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BackgroundDexmedetomidine sedation has been associated with favourable outcomes after surgery. We aimed to assess whether perioperative dexmedetomidine use is associated with improved survival after cardiac surgery.MethodsThis retrospective cohort study included 2068 patients undergoing on-pump coronary artery bypass grafting and/or valve surgery. Among them, 1029 patients received dexmedetomidine, and 1039 patients did not. Intravenous dexmedetomidine infusion of 0.007 μg kg-1 min-1 was initiated before or immediately after cardiopulmonary bypass and lasted for < 24 h. The primary outcome was 5-year survival after cardiac surgery. The propensity scores matching (PSM), inverse probability of treatment weighting (IPTW), and overlap weighting approaches were used to minimise bias. Survival analyses were performed with Cox proportional-hazard models.ResultsThe median age was 63 yr old and the male to female ratio was 71:29 in both groups. Baseline covariates were balanced between groups after adjustment using PSM, IPTW, or overlap weighting. Patients receiving dexmedetomidine in cardiac surgical procedures had higher survival during postoperative 5 yr in unadjusted analysis (hazard ratio [HR]=0.63; 95% confidence interval [CI], 0.51-0.78; P

Induction of fetal hemoglobin (HbF) has been shown to be a viable therapeutic approach to treating sickle cell disease and potentially other β-hemoglobinopathies. To identify targets and target-modulating small molecules that enhance HbF expression, we engineered a human umbilical-derived erythroid progenitor reporter cell line (HUDEP2_HBG1_HiBiT) by genetically tagging a HiBiT peptide to the carboxyl (C)-terminus of the endogenous HBG1 gene locus, which codes for γ-globin protein, a component of HbF. Employing this reporter cell line, we performed a chemogenomic screen of approximately 5000 compounds annotated with known targets or mechanisms that have achieved clinical stage or approval by the US Food and Drug Administration (FDA). Among them, 10 compounds were confirmed for their ability to induce HbF in the HUDEP2 cell line. These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens. We orthogonally confirmed HbF induction activities of the top hits in both parental HUDEP2 cells as well as in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs). Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics for sickle cell disease and other β-hemoglobinopathies. [ABSTRACT FROM AUTHOR]

Deterioration evaluation of tunnel structures is the prerequisite for the tunnel's daily traffic safety management, maintenance planning, and service life prediction. Previous studies primarily rely on material degradation tests and theoretical analysis, often lacking the support of long‐term field monitoring data. This study aims to address this gap by implementing a structural health monitoring system including 48 strain gauges installed in an underwater shield tunnel in 2013. More than 8 years of data were obtained, and an irreversible strain‐based evaluation framework was proposed. This framework operates in two steps: first, it separates the irreversible strain and its damage‐induced part from the total strain. Second, it assesses the segments' damage status using the hypothesis test method. Results show that the mean irreversible strain of 41 monitoring points is 43 με over 8 years, agreeing well with the predictions based on the concrete shrinkage and creep theory. It is also found that the irreversible strain and elastic strain at different monitoring points vary significantly but they are highly correlated. Quantitative results from the hypothesis test show that the irreversible strain is induced mainly by the concrete shrinkage and creep, rather than segment damage. This study provides a method for early‐stage performance diagnosis of the tunnel segment during its service life. [ABSTRACT FROM AUTHOR]

BackgroundStroke volume variation (SVV) is a robust indicator of fluid responsiveness during volume change. We compared the sensibility of SVV by Vigileo/Flotrac to central venous pressure (CVP) when volume changes in patients undergoing intraoperative acute normovolemic hemodilution (ANH) and acute hypervolemic hemodilution (AHH).MethodsForty patients were randomly divided into an ANH group (n = 20) and an AHH group (n = 20). All patients received general anesthesia and were mechanically ventilated. Data were collected from 7 different time-points in the ANH group: baseline, after withdrawal of 5%, 10%, and 15% of the estimated blood volume (EBV) and after replacement with an equal volume of 6% hydroxyethyl starch 130/0.4 (HES) in 5% EBV increments to baseline. There were four time points in the AHH group: baseline, after 5%, 10%, and 15% expansion of the EBV with 6% HES. At each time-point, CVP, SVV and other hemodynamic parameters measurements were obtained.ResultsAfter removal of 10% and 15% EBV, SVV significantly increased from 10.9 ± 3.0 to 14.1 ± 3.4 and 10.9 ± 3.0 to 16.0 ± 3.3 (P < 0.01), and returned to a final value of 10.6 ± 3.4 after volume replacement. The CVP value was unchanged after removal and replacement of 15% of the EBV. There were no significant changes in SVV after 5%, 10% whereas there was a significant reduction after 15% (8.2 ± 1.7) expansion of the EBV compared with baseline (9.9 ± 1.8) (P = 0.033). However, there was a significant increase in CVP after 10% (10.3 ± 2.4), 15% (11.3 ± 2.2) expansion of the EBV compared with baseline (8.2 ± 2.7) (P < 0.01).ConclusionSVV is a more sensitive parameter for volume than CVP during hypovolemia, on the contrary CVP is more sensitive than SVV during hypervolemia.

To solve the problems of slow training, weak generalization ability, and low prediction accuracy in the traditional prediction model established in terms of the BP neural network, a method of the quality prediction of the continuous casting bloom based on the extreme learning machine (ELM) was proposed to predict the degree of the center porosity and the central segregation of 60Si2Mn continuous casting bloom produced by Fangda Special Steel. Comparing the prediction models of the BP neural network and the GA-BP neural network, the results show that the prediction accuracy of the model based on ELM is improved to 85% and 82.5% in the center loose and central segregation, respectively, and the operation time is reduced to 0.1 s. The model can rapidly and accurately analyze the quality of a continuous casting billet, thus providing a new method for the online application of continuous casting billet quality prediction.

The electromagnetic properties of high-carbon ferrochrome powders(HCFCP) obtained at different cooling rates were investigated by means of the vector network method in the frequency range of 1 to 18 GHz. It is found that both the real part and the imaginary part of the relative complex permittivity of HCFCP show an increasing order with a rising in cooling rate at most frequencies,of which prominent peaks occur in the imaginary part of the air-cooled and water-cooled powders on account of polarization relaxation.For comparison,both the relative complex permeability and magnetic loss factor present complex change histories,where the real part of the relative complex permeability decreases as the cooling rate rises,and the imaginary part of the water-cooled powders occupies the dominant except for the frequency range from 3 to 5 GHz. While peaks in the imaginary part of each cooling sample principally result from the effect of nature resonance and magnetic hysteresis respectively corresponding to low frequency and high frequency. The reflection losses of furnace-cooled,air-cooled and water-cooled HCFCP with the values of -2.30,-2.15 and -2.07 d B severally at 2.45 GHz,could meet the need of microwave heating in principle. By overall consideration,the water-cooled powders are determined as the optimal materials for solid-phase decarburization of HCFCP in a microwave field,attributed to a higher dielectric loss factor as well as a higher magnetic loss factor.

Abstract Background Previous studies have demonstrates that, after nerve injury, extracellular signal-regulated protein kinase (ERK) activation in the spinal cord-initially in neurons, then microglia, and finally astrocytes. In addition, phosphorylation of ERK (p-ERK) contributes to nociceptive responses following inflammation and/or nerve injury. However, the role of spinal cells and the ERK/MAPK pathway in cancer-induced bone pain (CIBP) remains poorly understood. The present study analyzed activation of spinal cells and the ERK/MAPK pathway in a rat model of bone cancer pain. Results A Sprague Dawley rat model of bone cancer pain was established and the model was evaluated by a series of tests. Moreover, fluorocitrate (reversible glial metabolic inhibitor) and U0126 (a MEK inhibitor) was administered intrathecally. Western blots and double immunofluorescence were used to detect the expression and location of phosphorylation of ERK (p-ERK). Our studies on pain behavior show that the time between day 6 and day 18 is a reasonable period ("time window" as the remaining stages) to investigate bone cancer pain mechanisms and to research analgesic drugs. Double-labeling immunofluorescence revealed that p-ERK was sequentially expressed in neurons, microglia, and astrocytes in the L4-5 superficial spinal cord following inoculation of Walker 256 cells. Phosphorylation of ERK (p-ERK) and the transcription factor cAMP response element-binding protein (p-CREB) increased in the spinal cord of CIBP rats, which was attenuated by intrathecal injection of fluorocitrate or U0126. Conclusions The ERK inhibitors could have a useful role in CIBP management, because the same target is expressed in various cells at different times.

Abstract Background G protein coupled receptors (GPCRs) represent the largest family of membrane proteins in the human genome and the richest source of targets for the pharmaceutical industry. A major limitation to characterizing GPCRs has been the difficulty in developing high-level heterologous expression systems that are cost effective. Reasons for these difficulties include inefficient transport and insertion in the plasma membrane and cytotoxicity. Additionally, GPCR purification requires detergents, which have a negative effect on receptor yields and stability. Results Here we report a detergent-free cell-free protein expression-based method to obtain pharmacologically active GPCRs in about 2 hours. Our strategy relies on the co-translational insertion of modified GPCRs into nanometer-sized planar membranes. As a model we employed an engineered β2-adrenergic receptor in which the third intracellular loop has been replaced with T4 lysozyme (β2AR -T4L). We demonstrated that nanolipoprotein particles (NLPs) are necessary for expression of active β2AR -T4L in cell-free systems. The binding specificity of the NLP- β2AR-T4L complex has been determined by competitive assays. Our results demonstrate that β2AR-T4L synthesized in vitro depends on similar oxidative conditions as those required by an in vivo-expressed receptor. Conclusions Although the activation of β2AR-T4L requires the insertion of the T4 lysozyme sequence and the yield of that active protein limited, our results conceptually prove that cell-free protein expression could be used as a fast approach to express these valuable and notoriously difficult-to-express proteins.