Search

Background The clinical utility and long-term effects of endothelin receptor antagonists (ERAs) in Fontan-palliated patients remain unclear and there are currently no approved therapies. A decline in peak VO2 between consecutive cardiopulmonary exercise tests (CPETs) is highly prognostic for death or transplant in adult Fontan patients, hence its use as a primary endpoint in clinical trials of ERAs in patients with Fontan circulation. Purpose The RUBATO trial aimed to assess the efficacy and safety of macitentan, an endothelin receptor antagonist, in Fontan-palliated patients over 52 weeks. Methods In the multicentre, double-blind, randomised, placebo-controlled, phase 3 RUBATO trial, Fontan-palliated patients were randomised 1:1 to macitentan 10 mg once-daily or placebo for 52 weeks. Eligible patients were aged ≥12 years, in New York Heart Association functional class II or III, had no limitations for CPET (including no pacemakers), had undergone lateral tunnel or extracardiac conduit Fontan (total cavopulmonary connection) >1 year before screening and showed no signs of Fontan failure or clinical deterioration within 3 months before screening. Primary efficacy endpoint was change in peak VO2 from baseline to week 16. Secondary endpoints were change in peak VO2 from baseline over 52 weeks and change in mean count per minute of daily physical activity from baseline to week 16 as measured by an accelerometer. Adverse events were also assessed. Results 137 patients were randomised to macitentan (n=68) or placebo (n=69). 92.7% of patients completed 52 weeks of double-blind treatment: 7 and 3 patients prematurely discontinued study treatment in macitentan and placebo arms, respectively. Patient baseline characteristics are shown in Table 1. At week 16, the mean (SD) change from baseline in peak VO2 was –0.16 (2.86) with macitentan vs –0.67 (2.66) mL/kg/min with placebo (median unbiased estimate of the difference between macitentan and placebo: 0.62 mL/kg/min [99% repeated confidence interval –0.62; 1.85], p=0.1930). No treatment effect was observed in the two secondary endpoints (Table 2): mean (SD) count per minute of daily physical activity decreased from baseline to week 16 by 3.02 (92.44) with macitentan and by 14.34 (117.56) with placebo (p=0.4512). The most common AEs were headache (10.3% vs 8.7% on placebo), nasopharyngitis (5.9% vs 4.3%), and pyrexia (5.9% vs 4.3%). AEs leading to treatment discontinuation were reported in 3 (4.4%) and 1 (1.4%) of macitentan and placebo patients. Conclusion The 52-week RUBATO trial provides an important addition to data on the clinical utility of ERAs in Fontan-palliated patients. The primary efficacy endpoint was not met and no treatment effect was observed for the two secondary endpoints. Macitentan was well tolerated; safety findings were consistent with the known safety profile of macitentan 10 mg. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Actelion Pharmaceuticals Ltd., a Janssen pharmaceutical company of Johnson & Johnson.

Siwei Jianbu Decoction (SJD) has been shown to be effective in treating atherosclerosis (AS). However, its mechanism is still unclear.The active compounds and targets of SJD were identified from the Traditional Chinese Medicine System Pharmacology (TCMSP) database. The target genes of AS were obtained from the Online Mendelian Inheritance in Man (OMIM), GeneCards, DrugBank, and Therapeutic Target (TTD) databases. Interactions between drug and disease targets were analyzed to obtain common targets. Subsequently, "herb-compound-target" and protein-protein interaction (PPI) networks were constructed and analyzed using the Cytoscape software. Thereafter, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed by DAVID online database. Then, the results were visualized by R software. Finally, molecular docking was performed using AutoDockTools and PyMOL software.A total of 61 active compounds and 377 target genes were identified for SJD, as well as 726 target genes for AS. Interactive analyses revealed 126 common genes between SJD and AS. Quercetin, ellagic acid, baicalein, and kaempferol were the 4 key compounds in SJD. Moreover, eight key targets, namely TNF, SRC, RELA, AKT1, STAT3, JUN, MAPK1 and FOS were found. Results from enrichment analysis indicated that the MAPK pathway may play an important role. The analysis of molecular docking revealed that the key compounds formed strong bonds with their corresponding key targets.These findings indicate that SJD could prevent AS by inhibiting the expression of genes associated with MAPK pathway such as MAPK1, RELA, and FOS.

口腔黏膜病是发生在口腔黏膜及软组织上的类型各异、种类众多的疾病总称。在临床工作中，口腔黏膜病常表现为不典型损害或伴有全身损害等情况，再加上其更迭、重叠和共存的特性，口腔黏膜病的诊断常是临床难题。因此，本文提出口腔黏膜病的临床辨析策略：根据全面的病史采集和详细的临床检查，结合必要的辅助手段，充分利用文献、指南和共识，借助多学科专家会诊的模式，做到高效、正确的诊断和治疗。.

Heart rate variability (HRV) is commonly used in sport science for monitoring the physiology of athletes but not as an indicator of physiological state from a psychological perspective. Since HRV is established to be an indicator of emotional responding, it could be an objective means of quantifying an athlete's subjective physiological state before competition. A total of 61 sport shooters participated in this study, of which 21 were novice shooters, 19 were intermediate shooters, and 21 were advanced level shooters. HRV, self-efficacy, and use of mental skills were assessed before they completed a standard shooting performance task of 40 shots, as in a competition qualifying round. The results showed that HRV was significantly positively correlated with self-efficacy and performance and was a significant predictor of shooting performance. In addition, advanced shooters were found to have significantly lower average heart rate before shooting and used more self-talk, relaxation, imagery, and automaticity compared to novice and intermediate shooters. HRV was found to be useful in identifying the physiological state of an athlete before competing, and as such, coaches and athletes can adopt practical strategies to improve the pre-performance physiological state as a means to optimize performance.

A charge-steering based latch hardening technique with very low performance tradeoff and significant SEU hardness is presented. Mixed-mode 3D-TCAD simulations are used to illustrate the effect of charge steering in reducing the amount of collected charge at the critical sensitive nodes. Circuit simulations also highlight that the tradeoffs in terms of area, speed and power penalties are much lower compared to other hardening approaches, such as hysteresis and spatial-redundancy techniques. Alpha particle, heavy-ion, and proton test results for circuits designed in a 16 nm FinFET process indicate significant SEU hardness, comparable to DICE FF design, for low LET particles.

To investigate whether MOTS-c can regulate the synthesis of type I collagen in osteoblasts by regulating TGF-β/SMAD pathway, thereby improving osteoporosis.Viability of hFOB1.19 cells treated with MOTS-c was detected by CCK-8 assay. The mRNA and protein levels of TGF-β, SMAD7, COL1A1 and COL1A2 in hFOB1.19 cells were detected by quantitative Real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. We then changed expressions of TGF-β and SMAD7 by plasmids transfection to detect levels of COL1A1 and COL1A2 in hFOB1.19 cells by qRT-PCR and Western blot, respectively.Cell viability was significantly increased after treatment of 1.0 μM MOTS-c for 24 h or 0.5 μM MOTS-c for 48 h in a time-dependent manner. The mRNA and protein expressions of TGF-β, SMAD7, COL1A1 and COL1A2 in hFOB1.19 cells were dependent on the concentration of MOTS-c. In addition, MOTS-c increased the expressions of COL1A1 and COL1A2, which were partially reversed by knockdown of TGF-β or SMAD7.MOTS-c could promote osteoblasts to synthesize type I collagen via TGF-β/SMAD pathway.

A pulsed-DICE latch design that operates similar to an edge-triggered flip-flop with improved SER performance is presented. Design was implemented along with conventional D-flip-flop and conventional DICE flip-flop in 16 nm and 7 nm bulk FinFET CMOS processes. The pulsed-DICE latch did not show any upsets with alpha particles and neutrons and has more than 2 orders of magnitude improvement in heavy-ion cross-section compared to conventional D-FF. The proposed design benefits from 60% higher speed than the conventional DICE flip-flop design along with significantly lower area and power penalties.

Fanout Wafer Level Packaging (FoWLP) is a very attractive solution for microelectronics applications requiring optimized performance, smaller form factor, and low cost. By utilizing such an approach where system integration is done to multiple chips on a single package frame, the need to ensure much higher levels of process integrity, quality, and reliability becomes absolutely critical, especially if the total product volume lies in the range of tens of millions of units. A single defect type may negate the benefits of such an approach because the cost of losing one FoWLP unit results in the loss of multiple devices. Thus, yield, quality, and reliability optimization using such a package solution is critical for successful large scale manufacturing. In this talk, the issue of defectivity and its impact on quality and reliability on Wafer-Level (WL) devices with regards to the issue of Die Edge Delamination (DED) and Chip Mechanical Integrity (CMI) is discussed. Through this discussion and the resulting solutions found to improve WL quality and reliability, better understanding on how to assess the quality and reliability of a given FoWLP solution for large scale production will be demonstrated.

With fabrication processes migrating from planar devices to FinFETs, the differences in physical structure necessitate evaluating the SEU mechanisms of FinFET-based circuits. Since FinFET-based bi-stable circuits have shown better stability at low supply voltages and hence improved power dissipation, it is also necessary to assess the SEU performance over a range of voltages. In this work, the SEU cross section of FinFET-based D-flip-flops was measured with alpha particles, protons, neutrons, and heavy-ions. Results show a strong exponential increase in the SEU rate with reduction in bias for low-LET particles. Technology Computer Aided Design (TCAD) simulations show that the weak variation of collected charge with supply voltage, combined with the standard bias dependence of critical charge, is responsible for this trend.

To investigate the regulatory effect of long non-coding ribonucleic acid (lncRNA) FER1L4 on biological behaviors of esophageal squamous cell carcinoma (ESCC) cells, such as proliferation and invasion.The expressions of FER1L4 were detected in 42 pairs of ESCC tissues and corresponding para-carcinoma tissues and 5 kinds of ESCC cell lines via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Polyethyleneimine (PEI) and liposomes were used for FER1L4 expression or interference elimination assays, respectively. The proliferation and invasion of ESCC cells were detected via MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), apoptosis assay, cell cycle assay, and transwell chamber.Results of qRT-PCR showed that, compared with that in normal tissues, FER1L4 was lowly expressed in ESCC tissues. Overexpression of FER1L4 could inhibit cell proliferation and invasion, promote apoptosis and increase the cell cycle distribution in G0/G1 phase. Knockout of FER1L4 could promote the proliferation and invasion of ESCC cells, inhibit apoptosis and decrease the cell cycle distribution in G0/G1 phase.FER1L4 is involved in the occurrence and development of ESCC and plays a key role as a tumor suppressor gene in ESCC.

The current study was conducted to investigate the effects of dietary supplementation of biotin, intramuscular injections of vitamin B

Soft error rates for triple-well and dual-well SRAM circuits over the past few technology generations have shown an apparently inconsistent behavior. This work compares the heavy-ion induced upset cross-section in 28, 40, and 65 nm dual- and triple-well SRAMs over a wide range of particle LETs. Similar experiments on identical layouts for all these technologies along with 3-D TCAD simulations are used to identify the dominant mechanisms for single-event upsets. Results demonstrate that the well-engineering strongly influence the single-event response of SRAMs. Layout also plays an important role and the combined effects of well-engineering and layout determine the soft-error sensitivity of SRAMs fabricated in advanced technology nodes.

Navigation is a primary task for mobile robot to accomplish its tasks. Conventionally, these navigation methods require lots of parameters to be tuned artificially. In this paper, we propose a navigation method to learn the end-to-end control policy using convolution neural network, which directly outputs the velocity and angular rates using only the current observation and the target. Besides, a sliding window of past information is incorporated to add the memory to the controller, so that the hesitation is reduced when ambiguity occurs. To train the model, the data is generated from expert planner in the simulation environment, leading to a low cost for massive data. To validate the trained end-to-end controller, we compare our method with the expert global planner both in the training map and complex map in the simulation environment.

With the rapid development of computer graphics, the importance of battlefield visualization in information warfare is becoming increasingly obvious. As a component of the battlefield visualization system, military plotting system of battlefield image reflects natural environment, humanistic environment, military targets, military operations and other detailed information. This research mainly aims at the shortcomings of the existing military plotting system, which are secondary development and convenience, so a new military plotting system framework based on AutoCAD secondary development is proposed and the new military plotting system has been developed. The functions of the system have been verified by practice.

The current study was conducted to investigate the effects of 5,6-dimethylbenzimidazole (DMB) supplementation to the feed during the transition period and early lactation on the vitamin B

Oral lichen planus (OLP) is a common oral mucosal disease. The etiology of OLP is not clear. The treatment of OLP is difficult as some of the OLP patients have little effects to the conventional mucosal treatments. In recent years, laser therapy has been adopted to treat patients with OLP. The CO(2) laser therapy has drawn much attention of doctors and scholars because of its advantages in treating the OLP. This review article mainly discusses the principle, effects and some state-of-the-art progresses in OLP treatment using CO(2) laser.口腔扁平苔藓（oral lichen planus，OLP ）是常见的口腔黏膜病，其病因不明，治疗较困难，传统疗法对部分患者无效。近年来激光疗法在治疗OLP上取得一定的效果，其中CO(2)激光因其较好的疗效得到国内外医师和学者的关注。本文主要探讨CO(2)激光治疗OLP的原理、疗效及新进展。.

SRAM physical unclonable function (PUF) provides a low-cost security key to address hardware attacks such as cloning as well as for reliability tracking of ICs in the field. In this work the quality and aging reliability of 28 nm high-K metal gate planar and 16 nm FinFET based SRAMs are discussed in detail with regards to their use in PUF. Data indicates that 16 nm FinFET process has a better SRAM PUF quality without any design modifications compared to the 28 nm planar process. In addition, the aging-induced bit instability is shown to be a reasonably small percentage of the overall bit counts.

By analyzing MSCT (multi-slice computed tomography) signs with different risks in gastrointestinal stromal tumors, this paper aimed to discuss the predictive value and modeling analysis of MSCT signs in GISTs (gastrointestinal stromal tumor) to pathological risk degree.100 cases of primary GISTs with abdominal and pelvic MSCT scan were involved in this study. All MSCT scan findings and enhanced findings were analyzed and compared among cases with different risk degree of pathology. Then GISTs diagnostic model was established by using support vector machine (SVM) algorithm, and its diagnostic value was evaluated as well.All lesions were solitary, among which there were 46 low-risk cases, 24 medium-risk cases and 30 high-risk cases. For all high-risk, medium-risk and low-risk GISTs, there were statistical differences in tumor growth pattern, size, shape, fat space, with or without calcification, ulcer, enhancement method and peritumoral and intratumoral vessels (p0.05). However, there were no statistical differences in the location of tumor and CT value at each period (plain scan, arterial phase, venous phase) (p0.05). The apparent difference lied in plain scan, arterial phase and venous phase for each risk degree. The diagnostic accuracy of SVM diagnostic model established with 10 imaging features as indexes was 70.0%, and it was especially reliable when diagnosing GISTs of high or low risk.Preoperative analysis of MSCT features is clinically significant for its diagnosis of risk degree and prognosis; GISTs diagnostic model established on the basis of SVM possesses high diagnostic value.

This study deals with the diagenesis of sandstones of the Funing Formation at Gaoji Oilfield, Subei Basin, east of China. Mineralogy was determined by X-ray diffraction and scanning electron microscopy. The sandstones are lithic arokose and feldspathic litharenite, with less subarkose and sublitharenite. The diagenetic processes include compaction, cementation, replacement, and dissolution, indicating an opportunity to study the diagenetic sequence. Among the diagenetic minerals, carbon forms the major cement, appearing as dominate pore occluding cement in the Funing sandstones. Smectite is helpful for the formation of chlorite. Quartz overgrowth may be inhibited by illite and chlorite. Pore types existing in the study area include a mix of primary intergranular, secondary intergranular, secondary intragranular, moldic pores, and micropores. The quality of reservoir sandstones is environmentally selective, and pores are mainly developed in sand bars, distributary channels, underwater distributary channels...

We present experimental evidence of single-event upsets in 28 and 45 nm CMOS SRAMs produced by single energetic electrons. Upsets are observed within 10% of nominal supply voltage for devices built in the 28 nm technology node. Simulation results provide supporting evidence that upsets are produced by energetic electrons generated by incident X-rays. The observed errors are shown not to be the result of “weak bits” or photocurrents resulting from the collective energy deposition from X-rays. Experimental results are consistent with the bias sensitivity of critical charge for direct ionization effects caused by low-energy protons and muons in these technologies. Monte Carlo simulations show that the contributions of electron-induced SEU to error rates in the GEO environment depend exponentially on critical charge.

The effect of notch types and stress concentration factors (Kt) on low cycle fatigue life and cracking of the DZ125 directionally solidified superalloy has been experimentally investigated. Single-edge notched specimens with V and U type geometries were tested at 850 °C with stress ratio R = 0.1. High temperature in situ optical method was used to observe crack initiation and short crack propagation. Scanning electron microscope observation of fracture was used to analyse the failure mechanism. The results reveal that fatigue resistance decreases with Kt increasing from 1.76 to 4.35. The ratcheting is found to be affected by both Kt and the nominal stress from the displacement–force curve. In situ observations indicate that the cracking does not occur at the notch apex but at the location where the max principal stress or Hill's stress is the highest. According to the scanning electron microscope observations, the failure of the notched specimens strongly depends on the anisotropy microstructures.

A simple method to analyse the notch sensitivity of specimens in fatigue tests is presented. The parameter m, which can be used to measure the notch sensitivity, the nominal stress and the stress concentration factor (Kt) are used to establish the method. In order to verify the feasibility of the method, notch fatigue test results from our group and literatures were collected. The results reveal that an optimal value of parameter m does exist for each material. Life predictions indicated that the model is able to describe the life evolution for notched specimens under high cycle fatigue and low cycle fatigue tests. Because the geometry effect is accounted for Kt, the method is suitable for the conditions when the notch geometries and the absolute dimensions are similar to the tested specimens.

A novel D-Flip-Flop design using hysteresis to improve single-event hardness with low performance overhead is presented. Layout-aware sensitive area simulations were used to estimate the improvement in cross-section for the proposed hysteresis DFF (HDFF) vs. a standard DFF. A test chip with the standard DFF, HDFF, and the DICE FF was designed in a 28 nm CMOS process and exposed to alpha, neutron, and heavy-ion beams. The HDFF design shows 14× and 3× improvements in the alpha and neutron SER, respectively, compared with a standard DFF.

Nuclear factor kB (NF-kB) is a transcriptional factor that regulates a large number of genes that controls diverse biological functions, ranging from inflammation, cell proliferation and tumor development to learning and memory. MicroRNAs (miRNAs) are small non-coding RNA molecules involved in most aspects of physiological and pathological processes, including cancer, viral infections, inflammation and autoimmune diseases. miRNAs also play an important role in the regulation of NF-kB signaling pathway, some being inhibitory and others activating. Here, we analyzed the convergence of miRNAs involved in NF-kB signaling regulation and dysregulation of miRNAs and NF-kB activation in human diseases, particularly in cancer. The function of miR-146, miR-125b, miR-21, miR-301a, miR-30b, and miR-199 and their impacts on tumorigenesis are analyzed in this work. miRNAs as one of the most abundant classes of regulatory molecules, deciphering their biological function and pathological contribution in NF-kB dysregulation is essential to understand the complexity of immune systems and to develop therapeutics against cancer.

Alpha particle-induced flip-flop soft-error rates (SER) for 20-nm bulk planar and 16-nm bulk FinFET technologies are characterized over temperature with different supply voltages. Experimental results indicate that the 16-nm FinFET SER changes insignificantly with temperature while the 20-nm planar SER increases by ∼2x over the same temperature range. 3D TCAD and circuit-level simulations show changes in single-event transient (SET) pulse width and logic gate delay are the controlling factors, with opposing influences on SER.

There is structural damage to myelin and secondary immune injury in the development of delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP). In order to assess the role of genetic factors in this mechanism, we studied the association between tumor necrosis factor-α308 (TNF-α308) and myelin basic protein (MBP) 5'-side tetranucleotide repetitive sequence (TGGA) n gene polymorphism and DEACMP. We selected 109 DEACMP patients from the Han population in the Northern Henan Province as the case group, and 115 patients without delayed encephalopathy (called the acute CO poisoning group or the control group). There were no significant differences in TNF-α308 and MBP 5'-side TGGA n genotype distribution and allele frequency between the DEACMP group and the acute CO poisoning group (all P > 0.05). When the population was stratified by gender, only the MBP 5'-side TGGA n allele frequency was significantly different, and the frequency of allele L in the DEACMP group was significantly higher than that of the acute CO poisoning group in males (χ(2) = 4.089, P = 0.043, odds ratio = 2.103, 95% confidence interval = 1.014-4.363). The results showed that there was association between MBP 5'-side TGGA n gene polymorphism and DEACMP, and that allele L could increase the risk of occurrence in male patients with DEACMP. DEACMP may be the result of interaction of environmental and genetic factors.