Genetically supported causality between gut microbiota and frailty: a two-sample Mendelian randomization study.

Background: A mounting body of evidence suggests a strong connection between gut microbiota and the risk of frailty. However, the question of causality remains unanswered. In this study, we employed a Mendelian randomization (MR) approach to assess potential causal relationships between gut microbiota and the risk of frailty. Materials and methods: Summary statistics for the gut microbiome were obtained from a genome wide association study (GWAS) meta-analysis of the MiBioGen consortium (N = 18,340). Summary statistics for frailty were obtained from a GWAS meta-analysis, including the UK Biobank and TwinGene (N = 175,226). Our primary analysis utilized the inverse variance weighted (IVW) method. To enhance the robustness of our results, we also applied weighted median methods, MR Egger regression, and MR pleiotropy residual sum and outlier test. Finally, we conducted reverse MR analysis to investigate the potential for reverse causality. Results: IVW method identified 7 bacterial taxa nominally associated with the risk of FI. Class Bacteroidia (p = 0.033) and genus Eubacterium ruminantium group (p = 0.028) were protective against FI. In addition, class Betaproteobacteria (p = 0.042), genus Allisonella (p = 0.012), genus Bifidobacterium (p = 0.013), genus Clostridium innocuum group (p = 0.036) and genus Eubacterium coprostanoligenes group (p = 0.003) were associated with a higher risk of FI. No pleiotropy or heterogeneity were found. Conclusion: The MR analysis indicates a causal relationship between specific gut microbiota and FI, offering new insights into the mechanisms underlying FI mediated by gut microbiota.

Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study.

Background: Previous researches have suggested a significant connection between the gut microbiota/immune cells and morphine tolerance (MT), but there is still uncertainty regarding their causal relationship. Hence, our objective is to inverstigate this causal association and reveal the impact of gut microbiota/immune cells on the risk of developing MT using a two-sample Mendelian randomization (MR) study. Methods: We conducted a comprehensive analysis using genome-wide association study (GWAS) summary statistics for gut microbiota, immune cells, and MT. The main approach employed was the inverse variance-weighted (IVW) method in MR. To assess horizontal pleiotropy and remove outlier single-nucleotide polymorphisms (SNPs), we utilized the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) technique as well as MR-Egger regression. Heterogeneity detection was performed using Cochran's Q-test. Additionally, leave-one-out analysis was carried out to determine if any single SNP drove the causal association signals. Finally, we conducted a reverse MR to evaluate the potential of reverse causation. Results: We discovered that 6 gut microbial taxa and 16 immune cells were causally related to MT (p < 0.05). Among them, 2 bacterial features and 9 immunophenotypes retained a strong causal relationship with lower risk of MT: genus. Lachnospiraceae NK4A136group (OR: 0.962, 95% CI: 0.940-0.987, p = 0.030), genus. RuminococcaceaeUCG011 (OR: 0.960, 95% CI: 0.946-0.976, p = 0.003), BAFF-R on B cell (OR: 0.972, 95% CI: 0.947-0.998, p = 0.013). Furthermore, 4 bacterial features and 7 immunophenotypes were identified to be significantly associated with MT risk: genus. Flavonifractor (OR: 1.044, 95% CI: 1.017-1.069, p = 0.029), genus. Prevotella9 (OR: 1.054, 95% CI: 1.020-1.090, p = 0.037), B cell % CD3-lymphocyte (OR: 1.976, 95% CI: 1.027-1.129, p = 0.026). The Cochrane's Q test revealed no heterogeneity (p > 0.05). Furthermore, the MR-Egger and MR-PRESSO analyses reveal no instances of horizontal pleiotropy (p > 0.05). Besides, leave-one-out analysis confirmed the robustness of MR results. After adding BMI to the multivariate MR analysis, the gut microbial taxa and immune cells exposure-outcome effect were attenuated. Conclusion: Our research confirm the potential link between gut microbiota and immune cells with MT, shedding light on the mechanism by which gut microbiota and immune cells may contribute to MT. These findings lay the groundwork for future investigations into targeted prevention strategies.

Piezo2 Contributes to Traumatic Brain Injury by Activating the RhoA/ROCK1 Pathways.

Traumatic brain injury (TBI) can lead to short-term and long-term physical and cognitive impairments, which have significant impacts on patients, families, and society. Currently, treatment outcomes for this disease are often unsatisfactory, due at least in part to the fact that the molecular mechanisms underlying the development of TBI are largely unknown. Here, we observed significant upregulation of Piezo2, a key mechanosensitive ion channel protein, in the injured brain tissue of a mouse model of TBI induced by controlled cortical impact. Pharmacological inhibition and genetic knockdown of Piezo2 after TBI attenuated neuronal death, brain edema, brain tissue necrosis, and deficits in neural function and cognitive function. Mechanistically, the increase in Piezo2 expression contributed to TBI-induced neuronal death and subsequent production of TNF-α and IL-1ß, likely through activation of the RhoA/ROCK1 pathways in the central nervous system. Our findings suggest that Piezo2 is a key player in and a potential therapeutic target for TBI.

Temporal Distribution Patterns of Cryptic Brachionus calyciflorus (Rotifera) Species in Relation to Biogeographical Gradient Associated with Latitude.

Sympatric distribution and temporal overlap of cryptic zooplankton species pose a challenge to the framework of the niche differentiation theory and the mechanisms allowing competitor coexistence. We applied the methods of phylogenetic analysis, DNA taxonomy, and statistical analysis to study the temporal distribution patterns of the cryptic B. calyciflorus species, an excellent model, in three lakes, and to explore the putative mechanisms for their seasonal succession and temporal overlap. The results showed that in the warm-temperate Lake Yunlong, B. fernandoi and B. calyciflorus s.s. underwent a seasonal succession, which was largely attributed to their differential adaptation to water temperature. In the subtropical Lake Jinghu, B. fernandoi, B. calyciflorus s.s., and B. dorcas exhibited both seasonal succession and temporal overlap. Seasonal successions were largely attributed to their differential adaptation to temperature, and temporal overlap resulted from their differential responses to algal food concentration. In the tropical Lake Jinniu, B. calyciflorus s.s. persisted throughout the year and overlapped with B. dorcas for 5 months. The temporal overlap resulted from their differential responses to copepod predation. These results indicated that the temporal distribution pattern of the cryptic B. calyciforus species and the mechanism that allows competitor coexistence vary with different climate zones.

Effect of trans-nasal humidified rapid insufflation ventilatory exchange on reflux and microaspiration in patients undergoing laparoscopic cholecystectomy during induction of general anesthesia: a randomized controlled trial.

Background: Reflux aspiration is a rare but serious complication during induction of anesthesia. The primary aim of this study is to compare the incidence of reflux and microaspiration in patients undergoing laparoscopic cholecystectomy during induction of general anesthesia using either a facemask or trans-nasal humidified rapid insufflation ventilatory exchange. Methods: We conducted a single-center, randomized, controlled trial. Thirty patients were allocated to either a facemask or a trans-nasal humidified rapid insufflation ventilatory exchange (THRIVE) group. Pre-oxygenation for 5 min with a facemask or THRIVE, positive pressure ventilation for 2 min or THRIVE for 2 min after anesthesia induction was followed. Before endotracheal intubation, the secretion above and below the glottis was collected to measure pepsin content and analyze blood gas. The ELISA assay for supra- and subglottic human pepsin content was used to detect the presence of reflux and microaspiration. The primary outcome was the incidence of reflux and microaspiration. Secondary outcomes were apnea time, PaO2 before tracheal intubation, and the end-expiratory carbon dioxide partial pressure. Results: Patients in the THRIVE group had a significantly longer apnea time (379.55 ± 94.12 s) compared to patients in the facemask group (172.96 ± 58.87 s; p < 0.001). There were no differences observed in PaO2 between the groups. A significant difference in gastric insufflation, reflux, and microaspiration was observed between the groups. Gastric insufflation was 6.9% in the THRIVE group vs. 28.57% kPa in the facemask group (p = 0.041); reflux was 10.34% in the THRIVE group vs. 32.14% kPa in the facemask group (p = 0.044); and microaspiration was 0% in the THRIVE group vs. 17.86% kPa in the facemask group (p = 0.023). Conclusion: The application of THRIVE during induction of general anesthesia reduced the incidence of reflux and microaspiration while ensuring oxygenation and prolonged apnea time in laparoscopic cholecystectomy patients. THRIVE may be an optimal way to administer oxygen during the induction of general anesthesia in laparoscopic cholecystectomy patients. Clinical trial registration: Chinese Clinical Trial Registry, No: ChiCTR2100054086, https://www.chictr.org.cn/indexEN.html.

Ultrasound assessment of gastric content in patients undergoing laparoscopic cholecystectomy after preoperative oral carbohydrates: a prospective, randomized controlled, double-blind study.

Background: To evaluate the gastric volume and nature after drinking preoperative oral carbohydrates in patients undergoing laparoscopic cholecystectomy via ultrasonography. Methods: One hundred patients who had been scheduled for elective laparoscopic cholecystectomy were enrolled and randomized into the traditional fasting group (Control group, n = 50) and the carbohydrate group (CHO group, n = 50). Patients in the Control group fasted solids and drink from midnight, the day before surgery. Patients in the CHO group drank 800 ml and 400 ml of oral carbohydrates 11 and 3 h before surgery, respectively. At 2 h after oral carbohydrates (T1), all patients underwent an ultrasound examination of residual gastric contents; if the patients had a full stomach, the assessment was performed again 1 h later (T2). A stomach containing solid contents or >1.5 ml/kg of liquid was considered "full". The primary outcome was full stomach incidences at the above time points. The secondary outcomes included gastric antral CSA in the right lateral decubitus (RLD) and semi-sitting positions, as well as gastric volume (GV), GV per weight (GV/kg), and Perla's grade at T1. Results: Compared with the Control group, the incidence of entire stomach was significantly high in the CHO group 2 h after oral carbohydrates. At the T1 time point, 6 patients (13.3%) in the Control group and 14 patients (30.4%) in the CHO group presented with a full stomach [95% confidence interval (CI), (0.96-5.41), P = 0.049]. At T2, 3 patients (6.7%) in the Control group and 4 patients (8.7%) in the CHO group had a full stomach, with no marked differences between the two groups [95% CI, (0.31-5.50), P = 0.716]. Compared with the Control group, CSA in the semi-sitting and RLD positions, GV and GV/W were significantly high in the CHO group at T1 (P < 0.05). The median (interquartile range) of the Perlas grade was 1 (0-1) in the Control group and 1(1-1.25) in the CHO group (P = 0.004). Conclusion: Cholecystectomy patients experience a 2 h delay in gastric emptying after receiving preoperative carbohydrates. In LC patients, the fasting window for oral carbohydrates before surgery should be adequately prolonged. Clinical Trail registration: Chinese Clinical Trail Registry, No: ChiCTR2200055245.

Comparison of Carotid Blood Flow Measured by Ultrasound and Cardiac Output in Patients Undergoing Cardiac Surgery.

BACKGROUND: In general, cerebral blood flow accounts for 10-15% of cardiac output (CO), of which about 75% is delivered through the carotid arteries. Hence, if carotid blood flow (CBF) is constantly proportional to CO with high reproducibility and reliability, it would be of great value to measure CBF as an alternative to CO. The aim of this study was to investigate the direct correlation between CBF and CO. We hypothesized that measurement of CBF could be a good substitute for CO, even under more extreme hemodynamic conditions, for a wider range of critically ill patients. METHODS: Patients aged 65-80 years, undergoing elective cardiac surgery were included in this study. CBF in different cardiac cycles were measured by ultrasound: systolic carotid blood flow (SCF), diastolic carotid blood flow (DCF), and total (systolic and diastolic) carotid blood flow (TCF). CO simultaneously was measured by transesophageal echocardiography. RESULTS: For all patients, the correlation coefficients between SCF and CO, TCF and CO were 0.45 and 0.30, respectively, which were statistically significant, but not between DCF and CO. There was no significant correlation between either SCF, TCF or DCF and CO, when CO was <3.5 L/min. CONCLUSIONS: Systolic carotid blood flow may be used as a better index to replace CO. However, the method of direct measurement of CO is essential when the patient's heart function is poor.

Combination of single-nucleus and bulk RNA-seq reveals the molecular mechanism of thalamus haemorrhage-induced central poststroke pain.

Central poststroke pain (CPSP) induced by thalamic haemorrhage (TH) can be continuous or intermittent and is accompanied by paresthesia, which seriously affects patient quality of life. Advanced insights into CPSP mechanisms and therapeutic strategies require a deeper understanding of the molecular processes of the thalamus. Here, using single-nucleus RNA sequencing (snRNA-seq), we sequenced the transcriptomes of 32332 brain cells, which revealed a total of four major cell types within the four thalamic samples from mice. Compared with the control group, the experimental group possessed the higher sensitivity to mechanical, thermal, and cold stimuli, and increased microglia numbers and decreased neuron numbers. We analysed a collection of differentially expressed genes and neuronal marker genes obtained from bulk RNA sequencing (bulk RNA-seq) data and found that Apoe, Abca1, and Hexb were key genes verified by immunofluorescence (IF). Immune infiltration analysis found that these key genes were closely related to macrophages, T cells, related chemokines, immune stimulators and receptors. Gene Ontology (GO) enrichment analysis also showed that the key genes were enriched in biological processes such as protein export from nucleus and protein sumoylation. In summary, using large-scale snRNA-seq, we have defined the transcriptional and cellular diversity in the brain after TH. Our identification of discrete cell types and differentially expressed genes within the thalamus can facilitate the development of new CPSP therapeutics.

Apoptotic mechanism of propofol-induced developmental toxicity in zebrafish embryos.

General anesthetics can cause neurological damage and long-term behavioral/cognitive impairment during fetal and early postnatal life. However, the adverse influence on embryo development induced by propofol is unclear. We used embryonic zebrafish to explore the effects of propofol on embryonic and larval growth and development, and the related apoptotic mechanism. Zebrafish embryos were immersed in propofol (1, 2, 3, 4, and 5 µg/ml) dissolved in E3 medium from 6 to 48 hours post fertilization (hpf). The survival rate, locomotion, heart rate, hatchability, deformity rate, and body length were analyzed at defined stages. Terminal deoxynucleotidyl transferase nick-end-labeling was used to detect zebrafish embryo apoptosis, and the expression levels of apoptosis-related genes were determined using quantitative real-time reverse transcription PCR and whole-mount in situ hybridization. Larvae at 48 hpf were anesthetized by immersion in E3 culture medium containing 2 µg/ml propofol, the reasonable anesthetic concentration for zebrafish embryos, which caused significant caudal fin dysplasia, light pigmentation, edema, hemorrhage, and spinal deformity, and decreased the hatchability, body length, and heart rate. The numbers of apoptotic cells in propofol-treated 12, 48 and 72 hpf embryos increased significantly, and the mRNA expression levels of intrinsic apoptosis pathway-related casp3a, casp3b, casp9, and baxb genes were upregulated, mainly in the head and tail. Propofol decreased apoptosis in the head and back of 24 hpf zebrafish, which was consistent with the mRNA expression analysis. Our findings demonstrated that zebrafish embryos and larvae exposed to propofol experienced developmental toxicity, which correlated with the intrinsic apoptosis pathway with casp3a, casp3b, casp9, and baxb as the key genes.

Evolution Under Dietary Restriction Increases Reproduction at the Cost of Decreased Somatic Growth.

Dietary restriction (DR) is cited as the most reliable means of extending life span in a wide range of taxa, yet the evolutionary basis of the DR effect on life span remains unclear. The resource reallocation hypothesis proposes that the longevity-extending response of DR is adaptive and stems from the reallocation of resources from reproduction to somatic maintenance under food-limited conditions. However, if DR continues for multiple generations, such a response becomes maladaptive, and genotypes with higher fecundity should be selectively favored over genotypes with longer longevity. To test this prediction, we exposed replicate populations of the rotifer Brachionus dorcas, a model organism for aging and experimental evolution studies, to DR and ad-libitum (AL) diets for 100 days. During the selection experiment, AL-selected populations showed higher growth rates and mictic ratios than DR-selected populations. After approximately 27 asexual generations of selection, populations with a DR selection history had a higher net reproductive rate but lower body volume and ingestion rate in the absence of survival costs than populations with an AL selection history when they were assayed on an AL diet. Our results are inconsistent with the prediction that evolution on sustained DR increases reproduction and reduces life span, and show for the first time that sustained DR selects for clones with higher energy investment in reproduction but lower investment in somatic growth.

The use of multiple datasets to identify autophagy-related molecular mechanisms in intracerebral hemorrhage.

Background: Intracerebral hemorrhage (ICH) is a stroke syndrome with high mortality and disability rates, but autophagy's mechanism in ICH is still unclear. We identified key autophagy genes in ICH by bioinformatics methods and explored their mechanisms. Methods: We downloaded ICH patient chip data from the Gene Expression Omnibus (GEO) database. Based on the GENE database, differentially expressed genes (DEGs) for autophagy were identified. We identified key genes through protein-protein interaction (PPI) network analysis and analyzed their associated pathways in Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Gene-motif rankings, miRWalk and ENCORI databases were used to analyze the key gene transcription factor (TF) regulatory network and ceRNA network. Finally, relevant target pathways were obtained by gene set enrichment analysis (GSEA). Results: Eleven autophagy-related DEGs in ICH were obtained, and IL-1B, STAT3, NLRP3 and NOD2 were identified as key genes with clinical predictive value by PPI and receiver operating characteristic (ROC) curve analysis. The candidate gene expression level was significantly correlated with the immune infiltration level, and most of the key genes were positively correlated with the immune cell infiltration level. The key genes are mainly related to cytokine and receptor interactions, immune responses and other pathways. The ceRNA network predicted 8,654 interaction pairs (24 miRNAs and 2,952 lncRNAs). Conclusion: We used multiple bioinformatics datasets to identify IL-1B, STAT3, NLRP3 and NOD2 as key genes that contribute to the development of ICH.

miR-223 ameliorates thalamus hemorrhage-induced central poststroke pain via targeting NLRP3 in a mouse model.

Central poststroke pain (CPSP) is a central neuropathic pain syndrome that occurs following a stroke and mainly manifests as pain and paresthesia in the body region corresponding to the brain injury area. At present, due to the lack of clinical attention given to CPSP, patients suffer from long-term pain that seriously affects their quality of life. Current literature indicates that microRNA (miR)-223 can impede inflammation and prevent collateral damage. The NLR family pyrin domain containing 3 (NLRP3) inflammasome induces IL-18 and IL-1ß secretion and maturation and participates in the inflammatory response. Previous evidence has confirmed that miR-223 can negatively regulate NLRP3 in the development of inflammatory responses. However, whether the miR-223 targeting of NLRP3 is involved in CPSP remains unclear. In the present study, the expression of miR-223 was detected by reverse transcription-quantitative PCR analysis. The expression levels of NLRP3, caspase-1, ASC, IL-18, IL-1ß, ERK1/2, p-ERK1/2 and GFAP were detected by western blot analysis. The results demonstrated that thalamic hemorrhagic stroke triggered by microinjection of collagenase Ⅳ (Coll IV) into the ventral posterior lateral (VPL) nucleus results in pain hypersensitivity. miR-223 expression level were significantly reduced in the CPSP model. The expression levels of NLRP3, caspase-1, ASC, IL-18 and IL-1ß were significantly increased in the CPSP model. The expression level of GFAP was detected to determine astrocyte activation. The results demonstrated that astrocyte activation induced by Coll IV produced a CPSP model. The p-ERK1/2 expression level was demonstrated to be significantly increased in the CPSP model. The introduction of an miR-223 agomir significantly attenuated thalamic pain and significantly decreased the levels of NLRP3, caspase-1, ASC and proinflammatory cytokines (IL-18 and IL-1ß). Furthermore, introducing a miR-223 antagomir into the VPL nucleus of naïve mice mimicked thalamic pain and significantly increased the levels of NLRP3, caspase-1, ASC and proinflammatory cytokine levels (IL-18 and IL-1ß). These results indicated that miR-223 inhibited NLRP3 inflammasome activity (caspase-1, NLRP3 and ASC), which ameliorated thalamus hemorrhage-induced CPSP in mice via NLRP3 downregulation. In conclusion, these results may determine the mechanisms underlying CPSP and facilitate development of targeted therapy for CPSP.

Intraoperative venous congestion rather than hypotension is associated with acute adverse kidney events after cardiac surgery: a retrospective cohort study.

BACKGROUND: The pathophysiological mechanisms by which venous congestion and hypotension lead to acute adverse kidney events after cardiac surgery with cardiopulmonary bypass have not been elucidated. We tested the hypothesis that intraoperative hypotension and venous congestion are associated with acute kidney injury and acute kidney disease. METHODS: Primary exposures were venous congestion and intraoperative hypotension defined by central venous pressure ≥12, 16, or 20 mm Hg or mean arterial pressure ≤55, 65, or 75 mm Hg. The primary outcomes were acute kidney injury and acute kidney disease. Multivariable logistic regression and Cox proportional hazard models were used, adjusted for relevant confounding factors and multiple comparisons. RESULTS: Of 5127 eligible subjects, 1070 (20.9%) and 327 (7.2%) developed acute kidney injury and acute kidney disease, respectively. The occurrence of acute kidney injury was statistically associated with both venous congestion and intraoperative hypotension. The cumulative incidence rate for new onset acute kidney disease was 1.34 (95% confidence interval [CI], 1.21-1.60) per 100 person-days. Acute kidney disease was significantly associated with each 10 min epoch of central venous pressure ≥12 mm Hg (hazard ratio [HR]=1.03; 99% CI, 1.01-1.06; P<0.001), ≥16 mm Hg (HR=1.04; 99% CI, 1.01-1.07; P<0.001), and ≥20 mm Hg (HR=1.07; 99% CI, 1.02-1.13; P<0.001). Venous congestion was associated with an 8-17% increased risk for de novo renal replacement therapy. In contrast, intraoperative hypotension was not associated with development of acute kidney disease. CONCLUSION: Although both venous congestion and intraoperative hypotension are associated with acute kidney injury, only venous congestion correlates with acute kidney disease among patients undergoing cardiac surgery requiring cardiopulmonary bypass. The reported associations are suggestive of a pathophysiological role of venous congestion in acute kidney disease.

Comparison of the effective orifice area of prosthetic mitral valves using two-dimensional versus three-dimensional transesophageal echocardiography.

OBJECTIVE: This study compared the continuity equation-based effective orifice area (EOA) of prosthetic mitral valves between two-dimensional (2D) and 3D transesophageal echocardiography (TEE). METHODS: Thirty-four patients without major aortic valve abnormalities underwent mitral valve replacement surgery. The EOAs of prosthetic mitral valves were calculated using the continuity equation with 2D and 3D TEE. For 18/34 patients using a biological valve prosthesis, the EOA of the prosthesis was obtained from commercial records. RESULTS: The EOA of prosthetic mitral valves significantly varied between the 2D and 3D methods (2.22 ± 0.71 vs 2.35 ± 0.70 cm2, n = 34). The area of the diameter of the left ventricular outflow tract as determined by the 3D method was significantly higher than that by the 2D method (mean difference: -0.14 ± 0.20 cm2), with 95% coherence boundaries of -0.53 and 0.25 cm2. The regression equation for the EOA by 3D and 2D TEE was y = 0.27 + 0.94x, with a good correlation. CONCLUSIONS: The EOA of prosthetic mitral valves is underestimated using the 2D TEE method compared with the 3D TEE method. The 3D-TEE method has the advantage of higher precision over the 2D TEE method, and it may be helpful for better assessment of prosthetic mitral valves intraoperatively.

Dexmedetomidine effect on delirium in elderly patients undergoing general anesthesia: A protocol for systematic review and meta-analysis.

BACKGROUND: Delirium is a common postoperative complication. Many studies have found that dexmedetomidine is associated with a reduced incidence of postoperative delirium (POD). This meta-analysis aimed to analyze the effects of dexmedetomidine on POD incidence among elderly patients undergoing general anesthesia. METHODS: We searched 4 electronic databases (i.e., Pubmed, Embase, Cochrane, and Web of Science) from inception to November 30, 2020, for randomized controlled trials that evaluated the effects of dexmedetomidine in preventing the occurrence of POD in elderly patients (aged ≥60 years). The study protocol was registered in PROSPERO (CRD42020192114). RESULTS: 14 studies with 4173 patients showed that dexmedetomidine was significantly associated with a decreased POD incidence among elderly patients (relative risk [RR] = 0.58; 95% confidence interval [CI] = 0.44-0.76). The incidence of POD was significantly reduced in the noncardiac surgery group (RR 0.51; 95% CI 0.37-0.72), when dexmedetomidine was applied during the postoperative period (RR = 0.53; 95% CI = 0.40-0.70), and in patients received low-doses (RR = 0.54; 95% CI = 0.34-0.87) and normal-doses (RR = 0.59; 95% CI = 0.42-0.83). There were no significant differences in POD incidence in the cardiac surgery group (RR = 0.71; 95% CI = 0.45-1.11), and when dexmedetomidine was applied during the intra- (RR = 0.55; 95% CI = 0.29-1.01) or perioperative period (RR = 0.95; 95% CI = 0.64-1.40). CONCLUSIONS: Our meta-analysis suggests that dexmedetomidine may significantly reduce POD incidence in elderly noncardiac surgery patients and when applied during the postoperative period, in addition, both low- and normal-doses of dexmedetomidine may reduce POD incidence. However, its use in cardiac surgery patients and during the intra- or perioperative period may have no significant effects on POD incidence.

NecroX-5 alleviate lipopolysaccharide-induced acute respiratory distress syndrome by inhibiting TXNIP/NLRP3 and NF-κB.

The activation of NLRP3 inflammasome and NF-κB pathway, associating with oxidativestress, have been implicated in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). NecroX-5 has been reported to exhibit theeffectsofanti-oxidation and anti-stress in various diseases. However, the role of NecroX-5 in ALI has not been explicitly demonstrated. The aim of this study was to explore the therapeutic effects and potential mechanism action of NecroX-5 on ALI. Here, we found that NecroX-5 pretreatment dramatically diminished the levels of IL-1ß, IL-18 and ROS in in RAW264.7 cells challenged with LPS and ATP. Furthermore, NecroX-5 suppressed the activation of NLRP3 inflammasome and NF-κB signalpathway. In addition, NecroX-5 also inhibited the thioredoxin-interacting protein (TXNIP) expression. In vivo, NecroX-5 reduced the LPS-induced lung histopathological injury, the number of TUNEL-positive cells, lung wet/dry (W/D) ratio, levels of total protein and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) in mice. Additionally, LPS-induced upregulation of myeloperoxidase (MPO), ROS production and malondialdehyde (MDA) were inhibited by NecroX-5 administration. Thus, our results demonstrate that NecroX-5 protects against LPS-induced ALI by inhibiting TXNIP/NLRP3 and NF-κB.

Value of respiratory variation of aortic peak velocity in predicting children receiving mechanical ventilation: a systematic review and meta-analysis.

BACKGROUND: Accurate volume assessment is crucial in children under fluid therapy. Over the last decade, respiratory variation of aortic peak velocity (△VPeak) has been applied in intensive care unit and surgeries to help clinicians guide fluid management. The aim of this systematic review and meta-analysis was to test diagnostic performance of △VPeak in predicting fluid responsiveness of ventilated children and to explore the potential factors that influence the accuracy of △VPeak. METHODS: We searched PubMed, Embase, and Cochrane from inception to April 2019 that evaluated association between △VPeak and fluid responsiveness after fluid challenge in children receiving mechanical ventilation. Data synthesis was performed within the bivariate mixed-effects regression model modified for synthesis of diagnostic test data. RESULTS: Eleven studies with a total of 302 pediatric patients were included in our meta-analysis. The pooled sensitivity and specificity of △VPeak was 0.89 (95%CI = 0.77 to 0.95) and 0.85 (95%CI = 0.77 to 0.91), respectively. The diagnostic odds ratio (DOR) of △VPeak was 48 (95%CI = 15 to 155). SROC yielded an area under the curve of 0.91 (95%CI = 0.88-0.93). The △VPeak cutoff value was nearly conically symmetrical distribution and varied from 7 to 20%. After excluding several extreme studies, most data were centered between 12 and 13%. The medium and mean cutoff values of △VPeak were 12.2% and 12.7%, respectively. In subgroup analysis, compared to total data analysis, △VPeak performed weaker in the younger children group (mean ages < 25 months), with lower area under the summary receiver operating characteristic curve (AUSROC) of 0.80 (0.76 to 0.83), but stronger in the older children group (mean ages > 25 months), with AUSROC of 0.96 (0.94 to 0.97). CONCLUSIONS: Overall, △VPeak has a good ability in predicting fluid responsiveness of children receiving mechanical ventilation, but this ability decreases in younger children (mean age < 25 months). The optimal threshold of △VPeak to predict fluid responsiveness in ventilated children is reliable between 12 and 13%. TRIAL REGISTRATION: The study protocol was registered prospectively on PROSPERO no. CRD42019129361.

MCP-induced protein 1 attenuates sepsis-induced acute lung injury by modulating macrophage polarization via the JNK/c-Myc pathway.

Sepsis is a potentially fatal systemic inflammatory response syndrome caused by infection. In this study, we evaluated the effects of MCP-induced protein 1 (MCPIP1), a recently discovered inflammation-related ribonuclease, on sepsis-induced acute lung injury (ALI) and investigated the underlying mechanisms. Cecal ligation puncture and lipopolysaccharide induction were performed on Sprague-Dawley rats and RAW264.7 cells, respectively, to establish sepsis-induced ALI models. The proteasome inhibitor MG132 used as an activator of MCPIP1 overexpression, and we showed that MG132 can indeed increase the expression of MCPIP1. MCPIP1 overexpression induced by MG132 alleviated sepsis-induced pathologic changes, water content and protein leakage in the lungs, and induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats. We also showed that MCPIP1 p showed romoted macrophage polarization from the M1 to the M2 type in sepsis-induced ALI. Furthermore, MCPIP1-enhanced M2 polarization was inhibited by an MCPIP1-targeting small interfering RNA (siMCPIP1) in RAW264.7 cells. Further mechanistic studies showed that the promotive effect of MCPIP1 on M2 polarization was related to the inhibition of c-Jun N-terminal kinase (JNK) and its downstream transcription factor c-Myc in the in vitro model. Conversely, siMCPIP1 transfection resulted in the recovery of JNK and c-Myc expression in LPS-treated cells. Taken together, these findings indicate that MCPIP1 plays a protective role in sepsis-induced ALI by modulating macrophage polarization through inhibition of the JNK/c-Myc signaling pathway. Our study presents a potentially novel therapeutic strategy for the treatment of lung injury involving the inflammatory cascade.