Development and optimization of a new synthetic process for lorcaserin

A two-step process to synthesize racemic lorcaserin was developed from 2-(4-chlorophenyl)ethanol via formation of bromide or tosylate derivatives. These derivatives were reacted with allylamine in neat conditions to provide pure N-(4-chlorophenethyl)allylammonium chloride. This compound was cyclized in neat conditions using aluminum or zinc chloride to give racemic lorcaserin. After resolution of enantiomers, the wrong enantiomer was racemized and recycled to give new R-lorcaserin.     

Integration of multi-objective structural optimization into cementless hip prosthesis design: Improved Austin-Moore model

A new strategy of multi-objective structural optimization is integrated into Austin-Moore prosthesis in order to improve its performance. The new resulting model is so-called Improved Austin-Moore. The topology optimization is considered as a conceptual design stage to sketch several kinds of hollow stems according to the daily loading cases. The shape optimization presents the detailed design stage considering several objectives. Here, A new multiplicative formulation is proposed as a performance scale in order to define the best compromise between several requirements. Numerical applications on 2D and 3D problems are carried out to show the advantages of the proposed model.     

On partial local smoothing rules for curve estimation

We compare the performances of local and global rules for smoothingparameter choice, in terms of asymptotic mean squared errorsof the resulting estimators. In some instances there is surprisinglylittle to choose between local and global approaches; our analysisidentifies contexts where the differences are small or large.This work motivates development of smoothing rules that forma ‘half-way house’ between local and global smoothing.There, interpolation provides a basis for partial local smoothing.A key result shows that interpolation on even a coarse gridcan produce a very good approximation to full local smoothing.Our theoretical and numerical results lead us to suggest linearinterpolation of a bandwidth obtained by integral approximationson discrete intervals.     

Range optimization for target and organs at risk in dynamic adaptive passive scattering proton beam therapy – A proof of concept

PurposeThe purpose of this study was to design and develop a new range optimization for target and organs at risk (OARs) in dynamic adaptive proton beam therapy (PBT).MethodsThe new range optimization for target and OARs (RO-TO) was optimized to maintain target dose coverage but not to increase the dose exposure of OARs, while the other procedure, range optimization for target (RO-T), only focused on target dose coverage. A retrospective analysis of a patient who received PBT for abdominal lymph node metastases was performed to show the effectiveness of our new approach. The original plan (OP), which had a total dose of 60 Gy (relative biological effectiveness; RBE), was generated using six treatment fields. Bone-based registration (BR) and tumor-based registration (TR) were performed on each pretreatment daily CT image dataset acquired once every four fractions, to align the isocenter.ResultsBoth range adaptive approaches achieved better coverage (D_95%) and homogeneity (D_5%−D_95%) than BR and TR only. However, RO-T showed the greatest increases in D_2cc and D_mean values of the small intestine and stomach and exceeded the limitations of dose exposure for those OARs. RO-TO showed comparable or superior dose sparing compared with the OP for all OARs.ConclusionsOur results suggest that BR and TR alone may reduce target dose coverage, and that RO-T may increase the dose exposure to the OARs. RO-TO may achieve the planned dose delivery to the target and OARs more efficiently than the OP. The technique requires testing on a large clinical dataset.     

Effect of shoulder model complexity in upper-body kinematics analysis of the golf swing

The golf swing is a complex full body movement during which the spine and shoulders are highly involved. In order to determine shoulder kinematics during this movement, multibody kinematics optimization (MKO) can be recommended to limit the effect of the soft tissue artifact and to avoid joint dislocations or bone penetration in reconstructed kinematics. Classically, in golf biomechanics research, the shoulder is represented by a 3 degrees-of-freedom model representing the glenohumeral joint. More complex and physiological models are already provided in the scientific literature. Particularly, the model used in this study was a full body model and also described motions of clavicles and scapulae. This study aimed at quantifying the effect of utilizing a more complex and physiological shoulder model when studying the golf swing. Results obtained on 20 golfers showed that a more complex and physiologically-accurate model can more efficiently track experimental markers, which resulted in differences in joint kinematics. Hence, the model with 3 degrees-of-freedom between the humerus and the thorax may be inadequate when combined with MKO and a more physiological model would be beneficial. Finally, results would also be improved through a subject-specific approach for the determination of the segment lengths.     

基于多尺度协同的长沙市生态网络构建与层级优化

城市化背景下人类与自然环境的矛盾呈现出多尺度、层级化特征，而传统生态网络的构建方式较少考虑不同尺度下生态要素的关系，无法从区域落实到中心城区，难以形成系统性的解决方案。研究在综合梳理各尺度生态网络构建方法的基础上，以长沙市为例，基于形态学空间格局分析（Morphological Spatial Pattern Analysis，MSPA）、景观连通性原理和生态斑块重要性评价识别生态源地，并通过多层级生态阻力面的确定，综合运用最小费用路径（Least-cost path method，LCP）、电路理论、层级传导理论、尺度嵌套等方法对市域、都市区、中心城区的生态网络进行了协同构建和层级优化，最后基于不同尺度生态网络的特点应用并落实到多层级的国土空间规划体系中。研究结果表明：（1）长沙市域生态网络和都市区生态网络具有较好的层级嵌套特征；共识别两尺度生态叠合源地14个、生态叠合廊道15条，主要通过中心城区内的湘江、浏阳河和捞刀河部分河段与外围生态绿圈相衔接，形成"外环内楔"的空间格局。（2）确定市域重要廊道、市域潜在廊道、生态叠合廊道、都市区重要廊道、都市区潜在廊道的核心保护面积共501.14 km²，并提取位于生态廊道核心保护区范围内的生态夹点和生态障碍点，以进一步落实生态保护修复策略。（3）得到具有重要生态连通功能的中心城区生态绿道长度441.2 km，生态修复单元56个，并结合生态阻力值划分为5级进行针对性修复。（4）基于不同尺度生态网络的衔接、嵌套，最终构建"市域总体生态安全格局-都市区城市生态空间发展格局-以城市绿道为基础的中心城区生态修复单元"，并与不同层级的国土空间规划体系相对应。研究结果将为以大城市为中心的跨尺度生态系统修复和生态安全格局构建提供科学参考。     

Saroglitazar is noninferior to fenofibrate in reducing triglyceride levels in hypertriglyceridemic patients in a randomized clinical trial

Saroglitazar, being a dual PPAR-α/γ agonist, has shown beneficial effect in diabetic dyslipidemia and hypertriglyceridemia. Fibrates are commonly used to treat severe hypertriglyceridemia. However, the effect of saroglitazar in patients with moderate to severe hypertriglyceridemia was not evaluated. We conducted a study to compare the efficacy and safety of saroglitazar (4 mg) with fenofibrate (160 mg) in patients with moderate to severe hypertriglyceridemia. This was a multicenter, randomized, double-blinded, double-dummy, active-control, and noninferiority trial in adult patients with fasting triglyceride (TG) levels of 500–1,500 mg/dl. The patients were randomized in a 1:1 ratio to receive daily dose of saroglitazar or fenofibrate for 12 weeks. The primary efficacy end point was the percent change in TG levels at week 12 relative to baseline. The study comprised of 41 patients in the saroglitazar group and 41 patients in the fenofibrate group. We found that the percent reduction from baseline in TG levels at week 12 was significantly higher in the saroglitazar group (least square mean = ?55.3%; SE = 4.9) compared with the fenofibrate group (least square mean = ?41.1%; SE = 4.9; P = 0.048). Overall, 37 treatment-emergent adverse events (AEs) were reported in 24 patients (saroglitazar: 13; fenofibrate: 11). No serious AEs were reported, and no patient discontinued the study because of AEs. We conclude that saroglitazar (4 mg) is noninferior to fenofibrate (160 mg) in reducing TG levels after 12 weeks of treatment, was safe, and well tolerated.     

Reductive Biotransformation of Benzaldehyde Derivatives by Baker's Yeast in Non-Conventional Media: Effect of Substrate Hydrophobicity on the Biocatalytic Reaction

The reduction of six derivatives of benzaldehyde, α,α,α-trifluorotolualdehyde, nitrobenzaldehyde, anisaldehyde, fluorobenzaldehyde, tolualdehyde, chlorobenzaldehyde, each of which was substituted in the ortho-, meta- and para-positions, was investigated in whole cell yeast biotransformations conducted in non-conventional media. Correlation between hydrophobic (π) and electronic (σ) parameters of the substituent of the substrate and biocatalytic activity in organic solvent media (hexane containing 2% v/v water) was evaluated. While catalytic activity in general decreased as the substituent hydrophobicity (π) increased, the trend was more pronounced for ortho- substituents compared to meta- and para-. When the electronic parameters (σ) of the meta- and para- substituents were correlated with the catalytic activity, the opposite was observed, namely the catalytic activity increased as the electronic parameter of the substituent increased. This observation was similar for meta- and para- substituents.

Preliminary studies on the relationships between solvent and substrate polarity on the one hand and catalytic activity on the other are also presented and discussed.