In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field.     

不同规格怀牛膝不同极性部位HPLC指纹图谱

目的研究并比较不同规格怀牛膝不同极性部位的HPLC指纹图谱,探索其内部质量差异,为该药材的规格标准完善及临床用药提供参考。方法将怀牛膝用体积分数75%乙醇水浴回流提取,得体积分数75%乙醇回流提取物,用40 mL水溶解后,依次用石油醚、三氯甲烷、乙酸乙酯、正丁醇进行萃取,得到各萃取相及萃取后的水相,浓缩至浸膏,采集各部位HPLC指纹图谱;运用相似度、综合聚类法进行数据分析,同时对其不同部位的指纹图谱进行比对分析。结果石油醚、氯仿部位均标定了11个共有峰,乙酸乙酯部位标定了10个共有峰,正丁醇部位标定了19个共有峰,水部位标定8个共有峰;氯仿部位指纹图谱相似度差异较大,其他部位指纹图谱相似度差异较小,均在0.9以上;石油醚部位指纹图谱差异主要体现在峰高,乙酸乙酯部位、氯仿部位、水部位的化学成分种类及峰高均存在差异;综合聚类分析能将不同规格怀牛膝区分开。结论不同规格怀牛膝内部质量存在差异;实验中所建立的HPLC指纹图谱可以全面反映不同规格怀牛膝的化学成分分布,为不同规格怀牛膝的整体质量评价提供参考。     

Association Between Patient and Physician Sex and Physician-Estimated Stroke and Bleeding Risks in Atrial Fibrillation

Background

Physicians treating nonvalvular atrial fibrillation (AF) assess stroke and bleeding risks when deciding on anticoagulation. The agreement between empirical and physician-estimated risks is unclear. Furthermore, the association between patient and physician sex and anticoagulation decision-making is uncertain.

Risk communication in a patient decision aid for radiotherapy in breast cancer: How to deal with uncertainty?

Background and aimPatient decision aids for oncological treatment options, provide information on the effect on recurrence rates and/or survival benefit, and on side-effects and/or burden of different treatment options. However, often uncertainty exists around the probability estimates for recurrence/survival and side-effects which is too relevant to be ignored. Evidence is lacking on the best way to communicate these uncertainties. The aim of this study is to develop a method to incorporate uncertainties in a patient decision aid for breast cancer patients to support their decision on radiotherapy.MethodsFirstly, qualitative interviews were held with patients and health care professionals. Secondly, in the development phase, thinking aloud sessions were organized with four patients and 12 health care professionals, individual and group-wise.ResultsConsensus was reached on a pictograph illustrating the whole range of uncertainty for local recurrence risks, in combination with textual explanation that a more exact personalized risk would be given by their own physician. The pictograph consisted of 100 female icons in a 10 x 10 array. Icons with a stepwise gradient color indicated the uncertainty margin. The prevalence and severity of possible side-effects were explained using verbal labels.ConclusionsWe developed a novel way of visualizing uncertainties in recurrence rates in a patient decision aid. The effect of this way of communicating risk uncertainty is currently being tested in the BRASA study (NCT03375801).     

Sleep time and sleep-related symptoms across two generations – results of the community-based RHINE and RHINESSA studies

Study objectivesTo analyze the association between sleep-related symptoms and sleep length in parents and their children in relation to other risk factors in both generations.MethodThe participants were parents (n = 5,855, age 54.3 ± 6.5 years, 45.2% men) who participated in the community-based Respiratory Health in Northern Europe (RHINE) study and one random member of their adult offspring (n = 5,855, age 30.2 ± 7.7 years, 41.5% men) who participated in the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) study. Both generations responded to identical questionnaires on sleep symptoms, including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), snoring, nocturnal sweating, nocturnal gastroesophageal reflux (nGER), sleep time and excessive daytime sleepiness (EDS). Insomnia was defined as either, or both, DIS and DMS in combination with EDS.ResultsAll sleep variables except nocturnal sweating were more common in offspring whose parents had reported the same symptom. After adjusting for age, gender, BMI, smoking, physical activity, education, center and parents' total number of children, there were independent associations between sleep symptoms in parents and offspring for DIS (adj. OR, 95% CI: 1.52, 1.20–1.93), DMS (1.34, 1.15–1.56), snoring (1.45, 1.15,1.83), nGER (1.65, 1.15–2.37), insomnia (1.39, 1.13–1.73), short sleep time (<6 h/night) (2.51, 1.72–3.68) and EDS (1.48, 1.26,1.72). There were no independent relationships between symptoms in parents and offspring for EMA, nocturnal sweating or long sleep time (>9 h/night).ConclusionThe familiar aggregation of many sleep disturbances was not explained by investigated lifestyle and environmental factors. This supports a heritable factor in sleep problems.     

社区老年患者拔牙的临床特点分析

目的：通过对近两年社区卫生服务中心327例老年病人拔牙临床观察，探讨基层社区老年病人的特点。方法：通过心理、精神和技术方面的配合，安全顺利地完成拔牙术。结果：除5例病人术后感头晕外，其余均顺利完成且病人满意。结论：社区卫生服务中心除具备熟练的技术外，医患之间心理沟通是必不可少的。     

肝癌间质及癌旁病变的病理分析

目的　研究肝癌间质及癌旁病变的临床病理意义。方法　在 2 0例肝癌组织标本中取 45个癌结节 ,分别在癌结节中间、癌旁肝组织等部位取组织 4块 ,连续切片 ,显微镜下观察。结果　 19个结节有完整窦内皮细胞围绕癌巢 ,其中癌结节肉眼小于3cm者 13个 ,大于 3cm者 6个。 2 6个癌结节无完整窦内皮细胞围绕癌巢 ,其中癌结节直径大于 3cm者 2 4个 ,小于 3cm者 2个。2 0例中有 13例合并肝硬化 ,17例有乙型肝炎病毒感染和HBsAg阳性。 结论　病理连续切片 ,显微镜下观察肝癌间质及癌旁病变是预测肝癌患者预后的重要病理学指标     

WHAT KIND OF BENEFIT DO WE EXPECT FOR PERORAL PANCREATOSCOPY IN THE DIAGNOSIS OF INTRADUCTAL PAPILLARY MUCINOUS TUMOR OF THE PANCREAS?

Intraductal papillary mucinous tumor (IPMT) of the pancreas is characterized by slow growth and a relatively favorable prognosis, however, invasive cancer originating in an IPMT is associated with a poor prognosis. Although various parameters in imaging modalities have been advocated to differentiate between benign IPMN and malignant ones, it is not easy to obtain definite diagnosis based on these parameters. Peroral pancreatoscopy (POPS) allows a clear and direct visualization of the pancreatic duct, providing useful information regarding tumor nature in IPMT. The authors have studied the usefulness of POPS in the diagnosis of IPMT. Nevertheless, its usefulness is not necessarily widely accepted and the significance of POPS is still controversial. In this review, the authors intended to address the diagnostic value of POPS and to clarify its role in the diagnosis of IPMT. The authors think treatment of IPMT can be improved by introducing POPS because the determination of surgical procedure as well as the area of resection based on the preoperative diagnosis of the involvement of the main pancreatic duct and branch duct is inevitable.