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Abstract Background Previous studies have shown that high-density lipoprotein cholesterol (HDL-C) levels are positively associated with cognitive function across a range of concentrations. However, recent studies have suggested that very high HDL-C levels may lead to poorer outcomes. Therefore, we aimed to investigate the relationship between different concentrations of HDL-C and cognitive impairment risk. Methods We collected data from 3632 participants aged over 60 years from the U.S. National Health and Nutrition Examination Survey (NHANES) between 2011 and 2014 to assess the relationship between HDL-C and cognitive function. Cognitive function was evaluated with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test, the animal fluency test (AFT), and the digit symbol substitution test (DSST). We used restricted cubic spline models and logistic regression to examine the association between HDL-C and cognitive function. Results A U-shaped was observed between HDL-C and cognitive outcomes, individuals with higher risk in those with both low and very high HDL-C levels compared with those with midrange values. Very high HDL-C levels (≥ 2.50 mmol/L) were associated with increased risk of cognitive impairment (OR = 2.19; 95% CI, 1.12–4.28) compared with those with HDL-C levels in the range of 1.50 to 1.99 mmol/L in older adults after adjustment for confounding factors. Interaction test demonstrated that relationship between very high HDL-C and the risk of cognitive impairment was not changed in different sex and race group (P for interaction > 0.05). Conclusions Very high HDL-C levels were associated with an increased risk of cognitive impairment. HDL-C may not be a protective factor for maintaining brain health in older adults at very high levels.

Abstract Postoperative multi-organ dysfunction (MOD) is associated with significant mortality and morbidity. Necroptosis has been implicated in different types of solid organ injury; however, the mechanisms linking necroptosis to inflammation require further elucidation. The present study examines the involvement of necroptosis and NLR family pyrin domain containing 3 (NLRP3) inflammasome in small intestine injury following traumatic surgery. Kidney transplantation in rats and renal ischaemia-reperfusion (I/R) in mice were used as traumatic and laparotomic surgery models to study necroptosis and inflammasome activation in the small intestinal post-surgery; additional groups also received receptor-interacting protein kinase 1 (RIPK1) inhibitor necrostatin-1s (Nec-1s). To investigate whether necroptosis regulates inflammasome activity in vitro, necroptosis was induced in human colonic epithelial cancer cells (Caco-2) by a combination of tumour necrosis factor-alpha (TNFα), SMAC mimetic LCL-161 and pan-caspase inhibitor Q-VD-Oph (together, TLQ), and necroptosis was blocked by Nec-1s or mixed lineage kinase-domain like (MLKL) inhibitor necrosulfonamide (NSA). Renal transplantation and renal ischaemia-reperfusion (I/R) upregulated the expression of necroptosis mediators (RIPK1; RIPK3; phosphorylated-MLKL) and inflammasome components (P2X purinoceptor subfamily 7, P2X7R; NLRP3; caspase-1) in the small intestines at 24 h, and Nec-1s suppressed the expression of inflammasome components. TLQ treatment induced NLRP3 inflammasome, promoted cleavage of caspase-1 and interleukin-1 beta (IL-1β), and stimulated extracellular ATP release from Caco-2 cells, and MLKL inhibitor NSA prevented TLQ-induced inflammasome activity and ATP release from Caco-2 cells. Our work suggested that necroptosis and inflammasome interactively promote remote postoperative small intestinal injury, at least in part, through ATP purinergic signalling. Necroptosis-inflammasome axis may be considered as novel therapeutic target for tackling postoperative MOD in the critical care settings.

Objective: YZJ-4729 is a novel G protein-biased μ-opioid receptor agonist for the treatment of acute pain in adult patients who require intravenous opioid analgesic therapy. The aim of this study was to assess the pharmacokinetics, metabolite profiling, safety and tolerability of YZJ-4729 in healthy Chinese subjects following the single intravenous doses ranged from 0.2 mg to 6 mg.Methods: This single-center, randomized, double-blind, placebo-controlled clinical study was conducted in 54 healthy male and female Chinese subjects after single ascending doses of YZJ-4729 tartrate (0.2, 0.5, 1.5, 3, 4.5, and 6 mg). Subjects in each cohort were assigned randomly to receive a single intravenous dose of YZJ-4729 tartrate injection or placebo at a ratio of 4:1. Pharmacokinetic characteristics, metabolite profiling, safety and tolerability profiles of the study drug were evaluated.Results: Overall, YZJ-4729 was safe and well tolerated in healthy Chinese subjects. The study drug reached peak plasma concentrations nearly at the end of the infusion. After administration, YZJ-4729 was eliminated rapidly with a terminal elimination half-life of 0.862–2.50 h, and excreted little in human excreta. The maximum drug concentration and area under the plasma concentration-time curve increased with dose escalation across the entire dose range. YZJ-4729 experienced extensive metabolism in human body. A total of 19 metabolites were identified and the characteristic metabolic pathways involved hydroxylation, ketone formation, N-dealkylation and glucuronide conjugation. Metabolite M10 was the most abundant circulating metabolite, and represented over 10% of total drug-related systemic exposure. Further PK and safety evaluation of M10 was necessary.Conclusion: The clinical study results laid a foundation for the further clinical studies of YZJ-4729 in patients.Clinical Trial Registration:http://www.chinadrugtrials.org.cn, identifier CTR20222574.

Shaking is an innovative technology employed in black tea processing to enhance flavor. However, the effects of shaking on the evolutionary mechanisms of volatile metabolites (VMs) remain unclear. In this study, we compared the effects of a shaking–withering method with those of traditional withering on the flavor and VMs transformation of black tea. The results showed that black tea treated with shaking exhibited excellent quality with floral and fruity aroma. Based on gas chromatography-tandem mass spectrometry, 128 VMs (eight categories) were detected. Combining variable importance projection with odor activity value analysis, eight key differential VMs were identified. Shaking could promote the oxidative degradation of fatty acids and carotenoids and modulate the biosynthesis of terpenoids to facilitate the formation of floral/fruity VMs (such as (Z)-hexanoic acid-3-hexenyl ester, ethyl hexanoate, trans-β-ionone, and decanal). Our findings provide theoretical guidance for the production of high-quality black tea with floral and fruity aromas.

Despite the importance of fixation in determining green tea quality, its role in reducing the bitter and astringent taste of this beverage remains largely unknown. Herein, an electromagnetic roller-hot-air–steam triple-coupled fixation (ERHSF) device was developed, and its operating parameters were optimized (steam volume: 20 kg/h; hot-air temperature: 90 °C; hot-air blower speed: 1200 r/min). Compared with conventional fixation treated samples, the ratio of tea polyphenols to free amino acids and ester-catechins to simple-catechins in ERHSF-treated samples was reduced by 11.0% and 3.2%, reducing bitterness and astringency of green tea; amino acids, soluble sugars, and chlorophyll contents were significantly increased, enhancing the freshness, sweetness, and greenness; the color indexes, such as L/L* value of brightness and -a/-a* value of greenness, were also improved, and ERHSF-treated samples had the highest sensory scores. These results provided theoretical support and technical guidance for precise quality improvement of summer-autumn green tea.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal and irreversible interstitial lung disease. The specific mechanisms involved in the pathogenesis of IPF are not fully understood, while metabolic dysregulation has recently been demonstrated to contribute to IPF. This study aims to identify key metabolism-related genes involved in the progression of IPF, providing new insights into the pathogenesis of IPF.Methods: We downloaded four datasets (GSE32537, GSE110147, GSE150910, and GSE92592) from the Gene Expression Omnibus (GEO) database and identified differentially expressed metabolism-related genes (DEMRGs) in lung tissues of IPF by comprehensive analysis. Then, we performed GO, KEGG, and Reactome enrichment analyses of the DEMRGs. Subsequently, key DEMRGs were identified by machine-learning algorithms. Next, miRNAs regulating these key DEMRGs were predicted by integrating the GSE32538 (IPF miRNA dataset) and the miRWalk database. The Cytoscape software was used to visualize miRNA-mRNA regulatory networks. In addition, the relative levels of immune cells were assessed by the CIBERSORT algorithm, and the correlation of key DEMRGs with immune cells was calculated. Finally, the mRNA expression of the key DEMRGs was validated in two external independent datasets and an in vivo experiment.Results: A total of 101 DEMRGs (51 upregulated and 50 downregulated) were identified. Six key DEMRGs (ENPP3, ENTPD1, GPX3, PDE7B, PNMT, and POLR3H) were further identified using two machine-learning algorithms (LASSO and SVM-RFE). In the lung tissue of IPF patients, the expression levels of ENPP3, ENTPD1, and PDE7B were upregulated, and the expression levels of GPX3, PNMT, and POLR3H were downregulated. In addition, the miRNA-mRNA regulatory network of key DEMRGs was constructed. Then, the expression levels of key DEMRGs were validated in two independent external datasets (GSE53845 and GSE213001). Finally, we verified the key DEMRGs in the lung tissue of bleomycin-induced pulmonary fibrosis mice by qRT-PCR.Conclusion: Our study identified key metabolism-related genes that are differentially expressed in the lung tissue of IPF patients. Our study emphasizes the critical role of metabolic dysregulation in IPF, offers potential therapeutic targets, and provides new insights for future studies.

BackgroundHyperglycemia has been reported to be associated with the outcomes of patients in the intensive care unit (ICU). However, the relationship between hemoglobin A1c (HbA1c) and long-term or short-term mortality in the ICU is still unknown. This study used the Medical Information Mart for Intensive Care (MIMIC)-IV database to investigate the relationship between HbA1c and long-term or short-term mortality among ICU patients without a diabetes diagnosis.MethodsA total of 3,154 critically ill patients without a diabetes diagnosis who had HbA1c measurements were extracted and analyzed from the MIMIC-IV. The primary outcome was 1-year mortality, while the secondary outcomes were 30-day mortality and 90-day mortality after ICU discharge. HbA1c levels were classified into four levels according to three HbA1c values (5.0%, 5.7%, and 6.5%). The Cox regression model was used to investigate the relationship between the highest HbA1c measurement and mortality. Finally, this correlation was validated using the XGBoost machine learning model and Cox regression after propensity score matching (PSM).ResultsThe study eventually included 3,154 critically ill patients without diabetes who had HbA1c measurements in the database. HbA1c levels of below 5.0% or above 6.5% were significantly associated with 1-year mortality after adjusting for covariates in Cox regression (HR: 1.37; 95% CI: 1.02–1.84 or HR: 1.62; 95% CI: 1.20–2.18). In addition, HbA1c 6.5% was linked to 30-day mortality (HR: 1.81; 95% CI: 1.21–2.71) and 90-day mortality (HR: 1.62; 95% CI: 1.14–2.29). The restricted cubic spline demonstrated a U-shaped relationship between HbA1c levels and 1-year mortality. The AUCs of the training and testing datasets in the XGBoost model were 0.928 and 0.826, respectively, while the SHAP plot revealed that HbA1c was somewhat important for the 1-year mortality. Higher HbA1c levels in Cox regression were still significantly associated with 1-year mortality after PSM for other factors,ConclusionsThe 1-year mortality, 30-day mortality, and 90-day mortality rates for critically ill patients after discharge from ICU are significantly associated with HbA1c. HbA1c < 5.0% and ≥6.5% would increase 30-day, 90-day, and 1-year mortality, while levels between 5.0% and 6.5% of HbA1c did not significantly affect these outcomes.

BackgroundPostoperative cognitive dysfunction (POCD) is a common complication in elderly patients following surgery. The preventive and/or treatment strategies for the incidence remain limited.ObjectiveThis study aimed to investigate the preventive effect of perioperative probiotic treatment on POCD in elderly patients undergoing hip or knee arthroplasty.MethodsAfter obtaining ethical approval and written informed consent, 106 patients (age ≥60 years) were recruited, who scheduled elective hip or knee arthroplasty, from 16 March 2021 to 25 February 2022 for this randomized, double-blind, and placebo-controlled trial. They were randomly assigned with a 1:1 ratio to receive either probiotics or placebo treatment (four capsules, twice/day) from hospital admission until discharge. Cognitive function was assessed with a battery of 11 neuropsychological tests on the admission day and the seventh day after surgery, respectively.ResultsA total of 96 of 106 patients completed the study, and their data were finally analyzed. POCD occurred in 12 (26.7%) of 45 patients in the probiotic group and 29 (56.9%) of 51 patients in the placebo group (relative risk [RR], 0.47 [95% confidence interval [CI], 0.27 to 0.81]; P = 0.003). Among them, mild POCD occurred in 11 (24.4%) in the probiotic group and 24 (47.1%) in the placebo group (RR, 0.52 [95% CI, 0.29 to 0.94]; P = 0.022). No significant difference in severe POCD incidence was found between the two groups (P = 0.209). Compared with the placebo group, the verbal memory domain cognitive function was mainly improved in the probiotic group.ConclusionProbiotics may be used perioperatively to prevent POCD development and improve verbal memory performance in elderly patients receiving hip or knee arthroplasty.Clinical trial registrationwww.chictr.org.cn, identifier: ChiCTR2100045620.

Abstract Accumulating evidence has revealed the role of microRNAs (miRs) in hepatocellular carcinoma (HCC). Dexmedetomidine, a highly selective α2-adrenergic agonist, is widely used in perioperative settings for analgesia and sedation. Herein, we aimed to determine whether dexmedetomidine might directly regulate miR-130a/early growth response 1 (EGR1) axis in HCC and explore the related mechanisms. miR-130a and EGR1 expression were determined in HCC tissues and their correlation was evaluated. Human HCC cell line HCCLM3 was selected. Upon the determination of the optimal concentration of dexmedetomidine, HCCLM3 cells were treated with dexmedetomidine, miR-130a- or EGR1-related oligonucleotides or plasmids were transfected into cells to explore their functions in cell biological behaviors. miR-130a and EGR1 levels in cells were tested. The targeting relationship between miR-130a and EGR1 was verified. miR-130a was inhibited while EGR1 was elevated in HCC tissues and they were negatively correlated. EGR1 was targeted by miR-130a. With the increase of dexmedetomidine concentration, HCCLM3 cell viability was correspondingly inhibited, miR-130a expression was elevated and EGR1 expression was decreased. Dexmedetomidine, upregulating miR-130a or downregulating EGR1 inhibited proliferation, invasion and migration, and promoted apoptosis of HCCLM3 cells. MiR-130a upregulation/downregulation enhanced/impaired the effect of dexmedetomidine on cell biological behaviors. Our study provides evidence that raising miR-130a enhances the inhibitory effects of dexmedetomidine on HCC cellular growth via inhibiting EGR1. Thus, miR-130a may be a potential candidate for the treatment of HCC.

Background To establish and validate a risk stratification scoring system (we name it as PreOp-BFS, which represents Pre-Operative Brain Fragility Score) for postoperative cognitive impairment containing postoperative cognitive dysfunction (POCD) and postoperative delirium (POD) in elderly patients undergoing non-cardiac surgery. Methods We searched for relevant literatures and reviews reported in PubMed and ScienceDirect databases from January 1994 to December 2017. We performed a preoperative risk factor for cognitive impairment in elderly patients (age ≥ 60 years) who underwent non-cardiac surgery, and finally constructed a risk scoring system to predict postoperative cognitive impairment. Results The test data included 49 patients with postoperative cognitive impairment and 31 patients without postoperative cognitive impairment. The postoperative risk scale score ranged from 0 to 8 points. The incidence of postoperative cognitive impairment was 16.2%, 62.9% and 96.2% in the low (0–2 scores), medium (3–4 scores) and high (5–8 scores) risk groups, respectively. In addition, the risk of postoperative cognitive impairment was significantly higher in high and medium risk groups than in low risk group. Receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of the risk scoring system was 0.862 [95% CI 0.784–0.941]. Conclusions The preoperative risk stratification scoring system (PreOp-BFS) established in this study had a good prediction effect, which was helpful for rapid identification and screening of high-risk susceptible patients with early postoperative cognitive impairment, and for performing targeted perioperative prevention.

ObjectiveTo establish a nomogram model for the prediction of postoperative cognitive dysfunction (POCD) in elderly patients undergoing gastrointestinal tumor resection.MethodsA total of 369 elderly patients scheduled for elective gastrointestinal tumor resection under general anesthesia were included. The cognitive function of each participant was assessed by the Mini-Mental State Examination (MMSE) 1 day before surgery and 7 days after surgery for the diagnosis of POCD. According to the results, patients were divided into a POCD group and a non-POCD group. The differences in hospitalization data and examination results between the two groups were compared. A logistic regression model was used to explore the risk factors for POCD in elderly patients undergoing gastrointestinal tumor resection, and a nomogram was then constructed based on these factors. The diagnostic performance of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUROC) and a calibration plot. The clinical usefulness of the nomogram was estimated using decision curve analysis (DCA).ResultsAmong the 369 patients undergoing gastrointestinal tumor resection, 79 patients had POCD, with a positive rate of 21.4%. The nomogram model comprised the following variables: age, body mass index (BMI), history of cerebrovascular disease, preoperative white blood cell (WBC) count, preoperative hemoglobin (Hb) level, intra-operative blood loss, and operation time. The model showed good discrimination, with an area under the curve (AUC) of 0.710 (95% CI = 0.645–0.775), and good calibration (Hosmer–Lemeshow test, χ2 = 5.133, p = 0.274). Internal validation also maintained ideal discrimination and calibration. Decision curves indicated that when the threshold probability was above 0.1, the nomogram achieved more benefit than both the treat-all and treat-none policies.ConclusionThis scoring system is the first nomogram model developed for the prediction of POCD in elderly patients undergoing gastrointestinal tumor resection. It has good efficacy in the prediction of POCD risk and could provide an important reference for the prevention, management, and treatment of POCD.

Background: With the development of fiberoptic bronchoscopy in the diagnosis and treatment of various pulmonary diseases, the anesthesia/sedation requirements are becoming more demanding, posing great challenges for patient safety while ensuring a smooth examination/surgery process. Remimazolam, a brand-new ultra-short-acting anesthetic, may compensate for the shortcomings of current anesthetic/sedation strategies in bronchoscopy.Methods: This study was a prospective, multicenter, randomized, double-blind, parallel positive controlled phase 3 clinical trial. Subjects were randomized to receive 0.2 mg/kg remimazolam besylate or 2 mg/kg propofol during bronchoscopy to evaluate the efficacy and safety of remimazolam.Results: A total of 154 subjects were successfully sedated in both the remimazolam group and the propofol group, with a success rate of 99.4% (95%CI of the adjusted difference −6.7 × 10%–6% to −5.1 × 10%–6%). The sedative effect of remimazolam was noninferior to that of propofol based on the prespecified noninferiority margin of −5%. Compared with the propofol group, the time of loss of consciousness in the remimazolam group (median 61 vs. 48s, p < 0.001), the time from the end of study drug administration to complete awakening (median 17.60 vs. 12.80 min, p < 0.001), the time from the end of bronchoscopy to complete awakening (median 11.00 vs. 7.00 min, p < 0.001), the time from the end of study drug administration to removal of monitoring (median 19.50 vs. 14.50 min, p < 0.001), and the time from the end of bronchoscopy to removal of monitoring (median 12.70 vs. 8.60 min, p < 0.001) were slightly longer. The incidence of Adverse Events in the remimazolam group and the propofol group (74.8% vs. 77.4%, p = 0.59) was not statistically significant, and none of them had Serious Adverse Events. The incidence of hypotension (13.5% vs. 29.7%, p < 0.001), hypotension requiring treatment (1.9% vs. 7.7%, p = 0.017), and injection pain (0.6% vs. 16.8%, p < 0.001) were significantly lower in the remimazolam group than in the propofol group.Conclusion: Moderate sedation with 0.2 mg/kg remimazolam besylate is effective and safe during bronchoscopy. The incidence of hypotension and injection pain was less than with propofol, but the time to loss of consciousness and recovery were slightly longer.Clinical Trial Registration:clinicaltrials.gov, ChiCTR2000039753

PurposeTo evaluate the outcomes of immune checkpoint inhibitor (ICI)-based treatments versus classical chemotherapy for metastatic non-small cell lung cancer (NSCLC) patients who develop epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance and to explore the population that may benefit from ICI-based therapy.Materials and methodsAll patients who had previously received EGFR-TKI therapy at two cancer centers in China and developed resistance to targeted therapies were included. Progression-free survival (PFS) and overall survival (OS) were utilized to evaluate the outcomes of the study cohort.ResultsA total of 132 patients were included. The median follow-up time for this cohort was 21.7 months (IQR, 14.8–28.8 months), calculated from the date of EGFR-TKI resistance. The median PFS and OS were 4.9 months (IQR, 2.8–9.2) and 13.5 months (IQR, 6.6–26.5 months), respectively. Multivariate analysis showed that ICI-based therapy could significantly improve OS when compared to the classic chemotherapy (hazard ratio [HR], 0.55; 95% CI, 0.34–0.88; P = 0.01) after adjusting for variables such as gender, age, mutation status, and brain or liver metastasis status. The combined modality of ICI plus chemotherapy could offer a long-term OS benefit in most subgroups, such as young (

Background: Dexmedetomidine is a commonly used clinical sedative; however, the drug response varies among individuals. Thus, the purpose of this study was to explore the association between dexmedetomidine response and gene polymorphisms related to drug-metabolizing enzymes and drug response (CYP2A6, UGT2B10, UGT1A4, ADRA2A, ADRA2B, ADRA2C, GABRA1, GABRB2, and GLRA1).Methods: This study was a prospective cohort study. A total of 194 female patients aged 18–60 years, American Society of Anesthesiologists (ASA) score I-II, who underwent laparoscopy at the Third Xiangya Hospital of Central South University, were included. The sedative effect was assessed every 2 min using the Ramsay score, and the patient’s heart rate decrease within 20 min was recorded. Peripheral blood was collected from each participant to identify genetic variants in the candidate genes of metabolic and drug effects using the Sequenom MassARRAY® platform. Furthermore, additional peripheral blood samples were collected from the first 99 participants at multiple time points after dexmedetomidine infusion to perform dexmedetomidine pharmacokinetic analysis by Phoenix® WinNonlin 7.0 software.Results: Carriers of the minor allele (C) of CYP2A6 rs28399433 had lower metabolic enzyme efficiency and higher plasma concentrations of dexmedetomidine. In addition, the participants were divided into dexmedetomidine sensitive or dexmedetomidine tolerant groups based on whether they had a Ramsay score of at least four within 20 min, and CYP2A6 rs28399433 was identified to have a significant influence on the dexmedetomidine sedation sensitivity by logistic regression with Plink software [p = 0.003, OR (95% CI): 0.27 (0.11–0.65)]. C allele carriers were more sensitive to the sedative effects of dexmedetomidine than A allele carriers. GABRA2 rs279847 polymorphism was significantly associated with the degree of the heart rate decrease. In particular, individuals with the GG genotype had a 4-fold higher risk of heart rate abnormality than carriers of the T allele (OR = 4.32, 95% CI: 1.96–9.50, p = 0.00027).Conclusion:CYP2A6 rs28399433 polymorphism affects the metabolic rate of dexmedetomidine and is associated with susceptibility to the sedative effects of dexmedetomidine; GABRA2 rs279847 polymorphism is significantly associated with the degree of the heart rate decrease.

BackgroundStroke is the leading cause of death and disability worldwide, with ischemic stroke (IS) being the most prevalent type. Circular RNAs (circRNAs) are involved in the pathological process of IS and are promising biomarkers for the diagnosis of IS. However, studies focusing on circRNAs acting as microRNAs (miRNAs) sponges in regulating mRNA expression are currently scarce.MethodsIn this study, expression profiles of circRNAs (GSE195442), miRNAs (GSE117064), and mRNAs (GSE58294) from the Gene Expression Omnibus (GEO) database were analyzed. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) were identified by R software. The target miRNAs and target genes were predicted by several bioinformatics methods. Then, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEmRNAs. Subsequently, the protein-protein interaction (PPI) network and the competing endogenous RNA (ceRNA) regulatory network were visualized by Cytoscape software. Finally, we further constructed an immune-related circRNA-miRNA-mRNA regulatory sub-network in IS.ResultsA total of 35 DEcircRNAs, 141 DEmiRNAs, and 356 DEmRNAs were identified. By comprehensive analysis of bioinformatics methods, we constructed a circRNA-miRNA-mRNA regulatory network, including 15 DEcircRNAs, eight DEmiRNAs, and 39 DEmRNAs. FGF9 was identified as an immune-related hub gene. Immune cell analysis indicated a significantly higher level of neutrophils in IS, and the expression of FGF9 was significantly negatively correlated with the level of neutrophils. Eventually, miR-767-5p was predicted as the upstream molecules of FGF9, and circ_0127785 and circ_0075008 were predicted as the upstream circRNAs of miR-767-5p.ConclusionOur study provides novel insights into the molecular mechanisms governing the progression of IS from the perspective of immune-related ceRNA networks.

Second-drying is a key process of green tea manufacturing, however, hitherto the effect of second-drying methods on green tea quality has not been assessed. In this study, we compared the effect of three heat transfer drying methods (heat radiation, heat convection, and heat conduction) on green tea quality. Gas chromatography-tandem dual mass spectrometry was used to detect volatile compounds, while absolute quantitative methods were used to detect the non-volatile ones. We identified 45 non-volatile metabolites, 101 volatile metabolites, and 15 objective flavor indicators. Seventeen differential non-volatiles and 8 differential volatiles were screened. Microwave second-drying in heat radiation was the optimal method for green tea flavor, as it can promote the retention of chlorophyll, the degradation of flavonoid glycosides, and the enrichment of amino acids, soluble sugars, nonanal, trans-β-ionone, linalool, and jasmone. The results provide a theoretical basis and technical guidance for the precise and directional processing of high-quality green tea.

Background: It is well demonstrated that intraoperative blood pressure is associated with postoperative acute kidney injury (AKI); however, the association between severity and duration of abnormal intraoperative blood pressure (BP) with AKI in patients undergoing laparoscopic surgery remains unknown. Methods: This retrospective cohort study included 12,414 patients aged ≥ 18 years who underwent a single elective laparoscopic abdominal surgery during hospitalization between October 2011 and April 2017. Multivariate stepwise logistic regressions were applied to determine the correlation between the severity and duration of intraoperative mean arterial pressure (MAP, (systolic BP + 2 × diastolic BP)/3), acute intraoperative hypertension (IOTH) and postoperative AKI, in different periods of surgery. Results: A total of 482 hospitalized patients (3.9%) developed surgery-related AKI. Compared with those without IOTH or with preoperative mean MAP (80–85 mmHg), acute elevated IOTH (odds ratio, OR, 1.4, 95% CI, 1.1 to 1.7), mean MAP 95–100 mmHg (OR, 1.8; 95% CI, 1.3 to 2.7), MAP 100–105 mmHg (OR, 2.4; 95% CI, 1.6 to 3.8), and more than 105 mmHg (OR, 1.9; 95% CI, 1.1 to 3.3) were independent of other risk factors in a diverse cohort undergoing laparoscopic surgery. In addition, the risk of postoperative AKI appeared to result from long exposure (≥20 min) to IOTH (OR, 1.9; 95% CI, 1.5 to 2.5) and MAP ≥ 115 mmHg (OR, 2.2; 95% CI, 1.6 to 3.0). Intraoperative hypotension was not found to be associated with AKI in laparoscopic surgery patients. Conclusions: Postoperative AKI correlates positively with intraoperative hypertension in patients undergoing laparoscopic surgery. These findings provide an intraoperative evaluation criterion to predict the occurrence of postoperative AKI.

Round green tea (RGT) is widely distributed and presents a high yield in China. The quality of RGT can be determined by its aroma; however, the transformation and formation of volatile metabolites during RGT processing remain unclear. In this study, 173 volatile compounds (nine categories) were identified totally from RGT via gas chromatography-mass spectrometry with infrared-assisted headspace-solid phase microextraction. These substances exhibited different changing trends during various procedures, with the most intense transformation occurring during fixation, followed by pan-frying and second drying; moreover, 51 substances were screened, mainly containing fatty acid-derived volatiles (i.e., (E)-2-hexen-1-ol, Hexanal, pentanal, hexanal) and glycoside-derived volatiles (i.e., linalool, geraniol, benzyl alcohol, benzaldehyde), and their evolution during processing was clarified. Furthermore, the effect of the second-drying temperature on volatile compound metabolism was clarified, and 90°C was the best temperature for RGT aroma. This research lays a foundation for in-depth quality control and the aroma formation mechanism of RGT.

Abstract Background Utrophin (UTRN), as a tumor suppressor gene, is involved in various cancer progression. The function of UTRN in the melanoma process and the related molecular mechanisms are still unclear. Herein, we studied the function of UTRN in melanoma growth and the relevant molecular mechanisms. Methods Using the GEO database and UCSC Xena project, we compared the expression of UTRN in non-cancerous and melanoma tissues. Immunohistochemistry (IHC) staining, qRT-PCR and Western Blot (WB) were performed to evaluate UTRN expression in clinical samples. A total of 447 cases with UTRN expression data, patient characteristics and survival data were extracted from TCGA database and analyzed. After stable transduction and single cell cloning, the proliferation ability of A375 human melanoma cells was analyzed by Cell Counting Kit‑8 (CCK) and 5‑ethynyl‑2′‑deoxyuridine (EdU) incorporation assays. GSEA was performed to predict the mechanism by which UTRN regulated melanoma growth. Then WB analysis was used to assess the protein expression levels of pathway signaling in overexpression (EXP) melanoma cells. Epac activator 8-pCPT-2′-O-Me-cAMP was then used to evaluate the proliferation ability by activation of p38 and JNK/c-Jun signaling pathways. Results Data from GEO and UCSC Xena project indicated that UTRN expression was decreased in melanoma. Experiment on clinical samples further confirmed our finding. TCGA results showed that a reduced expression of UTRN in 447 melanoma samples was associated with advanced clinical characteristics (T stage, Clark level, ulceration), shorter survival time and poorer prognosis. In addition, up-regulated UTRN expression inhibited melanoma cell proliferation when compared to control group. MAPK signaling pathway was presented in both KEGG and BioCarta databases by using GSEA tool. WB results confirmed the down-regulated expression of p38, JNK1 and c-Jun in EXP group when compared to control group. Epac activator 8-pCPT-2′-O-Me-cAMP treatment could partially rescue proliferation of tumor cells. Conclusion We have demonstrated that reduced UTRN predicted poorer prognosis and UTRN inhibited melanoma growth via p38 and JNK1/c-Jun pathways. Therefore, UTRN could serve as a tumor suppressor and novel prognostic biomarker for melanoma patients.

Background and purpose: The value of prophylactic cranial irradiation (PCI) for extensive-stage small-cell lung cancer (ES-SCLC) has recently been challenged. This study was conducted to evaluate the role of PCI for ES-SCLC under active brain magnetic resonance imaging (MRI) surveillance. Materials and methods: Patients with ES-SCLC who showed any responses after first-line chemotherapy and no initial brain metastasis (BM) were retrospectively included. Active brain MRI surveillance was performed for all patients. Progression-free survival (PFS) and overall survival (OS) were compared between PCI and non-PCI patients. The time-related hazard of BM was evaluated in non-PCI patients. Results: One hundred and eighteen consecutive patients were included in the study. The median follow-up time was 26.5 months (3–72 months). The median PFS and OS were better in the PCI cohort than in the non-PCI group. Multivariate analyses revealed first-line chemotherapy cycles (> 4 vs. ≤ 4 cycles, HR: 0.29; 95% CI: 0.15–0.55, P

BackgroundThis study was conducted to investigate the relationship between the Neutrophil-Lymphocyte Ratio (NLR) and the incidence of surgery-related acute kidney injury (AKI) in non-cardiac surgery patients under general anaesthesia.MethodsIn this retrospective study, 5057 patients from Third Xiangya hospital from January 2012 to December 2016 and 1686 patients from Second Xiangya hospital from January 2016 to December 2016 for non-cardiac surgery under general anesthesia were included. According to receiver operating characteristic (ROC) curve constructed by NLR for postoperative AKI, the cut-off point was obtained as the basis for grouping low or high NLR. The baseline characteristics of two sets were compared with each other. A multi-factor model was constructed by Least absolute shrinkage and selection operator (LASSO) method with the training set, and verified by outside validation set.Results243 patients (3.604%) developed postoperative AKI. The ROC curve showed that the AUC of the NLR for predicting postoperative AKI in non-cardiac surgery was 0.743 (95% CI, 0.717-0.769), and the cut-off value was 3.555 (sensitivity, 86.4%; specificity 51.9%). There was no significant difference in the baseline characteristics of training set and validation set. The AUC in the training set was 0.817 (95% CI, 0.784-0.850), and the AUC in the validation set was 0.804 (95% CI, 0.749-0.858), the AUC deviation was 0.012 (P > 0.05) from validation set, and the likelihood ratio test showed P < 0.05.ConclusionThis study showed that preoperative high NLR (NLR≥3.555) was an independent risk factor associated with postoperative AKI (OR, 2.410; 95% CI, 1.371-4.335) in patients for non-cardiac surgery under general anesthesia.

Abstract Background NSCLC patients with EGFR mutation were at a higher incidence of developing brain metastasis (BM). Patients with BM are associated with high mortality. Reducing BM incidence becomes increasingly significant for NSCLC patients to achieve prolonged survival. The aim of the study was to explore the possible risk factors of developing metachronous BM during EGFR-TKIs treatment, and to identify the potential candidates for prophylactic cranial irradiation (PCI) or the first-line Osimertinib treatment. Methods A total of 157 consecutive EGFR-mutated advanced NSCLC patients without BM at initial diagnosis in our institution from 2012 and 2018 were retrospectively reviewed. Comparisons of OS were performed based on BM status. The cumulative incidence of metachronous BM was calculated by the Kaplan-Meier method, and the independent risk factors of metachronous BM were investigated by multivariate analysis. Results Patients developing metachronous BM had worse survival (mOS: 22.1 months) than patients not-developing BM (mOS: 44.8 months). Moreover, the multivariate analysis indicated that age ≤ 49 years (P = 0.035), number of extracranial metastases (P = 0.013), and malignant pleural effusion (P = 0.002) were independent risk factors of metachronous BM. Furthermore, the 1-year actuarial incidence of developing metachronous BM in patients with no risk factor (n = 101), 1 risk factor (n = 46), and 2 risk factors (n = 10) were 7.01, 14.61, and 43.75%, respectively (P

The rapid development of wireless power transfer technology brings forth innovative vehicle energy solutions and breakthroughs utilizing wireless sensor networks (WSNs). In most existing schemes, wireless rechargeable sensor networks (WRSNs) are generally equipped with one or more wireless charging vehicles (vehicles) to serve sensor nodes (SNs). These schemes solve the energy issue to some extent; however, due to off-road and speed limitations of vehicles, some SNs still cannot be charged in time, negatively affecting the lifetime of the networks. Our work proposes a new WRSN model equipped with one wireless charging drone (drone) with a constrained flight distance coupled with several wireless charging pads (pads) deployed to charge the drone when it cannot reach the subsequent stop. Our model solves this charging issues effectively and overcomes energy capacity limitations of the drone. Thus, a wireless charging pad deployment problem is formulated, which aims to apply the minimum number of pads so that at least one feasible routing path can be established for the drone to reach every SN in a given WRSN. Four feasible heuristics, three based on graph theory and one on geometry, are proposed for this problem. In addition, a novel drone scheduling algorithm, the shortest multi-hop path algorithm, is developed for the drone to serve charging requests with the assistance of pads. We examine the proposed schemes through extensive simulations. The results compare and demonstrate the effectiveness of the proposed schemes in terms of network density, region size and maximum flight distance.

Abstract Background The clinical target volume (CTV) for postoperative radiotherapy for thoracic esophageal squamous cell carcinoma (TESCC) needs to be defined. The study aim was to map metastatic lymph nodes (LNMs) in a computed tomography (CT)-based atlas and delineate the postoperative radiotherapy target area. Methods Sixty-nine TESCC patients with first recurrent regional LNMs after esophagectomy were included. The LNM epicenters were registered onto corresponding anatomic axial CT images of a standard patient in the treatment position, with reference to the surrounding vascular and bony structures. The LNM sites were based on lymph node map of esophageal cancer, AJCC 8th. The lymph metastasis risk for different segments of thoracic esophagus was assessed. Results One hundred and seventy-nine LNMs were mapped onto standard axial CT images. The upper-middle mediastinum region (station 1 to 8 M) contained 97% of metastases in the upper segment of thoracic esophagus, 90% in the middle segment, and 66% in the lower one. Advanced pathological stage (≥IIIB) might be a predictive factor for upper abdominal region (UAR) relapse in lower TESCC. Lower cervical para-tracheal LNMs were within a 4.3-cm bilaterally expanded area from the midline of the body and a 2.2-cm expanded area from the anterior of vertebral body, from the superior border of the C7, to the inferior border of the first thoracic vertebra. Conclusion A modified target from the upper border of C7 to the lower border of caudal margin of the inferior pulmonary vein level could cover the high-risk area of TESCC underwent postoperative radiotherapy. UAR seems to be an elective irradiation target for lower TESCC at pathological IIIB stage and higher.

Background: The brain contains the highest level of cholesterol in the body, and the total amount of serum cholesterol in the blood has a huge impact on brain aging and cognitive performance. However, the association of total serum cholesterol with cognitive function remains uncertain. This study determines whether there is an association between the total amount of cholesterol in the blood and cognitive performance in elderly females without a history of stroke. Methods: This population-based cross-sectional study was conducted on elderly (over 60 years old) females and males without a history of stroke from 2011 to 2014 in the US National Health and Nutrition Examination Survey (NHANES). The primary exposure was total blood cholesterol, and the main outcome was cognitive performance; this association was assessed with logistic regression analysis and restricted cubic splines. Results: 1309 female and 1272 male participants were included. In females, higher total cholesterol was significantly associated with higher cognitive scores, particularly in the digit symbol substitution test (OR 0.51, 95% CI (0.36–0.72)) and the animal fluency test (OR 0.64, 95% CI (0.45–0.91)). This association remained significant in models adjusted for age, race, smoking status, education level, and chronic conditions (OR 0.40, 95% CI (0.25–0.63)). This association was not significant in males, however. Conclusions: A higher concentration of total cholesterol measured in later life may be a protective factor for cognitive performance among females over 60 years old without a history of stroke. Further, this association was more pronounced among women with higher levels of education than women with lower or no education.

Abstract N‐methyl‐D‐aspartate (NMDA) receptors mediate excitatory neurotransmission in the nervous system and are preferentially inhibited by general anesthetics such as sevoflurane. Spontaneous movement is a common complication during sevoflurane anesthesia induction and seriously affects operations. In this study, we investigated the relationship between NMDA polymorphisms and spontaneous movement during sevoflurane induction. This prospective clinical study enrolled 393 patients undergoing sevoflurane anesthesia as part of their surgical routine. In the GRIN1, GRIN2A, and GRIN2B genes, 13 polymorphisms that form a heteromeric complex as part of the NMDA receptor were selected using Haploview and genotyped using matrix‐assisted laser desorption ionization–time of flight mass spectrometry MassARRAY. Both RNAfold and Genotype‐Tissue Expression portals were used to identify gene expression profiles. Our data showed that 35.8% of subjects exhibited spontaneous movement. The GRIN2A rs12918566 polymorphism was associated with spontaneous movement during sevoflurane induction. A logistic regression analysis of additive, dominant, and recessive models indicated a significant association (odds ratio [OR] (95% confidence limit [CI]): 0.58 (0.42–0.80), p = .00086; OR (95% CI): 0.51 (0.31–0.84), p = .0075, and OR (95% CI): 0.47 (0.27–0.81), p = .0060, respectively). After false discovery rate (FDR) correction, the additive model was still significant with a PFDR =0.010. Bioinformatics demonstrated that the rs12918566 genomic variation affected GRIN2A expression in brain tissue. We also revealed that GRIN2A rs12918566 was significantly associated with spontaneous movement during sevoflurane induction. We believe the NMDA receptor plays an important role in regulating the anesthetic effects of sevoflurane.

The characteristic aroma of Chinese black tea (BT) produced in summer usually lacks intensity and persistence, reducing consumer acceptance and market demand. Strobilanthes tonkinensis Lindau (STL) possesses excellent biological characteristics, making it a promising novel tea ingredient. We investigated the effects of different addition methods and concentrations for the novel additive STL on the sensory quality of BT. A 20:1500 g/g addition to rolled tea leaves was identified as the best BT with STL (BoS) treatment. We identified 141 volatile metabolites (VMs) for the first time in STL, with high alcohol, ester, ketone, enyne, alkyne, and alkane contents. Partial least-squares discriminant analysis distinguished the samples and revealed 28, 26, and 14 differential VMs in STL vs. BoS, BT vs. STL, and BT vs. BoS comparisons, respectively. Using a combination of Venn, multiple experiment viewer, and odor activity value analysis, 16 key differential VMs were identified. Compared to BT, the 1-octen-3-ol, 1-hexanol, 1-dodecanol, (E)-3-hexen-1-ol, phenylethyl alcohol, and 2-methoxy-3-(2-methylpropyl)-pyrazine contents in BoS were 394.7%, 53.6%, 34.1%, 24.4%, 9.9%, and 5.7% higher, respectively. BoS combined the aromatic properties of BT and STL into a sweet and glutinous rice flavor. The results provide theoretical support for future research and development of novel BT-based products.

Yunnan Congou black tea (YCBT) is a typical black tea in China, and is rich in theaflavins (TFs), thearubigins (TRs), and theabrownins (TBs). However, the influence of the fermentation temperature and time on the liquor and appearance color and the correlation between the tea pigments and its color attributes remain unclear. We investigated the effects of the fermentation temperature and time on the color attributes and tea pigments of YCBT. A low fermentation temperature was beneficial to maintain a bright orange-red liquor color and promote the accumulation of TFs and TRs. In contrast, a high temperature gave the liquor a glossy appearance and was beneficial for the formation of TBs. A correlation analysis showed that the 10TFRB index best represented the contribution of tea pigments to the quality of black tea. Moreover, TRs and TBs content prediction models were established based on the liquor L and H values, where the former value can be used as an important index to judge the fermentation process. This study will further enrich the theory of black tea processing chemistry and provide technical support for the precise and directional production of black tea.

B cell precursor acute lymphoblastic leukemia (BCP-ALL) is a blood cancer that originates from the abnormal proliferation of B-lymphoid progenitors. Cell population components and cell–cell interaction in the bone marrow microenvironment are significant factors for progression, relapse, and therapy resistance of BCP-ALL. In this study, we identified specifically expressed genes in B cells and myeloid cells by analyzing single-cell RNA sequencing data for seven BCP-ALL samples and four healthy samples obtained from a public database. Integrating 1356 bulk RNA sequencing samples from a public database and our previous study, we found a total of 57 significant ligand–receptor pairs (24 upregulated and 33 downregulated) in the autocrine crosstalk network of B cells. Via assessment of the communication between B cells and myeloid cells, another 29 ligand–receptor pairs were discovered, some of which notably affected survival outcomes. A score-based model was constructed with least absolute shrinkage and selection operator (LASSO) using these ligand–receptor pairs. Patients with higher scores had poorer prognoses. This model can be applied to create predictions for both pediatric and adult BCP-ALL patients.

Abstract Purpose The aim of the study was to evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) for pulmonary lesions in oligometastatic non‐small cell lung cancer (NSCLC) patients, to explore prognostic factors of progression‐free survival (PFS) and overall survival (OS), to validate improved survival contributed by SBRT in oligometastatic NSCLC patients. Patients and methods A total of 71 oligometastatic NSCLC patients with 86 pulmonary lesions treated with SBRT in our institute between 2012 and 2018 were included. Local control (LC), progression‐free survival (PFS), and overall survival (OS) were calculated using Kaplan‐Meier method. Prognostic factors of PFS and OS were analyzed using univariate and multivariate Cox analyses. Subgroup analyses were performed to investigate the impact of SBRT on PFS and OS during first line systemic treatment. Results After a median follow‐up of 17.6 months, 2‐year LC and OS rates were 82.6% and 55.3%, respectively. No grade 4 or more toxicities were observed. Multivariate analysis showed systemic treatment regimen before SBRT was an independent prognostic factor of PFS, but not for OS. Among this cohort, patients receiving first line target therapy could show a better PFS and OS than those undergoing first line chemotherapy (target therapy vs chemotherapy, PFS, 26.4 m vs 6.9 m; OS, 34.8 m vs 15.5 m). Conclusions SBRT for pulmonary lesions was a feasible and tolerable option for oligometastatic NSCLC patients. Delivery of SBRT for pulmonary lesions improved outcomes of oligometastatic NSCLC patients. Finally, SBRT combined with first line target therapy might have optimal outcomes.

Background/Aims: Intraoperative hypotension (IOH) may be associated with surgery-related acute kidney injury (AKI). However, the duration of hypotension that triggers AKI is poorly understood. The incidence of AKI with various durations of IOH and mean arterial pressures (MAPs) was investigated. Materials: A retrospective cohort study of 4,952 patients undergoing noncardiac surgery (2011 to 2016) with MAP monitoring and a length of stay of one or more days was performed. The exclusion criteria were a preoperative estimated glomerular filtration (eGFR) ≤60 mL min–1 1.73 m2–1, a preoperative MAP less than 65 mm Hg, dialysis dependence, urologic surgery, age older than 60 years, and a surgical duration of less than 60 min. The primary exposure was IOH, and the primary outcome was AKI (50% or 0.3 mg dL–1 increase in creatinine) during the first 7 postoperative days. Multivariable logistic regression was used to model the exposure-outcome relationship. Results: AKI occurred in 186 (3.76%) noncardiac surgery patients. The adjusted odds ratio for surgery-related AKI for a MAP of less than 55 mm Hg was 14.11 (95% confidence interval: 5.02–39.69) for an exposure of more than 20 min. Age was not an interaction factor between AKI and IOH. Conclusion: There was a considerably increased risk of postoperative AKI when intraoperative MAP was less than 55 mm Hg for more than 10 min. Strict blood pressure management is recommended even for patients younger than 60 years old.

Objective: The mortality rate of critically ill patients in ICUs is relatively high. In order to evaluate patients’ mortality risk, different scoring systems are used to help clinicians assess prognosis in ICUs, such as the Acute Physiology and Chronic Health Evaluation III (APACHE III) and the Logistic Organ Dysfunction Score (LODS). In this research, we aimed to establish and compare multiple machine learning models with physiology subscores of APACHE III—namely, the Acute Physiology Score III (APS III)—and LODS scoring systems in order to obtain better performance for ICU mortality prediction. Methods: A total number of 67,748 patients from the Medical Information Database for Intensive Care (MIMIC-IV) were enrolled, including 7055 deceased patients, and the same number of surviving patients were selected by the random downsampling technique, for a total of 14,110 patients included in the study. The enrolled patients were randomly divided into a training dataset (n = 9877) and a validation dataset (n = 4233). Fivefold cross-validation and grid search procedures were used to find and evaluate the best hyperparameters in different machine learning models. Taking the subscores of LODS and the physiology subscores that are part of the APACHE III scoring systems as input variables, four machine learning methods of XGBoost, logistic regression, support vector machine, and decision tree were used to establish ICU mortality prediction models, with AUCs as metrics. AUCs, specificity, sensitivity, positive predictive value, negative predictive value, and calibration curves were used to find the best model. Results: For the prediction of mortality risk in ICU patients, the AUC of the XGBoost model was 0.918 (95%CI, 0.915–0.922), and the AUCs of logistic regression, SVM, and decision tree were 0.872 (95%CI, 0.867–0.877), 0.872 (95%CI, 0.867–0.877), and 0.852 (95%CI, 0.847–0.857), respectively. The calibration curves of logistic regression and support vector machine performed better than the other two models in the ranges 0–40% and 70%–100%, respectively, while XGBoost performed better in the range of 40–70%. Conclusions: The mortality risk of ICU patients can be better predicted by the characteristics of the Acute Physiology Score III and the Logistic Organ Dysfunction Score with XGBoost in terms of ROC curve, sensitivity, and specificity. The XGBoost model could assist clinicians in judging in-hospital outcome of critically ill patients, especially in patients with a more uncertain survival outcome.

Adverse drug reactions (ADRs) are a major public health concern, and early detection is crucial for drug development and patient safety. Together with the increasing availability of large-scale literature data, machine learning has the potential to predict unknown ADRs from current knowledge. By the machine learning methods, we constructed a Tumor-Biomarker Knowledge Graph (TBKG) which contains four types of node: Tumor, Biomarker, Drug, and ADR using biomedical literatures. Based on this knowledge graph, we not only discovered potential ADRs of antitumor drugs but also provided explanations. Experiments on real-world data show that our model can achieve 0.81 accuracy of three cross-validation and the ADRs discovery of Osimertinib was chosen for the clinical validation. Calculated ADRs of Osimertinib by our model consisted of the known ADRs which were in line with the official manual and some unreported rare ADRs in clinical cases. Results also showed that our model outperformed traditional co-occurrence methods. Moreover, each calculated ADRs were attached with the corresponding paths of “tumor-biomarker-drug” in the knowledge graph which could help to obtain in-depth insights into the underlying mechanisms. In conclusion, the tumor-biomarker knowledge-graph based approach is an explainable method for potential ADRs discovery based on biomarkers and might be valuable to the community working on the emerging field of biomedical literature mining and provide impetus for the mechanism research of ADRs.

BackgroundMembers of the aging population who undergo surgery are at risk of postoperative cognitive dysfunction (POCD). Exploring an effective and reliable early predictor of POCD is essential to the identification of high-risk patients and to making prospective decisions. The purpose of this study was to examine whether preoperative insulin resistance is an independent predictor of POCD.MethodsA total of 124 patients aged 60 years and older and who were scheduled for gastrointestinal surgery were enrolled in a prospective observational clinical study. All participants completed a battery of neuropsychological tests before surgery and 7 days later. POCD was defined as a decline of at least 1.5 SD on two or more of neuropsychological tests. Plasma concentration of the tumor necrosis factor α (TNF-α), C-reactive protein (CRP), and S-100β protein were measured. The status of insulin resistance was assessed by Homeostasis Model Assessment–Insulin Resistance (HOMA-IR). The relationship between HOMA-IR and POCD was assessed by Multivariable logistic regression models and the receiver operating characteristic (ROC) curve.ResultsFifty one patients (41.1%) were diagnosed with POCD at 7 days after surgery. Preoperative HOMA-IR values of the POCD group were significantly higher than the non-POCD group. Furthermore, CRP and TNF-α levels of the POCD group were significantly higher at each postoperative time point (P < 0.05). The preoperative HOMA-IR value was an independent predictor of POCD (adjusted OR 1.88, 95% CI, 1.18–2.99) even after adjust for confounding variables, and when dichotomized, individuals above the HOMA-IR threshold (HOMA-IR > 2.6) had a three-times higher risk of POCD (OR 3.26; 95% CI, 1.07–9.91) compared to individuals below the threshold. The areas under the ROC curve of HOMA-IR was 0.804 (95% CI, 0.725–0.883; P < 0.001). The optimal cut-off value was found to be 0.583, with a sensitivity of 84.3% and specificity of 74%. The HOMA-IR value was positively associated with the TNF-α concentration at baseline (R2 = 0.43, P < 0.01) and 1 day after surgery (R2 = 0.3861, P < 0.01).ConclusionPreoperative insulin resistance is an effective predictor for the occurrence of POCD. Targeted prevention and treatment strategies of insulin resistance may be effective interventions of patients at risk for POCD.

Background LncRNA MIR4435-2HG is observed in a variety of cancers, while its role in colorectal cancer is unknown. We aimed to demonstrate the relationship between MIR4435-2HG and colorectal cancer based on The Cancer Genome Atlas (TCGA) database. Materials and Methods Patients with colorectal cancer were collected from TCGA. We compared the expression of MIR4435-2HG in colorectal cancer and normal tissues with Wilcoxon rank sum test, and logistic regression was used to evaluate the relationship between MIR4435-2HG and clinicopathological characters. Moreover, Kaplan–Meier and Cox regression was performed to evaluate the correlation between MIR4435-2HG and survival rate. Gene set enrichment analysis (GSEA) was also conducted to annotate biological function of MIR4435-2HG. Results MIR4435-2HG level was elevated in colorectal cancer tissues. Increased level of MIR4435-2HG was significantly correlated with TNM stage (OR = 1.66 for T1/T2 vs. T3/T4; OR = 1.68 for N0 vs. N1/N2), stage (OR = 1.66 for stage 1/2 vs. stage 3/4), and carcinoembryonic antigen level before treatment (OR = 1.70 for

Mounting evidence shows that chronic stress can affect both the structure and function of the brain resulting in decreased synaptic plasticity and cognitive dysfunction. Although several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown how to prevent stress-induced memory deficits in aged animals. Neuroinflammation plays an important role in the pathogenesis of chronic stress-related brain dysfunction. Receptor-interacting protein 1 (RIP1) is a key molecule that can modulate inflammation, apoptosis, and necroptosis. Here, we investigated whether inhibiting RIP1 using necrostatin-1 during chronic stress could improve chronic stress-related brain dysfunction in D-galactose-induced aging mice. The stressed mice underwent restraint stress for 14 days. Necrostatin-1 (6.25 mg/kg) or vehicle was administered intraperitoneally once every 3 days during the stress period. Locomotor activity was tested using the open field test and cognitive function was assessed using the novel object recognition and Barnes maze tests. The hippocampus was collected to assess neuroinflammation (Iba1, IL-1α, IL-1β, TNF-α, and C1q), necroptosis [RIP1, RIP3, mixed lineage kinase domain-like (MLKL), and NF-κB], neuroplasticity (doublecortin, NR1, NR2A, NR2B, GluA1, and GluA2), and the expression of glucocorticoid and mineralocorticoid receptors. Blood samples were collected to quantify the levels of corticosterone. We found that chronic stress induced obvious memory impairment and neuroinflammation, decreased neurogenesis and GluA2 expression, and increased the expression of RIP1 and NF-κB. Inhibiting RIP1 by necrostatin-1 during chronic stress rescued the memory impairment and alleviated the pathological changes induced by stress. These suggest that inhibiting RIP1 using necrostatin-1 improves chronic stress-related brain dysfunction in D-galactose-induced aging mice. The potential mechanisms include limitation of neuroinflammation and the rescue of neurogenesis and GluA2 expression.

Occurrence of postoperative cognitive dysfunction (POCD) is age-dependent and heterogenous. Factors deciding the occurrence of POCD in patients of the same age undergone same surgeries remain unclear. Here we investigated the effects of pre-existing weakness on the occurrence of POCD in mice of the same age. Pre-existing weakness of mice was induced by intraperitoneal injection of lipopolysaccharide (8mg/kg) and was evaluated by physical frailty index (by open field test), neuroinflammation level (by Iba1 immunostaining and inflammatory factors TNF-α and IL-1β), and neuronal activity (by p-CREB immunostaining). POCD was induced by partial hepatolobectomy and was evaluated by puzzle box test and Morris water maze test. The brains were collected to detect the levels of neuroinflammation, synaptophysin and NMDA receptor subunits NR2A, NR2B and NR1 (by western blot), and oxidative stress (by Dihydroethidium). Compared to the normal adult mice of the same age, LPS pretreated mice had increased physical frailty index, higher levels of neuroinflammation, and lower neuronal activity. Partial hepatolobectomy induced obvious impairments in executive function, learning and memory in LPS pretreated mice after surgery, but not in normal mice of the same age. Partial hepatolobectomy also induced heightened neuroinflammation, obvious loss of NMDA receptor subunits, strong oxidative stress in LPS pretreated mice on the 1st and 3rd postoperative day. However, the POCD-associated pathological changes didn't occur in normal mice of the same age after surgery. These results suggest that pre-existing weakness is critical for the occurrence of POCD in mice of the same age.

Sepsis-induced neuroinflammation plays an important role in sepsis-related brain dysfunction. However, the molecules that are targeted during neuroinflammation resulting from sepsis-induced brain dysfunction remain unclear. Herein, we tried to investigate the expression and roles of NMDA receptor subunits during sepsis-related brain dysfunction.Sepsis was induced by cecal ligation and perforation (CLP) or by a single intraperitoneal injection of lipopolysaccharide (LPS, 8 mg/kg) in C57BL/6J mice. The NMDA receptor co-agonist D-serine was injected intraperitoneally for 3 days (500 mg/kg/day) to compensate for the loss of NMDA receptors. The behaviors of mice were tested in the Barnes maze and in the open field test. The mice were euthanized at the indicated time points. The brains were collected to detect the following: the levels of synaptophysin and NMDA receptor subunits GluN2A, GluN2B and GluN1 (by Western blot and RT-PCR); the number of CA1 neurons (by Nissl staining); neuronal activity (by p-CREB staining); neuroinflammation (by staining of Iba-1 and inflammatory factors IL-1β, TNF-α, NLRP3); and the levels of oxidative stress [by dihydroethidium (DHE)].Sepsis selectively decreased the protein and mRNA levels of GluN2A, GluN2B and GluN1 but not the levels of synaptophysin or the neuronal number in the hippocampus of mice in either of the classic CLP-induced or LPS-induced sepsis models during the first 7 days after sepsis. Intraperitoneal injection of D-serine obviously limited the lipopolysaccharide-induced changes, including the impairment of learning and memory, the loss of NMDA receptor subunits, robust neuroinflammation, the levels of ROS stress and the decrease of p-CREB in the hippocampus of mice.These data suggest that the sepsis-induced selective loss of NMDA receptors modulates hippocampal neuropathology in the mice that survived sepsis, and the data show that NMDA receptors are potential targets for the improvement of brain dysfunction in sepsis survivors.

To investigate the effects and underlying mechanism of dexmedetomidine on the cultured human dendritic cells (DCs).Human DCs and cytotoxic T lymphocytes (CTLs) were obtained from human cord blood mononuclear cells by density gradient centrifugation. Cultured DCs were divided into three groups: dexmedetomidine group, dexmedetomidine plus yohimbine (dexmedetomidine inhibitor) group and control group. DCs in the three groups were treated with dexmedetomidine, dexmedetomidine plus yohimbine and culture medium, respectively. After washing, the DCs were co-incubated with cultured CTLs. The maturation degree of DCs was evaluated by detecting (1) the ratios of HLA-DR-, CD86-, and CD80-positive cells (flow cytometry), and (2) expression of IL-12 and IL-23 (PCR and Elisa). The function of DCs was evaluated by detecting the proliferation (MTS assay) and cytotoxicity activity (the Elisa of IFN-γ) of CTLs. In addition, in order to explore the mechanisms of dexmedetomidine modulating DCs, α2-adrenergic receptor and its downstream signals in DCs were also detected.The ratios of HLA-DR-, CD86-, and CD80-positive cells to total cells were similar among the three groups (P>0.05). Compared to the control group, the protein levels of IL-12 and IL-23 in the culture medium and the mRNA levels of IL-12 p35, IL-12 p40 and IL-23 p19 in the DCs all decreased in dexmedetomidine group (P

Both wireless sensor networks and service-oriented architectures (SOA) are very popular distributed computing paradigm. Web service is a widely accepted implementation of SOA. However, web service is based on Internet protocols and requires adaptation to suit the restrictions posed by WSNs. The development of Internet of Things has triggered research of web services of WSNs which made the consolidation of these technologies possible. At the same time, web service integration enables the support of more functionalities since many applications rely on not just one web service, but a whole school of them. Thus, how to compose and integrate different web services efficiently to provide complicated services becomes an essential topic. This paper investigates a problem which minimizes the number of hops of web services while integrating these web services to finish a set of tasks. We call this problem Minimum Hops of Service Integration Problem. It is proved that, when there are no precedence relationships between the tasks, the decision problem is NP-complete. This implies that this web services integration problem is NP-hard. For the case when the relationships between the tasks are in linear order, a polynomial-time, optimal web service integration algorithm, using greedy strategy, is provided.

It is known that age is an important factor for postoperative cognitive dysfunction (POCD) and the patients with POCD suffer from the impairment of multiple brain regions and multiple brain functions. However currently animal studies of POCD mainly focus on hippocampus region, therefore in this study we performed partial hepatectomy in young adult and aged rats to test the questions (1) whether POCD in animals involves other brain areas besides hippocampus; (2) how age influences POCD of young adult and aged animals. We found that (1) in young adult rats, the memory was not significantly affected (P>0.05) 1d, 3d and 7d after partial hepatectomy, but was significantly impaired (p0.05, respectively) 1d and 3d post-surgery, but the spine densities at CA1 and DG of aged rats were significant reduced 1d and 3d post-surgery (p0.05); (3) In young adult rats, surgery didn't affect the activation of microglia and levels of TNF-α and IL-1β at hippocampus (P>0.05), but significantly activated microglia and increased levels of TNF-α and IL-1β at hippocampus of aged rats (P

BACKGROUND: Postoperative cognitive dysfunction (POCD) is common following cardiac and non-cardiac surgery, but the pathogenic mechanisms remain unknown. Many studies suggest that an inflammatory response is a key contributor to POCD. The current meta-analysis shows that the levels of peripheral inflammatory markers are associated with POCD. METHODS: An online search was performed to identify peer-reviewed studies without language restriction that measured peripheral inflammatory markers of patients with and without POCD, using PubMed, ScienceDirect, SinoMed and the National Knowledge Infrastructure database. Extracted data were analyzed with STATA (version 12).The standardized mean difference (SMD) and the 95% confidence interval (95%CI) were calculated for each outcome using a random effect model. Tests of heterogeneity assessment of bias, and meta-regression were performed in the meta-analysis. RESULTS: A total of 13 studies that measured the concentrations of peripheral inflammatory markers were included. The current meta-analysis found significantly higher concentrations of S-100β(SMD[95%CI]) (1.377 [0.423, 2.331], p-value < 0.001, N [POCD/non-POCD] =178/391, 7 studies), and interleukin(IL)-6 (SMD[95%CI]) (1.614 [0.603,2.624], p-value < 0.001, N[POCD/non-POCD] = 91/99, 5 studies), but not of neuron specific enolase, interleukin-1β, or tumor necrosis factor-α , in POCD compared with patients without POCD. In meta-regression analyses, a significant positive association was found between the SMD and the preoperative interleukin-6 peripheral blood concentration in patients with POCD (Coef.= 0.0587, p-value=0.038, 5 studies). CONCLUSIONS: This study shows that POCD is indeed correlated with the concentrations of peripheral inflammatory markers, particularly interleukin-6 and S-100β.