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. 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. 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). 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 × 10⁶ 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.

Background: To develop a machine learning model for predicting acute respiratory distress syndrome (ARDS) events through commonly available parameters, including baseline characteristics and clinical and laboratory parameters. Methods: A secondary analysis of a multi-centre prospective observational cohort study from five hospitals in Beijing, China, was conducted from January 1, 2011, to August 31, 2014. A total of 296 patients at risk for developing ARDS admitted to medical intensive care units (ICUs) were included. We applied a random forest approach to identify the best set of predictors out of 42 variables measured on day 1 of admission. Results: All patients were randomly divided into training (80%) and testing (20%) sets. Additionally, these patients were followed daily and assessed according to the Berlin definition. The model obtained an average area under the receiver operating characteristic (ROC) curve (AUC) of 0.82 and yielded a predictive accuracy of 83%. For the first time, four new biomarkers were included in the model: decreased minimum haematocrit, glucose, and sodium and increased minimum white blood cell (WBC) count. Conclusions: This newly established machine learning-based model shows good predictive ability in Chinese patients with ARDS. External validation studies are necessary to confirm the generalisability of our approach across populations and treatment practices.

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.

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.

The ProCESS, ARISE, and ProMISe trials have failed to show that early goal-directed therapy (EGDT) reduces mortality in patients with severe sepsis and septic shock. Although lactate-guided therapy (LGT) has been shown to result in significantly lower mortality, its use remains controversial. Therefore, we performed a meta-analysis to evaluate EGDT vs. LGT or usual care (UC) in adult patients with severe sepsis and septic shock. Relevant randomized controlled trials published from January 1, 2001 to March 30, 2017 were identified in PubMed, EMBASE, Web of Science, and the Cochrane Library. The primary outcome was mortality; secondary outcomes included red cell transfusions, dobutamine use, vasopressor infusion, and mechanical ventilation support within the first 6 h and Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Sixteen studies enrolling 5968 patients with 2956 in EGDT, 2547 in UC, and 465 in LGT were included in this meta-analysis. Compared with UC, EGDT was associated with a lower mortality (10 trials; RR 0.85, 95% CI 0.74–0.97, P = 0.01), and this difference was more pronounced in the subgroup of UC patients with mortality > 30%. In addition, EGDT patients received more red cell transfusions, dobutamine, and vasopressor infusions within the first 6 h. Compared with LGT, EGDT was associated with higher mortality (6 trials; RR 1.42, 95% CI 1.19–1.70, P = 0.0001) with no heterogeneity (P = 0.727, I² = 0%). EGDT seems to reduce mortality in adult patients with severe sepsis and septic shock, and the benefit may primarily be attributed to red cell transfusions, dobutamine administration, and vasopressor infusions within the first 6 h. However, LGT may result in a greater mortality benefit than EGDT.