Dose-response relationship between risk factors and incidence of COVID-19 in 325 hospitalized patients:A multicenter retrospective cohort study

BACKGROUND The epidemiological and clinical characteristics of coronavirus disease 2019(COVID-19)patients have been widely reported,but the assessment of doseresponse relationships and risk factors for mortality and severe cases and clinical outcomes remain unclear.AIM To determine the dose-response relationship between risk factors and incidence of COVID-19.METHODS In this retrospective,multicenter cohort study,we included patients with confirmed COVID-19 infection who had been discharged or had died by February 6,2020.We used multivariable logistic regression and Cox proportional hazard models to determine the dose-response relationship between risk factors and incidence of COVID-19.RESULTS It clarified that increasing risk of in-hospital death were associated with older age(HR:1.04,95%CI:1.01-1.09),higher lactate dehydrogenase[HR:1.04,95%confidence interval(CI):1.01-1.10],C-reactive protein(HR:1.10,95%CI:1.01-1.23),and procalcitonin(natural log-transformed HR:1.88,95%CI:1.22-2.88),and D-dimer greater than 1μg/m L at admission(natural log transformed HR:1.63,95%CI:1.03-2.58)by multivariable regression.D-dimer and procalcitonin were logarithmically correlated with COVID-19 mortality risk,while there was a linear dose-response correlation between age,lactate dehydrogenase,D-dimer and procalcitonin,independent of established risk factors.CONCLUSION Higher lactate dehydrogenase,D-dimer,and procalcitonin levels were independently associated with a dose-response increased risk of COVID-19 mortality.

Serum Ferritin and the Risk of Metabolic Syndrome:A Systematic Review and Dose-Response Meta-Analysis of Cross-sectional Studies

Objective This study aims to assess the dose-response relationship between serum ferritin(SF)and metabolic syndrome(MetS)in the two sexes.Methods We searched for articles on PubMed,the Cochrane Library,EMBASE,and the Web of Science databases that were published from 1950 to 2020.The summary odds ratio(OR)and 95%confidence interval(CI)of the association between SF and MetS were estimated using a random-effects model through a meta-analysis.Based on the methods described by Greenland and Longnecker,we explored the dose-response relationship between the two sexes.Results This study included 14 studies and 74,710 samples.The results of the classical meta-analysis showed that SF was positively associated with MetS(OR=1.77,95%CI:1.59–1.98).Regarding the components of MetS(8 studies included),the results showed that SF was positively associated with abdominal obesity(OR=1.42,95%CI:1.24–1.62),elevated fasting plasma glucose(OR=1.84,95%CI:1.50–2.25),elevated blood pressure(OR=1.17,95%CI:1.08–1.26),elevated triglycerides(OR=2.09,95%CI:1.72–2.54),and reduced high-density lipoprotein cholesterol(OR=1.33,95%CI:1.19–1.49).In the linear dose-response meta-analysis,the ORs of males,females,and postmenopausal females were 1.14(95%CI:1.13–1.16),1.32(95%CI:1.26–1.39),and 1.34(95%CI:1.22–1.47),respectively.Conclusions Our study shows that SF is significantly and positively associated with MetS,and the risk in the male population is higher than that in the female population.This finding also supports the recommendation of using SF as an early warning marker of MetS.

Structure-Property Relationships and Models of Controlled Drug Delivery of Biodegradable Poly (D, L-lactic acid) Microspheres

An oil-in-water (O/W) solvent evaporation method was used to prepare biodegradable microspheresbased on poly(D,L-lactic acid) (PLA). Nifedipine, a hydrophobic drug, was chosen as a model molecule in the studyof drug entrapment and release. Effect of preparation conditions on the size, morphology, drug loading, and releaseprofiles of micropheres was investigated. Based on in vitro release experimental findings, a diffusion/dissolutionmodel was presented for quantitative description of the resulting release behaviors and drug release kinetics fromPLA microspheres analyzed. The mathematical models were used to predict the effect of microstructure on theresulting drug release. It provided an approach to determine the suitable structure parameters for microspheres toachieve desired drug release behaviors.

Quantitative Structure Activity Relationship Studies of Benzoxazinone Derivative Antithrombotic Drug Using New Three-dimensional Structure Descriptors

A novel three-dimensional holographic vector of atomic interaction field(3D-HoVAIF) was used to describe the chemical structures of 23 benzoxazinone derivatives as antithrombotic drugs.Here a quantitative structure activity relationship(QSAR) model was built by partial least-squares(PLS) regression.The estimation stability and prediction ability of the model were strictly analyzed by both internal and external validations.The correlation coefficients of established PLS model,leave-one-out(LOO) cross-validation,and predicted values versus experimental ones of external samples were R2=0.899,RCV2=0.854 and Qext2=0.868,respectively.These values indicated that the built PLS model had both favorable estimation stability and good prediction capabilities.Furthermore,the satisfactory results showed that 3D-HoVAIF could preferably express the information related to the biological activity of benzoxazinone derivatives.

他汀类药物与骨密度:一项药物靶向孟德尔随机化分析

背景:观察性研究表明他汀类药物可能对骨密度具有保护作用,这使其成为潜在的骨质疏松症治疗药物之一。目的:通过孟德尔随机化方法来评估药物靶点介导的脂质表型与骨密度之间的因果关系。方法:从IEU Open GWAS数据库获取了与他汀类药物相关的单核苷酸多态性以及骨密度相关数据。主要分析方法是逆方差加权法,同时也使用了加权中位数法、简单中位数法、加权中值方法和MR-Egger回归法。使用β值和95%CI来评估他汀类药物与骨密度之间的因果关系;另外,进行敏感性分析以验证结果的可靠性,使用Cochran’s Q检验来评估异质性,使用MR-Egger截距检验是否存在水平多效性。使用留一法分析确定是否有单个或多个单核苷酸多态性影响了结果。结果与结论:他汀类药物作用靶点——3-羟基-3-甲基戊二酰辅酶A还原酶介导的低密度脂蛋白胆固醇与足跟定量超声骨密度(β=-0.086,95%CI:-0.117至-0.055,P=5.42×10^(-8))和全身骨密度(β=-0.193,95%CI:-0.288至-0.098,P=7.35×10^(-5))呈显著相关。该研究结果支持了他汀类药物对骨密度的保护作用。这些发现不仅加深了对胆固醇相关基因和骨骼健康关系的理解,还揭示了改善骨密度的潜在治疗靶点。

β-咔啉杂合咪唑类化合物的合成及体外抗肿瘤活性

以L-色氨酸为原料,经Pictet-Spengler环化反应、氧化脱羧、N^(9)-烷基化等反应步骤,合成了一系列β-咔啉杂合咪唑类化合物。目标化合物经1HNMR、13CNMR和HRMS确证结构。采用MTT(噻唑蓝)法检测了目标化合物对肺癌细胞(A-549)、胃癌细胞(BGC-823)、结肠癌细胞(CT-26)、肝癌细胞(Bel-7402)和乳腺癌细胞(MCF-7)的体外抗肿瘤活性。结果表明,大部分化合物对这5种肿瘤细胞株表现出了中等及优良的抑制活性。特别是3-苄基-11-(3-苯基丙基)-11H-咪唑并[1',5':1,2]吡啶并[3,4-b]吲哚(Ⅴr)对CT-26、Bel-7402和MCF-7细胞株的体外抗肿瘤活性较高,对应的半数抑制浓度(IC_(50))分别为(9.5±0.4)、(7.4±0.3)和(8.8±0.6)µmol/L。分子对接结果表明,3-苄基-11-甲基-11H-咪唑并[1',5':1,2]吡啶并[3,4-b]吲哚(Ⅴa)、3-苄基-11-丁基-11H-咪唑并[1',5':1,2]吡啶并[3,4-b]吲哚(Ⅴf)和Ⅴr与VEGFR^(2)激酶的多个氨基酸残基具有良好的结合作用。

白芥子穴位给药配伍对延胡索乙素药效动力学影响的研究

目的:探讨“冬病夏治”全方配伍和无白芥子配伍延胡索乙素在模型家兔“肺俞”穴皮下药代动力学特征及药代动力学-药效动力学(PK-PD)模型的相关性。方法:支气管哮喘模型家兔随机分成延胡索单方组、缺白芥子组、全方组,微透析技术收集14 h穴位皮下透析液,液相色谱-质谱法(Liquid Chromatography Mass Spectrometry,LCMS)法检测方中君药延胡索主要成分延胡索乙素浓度,获得药代动力学参数;酶联免疫吸附试验(ELISA)法检测对应时间点模型动物血清中IgE水平,获得药效学参数;对药动学、药效学参数进行PK-PD模型拟合。结果:白芥子配伍后的药峰浓度(C_(max))、药时曲线下面积(AUC_(0-t))、平均滞留时间(MRT_(0-t))均显著增加(P<0.01,P<0.01,P<0.05),达峰时间(T_(max))提前(P<0.01);“浓度-时间-效应”三维曲线表明,方中有白芥子配伍时,药效出现更快、消退更慢,起效时间晚于峰浓度,具有一定滞后性。结论:动力学参数、PK-PD模型结果表明,白芥子配伍能够改变“方中君药”——延胡索的主要成分延胡索乙素穴位局部的皮下分布,促进方中君药有效成分快速吸收,延长滞留时间,在方剂中起到主药、改善其他药物分布的“双重”作用。

不同体位对膝关节镜手术患者蛛网膜下腔阻滞罗哌卡因ED50的影响

目的研究不同体位对膝关节镜手术患者蛛网膜下腔阻滞罗哌卡因半数有效剂量(ED50)的影响。方法选取90例需要进行择期单侧膝关节镜手术的患者,年龄18~64岁,ASA分级为I或Ⅱ级,体质量指数(BMI)为18~24 kg/m^(2),根据不同的体位,这些患者被分为三组,分别是头高脚低0°组、10°组和20°组。试验采用序贯法,每组第1例患者均获得蛛网膜下腔注射0.75%罗哌卡因11.25 mg,接下来根据前1例患者蛛网膜下腔阻滞是否有效,决定下一位患者的剂量是否减少或增加0.75 mg。使用概率单位回归分析法,计算罗哌卡因在不同体位下的蛛网膜下腔阻滞ED50。结果三组的ED50分别为:0°组为11.625 mg(95%CI:11.259~11.991 mg);10°组为11.325 mg(95%CI:10.968~11.669 mg);20°组为9.373 mg(95%CI:8.963~9.765 mg)。与0°组比较,10°组和20°组运动阻滞恢复时间缩短,20°组ED50降低、最高感觉阻滞平面下降、运动阻滞起效时间延长(P<0.05);与10°组比较,20°组ED50降低、运动阻滞恢复时间缩短(P<0.05)。三组术中低血压和恶心呕吐发生率比较差异无统计学意义(P>0.05)。结论膝关节镜手术患者在保持头高脚低0°、10°、20°体位时,蛛网膜下腔阻滞罗哌卡因的ED50分别为11.625 mg、11.325 mg和9.373 mg。通过头高脚低20°的姿势可以降低蛛网膜下腔阻滞的罗哌卡因ED50。

Prediction of Blood-to-Brain Barrier Partitioning of Drugs and Organic Compounds Using a QSPR Approach

The purpose of this study was to develop a quantitative structure–property relationship(QSPR) model based on the enhanced replacement method(ERM) and support vector machine(SVM) to predict the blood-to-brain barrier partitioning behavior(log BB) of various drugs and organic compounds. Different molecular descriptors were calculated using a dragon package to represent the molecular structures of the compounds studied. The enhanced replacement method(ERM) was used to select the variables and construct the SVM model. The correlation coefficient, R^2, between experimental results and predicted log BB was 0.878 and 0.986, respectively. The results obtained demonstrated that, for all compounds, the log BB values estimated by SVM agreed with the experimental data, demonstrating that SVM is an effective method for model development, and can be used as a powerful chemometric tool in QSPR studies.

The relationship between antimicrobial consumption and the rates of resistance of Klebsiela pneumoniae in respiratory unit

Objective To investigate the relationship between the consumption of antibacterial agents and resistance rate of Klebsiela pneumoniae(KP)in the hospital respiratory unit for 3 consecutive years in 2005-2007.Methods The total antibacterial consumption expressed as defined DDDs/100BD,as well as resistance rate of total KP and producing ESBLs KP were collected,and their correlation was analyzed.Results The rate of resistance of KP to cefoperazone/sulbactam,Cefepime,Imipenem,Moxifloxacin was significantly positively associated with the consumption of Cefotaxime,Ceftazidime,Moxifloxacin,Amikacin respectively;A significant positive association was observed between the rate of resistance of KP to Piperacillin/Tazobactam,Ceftriaxone and the consumption of Imipenem;The rate of resistance of KP to Piperacillin,Cefotaxime,Ciprofloxacin was significantly positively associated with the consumption of Levofloxacin.ESBLs producing bacilli of KP were detected in 44 of 75 isolates(58.7%),The rate of resistance of producing ESBLs KP to Piperacillin/Tazobactam,Ceftriaxone was significantly positively associated with the consumption of Imipenem,Ceftazidime;A significant positive association was observed between the rate of resistance of producing ESBLs KP to Piperacillin,Imipenem and the consumption of Moxifloxacin.There was no significant correlation in other drugs.Conclusions A relationship existed between antimicrobial consumption and rates of resistance of KP in the hospital respiratory unit.We must use antibiotics carefully and with reason to control and lessen the drug resistance of bacterial.

The Impact of a Drug Safety Warning on Discussions between Doctors and Their Patients;the Case of Rosiglitazone

The goal of this study was to track the influence of a highly publicized report on discussions between doctors and their patients and prescribing decisions made in response to concerns about potential medication adverse side effects. This was a retrospective analysis of a primary care network’s electronic medical record database. From a diabetes registry of 12, 246 patients, 329 were identified as taking rosiglitazone prior to the June 14, 2007 release of an article in the New England Journal of Medicine;the article suggesting an increased risk of myocardial events. The entire content of all office visits, telephone messages, and medication lists for each patient were reviewed over a 2-year period subsequent to the article’s publication. Doctor/patient discussions regarding concerns for rosiglitazone were catalogued including the physician’s treatment recommendations. There were documented discussions on rosiglitazone’s potential adverse side effects for 64 patients;19.5 percent of this population. All of the discussions occurred between June 15 and October 30, 2007. Of the entire group, 59.3 percent (N = 195) remained on rosiglitazone. For those advised to continue rosiglitazone, the provider indicated that he/she wanted more data before determining if the drug was not safe or discounted the validity of the safety concerns. For those advised to discontinue rosiglitazone, 112 (83.6 percent) were placed on pioglitazone. An article suggesting potential adverse effects of rosiglitazone resulted in a documented discussion in 19.5 percent of patients on this medication. These findings suggest an awareness of this publication by patients, presumably derived from media reports. However, an awareness of this concern did not result in a substantial change in practice.The majority of patients remained on rosiglitazone. The content of these discussions suggest that most physicians’ recommended waiting for more published data before considering a change. While many factors influence physician’s prescribing behavior, this study demonstrates how a highly publicized report influences the doctor/ patient dialogue.

Chemoinformatic Resources for Organometallic Drug Discovery

Medicinal Organometallic Chemistry keeps contributing to drug discovery efforts including the development of diagnostic compounds. Despite the limiting issues of metal-based molecules, e.g., such as toxicity, there are drugs approved for clinical use and several others are under clinical and pre-clinical development. Indeed, several research groups continue working on organometallic compounds with potential therapeutic applications. For arguably historical reasons, chemoinformatic methods in drug discovery have been applied thus far mostly to organic compounds. Typically, metal-based molecules are excluded from compound data sets for analysis. Indeed, most software and algorithms for drug discovery applications are focused and parametrized for organic molecules. However, considering the emerging field of material informatics, the objective of this Commentary we emphasize the need to develop cheminformatic applications to further develop metallodrugs. For instance, one of the starting points would be developing a compound database of organometallic molecules annotated with biological activity. It is concluded that chemoinformatic methods can boost the research area of Medicinal Organometallic Chemistry.

替加环素致低纤维蛋白原血症与血药浓度的相关性

目的评估替加环素致低纤维蛋白原血症是否与浓度有相关性,并确定造成该不良反应发生的浓度阈值。方法回顾性分析2019年4月—2021年4月使用替加环素的患者,记录其用药后血药浓度监测结果和用药前后纤维蛋白原值及其他临床指标,按设定的标准将患者分为不良反应(ADR)组49例,对照组74例。分析两组患者替加环素的血药浓度值差异,通过受试者工作特征曲线(ROC)获得发生ADR的浓度折点。结果ADR组和对照组年龄、性别、替加环素剂量、疗程等临床特征均差异无统计学意义;替加环素谷浓度(C_(min))、峰浓度(C_(max))和24 h浓度-时间曲线下面积(AUC_(0-24 h))均差异有统计学意义(均P<0.001)。通过ROC曲线得到替加环素导致低纤维蛋白原血症的折点为C_(min)=0.775μg·mL^(-1),AUC_(0-24 h)=28.38μg·h·mL^(-1)。结论替加环素血药浓度与导致低纤维蛋白原血症有关。临床在应用替加环素治疗重症感染时,一方面要考虑疗效,另一方面也不能忽视替加环素可能导致的不良反应,有必要定期进行血药浓度监测。

氟喹诺酮类杂合体的抗耐药菌活性

抗生素是治疗细菌感染的主要手段。然而,由于长时间对其不恰当使用甚至滥用,耐药菌不断涌现,导致传统抗生素的疗效不断下降。目前,治疗耐药菌感染的疗法屈指可数。因此,耐药菌已严重威胁人类生命健康,开发新型抗耐药菌药物势在必行。喹诺酮尤其是氟喹诺酮类抗生素是仅次于头孢菌素类药物的第二大类抗生素,具有抗菌谱广、抗菌活性高和毒副作用低等特点,在临床上广泛用于各种细菌感染的治疗。尽管致病菌对喹诺酮类抗生素也产生了耐药性,喹诺酮杂合体由于嵌入了其他抗菌药效团,可同时作用于不同的药物靶点,具有克服耐药性的潜力。本文将着重介绍近5年来所开发的具有抗耐药菌活性的喹诺酮杂合体的最新研究进展,为进一步合理设计此类杂合体提供一定的理论支持。

木质素抗氧化活性的构效关系研究及应用进展

木质素是一种储量丰富、环境友好的多酚类生物聚合物,可作为天然抗氧化剂使用。同时,木质素具有光稳定性好、抗紫外、可生物降解等优势,如何更好地开发和利用其抗氧化功能引起了研究者的广泛关注。首先,该文重点回顾了国内外在木质素抗氧化构效关系方面的研究进展,归纳总结了木质素结构对其抗氧化能力的影响规律及其作用机制,并讨论了目前木质素抗氧化构效关系研究面临的主要问题;其次,从分级纯化、纳米化和化学改性3种技术方法出发,介绍了近年来研究人员在强化木质素抗氧化能力方面做出的努力;最后,基于木质素在防晒护肤品、高分子功能复合材料和医药材料中的应用现状,评述了木质素抗氧化特性对紫外防护、热氧稳定性、抑菌等性能的贡献,为今后木质素基功能材料的制备及应用提供一定参考。

口服抗高血压药物研究进展

对2011年以来FDA (美国食品药品监督管理局)批准上市的血管扩张药、β受体阻断药和血管紧张素Ⅱ受体拮抗剂类抗高血压药物研究进行了综述,包括药物先导化合物的发现、作用机理、结构修饰、构效关系、合成方法等,为抗高血压药物研发提供参考。

Comparison of Two Dose-response Relationship of Noise Exposure Evaluation Results with High Frequency Hearing Loss

Background： Complex noise and its relation to hearing loss are difficult to measure and evaluate. In complex noise measurement, individual exposure results may not accurately represent lifetime noise exposure. Thus, the mean LAcq.8h values of individuals in the same workgroup were also used to represent LAcq.8h in our study. Our study aimed to explore whether the mean exposure levels of workers in the same workgroup represented real noise exposure better than individual exposure levels did. Methods： A cross-sectional study was conducted to establish a model for cumulative noise exposure （CNE） and hearing loss in 205 occupational noise-exposed workers who were recruited from two large automobile manufacturers in China. We used a personal noise dosimeter and a questionnaire to determine the workers＇ occupational noise exposure levels and exposure times, respectively. A qualified audiologist used standardized audiometric procedures to assess hearing acuity after at least 16 h of noise avoidance. Results： We observed that 88.3% of workers were exposed to more than 85 dB（A） of occupational noise （mean： 89.3 ± 4.2 dB（A））. The personal CNE （CNEp） and workgroup CNE （CNEg） were 100.5 ± 4.7 dB（A） and 100.5 ± 2.9 dB（A）, respectively. In the binary logistic regression analysis, we established a regression model with high-frequency hearing loss as the dependent variable and CNE as the independent variable. The Wald value was 5.014 with CNEp as the independent variable and 8.653 with CNEg as the independent variable. Furthermore, we found that the figure for CNEg was more similar to the stationary noise reference than CNEp was. The CNEg model was better than the CNEp model. In this circumstance, we can measure some subjects instead of the whole workgroup and save manpower. Conclusions： In a complex noise environment, the measurements of average noise exposure level of the workgroup can improve the accuracy and save manpower.

英夫利西单抗用于克罗恩病患者的治疗药物监测研究进展

英夫利西单抗(IFX)是目前临床广泛用于治疗克罗恩病(CD)的肿瘤坏死因子α抑制剂,但其常规剂量难以获得较佳疗效,建议疗效欠佳的患者进行治疗药物监测(TDM)以指导临床决策。本文综述了IFX的药动学特点、暴露-效应关系、药动学差异的影响因素、TDM方法等内容。IFX不经肝肾代谢,在CD诱导期和维持期均具有明显的暴露-效应关系,疾病活动度、白蛋白和抗IFX抗体(ATI)等因素影响其体内暴露。建议CD维持期患者通过TDM将IFX谷浓度保持在3μg/mL以上,对于疾病程度重、白蛋白水平低下、形成ATI等患者应考虑增加IFX剂量或缩短给药间隔,以提高IFX的疗效。建议同一患者采用同一种检测方法进行IFX的TDM。

低剂量利伐沙班对老年非瓣膜性心房颤动患者的血栓栓塞与出血事件及再入院率的影响

目的比较低剂量(10 mg/d)利伐沙班、15 mg/d利伐沙班和华法林对老年非瓣膜性心房颤动患者的血栓栓塞与出血事件及再入院率的影响。方法选择2020年1月1日至2021年8月31日于中国科学技术大学附属第一医院(安徽省立医院)心血管内科就诊的96例使用利伐沙班或华法林抗凝的老年非瓣膜性心房颤动患者,按用药种类及用药剂量分为10 mg/d利伐沙班组34例,15 mg/d利伐沙班组28例,华法林组34例;随访并记录用药1年内发生的血栓栓塞性事件和出血性事件及再入院的情况。并采用多元logistic回归分析评估3组患者用药后的出血风险。结果3组患者的血栓栓塞性事件总发生率相比较,差异无统计学意义(P>0.05);在出血事件方面,15 mg/d利伐沙班组相较于10 mg/d利伐沙班组和华法林组消化道出血的发生率增加,差异有统计学意义(P<0.05);10 mg/d利伐沙班组与华法林组消化道出血的发生率相比较,差异无统计学意义(P>0.05);多元logistic回归分析发现,在校正年龄、性别、体重指数、消化道疾病史等因素后,15 mg/d利伐沙班组消化道出血的风险较10 mg/d利伐沙班组高(OR=14.09,95%CI:1.180~168.730);3组患者的其他出血事件发生率、再入院率相比较,差异无统计学意义(P>0.05)。结论10 mg/d利伐沙班与15 mg/d利伐沙班、华法林对于老年非瓣膜性心房颤动患者的抗凝效果相当,15 mg/d利伐沙班与10 mg/d利伐沙班相比可能会增加老年非瓣膜性心房颤动患者消化道出血的风险。