Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain

AimsThe aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.MethodsIndividual concentration–time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post‐dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme‐linked immunosorbent assay.ResultsA two compartment model with parallel linear and non‐linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V ₁), peripheral volume (V ₂), inter‐compartmental clearance, maximum elimination capacity (VM) and concentration at half‐maximum elimination capacity were 0.135 l day^–1, 2.71 l, 1.98 l, 0.371 l day^–1, 8.03 μg day^–1 and 27.7 ng ml^–1, respectively. Inter‐individual variability (IIV) was included on CL, V ₁, V ₂ and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V ₁ and V ₂ significantly reduced IIV.ConclusionsThe small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.     

Tedium vitae in stroke survivors: a comparative cross-sectional study

Objectives: Suicide is best studied by deconstructing the psychological experiences preceding suicidal death. We assessed the characteristics of tedium vitae (feeling tired of life) after first ever stroke in Nigerian survivors.

Methods: Using the Schedule for Clinical Assessment in Neuropsychiatry, tedium vitae was assessed in 130 stroke survivors attending rehabilitation in a large Nigerian university hospital. Global cognitive and executive dysfunctions were evaluated, respectively, using the Mini Mental State Examination and the modi?ed Indiana University Token test. All participants had their index stroke 3 to 24 months before recruitment into the study. We also examined a comparative group of 130 age, gender, and education matched apparently normal persons who were unrelated to the stroke survivors. Associations were explored using univariate and multivariate logistic regression analyses.

Results: Tedium vitae was experienced by 16 (12.3%) stroke survivors compared with 5 (3.9%) in the comparative group (O. R = 3.5, 95% C. I = 1.3–9.9, p = 0.018). Among stroke survivors, those who were retired were more likely to experience tedium vitae (56.2%, p = 0.045). In analyses adjusting for the effect of systemic hypertension, cognitive dysfunction, retirement and marital separation, there was a 3.5-fold increase in the odds of experiencing tedium vitae after surviving a stroke (O. R = 3.5, 95% C. I = 1.1–11.6, p = 0.042).

Conclusions: Tedium vitae is a common suicidal experience after stroke and may be among the earliest perceptible pointer to impending poststroke suicide. It is easy to assess and may be less costly to obtain an adequate sample size in studies aiming to understand the phenomenon of suicide in the stroke population.     

2019年重庆市30岁及以上人群归因于被动吸烟的肺癌疾病负担研究

目的 分析重庆市肺癌发病死亡和疾病负担归因于被动吸烟的情况,为开展肺癌防治提供建议。 方法 肺癌死亡个案数据来源于2019年重庆市肿瘤登记报告系统,被动吸烟率来自2013年重庆市慢性病及危险因素监测。计算人群归因危险度百分比(population attributable risk percent, PAR%)、被动吸烟导致的肺癌发病、死亡和疾病负担。采用Excel 2010与SPSS 25.0进行统计分析,率的比较采用χ²检验。 结果 2013年30岁及以上成年人被动吸烟率为52.37%。2019年重庆市30岁及以上人群肺癌发病率与标化发病率分别为118.44/10万与80.83/10万,死亡率与标化死亡率分别为96.51/10万、63.58/10万。肺癌发病率和死亡率归因于被动吸烟的PAR%分别为19.76和19.04,归因发病率与归因标化发病率分别为23.41/10万和16.34/10万,归因死亡率与归因标化死亡率分别为18.38/10万和12.40/10万。2019年重庆市30岁及以上肺癌早死所致寿命损失年率(years of life lost,YLL)、残疾所致寿命损失年率(years lived with disability,YLD)、调整伤残寿命损失年率(disability adjusted life year,DALY)分别为21.16‰、0.31‰、21.47‰,YLL率、YLD率、DALY率归因于被动吸烟的PAR%分别为21.16、19.76和20.49,归因YLL率为4.34‰,归因YLD率为0.06‰,归因DALY率为4.40‰。 结论 2019年重庆市30岁及以上人群肺癌发病率、死亡率、YLL率、DALY率高,被动吸烟率高,肺癌归因于被动吸烟的疾病负担重,应加强落实控烟工作。     

Mental health in the population approaching retirement age. Preliminary findings of the TURVA project

The present paper deals with a Finnish long-term prospective study, the objective of which is to shed light on adjustment to retirement and old age. In this phase, only the preliminary findings of the initial survey carried out in 1982 are available. For the purposes of the study, a random sample of 200 individuals was drawn from among Turku inhabitants born in 1920. Another sample, consisting of 189 persons of the same age, was drawn from rural municipalities in the neighborhood of Turku. An extensive structured psychosocial interview could be conducted with a total of 339 subjects. The research methods used included e.g. the 36-item version of Goldberg's General Health Questionnaire (GHQ). Relatively little mental disturbance was revealed in the interview, and no major differences occurred between the urban and the rural sample. Somewhat over one-third of both samples were probable psychiatric cases as defined according to the GHQ.     

The role of Self-Defined Race/Ethnicity in Population Structure Control

Population-based association studies are powerful tools for the genetic mapping of complex diseases. However, this method is sensitive to potential confounding by population structure. While statistical methods that use genetic markers to detect and control for population structure have been the focus of current literature, the utility of self-defined race/ethnicity in controlling for population structure has been controversial. In this study of 1334 individuals, who self-identified as either African American, European American or Hispanic, we demonstrated that when the true underlying genetic structure and the self-defined racial/ethnic groups were roughly in agreement with each other, the self-defined race/ethnicity information was useful in the control of population structure.     

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.     

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.     

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.