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Increased evidence shows that gut microbiota acts as the primary regulator of the liver; however, its role in sepsis-related liver injury (SLI) in the elderly is unclear. This study assessed whether metformin could attenuate SLI by modulating gut microbiota in septic-aged rats. Cecal ligation and puncture (CLP) was used to induce SLI in aged rats. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in these pathologies. The composition of gut microbiota was analysed by 16S rRNA sequencing. Moreover, the liver and colon tissues were analysed by histopathology, immunofluorescence, immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR). Metformin improved liver damage, colon barrier dysfunction in aged SLI rats. Moreover, metformin improved sepsis-induced liver inflammation and damage under gut microbiota. Importantly, FMT assay showed that rats gavaged with faeces from metformin-treated SLI rats displayed less severe liver damage and colon barrier dysfunctions than those gavaged with faeces from SLI rats. The gut microbiota composition among the sham-operated, CLP-operated and metformin-treated SLI rats was different. In particular, the proportion of Klebsiella and Escherichia_Shigella was higher in SLI rats than sham-operated and metformin-treated SLI rats; while metformin could increase the proportion of Bifidobacterium, Muribaculaceae, Parabacteroides_distasonis and Alloprevitella in aged SLI rats. Additionally, Klebsiella and Escherichia_Shigella correlated positively with the inflammatory factors in the liver. Our findings suggest that metformin may improve liver injury by regulating the gut microbiota and alleviating colon barrier dysfunction in septic-aged rats, which may be an effective therapy for SLI.

Background Recent studies have reported that preadmission metformin users had lower mortality than non-metformin users in patients with sepsis and diabetes mellitus; however, these results are still controversial. Therefore, we conducted a systematic review and meta-analysis of published observational cohort data to determine the association between preadmission metformin use and mortality in septic adult patients with diabetes mellitus. Methods The MEDLINE, EMBASE, and Cochrane CENTRAL databases were searched from their inception to September 30, 2018. Cohort studies that evaluated the use of metformin in septic adult patients with diabetes mellitus were included. The quality of outcomes was evaluated using the Newcastle-Ottawa Scale (NOS). The inverse variance method with random effects modelling was used to calculate the pooled odds ratios (ORs) and 95% CIs. Results Five observational cohort studies (1282 patients) that were all judged as having a low risk of bias were included. In this meta-analysis, metformin use was associated with a significantly lower mortality rate (OR, 0.59; 95% CI, 0.43–0.79, P  = 0.001). Conclusions This meta-analysis indicated an association between metformin use prior to admission and lower mortality in septic adult patients with diabetes mellitus. This finding suggested that the possible effect of metformin should be evaluated in future clinical trials.

Background We hypothesized that adipose-derived mesenchymal stem cells (ADMSCs) may ameliorate sepsis-induced acute lung injury (ALI) and change microorganism populations in the gut microbiota, such as that of Firmicutes and Bacteroidetes. Methods A total of 60 male adult Sprague-Dawley (SD) rats were separated into three groups: the sham control (SC) group, the sepsis induced by cecal ligation and puncture (CLP) group, and the ADMSC treatment (CLP-ADMSCs) group, in which rats underwent the CLP procedure and then received 1 × 10 6 ADMSCs. Rats were sacrificed 24 h after the SC or CLP procedures. To study the role of ADMSCs during ALI caused by sepsis and examine the impact of ADMSCs on the gut microbiome composition, rat lungs were histologically evaluated using hematoxylin and eosin (H&E) staining, serum levels of pro-inflammatory factors were detected using enzyme-linked immunosorbent assay (ELISA), and fecal samples were collected and analyzed using 16S rDNA sequencing. Results The serum levels of inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-6, were significantly increased in rats after the CLP procedure, but were significantly decreased in rats treated with ADMSCs. Histological evaluation of the rat lungs yielded results consistent with the changes in IL-6 levels among all groups. Treatment with ADMSCs significantly increased the diversity of the gut microbiota in rats with sepsis. The principal coordinates analysis (PCoA) results showed that there was a significant difference between the gut microbiota of the CLP-ADMSCs group and that of the CLP group. In rats with sepsis, the proportion of Escherichia – Shigella ( P  = 0.01) related to lipopolysaccharide production increased, and the proportion of Akkermansia ( P  = 0.02) related to the regulation of intestinal mucosal thickness and the maintenance of intestinal barrier function decreased. These changes in the gut microbiota break the energy balance, aggravate inflammatory reactions, reduce intestinal barrier functions, and promote the translocation of intestinal bacteria. Intervention with ADMSCs increased the proportion of beneficial bacteria, reduced the proportion of harmful bacteria, and normalized the gut microbiota. Conclusions Therapeutically administered ADMSCs ameliorate CLP-induced ALI and improves gut microbiota, which provides a potential therapeutic mechanism for ADMSCs in the treatment of sepsis.

Corticosteroids are a common option used in sepsis treatment. However, the efficacy and potential risk of corticosteroids in septic patients have not been well assessed. This review was performed to assess the efficacy and safety of corticosteroids in patients with sepsis. PubMed, Embase, and Cochrane library databases were searched from inception to March 2021. Randomized controlled trials (RCTs) that evaluated the effect of corticosteroids on patients with sepsis were included. The quality of outcomes in the included articles was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation methodology. The data were pooled by using risk ratio (RR) and mean difference (MD). The random-effects model was used to evaluate the pooled MD or RR and 95% confidence intervals (CIs). Fifty RCTs that included 12,304 patients with sepsis were identified. Corticosteroids were not associated with the mortality in 28-day (RR, 0.94; 95% CI, 0.87-1.02; evidence rank, moderate) and long-term mortality (>60 days) (RR, 0.96; 95% CI, 0.88-1.05) in patients with sepsis (evidence rank, low). However, corticosteroids may exert a significant effect on the mortality in the intensive care unit (ICU) (RR, 0.9; 95% CI, 0.83-0.97), in-hospital (RR, 0.9; 95% CI, 0.82-0.99; evidence rank, moderate) in patients with sepsis or septic shock (evidence rank, low). Furthermore, corticosteroids probably achieved a tiny reduction in the length of hospital stay and ICU. Corticosteroids were associated with a higher risk of hypernatremia and hyperglycemia; furthermore, they appear to have no significant effect on superinfection and gastroduodenal bleeding. Corticosteroids had no significant effect on the 28-day and long-term mortality; however, they decreased the ICU and hospital mortality. The findings suggest that the clinical corticosteroids may be an effective therapy for patients with sepsis during the short time. https://inplasy.com/wp-content/uploads/2021/05/INPLASY-Protocol-1074-4.pdf.

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-1β) 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.

The aim of this study was to summarize the existing evidence about the effectiveness of double defibrillation (DD) in comparison to standard defibrillation for patients with refractory ventricular fibrillation (RVF). DD encompasses double “sequential” external defibrillation (DSeq-D) and double “simultaneous” defibrillation (DSim-D), with the study also shedding light on the respective effects of DSeq-D and DSim-D. Investigators systematically searched PubMed, EMBASE and Cochrane Central databases for randomized controlled trials (RCTs) and cohort studies from their inception until June 06, 2024. The rate of survival to hospital discharge was the primary outcome, while the incidence of return of spontaneous circulation (ROSC), termination of ventricular fibrillation (VF), survival to hospital admission and good neurologic outcome were secondary outcomes. Relative ratios (RR) and 95% confidence intervals (CIs) were calculated for each outcome. Heterogeneity was assessed using I square value. A total of 6 trials, comprising 1360 patients, were included. One was an RCT, and five were observational cohort studies. The RCT showed that, compared to standard defibrillation, DSeq-D was associated with higher incidences of survival to hospital discharge, termination of VF, ROSC and good neurologic outcome. However, the pooled results of cohort studies found no benefit of DD over standard defibrillation in survival to hospital discharge (RR, 0.91; 95% CI, 0.46–1.78), nor in secondary outcomes. Furthermore, subgroup analysis suggested DSim-D was linked with lower ROSC rate compared to standard defibrillation (RR, 0.65; 95% CI, 0.49–0.86), while there was no significance between DSeq-D and standard defibrillation (RR, 1.00; 95% CI, 0.70–1.42). The benefit of DSeq-D in survival to hospital discharge for RVF patients was found in the RCT, but not in cohort studies. Additionally, DSim-D should be applied with greater caution for RVF patients. Further validation is needed through larger-scale and higher-quality trials. INPLASY; Registration number: INPLASY202340015; URL: https://inplasy.com/

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. 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. Sivelestat administration significantly improved the survival of septic rats (80% vs 50%, = 0.047). Microbiome analysis showed that the microbiota composition of rats in the CLP group was significantly disturbed, as potential pathogens such as and became dominant, and the beneficial microbiota represented by 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 <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 ( < 0.05), such as s and some amino acids, suggesting that the Sivelestat-induced metabolic profile differences were in part due to its influence on the gut microbiome. Sivelestat administration in septic rats improved survival, gut microbiota composition and associated metabolites, which could provide new options for sepsis treatment.

Recent studies have shown that prior antiplatelet drug use could ameliorate the risk and mortality of acute respiratory distress syndrome (ARDS). However, the connection between prior acetylsalicylic acid (aspirin) use and the risk of ARDS is unknown. Our primary objective was to perform a meta-analysis on the currently available studies to assess the association between aspirin use prior to ARDS onset and ARDS incidence in at-risk patients. Two investigators separately searched four research databases: MEDLINE, EMBASE, Cochrane Library, and Web of Science for relevant articles from the earliest available data through to July 14, 2019. In this paper, we performed a meta-analysis of the fixed effects model using the inverse variance-weighted average method to calculate the pooled odds ratios (ORs) and 95% confidence intervals (CIs). The primary outcome was risk of ARDS, and the secondary outcome was the hospital mortality of at-risk patients. This article included seven studies altogether, enrolling 6,764 at-risk patients. Our meta-analysis revealed that, compared to non-aspirin use, prior aspirin use was linked with a significantly lower incidence of ARDS in at-risk patients (OR, 0.78; 95% CI, 0.64-0.96; = 0.018) with low statistical heterogeneity ( = 1.7%). Additionally, difference between prior aspirin use and non-aspirin use was not remarkable for hospital mortality in at-risk patients (OR, 0.88; 95% CI, 0.73-1.07; = 0.204), and this analysis did not involve statistical heterogeneity ( = 0%). This article indicates an association between prior aspirin use and a lower incidence of ARDS in at-risk patients, suggesting that aspirin use could potentially lower the risk of ARDS, and the investigation of such an effect is an interesting area for future clinical studies.

Given the high mortality associated with sepsis, there is an urgent need for a full understanding of sepsis pathophysiology and finding new therapeutic regimens. Adipose-derived mesenchymal stem cells (ADMSCs) has been proven to have anti-inflammatory effects and could be used to treat cecal ligation and puncture (CLP) induced lung and liver injury in septic rat models. In this study, we used metabolomics to investigate small molecule metabolites between CLP and ADMSCs treatment groups. Sixty SD rats were randomly assigned to the sham operation group (SC group), the CLP group, and the CLP+ADMSCs group (CLP-ADMSCs group). We used liquid mass spectrometry-chromatography to detect metabolic changes in plasma and lung tissues. Compared with the SC group, the metabolic profile of plasma and lung tissues changed significantly 24 h after CLP. Moreover, 22 and 11 main differential metabolites involved in amino acid and glycerophospholipid metabolism were found in plasma and lung tissues, respectively. After the rats were injected with ADMSCs, these differential metabolites were reverse-regulated both in plasma and lung tissues. Besides, ADMSCs improved the survival rate and down-regulated the concentration of TNF-α and IL-6 at 24 h after CLP. The correlational analysis between plasma of IL-6/TNF-α and metabolites suggested that acetylcholine, spermine, phenylalanine, threonine of plasma and phosphatidylcholine (36:4) of lung tissues were significantly associated with IL-6/TNF-α in CLP and CLP-ADMSCs groups. ADMSCs might reverse abnormal metabolic pathways by reducing anti-inflammatory factors in sepsis-induced ALI. Our findings may provide novel metabolic mechanism of ADMSCs therapy for sepsis.