Fisher information matrix for nonlinear mixed effects multiple response models: Evaluation of the appropriateness of the first order linearization using a pharmacokinetic/pharmacodynamic model

We focus on the Fisher information matrix used for design evaluation and optimization in nonlinear mixed effects multiple response models. We evaluate the appropriateness of its expression computed by linearization as proposed for a single response model. Using a pharmacokinetic–pharmacodynamic (PKPD) example, we first compare the computation of the Fisher information matrix with approximation to one derived from the observed matrix on a large simulation using the stochastic approximation expectation–maximization algorithm (SAEM). The expression of the Fisher information matrix for multiple responses is also evaluated by comparison with the empirical information obtained through a replicated simulation study using the first‐order linearization estimation methods implemented in the NONMEM software (first‐order (FO), first‐order conditional estimate (FOCE)) and the SAEM algorithm in the MONOLIX software. The predicted errors given by the approximated information matrix are close to those given by the information matrix obtained without linearization using SAEM and to the empirical ones obtained with FOCE and SAEM. The simulation study also illustrates the accuracy of both FOCE and SAEM estimation algorithms when jointly modelling multiple responses and the major limitations of the FO method. This study highlights the appropriateness of the approximated Fisher information matrix for multiple responses, which is implemented in PFIM 3.0, an extension of the R function PFIM dedicated to design evaluation and optimization. It also emphasizes the use of this computing tool for designing population multiple response studies, as for instance in PKPD studies or in PK studies including the modelling of the PK of a drug and its active metabolite. Copyright © 2009 John Wiley & Sons, Ltd.     

中、老年代谢综合征患者的临床特点分析

目的 比较中、老年代谢综合征(MS)患者的临床特点.方法 收集1996～2006年在解放军总医院门诊查体且符合中国人MS诊断标准(CDS)的947例中、老年患者的临床资料.其中老年人679例,中年人268例.分析中、老年患者MS各组分的差异,以及各组分的相关因素等.结果 947例患者中,男性582例(老年423例,中年159例),女性365例(老年256例,中年109例).老年男性患者的年龄大于老年女性(81.5±6.5 vs 74.5±8.8岁,P＜0.01),老年男性的体重指数(BMI)高于中年男性(27.14±2.51 vs 25.98±2.38,P＜0.01).老年患者的空腹、餐后血糖和收缩压均高于同性别的中年患者,而舒张压无显著差异.中年男性的甘油三酯高于老年男性.中年女性的高密度脂蛋白胆固醇高于男性.多元回归分析显示,男女患者空腹血糖均与餐后2h血糖有相关性(男性R2＝0.463,P＜0.05;女性R2＝0.613,P＜0.05).餐后2h血糖与年龄存在相关性(男性,R2＝0.522,P＜0.01;女性R2＝0.716,P＜0.05).收缩压与多种指标均有相关性,男性患者收缩压与年龄(R2＝0.396,P＜0.01)和舒张压(R2＝0.535,P＜0.05)均有相关性;女性患者的收缩压与BMI(R2＝0.557,P＜0.05)、舒张压(R2＝0.434,P＜0.05)、餐后2h血糖(R2＝0.434,P＜0.01)及空腹血糖(R2＝0.473,P＜0.05)均有相关性.Logistic回归分析示年龄(OR=2.1,95%CI:1.3～2.7)、空腹血糖(OR=1.7,95%CI:1.2～3.1)和收缩压(OR=1.4,95%CI:1.2～2.9)是预测代谢综合征组分含量的影响因素.结论 中老年代谢综合征患者的代谢指标有差异,年龄、空腹血糖和收缩压可作为代谢综合征的筛选指标.     

水分胁迫条件下不同栽培居群菘蓝中4种有机酸的变化

目的:检测北京、内蒙古、河北和陕西等4个栽培居群菘蓝叶片中草酸、苹果酸、柠檬酸和抗坏血酸等4种有机酸成分含量的差异及在淹水胁迫下的变化.方法:采用高效液相色谱法测定正常及水分胁迫下不同栽培居群的菘蓝叶片中4种有机酸的含量.结果:不同栽培居群叶片中有机酸含量不同,而在水分胁迫条件下,各栽培居群有机酸含量变化趋势相同,草酸、苹果酸和柠檬酸含量升高,抗坏血酸含量下降.结论:不同栽培居群的菘蓝所含各有机酸存在一定差异,在水淹等逆境条件下,其叶片中有机酸含量发生不同程度地变化,并与其逆境生理密切相关.     

Patient comprehension and recall of laparoscopic surgery and outcomes in a non-English speaking population.

BACKGROUND AND OBJECTIVES: The purpose of this study was to determine patient recall and comprehension after laparoscopic appendectomy in an underserved population. Laparoscopic surgery can lead to diagnostic uncertainty secondary to poor recall and variable port placement. METHODS: After institutional review board approval, we identified a cohort of patients who underwent laparoscopic appendectomy from 2000 to 2004 at a single institution. We then attempted to contact the patients to conduct a 10-question telephone survey, which determined whether the patient spoke English or Spanish as a primary language, ethnicity, educational level, and questions about recall of perioperative events and diagnoses. If we could not reach the patient, we tried to call back on 2 different occasions. RESULTS: Between 2000 and 2004, 186 patients underwent laparoscopic appendectomy. Of these, 65% were Hispanic. We found that only 17% of these patients returned for a postoperative visit. Only 19.3% could be contacted by phone. Forty-seven percent of the patients contacted by phone spoke Spanish exclusively. Overall 92% of patients contacted knew what operation they had, and gave their correct diagnosis. CONCLUSIONS: The low percentage of patients available to follow-up makes this study statistically insignificant. However, we believe that fact in itself is important. In Southwestern states, we see a large migrant population. This highlights the need to communicate effectively with the patients at the time of surgery, which we speculate we did based on the percentage of patients that knew their diagnosis.     

血管内皮型一氧化氮合酶基因Glu298 Asp多态性与老年脑梗死的相关性研究

目的　通过病例对照研究 ,了解中国老年人群血管内皮型一氧化氮合酶 (eNOS)基因目的　通过病例对照研究 ,了解中国老年人群血管内皮型一氧化氮合酶 (eNOS)基因Glu2 98Asp多态性的分布 ,分别探讨其与老年脑梗死及血脂以及一氧化氮等脑梗死危险因素的关系。 方法对门诊及住院中确诊的 4 0例老年脑梗死和 16 9例性别、年龄相匹配的老人 ,测量他们的身高、体重及座位血压 ,并测定他们的空腹血脂、空腹血糖 (FBS)及一氧化氮 (NO)等 ,应用聚合酶链反应 (PCR)和限制性片断长度多态性 (RFLP)检测eNOS基因Glu2 98Asp多态性。结果　脑梗死和对照组eNOS基因Glu2 98Asp多态性构成有显著性差异 (χ2 =4 31,P =0 0 38) ,脑梗死组Glu/Asp基因型高于对照组(32 5 %vs 17 8% ) ;脑梗死组 2 98Asp等位基因频率高于对照组 (16 2 5 %vs 8 9% ) ,但是两组等位基因频率的分布比较 ,没有显著性差异 (χ2 =3 81,P =0 0 5 1)。结论　eNOS基因Glu2 98Asp多态性在中国老年人群中存在 ,并且基因...     

外加磁场对半乳糖化白蛋白磁性阿霉素纳米粒在大鼠体内分布影响的研究

目的观察半乳糖化白蛋白磁性阿霉素纳米粒(ADR-GHMN)在正常肝脏中的靶向性,并观察ADR-GHMN在全身各脏器的分布特征及外加磁场对其分布的影响.方法大鼠正中开腹,肝动脉插管并固定,肝动脉注射125I-ADR-GHMN(相当于阿霉素0.5 mg/kg),左外叶加磁场,磁场应用30 min,移去磁场后,动物立即处死;对照组:肝动脉注射ADR-GHMN,左外叶不加磁场,30min后,移去磁场后,动物立即处死,立即取靶区肝、非靶区肝、肾、心、肺、小肠、脾及周围血作γ计数.肝组织作病理切片.结果注入的纳米粒75～85%分布于肝脏,其它脏器极少.病理切片显示磁区小动脉见大量纳米粒存在,对照组及非磁区肝中纳米粒很少见.结论ADR-GHMN在正常肝组织中有明显的磁靶向性;在磁场作用下,ADR-GHMN主要分布于肝脏,其它脏器含量很少;试验组肾、心、肺、小肠、脾及外周血于对照组的放射活性比较明显降低,表明磁性物质的存在使这些脏器的相对药物暴露明显减少.     

上海市流动人口血吸虫病、疟疾、丝虫病监测结果分析

目的：评价外来流动人口对上海市人群传播血吸虫病、疟疾、丝虫病(简称“三病”)的潜在危害，从而预防和控制外源性“三病”在本市传播。方法：对外省市来沪居留3个月以上人员，进行“三病”血清免疫学检测，达到规定的阳性滴度时进行病原学追踪及治疗。结果：2001—2003年共监测外来流动人口909960人次，血吸虫病、疟疾、丝虫病抗体阳性率分别为0．55％、0.28％和0．02％；质量抽检符合率分别为98、42％、94．21％和99．84％。结论:必须加强外来流动人口“三病”监测和防治管理，以有效预防和控制外源性“三病”在本市传播。     

医保对象对职工医疗保险制度反应性的分析

该文对享受上海市城镇职工基本医疗保险的市民进行随机抽样调查,就其对医保政策的评价和就医行为反应性改变,分析医保改革的有效性和震荡度.提出加强医保法制建设,强化费用分担意识,完善医保政策,进一步体现福利性、公益性、公平性.     

产后小鼠子宫内膜边缘群干/祖细胞的分离纯化

目的分离和纯化小鼠子宫内膜边缘群(side population,SP)干/祖细胞,为进一步探讨产后子宫修复的细胞机制奠定基础。方法分别采用酶消化和机械分离结合法与机械研磨分离的方法,原代分离小鼠子宫内膜上皮细胞与基质细胞,通过Hoechst33342-SP法(对照加入维拉帕米),使用流式细胞仪检测子宫内膜SP细胞。结果未孕小鼠子宫内膜上皮与基质中均无明确SP干/祖细胞,产后哺乳期后的小鼠子宫内膜基质中含有SP干/祖细胞达(3.44±1.59)%。结论本研究初步检测到小鼠产后子宫内膜中含有SP干/祖细胞。产后更多SP细胞的出现可能与修复损伤的子宫内膜有关。这群SP细胞是子宫原位干细胞还是有其他来源,如何参与子宫内膜的修复,其分子机制如何,尚待进一步研究。     

~99m锝-葡聚糖淋巴系统显像剂研制及其初步临床应用

作者采用沉淀法对药用葡聚糖进行分级纯化,通过家兔实验筛选出合乎淋巴系统定向要求分子量(105000)的葡聚糖,并制成一步标记法的亚锡葡聚糖药盒,4℃贮存8个月,标记率大于95％。~(99)m锝-葡聚糖的体内外稳定性均佳。家兔研究表明:(1)淋巴结内聚集量最高,其他非靶器(除肝脏、肾脏外)均处于极低水平;(2)显像速度快、图像清晰,既显示淋巴结又显示淋巴管;(3)注射部位清除速度快,6.5h清除95％。安全试验表明:~(99)m锝-葡聚糖是一种毒性极低、非常安全的药物。临床试用100余例,均获满意图像,检查全过程1h内完成,检查结果与诊断基本相符,故~(99)m锝-葡聚糖是目前临床上比较理想的淋巴系统显像剂,可进一步推广应用。