虚拟中国人足底韧带结构失效后的足弓负荷机制研究

目的　建立虚拟中国人的足内侧纵弓与外侧纵弓的有限元模型,研究跖腱膜松解术或足底韧带损伤后足骨与内在肌群的生物力学特性,探讨骨性结构、足底韧带、足底腱膜、足底固有肌群之间的协调作用机制。方法　采用虚拟中国人“女性1号”CT图像和MRI图像;采用非线性有限元方法进行足弓术后或韧带损伤后的平衡直立负荷状态仿真;并应用足底固有肌群的3种被动张力（微弱、适度、强烈）模拟术后或韧带损伤后的肌肉状态。结果　建立了虚拟中国人“女性1号”足内侧纵弓第2跖列与外侧纵弓第5跖列的生物力学有限元模型,计算得到内侧纵弓和外侧纵弓在平衡直立时,韧带损伤时,固有肌群活动时的张应力矢量图、压应力矢量图和von Mises应力整体分布数据。结论　跖腱膜松解术和足底韧带损伤等增加了足纵弓von Mises应力峰值,改变了张应力与压应力的流向;而足底固有肌活动的被动张力能降低足纵弓von Mises应力集中程度,调节张应力、压应力矢量接近平衡状态,减小了并发骨折和腱炎的危险性。骨性结构、韧带、腱膜、固有肌群的内在应力具有定量的相互调节功能。     

Target-mediated drug disposition model: relationships with indirect response models and application to population PK–PD analysis

The paper focuses on approximations of the target-mediated drug disposition (TMDD) model as applied to pharmacodynamic (target kinetics) modeling. The TMDD equation for the total target concentration is shown to coincide with the indirect response model with stimulation or inhibition of elimination. This correspondence allows estimation of pharmacodynamic TMDD parameters and unobservable free target concentrations using indirect-response models. The ability of the TMDD model and its approximations to estimate the unobservable free target concentration is investigated by simulation. Pharmacokinetic parameters used for simulations were parameters typical for monoclonal antibodies. TMDD binding and target turnover parameters were similar to those estimated for omalizumab. Free drug and total target concentrations were measured. The simulated population PK–PD study demonstrated that for drugs with TMDD, indirect-response models are in fact mechanistic models that can be used to estimate TMDD model parameters and unobservable free target concentrations that are important for pharmacodynamic modeling.     

Noninvasive ultrasound elasticity imaging (UEI) of Crohn's disease: animal model

Inflammation occurs in episodic flares in Crohn's disease, which are part of the waxing and waning course of the disease. Healing between flares allows the intestine to reconstitute its epithelium, but this healing results in the deposition of fibrotic scar tissue as part of the healing process. Repeated cycles of flares and healing often lead to clinically significant fibrosis and stenosis of the intestine. Patients are treated empirically with steroids, with their many side effects, in the hope that they will respond. Many patients would be better treated with surgery if we could identify which patients truly have intestinal fibrosis. Ultrasound elasticity imaging (UEI) offers the potential to radically improve the diagnosis and management of local tissue elastic property, particularly intestinal fibrosis. This method allows complete characterization of local intestine tissue with high spatial resolution. The feasibility of UEI on Crohn's disease is demonstrated by directly applying this technique to an animal model of inflammatory bowel disease (IBD). Five female Lewis rats (150-180g) were prepared with phosphate buffered solution (PBS) as a control group and six were prepared with repeated intrarectal administration of trinitrobenzenesulfonic acid (TNBS) as a disease group. Preliminary strain measurements differentiate the diseased colons from the normal colons (p < 0.0002) and compared well with direct mechanical measurements and histology (p < 0.0005). UEI provides a simple and accurate assessment of local severity of fibrosis. The preliminary results on an animal model also suggest the feasibility of translating this imaging technique directly to human subjects for both diagnosis and monitoring.     

Derivation of various NONMEM estimation methods

Various estimation methods and the lack of a systematic derivation of the core objective function implemented in NONMEM for nonlinear mixed effect modeling has caused consistent confusion and inquiry among scientists who routinely use NONMEM for data analysis. This paper provides a detailed derivation of the objective functions for the most commonly used estimation methods in NONMEM, such as the Laplacian method, the first-order conditional estimation method (FOCE) with or without interaction, and the first-order method (FO). In addition, models with homogenous or heterogeneous residual error were used to demonstrate the relationship between the objective functions derived from two different types of approximation, namely Laplacian approximation of log-likelihood and linearized model approximation. The relationship between these estimation methods and those implemented in SAS and Splus is discussed.     

Imposing Nonlinear Constraints When Estimating Genetic and Cultural Transmission Under Assortative Mating: A Simulation Study Using Mx and BUGS

Modeling both genetic and cultural transmission in parent-offspring data in the presence of phenotypic assortment requires the imposition of nonlinear constraints. This article reports a simulation study that determined how well the structural equation modeling software package Mx and the Bayesian-oriented BUGS software package can handle such nonlinear constraints under various conditions. Results generally showed good and comparable results for Mx and BUGS, although BUGS was much slower than Mx. However, since BUGS uses Markov-chain Monte Carlo estimation it could be used for parent-offspring models with non-normal data and/or item-response theory models. Edited by Stacey Cherny.     

一种非线性呼吸力学模型及其参数估计

本文报道了一个非线性呼吸力学模型,该模型可以反映深呼吸过程中呼吸气体流率、跨肺压力及肺容积变化之间的动态关系。模型参数分别反映气道阻力状态及肺弹性特性。敏感度分析表明,该模型肺弹性参数估计值的准确度高于气道阻力。实验测定了10名被试者的呼吸气体流率、食道压力及肺容积。参数估计结果表明,动、静态肺弹性参数之间存在显著差异(P<0.01)。我们认为肺组织及肺泡表面活性物质的应力松驰机制是造成这种差异的主要原因。     

心电QRS积分信号的非线性分析

QRS波群积分能反映心室去极化活动,为不少心电研究者所重视。本文采用了非线性的分析方法,在非线性去噪的基础上重构此积分信号的相空间,计算了吸引子的相关维数与最大L yapunov指数值,分析了QRS波群积分的混沌特征。利用MIT- BIH心电数据库数据分析了多种情况下QRS波群积分的非线性指标变化特点,并同HRV信号非线性分析相比较,发现在某些情况下对QRS波群积分序列分析更具有优势。结论是利用QRS波群积分信号的非线性指标可对心脏功能做出评价。     

群体药代动力学/群体药效动力学原理及研究方法

自美国食品药品管理局(FDA)允许群体分析法在新药Ⅱ期、Ⅲ期临床试验中用于特殊生理病理受试对象的药代动力学(PK)和药效动力学(PD)评价以来，群体药代动力学／群体药效动力学(PPK／PPD)的研究方法、统计分析、常用软件及其在临床药理学中的应用有了较大发展。作者介绍了PPK／PPD的基本原理、实验设计、模型确定和参数验证的进展。     

Nonlinear analysis of posturographic data

The aim of this work is to determine whether postural sway can be well described by nonlinear deterministic modelling. Since the results of nonlinear analysis depend on experimental data processing, emphasis was given to the assessment of a proper methodology to process posturographic data. Centre of Pressure (CoP) anterior-posterior (AP) displacements (stabilogram) were obtained by static posturography tests performed on control subjects. A nonlinear determinism test was applied to investigate the nature of data. A nonlinear filtering method allowed us to estimate properly the parameters of the nonlinear model without altering signal dynamics. The largest Lyapunov exponent (LLE) was estimated to quantify the chaotic behaviour of postural sway. LLE values were found to be positive although close to zero. This suggests that postural sway derives from a process exhibiting weakly chaotic dynamics.     

去甲万古霉素群体药代动力学与药效学分析及给药方案的优化

目的 了解去甲万古霉素在感染患者中群体药代动力学（PPK）和药效学（PD）。方法药代动力学（PK）分析在诊断或拟诊为革兰阳性菌感染的146例患者中进行，收集患者的临床资料，以NONMEM程序建立并验证去甲万古霉素PK模型。PD分析在同组感染者中进行，收集病原菌，以琼脂对倍稀释法测定去甲万古霉素对细菌最低抑菌浓度（MIC）。根据患者的PK参数和MIC测定结果，计算患者的PK／PD参数，分析其与去甲万古霉素临床和细菌学疗效的关系，制定最佳给药方案。结果去甲万古霉素基础PK模型为线性二房室模型，PK参数个体问变异为指数模型，个体内变异为加法模型。患者内生肌酐清除率（Ccr）的变化对去甲万古霉素清除率（CL）的影响不同，当患者。肾功能减退时（Ccr≤85mL／min），CL-2．54×（Ccr／50）020，Ccr的变化影响该药在体内清除速率，当患者肾功能正常时（Ccr＞85mL／min），CL=5．66×（体质量／60）0.52，患者Ccr的变化并不影响药物的廓清率。患者合并使用利尿剂后，去甲万古霉素周边室分布容积（V2）增大。CL、中央室分布容积（V1）、室间清除率（Q）和V2的患者个体间变异分别为35．92％、11．40％、0和79．75％，残差误差为3．05mg／L。葡萄球菌及肠球菌感染者经去甲万古霉素治疗后治愈组和未治愈组比较，在葡萄球菌感染者中两组间给药剂量、年龄、药时曲线下面积（AUC）24和AUC24／MIC的差异具有统计学意义（P〈0．05）。肠球菌感染者两组间AUC24和AUC24／MIC的差异亦具有统计学意义（P〈0．05）。多因素回归分析显示，仅AUC24／MIC是影响治愈率的因素。当葡萄球菌感染组和肠球菌感染组的AUC24／MIC平均值分别为579．90和637．67时，去甲万古霉素对患者的治愈率可达95％。结论 AUC24／MIC可作为去甲万古霉素治疗耐药革兰阳性菌感染时预测临床和细菌学疗效的指标，据此制定适用于不同感染患者群体的最佳给药方案。