Pharmacoepidemiologic study of association between apparent treatment resistant hypertension, cardiovascular disease and interaction effect by sex and age

BACKGROUND A limited number of studies have been conducted to test the magnitudes of the association between apparent treatment resistant hypertension(aTRH)and risk of cardiovascular disease(CVD).AIM To investigate the association between aTRH and risk of CVD and examine whether sex and age modify this association.METHODS We applied an observational analysis study design using data from the United States Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT).ALLHAT recruited participants(n=25516)from 625 primary care settings throughout the United States,Canada,Puerto Rico,and United States Virgin Islands,aged 55 and older with hypertension and at least one additional risk factor for heart disease.aTRH was assessed from the year 2 visit.CVD event was defined as one of the following from the year 2 follow-up visit:Fatal or non-fatal myocardial infarction,coronary revascularization,angina,stroke,heart failure,or peripheral artery disease.Cox proportional hazards regression was used to examine the effect of aTRH on CVD risk.Potential modifications of sex and age on this association were examined on the multiplicative scale by interaction term and additive scale by joint effects and relative excess risk for interaction.RESULTS Of the total study participants(n=25516),5030 experienced a CVD event during a mean of 4.7 years follow-up.aTRH was associated with a 30%increase in risk of CVD compared to non-aTRH[hazards ratio(HR)=1.3,95%CI:1.19-1.42].Sex and age modified this relationship on both multiplicative and additive scales independently.Stratified by sex,aTRH was associated with a 64%increase in risk of CVD(HR=1.64,95%CI:1.43–1.88)in women,and a 13%increase in risk of CVD(HR=1.13,95%CI:1.01–1.27)in men.Stratified by age,aTRH had a stronger impact on the risk of CVD in participants aged<65(HR=1.53,95%CI:1.32–1.77)than it did in those aged≥65(HR=1.18,95%CI:1.05–1.32).Significant two-way interactions of sex and aTRH,and age and aTRH on risk of CVD were observed(P<0.05).The observed joint effect of aTRH and ages≥65 years(HR=1.85,95%CI:1.22–2.48)in males was less than what was expected for both additive and multiplicative models(HR=4.10,95%CI:3.63–4.57 and 4.88,95%CI:3.66–6.31),although three-way interaction of sex,age,and aTRH on the risk of CVD and coronary heart disease did not reach a statistical significance(P>0.05).CONCLUSION aTRH was significantly associated with an increased risk of CVD and this association was modified by both sex and age.Further studies are warranted to test these mechanisms.

Hydrodynamic resistance of pore–throat structures and its effect on shale oil apparent permeability

Oil transport is greatly affected by heterogeneous pore–throat structures present in shale.It is therefore very important to accurately characterize pore–throat structures.Additionally,it remains unclear how pore–throat structures affect oil transport capacity.In this paper,using finite element(FE)simulation and mathematical modeling,we calculated the hydrodynamic resistance for four pore–throat structure.In addition,the influence of pore throat structure on shale oil permeability is analyzed.According to the results,the hydrodynamic resistance of different pore throat structures can vary by 300%.The contribution of additional resistance caused by streamline bending is also in excess of 40%,even without slip length.Fur-thermore,Pore–throat structures can affect apparent permeability by more than 60%on the REV scale,and this influence increases with heterogeneity of pore size distribution,organic matter content,and organic matter number.Clearly,modeling shale oil flow requires consideration of porous–throat structure and additional resistance,otherwise oil recovery and flow capacity may be overestimated.

Calculation of all-time apparent resistivity of large loop transient electromagnetic method with very fast simulated annealing

In large loop transient electromagnetic method(TEM),the late time apparent resistivity formula cannot truly reflect the geoelectric model,thus it needs to define the all-time apparent resistivity with the position information of measuring point.Utilizing very fast simulated annealing(VFSA) to fit the theoretical electromagnetic force(EMF) and measured EMF could obtain the all-time apparent resistivity of the measuring points in rectangular transmitting loop.The selective cope of initial model of VFSA could be confirmed by taking the late time apparent resistivity of transient electromagnetic method as the prior information.For verifying the correctness,the all-time apparent resistivities of the geoelectric models were calculated by VFSA and dichotomy,respectively.The results indicate that the relative differences of apparent resistivities calculated by these two methods are within 3%.The change of measuring point position has little influence on the tracing pattern of all-time apparent resistivity.The first branch of the curve of all-time apparent resistivity is close to the resistivity of the first layer medium and the last branch is close to the resistivity of the last layer medium,which proves the correctness of the arithmetics proposed.

已上市K-Ras^(G12C)靶向药物的研发及其耐药性的最新研究进展

在多种类型癌症中KRAS发生突变,KRAS是人类癌症中最常见的突变癌基因。KRAS突变阳性癌症的发病人数一直呈上升趋势。由于KRAS缺乏经典的药物结合位点,导致靶向KRAS的抑制剂药物研发一直以来面临着巨大挑战性。随着K-Ras^(G12C)抑制剂的出现,KRAS不可成药的神话已被攻破。目前全球范围内上市的两种K-Ras^(G12C)抑制剂是AMG-510和MRTX849,仍然面临着巨大的用药需求。了解成功上市药物有利于更好地研发新药。本文针对两款上市K-Ras^(G12C)抑制剂的研究以及该靶点面临的耐药机制研究进行总结和讨论,并总结了K-Ras^(G12C)抑制剂与其他治疗方法联合治疗克服耐药性的方法。

Electric potential and apparent resistivity in rocks containing non-uniformly distributed cracks

In this paper, the formula of electric field distribution and ground apparent resistivity of high resistance rock medium containing low resistance crack are deduced and simulated. The result shows that interstitial parameters, such as buried depth, scale, strike, and real resistivity, etc, have influence on observation and computing result of apparent resistivity. This study provided a useful foundation for earthquake prediction using apparent resistivity method.

Glass transition kinetics of La_(55)Al_(25)Ni_(10)Cu_(10) bulk metallic glass by electrical resistivity measurement

The glass transition behavior of La55A125-Ni10CU10 bulk metallic glass was investigated using elec-trical resistivity and differential-scanning calorimetry measurements. There are good agreements of the onset temperature （Tg-onset） and the end temperature （Tg-end） of the glass transition between the DSC curve and tempera-ture dependent electrical resistivity （TER） curve in the same heating rate. Kinetics of the glass transition is studied with the electrical resistivity data. The apparent activation energy of the glass transition （△Eg） is found to be 306.4 kJ.mol^-1. Fragility parameter D^＊ and VFT temper-ature To are 9.8 and 324.9 K, respectively.

The Effects of Negative Values of Apparent Resistivity in TEM Surveys

The calculation of apparent resistivity in electrical methods is relatively simple and consolidated in the literature. Furthermore, in the case of DC methods, the apparent resistivity values are for the most part, intuitive and enable an initial interpretation of the results. On the other hand, in TEM method the apparent resistivity values are not very intuitive and interpretation based only on the apparent resistivity values cannot be done reasonably. In this way, this paper presents a discussion about the reasons and effects of the negatives values of apparent resistivity in TEM soundings. The main objective of this paper is to clarify the meanings of these negatives values and the possible effects in TEM inversion.

Apparent resistivity of azimuthal anisotropy layered media

The electric field, equations of boundary conditions and calculation formula of apparent resistivity are derived for the azimuthal anisotropy layered media with the DC method based on the anisotropic Ohm's law. Taking the Schlumberger symmetric system as an example and using the recurrence formula of nuclear function, the paper theoretically simulates a model of four layers with the same anisotropy coefficient for each layer. The deep sounding curves of resistivity and the pattern of contours are obtained for the model. The results show that the theoretical formula is correct, and the deep sounding curves not only exhibit the difference of resistivity among layers but also indicate the anisotropy characteristics of layers.

A new approach for calculating the apparent resistivity tensor

The apparent resistivity tensor pB is an electromagnetic transfer function,which can be used to analyze and explain the underground electrical structure.Conventional method for obtaining the parameter requires controlled sources and can be easy to be disturbed by cultural noises.We present a new method for calculating the apparent resistivity tensor,the current density is first obtained by measuring the curl operator of the magnetic field on the Earth's surface.This approach is independent of the assumption of a plane wave,and may be used irrespective of source types and field areas.We derived the analytical expressions of the apparent resistivity tensor based on synthetic horizontally layered models with a vertical magnetic dipole source.We then calculate the responses of Pb through numerical modeling examples using both natural sources and controlled sources.Compared to traditional apparent resistivity definitions,our apparent resistivity tensor has the same amplitude value but with more sensitive phases in the far zone,and shows few distortions in the transition zone.And in the near-field zone,it is closer to the resistivity distribution under the ground.The simulation results have demonstrated the effectiveness of the proposed method for calculating the apparent resistivity tensor.

Inverse Spline Interpolation for All-time Resistivity of Central-Loop TEM

A convenient numerical calculation method (inverse spline interpolation) for all-time apparent resistivity intransient electromagnetic method (TEM) is proposed in this paper. Characteristic of early and late normalized inductiveelectromotive force was investigated. According to the turning point, the transient process is divided into the earlyphase, the turning point, and the late phase. Afterwards, apparent resistivity is obtained through inverse spline interpo-lation in the early and the late phases, respectively. Finally, the resistivities of the early-time and the late-time wereconnected together by the turning point. The result shows that the inverse spline method is feasible and the method alsolays a foundation for initial model construction in the TEM automatic inversion.

曲美替尼对K-ras突变直肠癌细胞恶性行为、耐药蛋白及巨噬细胞极化的作用机制的研究

目的探讨曲美替尼对K-ras突变直肠癌细胞恶性行为、耐药蛋白及巨噬细胞极化的作用机制。方法取K-ras突变直肠癌细胞HCT116,将其随机分为HCT116组(HC组)、西妥昔单抗+HCT116组(CE组)、低剂量曲美替尼+HCT116组(LT组)、中剂量曲美替尼+HCT116组(MT组)、高剂量曲美替尼+HCT116组(HT组),Transwell实验及划痕实验检测细胞恶性行为,MTT法检测药物敏感性,RT-PCR法检测耐药蛋白表达,免疫印迹法检测巨噬细胞极化相关指标。结果与HC组相比,其余四组细胞侵袭、迁移及GST-π、P-gp、TopoⅡ、CD163表达显著降低(P<0.05),CD40蛋白表达显著升高(P<0.05);与LT组相比,MT组、HT组细胞侵袭、迁移及GST-π、P-gp、TopoⅡ、CD163表达显著降低(P<0.05),CD40蛋白表达显著升高(P<0.05),且HT组比MT组变化明显(P<0.05);HCT116细胞对西妥昔单抗与曲美替尼均敏感,但与西妥昔单抗相比,曲美替尼的IC_(50)明显更低(P<0.05)。结论曲美替尼对K-ras突变直肠癌细胞具有显著疗效,可显著改善其恶性行为,抑制耐药蛋白表达,抑制巨噬细胞M2极化。

Analysis on Apparent Resistivity Variations of Garzê Station before the 2013 Lushan M_S 7. 0 Earthquake

A trend increase in apparent resistivity has been observed in the N30°E monitoring direction at Garzê Seismic Station since July 2011. This increase trend in geo-electric resistivity has been observed in the N60°W direction since 2012. During the period of the increase,the national highway No. 317 was expanded in the monitoring area,so the potential electrodes in the N30° E direction had to be moved 10 m towards the current electrodes. We interpreted the electric sounding data of Garzê Seismic Station with a horizontally layered model. Analysis based on this model showed that the shift of potential electrodes can cause a 4 Ω·m rise to the measurements in the N30°E direction. Therefore,apparent resistivity of the two directions increased in the same time in 2012 after offsetting the effects from electrodes shift. Sensitivity coefficients of the two observation directions were also obtained using the model. Sensitivity coefficients of both directions were negative for the shallow layers,which can well explain the unexpected annual variations of GarzêSeismic Station. In order to quantitatively analyze the effects from the expansion of the national highway on the observation,we constructed a finite element model based on the electrical structure. Analysis results also suggested that the expansion of the national highway could only cause a 0. 15 Ω·m decrease in the N60° W monitoring direction and0. 1Ω·m increase in the N30° E direction. Additionally,the valley values of annual variation of 2013 were distinctively higher than that of other years since 2008,meaning that there was an abnormal rise in apparent resistivity in the two observation directions at Garzê Seismic Station before the Lushan earthquake. However,the rise was contrary to the decline variation before the Wenchuan earthquake. Therefore, it is still unsure whether or not the rise variation is related to the Lushan earthquake.

RAS相关通路介导的结直肠癌药物联合治疗的应用

RAS相关信号通路在结直肠癌的发生、发展中起着重要作用,与该类肿瘤细胞的增殖、转移、凋亡密切相关。目前,包括靶向药物、化疗药物的单药治疗对结直肠癌的临床获益并不理想。近年来,在临床试验和临床前研究中RAS相关信号通路的抑制剂与其他药物的联合应用取得了良好效果,其中EGFR抑制剂、VEGF抑制剂、RAS直接抑制剂、MEK抑制剂和RAF抑制剂的表现尤为突出。本文就RAS相关信号通路与结直肠癌的作用关系、临床试验和临床前研究中的联合用药策略以及组合用药的耐药机制研究进行系统性综述,以期为未来临床多药治疗策略奠定基础。

miR-7a-5p负调控Rac1表达参与HepG2细胞胰岛素抵抗

目的:探讨软脂酸诱导胰岛素抵抗的HepG2细胞中微小RNA-7a-5p(microRNA-7a-5p,miR-7a-5p)是否通过调控Ras相关C3肉毒毒素底物1(Ras-related C3 botulinum toxin substrate 1,Rac1)表达参与细胞胰岛素抵抗。方法:应用生物信息学分析预测其下游靶分子,构建含Rac13'端非翻译区的野生型及突变型hsa-Rac1萤光素酶报告质粒,与miR-7a-5p表达慢病毒或对照空载慢病毒共转染293T细胞,检测萤光素酶活性。HepG2细胞分为软脂酸诱导的胰岛素抵抗组和正常对照组,RT-qPCR分析两组细胞miR-RNA-7a-5p的表达,Western blot分析下游靶分子蛋白的表达。HepG2细胞分为干扰慢病毒转染组和对照慢病毒转染组,转染之后,软脂酸诱导两组细胞胰岛素抵抗,分析两组HepG2细胞中脂质堆积及葡萄糖消耗情况。结果:生物信息学预测Rac1为miR-7a-5p下游分子。野生型hsa-Rac1萤光素酶报告质粒与miR-7a-5p表达慢病毒共转染后,萤光素酶较对照组显著降低(P<0.05)。胰岛素抵抗的HepG2与对照细胞组相比,miR-7a-5p表达显著下调(P<0.05),Rac1蛋白表达显著上调(P<0.05)。较对照相比,Rac1 mRNA的表达抑制增加了胰岛素抵抗HepG2细胞的葡萄糖消耗(P<0.05),降低了胞质内脂质堆积(P<0.05)。结论:miR-7a-5p的一个潜在靶点是Rac1。miR-7a-5p通过负调节Rac1表达参与软脂酸诱导的HepG2细胞胰岛素抵抗。

断层虚位错模式揭示的2022年1月8日青海门源M_(S)6.9地震前的地电阻率变化

选取2022年1月8日青海门源M_(S)6.9地震震中400 km范围内四个地电阻率观测台站的观测精度高、具有稳态年变、震前无显著干扰的地电阻率ρ_(s)观测数据,结合ERA5同化数据集中的多层土壤温度和土壤水分含量,在利用多项式拟合获取各台站(或测道)地电阻率正常年动态的基础上,分析了门源地震前地电阻率的异常变化。结果显示:金银滩台EW测道、武威台NS测道和山丹台EW测道、N45°W测道震前存在超阈值的异常变化,并呈现各向异性特征。基于断层虚位错模式分析了地电阻率异常变化与孕震过程之间的联系,结果表明:金银滩台震前处于压缩区并受到NNE方向的挤压,与主压应变近似正交的EW测道于震前10个月出现负异常;同样位于压缩区的武威台,受到了ENE向的挤压,NS测道的地电阻率在孕震早期(震前13个月)以负异常为主,孕震中晚期(震前3个月)出现了正异常;山丹台,位于膨胀区,受到近似NS向的拉张,与主张应变平行的NS测道未发现异常,但EW测道震前一年地电阻率出现正异常,N45°W测道的地电阻率也在震前半年左右出现超阈值并呈正异常。此外,金银滩台、山丹台和武威台距离门源地震震中的距离分别为92 km,113 km和139 km,相应的地电阻率异常最大变化幅值分别为−3.0σ,2.2σ和−2.1σ。此外,门源地震前地电阻率异常变化的时空特征与岩石实验结果及理论模型一致,也符合震源区应力应变积累程度较高、向外围方向逐渐衰减的分布特征。由此推断,2022年门源M_(S)6.9地震前地电阻率的时空变化可能与区域介质变形及应力变化有关。

综合物探方法在碎屑岩地区找水中的应用——以云南宣威大路边村为例

为探索地球物理方法在碎屑地区找水应用的有效性,文章以云南宣威大路边村为研究对象,选取高密度电阻率法、联合剖面法、音频大地电磁法对碎屑岩层进行找水研究。结果表明:三叠系上统飞仙关组(T1f)碎屑岩富水性中等,含水性较均匀;受地面场地狭窄限制,高密度电法及联合剖面法测线长度有限,探测深度较浅,受碎屑岩电阻率小的影响,其找水应用效果不佳,在可探测的深度范围内较难识别基岩裂隙等找水有效异常,需结合其他物探方法甄别异常;音频大地电磁法找水应用效果相对较好,具有较高的横向分辨率,可有效识别碎屑岩中的断裂破碎带及构造裂隙带,表现为相对低阻异常特征;视电阻率单支测深曲线能有效分辨不同深度的岩土层结构,具有较高的纵向分辨率,对裂隙破碎带有较好指示意义。在地面场地较为狭窄的碎屑岩地区开展找水工作,音频大地电磁法结合视电阻单支测深曲线能取得较好效果,以音频大地电磁法确定碎屑岩地区中的裂隙发育带位置,以视电阻单支测深曲线确定裂隙发育带的深度。

成像测井解释评价方法及其地质应用

为了系统梳理成像测井解释评价存在的问题并拓展其在地质与工程领域中的应用范围,首先回顾了成像测井采集系列的发展历程及资料处理步骤与解释流程,然后提出了“四个层次”为约束(图像直接解释、常规测井约束、岩心约束以及地质理论约束)的成像测井精细解释方法。成像测井相模式可划分出具有地质意义的块状、条带状、线状、斑状、杂乱、递变模式和对称沟槽状模式七大类。成像测井可用于岩心定向、地层产状获取、裂缝评价、断层性质分析、地应力方向判别、沉积特征拾取以及古水流方向判别等领域中。通过阿尔奇公式反算,成像测井数据矩阵可以生成孔隙度频谱以及视地层水电阻率谱,并可分别运用于储层质量评价以及流体性质识别。成像测井切片处理可凸显沉积纹层等信息,可实现细粒沉积岩纹层结构拾取及非常规油气储层高分辨率测井评价。Poro Tex图像结构分析技术可用于拾取孔洞缝等储集空间特征,并定量计算孔隙度和裂缝孔隙度等参数,因此被广泛运用至非均质性较强的碳酸盐岩储层测井综合评价工作中。研究成果可规避成像测井解释中的误区同时可扩展成像测井应用领域。

基于深度学习SSD算法的高密度电法智能解译方法技术研究

高密度电法在探测灰岩区地下溶洞病害体方面得到广泛应用,但高密度电法反演结果依赖于初始模型,存在多解性,地质解译容易受专业人员主观因素影响。为此,本文从具有唯一性的视电阻率数据出发,研究了基于深度学习的SSD(Single Shot Multi-box Detector)目标检测算法的视电阻率异常智能解译方法技术。针对岩溶地质病害,设计了不同填充类型、形状、规模、数量的溶洞电性异常模型,利用Res2dmod软件进行视电阻率正演计算,构建了包含1400个样本的高密度电法视电阻率智能解译学习样本库(样本和标签)。基于TensorFlow框架,建立了基于深度学习SSD算法的高密度电法视电阻率异常智能解译方法技术,使用学习样本库训练网络权值,训练结束后对高密电法温纳装置视电阻率异常进行智能解译,单个视电阻率剖面异常智能解译耗时不到1 s,各类目标(填充型溶洞、未填充型溶洞)平均准确率为90.68%。研究结果表明:基于SSD算法的高密度电法视电阻率异常智能解译技术可显著提高高密度电法视电阻率解译效率,避免专业人员主观因素影响。

大定源回线装置瞬变电磁法在煤矿采空区探测中的应用

该文通过研究大定源回线装置瞬变电磁法在煤矿采空区探测中的应用,旨在提高煤矿采空区探测的效率和准确性。深入探讨大定源回线装置瞬变电磁法的原理和工作机制。在此基础上,设计并实施适用于煤矿采空区的探测方案,并通过试验进行验证。结果表明,大定源回线装置瞬变电磁法在煤矿采空区探测中取得显著的效果。大定源回线装置瞬变电磁法具有高效、准确、可靠的特点,能够快速识别采空区位置,为后续生产建设提供保障,同时也为其他煤矿采空区勘察提供参考。

基于等值反磁通装置频率域电磁法研究

人工源近区频率域电磁法具有轻便、分辨率高及抗干扰能力强等优点,但提取地质体二次场响应难题困扰了该方法推广应用。基于等值反磁通原理提取二次场响应,首先,推导出了基于等值反磁通原理的频率域近场垂直磁场响应的表达式;然后,采用层状介质与均匀半空间介质的垂向磁场同相分量的比值定义视电阻率,并计算了典型层状介质垂直磁场的频率响应;最后,通过试验对比时间域与频率域方法对浅埋藏铝板的异常响应。研究结果表明:基于等值反磁通原理能够有效提取近场频率域二次场信号,近场垂向磁场的同相分量与大地电导率的二次方成正比;垂向磁场同相分量的比值定义视电阻率能够清晰反映A型、Q型、H型及K型地电断面的特征。