BACKGROUND & AIMS: :Although mean efficacy of multivalent pneumococcus vaccines has been intensively studied, variance in vaccine efficacy (VE) has been overlooked. Different net individual protection across settings can be driven by environmental conditions, local serotype and clonal composition, as well as by socio-demographic and genetic host factors. Understanding efficacy variation has implications for population-level effectiveness and other eco-evolutionary feedbacks. Here I show that realized VE can vary across epidemiological settings, by applying a multi-site-one-model approach to data post-vaccination. I analyse serotype prevalence dynamics following PCV7, in asymptomatic carriage in children attending day care in Portugal, Norway, France, Greece, Hungary and Hong-Kong. Model fitting to each dataset provides site-specific estimates for vaccine efficacy against acquisition, and pneumococcal transmission parameters. According to this model, variable serotype replacement across sites can be explained through variable PCV7 efficacy, ranging from 40% in Norway to 10% in Hong-Kong. While the details of how this effect is achieved remain to be determined, here I report three factors negatively associated with the VE readout, including initial prevalence of serotype 19F, daily mean temperature, and the Gini index. The study warrants more attention on local modulators of vaccine performance and calls for predictive frameworks within and across populations.

背景与目标： : 尽管已经深入研究了多价肺炎球菌疫苗的平均效力，但疫苗效力 (VE) 的差异却被忽略了。环境条件，当地血清型和克隆组成以及社会人口统计学和遗传宿主因素可以驱动不同环境的净个体保护。了解功效变化会对人口水平的有效性和其他生态进化反馈产生影响。在这里，我表明，通过将多站点一模型的方法应用于疫苗接种后的数据，实现的VE可以在流行病学设置中有所不同。我分析了PCV7之后在葡萄牙，挪威，法国，希腊，匈牙利和香港的日托儿童中无症状携带的血清型患病率动态。对每个数据集的模型拟合提供了针对采集的疫苗功效和肺炎球菌传播参数的特定站点估计。根据该模型，可以通过从挪威的40% 到香港的10% 的可变PCV7功效来解释跨位点的可变血清型替代。尽管如何实现这种效果的细节仍有待确定，但在这里我报告了与VE读数负相关的三个因素，包括血清型19F的初始患病率，每日平均温度和基尼指数。该研究需要更多地关注疫苗性能的局部调节剂，并呼吁在人群内部和人群之间建立预测框架。

BACKGROUND & AIMS: :Obesity affects multiple points along the breast cancer control continuum from prevention to screening and treatment, often in opposing directions. Obesity is also more prevalent in Blacks than Whites at most ages so it might contribute to observed racial disparities in mortality. We use two established simulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate the impact of obesity on race-specific breast cancer outcomes. The models use common national data to inform parameters for the multiple US birth cohorts of Black and White women, including age- and race-specific incidence, competing mortality, mammography characteristics, and treatment effectiveness. Parameters are modified by obesity (BMI of ≥ 30 kg/m(2)) in conjunction with its age-, race-, cohort- and time-period-specific prevalence. We measure age-standardized breast cancer incidence and mortality and cases and deaths attributable to obesity. Obesity is more prevalent among Blacks than Whites until age 74; after age 74 it is more prevalent in Whites. The models estimate that the fraction of the US breast cancer cases attributable to obesity is 3.9-4.5 % (range across models) for Whites and 2.5-3.6 % for Blacks. Given the protective effects of obesity on risk among women <50 years, elimination of obesity in this age group could increase cases for both the races, but decrease cases for women ≥ 50 years. Overall, obesity accounts for 4.4-9.2 % and 3.1-8.4 % of the total number of breast cancer deaths in Whites and Blacks, respectively, across models. However, variations in obesity prevalence have no net effect on race disparities in breast cancer mortality because of the opposing effects of age on risk and patterns of age- and race-specific prevalence. Despite its modest impact on breast cancer control and race disparities, obesity remains one of the few known modifiable risks for cancer and other diseases, underlining its relevance as a public health target.

背景与目标： : 肥胖会影响从预防到筛查和治疗的乳腺癌控制连续体的多个点，通常方向相反。在大多数年龄段，肥胖在黑人中也比白人更普遍，因此可能会导致观察到的种族死亡率差异。我们使用癌症干预和监测建模网络 (CISNET) 建立的两个模拟模型来评估肥胖对种族特异性乳腺癌结局的影响。这些模型使用通用的国家数据来告知美国多个黑人和白人女性出生队列的参数，包括特定于年龄和种族的发病率，竞争性死亡率，乳房x线摄影特征和治疗效果。通过肥胖 (BMI ≥ 30千克/m(2)) 及其年龄，种族，队列和时间段特异性患病率来修改参数。我们测量了年龄标准化的乳腺癌发病率和死亡率以及肥胖导致的病例和死亡。直到74岁，肥胖在黑人中比白人更普遍; 74岁以后，在白人中更普遍。这些模型估计，美国乳腺癌病例中肥胖的比例在白人中是3.9-4.5% (模型范围)，在黑人中是2.5-3.6%。鉴于肥胖对 <50岁女性风险的保护作用，消除该年龄组的肥胖可以增加两个种族的病例，但减少 ≥ 50岁女性的病例。总体而言，肥胖分别占白人和黑人乳腺癌死亡总数的4.4-9.2% 和3.1-8.4%。然而，肥胖患病率的变化对乳腺癌死亡率的种族差异没有净影响，因为年龄对风险以及年龄和种族特定患病率的模式有相反的影响。尽管肥胖对乳腺癌控制和种族差异的影响不大，但它仍然是癌症和其他疾病的少数已知可改变的风险之一，突显了其作为公共卫生目标的相关性。

BACKGROUND & AIMS: :Bsoft is a software package written for image processing of electron micrographs, interpretation of reconstructions, molecular modeling, and general image processing. The code is modularized to allow for rapid testing and deployment of new processing algorithms, while also providing sufficient infrastructure to deal with many file formats and parametric data. The design is deliberately open to allow interchange of information with other image and molecular processing software through a standard parameter file (currently a text-based encoding of parameters in the STAR format) and its support of multiple image and molecular formats. It also allows shell scripting of processes and allows subtasks to be distributed across multiple computers for concurrent processing. Bsoft has undergone many modifications and advancements since its initial release [Heymann, J.B., 2001. Bsoft: image and molecular processing in electron microscopy. J. Struct. Biol. 133, 156-169]. Much of the emphasis is on single particle analysis and tomography, and sufficient functionality is available in the package to support most needed operations for these techniques. The key graphical user interface is the program bshow, which displays an image and is used for many interactive purposes such as fitting the contrast transfer function or picking particles. Bsoft also offers various tools to manipulate atomic structures and to refine the fit of a known molecular structure to a density in a reconstruction.

背景与目标： : Bsoft是为电子显微照片的图像处理，重建的解释，分子建模和一般图像处理而编写的软件包。该代码是模块化的，以允许快速测试和部署新的处理算法，同时还提供足够的基础设施来处理许多文件格式和参数数据。该设计是故意开放的，以允许通过标准参数文件 (当前是星形格式的基于文本的参数编码) 及其对多种图像和分子格式的支持与其他图像和分子处理软件进行信息交换。它还允许对进程进行shell脚本编写，并允许将子任务分布在多台计算机上进行并发处理。自最初发布以来，Bsoft经历了许多修改和进步 [Heymann，J.B.，2001. Bsoft: 电子显微镜中的图像和分子处理。J. Struct. Biol. 133，156-169]。大部分重点放在单粒子分析和层析成像上，并且软件包中有足够的功能来支持这些技术最需要的操作。关键的图形用户界面是程序bshow，它显示图像并用于许多交互目的，例如拟合对比度传递函数或拾取颗粒。Bsoft还提供了各种工具来操纵原子结构并在重建过程中完善已知分子结构与密度的拟合。

BACKGROUND & AIMS: :Keratin intermediate filaments (IFs) form cross-linked arrays to fulfill their structural support function in epithelial cells and tissues subjected to external stress. How the cross-linking of keratin IFs impacts the morphology and differentiation of keratinocytes in the epidermis and related surface epithelia remains an open question. Experimental measurements have established that keratinocyte spreading area is inversely correlated to the extent of keratin IF bundling in two-dimensional culture. In an effort to quantitatively explain this relationship, we developed a mathematical model in which isotropic cell spreading is considered as a first approximation. Relevant physical properties such as actin protrusion, adhesion events, and the corresponding response of lamellum formation at the cell periphery are included in this model. Through optimization with experimental data that relate time-dependent changes in keratinocyte surface area during spreading, our simulation results confirm the notion that the organization and mechanical properties of cross-linked keratin filaments affect cell spreading; in addition, our results provide details of the kinetics of this effect. These in silico findings provide further support for the notion that differentiation-related changes in the density and intracellular organization of keratin IFs affect tissue architecture in epidermis and related stratified epithelia.

背景与目标： : 角蛋白中间丝 (IFs) 形成交联阵列，以在承受外部压力的上皮细胞和组织中实现其结构支持功能。角蛋白IFs的交联如何影响表皮和相关表面上皮中角质形成细胞的形态和分化仍然是一个悬而未决的问题。实验测量已经确定，如果在二维培养物中捆绑，角质形成细胞的扩散面积与角蛋白的程度成反比。为了定量解释这种关系，我们开发了一个数学模型，其中各向同性单元扩展被视为第一近似值。该模型中包括相关的物理特性，例如肌动蛋白突出，粘附事件以及细胞外围的薄片形成的相应响应。通过优化与扩散过程中角质形成细胞表面积随时间变化相关的实验数据，我们的模拟结果证实了交联角蛋白丝的组织和机械性能影响细胞扩散的概念; 此外，我们的结果提供了这种效应的动力学细节。这些计算机研究结果为以下观点提供了进一步的支持: 角蛋白IFs的密度和细胞内组织的分化相关变化会影响表皮和相关分层上皮的组织结构。

BACKGROUND & AIMS: :Oxidation of low-density lipoprotein (LDL) is one of the major factors in atherogenic process. Trapped oxidized LDL (Ox-LDL) in the subendothelial matrix is taken up by macrophage and leads to foam cell generation creating the first step in atherosclerosis development. Many researchers have studied LDL oxidation using in vitro cell-induced LDL oxidation model. The present study provides a kinetic model for LDL oxidation in intima layer that can be used in modeling of atherosclerotic lesions development. This is accomplished by considering lipid peroxidation kinetic in LDL through a system of elementary reactions. In comparison, characteristics of our proposed kinetic model are consistent with the results of previous experimental models from other researches. Furthermore, our proposed LDL oxidation model is added to the mass transfer equation in order to predict the LDL concentration distribution in intima layer which is usually difficult to measure experimentally. According to the results, LDL oxidation kinetic constant is an important parameter that affects LDL concentration in intima layer so that existence of antioxidants that is responsible for the reduction of initiating rates and prevention of radical formations, have increased the concentration of LDL in intima by reducing the LDL oxidation rate.

背景与目标： : 低密度脂蛋白 (LDL) 的氧化是动脉粥样硬化过程的主要因素之一。内皮下基质中捕获的氧化LDL (Ox-LDL) 被巨噬细胞摄取，并导致泡沫细胞的产生，从而形成动脉粥样硬化发展的第一步。许多研究人员使用体外细胞诱导的LDL氧化模型研究了LDL氧化。本研究提供了内膜层LDL氧化的动力学模型，可用于模拟动脉粥样硬化病变的发展。这是通过通过基本反应系统考虑LDL中的脂质过氧化动力学来实现的。相比之下，我们提出的动力学模型的特征与其他研究的先前实验模型的结果一致。此外，我们提出的LDL氧化模型被添加到传质方程中，以预测内膜层中的LDL浓度分布，这通常很难通过实验进行测量。根据结果，LDL氧化动力学常数是影响内膜层中LDL浓度的重要参数，因此抗氧化剂的存在负责降低起始速率和防止自由基形成，通过降低LDL氧化速率来增加内膜中LDL的浓度。

BACKGROUND & AIMS: :Molecular modeling studies were performed in order to gain insight into the binding mode and interaction of carborane-containing derivatives of indomethacin methyl ester with the cyclooxygenase-2 (COX-2) isoform, and to assess the predictive capability of the computational tools available for studying carboranes, a unique class of pharmacophores. Docking simulations were able to identify the correct binding mode and reproduced the experimental binding affinity trends with encouraging quality. Nevertheless, the docking results needed to be verified through extensive and resource-intensive quantum chemical calculations, and the interpretation of the theoretical results would not have been straightforward without the supporting experimental data. The inclusion of full receptor and ligand flexibility into the molecular modeling of carborane-containing drug molecules may yield more definitive results, but is currently hindered by the lack of appropriate carborane force field parameters.

背景与目标： : 进行了分子建模研究，以深入了解吲哚美辛甲酯含碳硼烷衍生物与cyclooxygenase-2 (COX-2) 同工型的结合模式和相互作用，并评估可用于研究碳硼烷的计算工具的预测能力，一类独特的药效团。对接模拟能够识别正确的结合模式，并以令人鼓舞的质量再现实验中的结合亲和力趋势。尽管如此，对接结果仍需要通过广泛且资源密集的量子化学计算来验证，并且如果没有支持的实验数据，对理论结果的解释将不会很简单。在含碳硼烷的药物分子的分子模型中包含完整的受体和配体灵活性可能会产生更明确的结果，但是目前由于缺乏适当的碳硼烷力场参数而受到阻碍。

BACKGROUND & AIMS: :Intervertebral disc spacers using bioactive ceramics have been used to treat degenerative spinal disease. Tooth-shaped spacers are commonly used to prevent migration, but there is a possibility of fracture when inserted or after insertion. Intervertebral disc spacers with either an isosceles triangle-shaped tooth (T1) or a right triangle-shaped tooth (T2) were used as a control group. The design factors for the experimental group were modified to prevent fractures induced by stress concentration, and the surfaces of the spacers were designed as either an isosceles triangle-shaped valley (V1) or a right triangle-shaped valley (V2). Linear analysis using finite element model (FEM) was performed, and Von Mises stress distribution was calculated by applying 1000 N of uniformly distributed load. Samples of the V2 design were made with bioactive glass-ceramics (BGS-7) and evaluated for compressive strength, fatigue degree, and impact strength. Von Mises stress was highest at the first tooth from the posterior side for the control group and at the center for the experimental group. Compared with the control group, the experimental group showed 18.4% and 82.5% reduction (V1 vs. T1 and V2 vs. T2, respectively) in the maximum stress at the bottom of the valleys. The FEM analysis revealed that the V2 design had the most even load distribution. The V2 samples with bioactive glass-ceramics were evaluated for compressive strength, and all six samples were not fractured up to 24 000 N. However, the average impact strength was 19.42 kN, suggesting that momentary force caused damage at a lower load than compression with a steady speed. The BGS-7 intervertebral disc spacer with V2 design was not fractured during the fatigue test at maximum pressure of 8000 N, R ≥10, 5 Hz, and 5 million cycles. These data confirm that the BGS-7 spacer with the V2 design may be clinically applicable. Collectively, the modified surface geometry of the experimental group significantly lowered Von Mises stress values at the bottom of the valleys, and thus the possibility of fracture by compressive load was greatly reduced. Also, impact during insertion was confirmed to cause fracture more easily, as the impact strength was lower than the compressive strength in the experimental group.

背景与目标： : 使用生物活性陶瓷的椎间盘垫片已用于治疗退行性脊柱疾病。通常使用齿形垫片来防止迁移，但是插入时或插入后有断裂的可能性。将具有等腰三角形牙齿 (T1) 或直角三角形牙齿 (T2) 的椎间盘间隔物用作对照组。修改了实验组的设计因素，以防止应力集中引起的裂缝，并将垫片的表面设计为等腰三角形谷 (V1) 或直角三角形谷 (V2)。使用有限元模型 (FEM) 进行线性分析，并通过1000 N均匀分布的载荷计算Von Mises应力分布。用生物活性玻璃陶瓷 (BGS-7) 制成V2设计的样品，并评估其抗压强度，乏力程度和冲击强度。对照组从后侧开始的第一颗牙齿和实验组的中心位置的Von Mises应力最高。与对照组相比，实验组在谷底的最大应力显示出18.4% 和82.5% 的降低 (分别为V1对T1和V2对T2)。有限元分析表明，V2设计的载荷分布最均匀。评估了具有生物活性微晶玻璃的V2样品的抗压强度，并且所有六个样品的断裂都达到24 000 N。但是，平均冲击强度为19.42 kN，这表明瞬时力在比稳定速度的压缩低的载荷下引起损坏。在最大压力为8000 N，R ≥ 10、5Hz和500万个循环的疲劳试验中，采用V2设计的BGS-7椎间盘垫片没有断裂。这些数据证实具有V2设计的BGS-7间隔物可以在临床上适用。总的来说，实验组的修改后的表面几何形状显着降低了谷底部的Von Mises应力值，因此大大降低了压缩载荷导致断裂的可能性。此外，由于插入过程中的冲击强度低于实验组的抗压强度，因此确认插入过程中的冲击更容易导致断裂。

BACKGROUND & AIMS: :The endoscope is a popular imaging modality used in many preevaluations and surgical treatments, and is also one of the essential tools in minimally invasive surgery. However, regular endoscopes provide only 2-D images. Even though stereoendoscopy systems can display 3-D images, the real anatomical structure of the observed lesion is unavailable and can only be judged by the surgeon's imagination. In this paper, we present a constraint-based factorization method for reconstructing 3-D structures registered to the patient, from 2-D endoscopic images. The proposed method incorporates the geometric constraints from the tracked surgical instrument into the traditional factorization method based on frame-to-frame feature motion on the endoscopically viewed scene. Experiments with real and synthetic data demonstrate good real-scale 3-D extraction, with greater accuracy than is available from traditional methods. The reconstruction process can also be accomplished in a few seconds, making it suitable for on-line surgical applications to provide surgeons with additional 3-D shape information, critical distance monitoring and warnings.

背景与目标： : 内窥镜是一种流行的成像方式，用于许多预评估和手术治疗，也是微创手术的重要工具之一。但是，常规内窥镜仅提供二维图像。即使立体内窥镜检查系统可以显示3-D图像，也无法获得观察到的病变的真实解剖结构，只能通过外科医生的想象力来判断。在本文中，我们提出了一种基于约束的因式分解方法，用于从2-D内窥镜图像重建患者注册的3-D结构。所提出的方法将来自跟踪的手术器械的几何约束结合到传统的因式分解方法中，该方法基于内窥镜观察场景上的帧到帧特征运动。使用真实数据和合成数据进行的实验证明了良好的真实尺度3-D提取，比传统方法具有更高的准确性。重建过程也可以在几秒钟内完成，使其适用于在线手术应用，为外科医生提供额外的3-D形状信息，关键距离监测和警告。

BACKGROUND & AIMS: :Computational protein design can be used to select sequences that are compatible with a fixed-backbone template. This strategy has been used in numerous instances to engineer novel proteins. However, the fixed-backbone assumption severely restricts the sequence space that is accessible via design. For challenging problems, such as the design of functional proteins, this may not be acceptable. Here, we present a method for introducing backbone flexibility into protein design calculations and apply it to the design of diverse helical BH3 ligands that bind to the anti-apoptotic protein Bcl-xL, a member of the Bcl-2 protein family. We demonstrate how normal mode analysis can be used to sample different BH3 backbones, and show that this leads to a larger and more diverse set of low-energy solutions than can be achieved using a native high-resolution Bcl-xL complex crystal structure as a template. We tested several of the designed solutions experimentally and found that this approach worked well when normal mode calculations were used to deform a native BH3 helix structure, but less well when they were used to deform an idealized helix. A subsequent round of design and testing identified a likely source of the problem as inadequate sampling of the helix pitch. In all, we tested 17 designed BH3 peptide sequences, including several point mutants. Of these, eight bound well to Bcl-xL and four others showed weak but detectable binding. The successful designs showed a diversity of sequences that would have been difficult or impossible to achieve using only a fixed backbone. Thus, introducing backbone flexibility via normal mode analysis effectively broadened the set of sequences identified by computational design, and provided insight into positions important for binding Bcl-xL.

背景与目标： : 计算蛋白质设计可用于选择与固定骨架模板兼容的序列。此策略已在许多情况下用于设计新型蛋白质。但是，固定主干假设严重限制了可通过设计访问的序列空间。对于具有挑战性的问题，例如功能性蛋白质的设计，这可能是不可接受的。在这里，我们提出了一种将骨架灵活性引入蛋白质设计计算的方法，并将其应用于与抗凋亡蛋白Bcl-xL (Bcl-2蛋白家族的成员) 结合的多种螺旋BH3配体的设计。我们演示了如何使用正常模式分析来采样不同的BH3主干，并表明与使用本机高分辨率Bcl-xL复合晶体结构作为模板可以实现的相比，这导致了更大和更多样化的低能解决方案集。我们通过实验测试了几种设计的解决方案，发现当使用正常模式计算使本机BH3螺旋结构变形时，这种方法效果很好，但当使用它们使理想化的螺旋变形时效果较差。随后的一轮设计和测试将问题的可能根源确定为螺旋螺距采样不足。总之，我们测试了17个设计的BH3肽序列，包括几个点突变体。其中，八个与Bcl-xL结合良好，另外四个显示出弱但可检测的结合。成功的设计显示出多种序列，仅使用固定的主干就很难或不可能实现。因此，通过正常模式分析引入主干灵活性有效地拓宽了通过计算设计确定的序列集，并提供了对结合Bcl-xL重要的位置的洞察力。

BACKGROUND & AIMS: :Polyhydroxyalkanoate-based polymers-being ecofriendly, biosynthesizable, and economically viable and possessing a broad range of tunable properties-are currently being actively pursued as promising alternatives for petroleum-based plastics. The vast chemical complexity accessible within this class of polymers gives rise to challenges in the rational discovery of novel polymer chemistries for specific applications. The burgeoning field of polymer informatics addresses this challenge via providing tools and strategies for accelerated property prediction and materials design via surrogate machine-learning models built on reliable past data. In this contribution, we use glass transition temperature Tg as an example target property to demonstrate promise of the data-enabled route to accelerated learning of accurate structure-property mappings in PHA-based polymers. Our analysis uses a data set of experimentally measured Tg values, polymer molecular weights, and a polydispersity index for PHA-based homo- and copolymers that was carefully assembled from the literature. A fingerprinting scheme that captures key properties based on topology, shape, and charge/polarity of specific chemical units or motifs forming the polymer backbone was devised to numerically represent the polymers. A validated statistical learning model is then developed to allow for a mapping of the polymer fingerprints onto the property space in a physically meaningful and reliable manner. Once developed, the model can not only rapidly predict the property of new PHA polymers but also provide uncertainties underlying the predictions. The model is further combined with an evolutionary-algorithm-based search strategy to efficiently identify multicomponent polymer compositions with a prespecified Tg. While the present contribution is focused specifically on Tg, the surrogate model development approach put forward here is general and can, in principle, be extended to a range of other properties.

背景与目标： : 基于聚羟基链烷酸酯的聚合物-生态友好，可生物合成，经济上可行，并具有广泛的可调性能-目前正积极寻求作为石油基塑料的有前途的替代品。这类聚合物中可以获得的巨大化学复杂性给合理发现用于特定应用的新型聚合物化学物质带来了挑战。聚合物信息学的新兴领域通过提供基于可靠的过去数据的替代机器学习模型来加速性能预测和材料设计的工具和策略来应对这一挑战。在此贡献中，我们使用玻璃化转变温度Tg作为示例目标属性，以证明数据支持的途径有望加速学习基于PHA的聚合物中的准确结构-属性映射。我们的分析使用了实验测得的Tg值，聚合物分子量以及PHA基均聚物和共聚物的多分散指数的数据集，这些数据是从文献中精心组装而成的。设计了一种指纹图谱方案，该指纹图谱方案可根据形成聚合物主链的特定化学单元或基序的拓扑，形状和电荷/极性捕获关键特性，以数字表示聚合物。然后开发经过验证的统计学习模型，以允许以物理上有意义且可靠的方式将聚合物指纹映射到属性空间上。一旦开发，该模型不仅可以快速预测新的PHA聚合物的性能，而且还提供了预测的不确定性。该模型进一步与基于进化算法的搜索策略相结合，以有效地识别具有预设Tg的多组分聚合物组合物。尽管目前的贡献专门针对Tg，但此处提出的替代模型开发方法是通用的，原则上可以扩展到其他一系列属性。

BACKGROUND & AIMS: PURPOSE:Quantitative relationships between treatment-induced changes in tumor size and circulating tumor cell (CTC) counts, and their links to overall survival (OS), are lacking. We present a population modeling framework identifying and quantifying such relationships, based on longitudinal data collected in patients with metastatic colorectal cancer (mCRC) to evaluate the value of tumor size and CTC counts as predictors of OS. EXPERIMENTAL DESIGN:A pharmacometric approach (i.e., population pharmacodynamic modeling) was used to characterize the changes in tumor size and CTC count and evaluate them as predictors of OS in 451 patients with mCRC treated with chemotherapy and targeted therapy in a prospectively randomized phase III study (CAIRO2). RESULTS:A tumor size model of tumor quiescence and drug resistance was used to characterize the tumor size time-course, and was, in addition to the total normalized dose (i.e., of all administered drugs) in a given cycle, related to the CTC counts through a negative binomial model (CTC model). Tumor size changes did not contribute additional predictive value when the mean CTC count was a predictor of OS. Treatment reduced the typical mean count from 1.43 to 0.477 (HR = 3.94). The modeling framework was applied to explore whether dose modifications (increased and reduced) would result in a CTC count below 1/7.5 mL after 1 to 2 weeks of treatment. CONCLUSIONS:Time-varying CTC counts can be useful for early predicting OS in patients with mCRC, and may therefore have potential for model-based treatment individualization. Although tumor size was connected to CTC, its link to OS was weaker.

背景与目标：

BACKGROUND & AIMS: :A formal modeling approach was used to characterize decision-making processes in bipolar disorder. Decision making was examined in 28 bipolar patients (14 acute and 14 remitted) and 25 controls using the Iowa Gambling Task (Bechara et al., 1994), a decision-making task used for assessing cognitive impulsivity. To disentangle motivational and cognitive aspects of decision-making processes, we applied a formal cognitive model to the performance on the Iowa Gambling Task. The model has three parameters: The relative impact of rewards and punishments on evaluations, the impact of recent and past payoffs, and the degree of choice consistency. The results indicated that acute bipolar patients were characterized by low choice consistency, or a tendency to make erratic choices. Low choice consistency improved the prediction of acute bipolar disorder beyond that provided by cognitive functioning and self-report measures of personality and temperament.

背景与目标： : 使用正式建模方法来表征双相情感障碍的决策过程。使用Iowa赌博任务 (Bechara等，1994) 在28位双相情感障碍患者 (14位急性和14位缓解) 和25位对照中检查了决策，这是一种用于评估认知冲动的决策任务。为了消除决策过程的动机和认知方面，我们将正式的认知模型应用于爱荷华州赌博任务的表现。该模型具有三个参数: 奖励和惩罚对评估的相对影响，近期和过去收益的影响以及选择的一致性程度。结果表明，急性双相情感障碍患者的选择一致性低，或倾向于做出不稳定的选择。低选择一致性改善了急性双相情感障碍的预测，超出了认知功能和自我报告的人格和气质测量所提供的预测。

BACKGROUND & AIMS: :This paper investigates a likelihood-based approach in meta-analysis of clinical trials involving the baseline risk as explanatory variable. The approach takes account of the errors affecting the measure of either the treatment effect or the baseline risk, while facing the potential misspecification of the baseline risk distribution. To this aim, we suggest to model the baseline risk through a flexible family of distributions represented by the skew-normal. We describe how to carry out inference within this framework and evaluate the performance of the approach through simulation. The method is compared with the routine likelihood approach based on the restrictive normality assumption for the baseline risk distribution and with the weighted least-squares regression. We apply the competing approaches to the analysis of two published datasets.

背景与目标： : 本文研究了将基线风险作为解释变量的临床试验的荟萃分析中基于可能性的方法。该方法考虑了影响治疗效果或基线风险度量的误差，同时面临基线风险分布的潜在错误指定。为此，我们建议通过以偏斜正态为代表的灵活分布族对基线风险进行建模。我们描述了如何在此框架内进行推理并通过仿真评估该方法的性能。将该方法与基于基准风险分布的限制性正态性假设和加权最小二乘回归的常规似然方法进行比较。我们将竞争方法应用于两个已发布数据集的分析。

BACKGROUND & AIMS: :This paper considers the problem of obtaining a dynamic prediction for 5-year failure free survival after bone marrow transplantation in ALL patients using data from the EBMT, the European Group for Blood and Marrow Transplantation. The paper compares the new landmark methodology as developed by the first author and the established multi-state modeling as described in a recent Tutorial in Biostatistics in Statistics in Medicine by the second author and colleagues. As expected the two approaches give similar results. The landmark methodology does not need complex modeling and leads to easy prediction rules. On the other hand, it does not give the insight in the biological processes as obtained for the multi-state model.

背景与目标： : 本文考虑了使用欧洲血液和骨髓移植组EBMT的数据获得所有患者骨髓移植后5年无失败生存率的动态预测的问题。本文比较了第一作者开发的新地标方法和第二作者及其同事最近在医学统计学中的生物统计学教程中描述的已建立的多状态建模。不出所料，这两种方法给出了相似的结果。具有里程碑意义的方法不需要复杂的建模，并且可以简化预测规则。另一方面，它没有像多状态模型那样提供对生物过程的洞察力。

BACKGROUND & AIMS: :Experimental approaches have been applied to address questions in understanding three-dimensional chromatin organization and function. As datasets increase in size and complexity, it becomes a challenge to reach a mechanistic interpretation of experimental results. Polymer simulations and mechanistic modeling have been applied to explain experimental observations and their links to different aspects of genome function. Here we provide a guide for biologists, explaining different simulation approaches and the contexts in which they have been used.

背景与目标： : 实验方法已用于解决理解三维染色质组织和功能的问题。随着数据集大小和复杂性的增加，对实验结果进行机械解释成为一项挑战。聚合物模拟和机械建模已用于解释实验观察结果及其与基因组功能不同方面的联系。在这里，我们为生物学家提供了指南，解释了不同的模拟方法以及使用它们的背景。