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With rapid development in medical research, the treatment of diseases including cancer has progressed dramatically and those survivors may die from causes other than the one under study, especially among elderly patients. Motivated by the Surveillance, Epidemiology, and End Results (SEER) female breast cancer study, background mortality is incorporated into the mixture cure proportional hazards (MCPH) model to improve the cure fraction estimation in population-based cancer studies. Here, that patients are "cured" is defined as when the mortality rate of the individuals in diseased group returns to the same level as that expected in the general population, where the population level mortality is presented by the mortality table of the United States. The semiparametric estimation method based on the EM algorithm for the MCPH model with background mortality (MCPH+BM) is further developed and validated via comprehensive simulation studies. Real data analysis shows that the proposed semiparametric MCPH+BM model may provide more accurate estimation in population-level cancer study., (© 2020 John Wiley & Sons, Ltd.)

Early-life stress (ELS) leads to stress-related psychopathology in adulthood. Although dysfunction of corticotropin-releasing hormone (CRH) signaling in the bed nucleus of the stria terminalis (BNST) mediates chronic stress-induced maladaptive affective behaviors that are historically associated with mood disorders such as anxiety and depression, it remains unknown whether ELS affects CRH function in the adult BNST. Here we applied a well-established ELS paradigm (24 h maternal separation (MS) at postnatal day 3) and assessed the effects on CRH signaling and electrophysiology in the oval nucleus of BNST (ovBNST) of adult male mouse offspring. ELS increased maladaptive affective behaviors, and amplified mEPSCs and decreased M-currents (a voltage-gated K + current critical for stabilizing membrane potential) in ovBNST CRH neurons, suggesting enhanced cellular excitability. Furthermore, ELS increased the numbers of CRH + and PACAP + (the pituitary adenylate cyclase-activating polypeptide, an upstream CRH regulator) cells and decreased STEP + (striatal-enriched protein tyrosine phosphatase, a CRH inhibitor) cells in BNST. Interestingly, ELS also increased BNST brain-derived neurotrophic factor (BDNF) expression, indicating enhanced neuronal plasticity. These electrophysiological and behavioral effects of ELS were reversed by chronic application of the CRHR1-selective antagonist R121919 into ovBNST, but not when BDNF was co-administered. In addition, the neurophysiological effects of BDNF on M-currents and mEPSCs in BNST CRH neurons mimic effects and were abolished by PKC antagonism. Together, our findings indicate that ELS results in a long-lasting activation of CRH signaling in the mouse ovBNST. These data highlight a regulatory role of CRHR1 in the BNST and for BDNF signaling in mediating ELS-induced long-term behavioral changes.

Rationale: Graphene oxide (GO) based nanomaterials have shown potential for the diagnosis and treatment of amyloid-β (Aβ)-related diseases, mainly on Alzheimer's disease (AD). However, these nanomaterials have limitations. How GO is beneficial to eliminate Aβ burden, and its physiological function in Aβ-related diseases, still needs to be investigated. Moreover, postoperative cognitive dysfunction (POCD) is an Aβ-related common central nervous system complication, however, nanomedicine treatment is lacking. Methods: To evaluate the effects of GO on Aβ levels, HEK293T-APP-GFP and SHSY5Y-APP-GFP cells are established. Intramedullary fixation surgery for tibial fractures under inhalation anesthesia is used to induce dysfunction of fear memory in mice. The fear memory of mice is assessed by fear conditioning test. Results: GO treatment maximally alleviated Aβ levels by simultaneously reducing Aβ generation and enhancing its degradation through inhibiting β-cleavage of amyloid precursor protein (APP) and improving endosomal Aβ delivery to lysosomes, respectively. In postoperative mice, the hippocampal Aβ levels were significantly increased and hippocampal-dependent fear memory was impaired. However, GO administration significantly reduced hippocampal Aβ levels and improved the cognitive function of the postoperative mice. Conclusion: GO improves fear memory of postoperative mice by maximally alleviating Aβ accumulation, providing new evidence for the application of GO-based nanomedicines in Aβ-related diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Pyroptosis is a recently characterized inflammatory form of programmed cell death that is thought to be involved in the pathogenesis of perioperative neurocognitive disorders (PND). Elamipretide (SS-31), a mitochondrial-targeted peptide with multiple pharmacological properties, including anti-inflammatory activity, has been demonstrated to protect against many neurological diseases. However, the effect of elamipretide on pyroptosis in PND has not been studied. We established an animal model of PND by performing an exploratory laparotomy on mice under isoflurane anesthesia and examined the effects of elamipretide on cognitive function, synaptic integrity, neuroinflammation, mitochondrial function, and signaling controlling pyroptosis. Our results showed that anesthesia and surgery caused mitochondrial dysfunction and abnormal morphology, activation of canonicalnod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1 dependent pyroptosis, and downregulation of synaptic integrity-related proteins in the hippocampus in aged mice, thus leading to learning and memory deficits in behavioral tests. Remarkably, treatment with the mitochondrial-targeted peptide elamipretide not only had protective effects against mitochondrial dysfunction but also attenuated surgery-induced pyroptosis and cognitive deficits. Our results provide a promising strategy for the treatment of PND involving mitochondrial dysfunction and pyroptosis., (Copyright © 2020 Zuo, Yin, Cheng, Li, Wu, Liu, Gu and Wu.)

The bulk supply of the antiviral C -nucleoside analogue remdesivir is largely hampered by a low-yielding C -glycosylation step in which the base is coupled to the pentose unit. Here, we disclose a significantly improved methodology for this critical transformation. By utilizing diisopropylamine as a cost-effective additive, the addition reaction furnishes an optimal yield of 75% of the desired ribofuranoside adduct, representing the highest yield obtained thus far for this key step. The method proved suitable for hectogram scale synthesis without column chromatographic operations., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Background: Stomach cancer (SC) is a type of cancer, which is derived from the stomach mucous membrane. As there are non-specific symptoms or no noticeable symptoms observed at the early stage, newly diagnosed SC cases usually reach an advanced stage and are thus difficult to cure. Therefore, in this study, we aimed to develop an integrated database of SC., Methods: SC-related genes were identified through literature mining and by analyzing the publicly available microarray datasets. Using the RNA-seq, miRNA-seq and clinical data downloaded from The Cancer Genome Atlas (TCGA), the Kaplan-Meier (KM) survival curves for all the SC-related genes were generated and analyzed. The miRNAs (miRanda, miRTarget2, PicTar, PITA and TargetScan databases), SC-related miRNAs (HMDD and miR2Disease databases), single nucleotide polymorphisms (SNPs, dbSNP database), and SC-related SNPs (ClinVar database) were also retrieved from the indicated databases. Moreover, gene_disease (OMIM and GAD databases), copy number variation (CNV, DGV database), methylation (PubMeth database), drug (WebGestalt database), and transcription factor (TF, TRANSFAC database) analyses were performed for the differentially expressed genes (DEGs)., Results: In total, 9990 SC-related genes (including 8347 up-regulated genes and 1643 down-regulated genes) were identified, among which, 65 genes were further confirmed as SC-related genes by performing enrichment analysis. Besides this, 457 miRNAs, 20 SC-related miRNAs, 1570 SNPs, 108 SC-related SNPs, 419 TFs, 44,605 CNVs, 3404 drug-associated genes, 63 genes with methylation, and KM survival curves of 20,264 genes were obtained. By integrating these datasets, an integrated database of stomach cancer, designated as SCDb, (available at http://www.stomachcancerdb.org/) was established., Conclusions: As a comprehensive resource for human SC, SCDb database will be very useful for performing SC-related research in future, and will thus promote the understanding of the pathogenesis of SC.

Objectives: Dexmedetomidine is widely used as an adjunct to general anesthesia. In this study, we evaluated the effects of perioperative dexmedetomidine infusion on postoperative analgesia in patients undergoing lateral thoracotomy for thoracic esophageal cancer., Methods: A total of 62 patients undergoing lateral thoracotomy for thoracic esophageal cancer were randomized to receive adjuvant therapy with either dexmedetomidine (0.5  μ g/kg intravenous bolus injection for 10 min before induction of anesthesia, followed by continuous infusion of 0.2-0.4  μ g/kg/h until the end of surgery, and 0.06  μ g/kg/h for 5 days after surgery) or equal volumes of saline. Acute postoperative pain was treated with patient-controlled intravenous sufentanil and flurbiprofen axetil. The primary outcomes of this study were the numbers of analgesic requirements in the first postoperative 72 h., Results: Perioperative dexmedetomidine did not decrease the numbers of analgesic requirements in the first postoperative 72 h (dexmedetomidine group: 12.14 ± 4.76, saline group: 10.89 ± 5.66; p =0.367). Likewise, the groups did not differ with respect to total postoperative analgesic requirements, postoperative pain, perioperative inflammation, blood cell count, incidence of adverse events, surgical recovery (assessed at postoperative days 2 and 5 using the surgical recovery scale), length of hospital stay, hospital cost, incidence of chronic pain, or quality of life. Notably, dexmedetomidine had beneficial effects on decreasing intraoperative opioid consumption and improving postoperative sleep quality. Discussion . Perioperative dexmedetomidine has limited analgesic benefits in lateral thoracotomy for esophageal cancer when added to an opioid-based multimodal anesthetic regimen but can reduce opioid consumption., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Yu Mao et al.)

Sodium-ion batteries (SIBs) have long been recognized as a potential substitute for lithium-ion batteries, while their practical application is greatly hindered owing to the absence of suitable cathode materials with improved rate capability and prolonged cycling life. Na 3 V 2 (PO 4 ) 3 (NVP) has drawn extensive attention among the cathode materials for SIBs because of its fast Na + -transportable framework which enables high-speed charge transfer, but the poor electric conductivity of NVP significantly restricts the Na + diffusion. To tackle this issue, in this work, porous NVP/reduced graphene oxide hollow spheres (NVP/rGO HSs) are constructed via a spray drying strategy. Due to the unique porous hollow architecture, the synthesized compound manifests a high reversible capacity of 116 mAh g -1 at 1 C (1 C = 118 mA g -1 ), an outstanding high-rate capability of 107.5 mAh g -1 at 10 C and 98.5 mAh g -1 at 20 C, as well as a stable cycling performance of 109 mAh g -1 after 400 cycles at 1 C and 73.1 mAh g -1 after 1000 cycles at 10 C. Moreover, galvanostatic intermittent titration technique demonstrates that the Na + diffusion coefficient of NVP/rGO HSs is an order of magnitude larger than the pristine NVP. The remarkable electrochemical properties of NVP/rGO HSs in full cells further enable it a potential cathode for SIBs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Full-color smart displays, which act both as a display and as a high-speed visible light communication (VLC) transmitter, can be realized by the integration of red-green-blue micron-sized light emitting diodes (micro-LEDs) onto a common platform. In this work, we report on the integration of aluminum gallium indium phosphide red micro-LEDs onto diamond and glass substrates by micro-transfer printing and their application in VLC. The device on-diamond exhibits high current density and bandwidth operation, enabled by diamond's superior thermal properties. Employing an orthogonal frequency division multiplexing modulation scheme, error-free data rates of 2.6 Gbps and 5 Gbps are demonstrated for a single micro-LED printed on-glass and on-diamond, respectively. In a parallel configuration, a 2x1 micro-LED array achieves error-free data rates of 3 Gbps and 6.6 Gbps, on-glass and on-diamond, respectively.

Enterococcus hirae WEHI01 is a potential probiotic strain isolated from a healthy Chinese infant. This strain has previously been characterized as having cholesterol-lowering potential and good dairy fermentation performance. In this study, we used rat models with obesity and type 2 diabetes mellitus (T2DM) induced by a high fat and sucrose diet and low-dose streptozotocin, respectively, and we evaluated the effect of E. hirae WEHI01 on glycolipid metabolism, glycolipid-related gene expression, organ histopathology, and intestinal flora changes in the 2 models. Our results showed that administration of 5.0 × 10 9 cfu of E. hirae WEHI01 for 4 wk decreased serum lipid levels and regulated glycolipid metabolism in the liver of obese rats. Following continuous administration of the same concentration of E. hirae WEHI01 to a T2DM rat model for another 5 wk, E. hirae WEHI01 improved glucose tolerance, recovered body weight loss, and led to significant decreases in tumor necrosis factor-α, IL-6, IL-10, and total bile acid in serum. We also found that E. hirae WEHI01 restored the morphology of the pancreas, kidney, and liver, and changed the composition of the gut microbiota (i.e., decreased the Shannon index, increased the Simpson index, and substantially increased the abundance of Lactobacillales). Combining the results for the obese model and the T2DM model, we speculated that beneficial effects of E. hirae WEHI01 on T2DM could be due to (1) a significant increase in PPARA expression and a tendency for increased CYP7A1 expression in the liver of obese rats, promoting the conversion of cholesterol into bile acid and reducing serum total bile acid levels in T2DM model rats; or (2) a change in gut microbial diversity, especially elevated Lactobacillales abundance, which reduced the total bile acid in T2DM model rats. These results demonstrated that E. hirae WEHI01 has the potential to ameliorate type 2 diabetes in rats and provide a promising rationale for further research into the prevention and treatment of T2DM., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Autophagy allows cancer cells to respond changes in nutrient status by degrading and recycling non-essential intracellular contents. Inhibition of autophagy combined with nutrient deprivation is an effective strategy to treat cancer. Pain is a primary determinant of poor quality of life in advanced cancer patients, but there is currently no satisfactory treatment. In addition, effective treatment of cancer does not efficiently relieve cancer pain, but may increase pain in many cases. Hence, few studies focus on simultaneous cancer therapy and pain relief, and made this situation even worse. Method : Ropivacaine was loaded into tumor-active targeted liposomes. The cytotoxicity of ropivacaine-based combination therapy in B16 and HeLa cells were tested. Moreover, a mice model of cancer pain which was induced by inoculation of melanoma near the sciatic nerve was constructed to assess the cancer suppression and pain relief effects of ropivacaine-based combination therapy. Results : Ropivacaine and ropivacaine-loaded liposomes (Rop-DPRL) were novelly found to damage autophagic degradation. Replicated administration of Rop-DPRL and calorie restriction (CR) could efficiently repress the development of tumor. In addition, administration of Rop-DPRL could relieve cancer pain with its own analgestic ability in a short duration, while repeated administration of Rop-DPRL and CR resulted in continuous alleviation of cancer pain through reduction of VEGF-A levels in advanced cancer mice. Further, dual inhibition of phosphorylation of STAT3 at Tyr705 and Ser727 by Rop-DPRL and CR contribute to the reduction of VEGF-A. Conclusion : Combination therapy with Rop-DPRL and nutrient deprivation simultaneously suppresses cancer growth and relieves cancer pain., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The bed nucleus of the stria terminalis (BNST) is a forebrain region highly responsive to stress that expresses corticotropin-releasing hormone (CRH) and is implicated in mood disorders, such as anxiety. However, the exact mechanism by which chronic stress induces CRH-mediated dysfunction in BNST and maladaptive behaviors remains unclear. Here, we first confirmed that selective acute optogenetic activation of the oval nucleus BNST (ovBNST) increases maladaptive avoidance behaviors in male mice. Next, we found that a 6 week chronic variable mild stress (CVMS) paradigm resulted in maladaptive behaviors and increased cellular excitability of ovBNST CRH neurons by potentiating mEPSC amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K + current that stabilizes membrane potential) in ex vivo slices. CVMS also increased c-fos + cells in ovBNST following handling. We next investigated potential molecular mechanism underlying the electrophysiological effects and observed that CVMS increased CRH + and pituitary adenylate cyclase-activating polypeptide + (PACAP; a CRH upstream regulator) cells but decreased striatal-enriched protein tyrosine phosphatase + (a STEP CRH inhibitor) cells in ovBNST. Interestingly, the electrophysiological effects of CVMS were reversed by CRHR1-selective antagonist R121919 application. CVMS also activated protein kinase A (PKA) in BNST, and chronic infusion of the PKA-selective antagonist H89 into ovBNST reversed the effects of CVMS. Coadministration of the PKA agonist forskolin prevented the beneficial effects of R121919. Finally, CVMS induced an increase in surface expression of phosphorylated GluR1 (S845) in BNST. Collectively, these findings highlight a novel and indispensable stress-induced role for PKA-dependent CRHR1 signaling in activating BNST CRH neurons and mediating maladaptive behaviors. SIGNIFICANCE STATEMENT Chronic stress and acute activation of oval bed nucleus of the stria terminalis (ovBNST) induces maladaptive behaviors in rodents. However, the precise molecular and electrophysiological mechanisms underlying these effects remain unclear. Here, we demonstrate that chronic variable mild stress activates corticotropin-releasing hormone (CRH)-associated stress signaling and CRH neurons in ovBNST by potentiating mEPSC amplitude and decreasing M-current in male mice. These electrophysiological alterations and maladaptive behaviors were mediated by BNST protein kinase A-dependent CRHR1 signaling. Our results thus highlight the importance of BNST CRH dysfunction in chronic stress-induced disorders., (Copyright © 2020 the authors.)

We present integration of singulated micron-sized light emitting diodes (micro-LEDs) directly onto a silicon CMOS drive chip using a transfer printing method. An 8x8 micro-LED device array with individual control over each pixel is demonstrated with modulation bandwidths up to 50 MHz, limited by the large modulation depth of the driver chip. The 2 kHz frame rate CMOS driver also incorporates a Single Photon Avalanche Diode device thus allowing detection and transmission functionality on a single integrated chip. Visible light communications at data rates up to 1 Mbps, and time-of-flight ranging with cm-scale resolution are demonstrated using this hybrid integrated system.

Background: Dexmedetomidine potentially confers an advantage to reduce the incidence of postoperative delirium (POD) in surgical patients. Anti-inflammation is important effect of this sedative drug. In this study, we aimed to investigate whether the effect of dexmedetomidine on the postoperative cognitive function is via inhibiting peripheral inflammation., Methods: A prospective, randomized, controlled study was conducted with patients 65 years of age or above who received total knee arthroplasty from January 2019 to May 2019. The patients were randomly assigned to receive spinal anesthesia supplemented with propofol or dexmedetomidine for sedation. The incidence of POD was the primary endpoint and was evaluated with the Confusion Assessment Method, and incidence of postoperative cognitive dysfunction was assessed with the Mini-Mental State Examination. Blood samples were collected postoperatively to test the plasma concentrations of interleukin-6, tumor necrosis factor-α, and S100β., Results: A total of 366 patients were randomly assigned to 2 groups. Patients who received dexmedetomidine sedation had lower incidences of POD and better postoperative cognitive function than patients sedated with propofol. There was no difference in postoperative plasma concentrations of tumor necrosis factor-α and interleukin-6 between the 2 groups. The concentration of S100β 48 hours after surgery was higher in patients sedated with propofol than in patients who received dexmedetomidine sedation., Conclusion: Intraoperative sedation with dexmedetomidine conferred better postoperative neurocognitive function for elderly patients who received total knee arthroplasty. This effect was unrelated to the modulation of dexmedetomidine on peripheral inflammation.

Background: Sleep disorders are commonly encountered in clinic. Evidences showed that sleep deprivation may modulate the effectiveness of general anesthetics in rats. However, this phenomenon has not been explored in humans. The study aimed to investigate whether the hypnotic potency of sevoflurane in patients with sleep disorders differ from patients with normal sleep habits., Methods: We recruited 44 patients scheduled for elective breast surgery and eventually analyzed 38 patients, including 19 subjects with normal sleep habits and 19 subjects with sleep disorders. According to the Dixon 'up-and-down' design, patients received sevoflurane at preselected concentrations starting at 1.0 vol%. After a steady-state period, a verbal command for testing awakening was performed. Based on the negative or positive response to the verbal command, we decreased or increased the concentration of sevoflurane by 0.2 vol% in the next patient accordingly. Plasma orexin-A was also measured before observation., Results: The MACawake of sevoflurane was 0.80% [95% confidence interval (CI), 0.683-0.926%] in the sleep disordered group vs 0.60% [95% CI, 0.493-0.689%] in the control group. The relative median potency between groups was 0.750 (95% CI, 0.236-0.969). Patients with sleep disorders had significantly higher orexin-A levels than control (72.17 ± 18.24 vs. 36.16 ± 14.18 pg/mL). A significant, positive relationship was detected between orexin-A level and probability of awakening (OR = 1.081, 95% CI is 1.020-1.146, P = 0.008)., Conclusions: MACawake of sevoflurane is higher in mild-aged women of breast surgery with sleep disorders compared to those with normal sleep habits. The increased anesthetic requirement may be related to changes of orexin-A levels. These findings suggest that sleep may have a potential impact on clinical anesthesia, including changes of sensitivity to anesthetics or postoperative complications. Further research is needed to confirm this hypothesis., Clinical Trial Registration: Chinese Clinical Trial Registry (ChiCTR1800016022), date of registration 07 May 2018.

Controllably manipulating the spectral response of broadband-absorbing semiconductors is crucial for developing wavelength-selective optoelectronic devices. In this article, we report for the first time, the bias-dependent spectral responses for a metal-halide perovskite photodiode. Tunable external quantum efficiencies in the short- and long-wavelength regimes, and the full spectral range (ca. 300-800 nm) are observed when the device is operated under short-circuit, and forward and reverse bias conditions, respectively. This observation is understood by the interplay of wavelength-dependent penetration depth and barrier formation within the photodiode device stack. The general applicability of this concept is confirmed by a systematic study on a series of mixed-halide perovskite devices. These results suggest that the proposed concept allows as a promising platform and should inspire further exploration of multispectral responsive optoelectronic devices.

Integrated multi-color micron-sized light emitting diode (micro-LED) arrays have been demonstrated in recent years for display applications; however, their potential as visible light communication (VLC) transmitters is yet to be fully explored. In this work, we report on the fabrication and characterization of on-chip dual-color micro-LED arrays and their application in VLC. For this purpose, blue-green and blue-violet micro-LED arrays were fabricated by transfer printing blue-emitting micro-LEDs onto the substrate of green and violet micro-LEDs, respectively. The potential of these dual-color micro-LED arrays as VLC transmitters is demonstrated with respective error-free data rates of 1.79 and 3.35 Gbps, achieved by the blue-green and blue-violet devices in a dual wavelength multiplexing scheme.

We present an electrically addressable optrode array capable of delivering light to 181 sites in the brain, each providing sufficient light to optogenetically excite thousands of neurons in vivo , developed with the aim to allow behavioral studies in large mammals. The device is a glass microneedle array directly integrated with a custom fabricated microLED device, which delivers light to 100 needle tips and 81 interstitial surface sites, giving two-level optogenetic excitation of neurons in vivo . Light delivery and thermal properties are evaluated, with the device capable of peak irradiances > 80    mW / mm 2 per needle site. The device consists of an array of 181 80    μ m × 80    μ m 2 microLEDs, fabricated on a 150 - μ m -thick GaN-on-sapphire wafer, coupled to a glass needle array on a 150 - μ m thick backplane. A pinhole layer is patterned on the sapphire side of the microLED array to reduce stray light. Future designs are explored through optical and thermal modeling and benchmarked against the current device.

Remifentanil postconditioning (RPC) has been shown to provide potent cardioprotection against ischemia/reperfusion (I/R) injury, but the underlying mechanism has not been fully elucidated. The current study was designed to investigate whether RPC protects cardiomyocytes against I/R injury through enhancement of autophagic flux. H9c2 cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to mimic myocardial I/R injury in vitro. Autophagosome formation was evaluated by detecting of light chain 3 (LC3) puncta number and LC3Ⅱ levels using immunofluorescence and western blotting, respectively. Additionally, dual fluorescent staining of LC3 and lysosomal-associated membrane protein 2, a lysosomal marker protein, were used to detect autolysosome formation. Moreover, autophagic flux integrity was tracked using changes in LC3Ⅱ and p62 levels. Lastly, myocardial injury was detected by Hoechst 33342 and propidium iodide staining and MTT assay. The results showed that RPC increased autophagosome formation and promoted autophagosome-lysosome fusion, thereby improving autophagic flux in H9c2 cells. Reversal of these effect by bafilomycin A1 or chloroquine co-administration at reoxygenation onset indicated that RPC improved the impaired autophagic flux following H/R injury. Induction of autophagy was associated with increased cell viability and decreased apoptosis. Autophagy inhibition with bafilomycin A1 or chloroquine and ATG7shRNA significantly abolished RPC-induced cardioprotection. In conclusion, our finding that RPC can protect cardiomyocytes against H/R injury through enhancement of autophagic flux suggests a new mechanism for myocardial protection of opioid postconditioning., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The "pseudo-durability" of antibiotics in estuaries is gaining increasing interest, especially in the Yangtze Estuary, a vital water supply source for the Shanghai city. To clearly describe the pollution level and risk of antibiotics in this estuary, the contents of 8 typical antibiotics in the surface water and the sediment along the nearshore zone and in the estuarine channel in the estuary were comprehensively analyzed. The results revealed that sulfonamides and tetracycline are the predominant antibiotics in the surface water, while tetracyclines and fluoroquinolones are the dominant ones in the sediments. The ranges of the eight antibiotic concentrations between the nearshore zone (not detected to 7.06 ng/L for water, below LOD to 10.94 ng/g for sediment) and the estuarine channel (not detected to 8.46 ng/L for water, not detected to 14.84 ng/g for sediment) showed no notable differences, but the degree of scatter was different for each antibiotic. The spatial distribution was different for each antibiotic in the north branch and the south branch; higher values for most of the target antibiotics were observed in the south branch of the estuary. The distribution and source analysis from a GIS map using the kriging method indicated that runoff input and the antibiotic residues from aquaculture were the two major sources of the antibiotic pollution in the Yangtze Estuary. A risk assessment of the individual antibiotic exposure in the surface water showed that sulfamethoxazole, ofloxacin and ciprofloxacin, tetracycline and oxytetracycline, and sulfadiazine, roxithromycin and erythromycin in this area exhibited a medium risk, low risk and almost no risk to the selected aquatic microorganisms, respectively., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rationale: For hip or knee arthroplasty, it is essential to develop a satisfied peripheral nerve block method that will benefit elderly patients or patients who are contraindicated to neuraxial anesthesia., Patients Concerns: Patient in Case 1 suffered from the right intertrochanteric fracture, combined with chronic obstructive pulmonary disease; Patient in Case 2 suffered from hip osteoarthritis; combined with ankylosing spondylitis; Patient in Case 3 suffered from rheumatoid arthritis, combined with ischemic encephalopathy., Diagnosis: Case 1: Right intertrochanteric fracture, chronic obstructive pulmonary disease. Case 2: hip osteoarthritis. Case 3: rheumatoid arthritis., Interventions: Ultrasound-guided lumbar selective nerve root block (SNRB) plus T12 paravertebral and sacral plexus block were performed in 2 patients who received hip arthroplasty and 1 patient who received knee arthroplasty., Outcomes: All patients successfully received surgeries with this peripheral nerve block method and no postoperative complication was reported., Lessons: Ultrasound-guided lumbar SNRB plus T12 paravertebral and sacral plexus block not only satisfied the analgesia requirement of surgery, but also reduced the consumption of local anesthetic.

Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK-875, AMG-837, and LY2881835. Among them, most promising compounds 7, 14, and 15 were obtained with EC 50 values of 82, 79, and 88 nM, exhibiting a powerful agonistic activity compared to TAK-875 (95.1 nM). During Oral glucose tolerance test in normal mice, compound 7, 14, and 15 had significant glucose-lowering effect at the dose of 50 mg/kg. Furthermore, compound 15 (50 mg/kg) also significantly improved in glucose tolerance in type 2 diabetic mice. Herein, we reported the discovery and optimization of a series of potent FFA1 agonists. The discovery supported further exploration surrounding this scaffold., (© 2019 John Wiley & Sons A/S.)

Background: Stent retriever thrombectomy of large-vessel occlusion results in better outcomes than medical therapy alone. Alternative thrombectomy strategies, particularly a direct aspiration as first pass technique, while promising, have not been rigorously assessed for clinical efficacy in randomised trials. We designed COMPASS to assess whether patients treated with aspiration as first pass have non-inferior functional outcomes to those treated with a stent retriever as first line., Methods: We did a multicentre, randomised, open label, blinded outcome, core lab adjudicated non-inferiority trial at 15 sites (ten hospitals and four specialty clinics in the USA and one hospital in Canada). Eligible participants were patients presenting with acute ischaemic stroke from anterior circulation large-vessel occlusion within 6 h of onset and an Alberta Stroke Program Early CT Score of greater than 6. We randomly assigned participants (1:1) via a central web-based system without stratification to either direct aspiration first pass or stent retriever first line thrombectomy. Those assessing primary outcomes via clinical examinations were masked to group assignment as they were not involved in the procedures. Physicians were allowed to use adjunctive technology as was consistent with their standard of care. The null hypothesis for this study was that patients treated with aspiration as first pass achieve inferior outcomes compared with those treated with a stent retriever first line approach. The primary outcome was non-inferiority of clinical functional outcome at 90 days as measured by the percentage of patients achieving a modified Rankin Scale score of 0-2, analysed by intent to treat; non-inferiority was established with a margin of 0·15. All randomly assigned patients were included in the safety analyses. This trial is registered at ClinicalTrials.gov, number: NCT02466893., Findings: Between June 1, 2015, and July 5, 2017, we assigned 270 patients to treatment: 134 to aspiration first pass and 136 to stent retriever first line. A modified Rankin score of 0-2 at 90 days was achieved by 69 patients (52%; 95% CI 43·8-60·3) in the aspiration group and 67 patients (50%; 41·6-57·4) in the stent retriever group, showing that aspiration as first pass was non-inferior to stent retriever first line (p non-inferiority =0·0014). Intracranial haemorrhage occurred in 48 (36%) of 134 in the aspiration first pass group, and 46 (34%) of 135 in the stent retriever first line group. All-cause mortality at 3 months occurred in 30 patients (22%) in both groups., Interpretation: A direct aspiration as first pass thrombectomy conferred non-inferior functional outcome at 90 days compared with stent retriever first line thrombectomy. This study supports the use of direct aspiration as an alternative to stent retriever as first-line therapy for stroke thrombectomy., Funding: Penumbra., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Histone deacetylase inhibitors (HDACIs), which interfere with the epigenetic process of histone acetylation, have shown analgesic effects in animal models of persistent pain. The HDAC family comprises 18 genes; however, the different effects of distinct classes of HDACIs on pain relief remain unclear. The aim of this study was to determine the efficacy of these HDACIs on attenuating thermal hyperalgesia in persistent inflammatory pain. Persistent inflammatory pain was induced by injecting Complete Freund's Adjuvant (CFA) into the left hind paw of rats. Then, HDACIs targeting class I (entinostat (MS-275)) and class IIa (sodium butyrate, valproic acid (VPA), and 4-phenylbutyric acid (4-PBA)), or class II (suberoylanilide hydoxamic acid (SAHA), trichostatin A (TSA), and dacinostat (LAQ824)) were administered intraperitoneally once daily for 3 or 4 days. We found that the injection of SAHA once a day for 3 days significantly attenuated CFA-induced thermal hyperalgesia from day 4 and lasted 7 days. In comparison with SAHA, suppression of hyperalgesia by 4-PBA peaked on day 2, whereas that by MS-275 occurred on days 5 and 6. Fatigue was a serious side effect seen with MS-275. These findings will be beneficial for optimizing the selection of specific HDACIs in medical fields such as pain medicine and neuropsychiatry.

In traditional survival analyses, hazard ratio (HR) is commonly used to evaluate treatment effects. However, HR may not be easy to interpret. Restricted mean survival time is a viable alternative to HR, particularly when the proportional hazards assumption is not satisfied. We developed a conditional restricted mean survival time (CRMST) estimator for a time interval of interest using counting process. The variance of CRMST was estimated using a perturbation re-sampling method for asymptotic normality. The utility of our CRMST seems promising based on comprehensive simulation studies and a real data case study.

Purpose: To correlate the imaging findings of treated hepatocellular carcinoma (HCC) after stereotactic body radiation therapy (SBRT) with explant pathology and alpha-fetoprotein (AFP) response., Methods and Materials: From 2007 to 2015, of 146 patients treated with liver SBRT for Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma, 10 were identified with inclusion criteria and had regular interval follow-up magnetic resonance imaging/triple phase computed tomography and explant pathology or declining AFP values for radiology-pathology response correlation. Reference standards for successful response were >90% necrosis on explant pathology or pretreatment AFP >75 ng/mL normalizing to <10 ng/mL within 1 year after SBRT without other treatment. Subjects were treated with 24 to 50 Gy in 3 to 5 fractions. Multiphasic magnetic resonance imaging or computed tomography performed at 3, 6, 9, and 12 months after SBRT was compared with pretreatment imaging by 2 expert radiologists. Descriptive statistics were calculated., Results: There were 10 subjects with 10 treated HCCs, classified as 3 Organ Procurement and Transplantation Network (OPTN) 5a, 4 OPTN 5b, and 3 OPTN 5x. All had successfully treated HCCs, according to explant pathology or declining AFP. Four of 10 HCCs had persistent central arterial hyperenhancement 3 to 12 months after SBRT; persistent wash-out was common up to 12 months (9 of 10). Of 10 treated HCCs, 9 exhibited decreased size at 12 months. Liver parenchyma adjacent to the lesion showed early (3-6 months) hyperemia followed by late (6-12 months) capsular retraction and delayed enhancement. No patient had a significant decline in liver function., Conclusions: In the absence of increasing size, persistent central arterial hyperenhancement and wash-out can occur within the first 12 months after SBRT in successfully treated HCCs and may not represent residual viable tumor. Liver parenchyma adjacent to the treated lesion showed inflammation followed by fibrosis, without significant change in hepatic function. Until a radiologic signature of tumor control is determined, freedom from local progression seems to be the best measure of HCC control after SBRT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: We sought to evaluate the safety, efficacy, and cost-effectiveness of intraoperative blood salvage (IBS) in off-pump coronary artery bypass grafting (OPCABG) surgery with different amount of bleeding., Methods: We retrospectively reviewed the medical records of 321 patients who underwent OPCABG between December 2012 and December 2016 at our hospital. Patients treated with IBS or allogeneic blood (AB) transfusions were divided into three groups depending on the amount of bleeding respectively: IBS1 or AB1 group (400-600 ml); IBS2 or AB2 group (600-1000 ml); IBS3 or AB3 group (1000-1500 ml). The intraoperative and postoperative conditions, blood transfusion volume, clinical and hematological outcomes, and total blood transfusion cost were examined., Results: The amount of allogeneic red blood cell (RBC) transfusion in the IBSs groups were significantly lower than that in the ABs groups (P < 0.01). Furthermore, drainage volume 24 h post-surgery (P < 0.05) and white blood cell count (WBC) 2 day post-surgery (P < 0.01) in IBS3 group were significantly higher compared with the AB3 group. Additionally, when IBS cost was 230 USD per set, the total blood transfusion cost in the IBSs groups was significantly higher than that in the ABs groups (P < 0.01); however, when 199 or 184 USD, only the IBS1 group, rather than IBS2 or IBS3, showed significantly higher cost of the total blood transfusion compared with the AB1 group (P < 0.05)., Conclusions: When the amount of bleeding was 600-1000 ml, IBS can significantly reduce the demand for allogeneic blood, and has no direct adverse effects on coagulation function and recuperation, and is cost-effective in OPCABG.

Background: During regional anesthesia, including combined spinal and epidural anesthesia (CSEA), patients may develop a perceptual alteration of limb position known as phantom limb syndrome (PLS). We aimed to identify factors that influence the PLS onset, to explore whether PLS predisposes to other postoperative symptoms, and to document the relationship between PLS and sensorimotor impairment during recovery., Methods: Psychological questionnaires for anxiety and depression were completed beforehand, then multimodal tests of sensory and motor function, especially tests of proprioception, were performed regularly afterward. Two hundred participants undergoing elective gynecological surgery under CSEA reported their experiences of PLS and other symptoms using Likert rating scales., Results: Prolonged preoperative fasting (odds ratio (OR) 2.34; 95% confidence intervals (CI) 1.21-4.52), and surgical history (OR 2.56; 95% CI 1.16-5.62) predisposed to PLS, but patients with more extensive anesthetic histories may be at lower risk (OR 0.57; 95% CI 0.31-1.08). Furthermore, significant correlations were observed between the recovery from PLS and the perception of joint movement within the deafferented area (R = 0.82, P < .01) and motor functions (R = 0.68). PLS increases the chance of experiencing postoperative fatigue, physical discomfort, and emotional upset., Conclusion: This study is the first to have identified the risk factors for PLS, assessed the relationship between PLS and postoperative sensorimotor impairment, and its influence on postoperative complications.

Purpose: The purpose of this study was to assess the efficacy of perineural dexamethasone with ropivacaine in multimodal analgesia for thoracic paravertebral block (TPVB) in patients undergoing elective thoracotomy., Patients and Methods: Ninety-six patients undergoing thoracotomy were enrolled in this trial and randomized to adjuvant therapy for TPVB: group S (saline), group R (0.5% ropivacaine), or group RD (5 mg dexamethasone and 0.5% ropivacaine). Postoperative analgesia, recovery duration, and chronic pain were recorded., Results: Groups R and RD spent less time in the postanaesthesia care unit, had earlier out-of-bed activity, and had shorter postoperative hospital stays compared with group S. The RD group regained consciousness faster and had lower acute pain scores and used less patient-controlled analgesia during the first 72 h after surgery compared with group S. Postthoracotomy pain was decreased in group RD (19.0%) compared with group S (47.6%) 3 months postoperatively, p = 0.050., Conclusion: Perineural dexamethasone with ropivacaine for TPVB improves postoperative analgesia quality, reduces recovery time, and may decrease the incidence of chronic pain after thoracotomy with an opioid-based anesthetic regimen., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Peripheral nerve block is a preferable method for elderly patients receiving hip arthroplasty. Sedation with dexmedetomidine may reduce postoperative delirium (POD). The aim of this study was to investigate whether intraoperative sedation with dexmedetomidine, as a supplementary to peripheral nerve block for elderly patients receiving total hip arthroplasty, can decrease the prevalence of POD., Methods: A prospective, randomized controlled study was conducted with patients 65 years of age or older who underwent total hip arthroplasty between June 2016 and June 2017. The patients were randomly assigned to receive a lumbosacral plexus plus T12 paravertebral block supplemented with propofol or dexmedetomidine for sedation. Incidence of POD was the primary endpoint and was determined with the confusion assessment method, and incidence of postoperative cognitive dysfunction (POCD) was assessed with the mini-mental state examination. The time of ambulation, discharge time, and complications over a 30-day postsurgery period were also recorded., Results: A total of 296 patients were randomly assigned to 2 groups. The patients sedated with dexmedetomidine had lower incidences of POD and POCD and were out of bed and discharged sooner than the patients sedated with propofol. There was no difference in complications between the 2 groups., Conclusions: As a supplementary to peripheral nerve block, intraoperative sedation with dexmedetomidine could be associated with a lower incidence of POD, which may have benefits on reducing the incidence of early POCD and offering a better short-term recovery for elderly patients receiving hip arthroplasty.

Background: Remifentanil postconditioning (RPC) confers robust cardioprotection against ischemia/reperfusion (I/R) injury. We recently determined that HDAC3 was involved in RPC-induced cardioprotection. However, the role of HDAC3 and its possible mechanisms in RPC-induced cardioprotection are unknown, which we aimed to evaluate in an in vitro hypoxia/reoxygenation (HR) model., Methods: Myocardium I/R injury was established after HR with H9c2 cardiomyoblasts. Cell viability and apoptosis were evaluated usingCCK-8 and flow cytometry of HR-injured cardiomyoblasts treated with or without RPC. Furthermore, effects of RPC on HDAC3 protein and mRNA expression were evaluated with Western blot and quantitative real-time PCR analyses, whereas GSK-3β expression was measured with Western blot., Results: RPC increased cell viability and reduced cell apoptosis (P < 0.05) in H9c2 cardiomyoblasts subjected to HR injury. In addition, RPC promoted the phosphorylation of GSK-3β at Ser9 site (P < 0.05) and suppressed the protein and mRNA expression of HDAC3 (P < 0.05). Lentiviral-transduced overexpression of HDAC3 had no significant effects on HR injury while attenuating the cardioprotective effects of RPC on cell viability and apoptosis (P < 0.05), GSK-3β phosphorylation (P < 0.05) in H9c2 cardiomyoblasts., Conclusions: RPC attenuates apoptosis in H9c2 cardiomyoblasts after HR injury by downregulating HDAC3-mediated phosphorylation of GSK-3β. Our findings suggest that HDAC3, and its cross talk function with GSK-3β, may be a promising target for myocardium I/R injury.

Mixed-halide perovskites have emerged as promising materials for optoelectronics due to their tunable band gap in the entire visible region. A challenge remains, however, in the photoinduced phase segregation, narrowing the band gap of mixed-halide perovskites under illumination thus restricting applications. Here, we use a combination of spatially resolved and bulk measurements to give an in-depth insight into this important yet unclear phenomenon. We demonstrate that photoinduced phase segregation in mixed-halide perovskites selectively occurs at the grain boundaries rather than within the grain centers by using shear-force scanning probe microscopy in combination with confocal optical spectroscopy. Such difference is further evidenced by light-biased bulk Fourier-transform photocurrent spectroscopy, which shows the iodine-rich domain as a minority phase coexisting with the homogeneously mixed phase during illumination. By mapping the surface potential of mixed-halide perovskites, we evidence the higher concentration of positive space charge near the grain boundary possibly provides the initial driving force for phase segregation, while entropic mixing dominates the reverse process. Our work offers detailed insight into the microscopic processes occurring at the boundary of crystalline perovskite grains and will support the development of better passivation strategies, ultimately allowing the processing of more environmentally stable perovskite films.

Objective: To assess different doses of nalbuphine with flurbiprofen compared to sufentanil with flurbiprofen in multimodal analgesia efficacy for elderly patients undergoing gastrointestinal surgery with a transverse abdominis plane block (TAPB)., Methods: 158 elderly patients scheduling for elective open gastrointestinal surgery under general anesthesia and TAPB were randomly assigned to four groups according to different doses of nalbuphine with flurbiprofen in postoperative intravenous analgesia (PCIA). Postoperative pain intensity, effective pressing numbers of PCIA, and adverse effects were recorded at 6, 12, 24, and 48 hours after surgery., Results: Postoperative pain intensity, effective pressing numbers, and the incidence of postoperative nausea and vomiting (PONV) were similar among the four groups after surgery, while the severity of PONV was decreased in Group L compared with Group S at 6, 12, and 48 h after surgery. No individual experienced pruritus, respiratory depression, or hypotension., Conclusions: Low dose of nalbuphine (15  μ g·kg -1 ·ml -1 ) combined with flurbiprofen is superior for elderly patients undergoing elective open gastrointestinal surgery with TAPB in terms of the efficient postoperative analgesia and decreased severity of PONV. This trial is registered with NCT02984865.

Background/aims: Autophagy is a well-known pathway to "clean" the misfolded mutant huntingtin protein (mHtt), which plays a considerable role in polyglutamine diseases. To date, there have been few studies of the choice of anesthetic during surgery in patients with polyglutamine diseases and evaluation of the effects and underlying mechanisms of anesthetics in these patients., Methods: GFP-Htt (Q74)-PC12 cells, which stably express green fluorescent protein-tagged Htt protein containing 74 glutamine repeating units, were used throughout this study. Cells were treated with 15 μM midazolam and 100 mM trehalose (positive control), and the induction of autophagy and autophagic degradation were assessed by detecting changes in autophagy-related proteins and substrates, and cell viability was assessed using the MTT assay. Overexpression of cathepsin D by plasmid transfection was used to restore midazolam-impaired autophagic degradation., Results: Midazolam increased intracellular mHtt levels in a time- and dose-dependent manner. Additionally, enhancing or blocking autophagic flux by trehalose or chloroquine could decrease or increase midazolam-induced mHtt elevation, respectively. Midazolam induced autophagy in the mTOR-dependent signaling pathway, but autophagic degradation was impaired, with a continuous rise in p62 and LC3 II levels and decrease in cathepsin D. However, overexpression of cathepsin D reversed the effects of midazolam. Midazolam led to a 20% decrease in GFP-Htt (Q74)-PC12 cell viability, which could be abrogated by overexpression of cathepsin D., Conclusions: Midazolam increased mHtt levels and decreased Htt (Q74)-PC12 cell viability via impairment of autophagic degradation, which could be restored by overexpression of cathepsin D., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background: Peripheral nerve block combined with general anesthesia is a preferable anesthesia method for elderly patients receiving hip arthroplasty. The depth of sedation may influence patient recovery. Therefore, we investigated the influence of peripheral nerve blockade and different intraoperative sedation levels on the short-term recovery of elderly patients receiving total hip arthroplasty., Methods: Patients aged 65 years and older undergoing total hip arthroplasty were randomized into 3 groups: a general anesthesia without lumbosacral plexus block group, and 2 general anesthesia plus lumbosacral plexus block groups, each with a different level of sedation (light or deep). The extubation time and intraoperative consumption of propofol, sufentanil, and vasoactive agent were recorded. Postoperative delirium and early postoperative cognitive dysfunction were assessed using the Confusion Assessment Method and Mini-Mental State Examination, respectively. Postoperative analgesia was assessed by the consumption of patient-controlled analgesics and visual analog scale scores. Discharge time and complications over a 30-day period were also recorded., Results: Lumbosacral plexus block reduced opioid intake. With lumbosacral plexus block, intraoperative deep sedation was associated with greater intake of propofol and vasoactive agent. In contrast, patients with lumbosacral plexus block and intraoperative light sedation had lower incidences of postoperative delirium and postoperative cognitive decline, and earlier discharge readiness times. The 3 groups showed no difference in complications within 30 days of surgery., Conclusions: Lumbosacral plexus block reduced the need for opioids and offered satisfactory postoperative analgesia. It led to better postoperative outcomes in combination with intraoperative light sedation (high bispectral index).

Inadvertent intraoperative hypothermia (core temperature <36 °C) is a frequent but preventable complication of general anesthesia. Accurate risk assessment of individual patients may help physicians identify patients at risk for hypothermia and apply preventive approaches, which include active intraoperative warming. This study aimed to develop and validate a risk-prediction model for intraoperative hypothermia. Two independent observational studies in China, the Beijing Regional Survey and the China National Survey, were conducted in 2013 and 2014, respectively, to determine the incidence of hypothermia and its underlying risk factors. In this study, using data from these two studies, we first derived a risk calculation equation, estimating the predictive risk of hypothermia using National Survey data (3132 patients), then validated the equation using the Beijing Regional Survey data (830 patients). Measures of accuracy, discrimination and calibration were calculated in the validation data set. Through validation, this model, named Predictors Score, had sound overall accuracy (Brier Score = 0.211), good discrimination (C-Statistic = 0.759) and excellent calibration (Hosmer-Lemeshow, P = 0.5611). We conclude that the Predictors Score is a valid predictor of the risk of operative hypothermia and can be used in deciding whether intraoperative warming is a cost-effective measure in preventing the hypothermia.

Background/objective: Inadvertent intraoperative hypothermia (core temperature <36°C) is a frequently preventable complication with several adverse consequences. Our study aimed to determine the overall incidence of inadvertent intraoperative hypothermia and its risk factors associated with clinical outcomes in this national survey in China., Methods: We conducted a national cross-sectional study with 30 days postoperative follow-up from November 2014 through August 2015. A total of 3132 eligible patients underwent general anesthesia were randomly selected from 28 hospitals in the nationwide of China., Results: The overall incidence of intraoperative hypothermia was as high as 44.3%, in which cumulative incidence rates of hypothermia being 17.8%, 36.2%, 42.5% and 44.1% within 1 h, 2 h, 3 h and 4 h respectively following induction of anesthesia. All patients were warmed passively by covering of surgical draping, sheets or cotton blankets, whereas only 14.2% of patients received active warming with space heaters or electric heater or electronic blankets. Compared to normothermic patients, patients with hypothermia is associated with more postoperative ICU admit, longer PACU and more postoperative hospital days, but no difference in surgical site infection (SSI) rates or 30-day mortality. Several factors were shown to be associated with decreased risk of hypothermia. They are active warming (OR = 0.46, 95% CI 0.26-0.81), BMI ≥ 25 (OR = 0.54, 95% CI 0.45-0.65), higher baseline core temperature (OR = 0.04, 95% CI 0.03-0.06), and higher ambient temperature (OR = 0.83, 95% CI 0.78-0.88). Risk factors associated with an increased risk of hypothermia included major-plus surgery (OR = 1.49, 95% CI 1.23-1.79), and long anesthesia (>2 h) (OR = 2.60, 95% CI 2.09-3.24)., Conclusions: The incidence of intraoperative hypothermia in China is high, and the rate of active warming of patients during operation is low. Hypothermia is associated with more postoperative shivering, increased ICU admissions, and longer postoperative hospital days.

Remifentanil postconditioning (RPC) elicits cardioprotection against ischemia/reperfusion injury (IRI) by attenuating apoptosis associated with endoplasmic reticulum stress (ERS). Histone H3, acetylation modifications of histone H3, and histone deacetylases (HDAC) also have key roles in the mediation of the survival and apoptosis of cardiomyocytes. In this study, an in vitro IRI model was established with H9c2 cardiomyoblasts to investigate the role of histone H3 acetylation and HDAC3 in RPC-induced attenuation of ERS-associated apoptosis. Briefly, H9c2 cardiomyoblasts were randomly subjected to hypoxia/reoxygenation with and without remifentanil administered at the onset of reoxygenation. Results showed that RPC increased cell viability and prevented cell apoptosis (evidenced by CCK-8 cell viability assays and flow cytometry), and these effects were accompanied by lower levels of expression of GRP78, CHOP, cleaved caspase-12, and cleaved caspase-3. RPC also mimicked the effects of SAHA by increasing the amount of histone H3 deacetylation and decreasing up-regulation of HDAC at both the mRNA and protein levels in response to HR. Finally, RPC-induced protective effects against HR, including attenuation of ERS-associated protein markers, deacetylation of histone H3, and down-regulation of HDAC3 were completely abolished by pretreatment with thapsigargin (TG, a specific ERS activator). In contrast, these effects were not found to be enhanced after pretreatment with 4-phenyl butyric acid (4-PBA, a widely used ERS inhibitor). The present results demonstrate that RPC protects H9c2 cardiomyoblasts from HR injury, and this protection involves an attenuation of ERS-associated apoptosis, which mediates a reduction in HDAC3 expression and an increase in histone H3 deacetylation.

The possible adverse effects of engineered nanomaterials on human health raise increasing concern as our research on nanosafety intensifies. Upon entry into a human body, whether intended for a theranostic purpose or through unintended exposure, nanomaterials tend to accumulate in the liver, leading to hepatic damage. A variety of nanoparticles, including rare earth upconversion nanoparticles (UCNs), have been reported to elicit hepatotoxicity, in most cases through inducing immune response or activating reactive oxygen species. Many of these nanoparticles also induce autophagy, and autophagy inhibition has been shown to decrease UCN-induced liver damage. Herein, using UCNs as a model engineered nanomaterial, this study uncovers a critical role for Kupffer cells in nanomaterial-induced liver toxicity, as depletion of Kupffer cells significantly exacerbates UCN-induced liver injury. Furthermore, UCN-induced prodeath autophagy in Kupffer cells, and inhibition of autophagy with 3-MA, a well-established chemical inhibitor of autophagy, enhances Kupffer cell survival and further abrogates UCN-induced liver toxicity. The results reveal the critical importance of Kupffer cell autophagy for nanoparticle-induced liver damage, and inhibition of autophagy may constitute a novel strategy for abrogating nanomaterial-elicited liver toxicity., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a CMOS integrated micro-LED array capable of generating discrete optical output power levels. A 16 × 16 array of individually addressable pixels are on-off controlled through parallel logic signals. With carefully selected groups of LEDs driven together, signals suitable for discrete transmission schemes are produced. The linearity of the device is assessed, and data transmission using pulse amplitude modulation (PAM) and orthogonal frequency division multiplexing (OFDM) is performed. Error-free transmission at a symbol rate of 100 MSamples/s is demonstrated with 4-PAM, yielding a data rate of 200 Mb/s. For 8-PAM, encoding is required to overcome the baseline wander from the receiver, reducing the data rate to 150 Mb/s. We also present an experimental proof-of-concept demonstration of discrete-level OFDM, achieving a spectral efficiency of 3.96 bits/s/Hz.

We demonstrate a novel approach to control β-phase content generated in poly(9,9-dioctylfluorene) (PFO) films. A very small amount of paraffin oil was used as the additive to the PFO solution in toluene. The β-phase fraction in the spin-coated PFO films can be modified from 0% to 20% simply by changing the volume percentage of paraffin oil in the mixed solution. Organic light emitting diodes (OLEDs) and amplified spontaneous emission (ASE) study confirmed low β-phase fraction promise better OLEDs device, while high β-phase fraction benefits ASE performance.

Background: Remote precoditioning of trauma (RPCT) confers cardioprotective effects against myocardial ischemia/reperfusion injury, which are mediated by spinal opioid receptors. The aim of this study was to identify the roles of opioid receptor subtypes in the cardioprotective effect of RPCT and possible mechanisms., Methods: In this study, 192 Sprague-Dawley rats were allocated to 12 groups. Except for the sham group, rats in all groups were subjected to myocardial ischemia reperfusion. Rats in the ischemia precondition (IPC) group were treated with IPC. In the RPCT groups, an abdominal incision was made 15 min before inducing ischemia. The selective delta-, kappa-, and mu-opioid receptor antagonists were administered to groups of animals receiving RPCT, respectively. Data were collected for myocardial infarct size, intercellular adhesion molecule 1 (ICAM-1), plasma cardiac troponin I (cTnI) concentrations, activation of protein kinase C epsilon (PKCe) in myocardial cell membranes, and adenosine release in the spinal cord., Results: Compared with the control groups, infarct size, plasma concentrations of cTnI, and myocardial ICAM-1 expression were significantly lower, while adenosine release and PKCe activation were enhanced in the IPC and RPCT groups. Compared with the RPCT group, infarct size, plasma cTnI concentration, and myocardial ICAM-1 expression were greater and adenosine release and PKCe activation were reduced in the mu-opioid receptor antagonist plus RPCT group., Conclusions: The spinal mu-opioid receptor mediated the cardiac protective effect of RPCT. The mechanism may be enhanced by adenosine release in the spinal cord and PKCe activation in the myo-cardium, thereby inhibiting inflammation induced by ischemia/reperfusion injury.

Background and Objectives: Hemangeol, approved for the treatment of proliferative infantile hemangiomas requiring systemic therapy, is metabolized by cytochrome P450 2D6 (CYP2D6), which is a highly polymorphic enzyme that metabolizes a large number of drugs. More than 100 CYP2D6 allelic variants have been reported so far, including 22 novel variants that discovered in our lab in the Chinese population. Our study aimed to probe the enzymatic activity of these variants toward hemangeol in vitro with recombinant microsomes that expressed in sf21 insect cells using a baculovirus-mediated expression system., Methods: The wild-type CYP2D6.1 and other variants (CYP2D6.2, CYP2D6.10 and 22 novel CYP2D6 variants) were incubated with 1-200 μM hemangeol for 50 min at 37 °C. Then the products were extracted, and signal detection was performed by high-performance liquid chromatography with fluorescence detector., Results: All of the variants exhibited changed apparent Michaelis-Menten constant (Km) or maximum velocity of the reaction (V max ) values compared with that of wild-type protein. The intrinsic clearances (V max /Km) were significantly decreased by 0.37 to 42.74 %. However, CYP2D6.92 and CYP2D6.96 showed no or minimal enzymatic activity as no concentration of 4'-hydroxypropranolol was detected., Conclusions: The comprehensive in vitro assessment of CYP2D6 variants provides significant insights into allele-specific activity towards hemangeol in vivo.

Objective: To investigate the effect of goal-directed haemodynamic management based on stroke volume variation (SVV), cardiac index (CI) and mean arterial blood pressure (MAP) on the postoperative outcome in elderly patients with fragile cardiac function undergoing gastrointestinal surgery. Methods: Ninety patients with fragile cardiac function, aged 65-90 years old, ASAⅡ or Ⅲ, NYHA Ⅱor Ⅲ, scheduled for abdominal surgery were enrolled in this study.The patients were randomly assigned to two groups: Experience anesthesia group (group E, n =45) and goal-directed hemodynamic management group (G group, n =45). After anesthesia induction, in group G, the SVV and CI were monitored by Vigileo and according SVV (≤12%), CI (≥2.5 L·min -1 ·m -2 ) and MAP (maintain the base value of ±20%) to adjust the preloaded infusion fluid and give positive inotropic drugs and positive pressure drugs; in group E, fluid and vasoactive agent were used according to the experience of anesthesiologist.Multi-mode monitoring anesthesia management using BIS, TCI of propofol, low-tidal-volume lung protective ventilation management strategy, body temperature protection, and postoperative multimodal analgesia techniques was performed in the two groups.Values of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) were recorded before operation, at the end of operation, and postoperative 24 h. The incidence of myocardial infarction/angina, heart failure, arrhythmia and cerebral infarction, renal failure, length of hospitalization, and complications in 30-days after surgery were recorded by telephone follow-up. Results: Crystal, colloid, total liquid of group E were (1 110.20±332.00), (536.65±72.25), (1 677.20±424.44) ml and these of group G were (708.72±240.85), (414.41±74.31), (878.51±199.13) ml, respectively.Compared with group E, the fluid infusion were reduced in group G ( t =6.057, 2.701, 9.742, all P <0.05). The lactic acid value of 24 hours after surgery in group G was significantly lower than that in group E [(0.89±0.31) mmol/L vs (1.11±0.43) mmol/L, t =-2.848, P <0.05]. Arterial partial pressure of oxygen at 24 hours after surgery in group G was higher than that in group E [(78.77±6.86) mmHg vs (76.46±10.96) mmHg, t =-1.108, P <0.05]. The length of hospitalization of group G was shorter than that of group E [(12.21±2.20) d vs (13.16±3.84) d, t =-1.341, P <0.05]. The incidence of total complication in hospital and in 30-days after surgery of group G were 10.26% and 5.13%, while these of group E were 29.73% and 24.32%, (χ 2 =4.545, 4.520, all P <0.05). ΔNT-proBNP 1 (the base value of NT-proBNP's minus the value of NT-proBNP's at the end of the operation) and ΔNT-proBNP 2 (the base value of NT-proBNP's minus the value of NT-proBNP's 24 hours postoperatively) of group G were 12.0(-291.0, 1 517.0) and 0(-6 770.0, 291.0), both higher than these of group E [0(-440.0, 200.0) and -12.0(-7 200, 22.0), ( Z =-2.412, -2.163, all P <0.05)]. Conclusion: Goal-directed haemodynamic management based on SVV, CI and MAP could improve the outcome of the elderly patients with fragile heart function undergoing abdominal surgery.

Cytochrome P450 enzyme 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily, with more than 100 CYP2D6 allelic variants being previously reported. The aim of this study was to assess the catalytic characteristics of 25 alleles (CYP2D6.1 and 24 CYP2D6 variants) and their effects on the metabolism of propafenone in vitro. Twenty-five CYP2D6 alleles were expressing in 21 Spodoptera frugiperda (Sf) insect cells, and each variant was evaluated using propafenone as the substrate. Reactions were performed at 37 °C with 1-100 μmol/L propafenone for 30 min. After termination, the product 5-OH-propafenone was extracted and used for signal collection by ultra-performance liquid chromatography (UPLC). Compared with wild type CYP2D6.1, the intrinsic clearance (Vmax and Km) values of all variants were significantly altered. Three variants (CYP2D6.87, CYP2D6.90, CYP2D6.F219S) exhibited markedly increased intrinsic clearance values (129% to 165%), whereas 21 variants exhibited significantly decreased values (16% to 85%) due to increased Km and (or) decreased Vmax values. These results indicated that the majority of tested alleles had significantly altered catalytic activity towards propafenone hydroxylation in this expression system. Attention should be paid to subjects carrying these rare alleles when treated with propafenone.

Background: Hyperglycemia is proposed to be an independent risk factor for cardiovascular morbidity and mortality. Preclinical studies suggest that diabetes mellitus exacerbates myocardial ischemia/reperfusion injury and attenuates the effects of cardioprotective strategies. The cardioprotective effects of postconditioning with the opioid analgesic remifentanil against ischemia/reperfusion injury under the hyperglycemic condition remain contradictory. Therefore, the aim of this study was to investigate the mechanisms by which hyperglycemia affects cardioprotection induced by remifentanil postconditioning., Materials and Methods: H9c2 cardiomyoblasts were cultured under the normoglycemic or hyperglycemic condition. Cells were exposed to hypoxia/reoxygenation (H/R) injury followed by hypoxia postconditioning (HPC group) or remifentanil postconditioning (RPC group). Cell viability, injury, and apoptosis were measured after each postconditioning treatment. Activation of endoplasmic reticulum stress (ERS) was analyzed by examining the protein levels of GRP78, CHOP, cleaved caspase-12 and cleaved caspase-3., Results: RPC significantly increased cell viability and reduced apoptosis in normoglycemic cardiomyoblasts, but not in hyperglycemic cardiomyoblasts. HPC and RPC markedly decreased the upregulation of GRP78, CHOP, cleaved caspase 12, and cleaved caspase 3 in response to H/R injury under the normoglycemic condition. Hyperglycemia significantly increased these ERS-associated biomarkers and apoptosis, which could not be reduced by HPC or RPC., Conclusions: Remifentanil postconditioning protected cardiomyoblasts from H/R injury under normoglycemia, at least in part, through inhibiting ERS-induced apoptosis. Hyperglycemia attenuated the cardioprotection conferred by remifentanil postconditioning, likely as a result of the exacerbated ERS. Inhibiting the ERS response may be an attractive strategy to enhance the cardioprotective effects of postconditioning in diabetic patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sufentanil, a commonly used opioid analgesic, could mimic ischemia postconditioning to attenuate ischemia reperfusion injury, but this effect might be hindered in diabetic animals by inhibition of glycogen synthase kinase-3β phosphorylation. Also, diabetes can abrogate the cardioprotection of sevoflurane (an inhaled anesthetic) against ischemia reperfusion injury, and short-term insulin treatment does not restore protection by sevoflurane postconditioning. We hypothesized that long-term insulin treatment might restore the cardioprotective effect of sufentanil postconditioning in diabetic rats via phosphorylation of glycogen synthase kinase-3β. Streptozotocin (55 mg/kg)-induced diabetic rats received insulin (Novolin N, 6-8 u/d) for two days or two weeks, then were exposed to 30-min ischemia and 120-min reperfusion. Sufentanil postconditioning was performed 5 min before the onset of reperfusion. Controls included non-diabetic rats, sham surgery for ischemia/reperfusion, and sufentanil vehicle. Infarct size, cardiac troponin I, and phosphorylated glycogen synthase kinase-3β were examined. Sufentanil postconditioning reduced infarct size by 46% in non-diabetic rats (P < 0.001), but diabetes prevented this protective effect. Two-day insulin treatment was not effective, but two-week treatment reduced infarct size by 45% (P < 0.001), reduced cardiac troponin I by 33% (P < 0.001), and increased phosphorylated glycogen synthase kinase-3β levels (P < 0.001) in the diabetic sufentanil postconditioning group. In conclusion, sufentanil-induced cardioprotection was restored by long-term insulin treatment. The underlying mechanism may be increased phosphorylation of glycogen synthase kinase-3β., (© 2016 by the Society for Experimental Biology and Medicine.)

Oxcarbazepine (OXC), a second-generation antiepileptic drug, undergoes rapid reduction with formation of the active metabolite 10,11-dihydro-10-hydroxy-carbazepine (MHD) in vivo. In this study, a method for simultaneous determination of OXC and MHD in rat plasma using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS-MS) was developed and validated. Under given chromatographic conditions, OXC, MHD and internal standard diazepam were separated well and quantified by electrospray positive ionization mass spectrometry in the multiple reaction monitoring transitions mode. The method validation demonstrated good linearity over the range of 10-2,000 ng/mL for OXC and 5-1,000 ng/mL for MHD. The lower limit of quantification was 5 ng/mL for OXC and 2.5 ng/mL for MHD, respectively. The method was successfully applied to the evaluation of the pharmacokinetics of OXC and MHD in rats, with or without pretreatment by ketoconazole (KET) and voriconazole (VOR). Statistics indicated that KET and VOR significantly affected the disposition of OXC and MHD in vivo, whereas VOR predominantly interfered with the disposition of MHD. This method is suitable for pharmacokinetic study in small animals., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Flexible vertical InGaN micro-light emitting diode (micro-LED) arrays have been fabricated and characterized for potential applications in flexible micro-displays and visible light communication. The LED epitaxial layers were transferred from initial sapphire substrates to flexible AuSn substrates by metal bonding and laser lift off techniques. The current versus voltage characteristics of flexible micro-LEDs degraded after bending the devices, but the electroluminescence spectra show little shift even under a very small bending radius 3 mm. The high thermal conductivity of flexible metal substrates enables high thermal saturation current density and high light output power of the flexible micro-LEDs, benefiting the potential applications in flexible high-brightness micro-displays and high-speed visible light communication. We have achieved ~40 MHz modulation bandwidth and 120 Mbit/s data transmission speed for a typical flexible micro-LED.