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The Awakening is a story about women awakening, and it is also a story about extramarital affairs. By using feminist narration theory to analyze the relationship between Edna and the four men, namely Mr. Pontellier, Edna’s father, Arobin and Robert, we can have a deeper understanding of Edna’s emotional attitudes and values, and reflect on the relationship between people and the choice of life path.

The crystallization blockage of the tunnel drainage pipes in karst areas often threatens the normal construction of tunnels and affects operation of drainage systems. Based on basic theory of CaCO3 crystallization, this study analyses the law of the crystalline scale formation rate of tunnel drainage pipes in karst areas through three mass transfer mechanisms: convective mass transfer, molecular diffusion and wall ion reactions, obtains the calculation model of crystalline scale formation rate of drainage pipes, and verifies model by simulating crystalline scale formation tests of tunnel drainage pipes. The results show that factors such as the flow rate of karst water, the inner diameters of tunnel drainage pipes, the molecular diffusion coefficient, the dynamic viscosity of karst water, the molecular diffusion coefficient of calcium carbonate, the temperature of karst water, and the slopes of tunnel drainage pipes have certain influences on the crystallization of the tunnel drainage pipes in karst areas, and they promote or inhibit the formation of scale layers on the inner walls of the tunnel drainage pipes in karst areas by affecting the efficiency of convective mass transfer, molecular diffusion and wall ion reactions; under different test conditions, the average relative errors between the calculated results of the crystalline scale formation rate of drainage pipes and those of the pipes in the test group are 9.1%, 13.7%, 14.2% and 16.1% respectively. Considering the scouring effect of water flow on crystalline scale layers, although there are certain errors in the results, this does not affect the overall results

This paper aims at the problem of finite-time prescribed performance adaptive fuzzy control for a class of unknown nonlinear systems. An adjustable finite-time performance function with faster convergence rate is applied to the procedure of the controller design, whose parameters can be adjusted in real time on the basis of the tracking error. Furthermore, a finite-time prescribed performance adaptive fuzzy tracking controller is designed by the backstepping method, which can guarantee that all the signals in the closed-loop system are bounded. Simultaneously, the output tracking error always stays within an adjustable boundary and converges to a fixed region at finite-time settling time. Besides, the tracking performance in transient state is slightly optimized. Simulation results demonstrate the effectiveness of the proposed controller.

Background and ObjectivesPompe disease is a rare, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA) and subsequent glycogen accumulation. Avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy designed for increased cellular uptake and glycogen clearance, has been studied for long-term efficacy and safety in patients with late-onset Pompe disease (LOPD). Here, we report up to 6.5 years' experience with avalglucosidase alfa during the NEO1 and NEO-EXT studies.MethodsNEO1 participants with LOPD, either treatment naive (Naive Group) or receiving alglucosidase alfa for ≥9 months (Switch Group), received avalglucosidase alfa (5, 10, or 20 mg/kg every other week [qow]) for 6 months before entering NEO-EXT and continued their NEO1 dose until all proceeded with 20 mg/kg qow. Safety and efficacy, a prespecified exploratory secondary outcome, were assessed; slopes of change for efficacy outcomes were calculated from a repeated mixed-measures model.ResultsTwenty-four participants enrolled in NEO1 (Naive Group, n = 10; Switch Group, n = 14); 21 completed and 19 entered NEO-EXT; in February 2020, 17 participants remained in NEO-EXT, with data up to 6.5 years. Avalglucosidase alfa was generally well tolerated during NEO-EXT, with a safety profile consistent with that in NEO1. No deaths or treatment-related life-threatening serious adverse events occurred. Eighteen participants developed antidrug antibodies without apparent effect on clinical outcomes. No participants who were tested developed immunoglobulin E antibodies. Upright forced vital capacity %predicted remained stable in most participants, with slope estimates (95% CIs) of −0.473 per year (−1.188 to 0.242) and −0.648 per year (−1.061 to −0.236) in the Naive and Switch Groups, respectively. Six-minute walk test (6MWT) %predicted was also stable for most participants, with slope estimates of −0.701 per year (−1.571 to 0.169) and −0.846 per year (−1.567 to −0.125) for the Naive and Switch Groups, respectively. Improvements in 6MWT distance were observed in most participants aged DiscussionAvalglucosidase alfa was generally well tolerated for up to 6.5 years in adult participants with LOPD either naive to alglucosidase alfa or who had previously received alglucosidase alfa for ≥9 months.Classification of EvidenceThis study provides Class IV evidence of long-term tolerability and sustained efficacy of avalglucosidase alfa in patients with LOPD after up to 6.5 years.Trial Registration InformationNCT01898364 (NEO1 first posted: July 12, 2013; clinicaltrials.gov/ct2/show/NCT01898364); NCT02032524 (NEO-EXT first posted: January 10, 2014; clinicaltrials.gov/ct2/show/NCT02032524). First participant enrollment: NEO1—August 19, 2013; NEO-EXT—February 27, 2014.

In a seamless phase II/III/IIIb trial, K (K ≥ 2) doses versus placebo control are evaluated at phase II. Based on phase II results, one dose will be selected for phases III and IIIb. Pre-specified ...

The triple-shelled hollow CuCo2O4 (T-CuCo2O4) microspheres were synthesized by a solvothermal/calcination method. The unique structure with a large internal void volume and porous distribution shortened the ions/electrons transport distance and strengthened the electrochemical reaction. The triple-shelled architecture buffered the volume expansion/contraction to enhance structural stability due to the reduced stress and strain during the charge/discharge process. As a three-electrode cell, the T-CuCo2O4 electrode demonstrated a specific capacitance of 691 F/g (current density: 1 A/g), rate capability of 470 F/g (current density: 20 A/g) and capacitance retention of 93% after 6000 cycles. The all-solid-state asymmetrical supercapacitor achieved an energy density of 25.2 W h/kg at a power density of 1.05 kW/kg, using activated carbon as a negative electrode. The specific capacitance can still maintain 80.3 F/g at a current density of 2 A/g with 6% capacity loss after 2000 cycles.

In order to obtain the accurate B340LA material parameter, in this paper, a dynamic optimization approach was proposed to inverse determine the material parameters in bending springback process. After the inverse determination for material parameters, the finite element simulation result indicates a close agreement with actual experiment, and the relative errors between inverse determined and actual material parameters are also very small. It can be concluded that proposed optimization approach to inverse determine the material parameters is efficient and accurate.

Summary Background Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease. Methods We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov , NCT02782741 . We report results of the 49-week primary analysis period. Findings Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI −0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]). Interpretation We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease. Funding Sanofi Genzyme.

Axial fans play a pivotal role in the road tunnel ventilation system. Qualified performance of the axial fan is important for both safety and air quality maintenance reasons. Axial fans performance in situ test of Qinling Zhongnan Mountain highway tunnel, the second longest road tunnel in the world, is presented in this research. Performance test items and the qualification criterion, as well as a general framework for the road tunnel axial fan assessment, are recommended. Log-Tchebycheff method is suggested to confirm the location for the measuring lines and points. The precision of the log-Tchebycheff method in air flow rate measuring is verified by comparing with the biharmonic spline interpolation fitting result. The research shows that the log-Tchebycheff method has high precision and good efficiency in the air flow rate measurement of the road tunnel air duct. What is more, the biharmonic spline interpolation fitting method can be applied to obtain a more accurate result. The number of interpolation points of the biharmonic spline interpolation fitting method should be bigger than 2000 to provide quality results.

OBJECTIVE To evaluate efficacy and safety of LixiLan (iGlarLixi), a novel titratable fixed-ratio combination of insulin glargine (iGlar) and lixisenatide (Lixi), compared with both components, iGlar and Lixi, given separately in type 2 diabetes inadequately controlled on metformin with or without a second oral glucose-lowering drug. RESEARCH DESIGN AND METHODS After a 4-week run-in to optimize metformin and stop other oral antidiabetic drugs, participants (N = 1,170, mean diabetes duration ∼8.8 years, BMI ∼31.7 kg/m2) were randomly assigned to open-label once-daily iGlarLixi or iGlar, both titrated to fasting plasma glucose RESULTS Greater reductions in HbA1c from baseline (8.1% [65 mmol/mol]) were achieved with iGlarLixi compared with iGlar and Lixi (−1.6%, −1.3%, −0.9%, respectively), reaching mean final HbA1c levels of 6.5% (48 mmol/mol) for iGlarLixi versus 6.8% (51 mmol/mol) and 7.3% (56 mmol/mol) for iGlar and Lixi, respectively (both P < 0.0001). More subjects reached target HbA1c CONCLUSIONS iGlarLixi complemented iGlar and Lixi effects to achieve meaningful HbA1c reductions, close to near normoglycemia without increases in either hypoglycemia or weight, compared with iGlar, and had low gastrointestinal adverse effects compared with Lixi.

During the Wenchuan Earthquake, with a magnitude of 5.12, collapses and rockfall hazards persisted for a long time after the initial investigations carried out by research fellow S. M. He and his team at the scene of the disaster in October 2008. It is possible that additional incidents of rockfalls in large quantities may continue in the same areas over the next ten to fifteen years. Furthermore, in the vast mountainous region of western China, the topographic relief is evident, and earthquakes occur frequently. Therefore, it is difficult to effectively defend against rockfall hazards. When designing protective structures, the key issue is the analysis of the mechanical response mechanism of the soil cushion layer of the upper cushion when subjected to the impact of rockfall. As such, a theoretical method was used to perform such an analysis. The cavity expansion and energy conservation model were adopted. Analytical solutions for the impact force and penetration depth were then derived. Furthermore, the impact force and penetration depth of rockfall were studied with the LS-DYNA software to obtain values for the impact forces and the penetration depth. Finally, the reliability of the theoretical method was evaluated using the cavity expansion, energy conservation, numerical simulation, Hertz, Japanese, Swiss, Australian, B. S. Guan, tunnel manual, and subgrade methods based on an engineering model. The results show that the cavity expansion and the energy conservation methods yielded consistent results. Meanwhile, the cavity expansion and the energy conservation methods also yielded consistent results with the numerical simulation, Japanese (obtained by laboratory experiment), Swiss (obtained by laboratory experiment), and Australian (obtained by field experiment) methods. The relevant methods and conclusions shall therefore be applied to the design of rockfall protection structure in future investigations.

An oriented nanograss array consisting of CuCo

Honeycomb-like nickel cobalt sulfide (NiCo

AimsTo assess efficacy and safety of lixisenatide once-daily versus placebo in Type 2 diabetes mellitus (T2DM) patients inadequately controlled on sulfonylurea (SU)±metformin.MethodsIn this randomized, double-blind, two-arm, parallel-group, multicenter study, patients received lixisenatide 20μg once-daily or placebo for 24 weeks in a stepwise dose increase on top of SUs±metformin. Primary outcome was change in HbA1c from baseline to Week 24.ResultsLixisenatide provided a significant reduction in HbA1c at Week 24 versus placebo (LS mean: −0.85% vs. −0.10%; p

OBJECTIVE This study assessed the efficacy and safety of LixiLan, a fixed-ratio, titratable, combination of 2 units insulin glargine (Gla-100) and 1 μg lixisenatide administered once daily via a single pen, versus Gla-100 in insulin-naïve type 2 diabetes on metformin. RESEARCH DESIGN AND METHODS Participants were randomized to once-daily LixiLan (n = 161) or Gla-100 (n = 162) for 24 weeks, while continuing metformin. LixiLan and Gla-100 were started at 10 units/5 μg and 10 units, respectively, and titrated based on the Gla-100 requirement according to fasting plasma glucose levels. The primary objective was to test noninferiority (upper bound of the 95% CI ≤0.4%) of LixiLan in reducing HbA1c; if met, statistical superiority was tested. Secondary objectives included body weight changes, hypoglycemia, and safety. RESULTS Baseline characteristics (mean age 57 years, diabetes duration 6–7 years, BMI 32 kg/m2) were similar between groups. At week 24, mean HbA1c was reduced from 8.0% (64 mmol/mol) at baseline to 6.3% (45 mmol/mol) and 6.5% (48 mmol/mol) with LixiLan and Gla-100, respectively, establishing statistical noninferiority and superiority of LixiLan (least-squared mean [95% CI] difference: −0.17% [−0.31, −0.04] {−1.9 mmol/mol [−3.4, −0.4]}; P = 0.01). HbA1c CONCLUSIONS LixiLan achieved statistically significant reductions to near-normal HbA1c levels with weight loss and no increased hypoglycemic risk, compared with insulin glargine alone, and a low incidence of gastrointestinal adverse events in type 2 diabetes inadequately controlled on metformin.

Maximum likelihood is a widely used estimation method in statistics. This method is model dependent and as such is criticized as being non robust. In this article, we consider using weighted likelihood method to make robust inferences for linear mixed models where weights are determined at both the subject level and the observation level. This approach is appropriate for problems where maximum likelihood is the basic fitting technique, but a subset of data points is discrepant with the model. It allows us to reduce the impact of outliers without complicating the basic linear mixed model with normally distributed random effects and errors. The weighted likelihood estimators are shown to be robust and asymptotically normal. Our simulation study demonstrates that the weighted estimates are much better than the unweighted ones when a subset of data points is far away from the rest. Its application to the analysis of deglutition apnea duration in normal swallows shows that the differences between the weighted ...

An oriented nanograss array consisting of CuCo2S4 nanocrystallines was directly prepared on Ni foam by a hydrothermal method. The uniform arrays with a single blade diameter of ∼100 nm and length of ∼4 μm can grow tightly on Ni foam without any binders. The ordered one-dimensional structure facilitates the electron transport to Ni substrates along the axial direction. The electrochemical properties were presented in three- and two-electrode configurations, demonstrating an enhanced specific capacitance and a long-term cycling stability. As a practical all-solid-state device, it achieved a high energy density of 31.88 W h kg-1 at a power density of 3.20 kW kg-1. Even at a higher power density of 15.23 W h kg-1, the device still had an energy density of 16.5 kW kg-1. After 5000 cycles, the retention ratio was higher than 99% at high current density of 11.36 A g-1.

Linear mixed models based on the normality assumption are widely used in health related studies. Although the normality assumption leads to simple, mathematically tractable, and powerful tests, violation of the assumption may easily invalidate the statistical inference. Transformation of variables is sometimes used to make normality approximately true. In this paper we consider another approach by replacing the normal distributions in linear mixed models by skew-t distributions, which account for skewness and heavy tails for both the random effects and the errors. The full likelihood-based estimator is often difficult to use, but a 3-step estimation procedure is proposed, followed by an application to the analysis of deglutition apnea duration in normal swallows. The example shows that skew-t models often entail more reliable inference than Gaussian models for the skewed data.

Honeycomb-like nickel cobalt sulfide (NiCo2S4) nanosheets were directly deposited on fluorine-doped tin oxide substrate by a rapid voltammetric deposition method. The method was also controllable and feasible for preparing NiCo2S4 on flexible Ti foil without any heating processes. Compared with Pt, CoS and NiS, NiCo2S4 exhibited low charge-transfer resistances and excellent electrocatalytic activity for [Formula: see text] reduction, acting as a counter electrode for a dye-sensitized solar cell. The NiCo2S4-based solar cell showed higher power conversion efficiency (7.44%) than that of Pt-based solar cell (7.09%) under simulated illumination (AM 1.5 G, 100 mW cm-2). The device based on the flexible NiCo2S4/Ti foil achieved a power conversion efficiency of 5.28% under the above illumination conditions. This work can be extended to flexible and wearable technologies due to its facile technique.

To evaluate efficacy and safety of LixiLan (iGlarLixi), a novel titratable fixed-ratio combination of insulin glargine (iGlar) and lixisenatide (Lixi), compared with both components, iGlar and Lixi, given separately in type 2 diabetes inadequately controlled on metformin with or without a second oral glucose-lowering drug.After a 4-week run-in to optimize metformin and stop other oral antidiabetic drugs, participants (N = 1,170, mean diabetes duration ∼8.8 years, BMI ∼31.7 kg/mGreater reductions in HbAiGlarLixi complemented iGlar and Lixi effects to achieve meaningful HbA