Design,synthesis and biological evaluation of HIV-1 protease inhibitors with morpholine derivatives as P2 ligands in combination with cyclopropyl as P1′ ligand

A series of novel HIV-1 protease inhibitors has been designed and synthesized, which contained morpholine derivatives as the P2 ligands and hydrophobic cyclopropyl as the P1′ ligand at the meantime in this study, with the aim of improving the interactions between the active sites of HIV-1 protease and the inhibitors. Twenty-eight compounds were synthesized and assessed, among which inhibitors m18 and m1 exhibited excellent inhibitory effect on the activity of HIV-1 protease with IC₅₀ value of 47 nM and 53 nM, respectively. The molecular modeling of m1 revealed possible hydrogen bondings or van der Waals between the inhibitor and the protease, worthy of in-depth study.     

基于景观地形的小流域单元减灾调控评价研究

近年来,中国诸多大中城市内涝灾害频发。武汉市作为城市内涝频发的典型城市,其建成区地表高度（20.0~24.0 m）大多低于外江常年所处的洪水位高度（23.9 m）,在区域性暴雨条件下,极易引发内涝灾害。武汉由于其内涝典型性,2013年被列为全国31个重点防洪城市之一,2015年被列入首批海绵城市试点城市之一。从城市内涝发生机理出发,以水文角度的小流域单元作为内涝风险区划的基本单元,利用小流域单元分析武汉市景观地形要素（地表高程、地表起伏度、地表粗糙度）与城市内涝积水密度的相关性及其影响程度,量算统计出小流域单元的内涝风险等级。基于此,提出武汉市小流域单元减灾地形调控评价。以武汉市作为城市内涝问题的研究案例,以期为武汉市内涝缓解提供新的思考路径,具有典型性和必要性。     

腰大池引流联合法舒地尔治疗动脉瘤性蛛网膜下腔出血的疗效及对血清sICAM-1、FABP、MCP-1水平和脑积水形成的影响

目的:分析腰大池引流联合法舒地尔治疗动脉瘤性蛛网膜下腔出血的疗效及对血清可溶性细胞间黏附分子-1(sICAM-1)、脂肪酸结合蛋白质(FABP)、核细胞趋化蛋白(MCP-1)水平和脑积水形成的影响。方法:选择我院2016年3月~2018年3月收治的112例动脉瘤性蛛网膜下腔出血患者,按随机数字表法分为对照组(n=48)和研究组(n=64)。对照组采用腰大池引流治疗,研究组基于对照组联合法舒地尔治疗。比较两组临床疗效,治疗前后血清sICAM-1、FABP、MCP-1水平、血压、大脑中动脉血流参数水平和神经功能的变化,脑积水发生率及不良反应发生情况。结果:治疗后,研究组总有效率显著高于对照组(89.02%vs.72.91%,P<0.05)。两组治疗后血清sICAM-1、FABP、MCP-1、血压、大脑中动脉血流参数水平和神经功能缺损评分量表(NIHSS)均较治疗前下降,格拉斯哥昏迷评分(GCS)均较治疗前上升,研究组以上指标较对照组改变更明显(均P<0.05)。两组不良反应发生情况比较差异无统计学意义(P>0.05)。结论:腰大池引流联合法舒地尔治疗动脉瘤性蛛网膜下腔出血的疗效明显优于单用腰大池引流治疗,其可显著降低血清sICAM-1、FABP、MCP-1水平,降低脑积水发生率,改善患者预后。     

伤椎置钉联合短节段内固定与单纯短节段固定治疗胸腰椎爆裂性骨折的比较研究

目的:比较伤椎置钉联合短节段内固定与单纯短节段固定治疗胸腰椎爆裂性骨折的临床疗效、固定效果及其对患者炎症反应和脊髓损伤的影响。方法:选取2014年3月到2016年12月期间我院收治的胸腰椎爆裂性骨折患者94例,根据手术方法的不同将患者分为伤椎置钉组(40例)和短节段内固定组(44例)。短节段内固定组患者采用单纯后路短节段椎弓根螺钉内固定进行治疗,伤椎置钉组采用伤椎置钉联合后路短节段椎弓根螺钉内固定进行治疗。比较两组患者的手术时间、术中出血量、住院时间、伤椎前沿高度比、Cobb’s角、伤椎椎体楔形变角、视觉模拟评分(VAS)和Oswestry功能障碍指数(ODI),炎性因子指标、脊髓损伤指标及术后并发症。结果:伤椎置钉组的手术时间长于短节段内固定组(P<0.05),术后6个月、术后12个月伤椎置钉组的伤椎前沿高度比明显高于短节段内固定组,Cobb’s角、伤椎椎体楔形变角明显低于短节段内固定组(P<0.05),术前、术后1周、术后6个月、术后12个月两组患者的VAS评分和ODI比较差异无统计学意义(P>0.05),术后3 d两组患者血清中IL-1β、IL-6、IL-8、TNF-α和pNF-H、NSE、S100β、GFAP水平比较差异均无统计学意义(P>0.05)。随访期间两组患者均未出现严重并发症。结论:伤椎置钉联合后路短节段椎弓根螺钉内固定可有效改善胸腰椎爆裂性骨折患者的椎体高度、Cobb’s角和伤椎椎体楔形变角,并且不会增加脊髓损伤和机体的炎症反应。     

初始小剂量甲巯咪唑对Graves病甲亢患者甲状腺功能和Visfatin、TNF-α、IL-6水平的影响

目的:分析初始小剂量甲巯咪唑治疗对Graves病甲状腺功能亢进症(甲亢)患者甲状腺功能和内脂素(Visfatin)、肿瘤坏死因子-α(Tumor necrosis factor-alpha, TNF-α)、白介素-6(Interleukin-6, IL-6)水平的影响。方法:选择我院2017年1月-2018年6月诊治的125例Graves病甲亢患者,根据入院编号随机数字表法分为两组。对照组63例给予甲硫咪唑15 mg/次,2次/d;研究组62例给予甲硫咪唑10 mg/次,2次/d,两组均连续治疗6个月,对比两组治疗总有效率、治疗前后甲状腺功能和血清Visfatin、TNF-α、IL-6水平的变化。结果:治疗后,研究组的治疗总有效率显著高于对照组(90.32%vs. 77.78%,P<0.05);两组患者的甲状腺功能指标血清游离三碘甲状腺原氨酸(Free triiodothyronine, FT3)、血清游离甲状腺素(FT4)水平均显著降低、敏感促甲状腺激素(Sensitive thyroid stimulating hormone, s TSH)水平均显著升高,且研究组以上指标变化较对照组更显著(P<0.05);两组患者的血清Visfatin、TNF-α、IL-6水平均较治疗前显著下降,且研究组以上指标均显著低于对照组(P<0.05)。结论:初始小剂量(10 mg/次)甲巯咪唑治疗Graves病甲亢的疗效显著优于甲硫咪唑15 mg/次治疗,可能与其有效改善患者的甲状腺功能和血清Visfatin、TNF-α、IL-6等炎症因子水平有关。     

解毒颗粒联合阿帕替尼治疗中晚期肝癌的回顾性研究

目的:评估解毒颗粒联合阿帕替尼治疗中晚期肝癌患者的疗效及其不良反应。方法:对2018年12月至2019年6月收治于海军军医大学第一附属医院口服解毒颗粒联合阿帕替尼的27例肝癌患者的临床资料进行回顾性研究。无法切除或复发的中晚期肝癌患者被纳入研究,给予解毒颗粒联合阿帕替尼治疗直至疾病进展或不可耐受其毒副反应,随访观察治疗效果、生存期、炎症因子指标及不良反应。结果:治疗后完全缓解(CR)4例(14.81%),部分缓解(PR)4例(14.81%),稳定(SD)8例(29.63%),进展(PD)11名患者(40.74%),疾病控制率(DCR)为59.26%(16/27),客观缓解率(ORR)为29.63%(8/27)。中位无进展生存期(PFS)为3.630个月,中位总生存期(OS)为13.667个月。常见的不良反应是高血压59.26%(16/27)、蛋白尿59.26%(16/27)、腹泻74.07%(20/27)以及手足综合征62.96%(17/27)。治疗后炎症因子指标中C反应蛋白、白介素2水平下降,存在统计学差异(P0.05)。结论:解毒颗粒联合阿帕替尼治疗中晚期肝癌安全、有效,可降低患者炎症反应,不良反应可耐受。     

不同分级及转归脓毒症患者血清PCT、D-D、CRP及血小板相关参数检测的临床意义

目的:探讨不同分级及转归脓毒症患者的血清降钙素原(PCT)、D-二聚体(D-D)、C反应蛋白(CRP)及血小板相关参数检测的临床意义。方法:回顾性分析2015年3月至2018年8月期间中国人民解放军西部战区总医院收治的92例脓毒症患者的临床资料,分析不同分级及转归脓毒症患者的血清中PCT、D-D和CRP水平、急性病生理与慢性健康评价系统Ⅱ(APACHEⅡ)评分及血小板相关参数[血小板计数(PLT)、血小板平均容积(MPV)、血小板分布宽度(PDW)、大型血小板比率(P-LCR)],并分析脓毒症患者PCT、D-D、CRP水平以及血小板相关参数与APACHEⅡ评分的相关性。结果:全身炎症反应综合征组、轻度脓毒症组、严重脓毒症组、脓毒性休克组血清PCT、D-D和CRP水平、MPV、PDW、P-LCR、APACHEⅡ评分逐渐升高(P0.05),PLT逐渐降低(P0.05)。存活组患者血清PCT、D-D、CRP水平、MPV、PDW、P-LCR、APACHEⅡ评分均低于死亡组(P0.05),PLT高于死亡组(P0.05)。Pearson相关分析显示,脓毒症患者血清PCT、D-D、CRP、MPV、PDW、P-LCR与APACHE II评分呈正相关(P0.05),PLT与APACHE II评分呈负相关(P0.05)。结论:脓毒症患者血清PCT、D-D、CRP及血小板相关指标可能参与了脓毒症的发展,通过检测其血清PCT、D-D、CRP水平及血小板相关参数可评估脓毒症患者的病情和预后。     

Comparison of forest above‐ground biomass from dynamic global vegetation models with spatially explicit remotely sensed observation‐based estimates

Gaps in our current understanding and quantification of biomass carbon stocks, particularly in tropics, lead to large uncertainty in future projections of the terrestrial carbon balance. We use the recently published GlobBiomass data set of forest above‐ground biomass (AGB) density for the year 2010, obtained from multiple remote sensing and in situ observations at 100 m spatial resolution to evaluate AGB estimated by nine dynamic global vegetation models (DGVMs). The global total forest AGB of the nine DGVMs is 365 ± 66 Pg C, the spread corresponding to the standard deviation between models, compared to 275 Pg C with an uncertainty of ~13.5% from GlobBiomass. Model‐data discrepancy in total forest AGB can be attributed to their discrepancies in the AGB density and/or forest area. While DGVMs represent the global spatial gradients of AGB density reasonably well, they only have modest ability to reproduce the regional spatial gradients of AGB density at scales below 1000 km. The 95th percentile of AGB density (AGB₉₅) in tropics can be considered as the potential maximum of AGB density which can be reached for a given annual precipitation. GlobBiomass data show local deficits of AGB density compared to the AGB₉₅, particularly in transitional and/or wet regions in tropics. We hypothesize that local human disturbances cause more AGB density deficits from GlobBiomass than from DGVMs, which rarely represent human disturbances. We then analyse empirical relationships between AGB density deficits and forest cover changes, population density, burned areas and livestock density. Regression analysis indicated that more than 40% of the spatial variance of AGB density deficits in South America and Africa can be explained; in Southeast Asia, these factors explain only ~25%. This result suggests TRENDY v6 DGVMs tend to underestimate biomass loss from diverse and widespread anthropogenic disturbances, and as a result overestimate turnover time in AGB.     

Determination of inflection points of CyberKnife dose profiles within acceptability criteria of deviations in measurements

AimThe aim of this study was to determine the Inflection Points (IPs) of flattening filter free (FFF) CyberKnife dose profiles for cone-based streotactic radiotherapy. In addition, dosimetric field sizes were determined.BackgroundThe increased need for treatment in the early stages of cancer necessitated the treatment of smaller tumors. However, efforts in that direction required the modeling accuracy of the beam. Removal of the flattening filter (FF) from the path of x-ray beam has provided the solution to those efforts, but required a different normalization approach for the beam to ensure the delivery of the dose accurately. As a solution, researchers proposed a normalization factor based on IPs.Materials and methodsMeasurements using microDiamond (PTW 60019), Diode SRS (PTW 60018) and Monte Carlo (MC) calculations of dose profiles were completed at SAD 80 cm and 5 cm depth for 15–60 mm cones. Performance analysis of detectors with respect to MC calculation was carried out. Gamma evaluation method was used to determine achievable acceptability criteria for FFF CyberKnife beams.ResultsAcceptability within (3%–0.5 mm) was found to be anachievable criterion for all dose profile measurements of the cone beams used in this study. To determine the IP, the first and second derivatives of the dose profile were determined via the cubic spline interpolation technique.ConclusionDerivatives of the interpolated profiles showed that locations of IPs and 50% isodose points coincide.     

Detailed evaluation of Mobius3D dose calculation accuracy for volumetric-modulated arc therapy

PurposeTo perform a detailed evaluation of dose calculation accuracy and clinical feasibility of Mobius3D. Of particular importance, multileaf collimator (MLC) modeling accuracy in the Mobius3D dose calculation algorithm was investigated.MethodsMobius3D was fully commissioned by following the vendor-suggested procedures, including dosimetric leaf gap (DLG) optimization. The DLG optimization determined an optimal DLG correction factor which minimized the average difference between calculated and measured doses for 13 patient volumetric-modulated arc therapy (VMAT) plans. Two sets of step-and-shoot plans were created to examine MLC and off-axis open fields modeling accuracy of the Mobius3D dose calculation algorithm: MLC test set and off-axis open field test set. The test plans were delivered to MapCHECK for the MLC tests and an ionization chamber for the off-axis open field test, and these measured doses were compared to Mobius3D-calculated doses.ResultsThe mean difference between the calculated and measured doses across the 13 VMAT plans was 0.6% with an optimal DLG correction factor of 1.0. The mean percentage of pixels passing gamma from a 3%/1 mm gamma analysis for the MLC test set was 43.5% across the MLC tests. For the off-axis open field tests, the Mobius3D-calculated dose for 1.5 cm square field was −4.6% lower than the chamber-measured dose.ConclusionsIt was demonstrated that Mobius3D has dose calculation uncertainties for small fields and MLC tongue-and-groove design is not adequately taken into consideration in Mobius3D. Careful consideration of DLG correction factor, which affects the resulting dose distributions, is required when commissioning Mobius3D for patient-specific QA.