The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.     

Papnet-assisted cytological diagnosis intensifies the already marked variability among cytological laboratories

OBJECTIVE: The main objective was to assess the sensitivity, specificity and reliability of PAPNET-assisted diagnosis in comparison with conventional screening. SETTING: Seven Italian and one English University or Research Institutes, and a random sample of an other 20 Italian Laboratories of the Italian National Health Service (INHS) provided the cervical smears. METHODS: During the training phase every center examined in rotation four sets of slides for a total of 300 representative slides. Afterwards, 900 "positive" slides were added to the 3,100 slides which were collected consecutively without any selection or exclusion. The eight main centers were divided into four couples and each couple of centers examined 775 slides with the PAPNET system, "blindly" to the original diagnosis. An expert cytopathologist (M.A.) of the National Institute of Health (NIH) reassessed 40% of the slides with an original negative diagnosis to evaluate the false negative rate. Two expert NIH cytopathologists (M.A., G.M.) re-examined all slides where a disagreement had been observed between the original and one or both of the study diagnoses. The main analyses concerned the following three main categories: WNL and unsatisfactory for evaluation; ASCUS, AGUS and LSIL; HSIL and carcinoma. A special algorithm was devised to define the reference diagnosis for sensitivity and specificity assessment. RESULTS: Laboratories, even belonging to the same couple, classified as "no review" a very different proportion of slides ranging from 35% to 74%. The index of kappa agreement between the members of couples examining the same sets of slides was low or very low, ranging from 0.30 to 0.03. The sensitivity of the review classification was particularly low in some laboratories. Surprisingly, only a small correlation was observed between the sensitivity of the review classification and the proportion of slides classified as "review". The "tentative" diagnosis on PAPNET tiles of the "review" slides was almost as reliable as the microscopic diagnosis. In the overall performance, there were many significant differences among the eight laboratories. The best laboratory had a sensitivity of 95% and a specificity of 96%. At least three laboratories displayed unacceptably low sensitivity and one a very low specificity. CONCLUSION: Altogether these results seem to confirm that there are wide differences among cytological laboratories per se, and that these differences are intensified by the use of an instrument like PAPNET. The huge variation in performance may be explained by differences in basic skills and by different training, but it is difficult to understand exactly what could have been done to reduce it.     

双向气道正压通气与不同流速模式同步间歇指令通气在心脏术后的比较研究

目的通过与两种不同流速模式(恒速和减速)同步间歇指令通气(SIMV)比较,评价双相气道正压通气(DuoPAP)在心脏术后应用的安全性和有效性。方法选取心内直视手术者40例,术后分别采用恒速、减速SIMV和DuoPAP模式通气,比较血流动力学、血气、呼吸力学参数及呼吸肌做功指标的变化。结果DuoPAP和减速SIMV的气道压峰值(Ppeak)、气道阻力(Raw)和吸气功(WI)较恒速型SIMV明显降低(p<0·01);前两种通气模式之间比较无统计学差异(p>0·05);三种通气模式的其他指标无统计学差异(p>0·05)。结论与传统的SIMV模式比较,DuoPAP模式对血流动力学、血气参数无明显影响,且与恒速型SIMV比较,可明显降低吸气时的Ppeak、Raw和WI,应用于心脏术后是安全、有效的。     

Surgical treatment of the sleep-disordered breathing patient; a consensus report

Sleep disordered breathing patients may undergo surgical treatment after history, clinical examination and polysomnographic study if they demonstrate upper airway obstruction. This article focus on the surgical treatment designed for these patients. Sino-nasal surgery, rhinopharyngeal procedure, velopharyngeal procedures (Uvulopalato-pharyngoplasty, Laser assisted uvulopalatoplasty, Radiofrequency tissue volume reduction) as well as base of the tongue procedures were discussed among a panel of Belgian ENT specialists offering their experience in this field. Algorithm on corrective surgery as well as guidelines for postoperative management are proposed in the management of sleep disordered breathing patients.     

论医科院校准确定位与科学发展——以蚌埠医学院为例

对大学准确的目标定位是办好大学的基础，定位决定了大学的规格和模式，也决定了大学发展的方向和目标。大学在选择目标定位时既要根据经济和社会发展的需求，又要根据自身的历史和现实条件；既要量力而行，实事求是，又应寻找特色，大胆突破。文章以蚌埠医学院为例，讨论了医学院校准确定位与科学发展的关系。     

When inflicted skin injuries constitute child abuse

Child abuse should be considered as the most likely explanation for inflicted skin injuries if they are nonaccidental and there is any injury beyond temporary reddening of the skin. Minor forms of abuse may lead to severe abuse unless abusive skin injuries are identified and labeled as such and interventions are made.     

腺嘌呤所致大鼠慢性肾功能衰竭的实验研究

目的:研究慢性肾功能衰竭(chronic renal failure,CRF)大鼠模型的肾功能改变.方法:采用腺嘌呤灌胃大鼠,诱导肾衰模型,并检测血清肌酐、尿素氮和24 h尿蛋白定量及肾脏标本.结果:发现上述指标有较理想的结果.结论:提示腺嘌呤按体重灌胃给药,结果稳定、可控,能达到慢性肾功能衰竭的造模要求.