Identification of distinct clinical phenotypes of acute respiratory distress syndrome with differential responses to treatment.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome, and the identification of homogeneous subgroups and phenotypes is the first step toward precision critical care. We aimed to explore whether ARDS phenotypes can be identified using clinical data, are reproducible and are associated with clinical outcomes and treatment response. METHODS: This study is based on a retrospective analysis of data from the telehealth intensive care unit (eICU) collaborative research database and three ARDS randomized controlled trials (RCTs) (ALVEOLI, FACTT and SAILS trials). We derived phenotypes in the eICU by cluster analysis based on clinical data and compared the clinical characteristics and outcomes of each phenotype. The reproducibility of the derived phenotypes was tested using the data from three RCTs, and treatment effects were evaluated. RESULTS: Three clinical phenotypes were identified in the training cohort of 3875 ARDS patients. Of the three phenotypes identified, phenotype I (n = 1565; 40%) was associated with fewer laboratory abnormalities, less organ dysfunction and the lowest in-hospital mortality rate (8%). Phenotype II (n = 1232; 32%) was correlated with more inflammation and shock and had a higher mortality rate (18%). Phenotype III (n = 1078; 28%) was strongly correlated with renal dysfunction and acidosis and had the highest mortality rate (22%). These results were validated using the data from the validation cohort (n = 3670) and three RCTs (n = 2289) and had reproducibility. Patients with these ARDS phenotypes had different treatment responses to randomized interventions. Specifically, in the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on ventilator-free days differed by phenotype (p = 0.001); in the FACTT cohort, there was a significant interaction between phenotype and fluid-management strategy for 60-day mortality (p = 0.01). The fluid-conservative strategy was associated with improved mortality in phenotype II but had the opposite effect in phenotype III. CONCLUSION: Three clinical phenotypes of ARDS were identified and had different clinical characteristics and outcomes. The analysis shows evidence of a phenotype-specific treatment benefit in the ALVEOLI and FACTT trials. These findings may improve the identification of distinct subsets of ARDS patients for exploration in future RCTs.

Effects of Sevoflurane Inhalation Anesthesia on the Intestinal Microbiome in Mice.

In recent years, more and more attention has been paid to intestinal microbiome. Almost all operations will go through the anesthesia process, but it is not clear whether the intervention of anesthesia alone will affect the change in the intestinal microbiome. The purpose of this study was to verify the effect of sevoflurane inhalation anesthesia on the intestinal microbiome. The animal in the experimental group was used to provide sevoflurane inhalation anesthesia for 4 hours. The control group was not intervened. The feces of the experimental group and the control group were collected on the 1st, 3rd, 7th and 14th days after anesthesia. Sevoflurane inhalation anesthesia will cause changes in the intestinal microbiome of mice. It appears on the 1st day after anesthesia and is most obvious on the 7th day. The specific manifestation is that the abundance of microbiome and the diversity of the microbiome is reduced. At the same time, Untargeted metabonomics showed that compared with the control group, the experimental group had more increased metabolites related to the different microbiome, among which 5-methylthioadenosine was related to the central nervous system. Subsequently, the intestinal microbiome diversity of mice showed a trend of recovery on the 14th day. At the genus level, the fecal samples obtained on the 14th day after anesthesia exhibited significantly increased abundances of Bacteroides, Alloprevotella, and Akkermansia and significantly decreased abundances of Lactobacillus compared with the samples obtained on the 1st day after anesthesia. However, the abundance of differential bacteria did not recover with the changing trend of diversity. Therefore, we believe that sevoflurane inhalation anesthesia is associated with changes in the internal microbiome and metabolites, and this change may be completed through the brain-gut axis, while sevoflurane inhalation anesthesia may change the intestinal microbiome for as long as 14 days or longer.

Effects of continuous intravenous infusion of propofol on intestinal flora in rats.

Under normal circumstances, the gut microbiota, host, and external environment establish a dynamic ecological balance and maintain human health. Once this balance is broken, the intestinal flora dysregulation will form, manifested by changes in the diversity, richness, proportion, location and biological characteristics of the gut microbiota. The hypothesis that propofol alters gut microbes was tested in a rat model with continuous intravenous infusion of propofol. Eight male wistar rats underwent tail vein puncture and catheterization respectively, and were continuously pumped with propofol for 3 h. Feces were collected from each rat before and on the 1 st, 3rd, 7th and 14th days after intervention. Finally, the effect of continuous intravenous infusion of propofol on the intestinal flora of rats was analyzed by high-throughput 16S rRNA gene amplification sequencing. Through high-throughput 16S rRNA gene amplicon sequencing analysis, we found that continuous intravenous infusion of propofol had little effect on intestinal flora in rats. Analysis of Alpha (shannon diversity index) showed that group A-7 was different from group P and group A-1 (P = 0.034), and recovered on the 14th day. Although the species diversity analysis showed a significant difference among the five groups (P = 0.049), the distribution of most fecal samples in the PCoA showed a clustered distribution, indicating similarity. In addition, no significant difference was found in the statistical KEGG difference pathway through LEfSe analysis.

Intestinal microbiota and antibiotic-associated acute gastrointestinal injury in sepsis mice.

BACKGROUND: To investigate the changes of intestinal microbiota and metabolites in sepsis mice with acute gastrointestinal injury before and after the use of antibiotics, and to explore the possible effects of these changes on the body. METHODS: Twenty-four 6-8-w-old SPF-grade C57BL/6J male mice were selected, and the mice were randomly divided into three groups. The mice were treated by tail vein injection for 3 days. The intestinal motility of mice after administration was detected. The mice feces were collected for 16S rRNA and Untargeted metabonomics detection. RESULTS: The use of antibiotics in sepsis mice can change the composition of intestinal microbiota and metabolites. LD3, AD3 and LAD3 samples had significant differences in bacterial species. Desulfovibrio was the species with a significant difference in LAD3. In addition, we found that the composition of those intestinal microbiota were correlated with changes in intestinal motility. The untargeted metabolomics analysis showed that the fecal metabolites of LD3 and LAD3 samples were significantly different. In addition to the basic metabolites, Benzoic acid and 4-Hydroxybenzoic acid were also found, and Desulfovibrio was associated with them. CONCLUSIONS: The use of antibiotics in sepsis mice can lead to changes in the intestinal microbiota and metabolite levels, which may be related to the severity of acute gastrointestinal injury in sepsis mice. Inhibiting Desulfovibrio in the intestine and using Benzoic acid and 4-Hydroxybenzoic acid as a marker for the production of Desulfovibrio may reduce the inflammatory degree of acute gastrointestinal injury in sepsis.

Efficacy and safety of thromboprophylaxis in cancer patients: a systematic review and meta-analysis.

BACKGROUND: Thrombosis is a common complication in patients with cancer. Whether thromboprophylaxis could benefit patients with cancer is unclear. The aim of this systematic review was to determine the efficacy and safety of thromboprophylaxis in patients with cancer undergoing surgery or chemotherapy. METHODS: We searched the Cochrane Library, EMBASE, MEDLINE, EBSCOhost, and Web of Science for studies published before May 2018 to investigate whether thromboprophylaxis measures were more effective than a placebo in patients with cancer. RESULTS: In total, 33 trials with 11,942 patients with cancer were identified. In patients with cancer undergoing surgery, the administration of thromboprophylaxis was associated with decreasing trends in venous thromboembolism (VTE) [relative risk (RR) 0.51, 95% confidence interval (CI) 0.32-0.81] and DVT (RR 0.53, 95% CI 0.33-0.87). In patients with cancer undergoing chemotherapy, the administration of thromboprophylaxis reduced the incidences of VTE, DVT, and pulmonary embolism compared with no thromboprophylaxis (RR 0.54, 95% CI 0.40-0.73; RR 0.47, 95% CI 0.31-0.73; RR 0.51, 95% CI 0.32-0.81, respectively). The pooled results regarding major bleeding showed no significant difference between prophylaxis and no prophylaxis in either the surgical or the chemotherapy groups (RR 2.35, 95% CI 0.74-7.52, p = 0.1482, I2 = 0%; RR 1.30, 95% CI 0.93-1.83, p = 0.1274, I2 = 0%, respectively). CONCLUSION: Thromboprophylaxis did not increase major bleeding events or the incidence of thrombocytopenia. All-cause mortality was not significantly different between those who received thromboprophylaxis and those who did not. This meta-analysis provides evidence that thromboprophylaxis can reduce the number of VTE and DVT events, with no apparent increase in the incidence of major bleeding in patients with cancer.

Immunonutrition vs Standard Nutrition for Cancer Patients: A Systematic Review and Meta-Analysis (Part 1).

The aim of this study was to determine the efficacy of immunonutrition vs standard nutrition in cancer patients treated with surgery. Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, EBSCOhost, and Web of Science were searched. Sixty-one randomized controlled trials were included. Immunonutrition was associated with a significantly reduced risk of postoperative infectious complications (risk ratio [RR] 0.71 [95% CI, 0.64-0.79]), including a reduced risk of wound infection (RR 0.72 [95% CI, 0.60-0.87]), respiratory tract infection (RR 0.70 [95% CI, 0.59-0.84]), and urinary tract infection (RR 0.69 [95% CI, 0.51-0.94]) as well as a decreased risk of anastomotic leakage (RR 0.70 [95% CI, 0.53-0.91]) and a reduced hospital stay (MD -2.12 days [95% CI -2.72 to -1.52]). No differences were found between the 2 groups with regard to sepsis or all-cause mortality. Subgroup analyses revealed that receiving arginine + nucleotides + ω-3 fatty acids and receiving enteral immunonutrition reduced the rates of wound infection and respiratory tract infection. The application of immunonutrition at 25-30 kcal/kg/d for 5-7 days reduced the rate of respiratory tract infection. Perioperative immunonutrition reduced the rate of wound infection. For malnourished patients, immunonutrition shortened the hospitalization time. Therefore, immunonutrition reduces postoperative infection complications and shortens hospital stays but does not reduce all-cause mortality. Patients who are malnourished before surgery who receive arginine + nucleotides + ω-3 fatty acids (25-30 kcal/kg/d) via the gastrointestinal tract during the perioperative period (5-7 days) may show better clinical efficacy.

Effects of Immunonutrition on Chemoradiotherapy Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: We conducted a systematic review to assess the effects of immunonutrition on chemoradiotherapy patients. METHODS: We searched the Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, CINAHL, and the Web of Science. We assessed the risk of bias using the Cochrane Risk of Bias tool. Our primary outcomes were the incidence of oral mucositis and diarrhea. The secondary outcomes were the incidence of esophagitis, grade ≥3 oral mucositis, grade ≥3 diarrhea, grade ≥3 esophagitis, and body weight loss. RESULTS: A total of 1478 patients and 27 studies were included. There were no significant differences in the incidence of oral mucositis (relative risk [RR] = 0.91; 95% confidence interval [CI], 0.79-1.05), diarrhea (RR = 0.89; 95% CI, 0.76-1.05), or esophagitis (RR = 0.55; 95% CI, 0.11-2.86) between the immunonutrition group and standard nutrition/placebo group. Nevertheless, immunonutrition significantly reduced the incidence of grade ≥3 oral mucositis (RR = 0.45; 95% CI, 0.22-0.92), grade ≥3 diarrhea (RR = 0.56; 95% CI, 0.35-0.88), grade ≥3 esophagitis (RR = 0.15; 95% CI, 0.04-0.54), and losing >5% body weight (RR = 0.34; 95% CI, 0.18-0.64). CONCLUSIONS: In this study, immunonutrition failed to reduce the incidence rates of oral mucositis, diarrhea, or esophagitis but was conducive to significantly improving the severity of oral mucositis and diarrhea esophagitis and reducing the rate of body weight loss.

The Role of Toll-Like Receptors in Oncotherapy.

Toll-like receptors (TLRs) are associated with tumor growth and immunosuppression, as well as apoptosis and immune system activation. TLRs can activate apoptosis and innate and adaptive immunity pathways, which can be pharmacologically targeted for the development of anticancer oncotherapies. Several studies and clinical trials indicate that TLR agonists are promising adjuvants or elements of novel therapies, particularly when used in conjunction with chemotherapy or radiotherapy. An increasing number of studies suggest that the activation of TLRs in various cancer types is related to oncotherapy; however, before this finding can be applied to clinical practice, additional studies are required. Research suggests that TLR agonists may have potential applications in cancer therapy; nevertheless, because TLR signaling can also promote tumorigenesis, a critical and comprehensive evaluation of TLR action is warranted. This review focuses on recent studies that have assessed the strengths and weaknesses of utilizing TLR agonists as potential anticancer agents.

Determination of volatile organic compounds in SW620 colorectal cancer cells and tumor-bearing mice.

Early diagnosis and early treatment are important factors in reducing colorectal cancer (CRC) metastasis and mortality. Volatile organic compounds (VOCs) released by the human body have great potential for use in clinical diagnosis and therapeutic monitoring for CRC. The aim of our study was to identify VOCs with high specificity and high sensitivity for CRC and to provide a method for early diagnosis of CRC. Gas chromatography-mass spectrometry (GC-MS) was utilized to analyze metabolites in both the in vivo and in vitro experimental groups. In vivo, VOCs were analyzed in the blood of mice after cell inoculation and tumor resection. In vitro experiments were performed by comparing changes in VOCs in an HCoEpiC cell group, control group, SW620 cell group and Arsenic trioxide + SW620 group. We observed changes in VOCs in a series of CRC SW620 cells in vivo and in vitro. Among these changes, we found that the concentrations of 8 substances, including acetone, increased with tumor growth. Nine substances were found to be significantly elevated in the SW620 cancer cell group compared with the other groups. Only one substance was consumed by the tumor in both the in vivo and in vitro experiments. Our study showed that alkanes, lipids, alcohols, ketones, aldehyde, butylated hydroxytoluene (BHT) and hexamethylcyclotrisiloxane all existed at different levels in SW620 CRC cells compared to those in normal cells. We need more research to further confirm this hypothesis.