基于群体药代动力学模型仿真探索氨磺必利有效浓度范围

目的:以群体药动学模型仿真为基础,探索氨磺必利有效浓度范围,解决临床实际应用中血药浓度超过治疗参考范围的问题。方法:回顾性收集广州医科大学附属脑科医院2019至2020年接受氨磺必利治疗的精神科患者的治疗药物监测(therapeutic drug monitoring,TDM)数据及相关病历资料,采用非线性混合效应模型对氨磺必利血药浓度数据进行拟合分析,通过协变量筛选评估获得最终模型,模拟仿真各种剂量下氨磺必利血药浓度分布范围。结果:121名患者的330个血药浓度数据的68%可信区间血药浓度范围是185.59~650.94ng·mL^-1,采用建立的一室模型[最终模型:CL/F=61.1×(AGE/32)^-0.624,L·h^-1],模拟仿真发现当给药剂量在200~400mg·d^-1时,氨磺必利的平均血药浓度范围在《神经精神科治疗药物监测共识指南(2017版)》推荐有效浓度范围(100~320ng·mL^-1)内,在给药剂量400~800mg·d^-1时,平均血药浓度为300~600ng·mL^-1。结论:可根据临床治疗情况,将氨磺必利有效浓度范围暂定100~600ng·mL^-1,对应的推荐给药剂量为200~800mg·d^-1。     

噻唑-吡唑啉衍生物作为EGFR抑制剂的3D-QSAR和分子对接模型研究

目的 建立EGFR抑制剂结构和活性之间的关系模型,基于对分子活性产生影响的重要结构性因素的信息,设计新的抑制剂分子并预测其活性,为抑制剂分子的设计提供依据。方法 使用Discovery Studio 2019软件进行3D-QSAR的研究以及偏最小二乘的计算;利用Autodock进行分子对接;使用LigPlot研究二维相互作用。结果 模型具有较高的q²(0.521),和r²(r²_training=0.993,r²_test=0.916,r²_blind=0.940),表明模型具有较高的预测能力和拟合能力。结论 预测结果表明,新设计的化合物活性较高,为EGFR抑制剂分子的设计提供了参考。     

肛管直肠环肌群有限元模型应力分析

目的:从力学角度应用试验与仿真相结合对肛管直肠环进行有效预测评估与量化评判。方法:提取直肠癌术后组织标本获得肛管直肠环样本,进行静态拉伸试验,获得肛管直肠环肌群的应力-应变曲线;采用逆向工程的方法将使用MR扫描得到的盆底肛提肌、肛门扩约肌复合体转换为可导入仿真软件的三维几何模型;再使用ABAQUS有限元仿真软件进行仿真分析,模拟肛管直肠环肌群在不同排便条件下所承受的应力情况。结果:采用不同直径的圆柱作用于肛管直肠环,可以有效地模仿人静息状态、强忍状态,力排初状态以及增大腹压的各种活动状态如喷嚏、咳嗽、负重活动。结论:肛管直肠环有限元模型的建立为有效地模拟肛门不同手术方式导致的肛门控便功能障碍研究提供了有效真实的平台。     

Extracorporeal carbon dioxide removal requirements for ultraprotective mechanical ventilation: Mathematical model predictions

Extracorporeal carbon dioxide (CO₂) removal (ECCO₂R) facilitates the use of low tidal volumes during protective or ultraprotective mechanical ventilation when managing patients with acute respiratory distress syndrome (ARDS); however, the rate of ECCO₂R required to avoid hypercapnia remains unclear. We calculated ECCO₂R rate requirements to maintain arterial partial pressure of CO₂ (PaCO₂) at clinically desirable levels in mechanically ventilated ARDS patients using a six-compartment mathematical model of CO₂ and oxygen (O₂) biochemistry and whole-body transport with the inclusion of an ECCO₂R device for extracorporeal veno-venous removal of CO₂. The model assumes steady state conditions. Model compartments were lung capillary blood, arterial blood, venous blood, post-ECCO₂R venous blood, interstitial fluid and tissue cells, with CO₂ and O₂ distribution within each compartment; biochemistry included equilibrium among bicarbonate and non-bicarbonate buffers and CO₂ and O₂ binding to hemoglobin to elucidate Bohr and Haldane effects. O₂ consumption and CO₂ production rates were assumed proportional to predicted body weight (PBW) and adjusted to achieve reported arterial partial pressure of O₂ and a PaCO₂ level of 46 mmHg at a tidal volume of 7.6 mL/kg PBW in the absence of an ECCO₂R device based on average data from LUNG SAFE. Model calculations showed that ECCO₂R rates required to achieve mild permissive hypercapnia (PaCO₂ of 46 mmHg) at a ventilation frequency or respiratory rate of 20.8/min during mechanical ventilation increased when tidal volumes decreased from 7.6 to 3 mL/kg PBW. Higher ECCO2R rates were required to achieve normocapnia (PaCO2 of 40 mmHg). Model calculations also showed that required ECCO2R rates were lower when ventilation frequencies were increased from 20.8/min to 26/min. The current mathematical model predicts that ECCO2R rates resulting in clinically desirable PaCO2 levels at tidal volumes of 5-6 mL/kg PBW can likely be achieved in mechanically ventilated ARDS patients with current technologies; use of ultraprotective tidal volumes (3-4 mL/kg PBW) may be challenging unless high mechanical ventilation frequencies are used.     

The virtual visit: Using immersive technology to visit hospitals during social distancing and beyond

Medical trainees face substantial financial and scheduling burdens during the interview process at various levels of training. With current social distancing and travel restrictions in place, in‐person interviews now carry an additional health risk that make it difficult for training programs and applicants to conduct a thorough interview process. Virtual interviews and presentations are some of the technology‐driven solutions that have been accelerated in the current social context to mitigate financial burdens and health risks. By utilizing immersive technology to provide virtual tours of training sites, applicants have the opportunity to gain a comprehensive perspective before making the critical decision of where to continue their training. We provide our experiences with creating a 360‐degree virtual tour of our children's hospital and the methods for distribution to pediatric anesthesia fellowship applicants. Moving forward, training programs may consider immersive virtual tours as an alternative to face‐to‐face site visits to not only help alleviate the financial and scheduling burden for applicants but also to protect the well‐being of healthcare personnel and patients in the context of a global pandemic.     

A Higher Order Interpolation Scheme of Finite Volume Method for Compressible Flow on Curvilinear Grids

A higher order interpolation scheme based on a multi-stage BVD (Boundary Variation Diminishing) algorithm is developed for the FV (Finite Volume) method on non-uniform, curvilinear structured grids to simulate the compressible turbulent flows. The designed scheme utilizes two types of candidate interpolants including a higher order linear-weight polynomial as high as eleven and a THINC (Tangent of Hyperbola for INterface Capturing) function with the adaptive steepness. We investigate not only the accuracy but also the efficiency of the methodology through the cost efficiency analysis in comparison with well-designed mapped WENO (Weighted Essentially Non-Oscillatory) scheme. Numerical experimentation including benchmark broadband turbulence problem as well as real-life wall-bounded turbulent flows has been carried out to demonstrate the potential implementation of the present higher order interpolation scheme especially in the ILES (Implicit Large Eddy Simulation) of compressible turbulence.     

采用分子动力学模拟方法探究Ca~(2+)对VWF-A2结构域稳定性的影响

目的探究Ca~(2+)对VWF-A2结构域稳定性的影响。方法 A2和A2/Ca~(2+)的晶体结构取自PDB数据库。通过恒力拉伸分子动力学模拟,比较分析Ca~(2+)结合引起的构象变化、解折叠路径的差异以及酶切位点的暴露程度。结果 A2结构域的解折叠路径和酶切位点的暴露过程是力依赖的。Ca~(2+)结合不影响A2结构域的前期解折叠,但由于α3β4-环链局部构象重排所致柔性降低,约束了β1-β4-β5片层的运动,导致进一步解折叠受阻而停留在中间稳态,影响酶切位点的充分暴露。结论力可诱导A2结构域中β5片层的解折叠使酶切位点暴露,而Ca~(2+)的结合则通过稳定疏水核心结构,阻碍酶切位点的暴露,最终降低ADAMTS13的酶切效率。研究结果有助于加深对ADAMTS13酶切VWF-A2结构域进而调控VWF止血能力过程的理解,并为相关抗血栓药物设计提供指导。     

Acoustic excitations and elastic heterogeneities in disordered solids

In the recent years, much attention has been devoted to the inhomogeneous nature of the mechanical response at the nanoscale in disordered solids. Clearly, the elastic heterogeneities that have been characterized in this context are expected to strongly affect the nature of the sound waves which, in contrast to the case of perfect crystals, cannot be completely rationalized in terms of phonons. Building on previous work on a toy model showing an amorphization transition, we investigate the relationship between sound waves and elastic heterogeneities in a unified framework by continuously interpolating from the perfect crystal, through increasingly defective phases, to fully developed glasses. We provide strong evidence of a direct correlation between sound wave features and the extent of the heterogeneous mechanical response at the nanoscale.In crystals, molecules thermally oscillate around the periodic lattice sites and vibrational excitations are well understood in terms of quantized plane waves, the phonons (1). The vibrational density of states (vDOS) in the low-frequency regime is well described by the Debye model, where the vibrational modes are the acoustic phonons. In contrast, disordered solids, including structural glasses and disordered crystals, exhibit specific vibrational properties compared with the corresponding pure crystalline phases. It is not possible here to give a fair review of the extensive theoretical and experimental work generated by these issues; we therefore mention below a few facts that we consider the most relevant in the present context. The origin of the vDOS modes in excess over the Debye prediction around ω ∼1 THz, the so-called Boson peak (BP), is still debated (see, among many others, refs. 2 and 3). At the BP frequency, Ω^BP, localized modes have also been observed (4). Acoustic plane waves, which are exact normal modes in crystals, can still propagate in disordered solids. Indeed, at low frequencies, Ω, and long wavelengths, Λ, acoustic sound waves do not interact with disorder and can propagate conforming to the expected macroscopic limit. However, as Ω is increased beyond the Ioffe–Regel (IR) limit, Ω^IR, acoustic excitations interact with the disorder and are significantly scattered (5–7). Interestingly, this strong scattering regime occurs around the BP position, Ω^IR ∼ Ω^BP (8, 9). The exact origin of this phenomenon and its connection to the BP remain elusive.A possible rationalization of the above issues is based on the existence of elastic heterogeneities (10), which can originate from structural disorder, as in structural glasses (2), or disordered interparticle potentials, even in lattice structures such as disordered colloidal crystals (11). In the heterogeneous-elasticity theory of refs. 7 and 12 this amounts to consider spatial statistical fluctuations of the shear modulus. Within the framework of jamming approaches and using effective medium theories, elastic heterogeneities are related to the proximity of local elastic instabilities (13). Recent simulation work (14–16) has clearly demonstrated their existence in disordered solids. This is at variance with the case of simple crystals, which are characterized by a fully affine response and homogeneous moduli distributions (17). More specifically, in the large length scale limit, macroscopic moduli are observed. In contrast, as the length scale is reduced, moduli heterogeneities are detected, at a typical length scale ξ ≃ 10−15σ (15), where σ is the typical atomic diameter. Breakdown of both continuum mechanics (18) and Debye approximation (5, 6) has been demonstrated at the same mesoscopic length-scale ξ, where they are still valid for crystals. Remarkably, the wave frequency corresponding to the wavelength Λ ∼ ξ is very close to Ω^IR ∼ Ω^BP (19). Altogether these results indicate that a close connection must exist between elastic heterogeneities and acoustic excitations. In this paper we precisely address this point.In ref. 20 we considered a numerical model featuring an amorphization transition (21). We showed how to systematically deform the local moduli distributions, evaluated by coarse-graining the system in small domains of linear length scale w. We characterized the degree of elastic heterogeneity in terms of SD of those distributions and studied the effect on normal modes (eigenvalues of the Hessian matrix) and thermal conductivity. Building on that work, we are now in the position to investigate the relation between elastic heterogeneities and acoustic excitations, unifying in a single framework ordered and disordered solid states and considering quantities directly probed by experiments. By interpolating in a controlled way from perfect crystals, through increasingly defective phases, to fully developed amorphous structures, we (i) calculate the dynamical structure factors, extracting the relevant spectroscopic parameters; (ii) characterize the wave vector dependence of sound velocity and broadening of the acoustic excitations and clarify their nature in terms of the IR limit; and (iii) provide, for the first time to our knowledge, direct evidence of the correlation of the excitations lifetimes and Ω^IR with the magnitude of the elastic heterogeneities.     

In vitro performance of zirconia and titanium implant/abutment systems for anterior application

Objectives

To investigate the type of failure and fracture resistance behaviour of different zirconia and titanium implant/abutment systems for anterior application.

Methods

Eight groups of implant–abutment combinations (n = 8/system) were restored with identical full-contour zirconia crowns. The systems represented one-piece and multi-piece zirconia (Z) or titanium (T) implants/abutments with different types of connection (screwed = S, bonded = B). The following combinations (implant–abutment-connection) were investigated: ZZS, ZZB, ZZZB (three-piece), ZTS, TTS, TTS reference, and Z (one-piece, 2×). To simulate clinical anterior loading situations the specimens were mounted into the chewing simulator at an angle of 135° and subjected to thermal cycling (2 × 3000 × 5°/55 °C) and mechanical loading (1.2 × 10⁶ × 50 N; 1.6 Hz). Fracture resistance and maximum bending stress were determined for all specimens that survived ageing. Data were statistically analyzed with the Kolmogorov–Smirnov-test and one-way ANOVA (α = 0.05). Survival performance was calculated with the Kaplan–Meier Log-Rank test.

Results

Independent of the material combinations screwed systems showed partly failures of the screws during simulation (ZZS: 3×, ZTS: 8×, TTS: 3×). Screw failures were combined with implant/abutment fractures of zirconia systems. Zirconia one-piece implants and the reference system did not show any failures, and only one specimen of the systems with a bonded connection (ZZZB) fractured. Mean (±standard deviation) fracture forces and maximum bending stresses differed significantly (p = 0.000) between 187.4 ± 42.0 N/250.0 ± 56.0 N/mm² (ZZZB) and 524.3 ± 43.1 N/753.0 ± 61.0 N/mm² (Z).

Conclusions

Both material (zirconia or titanium) and the type of connection influenced failure resistance during fatigue testing, fracture force, and maximum bending stress.

Clinical significance

Different material combinations for implants and abutments as well as different types of connection achieved acceptable or even good failure and fracture resistance that may be satisfactory for anterior clinical application.