Within‐subject haemoglobin variation in elite athletes: a longitudinal investigation of 13 887 haemoglobin concentration readings

The Athlete Biological Passport (ABP) estimates individualized reference ranges for key blood markers, such as haemoglobin concentration ([Hb]), using predetermined population mean, between‐ and within‐subject variances. Here, we aim to reassess previously published estimates for within‐subject [Hb] variance and determine whether sex‐, analyzer‐, sport‐, or season‐specific values are required. Our reference population contains 7723 male (mean ± SD, 22.3 ± 4.6 years of age) and 6164 female (21.6 ± 4.3) athlete observations from 49 sports. [Hb] was calculated using one of three cytometers; Bayer‐H3 (1997–1999, n = 4554), ADVIA‐120 (1999–2010, n = 8636) and Sysmex XT‐2000i (2010–2012, n = 697). The final model was a linear mixed model for [Hb] with analyzer (H3, ADVIA, Sysmex), sex (male, female), sport (power‐endurance, endurance, skill, team, disabled and non‐athletes), season (summer, winter), and the interaction between sex and sport as fixed effects and athlete as a random effect. The model included an exponential correlation structure to allow for within‐subject autocorrelation, and allowed different within‐subject variances for each sport. Within‐subject [Hb] variance (g²/L²) was significantly less for power endurance (35.09, 95% CI 33.50 to 36.76), disabled (25.82, 95% CI 21.71 to 35.28) and non‐athletes (34.30, 95% CI 28.53 to 35.87) than for endurance (40.35, 95% CI 39.62 to 47.22) and team sports (38.70, 95% CI 37.68 to 39.76) athletes. No new evidence was found to justify adjusting the current within‐subject [Hb] variance estimate. Copyright © 2015 John Wiley & Sons, Ltd.     

Effect of heavy metal exposure on blood haemoglobin concentration and methemoglobin percentage in Lumbricus terrestris

The earthworm haemoglobin (Hb) is a large extracellular hemoprotein flowing in a closed circulatory system. In spite of the fundamental role of this respiratory pigment in earthworm physiology, little is known about its sensitivity to environmental pollutants. The aim of the present work was to investigate the possible effect of heavy metal (cadmium, copper, mercury) exposure on Hb concentration and oxidation state (methemoglobin formation) in the earthworm Lumbricus terrestris. In addition, the tissue concentration of metallothioneins, a well-known biomarker of heavy metal exposure, was determined as an indicator of metal uptake. The animals were exposed to increasing concentrations of Cd, Cu and Hg utilizing the standard acute toxicity test, “Filter paper test” for 48 h. Exposure to heavy metals (10⁻⁵–10⁻³ M for Cd, 10⁻⁴–10⁻³ M for Hg, and 10⁻⁴–10⁻² M for Cu) was found to increase haemoglobin concentration in L. terrestris, although the magnitude of such an increase was dependent on the metal. In addition, metal exposure led to the formation of methemoglobin. Compared to other known biological responses to heavy metals, such as metallothionein induction, methemoglobin increase showed a higher sensitivity and a higher percentage variation in exposed organisms, showing to be a possible suitable biomarker of exposure/effect to be included in a multi biomarker strategy in earthworm in soil monitoring assessment.     

地高辛血药浓度监测在临床中的应用

目的：探讨地高辛血药浓度监测的临床意义,为临床合理用药提供参考。方法：采用EMIT法测定地高辛血药浓度,对50例患者的79例次m药浓度监测结果进行回顾性分析。结果：79例次地高辛血药浓度测定值在治疗浓度0．8～2．2ng·ml^-1内的共40例次,占50．63％;低于治疗浓度范围下限（〈0．8ng·ml^-1）的18例次,占22．79％;高于治疗浓度上限（〉2．2ng·ml^-1的21例次,占26．58％。性别对地高辛血药浓度兀显著影响。随年龄增大,地高辛血药浓度呈增高的趋势。结论：通过监测地高辛血药浓度说明本院应用地高辛基本合理。对高龄患者应适当减少地高辛剂量。     

Clinical assessment of drug safety

The environment of drug safety is changing. In addition to the current system of pharmacovigilance based on spontaneous report of adverse events, clinical data observed in a given patient with a given symptom is taken into consideration and compared with information coming from pharmacovigilance data bases, which is then analyzed for causality by the experts of both the promotor and the public network. Such information is integrated into a risk management strategy, defined together by the French drug agency (Afssaps) and the marketing authorization holder. This strategy includes a pharmacovigilance plan and, if possible, a risk minimisation plan.     

Clinical risk assessment of GM foods

The main concerns about adverse effects of genetically modified (GM) foods on health are the transfer of antibiotic resistance, toxicity and allergenicity. There are two issues from an allergic standpoint. First, the transfer of a known allergen may occur from a crop into a non-allergenic target crop. The second scenario is the creation of a neo-allergen where de novo sensitisation occurs in the population. The first scenario occurred in 1996 when the 2S albumen protein from Brazil nut was transferred into soy bean (N. Engl. J. Med. 334 (1996) 688). 2S albumen was found to be a major Brazil nut allergen and the newly expressed protein in transgenic soy retained its allergenicity. Patients allergic to Brazil nuts and not to soy bean now showed an IgE mediated response towards GM soy bean. We argue that it is possible to prevent such occurrences by doing IgE-binding studies and taking into account physico-chemical characteristics of proteins and referring to known allergen databases. The second possible scenario of de novo sensitisation does not easily lend itself to risk assessment. We compare GM technology to traditional plant breeding and food processing methods. There is no evidence that the technology used for the production of GM foods poses an allergic threat per se compared to other methodologies widely accepted in the food industry. We need to proceed cautiously in the future, assessing individual GM foods on the basis of their individual merits and risks prior to introducing them into the market.     

失眠的临床诊断与疗效评估方法

诊断失眠的基本条件是病人存在睡眠始发和(或)睡眠维持发生障碍,导致睡眠时间或睡眠质量不能满足生理需要,并且影响白日的功能。失眠的诊断方法通常包括:问诊(睡眠现状、睡眠习惯、睡眠卫生和药物使用情况);仔细的体格检查能够排除可能存在的躯体疾病相关性失眠;客观评估方法(多导睡眠图、多次小睡潜伏期试验、夜帽、微动敏感床垫、肢体活动电图)和评估量表等。熟练掌握并合理选择应用和综合分析这些结果,能够为失眠的诊断、鉴别诊断和治疗效果的评估提供重要帮助。     

丙戊酸钠血药浓度临床分析

目的探讨丙戊酸钠的浓度与疗效及不良反应等各因素的关系,寻找最佳给药方案,提高临床治疗水平。方法收集病例资料,选取419例次丙戊酸钠血药浓度结果与临床情况进行分析。结果当血药浓度为50～110 mg/L时,控制率为47.4%～63.8%,疗效与血药浓度呈低度相关;当浓度高于110 mg/L时,控制率下降。不良反应在各阶段浓度范围内均有发生,随着浓度增加,发生率逐渐增加。缓释剂组血药浓度明显高于口服液组及普通片组。各年龄组血药浓度:0～3岁组平均53.3 mg/L(略低),60岁组64.9 mg/L(略高),各年龄组疗效差异无统计学意义。结论影响丙戊酸钠血药浓度及其疗效的因素众多,临床使用丙戊酸钠应充分考虑患者生理、病理、不良反应、剂型及合并用药等多方面因素。     

Health assessment of phosgene: approaches for derivation of reference concentration

This paper describes the derivation of the chronic reference concentration (RfC) for human inhalation of phosgene that was recently added to the Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) data base (U.S. EPA, 2005. Toxicological Review of Phosgene: In Support of Summary Information on the Integrated Risk Information System (IRIS). Available online at: ). The RfC is an estimate of daily phosgene exposure to the human population that is likely to be without appreciable risk of deleterious effects during a lifetime. [For this and other definitions relevant to EPA risk assessments refer to the glossary of terms in the US EPA IRIS website (http://www.epa.gov/IRIS).] Phosgene is a potential environmental pollutant that is primarily used as a catalyst in the polyurethane industry. It is a gas at room temperature, and in aqueous solution it rapidly hydrolyzes to CO2 and HCl. In the absence of chronic human health effects information and lifetime animal cancer bioassays, the RfC is based on two 12-week inhalation studies in F344 rats which measured immune response and pulmonary effects, respectively. The immune response study showed impaired clearance of bacteria that was administered into the lungs of rats immediately after exposure to phosgene at concentrations of 0.1, 0.2 and 0.5 ppm. It also showed that the immune response in uninfected rats was stimulated by phosgene exposure at all concentrations. The pulmonary effects study showed a progressive concentration-related thickening and inflammation in the bronchiolar regions of the lung that was mild at 0.1 ppm and severe at 1.0 ppm. An increase in collagen content, as observed with histological collagen stains, was observed at 0.2 ppm and above. Though there is considerable uncertainty associated with the species and exposure duration employed, this endpoint is considered an indication of chronic lung injury of potential relevance to humans. Three different approaches for RfC derivation were taken in analyzing these studies: (1) the traditional NOAEL/LOAEL method; (2) the benchmark dose (BMD); and (3) the categorical regression for the analysis of severity-graded pulmonary damage data using the recently revised USEPA CatReg software. The BMD approach was selected as the method of choice to determine the RfC for phosgene because it has several advantages compared to the NOAEL/LOAEL: (1) it is not restricted to the set of doses used in the experiments; (2) the result is not dependent on sample size; (3) it incorporates information on statistical uncertainty. The CatReg approach allowed the incorporation of data on the severity of the pathological lesions, and therefore it complemented the other approaches. The BMD approach could not be applied to the immune response data because it was not possible to define an adverse effect level for bacterial resistance. However, NOAEL/LOAEL values for immune responses were consistent with benchmark dose levels derived from lung pathology data and used in the derivation of the RfC. The preferred RfC method and derivation involved dividing the benchmark dose from the collagen staining data (0.03 mg/m3) by a composite uncertainty factor of 100: RfC=0.03/100=3E-4 mg/m3.     

Statistical issues of QT prolongation assessment based on linear concentration modeling

The ICH (2005) defined drug-induced prolongation of QT interval, i.e., the duration of depolarization and repolarization of ventricles, as evidenced by an upper bound of the 95% confidence interval around the mean effect on QTc (QT corrected for heart rate) of 10 ms. Furthermore, it defined that a negative thorough QT/QTc study is one in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms. This objective leads to the application of intersection-union tests by testing the mean difference between test treatment and placebo of QTc change from baseline at each of the matched time points at which the observations are collected. The nature of the higher false positive rate due to more observational time points leads to the concern of study efficiency. Based on the concept of clinical pharmacology, a concentration-response modeling approach is often adopted to assess the prolongation size of QTc interval induced by a drug without carefully examining the validity of the assumptions involved. In most of the applications, the model is assumed either to be linear, log-linear, or logistic. The supporter of the modeling often emphasizes the advantage of power improvement and reduction in estimation error. However, it has been often pointed out by statisticians and pharmacologists that modeling under an invalid uniformity assumption across study population often leads to severe bias in testing and estimation. In this article, we examine data sets of New Drug Applications to illustrate the bias and lack of validity of the linearity assumptions.