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

Classification of subtypes and identification of dysregulated genes in sepsis

BackgroundSepsis 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.MethodsThe 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.ResultsA 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.ConclusionThis 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

Evaluation of polymyxin B AUC/MIC ratio for dose optimization in patients with carbapenem-resistant Klebsiella pneumoniae infection

Polymyxin B has been used as a last-line therapy for the treatment of carbapenem-resistant gram-negative bacterial infection. The pharmacokinetic/pharmacodynamic index (AUC/MIC) of polymyxin B has not been clinically evaluated, given that the broth microdilution method for polymyxin susceptibility testing is rarely used in hospitals. This study analyzed data from 77 patients with carbapenem-resistant Klebsiella pneumoniae infections. Among the samples, 63 K. pneumoniae isolates had MIC values of 1.0 mg/L as measured by broth microdilution but 0.5 mg/L as measured using the Vitek 2 system. Polymyxin B AUC/MIC was significantly associated with clinical response (p = 0.002) but not with 30-day all-cause mortality (p = 0.054). With a target AUC/MIC value of 50, Monte Carlo simulations showed that a fixed dose of 100 mg/12 h and three weight-based regimens (1.25 mg/kg/12 h for 80 kg and 1.5 mg/kg/12 h for 70 kg/80 kg) achieved a cumulative fraction of response >90% regardless of renal function, but the risk of nephrotoxicity was high. For patients with carbapenem-resistant K. pneumoniae infections, the underestimation of polymyxin resistance in automated systems need to be taken into account when optimizing polymyxin B dosing based on pharmacokinetic/pharmacodynamic principles

Development of Keshen ultra-deep and ultra-high pressure gas reservoirs in the Kuqa foreland basin, Tarim Basin: Understanding and technical countermeasures

The Keshen Gas Field in the Kuqa foreland basin, Tarim Basin, is a rare fractured tight sandstone gas reservoir with ultra-depth and ultra-high pressure. During its pilot period of gas field development, the development effect is poor with a low development well success rate, a low utilization rate of production capacity and a rapid decline of gas well productivity. In view of these problems, development experiments and technological researches were carried out continuously after the geological characteristics of gas reservoirs, productivity control factors, reservoir connectivity, seepage characteristics, gas and water relations and water invasion laws were studied thoroughly. And consequently, the development countermeasures of “well placement in high position, moderate stimulation and early-stage drainage” were prepared, and five matching development technologies were formed, such as description technology of ultra-deep complex structures, well pattern optimization technology for fractured tight sandstone gas reservoirs, fracture net acid fracturing technology for fractured tight sandstone reservoirs, dynamic monitoring technology for ultra-deep and ultra-high pressure gas wells, wellbore integrity management and evaluation technology for high pressure gas wells. The following remarkable application results were achieved in the process of gas field development. First, the drilling depth error of the target formation drops from 125 m to less than 30 m. Second, the utilization rate of production capacity in the Keshen 8 Block reaches 100%. Third, the average absolute open flow rate is increased by 5 times to 273 × 104 m3/d from 50 × 104 m3/d before the stimulation. Fourth, safe and smooth production under high temperature and high pressure conditions is realized in the Keshen Gas Field. In conclusion, the successful and efficient development of the Keshen Gas Field provides experiences for the development of similar gas reservoirs at home and abroad, and its development countermeasures and matching technologies have important guidance and reference significance. Keywords: Tarim basin, Keshen gas field, Cretaceous, Bashijiqike Fm, Ultra-deep, Ultra-high pressure, High temperature, Fractured, Tight sandstone gas reservoir, Development technologies and countermeasur

HAT therapy for sepsis: A review of the therapeutic rationale and current clinical evaluation status

Vitamin C-based cluster therapy, which involves the combined application of hydrocortisone, vitamin C, and thiamine (HAT), is a recently proposed new treatment option for sepsis on top of conventional treatment. This therapy has a strong theoretical basis, but its clinical efficacy remains inconclusive. This review summarizes the rationale for HAT therapy for sepsis and describes the evaluation of its efficacy in clinical observational studies and randomized controlled trials, with the aim of providing a reference for the future clinical practice application of HAT therapy in sepsis

Intestinal Microbiota in Sepsis

Abstract Sepsis is defined as a life-threatening organ dysfunction, which is caused by a dysregulated host response to infection. The composition of the intestinal microbiota is significantly different between patients with sepsis and healthy individuals. Intestinal microbial imbalance plays an important role in the occurrence and development of sepsis. Our review mainly introduces the mechanism of intestinal microbiota involvement in sepsis, the effects of microbiota dysbiosis on the damage of multiple organs and concisely discusses the prospects for microbe-specific treatment of sepsis in the future

Detecting Leaks and Sensor Biases by Recursive Identification with Forgetting Factors

In industrial processes, pipes and tanks may leak and sensors may have biases since corrosion, measuring noises and instrument faults exist. In order to maintain production in normal and safe conditions, detecting possible faults of production equipment on time is crucial. In this paper, a process model is proposed to describe boiler tube leak problem. Based on this model, least-squares methods with constant and timevarying forgetting factors are presented to detect the leakage and sensor bias. The application in a boiler system shows that the proposed methods can detect the boiler tube leakage more effectively than the method without forgetting factors

Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies

Abstract 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