Efficacy and safety of tenofovir alafenamide in patients with chronic hepatitis B exhibiting suboptimal response to entecavir

BACKGROUND Entecavir(ETV)is a potent and safe antiviral agent for patients with chronic hepatitis B(CHB);however,some patients may exhibit suboptimal response or resistance to ETV.Tenofovir alafenamide(TAF)is a novel tenofovir prodrug with improved pharmacokinetics and reduced renal and bone toxicity compared with tenofovir disoproxil fumarate.AIM To evaluate the efficacy and safety of switching from ETV to TAF in patients with CHB exhibiting suboptimal response to ETV.METHODS A total of 60 patients with CHB who had been treated with ETV for at least 12 mo and had persistent or recurrent viremia[Hepatitis B virus(HBV)DNA≥20 IU/mL]or partial virologic response(HBV DNA<20 IU/mL,but detectable)were enrolled in the study.The patients were randomly assigned to either continue ETV(0.5 mg)daily or switch to TAF(25 mg)daily for 48 wk.The primary endpoint was the proportion of patients who achieved a virologic response(HBV DNA level<20 IU/mL)at week 48.Secondary endpoints included changes in serum alanine aminotransferase(ALT),hepatitis B surface antigen(HBsAg),hepatitis B e antigen(HBeAg),and anti-HBe levels,and renal and bone safety parameters.RESULTS At week 48,the proportion of patients who achieved a virologic response was significantly higher in the TAF group than in the ETV group(93.3%vs 66.7%,P=0.012).The mean reduction in HBV DNA from baseline was also significantly greater in the TAF group than in the ETV group(-3.8 vs-2.4 Log10 IU/mL,P<0.001).The rates of ALT normalization,HBeAg loss,HBeAg seroconversion,and HBsAg loss were not found to significantly differ between the two groups.None of the patients developed genotypic resistance to ETV or TAF.Both drugs were well tolerated,with no serious adverse events or discontinuations caused by adverse events.No significant changes were observed in the estimated glomerular filtration rate,serum creatinine level,or urine protein-to-creatinine ratio in either group.The TAF group had a significantly lower decrease in bone mineral density at the lumbar spine and hip than the ETV group(-0.8%vs-2.1%,P=0.004;-0.6%vs-1.8%,P=0.007,respectively).CONCLUSION Switching from ETV to TAF is effective and safe for patients with CHB exhibiting a suboptimal response to ETV and may prevent further viral resistance and reduce renal and bone toxicity.

Efficacy of switching to telbivudine plus adefovir in suboptimal responders to lamivudine plus adefovir

AIM:To examine the efficacy of telbivudine(LdT)+adefovir(ADV)vs continuation of lamivudine(LAM)+ADV in patients with LAM-resistant chronic hepatitis B(CHB)who show a suboptimal response to LAM+ADV.METHODS:This was a randomized,active-control,open-label,single-center,parallel trial.All eligible patients were enrolled in this study in Severance Hospital,Yonsei University College of Medicine,Seoul,South Korea,between March 2010 and March 2011.Hepatitis Be antigen(HBeAg)-positive CHB patients whose serum hepatitis B virus(HBV)DNA remained detectable despite at least 6 mo of LAM+ADV therapy were included.Enrolled patients were randomized to either switching to LdT(600 mg/d orally)plus ADV(10 mg/d orally)(LdT+ADV group)or to continuation with LAM(100 mg/d orally)plus ADV(10 mg/d orally)(LAM+ADV group),and were followed for 48 wk.One hundred and six patients completed the 48-wk treatment period.Serum HBV DNA,HBeAg status,liver biochemistry and safety were monitored at baseline and week 12,24,36 and 48.RESULTS:The duration of prior LAM+ADV treatment was 18.3(LdT+ADV)and 14.9 mo(LAM+ADV),respectively(P=0.131).No difference was seen in baseline serum HBV DNA between the two groups[3.66(LdT+ADV)vs 3.76(LAM+ADV)log10IU/mL,P=0.729].At week 48,although there was no significant difference in the mean reduction of serum HBV DNA from baseline between LdT+ADV group and LAM+ADV group(-0.81 vs-0.47 log10IU/mL,P=0.167),more patients in the LdT+ADV group had undetectable HBV DNA levels compared to those in the LAM+ADV group(30.2%vs 11.5%,P=0.019).Three patients with LdT+ADV treatment and 2 patients with LAM+ADV treatment achieved HBeAg loss.The patients in both groups tolerated the treatment well without serious adverse events.The proportion of patients with estimated glomerular filtration rate≥90 mL/min per 1.73 m2in the LdT+ADV group increased from 49.1%(26/53)at baseline to 58.5%(31/53)at week 48,while that in the LAM+ADV group decreased from 37.7%(20/53)at baseline to 30.2%(16/53)at week 48.CONCLUSION:The switch to LdT+ADV in suboptimal responders to LAM+ADV showed a significantly higher rate of virologic response at week 48.These results suggest that LdT+ADV could be a therapeutic option for patients who are unable to use enofovir disoproxil fumarate for any reason.

Time-varying sliding mode control of missile based on suboptimal method

This paper proposes a time-varying sliding mode control method to address nonlinear missile body kinematics based on the suboptimal control theory.The analytical solution of suboptimal time-varying sliding surface and the corresponding suboptimal control law are obtained by solving the state-dependent Riccati equation analytically.Then,the Lyapunov method is used to analyze the motion trend in sliding surface and the asymptotic stability of the closed-loop system is validated.The suboptimal control law is transformed to the form of pseudo-angle-of-attack feedback.The simulation results indicate that the satisfactory performance can be obtained and the control law can overcome the influence of parameter errors.

Improved suboptimal Bang-Bang control of aseismic buildings with variable friction dampers

One of the challenges in civil engineering is to find an innovative means of suppressing the structural vibration due to earthquake and wind loadings. This paper presents an approach for effectively suppressing vibrations of a structure with variable friction damper using a new Bang-Bang control input. A continuous function of story velocities is used to represent the improved control to reduce chatter, high frequency switching and avoid instability. With a genetic algorithm, the amplitudes of control and preloading friction forces individually prescribed in the controller and damper are optimized for enhancing the seismic performance of buildings. The control strategy for the friction damper is proposed for a three story building with one variable friction damper installed at the first story for seismic reduction. The numerical results indicate that a better reduction of peak response accelerations of floors can be achieved than those of the unmodified controller, and the adaptability of the control system is also improved greatly by comparison with the reduction ratios of the structural response energy excited by different earthquake intensities.

Nonlinear suboptimal tracking control of spacecraft approaching a tumbling target

We investigate the close-range relative motion and control of a spacecraft approaching a tumbling target. Unlike the traditional rigid-body dynamics with translation and rotation about the center of mass（CM）, the kinematic coupling between translation and rotation is taken into consideration to directly describe the motion of the spacecraft＇s sensors or devices which are not coincident with the CM. Thus, a kinematically coupled 6 degrees-of-freedom（DOF） relative motion model for the instrument（feature point） is set up. To make the chaser spacecraft＇s feature point track the target＇s, an optimal tracking problem is defined and a control law with a feedback-feedforward structure is designed. With quasi-linearization of the nonlinear dynamical system, the feedforward term is computed from a specified constraint about the dynamical system and the reference model, and the feedback action is derived starting from the state-dependent Ricca equation（SDRE）. The proposed controller is compared with an existing suboptimal tracking controller, and numerical simulations are presented to illustrate the effectiveness and superiority of the proposed method.

Suboptimal stochastic H-two/H-infinity design with spectrum constraint

This paper studies the problem of suboptimal state-feedback H-two/H-infinity control of stochastic systems with spectrum constraint. Concretely speaking, a mixed suboptimal H-two/H-infinity controller synthesis together with placing the spectrum into a strip region is considered, which is achieved via solving a convex optimization problem.

General space-efficient sampling algorithm for suboptimal alignment

Suboptimal alignments always reveal additional interesting biological features and have been successfully used to informally estimate the significance of an optimal alignment. Besides, traditional dynamic programming algorithms for sequence comparison require quadratic space, and hence are infeasible for long protein or DNA sequences. In this paper, a space-efficient sampling algorithm for computing suboptimal alignments is described. The algorithm uses a general gap model, where the cost associated with gaps is given by an affine score, and randomly selects an alignment according to the distribution of weights of all potential alignments. If x and y are two sequences with lengths n and m, respectively, then the space requirement of this algorithm is linear to the sum of n and m. Finally, an example illustrates the utility of the algorithm.

Conditionally Suboptimal Filtering in Nonlinear Stochastic Differential System

This paper presents a novel conditionally suboptimal filtering algorithm on estimation problems that arise in discrete nonlinear time-varying stochastic difference systems. The suboptimal state estimate is formed by summing of conditionally nonlinear filtering estimates that their weights depend only on time instants, in contrast to conditionally optimal filtering, the proposed conditionally suboptimal filtering allows parallel processing of information and reduce online computational requirements in some nonlinear stochastic difference system. High accuracy and efficiency of the conditionally suboptimal nonlinear filtering are demonstrated on a numerical example.

Suboptimal Control of Time-Varying Neutral Control Systems

In this paper,the optimal control of time-varying neutral control systems is investigated by means of the Maxmium Principle of time-delay systems.optimal control law is given. Then sub-optimal control of time-varying neutral control systems is studied by using sensitivity approach. Algorithm for suboptimal control is given.

Performance of Suboptimal Controllers for Affine-Quadratic Problems

In this article, affine-quadratic control problems are studied. Error bounds are derived for the difference between the performance indices corresponding to the optimal and a class of suboptimal controls. In particular, it is shown that the performance of these suboptimal controls is close to that of the optimal control whenever the error in estimating the costate initial condition is small.

Predicting the output error of the suboptimal state estimator to improve the performance of the MPC-based artificial pancreas

The error of single step-ahead output prediction is the information traditionally used to correct the state estimate while exploiting the new measurement of the system output.However,its dynamics and statistical properties can be further studied and exploited in other ways.It is known that in the case of suboptimal state estimation,this output prediction error forms a correlated sequence,hence it can be effectively predicted in real time.Such a suboptimal scenario is typical in applications where the process noise model is not known or it is uncertain.Therefore,the paper deals with the problems of analytical and empirical modeling,identification,and prediction of the output error of the suboptimal state estimator for the sake of improving the output prediction accuracy and ultimately the performance of the model predictive control.The improvements are validated on an empirical model of type 1 diabetes within an in-silico experiment focused on glycemia prediction and implementation of the MPC-based artificial pancreas.

Treatment of insomnia in suboptimal health status with Zhuang medicine herbal-thread moxibustion:A randomized clinical trial

Objective:The objective of this study is to explore the clinical effect and safety of Zhuang medicine herbal-thread moxibustion therapy for the treatment of suboptimal health status-related insomnia through a randomized clinical trial.Methods:A total number of 60 patients with insomnia of suboptimal health status(SHS) were enrolled from the Clinic of Zhuang Medicine,Renai Branch of the First Affiliated Hospital of Guangxi University of Chinese Medicine and the Clinic of Zhuang Medicine,the First Affiliated Hospital of Guangxi University of Chinese Medicine,as well as Guangxi University of Chinese Medicine.According to the random number table method,they were randomized into a Zhuang medicine herbal-thread moxibustion therapy group(30 patients) and a western medication group(30 partients).The outcome assessors were blinded for patients allocation.In the herbal-thread moxibustion group,Zhuang medicine herbal-thread moxibustion therapy was provided once daily.In the western medication group,alprazolam tablets were prescribed for oral administration once daily.One course consisted of 10 treatments.After three consecutive courses of treatment,the score of the Pittsburgh sleep quality index(PSQI) was compared between groups,and both clinical effect and safety were assessed.Results:Sixty eligible patients were enrolled,and thirty were assigned to each group and included in the data analysis.After treatment,the score of each PSQI indicator(sleep latency,sleep duration,sleep efficiency,sleep disturbance,and daytime dysfunction) and total PSQI score were compared with those before treatment in both groups(all changes were statistically significant when P <0.05).Scores in the herbal-thread moxibustion group were superior to those in the western medication group(all values were statistically significant at P <0.05).The total effective rate was 93.3% in the herbal-thread moxibustion group and 80.0% in the western medication group(P <0.05).During treatment,no adverse reactions were reported in the herbal-thread moxibustion group.In the western medication group,three patients reported dizziness and headache,and one patient reported dry mouth,the incidence of adverse reactions was 13.3%.Conclusion:The Zhuang medicine herbal-thread moxibustion therapy is a safe and effective management strategy for the clinical symptoms of suboptimal health status-related insomnia.

Signaling interactions among neurons impact cell fitness and death in Alzheimer's disease

The pathology of Alzheimer’s disease involves a long preclinical period,where the characteristic clinical symptoms of the changes in the brain are undetectable.During the preclinical period,homeostatic mechanisms may help prevent widespread cell death.Evidence has pointed towards selective cell death of diseased neurons playing a potentially protective role.As the disease progresses,dysregulation of signaling pathways that govern cell death contributes to neurodegeneration.Aberrant activation of the c-Jun N-terminal kinase pathway has been established in human and animal models of Alzheimer’s disease caused by amyloid-beta 42-or tau-mediated neurodegeneration.Clonal mosaic studies in Drosophila that examine amyloid-beta 42 in a subset of neurons suggest complex interplay between amyloid-beta 42-expressing and wild-type cells.This review examines the role of c-Jun N-terminal kinase signaling in the context of cell competition and short-range signaling interactions between amyloid-beta 42-expressing and wild-type neurons.Cell competition is a conserved phenomenon regulating tissue integrity by assessing the fitness of cells relative to their neighbors and eliminating suboptimal cells.Somatic clones of amyloid-beta 42 that juxtapose genetically distinct neuronal cell populations show promise for studying neurodegeneration.Generating genetic mosaics with labeled clones of amyloid-beta 42-or tau-expressing and wild-type neurons will allow us to understand how short-range signaling alterations trigger cell death in neurons and thereby contribute to the progression of Alzheimer’s disease.These approaches have the potential to uncover biomarkers for early Alzheimer’s disease detection and new therapeutic targets for intervention.

Screening of Low Temperature Resistance Germplasm Resources of Pigment Pepper

Objective The aim of this study was to explore the method and standard for rapidly screening low temperature-resistant pepper germplasm resources and provide a theoretical basis for the breeding of low temperature-resistant pepper. [ Method ] With 110 pigment pepper seeds as the materials, their germination vigor under optimum temperature and suboptimal temperature were determined by means of roll rapid germination, and seeds with different genetic types were evaluated from aspects of germination vigor and its interval division. [ Result ] 37 pepper seeds with stronger low temperature resistance were screened. [ Conclusion]This study provides an important basis for screening low temperature-resistant pepper germplasm resources.

Emerging concepts in liver graft preservation

The urgent need to expand the donor pool in order to attend to the growing demand for liver transplantation has obliged physicians to consider the use of suboptimal liver grafts and also to redefine the preservation strategies. This review examines the different methods of liver graft preservation, focusing on the latest advances in both static cold storage and machine perfusion(MP). The new strategies for static cold storage are mainly designed to increase the fatty liver graft preservation via the supplementation of commercial organ preservation solutions with additives. In this paper we stress the importance of carrying out effective graft washout after static cold preservation, and present a detailed discussion of the future perspectives for dynamic graft preservation using MP at different temperatures(hypothermia at 4 ℃, normothermia a t 3 7 ℃ and subnormothermia at 20 ℃- 2 5 ℃). Finally, we highlight some emerging applications of regenerative medicine in liver graft preservation. In conclusion, this review discusses the "state of the art" and future perspectives in static and dynamic liver graft preservation in order to improve graft viability.

Neural-Network-Based Control for Discrete-Time Nonlinear Systems with Input Saturation Under Stochastic Communication Protocol

In this paper,an adaptive dynamic programming(ADP)strategy is investigated for discrete-time nonlinear systems with unknown nonlinear dynamics subject to input saturation.To save the communication resources between the controller and the actuators,stochastic communication protocols(SCPs)are adopted to schedule the control signal,and therefore the closed-loop system is essentially a protocol-induced switching system.A neural network(NN)-based identifier with a robust term is exploited for approximating the unknown nonlinear system,and a set of switch-based updating rules with an additional tunable parameter of NN weights are developed with the help of the gradient descent.By virtue of a novel Lyapunov function,a sufficient condition is proposed to achieve the stability of both system identification errors and the update dynamics of NN weights.Then,a value iterative ADP algorithm in an offline way is proposed to solve the optimal control of protocol-induced switching systems with saturation constraints,and the convergence is profoundly discussed in light of mathematical induction.Furthermore,an actor-critic NN scheme is developed to approximate the control law and the proposed performance index function in the framework of ADP,and the stability of the closed-loop system is analyzed in view of the Lyapunov theory.Finally,the numerical simulation results are presented to demonstrate the effectiveness of the proposed control scheme.

Optimization therapy for the treatment of chronic hepatitis B

Chronic hepatitis B (CHB) is currently medically managed with either interferon-alpha or one of the five nucleos(t)ide analogs. However, there are still a large number of CHB patients whose response to the above therapies remains less than satisfactory, and their incomplete or non-response to antiviral therapies has plagued clinicians worldwide. In recent years, a newly proposed optimization therapy has provided us with a new approach to solve this problem. The key points in this optimization therapy are to initiate antiviral therapy with an appropriate agent at the correct time point, and to adjust treatments in patients with poor early responses by adding a second agent or switching to another more potent agent. In this review, we summarize recent developments in optimization therapy for the treatment of CHB, and provide an outlook for future research in this field. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

Nonlinear autopilot design for interceptors with tail fins and pulse thrusters via θ–D approach

The missile autopilot for an interceptor with tail fins and pulse thrusters is designed via the θ-D approach. The nonlin- ear dynamic model of the pitch and yaw motion of the missile is transformed into a linear-like structure with state-dependent coef- ficient （SDC） matrices. Based on the linear-like structure, a θ-D feedback controller is designed to steer the missile to track refer- ence acceleration commands. A sufficient condition that ensures the asymptotic stability of the tracking system is given based on Lyapunov＇s theorem. Numerical results show that the proposed autopilot achieves good tracking performance and the closed-loop tracking system is asymptotically stable.

Conflict and Coordination Problem of Carbon Tax' Diversity Targets in China-Based on the Tax Optimization Theory

Among all the emission reduction measures,carbon tax is recognized as the most effective way to protect our climate.That is why the Chinese government has recently taken it as a tax reform direction.In the current economic analysis,the design of carbon tax is mostly based on the target to maximize the efficiency.However,based on the theory of tax system optimization,we should also consider other policy objectives,such as equity,revenue and cost,and then balance different objectives to achieve the suboptimum reform of carbon tax system in China.

An Optimal Method for Solving the Linear Bilevel Programming Problem with No Upper-level Constraint

In this paper we propose an optimal method for solving the linear bilevel programming problem with no upper-level constraint. The main idea of this method is that the initial point which is in the feasible region goes forward along the optimal direction firstly. When the iterative point reaches the boundary of the feasible region, it can continue to go forward along the suboptimal direction. The iteration is terminated until the iterative point cannot go forward along the suboptimal direction and effective direction, and the new iterative point is the solution of the lower-level programming. An algorithm which bases on the main idea above is presented and the solution obtained via this algorithm is proved to be optimal solution to the bilevel programming problem. This optimal method is effective for solving the linear bilevel programming problem.