platelet count (PLT) and liver and kidney function. RESULTS: There were no significant differences in age, gender, underlying diseases, infection site, basic drugs, etiology, oxygenation index, biochemical indexes, SOFA and APACHE II scores between the two groups. Compared with the control group, the oxygenation index in 7 days was significantly increased [mmHg (1 mmHg ≈ 0.133 kPa): 233.5 (181.0, 278.0) vs. 202.0 (153.0, 243.0), P < 0.01], the levels of PCT, CRP, alanine aminotransferase (ALT) and APACHE II score were significantly decreased in the sivelestat sodium group [PCT (µg/L): 0.87 (0.41, 1.61) vs. 1.53 (0.56, 5.33), CRP (mg/L): 64.12 (19.61, 150.86) vs. 107.20 (50.30, 173.00), ALT (U/L): 25.0 (15.0, 43.0) vs. 31.0 (20.0, 65.0), APACHE II: 14 (11, 18) vs. 16 (13, 21), all P < 0.05]. However, there were no significant differences in SOFA, WBC, serum creatinine (SCr), PLT, total bilirubin (TBil), aspartate aminotransferase (AST) in 7 days between the sivelestat sodium group and the control group [SOFA: 6.5 (5.0, 10.0) vs. 7.0 (5.0, 10.0), WBC (×109/L): 10.5 (8.2, 14.7) vs. 10.5 (7.2, 15.2), SCr (µmol/L): 76.0 (50.0, 124.1) vs. 84.0 (59.0, 129.0), PLT (×109/L): 127.5 (59.8, 212.3) vs. 121.0 (55.0, 211.0), TBil (µmol/L): 16.8 (10.0, 32.1) vs. 16.6 (8.4, 26.9), AST (U/L): 31.5 (22.0, 62.3) vs. 37.0 (24.0, 63.0), all P > 0.05]. The ventilator supporting time and the length of ICU stay in the sivelestat sodium group were significantly shorter than those in control group [ventilator supporting time (hours): 147.50 (86.83, 220.00) vs. 182.00 (100.00, 360.00), the length of ICU stay (days): 12.5 (9.0, 18.3) vs. 16.0 (11.0, 23.0), both P < 0.05]. However, there were no significant differences in the length of hospital stay and ICU mortality between the sivelestat sodium group and the control group [the length of hospital stay (days): 20.0 (11.0, 27.3) vs. 13.0 (11.0, 21.0), ICU mortality: 17.1% (12/70) vs. 14.1% (10/71), both P > 0.05]. CONCLUSIONS: Sivelestat sodium is safe and effective in patients with sepsis. It can improve the oxygenation index and APACHE II score, reduce the levels of PCT and CRP, shorten ventilator supporting time and the length of ICU stay. No adverse reactions such as liver and kidney function injury and platelet abnormality are observed.

Diagnostic value of metagenomic next-generation sequencing in sepsis and bloodstream infection.

Objective: To evaluate the diagnostic value of metagenomic next-generation sequencing (mNGS) in sepsis and bloodstream infection (BSI). Methods: A retrospective analysis of patients diagnosed with sepsis and BSI at the First Affiliated Hospital of Zhengzhou University from January 2020 to February 2022 was conducted. All the patients underwent blood culture and were divided into mNGS group and non-mNGS group according to whether mNGS was performed or not. The mNGS group was further divided into early group (< 1 day), intermediate group (1-3 days), and late group (> 3 days) according to the time of mNGS inspection. Results: In 194 patients with sepsis and BSI, the positive rate of mNGS for identifying pathogens was significantly higher than that of blood culture (77.7% vs. 47.9%), and the detection period was shorter (1.41 ± 1.01 days vs. 4.82 ± 0.73 days); the difference was statistically significant (p < 0.05). The 28-day mortality rate of the mNGS group (n = 112) was significantly lower than that of the non-mNGS group (n = 82) (47.32% vs. 62.20%, p = 0.043). The total hospitalization time for the mNGS group was longer than that for the non-mNGS group (18 (9, 33) days vs. 13 (6, 23) days, p = 0.005). There was no significant difference in the ICU hospitalization time, mechanical ventilation time, vasoactive drug use time, and 90-day mortality between the two groups (p > 0.05). Sub-group analysis of patients in the mNGS group showed that the total hospitalization time and the ICU hospitalization time in the late group were longer than those in the early group (30 (18, 43) days vs. 10 (6, 26) days, 17 (6, 31) days vs. 6 (2, 10) days), and the ICU hospitalization time in the intermediate group was longer than that in the early group (6 (3, 15) days vs. 6 (2, 10) days); the differences were statistically significant (p < 0.05). The 28-day mortality rate of the early group was higher than that of the late group (70.21% vs. 30.00%), and the difference was statistically significant (p = 0.001). Conclusions: mNGS has the advantages of a short detection period and a high positive rate in the diagnosis of pathogens causing BSI and, eventually, sepsis. Routine blood culture combined with mNGS can significantly reduce the mortality of septic patients with BSI. Early detection using mNGS can shorten the total hospitalization time and the ICU hospitalization time of patients with sepsis and BSI.

Effects of Gabexate Mesylate on the Gut Microbiota and Metabolomics in Rats with Sepsis.

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. However, there is still no single drug that could reduce septic mortality. Previous studies have reported gabexate mesylate (GM) significantly reduced serum inflammatory factors, alleviated sepsis-induced lung injury and improved clinical outcomes. This study aimed to combine with microbiome sequencing and metabolomics analysis to explore the effects of GM administration in septic rats. Methods: Sixty SD rats were randomly divided into the sham control (SC), cecal ligation and puncture (CLP), and GM injection (GM) groups. The mortality was measured and colonic feces were collected to examine the gut microbiota and metabolism 24 h after the procedure. The lung tissues were collected for hematoxylin-eosin staining. Results: We observed the relative abundance of Pygmaiobacter, which contributed to short-chain fatty acids (SCFAs) promotion, Lactobacillus and Erysipelotrichaceae UCG-003 increased in the GM-treated rats, while Escherichia-Shigella and Akkermansia decreased compared to the sepsis-induced lung injury group. Furthermore, these 3 metabolites including Palmitoylethanolamide, Deoxycholic acid and Chenodeoxycholic acid correlated significantly to CLP- and GM-rich genus (P < 0.05). Besides, the lung tissues of CLP group showed more severe inflammatory infiltration and edema, and the mortality rate in the CLP group (10/20) was significantly higher than in the SC group (0/20) (P < 0.001) and GM group (4/20) (P < 0.05). Conclusion: Our findings showed that GM attenuated sepsis-induced lung injury rats and regulated metabolites related to gut microbiota, which may provide an effective treatment for sepsis patients.

Surface Condition Evolution and Fatigue Evaluation after Different Surface Processes for TiAl47Cr2Nb2 Alloy.

The TiAl47Cr2Nb2 alloy fatigue specimens were prepared by investment casting, and three kinds of surface processes were applied to fatigue specimens. These three processes were sand-blasting (SB), sand-blasting and shot-peening (SBSP) and sand-blasting and mechanical grinding (SBMG). The surface condition evolutions before and after thermal exposure at 700 °C for 24 h were investigated. The fatigue performances of specimens after thermal exposure were evaluated. The results show that the surface roughness Ra after SB, SBSP and SBMG processes were 3.14, 2.35 and 0.04 µm, respectively. After thermal exposure, they almost remained unchanged for all three processes. The SB process caused work hardening in the near-surface region and the work hardening reached saturation after the SB process. Due to the mechanical grinding (MG) process removing the uncertain thick hardening layer, the maximum hardness after SBMG process was noticeably lower than those after SB and SBSP processes. After thermal exposure, the maximum hardness after SB, SBSP and SBMG processes significantly recovered. The SBMG specimens had the highest fatigue limit of 350 MPa. This is attributed to the SBMG specimens having very smooth surfaces and some work hardening remaining near their surface layers.

FABP6 Expression Correlates with Immune Infiltration and Immunogenicity in Colorectal Cancer Cells.

Background: Immune checkpoint inhibitors (ICIs) have rapidly revolutionized colorectal cancer (CRC) treatment, but resistance caused by the heterogeneous tumor microenvironment (TME) still presents a challenge. Therefore, it is necessary to characterize TME immune infiltration and explore new targets to improve immunotherapy. Methods: The compositions of 64 types of infiltrating immune cells and their relationships with CRC patient clinical characteristics were assessed. Differentially expressed genes (DEGs) between "hot" and "cold" tumors were used for functional analysis. A prediction model was constructed to explore the survival of CRC patients treated with and without immunotherapy. Finally, fatty acid-binding protein (FABP6) was selected for in vitro experiments, which revealed its roles in the proliferation, apoptosis, migration, and immunogenicity of CRC tissues and cell lines. Results: The infiltration levels of several immune cells were associated with CRC tumor stage and prognosis. Different cell types showed the synergistic or antagonism infiltration patterns. Enrichment analysis of DEGs revealed that immune-related signaling was significantly activated in hot tumors, while metabolic process pathways were altered in cold tumors. In addition, the constructed model effectively predicted the survival of CRC patients treated with and without immunotherapy. FABP6 knockdown did not significantly alter tumor cell proliferation, apoptosis, and migration. FABP6 was negatively correlated with immune infiltration, and knockdown of FABP6 increased major histocompatibility complex (MHC) class 1 expression and promoted immune-related chemokine secretion, indicating the immunogenicity enhancement of tumor cells. Finally, knockdown of FABP6 could promote the recruitment of CD8+ T cells. Conclusion: Collectively, we described the landscape of immune infiltration in CRC and identified FABP6 as a potential immunotherapeutic target for treatment.

Identification of metabolomics-based prognostic prediction models for ICU septic patients.

Sepsis-related global mortality remains unacceptably high in intensive care units. Identifying the various molecular processes between survival and death in septic patients may assist in better treatment. Accurate prognostic evaluation of sepsis is an essentially unmet need. This study analyzed the metabolite changes in plasma between healthy controls and septic patients, as well as between survival and dead septic patients using liquid chromatography/mass spectrometry. Univariate and multivariate analyses were applied to identify differential metabolites. The differential metabolites and clinical indicators within 24 h after sepsis diagnosis were run through multivariate logistic regression models to determine the 28-day, hospital, and 90-day septic mortality prediction models. The results suggested markedly changed amino acids metabolism in septic patients compared to healthy controls; 10, 4, and 22 primary differential metabolites related to amino acid and fatty acid metabolisms were identified in the survival and death groups at 28-day, hospital, and 90-day, respectively. Further, we found that model 1 (indoleacetic acid, 3-methylene-indolenine, heart rate, respiratory support, and application of pressure drugs), model 2 (lymphocyte count, alkaline phosphatase, SOFA, and L-alpha-amino-1H-pyrrole-1-hexanoic acid), and model 3 (dopamine, delta-12-prostaglandin J2, heart rate, respiratory support, and application of pressure drugs) could predict 28-day, hospital, and 90-day mortality of sepsis with a sensitivity of 75.51%, 73.58%, and 83.33%, specificity of 78.72%, 72.09%, and 78.57%, and the area under the receiver operating characteristic curve of 0.881, 0.830, 0.886, respectively. Thus, this research presents three multiple-biomarker-based prognostic models for 28-day, hospital, and 90-day mortality septic patients and could be used to guide sepsis treatment.

Metformin Improves the Prognosis of Adult Mice with Sepsis-Associated Encephalopathy Better than That of Aged Mice.

Sepsis-associated encephalopathy (SAE) is often associated with increased ICU occupancy and hospital mortality and poor long-term outcomes, with currently no specific treatment. Pathophysiological mechanisms of SAE are complex and may involve activation of microglia, multiple intracranial inflammatory factors, and inflammatory pathways. We hypothesized that metformin may have an effect on microglia, which affects the prognosis of SAE. In this study, metformin treatment of mice with SAE induced by lipopolysaccharide (LPS) reduced the expression of microglia protein and related inflammatory factors. Poor prognosis of SAE is related to increased expression of tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1ß) in brain tissues. Levels of inflammatory cytokines produced by LPS-induced SAE mouse microglia were significantly increased compared with those in the sham group. In addition, ionized calcium-binding adapter molecule 1 (Iba-1) was significantly reduced in metformin-treated SAE mice compared with untreated SAE mice, suggesting that metformin can reduce microgliosis and inhibit central nervous system inflammation, thereby improving patient outcomes. In conclusion, our results stipulate that metformin inhibits inflammation through the adenosine 5'-monophosphate (AMP-) activated protein kinase pathway by inhibiting nuclear factor kappa beta (NF-κB). Metformin can partially reverse the severe prognosis caused by sepsis by blocking microglial proliferation and inhibiting the production of inflammatory factors.

Metformin Mitigates Sepsis-Related Neuroinflammation via Modulating Gut Microbiota and Metabolites.

Gut microbiota affects the functions of brains. However, its mechanism in sepsis remains unclear. This study evaluated the effect of metformin on ameliorating sepsis-related neurodamage by regulating gut microbiota and metabolites in septic rats. Cecal ligation and puncture (CLP) was used to establish the sepsis-related neurodamage animal models. Metformin therapy by gavage at 1 h after CLP administration was followed by fecal microbiota transplantation (FMT) to ensure the efficacy and safety of metformin on the sepsis-related neurodamage by regulating gut microbiota. The gut microbiota and metabolites were conducted by 16S rRNA sequencing and liquid chromatography-tandem mass spectrometry metabolomic analysis. The brain tissue inflammation response was analyzed by histopathology and reverse transcription-polymerase chain reaction (RT-PCR). This study reported brain inflammatory response, hemorrhage in sepsis-related neurodamage rats compared with the control group (C group). Surprisingly, the abundance of gut microbiota slightly increased in sepsis-related neurodamage rats than C group. The ratio of Firmicutes/Bacteroidetes was significantly increased in the CLP group than the C group. However, no difference was observed between the CLP and the metformin-treated rats (MET group). Interestingly, the abundance of Escherichia_Shigella increased in the MET group than the C and CLP groups, while Lactobacillaceae abundance decreased. Furthermore, Prevotella_9, Muribaculaceae, and Alloprevotella related to short-chain fatty acids production increased in the sepsis-related neurodamage of metformin-treated rats. Additionally, Prevotella_9 and Muribaculaceae correlated positively to 29 metabolites that might affect the inflammatory factors in the brain. The FMT assay showed that metformin improved sepsis-related neurodamage by regulating the gut microbiota and metabolites in septic rats. The findings suggest that metformin improves the sepsis-related neurodamage through modulating the gut microbiota and metabolites in septic rats, which may be an effective therapy for patients with sepsis-related neurodamage.

Identification of Prognostic Factors in Patients With Streptococcus Bloodstream Infection.

Aim: The purpose of this study was to explore prognostic factors of bloodstream infections (BSIs), a common severe infection and a major cause of mortality worldwide, so as to construct a prognosis model of patients with BSI. Materials and Methods: Clinical and biochemical test data were obtained retrospectively from the medical records of 562 patients with BSI who had been treated at a single center; the end point was 60 days of all-cause death. The chi-square test was used to compare the mortality of patients grouped by the types of antibiotic treatment. The logistic regression analysis was adopted to identify prognostic factors; the Kaplan-Meier survival curve and log-rank test were conducted to compare the survival rate of patients with different prognostic factors; the receiver operating characteristic (ROC) curve was used to estimate the predictive value of different prognostic factors. Results: Of the 562 patients, 455 survived (80.96%), and 107 died (19.04%). The mortality rate of patients treated with a combination of antibiotics (25.40%) was higher than that treated with a single antibiotic (15.82%). Univariate analysis identified 19 prognostic factors for patients with BSI, including gender, age, diabetes, malignant tumor (non-blood system), total hospitalization time, alanine aminotransferase, aspartate aminotransferase, total protein, albumin, total bilirubin, direct bilirubin, creatinine, ratio of granulocytes, fibrinogen, D-dimer, platelet, C-reactive protein, shock, and respiratory failure (P < 0.05). Multivariate analysis indicated that albumin (odds ratio [OR] = 0.94, 95% confidence interval [CI]: 0.89-0.99), fibrinogen (OR = 0.61, 95%CI: 0.46-0.82), shock (OR = 16.61, 95%CI: 7.00-39.41), and respiratory failure (OR = 47.53, 95%CI: 19.93-133.64) were independent factors. The combination of four indicators demonstrated a favorable predictive value for the 60-day outcome of patients with BSI, with an area under the ROC of 0.96 (95%CI: 0.94-0.99), sensitivity of 90.65%, specificity of 94.95%, and accuracy of 94.13%. Conclusions: Shock, respiratory failure, albumin, and fibrinogen are potential independent prognostic factors for 60-day mortality.

[The relationship between the lipid profiles and inflammation in patients with sepsis].

OBJECTIVE: To explore the relationship between the changes in the lipid profiles and the intensity of inflammatory response and disease severity in patients with sepsis, in order to find a biomarker that can quickly evaluate the condition and prognosis of sepsis. METHODS: A retrospective analysis was performed on 449 patients with sepsis admitted to department of critical care medicine of the First Affiliated Hospital of Zhengzhou University from October 2019 to May 2021, and 355 patients without sepsis hospitalized in the same period served as the control. The general demographic data, blood lipid and other clinical indicators within 24 hours after admission were collected and compared between the two groups. Bivariate correlation study was used to analyze the relationship between blood lipid levels and inflammation indicators and severity of illness in patients with sepsis. The receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive value of each blood lipid component on the 28-day mortality of patients with sepsis. According to the results of ROC curve analysis, the blood lipids were divided into two groups with different levels, and the Kaplan-Meier survival curve was used to compare the cumulative survival rates of the two groups without end-point event (the 28-day mortality was the end-point event). RESULTS: Compared with non-septic patients, the levels of plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were significantly lower in patients with sepsis [TC (mmol/L): 2.93±1.33 vs. 4.01±1.14, HDL-C (mmol/L): 0.78±0.47 vs. 1.16±0.40, LDL-C (mmol/L): 1.53±1.00 vs. 2.71±0.98, all P < 0.05]. In patients with sepsis, plasma cholesterol levels were correlated with the degree of inflammation and severity of the disease to varying degrees, but the HDL-C had the strongest correlation with interleukin-6 (IL-6; r = -0.551, P = 0.000), procalcitonin (PCT, r = -0.598, P = 0.000), sequential organ failure assessment (SOFA; r = -0.285, P = 0.000). The ROC curve analysis showed that among all blood lipid components, HDL-C had the highest predictive value for 28-day mortality of sepsis patients, and the area under the ROC curve (AUC) was 0.718, when the best cut-off value was 0.69 mmol/L, the sensitivity and specificity were 67.3% and 65.2% respectively, and the positive predictive value and negative predictive value were 60.6% and 71.5% respectively. According to Kaplan-Meier survival curve analysis, the mortality of sepsis patients with HDL-C ≤ 0.69 mmol/L was significantly higher than the patients with HDL-C > 0.69 mmol/L, and the difference was statistically significant (P < 0.000 1). In addition, the 28-day mortality [59.73% (135/226) vs. 28.70% (64/223)], the incidence of multiple organ dysfunction [41.15% (93/226) vs. 31.84% (71/223)], the probability of requiring mechanical ventilation and vasoactive drugs [mechanical ventilation: 56.64% (128/226) vs. 46.18% (103/223); vasoactive drugs: 54.42% (123/226) vs. 38.57% (86/223)], the positive rate of microbial culture [45.58% (103/226) vs. 35.43% (79/223)], and the probability of drug-resistant bacteria [19.91% (45/226) vs. 10.31% (23/223)] in the low HDL-C group of sepsis patients were all higher than the high HDL-C group, the differences were statistically significant (all P < 0.05). CONCLUSIONS: Plasma cholesterol levels, especially the HDL-C levels, can well reflect the intensity of inflammation and the severity of the disease in patients with sepsis. And the HDL-C levels can be used as a good biomarker for predicting the short-term prognosis of sepsis.

Positive Effects of Neutrophil Elastase Inhibitor (Sivelestat) on Gut Microbiome and Metabolite Profiles of Septic Rats.

Background: Neutrophil elastase (NE) is associated with sepsis occurrence and progression. We hypothesized that the NE inhibitor Sivelestat might modulate abnormal gut microbiota and metabolites during sepsis. Methods: Sixty Sprague-Dawley (SD) rats were randomly divided into sham control (SC), sepsis (CLP), and sepsis+Sivelestat (Sive) groups. The rats' survival status was monitored for 24 hours postoperatively, and feces were collected for microbiome and non-targeted metabolomics analyses. Results: Sivelestat administration significantly improved the survival of septic rats (80% vs 50%, P = 0.047). Microbiome analysis showed that the microbiota composition of rats in the CLP group was significantly disturbed, as potential pathogens such as Escherichia-Shigella and Gammaproteobacteria became dominant, and the beneficial microbiota represented by Lactobacillus decreased. These changes were reversed in Sive group, and the overall microbial status was restored to a similar composition to SC group. Differential analysis identified 36 differential operational taxonomic units and 11 metabolites between the Sive and CLP groups, such as 6-Aminopenicillanic acid, gamma-Glutamyl-leucine, and cortisone (variable importance in projection>1and P<0.05). These discriminatory metabolites were highly correlated with each other and mainly involved in the phenylalanine, tyrosine, and tryptophan biosynthesis pathways. Integrated microbiome and metabolome analyses found that almost all Sivelestat-modulated microbes were associated with differential metabolites (P < 0.05), such as Lactobacillus and some amino acids, suggesting that the Sivelestat-induced metabolic profile differences were in part due to its influence on the gut microbiome. Conclusion: Sivelestat administration in septic rats improved survival, gut microbiota composition and associated metabolites, which could provide new options for sepsis treatment.