Quantifying the limits of CAR T-cell delivery in mice and men

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10–100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.     

Kinetic analysis of magnesium aluminate spinel formation: Effect of MgO:Al2O3 ratio and titania dopant

The mechanistic pathway of MgO-Al₂O₃ reaction in solid state to form MgAl₂O₄ spinel was investigated to correlate the kinetic parameters with ratio of reactants (MgO:Al₂O₃) and with the presence of a doping agent, TiO₂. The time-temperature-expansion data of oxide compacts was analyzed using several model free analyses and model based (linear and non-linear) kinetic algorithms. These indicated that spinel formation process can be best described by single step with n-dimensional Avrami equation for every MgO:Al₂O₃ ratio, irrespective of titania dopant. The activation energy (E_a) of the process was proportional to % spinel formed in each system and validated with quantitative XRD analysis. The higher value of Avrami coefficient (n) in 90 wt% Al₂O₃ compositions has been explained with geometric considerations of powder packing. Incorporations of 1% TiO₂ in the MgO: Al₂O₃ oxide compact did not markedly affect the reaction model, frequency factor and Activation energy.     

防振条约束失效对蒸汽发生器传热管面内流弹失稳的影响研究

根据防振条布置以及面内支承连续失效个数，将防振条面内约束失效分析划分为多种工况，分析了不同工况下面内约束失效对传热管面内模态的影响，采用各位置阻尼在振型函数上进行加权平均的方法计算了各阶模态的阻尼比，进而研究了防振条面内不同约束对传热管面内流弹失稳的影响。分析结果表明，随着面内支承连续失效位置的增多，弯管段面内首阶模态频率不断降低，出现在弯管段的振型越加明显；弯管段面内首阶模态不一定是最大流弹失稳比值出现的模态，最大流弹失稳比值出现模态的振型几乎都出现在弯管段；随着面内支承连续失效位置的增多，面内流弹失稳比值不断增大，当连续3个及以上防振条面内约束失效时，将出现流弹失稳现象。     

Modelling and predicting the effect of social distancing and travel restrictions on COVID-19 spreading

To date, the only effective means to respond to the spreading of the COVID-19 pandemic are non-pharmaceutical interventions (NPIs), which entail policies to reduce social activity and mobility restrictions. Quantifying their effect is difficult, but it is key to reducing their social and economic consequences. Here, we introduce a meta-population model based on temporal networks, calibrated on the COVID-19 outbreak data in Italy and applied to evaluate the outcomes of these two types of NPIs. Our approach combines the advantages of granular spatial modelling of meta-population models with the ability to realistically describe social contacts via activity-driven networks. We focus on disentangling the impact of these two different types of NPIs: those aiming at reducing individuals’ social activity, for instance through lockdowns, and those that enforce mobility restrictions. We provide a valuable framework to assess the effectiveness of different NPIs, varying with respect to their timing and severity. Results suggest that the effects of mobility restrictions largely depend on the possibility of implementing timely NPIs in the early phases of the outbreak, whereas activity reduction policies should be prioritized afterwards.     

Group sequential crossover trial designs with strong control of the familywise error rate

Crossover designs are an extremely useful tool to investigators, and group sequential methods have proven highly proficient at improving the efficiency of parallel group trials. Yet, group sequential methods and crossover designs have rarely been paired together. One possible explanation for this could be the absence of a formal proof of how to strongly control the familywise error rate in the case when multiple comparisons will be made. Here, we provide this proof, valid for any number of initial experimental treatments and any number of stages, when results are analyzed using a linear mixed model. We then establish formulae for the expected sample size and expected number of observations of such a trial, given any choice of stopping boundaries. Finally, utilizing the four-treatment, four-period TOMADO trial as an example, we demonstrate that group sequential methods in this setting could have reduced the trials expected number of observations under the global null hypothesis by over 33%.     

水文序列相依变异识别的RIC定阶准则——以自回归模型为例

水文过程相依性是水文变异的主要表现形式之一,应用自回归模型对其进行拟合时合理确定模型阶数是一个难点问题。本文在分析AIC和BIC准则的基础上,提出了一种以原序列与其相依成分的相关系数作为拟合度指标,同时借用信息熵形式的函数式,作为模型不确定性度量指标的自回归模型定阶准则(简称RIC准则)。以AR(1)、AR(2)、AR(3)和AR(4)模型为例进行统计试验,将不同序列长度下该准则的定阶准确率与其他定阶准则进行比较,试验结果表明,RIC准则对于上述模型均具有较好的适应性,且定阶准确率远高于AIC准则,其中对于前三阶模型RIC准则优于BIC准则,但四阶模型略低于BIC准则。RIC准则的优势是可以同时满足模型定阶、相依程度分级与模型检验的需求,将其应用于实测水文序列分析,结果显示,该准则能较准确地识别自回归模型的阶数,且符合提出的"相依有变异而残差无变异的最小阶数"的检验标准。     

重力坝坝基多斜面抗滑稳定模糊体系可靠度研究

以基岩具有多斜面、多滑移通道的某实际重力坝工程为例,基于刚体极限平衡法,采用模糊理论和几种典型的体系可靠度计算方法,研究其典型坝段的坝基深层抗滑稳定模糊体系可靠度,探讨模糊理论中隶属函数形式、隶属度以及隶属函数中关键参数的取值对可靠度计算结果的影响。研究结果表明,采取限制失效概率模糊界限比的方法可使计算结果更具有参考性,考虑模糊性的抗滑稳定可靠指标的下限较常规可靠度计算值偏小,这在重力坝坝基抗滑稳定分析中应引起重视。     

萃取塔数学模型及过程强化的若干研究进展

萃取塔因生产能力大、占地面积小、密闭性好等优点，在石油、化工、生物、医药和环境工程等多领域被广泛应用。本文从以下几个方面介绍了萃取塔近些年的研究进展：综述了传统萃取塔（脉冲萃取塔、转盘塔与Kühni塔等）的水力学、轴向扩散与传质模型的发展，分析比较了表面张力、传质方向、放大效应等因素对模型的影响；介绍了计算流体动力学（CFD）在萃取塔中单液滴、单相流模拟、液-液两相流模拟、外加能量模拟、与群体平衡模型（PBM）耦合模拟中的应用进展；介绍了国内外设计开发的新型萃取塔，包括改变传统塔的内构件和引入多种外场能量等方式来强化相间传质。研究表明，将先进实验研究方法、准确经验模型和可靠理论计算相结合，将会是萃取塔研究的重要手段和方向。     

主/次显示器视距设计对头部关节舒适度的影响

以视平线可与显示器中心重合为准,分别探讨显示器中心在视平线上方、下方时不同视距对头部关节舒适度的影响. 实验自变量为视距(眼睛与显示器中心的水平距离),因变量为头部关节舒适度. 实验结果显示:1)显示器中心在人视平线上方时,头部舒适性状态始终处于不舒适状态,此时视距与人的头部舒适性关系成正比,即视距越大,头部舒适性越好;2)显示器中心在人视平线下方时,头部关节舒适状态始终处于正常范围,舒适性程度随视距增大而减小.