Frame Invariance and Scalability of Neural Operators for Partial Differential Equations

Partial differential equations (PDEs) play a dominant role in the mathematical modeling of many complex dynamical processes. Solving these PDEs often requires prohibitively high computational costs, especially when multiple evaluations must be made for different parameters or conditions. After training, neural operators can provide PDEs solutions significantly faster than traditional PDE solvers. In this work, invariance properties and computational complexity of two neural operators are examined for transport PDE of a scalar quantity. Neural operator based on graph kernel network (GKN) operates on graph-structured data to incorporate nonlocal dependencies. Here we propose a modified formulation of GKN to achieve frame invariance. Vector cloud neural network (VCNN) is an alternate neural operator with embedded frame invariance which operates on point cloud data. GKN-based neural operator demonstrates slightly better predictive performance compared to VCNN. However, GKN requires an excessively high computational cost that increases quadratically with the increasing number of discretized objects as compared to a linear increase for VCNN.     

Growth hormone secretagogue receptor signalling affects high‐fat intake independently of plasma levels of ghrelin and LEAP2, in a 4‐day binge eating model

The growth hormone secretagogue receptor (GHSR) is a G protein‐coupled receptor that is highly expressed in the central nervous system. GHSR acts as a receptor for ghrelin and for liver‐expressed antimicrobial peptide 2 (LEAP2), which blocks ghrelin‐evoked activity. GHSR also displays ligand‐independent activity, including a high constitutive activity that signals in the absence of ghrelin and is reduced by LEAP2. GHSR activity modulates a variety of food intake‐related behaviours, including binge eating. Previously, we reported that GHSR‐deficient mice daily and time‐limited exposed to a high‐fat (HF) diet display an attenuated binge‐like HF intake compared to wild‐type mice. In the present study, we aimed to determine whether ligand‐independent GHSR activity affects binge‐like HF intake in a 4‐day binge‐like eating protocol. We found that plasma levels of ghrelin and LEAP2 were not modified in mice exposed to this binge‐like eating protocol. Moreover, systemic administration of ghrelin or LEAP2 did not alter HF intake in our experimental conditions. Interestingly, we found that central administration of LEAP2 or K‐(D‐1‐Nal)‐FwLL‐NH₂, which are both blockers of constitutive GHSR activity, reduced binge‐like HF intake, whereas central administration of ghrelin or the ghrelin‐evoked GHSR activity blockers [D‐Lys3]‐GHRP‐6 and JMV2959 did not modify binge‐like HF intake. Taken together, current data indicate that GHSR activity in the brain affects binge‐like HF intake in mice independently of plasma levels of ghrelin and LEAP2.     

辨体-辨病-辨证诊疗模式在慢性病防治中的应用策略

依据中国防治慢性病中长期规划（2017-2025年），按照国医大师王琦教授倡导的"辨体-辨病-辨证诊疗模式"，提出慢性病"3+4+3"防治路向：面向三类人群（一般、高危、患病人群），朝向四种状态（无病、病前、病中、病后状态），指向三辨模式（辨体-辨病-辨证诊疗模式）。进而探讨其应用策略：对于一般人群无病状态——辨体养生，固本防病；对于高危人群病前状态——辨体干预，治本救萌；针对患病人群病中状态——"三辨"施治，标本兼顾；针对患病人群病后状态——辨体调理，固本防复。文中结合案例加以佐证，具有临床指导价值。     

Excitability of motor and sensory axons in multifocal motor neuropathy

ObjectiveTo assess excitability differences between motor and sensory axons of affected nerves in patients with multifocal motor neuropathy (MMN).MethodsWe performed motor and sensory excitability tests in affected median nerves of 20 MMN patients and in 20 age-matched normal subjects. CMAPs were recorded from the thenar and SNAPs from the 3rd digit. Clinical tests included assessment of muscle strength, two-point discrimination and joint position.ResultsAll MMN patients had weakness of the thenar muscle and normal sensory tests. Motor excitability testing in MMN showed an increased threshold for a 50% CMAP, increased rheobase, decreased stimulus-response slope, fanning-out of threshold electrotonus, decreased resting I/V slope, shortened refractory period, and more pronounced superexcitability. Sensory excitability testing in MMN revealed decreased accommodation half-time and S2-accommodation and less pronounced subexcitability. Mathematical modeling indicated increased Barrett-Barrett conductance for motor fibers and increase in internodal fast potassium conductance for sensory fibers.ConclusionsExcitability findings in MMN suggest myelin sheath or paranodal seal involvement in motor fibers and, possibly, paranodal detachment in sensory fibers.SignificanceExcitability properties of affected nerves in MMN differ between motor and sensory nerve fibers.     

替考拉宁在中国成人患者中的群体药动学研究

目的建立中国成年患者的替考拉宁(teicoplanin,TEC)群体药动学(population pharmacokinetics,PPK)模型,考察TEC药动学参数的影响因素。方法前瞻性收集139例革兰阳性球菌感染患者静脉注射TEC后的222份常规监测血药浓度和相关信息,采用一级消除的一室模型进行数据拟合,并应用非线性混合效应模型(nonlinear mixed effect model,NONMEM)程序建立PPK模型。采用Bootstrap、正态预测分布误差法(normalized predictive distribution error,NPDE)进行最终模型评价。利用蒙特卡洛模拟法对给药方案进行优化。结果确定了肌酐清除率(creatinine clearance,CLcr)、白蛋白(albumin,ALB)为影响TEC清除率的主要因素。最终模型为:CL(L·h^-1)=1.24×(CLcr/77)0.564×31/ALB;V(L)=69.2。验证表明,模型稳定、有效,且有较好的预测效能。对于不同ALB和CLcr的多数患者起始负荷剂量400 mg/q12h,iv,3次,维持剂量400~800 mg·d^-1的给药方案可达有效治疗谷浓度。严重感染者需调整负荷剂量至800 mg/q12h,iv,3次,维持剂量400~800 mg·d^-1的给药方案来确保血药浓度达到15 mg·L^-1以上。结论本实验报道了CLcr、ALB对TEC清除率有显著影响,所建模型对TEC在中国成人患者中实现个体化给药具有重要应用价值。     

辨体-辨病-辨证诊疗模式在慢性病防治中的应用策略

依据中国防治慢性病中长期规划(2017—2025年),按照国医大师王琦教授倡导的"辨体-辨病-辨证诊疗模式",提出慢性病"3+4+3"防治路向:面向三类人群(一般、高危、患病人群),朝向四种状态(无病、病前、病中、病后状态),指向三辨模式(辨体-辨病-辨证诊疗模式)。进而探讨其应用策略:对于一般人群无病状态——辨体养生,固本防病;对于高危人群病前状态——辨体干预,治本救萌;针对患病人群病中状态——"三辨"施治,标本兼顾;针对患病人群病后状态——辨体调理,固本防复。文中结合案例加以佐证,具有临床指导价值。     

内镜柔性器械腱鞘传动模型及实验研究

目的 建立内镜柔性器械腱鞘系统的推力传动模型，研究影响传动效率的关键因素。方法 建立腱鞘系统在器械推送作用下力和位移的传动模型并进行仿真计算；搭建腱鞘系统传动测试的实验平台以验证模型的准确性，研究传动速度、腱鞘直径比、弯曲半径等对传动效率的影响。结果 腱鞘传动过程中存在显著的非线性传递现象，传动模型仿真与实验结果基本符合；传动速度、腱鞘直径比、弯曲半径均对内镜柔性器械的推力传动有较大影响，对位移传动的影响相对小一些。结论 该模型可用于内镜柔性器械中腱鞘系统推力传动的计算，提供给医生器械工作末端的力反馈，以保证器械的安全操作和提高手术效果；在内镜柔性器械的精准控制中需要综合考虑传动速度、腱鞘传动比、弯曲半径等对运动传递的影响。     

The relationship between measurement of in vivo brain glutamate and markers of iron metabolism: A proton magnetic resonance spectroscopy study in healthy adults

Fundamental human studies which address associations between glutamate and iron metabolism are needed. Basic research reports associations between glutamate and iron metabolism. Human studies report sex differences in iron metabolism and glutamate concentrations, which suggest that these relationships may differ by sex. We hypothesised associations would be apparent between in vivo glutamate and peripheral markers of iron metabolism, and these associations would differ by sex. To test this, we recruited 40 healthy adults (20 men, 20 women) and measured (a) standard clinical biomarker concentrations for iron metabolism and (b) an in vivo proxy for glutamate concentration, glutamate with glutamine in relation to total creatine containing metabolites using proton magnetic resonance spectroscopy studies with a two‐dimensional chemical shift imaging slice, with voxels located in bilateral dorsolateral prefrontal cortices, anterior cingulate cortices and frontal white matter. Only the female group reported significant associations between peripheral markers of iron metabolism and Glx:tCr concentration: (a) right dorsolateral prefrontal cortex Glx:tCr associated positively with serum transferrin (r = .60, p = .006) and negatively with transferrin saturation (r = ?.62, p = .004) and (b) right frontal white matter Glx:tCr associated negatively with iron concentration (r = ?.59, p = .008) and transferrin saturation (r = ?.65, p = .002). Our results support associations between iron metabolism and our proxy for in vivo glutamate concentration (Glx:tCr). These associations were limited to women, suggesting a stronger regulatory control between iron and glutamate metabolism. These associations support additional fundamental research into the molecular mechanisms of this regulatory control.     

The Obesity Paradox: Body Mass Index Complication Rates Vary by Gender and Age Among Primary Total Hip Arthroplasty Patients

BackgroundHigh body mass index (BMI) has long been recognized as a risk factor for postoperative complication among total hip arthroplasty (THA) patients. However, recent studies showed mixed results in the effect of high BMI on surgical outcomes. Our study is to examine the association of preoperative BMI with complication incidence, stratified by age and gender.MethodsWe queried the American College of Surgeons National Surgical Quality Improvement Project database to identify patients who underwent elective primary THA between 2012 and 2016. We examined the associations between BMI as a continuous and a categorical variable and risk of 30-day postoperative complication, using 2 multiple polynomial logistic regression models. We also created predictive plots to graphically assess the relationship between BMI and complication by gender and age.ResultsIn total, 117,567 eligible patients were included in the analyses. The predictive probability of all-type postoperative complications showed a U-shaped relationship with continuous BMI values (range 10-65 kg/m²). The lowest complication risks occurred in patients with BMI between 35 and 40. Females had higher complication rate than males across all BMI values. This U-shaped relationship was only observed among patients younger than 60 years old, while the associations appear to be inversely linear among patients aged greater than 60 years.ConclusionOur results suggest that the current theory of a linear association between BMI and complication risk may not apply to elective primary THA. Strict BMI cutoffs may not minimize risk, especially among patients over 60 years old. Orthopedic surgeons should factor in patient-specific variables of age and gender when determining acceptable surgical risk given a particular BMI value.     

Nonlinear elasticity of biological basement membrane revealed by rapid inflation and deflation

Basement membrane (BM) is a thin layer of extracellular matrix that surrounds most animal tissues, serving as a physical barrier while allowing nutrient exchange. Although they have important roles in tissue structural integrity, physical properties of BMs remain largely uncharacterized, which limits our understanding of their mechanical functions. Here, we perform pressure-controlled inflation and deflation to directly measure the nonlinear mechanics of BMs in situ. We show that the BMs behave as a permeable, hyperelastic material whose mechanical properties and permeability can be measured in a model-independent manner. Furthermore, we find that BMs exhibit a remarkable nonlinear stiffening behavior, in contrast to the reconstituted Matrigel. This nonlinear stiffening behavior helps the BMs to avoid the snap-through instability (or structural softening) widely observed during the inflation of most elastomeric balloons and thus maintain sufficient confining stress to the enclosed tissues during their growth.

Basement membrane (BM) is a thin layer of fibrous matrix separating cells from the connecting tissues, which functions as a physical barrier and widely exists across multicellular organisms (1). The BM is typically composed of laminins, collagen IV, nidogens, and proteoglycans; laminin and collagen IV are the major components that constitute networks forming the structure of the BM, and nidogen and proteoglycans are associated with the laminin and collagen IV networks. As a physical barrier, the structural and mechanical properties of BM are important in the organization and morphogenesis of tissues and organs as well as in the maintenance of adult functions (2); abnormal BM has been associated with a variety of diseases such as cancer (3). For example, in metastasis, cancer cells must invade through BMs to escape from the primary tumor—a process that causes 90% of cancer-related death (4). Indeed, breaks in BMs can be observed in malignant tumors (5). Thus, mechanical properties of the BM are considered to play important roles in regulating cancer cell invasion (6, 7). Furthermore, as a physical barrier differentiating different parts of tissues, BMs are required to be permeable to small molecules to allow exchange of water and nutrients; the permeability of BM is thus one of the essential kinetic parameters regulating biomolecule exchange and activities of internal cells (8, 9). Given the importance of BMs as a semipermeable barrier maintaining tissue structural integrity, however, their permeability and mechanical properties remain largely unknown, mainly due to the lack of direct measurement methods, especially in situ. This limits our understanding of the physical role of BMs in various physiological and pathological processes such as tumor development and angiogenesis.Determining the mechanical properties of intact BMs in situ is challenging because of their irregular shape, small thickness, and tight connection to the cells inside. Due to these limitations, conventional mechanical tests such as tensile, compression, and bending tests are difficult to be applied to characterize the mechanical behavior of the BM in situ. Instead, previous measurements had been carried out on fragmented BMs isolated from various tissues (e.g., via atomic force microscopy [AFM] indentation) and found that the BM stiffness ranges from ∼kPa to ∼MPa (10–17). In addition, a constitutive relationship is required to extract the material parameters such as elastic modulus and permeability from these experimental measurements. However, like most biological tissues, a reliable constitutive model for the BM is not yet available, causing additional difficulties in obtaining its mechanical parameters from most traditional experiments.In this work, we demonstrate an in situ method to simultaneously measure both the elastic properties and permeability of intact BM in breast cancer spheroid by recording the deflation process of an inflated BM filled with phosphate buffered saline (PBS) by microinjection without requiring complex sample preparation and post-data processing. During the deflation of the BM, its elastic retraction generates a pressure difference to drive the liquid flow through the membrane; the liquid flux can be calculated from the reduction of the intact BM diameter. With the BM thickness measured by transmission electron microscopy (TEM), we can determine the shear modulus, permeability, and diffusivity of the intact BM. Moreover, we find from our measurements that the elasticity of BM is highly nonlinear with a strong strain-stiffening effect. Furthermore, we discuss the possible impact of the strain-stiffening effects of BM on its functions.