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.

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.

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.

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.

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.

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.

亚健康失眠的中医辨证分型及临床用药思路

失眠是亚健康状态的主要表现之一。在病因病机上可归于劳逸失度、阴血亏耗,情志不舒、肝郁化火,饮食偏嗜、痰湿内生3方面。在中医证型上可分为心神失养证、火扰心神证、气郁痰阻证3型。针对亚健康失眠的中医保健,应以辨证保健为主结合对症保健。辨证保健上以利尿导热、滋阴降火法清心安神缩短入睡时间,以补虚敛神、益精养血法养心安神维持睡眠深度,以理气化痰、利胆和胃法疏泄通滞调节寐寤表现;对症保健上以重镇与甘缓类药物改善烦躁不宁、心神不安的表现,以导阳入阴药物改善节律紊乱症状,实现辨证、对症相结合。

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.

考虑随机返工与紧急插单的可抢占设计项目群调度

鉴于多项目并行以及因随机返工和紧急插单而导致的任务抢占特征,使设计项目群调度问题难以求解,而传统随机动态规划方法因维数灾难只能获得小规模问题的最优策略,为构造面向大规模问题的高效近似方法,提出将原随机调度问题近似分解为各个状态下的确定性调度子问题,从而获得原问题的次优策略。建立了确定性调度子问题的混合整数规划模型,并提出基于元启发式算法和优先规则的求解方法。基于标准测试集PSPLIB设计了多组计算实验,在不同调度环境下验证了所构建模型和算法的有效性。实验结果表明,元启发式算法不但在单项目平均拖期比目标下较最优规则提升了12%以上,而且具有较高的计算效率,能够满足实际决策需求。

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.

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.

“物美质优”判断偏差对次优食物浪费的影响--心理机制及应对策略

全球因食物外形缺陷而产生的浪费问题日趋严重,这些外观有缺陷但仍可食用的食物被称为“次优食物”。次优食物浪费根源于消费者的审美偏差,但以往研究较少关注消费者回避次优食物的心理机制,对相关干预措施的有效性探讨不够。本文基于常人信念理论,研究消费者在次优食物购买中的常人信念,并提出“酷化拟人形象”的干预措施。通过四个实验发现,消费者存在“物美质优”信念,即次优食物的低外观水平会降低消费者对次优食物口味与健康的评价,而“酷化拟人形象”可以强化消费者对次优食物的自然性感知,增强消费者的购买意愿,消费者的自主性水平对此效应可产生调节作用。本文厘清了消费者的美学偏见对次优食物感知障碍的影响路径,创新性地提出新型视觉线索,促进消费者形成可持续性食物选择行为,系统地揭示了从食物浪费的认知偏差到视觉助推效应再到助推机制与效应边界的内在机理,为企业提供低成本、易执行的管理工具,有助于解决次优食物滞销问题,也在推动食物可持续发展方面为政府提供了高效率的政策方案。

车载GNSS/SINS/里程计分布式弹性融合导航方法

为提升复杂环境下低成本车载导航系统的容错性能,本文研究了基于次优增益融合(SGF)算法的GNSS/SINS/里程计分布式弹性融合方法。该方法首先根据阿克曼转向几何建立了四轮里程计测速补偿模型,提升了惯性测量单元(IMU)安装中心处的前向和侧向测速精度;然后设计了基于卡方检验统计量的故障检测与分类准则,充分利用了可获取的观测信息;最后构建了随机模型和信息分配因子(ISF)弹性优化模型,分别从传感器层和决策层减少了异常观测的影响,实现了车载多源信息的弹性融合。通过实际跑车数据对GNSS/SINS/里程计分布式弹性融合方法进行测试验证。试验结果表明,本文方法能有效减少子系统故障对全局状态估计的影响,提升复杂环境下系统的容错性能。此外,与经典的联邦卡尔曼滤波(FKF)算法相比,SGF算法全局融合精度损失有限,计算效率却显著提升,有利于多源信息弹性融合的实际工程应用。

转移概率部分未知的离散时间Markov跳变系统Nash微分博弈

考虑到转移概率矩阵元素无法完全获悉,如何在转移概率部分未知的情境下研究离散时间Markov跳变系统Nash微分博弈是有待解决的问题之一,这一问题可以为转移概率部分未知的Markov跳变系统Nash微分博弈理论在管理问题上的应用提供理论支撑。基于此,本文首先研究单人博弈情形,即ε-次优控制问题,借助自由连接权矩阵和配方法,得到了ε-次优控制策略存在的充分性条件,并给出了成本函数上界的显式表达;然后延伸至双人博弈进行分析,得到了ε-次优Nash均衡策略存在的条件等价于求解双线性矩阵不等式和矩阵不等式的优化问题,并通过启发式算法求解优化问题得到ε-次优Nash均衡策略;最后通过数值算例证明了主要结论的有效性。

次优理论视角下“城郊融合类”实用性村庄规划编制策略研究——以介休市西北里村为例

“城郊融合类”村庄是促进城乡要素双向流动和自由交换的重要空间载体,在新的时代背景下“城郊融合类”实用性村庄规划编制的理论依据和策略方法有待进一步研究和深化。本文首先分析了“城郊融合类”实用性村庄规划编制在认识层、标准层、实施层和组织层四方面的主要问题,然后借鉴经济学次优理论,从实施效用和资源组合比对视角,提出实现实用性效能最大化的规划编制路径选择。最后结合山西省介休市张兰镇西北里村实用性村庄规划编制实践,在分析其资源概况和发展问题的基础上,从资源判识、存量明晰、极核扩散、多元保障四方面提出规划编制的次优策略,以期为其他“城郊融合型”实用性村庄规划编制提供参考。

基于LMI和BP网络的非线性矩阵加权次优融合算法

为了解决互协方差未知的多传感器非线性系统融合估计问题,提出了一种改进的矩阵加权次优融合算法。利用舒尔补定理推导出线性最小方差意义下基于矩阵融合的最简约束条件。此约束条件可保证融合估计误差方差的正定性,以及所提出次优融合估计的一致性;基于线性矩阵不等式(LMI)提出了一种矩阵加权次优融合估计。考虑到LMI算法优化过程中存在的耗时问题,采用BP网络获取最优值;结合容积卡尔曼滤波算法(CKF),提出了基于LMI算法和BP网络的非线性矩阵加权次优融合算法。仿真分析结果证明了算法应用于非线性系统的有效性。

有限域(F_(2)^(8))^(8)上基于循环异或移位结构的次优扩散层研究

基于循环移位异或运算的MDS线性变换以其具有良好的扩散雪崩性能被广泛应用于分组密码扩散层的设计中.在现有研究中,小有限域(F_(2)^(n))^(4)上最优线性变换寻找工作已接近完备,而大有限域(F_(2)^(n))^(8)上异或项数为9和11时,却不存在最优线性变换.探寻大有限域(F_(2)^(8))^(8)上次优线性变换对64位环境的实际应用需求而言具有重要意义.本文基于现有的研究成果,以大有限域(F_(2)^(n))^(8)为研究对象,通过分析循环异或扩散层的结构特点,将分支数的测试问题转换为布尔可满足性问题,借助可满足性模理论求解器Boolector求解的过程,完成对大有限域(F_(2)^(n))^(8)上次优线性变换组进行探寻研究.实验结果显示,大有限域(F_(2)^(8))^(8)上存在分支数可以达到8的次优线性变换,结合测试并给出一种具体循环异或形式,为最优扩散层的实际需求提出一种候补方法.未来将进一步研究大有限域(F_(2)^(n))^(8)上次优线性变换的理论特征和推广应用.