BACKGROUND & AIMS: Many genotoxic agents kill tumor cells by inducing apoptosis; hence, mutations that suppress apoptosis produce resistance to chemotherapy. Although directly activating the apoptotic machinery may bypass these mutations, how to achieve this activation in cancer cells selectively is not clear. In this study, we show that the drug-resistant 293 cell line is unable to activate components of the apoptotic machinery-the ICE-like proteases (caspases)-following treatment with an anticancer drug. Remarkably, extracts from untreated cells spontaneously activate caspases and induce apoptosis in a cell-free system, indicating that drug-resistant cells have not only the apoptotic machinery but also its activator. Comparing extracts from cells with defined genetic differences, we show that this activator is generated by the adenovirus E1A oncogene and is absent from normal cells. We provide preliminary characterization of this oncogene generated activity (OGA) and show that partially purified OGA activates caspases when added to extracts from untransformed cells. We suggest that agents that link OGA to caspases in cells would kill tumor cells otherwise resistant to conventional cancer therapy. As this killing relies on an activity generated by an oncogene, the effect of these agents should be selective for transformed cells.

背景与目标： 许多遗传毒性剂通过诱导细胞凋亡杀死肿瘤细胞。因此，抑制细胞凋亡的突变产生了对化学疗法的抗性。尽管直接激活凋亡机制可能绕过这些突变，但是如何在癌细胞中选择性地实现这种激活尚不清楚。在这项研究中，我们显示了抗药性293细胞系无法激活凋亡机制的成分（如ICE样蛋白酶（胱天蛋白酶）），随后进行了抗癌药物治疗。值得注意的是，未经处理的细胞提取物会自发激活胱天蛋白酶并在无细胞系统中诱导凋亡，这表明耐药细胞不仅具有凋亡机制，还具有其激活剂。比较具有确定的遗传差异的细胞提取物，我们表明该激活剂是由腺病毒E1A癌基因产生的，而正常细胞中却不存在。我们提供了此致癌基因产生的活性（OGA）的初步表征，并表明当添加到未转化细胞的提取物中时，部分纯化的OGA会激活胱天蛋白酶。我们建议将OGA与细胞中的半胱氨酸蛋白酶连接的药剂会杀死肿瘤细胞，否则它们会对常规癌症治疗产生抵抗力。由于这种杀伤作用依赖于癌基因产生的活性，因此这些药剂对转化细胞的作用应该是选择性的。

BACKGROUND & AIMS: :Adenovirus infection results in the suppression of cellular protein synthesis, but the mechanism has not been established. In this report we demonstrate that the shut-off of cellular protein synthesis by adenovirus is prevented in cells by treatment with the drug 2-aminopurine. Treatment with 2-aminopurine is shown to prevent suppression of cellular translation without disrupting the normal viral block in the transport of cellular mRNAs from the nucleus to the cytoplasm. We show that viral suppression of cellular protein synthesis occurs concomitant with activation of the interferon-induced double-stranded RNA-activated inhibitor (DAI), a protein kinase, and phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha), but that prevention of host cell shut-off by 2-aminopurine occurs without a decrease in kinase activity or a dephosphorylation of eIF-2 alpha. Results are presented that indicate that activation of DAI kinase and phosphorylation of eIF-2 alpha may be required but are not sufficient to achieve inhibition of cellular protein synthesis during adenovirus infection. We suggest that other events, in particular the modification of additional initiation factors, are likely involved in viral inhibition of cellular translation.

背景与目标： ：腺病毒感染导致细胞蛋白质合成受到抑制，但该机制尚未建立。在本报告中，我们证明了通过用2-氨基嘌呤药物治疗可防止腺病毒关闭细胞蛋白质合成。已显示用2-氨基嘌呤处理可防止细胞翻译受到抑制，而不会破坏细胞mRNA从细胞核到细胞质的运输过程中的正常病毒阻滞。我们显示病毒抑制细胞蛋白质合成的发生与干扰素诱导的双链RNA激活的抑制剂（DAI），蛋白激酶和真核生物起始因子2（eIF-2 alpha）的α亚基的磷酸化的激活同时发生。 ，但可以防止2-氨基嘌呤阻止宿主细胞的关闭，而不会降低激酶活性或eIF-2α的去磷酸化。结果表明，可能需要DAI激酶的激活和eIF-2α的磷酸化，但不足以抑制腺病毒感染期间细胞蛋白质合成。我们建议其他事件，特别是其他起始因子的修饰，可能与细胞翻译的病毒抑制有关。

BACKGROUND & AIMS: CONTEXT:Chronic pain in patients with advanced cancer poses a serious clinical challenge. The Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (U.S. Adopted Name, nabiximols; Sativex(®)) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group. OBJECTIVES:This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer. METHODS:In total, 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing, who had participated in a previous three-arm (THC/CBD spray, THC spray, or placebo), two-week parent randomized controlled trial, entered this open-label, multicenter, follow-up study. Patients self-titrated THC/CBD spray (n=39) or THC spray (n=4) to symptom relief or maximum dose and were regularly reviewed for safety, tolerability, and evidence of clinical benefit. RESULTS:The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for "pain severity" and "worst pain" domains showed a decrease (i.e., improvement) at each visit in the THC/CBD spray patients. Similarly, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scores showed a decrease (i.e., improvement) from baseline in the domains of insomnia, pain, and fatigue. No new safety concerns associated with the extended use of THC/CBD spray arose from this study. CONCLUSION:This study showed that the long-term use of THC/CBD spray was generally well tolerated, with no evidence of a loss of effect for the relief of cancer-related pain with long-term use. Furthermore, patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time, suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit.

背景与目标： 背景：晚期癌症患者的慢性疼痛提出了严峻的临床挑战。 Δ9-四氢大麻酚（THC）/大麻二酚（CBD）口腔粘膜喷雾剂（美国采用名称，nabiximols;Sativex®）是一种新型大麻素制剂，目前正在接受治疗，作为该治疗组的辅助疗法。
目的：这项随访研究调查了THC / CBD喷雾剂和THC喷雾剂在缓解晚期癌症患者的疼痛方面的长期安全性和耐受性。
方法：总共有43例癌症相关疼痛患者尽管使用了阿片类药物长期服用，但仍没有足够的镇痛作用，他们参加了先前的三组试验（THC / CBD喷雾剂，THC喷雾剂或安慰剂），为期两周的父母随机对照试验，参加了这项开放性，多中心的后续研究。患者自行滴定THC / CBD喷雾剂（n = 39）或THC喷雾剂（n = 4）以缓解症状或最大剂量，并定期检查其安全性，耐受性和临床获益证据。
结果：THC / CBD喷剂患者每次就诊时，“疼痛严重程度”和“最严重疼痛”域的平均简短疼痛清单-简表得分的基线变化的功效终点显示出降低（即改善）。同样，欧洲癌症生活质量研究和治疗组织问卷-C30的得分显示，失眠，疼痛和疲劳程度较基线水平有所降低（即有所改善）。这项研究没有引起与广泛使用THC / CBD喷雾剂相关的新安全隐患。
结论：这项研究表明，长期使用THC / CBD喷雾剂通常具有良好的耐受性，没有证据表明长期使用THC / CBD喷雾剂可减轻癌症相关疼痛。此外，继续使用研究药物的患者并未寻求随时间增加这种药物或其他缓解疼痛药物的剂量，这表明在与癌症相关的疼痛中辅助使用大麻素可提供有益的益处。

BACKGROUND & AIMS: BACKGROUND:The Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] (CHADS(2)) score is a useful scheme for risk stratification of thromboembolism patients, but there is little information about its usefulness for the evaluation of antiarrhythmic drug (AAD) therapy. METHODS AND RESULTS:This study included 459 paroxysmal atrial fibrillation (AF) patients (309 men, mean age 66 ± 12 years, mean follow-up 50 ± 35 months) and prophylactic efficacy was analyzed on the basis of CHADS(2) score. (1) Survival rates free from AF recurrence at 1, 6, 12 and 24 months were, respectively, 89%, 74%, 63% and 47% in score-0 group (n=152); 92%, 68%, 59% and 48% in score-1 group (n=158); 86%, 64%, 56% and 46% in score-2 group (n=84); 81%, 65%, 51% and 35% in score-3 group (n=43); and 68%, 50%, 36% and 18% in ≥ score-4 group (n=22) (P<0.05; score-0, score-1 or score-2 vs. ≥ score-4 group). (2) Survival rates free from progression to chronic AF at 12, 36, 60 and 90 months were, respectively, 95%, 93%, 91% and 89% in score-0 group; 97%, 91%, 89% and 88% in score-1 group; 96%, 93%, 88% and 83% in score-2 group; 91%, 74%, 67% and 60% in score-3 group; and 91%, 82%, 68% and 55% in ≥ score-4 group (P<0.01; score-0, score-1 or score-2 vs. ≥ score-4 group). (3) In multivariate logistic regression analysis adjusted for potentially confounding variables, CHADS(2) score was associated with AF recurrence (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.16-1.81, P<0.001), and progression to chronic AF during AAD therapy (OR 1.64, 95% CI 1.04-2.69, P<0.001). CONCLUSIONS:When using a rhythm control strategy, the CHADS(2) score is a useful scheme for predicting the outcome of AAD treatment of patients with paroxysmal AF.  

背景与目标： 背景：心脏衰竭，高血压，年龄，糖尿病，中风[加倍]（CHADS（2））评分是对血栓栓塞患者进行风险分层的有用方案，但有关其对抗心律不齐药物（AAD）评估的有用性的信息很少） 治疗。
方法与结果：这项研究纳入459例阵发性房颤（AF）患者（309名男性，平均年龄66±12岁，平均随访50±35个月），并根据CHADS（2）评分分析了其预防性疗效。 （1）得分为0的组在1、6、12和24个月无房颤复发的生存率分别为89％，74％，63％和47％（n = 152）；得分1组（n = 158）为92％，68％，59％和48％；得分2组分别为86％，64％，56％和46％（n = 84）；得分3组（n = 43）分别为81％，65％，51％和35％； ≥分数4组的患者分别为68％，50％，36％和18％（n = 22）（P <0.05；分数≥0，分数1或得分2与≥分数4组相比）。 （2）在0级评分组中，在12、36、60和90个月无进展为慢性房颤的生存率分别为95％，93％，91％和89％；得分1组分别为97％，91％，89％和88％；得分2组分别为96％，93％，88％和83％；分数3组的比例分别为91％，74％，67％和60％； ≥4分组分别为91％，82％，68％和55％（P <0.01； 0分，1分或2分与≥4分组比较）。 （3）在针对潜在混杂变量进行调整的多因素logistic回归分析中，CHADS（2）评分与房颤复发相关（优势比[OR] 1.45、95％置信区间[CI] 1.16-1.81，P <0.001）和进展到AAD治疗期间的慢性房颤（OR 1.64，95％CI 1.04-2.69，P <0.001）。
结论：使用节律控制策略时，CHADS（2）评分是预测阵发性房颤患者AAD治疗结果的有用方案。

BACKGROUND & AIMS: :Improvements in health care are slow, in part because doctors and nurses lack skills in quality improvement, patient safety, and interprofessional teamwork. This article reports on the Retooling for Quality and Safety initiative of the Josiah Macy Jr. Foundation and the Institute for Healthcare Improvement, which sought to integrate improvement and patient safety into medical and nursing school curricula. In one academic year, 2009-10, the initiative supported new learning activities (87 percent of which were interprofessional, involving both medical and nursing students) in classrooms, simulation centers, and clinical care settings that involved 1,374 student encounters at six universities. The work generated insights-described in this article-into which learning goals require interprofessional education; how to create clinically based improvement learning for all students; and how to demonstrate the effects on students' behavior, organizational practice, and benefits to patients. A commonly encountered limiting factor for the programs was the lack of a critical mass of clinically based faculty members who were ready to teach about the improvement of care. What's more, the paucity of robust evaluation strategies for such programs suggests a future research agenda that deserves to be funded.

背景与目标： ：医疗保健方面的改进缓慢，部分原因是医生和护士缺乏提高质量，患者安全和跨专业团队合作的技能。本文报道了Josiah Macy Jr. Foundation和医疗保健改善研究所的“质量与安全重组”倡议，该倡议旨在将改善和患者安全纳入医疗和护理学校课程。在2009-10学年的一个学年中，该计划支持了教室，模拟中心和临床护理环境中的新学习活动（其中87％是跨专业的，涉及医学和护理学的学生），涉及六所大学的1,374名学生。这项工作产生了本文中介绍的见解，其中的学习目标需要跨专业的教育；如何为所有学生创建基于临床的改进学习；以及如何证明对学生的行为，组织实践和对患者的好处的影响。该计划的一个普遍遇到的限制因素是缺乏足够数量的临床教师来准备教授改善护理的知识。而且，此类计划缺乏强有力的评估策略，这表明未来的研究议程值得资助。

BACKGROUND & AIMS: :Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α(1A)-adrenoceptors (in the prostate), α(1D)-adrenoceptors (in the aorta), and an unknown mechanism (in the heart) are involved, respectively. We hypothesized that there is a chiral recognition of doxazosin enantiomers in the 3 targets. Using isolated rat aorta (α(1D)-adrenoceptors) and rabbit prostate (α(1A)-adrenoceptors), we examined pA(2) and pK(B) values of doxazosin enantiomers. We observed chronotropic and inotropic effects of doxazosin enantiomers in isolated rat and rabbit heart tissues. (-)Doxazosin and (+)doxazosin produced a shift to the right of concentration-contraction curves for noradrenalin (aorta) and phenylephrine (prostate smooth muscle). The pA(2) value of (-)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pK(B) values in rabbit prostate were the same. In rat and rabbit heart tissues, (+)doxazosin (3-30 µmol·L(-1)) significantly decreased atrial rate, and produced negative inotropic effects; however, (-)doxazosin did not affect the atrial rate, and produced positive inotropic effects in the atria. Thus, the chiral carbon atom of doxazosin does not affect its activity at the therapeutic target of α(1A)-adrenoceptors in the prostate, but significantly changes its blocking activity against α(1D)-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α(1)-adrenoceptor-independent mechanism.

背景与目标： ：多沙唑嗪用于前列腺增生症具有引起低血压和心力衰竭风险的副作用。 α（1A）-肾上腺素受体（在前列腺中），α（1D）-肾上腺素受体（在主动脉中）和未知机制（在心脏中）的3个靶点分别涉及。我们假设在3个靶标中有手性识别多沙唑嗪对映体。使用分离的大鼠主动脉（α（1D）-肾上腺素受体）和兔前列腺（α（1A）-肾上腺素受体），我们检查了多沙唑嗪对映体的pA（2）和pK（B）值​​。我们观察到了多沙唑嗪对映异构体在离体大鼠和兔心脏组织中的变时性和变力作用。 （-）多沙唑嗪和（）多沙唑嗪使去甲肾上腺素（主动脉）和去氧肾上腺素（前列腺平滑肌）的浓度-收缩曲线向右移动。大鼠主动脉中（-）恶唑烷的pA（2）值（8.625±0.053）小于（）恶唑烷（9.503±0.051），但它们在兔前列腺中的pK（B）值​​相同。在大鼠和兔子的心脏组织中，（）多沙唑嗪（3-30 µmol·L（-1））显着降低心房率，并产生负性变力作用；然而，（-）doxazosin不会影响心房率，并在心房产生正性肌力作用。因此，多沙唑嗪的手性碳原子不影响其对前列腺中α（1A）-肾上腺素受体治疗靶点的活性，但会显着改变其对主动脉中α（1D）-肾上腺素受体的阻断活性，并产生相反的正性肌力作用通过独立于α（1）-肾上腺素受体机制的心房。

BACKGROUND & AIMS: :A large-scale study was carried out in order to determine the contamination level of antineoplastic drugs in pharmacies and to investigate the suitability and effects of wipe sample monitoring at regular intervals. A specific study design was developed. The 130 participating pharmacies were divided into a study and a control group, carrying out five and two wipe sampling cycles, respectively. The work practice was analyzed using questionnaires to identify factors that influence the contamination level. From 1269 wipe samples, 774 (61%) were contaminated with at least one of the analyzed cytotoxic drugs: cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, methotrexate, and paclitaxel. A significant decrease of the contamination with cyclophosphamide and 5-fluorouracil was observed in the study group. The Monitoring-Effect Study of Wipe Sampling in Pharmacies method has proven to be a reliable and affordable tool for contamination control. Based on the 90th percentile of the contamination values, a substance-independent performance-based guidance value of 0.1ng cm(-2) has been derived.

背景与目标： ：进行了一项大规模研究，以确定药房中抗肿瘤药的污染水平，并定期调查擦拭样品监测的适用性和效果。开发了具体的研究设计。将130家参与活动的药店分为研究组和对照组，分别进行了5次和2次擦拭采样。使用调查表对工作实践进行了分析，以找出影响污染水平的因素。从1269个擦拭样品中，有774个（61％）被至少一种分析的细胞毒性药物污染：环磷酰胺，多西他赛，依托泊苷，5-氟尿嘧啶，吉西他滨，异环磷酰胺，甲氨蝶呤和紫杉醇。在研究组中观察到环磷酰胺和5-氟尿嘧啶的污染显着降低。药房擦拭采样的监测效果研究方法被证明是一种可靠且负担得起的污染控制工具。基于污染值的第90个百分位数，得出了与物质无关的基于性能的指导值0.1ng cm（-2）。

BACKGROUND & AIMS: :The objective of this study was to prepare a 72 h-release formulation of silybin (72 h-SLB) using a combination of solid dispersion, gel matrix and porous silica nanoparticles (PSNs) and to investigate the in vitro/in vivo correlations (IVIVCs). The results of scanning electron microscopy and N(2) adsorption demonstrated that empty PSNs possessed a spherical shape, a highly porous structure, a large specific surface area (385.89 ± 1.12 m(2)/g) and a small pore size (2.74 nm on average). The in vitro dissolution profiles of both 72 h-SLB and silybin-loaded PSNs in different concentrations (0.01, 0.06 and 0.08M) of Na(2)CO(3) solutions revealed that 0.06 M Na(2)CO(3) solution was the optimal medium in which silybin could be released from 72 h-SLB with first-order release kinetics and from PSNs with Higuchi kinetics. Furthermore, the IVIVCs of 72 h-SLB and silybin-loaded PSNs in beagle dogs were also established. Using 0.06 M Na(2)CO(3) solution as the in vitro dissolution medium, a good linear relationship could be achieved for both 72 h-SLB and silybin-loaded PSNs. The findings support the fact that the 72 h-SLB (consisting of solid dispersion, regular gel matrix and PSNs) together with Na(2)CO(3) solution as an in vitro dissolution medium can be developed into a promising formulation for poorly soluble drugs, which enjoys a good IVIVC.

背景与目标： ：这项研究的目的是使用固体分散体，凝胶基质和多孔二氧化硅纳米粒子（PSN）的组合制备水飞蓟宾（72 h-SLB）的72 h释放制剂，并研究体内/体外相关性（ IVIVC）。扫描电子显微镜和N（2）吸附的结果表明，空的PSN具有球形，高度多孔的结构，较大的比表面积（385.89±1.12 m（2）/ g）和较小的孔径（2.74 nm）一般）。 Nah（2）CO（3）解决方案中不同浓度（0.01、0.06和0.08M）的72 h-SLB和水飞蓟宾加载的PSNs的体外溶出曲线显示0.06 M Na（2）CO（3）解决方案是最佳的培养基，其中水飞蓟宾可以从72 h-SLB中以一级释放动力学释放，而从PSN中以Higuchi动力学释放。此外，还建立了比格犬中72 h-SLB和水飞蓟宾的PSN的IVIVC。使用0.06 M Na（2）CO（3）解决方案作为体外溶出介质，可以为72 h-SLB和水飞蓟宾加载的PSNs都实现良好的线性关系。这些发现支持以下事实：72 h-SLB（由固体分散体，规则的凝胶基质和PSN组成）与Na（2）CO（3）解决方案一起作为体外溶出介质，可以开发为溶解性较差的有前途的制剂药物，享有良好的IVIVC。

BACKGROUND & AIMS: BACKGROUND:Major advances in our understanding of the underlying biology of prostate cancer have helped to herald a new era in the treatment of castration-resistant prostate cancer (CRPC), with 5 new agents having shown a survival advantage in the last 3 years and an impressive number of promising novel agents now entering the clinic. CONTENT:We discuss the challenges facing drug development for CRPC and strategies to meet these challenges, with a focus not only on the development of predictive and intermediate endpoint biomarkers, but also on novel hypothesis-testing, biomarker-driven clinical trial designs. SUMMARY:With several promising agents now entering the clinic, there is increasing pressure to rethink drug development for CRPC to ensure that novel agents are appropriately evaluated and that patients and resources are appropriately allocated. We envision that biomarker-driven, reiterative clinical trials will have a major impact on CRPC treatment through the testing of robust scientific hypotheses with rationally designed drugs and drug combinations administered to selected patients.

背景与目标： 背景：我们对前列腺癌基础生物学的认识的重大进步帮助开创了去势抵抗性前列腺癌（CRPC）治疗的新时代，最近5年中有5种新药显示出生存优势，并且数量惊人的有希望的新型药物进入临床。
内容：我们讨论了针对CRPC的药物开发面临的挑战以及应对这些挑战的策略，不仅着眼于预测性和中间终点生物标志物的开发，还着重于新的假设检验，生物标志物驱动的临床试验设计。
简介：随着一些有前途的药物进入临床，对CRPC进行药物开发的重新思考的压力越来越大，以确保对新型药物进行适当评估，并适当分配患者和资源。我们设想，通过对合理设计的药物和给药于选定患者的药物进行可靠的科学假设测试，生物标记物驱动的重复性临床试验将对CRPC治疗产生重大影响。

BACKGROUND & AIMS: :Amyotrophic lateral sclerosis (ALS) is an unrelenting progressive neurodegenerative disease causing progressive weakness, ultimately leading to death. Despite aggressive research, the pathways leading to neuronal death are incompletely understood. Riluzole is the only drug clinically proven to enhance survival of ALS patients, but its mechanism of action is not clearly understood. In this article, the proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death. Based on these mechanisms, past major ALS drug studies will be reviewed as well as promising current ALS drug studies, focusing on the advancement of these studies from the bench to the patient's bedside.

背景与目标： 肌萎缩性侧索硬化症（ALS）是一种持续不断的进行性神经退行性疾病，会导致进行性无力，最终导致死亡。尽管进行了积极的研究，导致神经元死亡的途径仍未完全了解。利鲁唑是临床上唯一被证明可提高ALS患者生存率的药物，但其作用机理尚不清楚。在本文中，对ALS的拟议病理生理进行了综述，包括谷氨酸兴奋性毒性，氧化应激，线粒体功能障碍，自身免疫机制，蛋白质聚集，SOD1积累和神经元死亡。基于这些机制，将回顾过去的主要ALS药物研究以及有前途的当前ALS药物研究，重点是这些研究从实验台到患者床边的进展。

BACKGROUND & AIMS: OBJECT:Quality and safety are basic concerns in any medical practice. Especially in daily surgical practice, with increasing turnover and shortened procedure times, attention to these topics needs to be assured. Starting in 2007, the authors used a perioperative checklist in all elective procedures and extended the checklist in January 2011 according to the so-called team time-out principles, with additional assessment of patient identity and the planned surgical procedure performed immediately before skin incision, including the emergency cases. METHODS:The advanced perioperative checklist includes parts for patient identification, preoperative assessments, team time-out, postoperative treatment, and imaging controls. All parts are signed by the responsible physician except for the team time-out, which is performed and signed by the theater nurse on behalf of the surgeon immediately before skin incision. RESULTS:Between January 2007 and December 2010, 1 wrong-sided bur hole in an emergency case and 1 wrong-sided lumbar approach in an elective case (of 8795 surgical procedures) occurred in the authors' department. Using the advanced perioperative checklist including the team time-out principles, no error occurred in 3595 surgical procedures (January 2011-June 2012). In the authors' department all team members appreciate the chance to focus on the patient, the surgical procedure, and expected difficulties. The number of incomplete checklists and of patients not being transferred into the operating room was lowered significantly (p = 0.002) after implementing the advanced perioperative checklist. CONCLUSIONS:In the authors' daily experience, the advanced perioperative checklist developed according to the team time-out principles improves preoperative workup and the focus of the entire team. The focus is drawn to the procedure, expected difficulties of the surgery, and special needs in the treatment of the particular patient. Especially in emergency situations, the team time-out synchronizes the involved team members and helps to improve patient safety.

背景与目标： 对象：质量和安全性是任何医学实践中的基本问题。尤其是在日常外科手术中，随着人员流动的增加和手术时间的缩短，需要确保对这些主题的关注。从2007年开始，作者根据所谓的小组超时原则在所有选修程序中使用了围手术期检查表，并于2011年1月扩展了检查表，另外对患者的身份进行了评估，并计划在切开皮肤之前进行手术计划，包括紧急情况。
方法：围手术期高级检查清单包括患者识别，术前评估，团队超时，术后治疗和影像控制的部分。除团队超时外，所有部件均由负责的医生签名，团队超时是由手术室护士在皮肤切开之前代表外科医生执行并签名的。
结果：在2007年1月至2010年12月之间，在提交人的科室中发生了1例紧急情况下的错牙钻洞和1例选择性情况下的腰椎错位入路手术（共8795次手术）。使用包括团队超时原则在内的高级围手术期检查表，在3595例外科手术中没有发生错误（2011年1月至2012年6月）。在作者部门，所有团队成员都很高兴有机会专注于患者，手术程序和预期的困难。实施高级围手术期检查清单后，不完整检查清单的数量和未转移到手术室的患者的人数显着降低（p = 0.002）。
结论：根据作者的日常经验，根据团队超时原则制定的高级围手术期检查清单可以改善术前检查和整个团队的工作重点。重点是手术程序，手术的预期困难以及对特定患者进行治疗的特殊需要。尤其是在紧急情况下，团队超时可以同步参与团队的成员，并有助于提高患者的安全性。

BACKGROUND & AIMS: :The present study aimed to examine the long-term efficacy and safety of rotigotine treatment for restless legs syndrome (RLS), as well as the rate of clinically significant augmentation, in a 1-year open-label study of Japanese subjects. Japanese patients with RLS who had been treated with rotigotine or placebo in a double-blind trial were enrolled in a 1-year, open-label, uncontrolled extension study and treated with rotigotine at a dose of up to 3 mg/24 h after an 8-week titration phase. Outcomes included International Restless Legs Syndrome Study Group rating scale (IRLS scale), Pittsburgh Sleep Quality Index (PSQI), safety, and investigator-/expert panel-assessed augmentation (including Augmentation Severity Rating Scale). Overall, 185 patients entered the open-label study and 133 completed the study. IRLS and PSQI total scores improved throughout the 52-week treatment period (IRLS, from 23.2±5.1 to 7.8±7.6 and PSQI, from 8.0±3.1 to 5.0±2.9). Treatment-emergent adverse events were mild to moderate in severity, and included application site reactions (52.4%) and nausea (28.6%). Clinically significant augmentation occurred in five patients (2.7%). These results indicate a good long-term efficacy of rotigotine for treating RLS, with a relatively low risk of clinically significant augmentation.

背景与目标： ：本研究旨在对日本受试者进行为期1年的开放标签研究，以探讨罗替戈汀治疗躁动性腿综合征（RLS）的长期疗效和安全性，以及临床显着性增高的比率。曾在一项双盲试验中接受过罗替戈汀或安慰剂治疗的日本RLS患者参加了为期1年的开放标签，非对照扩展研究，并在接受罗格替汀治疗后3毫克/ 24小时内接受了剂量8周的滴定阶段。结果包括国际躁动腿综合症研究组评分量表（IRLS量表），匹兹堡睡眠质量指数（PSQI），安全性以及研究者/专家小组评估的增强（包括增强严重度评分量表）。总体而言，有185位患者进入了开放标签研究，其中133位完成了研究。在整个52周的治疗期间，IRLS和PSQI总分有所改善（IRLS从23.2±5.1降低到7.8±7.6，PSQI从8.0±3.1降低到5.0±2.9）。突发性治疗不良事件的严重程度为轻度至中度，包括应用部位反应（52.4％）和恶心（28.6％）。有五名患者（2.7％）发生了临床上明显的增强。这些结果表明罗替戈汀治疗RLS具有良好的长期疗效，临床上显着增强的风险相对较低。

BACKGROUND & AIMS: :The estrogenic activity of tamoxifen on the uterus increases the risk of developing benign and malignant uterine pathologies in breast cancer patients receiving this drug. This has led to gynecological interventions specifically in symptomatic women to exclude malignant disease. Given this known side effect associated with tamoxifen therapy, newer endocrine therapies such as the third-generation aromatase inhibitors have been compared to tamoxifen also in terms of their uterine effects. To date, studies that have directly compared the uterine effects of tamoxifen with that of aromatase inhibitors generally show that aromatase inhibitors such as anastrozole, letrozole, and exemestane are associated with less uterine pathologies compared to tamoxifen. Furthermore, aromatase inhibitors may even reverse uterine abnormalities induced by tamoxifen. This implies that the absence of a stimulatory effect on the uterus would be one of the benefits gained with aromatase inhibitor therapy and may decrease or even obviate the need for gynecological interventions.

背景与目标： ：他莫昔芬对子宫的雌激素活性增加了接受这种药物的乳腺癌患者发生良性和恶性子宫病变的风险。这导致专门针对有症状妇女的妇科干预措施，以排除恶性疾病。考虑到与他莫昔芬疗法有关的已知副作用，就其子宫作用而言，已将较新的内分泌疗法（如第三代芳香化酶抑制剂）与他莫昔芬进行了比较。迄今为止，直接将他莫昔芬与芳香酶抑制剂的子宫作用进行比较的研究通常显示，与他莫昔芬相比，芳香酶抑制剂（例如阿那曲唑，来曲唑和依西美坦）与子宫病变的发生率相关。此外，芳香酶抑制剂甚至可以逆转他莫昔芬引起的子宫异常。这意味着缺乏对子宫的刺激作用将是芳香化酶抑制剂治疗所获得的好处之一，并且可能减少甚至消除对妇科干预的需求。

BACKGROUND & AIMS: BACKGROUND CONTEXT:Although autogenous bone is still considered to be the gold standard graft material for promoting spinal fusion, other bone graft substitutes have been developed in an attempt to improve arthrodesis rates and avoid the complications associated with the procurement of autograft. The bone morphogenetic proteins (BMPs) represent a family of osteoinductive growth factors that are known to stimulate the osteoblastic differentiation of stem cells. Osteogenic protein-1 (OP-1) Putty is a commercially available BMP preparation that is already approved for use in humans. Previous clinical studies involving patients with degenerative spondylolisthesis have reported that the efficacy and safety of OP-1 Putty is comparable to that of autograft at both 1- and 2-year follow-up. PURPOSE:The purpose of this study was to evaluate the intermediate-term efficacy and safety of OP-1 Putty as an alternative to autogenous bone by comparing the 4-year radiographic, clinical, and safety data of these same patients who underwent decompression and uninstrumented fusion with either OP-1 Putty or iliac crest autograft. STUDY DESIGN/SETTING:A prospective, randomized, controlled, multicenter clinical pilot study. PATIENT SAMPLE:Thirty-six patients undergoing decompressive laminectomy and single-level uninstrumented fusion for degenerative spondylolisthesis and symptomatic spinal stenosis were randomized in a 2:1 fashion to receive either OP-1 Putty (24 patients) or autogenous iliac crest bone graft (12 patients). OUTCOME MEASURES:Patient-reported outcome measures consisting of Oswestry Disability Index and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) scores were used to evaluate clinical efficacy. Perioperative data including operative time, estimated blood loss, and duration of hospital stay were also recorded for each surgery. Postoperatively, a neurological examination and an assessment of donor-site pain (if applicable) were performed at every follow-up visit. Radiographic fusion success was defined as the presence of continuous bridging bone formation between the transverse processes at the level of the spondylolisthesis with minimal motion evident on dynamic lateral x-ray films. The primary efficacy endpoint was the overall success rate, a composite measure derived from both radiographic and clinical parameters. The safety of OP-1 Putty was confirmed by comparing the nature and frequency of all adverse events and complications that were prospectively observed in either of the groups. METHODS:Thirty-six patients with degenerative spondylolisthesis and symptoms of neurogenic claudication underwent decompressive laminectomy and single-level uninstrumented fusion with either OP-1 Putty or autograft. All patients were evaluated at 6 weeks and 3, 6, 9, 12, and 24 months, after which time they were instructed to return on a yearly basis. Multiple neuroradiologists blinded to the assigned treatment reviewed static and dynamic X-ray films with digital calipers to assess fusion status according to the presence of continuous bridging bone across the transverse processes as well as the amount of residual motion evident at the level of interest. Oswestry Disability Index surveys and SF-36 questionnaires were used to assess clinical outcomes. RESULTS:At the 48-month time point, complete radiographic and clinical data were available for 22 of 36 patients (16 OP-1 Putty and 6 autograft) and 25 of 36 patients (18 OP-1 Putty and 7 autograft), respectively. Radiographic evidence of a solid arthrodesis was present in 11 of 16 OP-1 Putty patients (68.8%) and 3 of 6 autograft patients (50%). Clinically successful outcomes defined as at least a 20% improvement in preoperative Oswestry scores were experienced by 14 of 19 OP-1 Putty patients (73.7%) and 4 of 7 autograft patients (57.1%); these clinical findings were corroborated by similar increases in SF-36 scores. The respective overall success rates of the OP-1 Putty and autograft group were 62.5% and 33.3%. In this study, there were no incidents of local or systemic toxicity, ectopic bone production, or other adverse events directly related to the use of OP-1 Putty. CONCLUSION:Despite the challenges associated with obtaining a solid uninstrumented fusion in patients with degenerative spondylolisthesis, the rates of radiographic fusion, clinical improvement, and overall success associated with the use of OP-1 Putty were at least comparable to that of the autograft controls for at least 48 months after surgery. These results appear to validate the short-term results previously reported for OP-1 Putty and suggest that this material may potentially represent a viable bone graft substitute for certain fusion applications.

背景与目标： 背景技术：尽管自体骨仍被认为是促进脊柱融合的金标准移植材料，但已开发出其他替代骨的方法，以试图提高关节固定率并避免与自体移植相关的并发症。骨形态发生蛋白（BMP）代表一类骨诱导生长因子，已知这些因子可刺激干细胞的成骨细胞分化。成骨蛋白1（OP-1）腻子是一种可商购的BMP制剂，已被批准用于人类。先前涉及退行性脊椎滑脱患者的临床研究报告，在1年和2年的随访中，OP-1油灰的功效和安全性与自体移植相当。
目的：本研究的目的是通过比较这些接受减压和不使用仪器的相同患者的4年影像学，临床和安全性数据来评估OP-1油灰替代自体骨的中期疗效和安全性与OP-1油灰或骨自体融合。
研究设计/设置：一项前瞻性，随机，对照，多中心临床试验研究。
患者样本：36例行减压椎板切除术和单级非器械融合治疗退行性腰椎滑脱和症状性椎管狭窄的患者以2：1方式随机接受OP-1腻子（24例）或自体骨植骨（12例）耐心）。
结局指标：采用Oswestry残疾指数和医学结局研究36项简表健康调查（SF-36）评分组成的患者报告结局指标，用于评估临床疗效。每次手术还记录了围手术期数据，包括手术时间，估计的失血量和住院时间。术后，每次随访均进行神经系统检查和对供体部位疼痛的评估（如果适用）。放射照相融合成功定义为在横向滑突之间在脊椎滑脱水平上存在连续桥接的骨形成，而在动态侧向X射线胶片上可见的运动极小。主要功效终点是总体成功率，这是一项从放射学和临床参数中得出的综合指标。 OP-1腻子的安全性通过比较两组中预期观察到的所有不良事件和并发症的性质和频率来确定。
方法：36例退行性腰椎滑脱并伴有神经源性symptoms行症状的患者接受减压椎板切除术和单层非器械融合OP-1腻子或自体移植。在第6周和第3、6、9、12和24个月对所有患者进行评估，然后指示他们每年返回一次。多家神经放射科医生对指定的治疗方法视而不见，并用数字卡尺检查了静态和动态X射线胶片，以根据横断过程中连续桥接骨的存在以及感兴趣水平上明显的残余运动量来评估融合状态。 Oswestry残疾指数调查和SF-36问卷用于评估临床结局。
结果：在48个月的时间点，分别可获得36例患者中的22例（16例OP-1腻子和6例自体移植）和36例患者中的25例（18例OP-1腻子和7例自体移植）的完整影像学和临床资料。 16例OP-1油灰患者中有11例（68.8％）和6例自体移植患者中有3例（50％）出现了牢固的关节固定的影像学证据。 19例OP-1腻子患者中的14例（73.7％）和7例自体移植患者中的4例（57.1％）经历了临床上成功的结果，即术前Oswestry评分至少提高了20％。这些临床发现被SF-36分数的类似提高所证实。 OP-1腻子和自体移植组的总体总体成功率分别为62.5％和33.3％。在这项研究中，没有发生局部或全身毒性，异位骨生成或与使用OP-1腻子直接相关的其他不良事件的事件。
结论：尽管在退行性脊椎滑脱患者中获得牢固的非器械融合具有挑战性，但与使用OP-1腻子相关的放射成像融合率，临床改善率和总体成功率至少可与自体植骨对照用于手术后至少48个月。这些结果似乎证实了先前报道的OP-1油灰的短期结果，并表明该材料可能是某些融合应用中可行的骨移植替代品。

BACKGROUND & AIMS: INTRODUCTION:This project addresses the validation study design of a test system using a telemetered non-human primate model for cardiovascular safety pharmacology evaluation. METHODS:The validation provided by the supplier evaluated installation (IQ) and operation (OQ) qualifications. This protocol was completed with tests evaluating electronic data management and accuracy and precision of transmitter (n=4) measurements for temperature and pressure criteria with a series of tested values. As part of performance qualification, physical activity (for 24 h) as well as cardiovascular, ECG (20 complexes for each animal) and systemic arterial blood pressure (SAP, 10 different measures), data were recorded simultaneously from the same animals (n=4) using certified equipment and the telemetry system. Reliability was evaluated over 60 days. RESULTS:The IQ and OQ were completed successfully. The electronic data management was performed successfully. The ex-vivo evaluation for temperature and pressure showed high correlation (R(2)>0.99) but with a slight pressure shift, as expected, with this transmitter model. For physical activity, the correlation coefficients were good to excellent with high activity counts but the comparison demonstrated a limited sensitivity of the telemetry system with animal presenting low activity levels. ECG interval measurement using the telemetry software was considered at least equivalent to manual measurement, but with some limitations in the reading of the ECG. The comparison between both methods of SAP measurement showed adequate precision (R(2)=0.969) but no accuracy. DISCUSSION:Reference monitoring methods are important to ensure proper test system validation. Monitoring with a reference methodology and the telemetry system is important in order to evaluate precision and accuracy of the test system. Computerized analysis may lack the capability to analyze ECG complexes with abnormal morphologies. This reinforces the need to have ECG evaluation prior to telemetry implantation along with visual evaluation of ECG tracing at standard speed (e.g. 50 mm/s) at all time points.

背景与目标： 简介：该项目致力于使用遥测非人类灵长类动物模型进行心血管安全药理学评估的测试系统的验证研究设计。
方法：供应商提供的验证评估了安装（IQ）和操作（OQ）资格。通过评估电子数据管理以及变送器（n = 4）测量的温度和压力标准的准确性和精度的测试，以及一系列测试值，完成了该协议。作为性能鉴定，身体活动（持续24小时）以及心血管，心电图（每只动物20种复合物）和全身动脉血压（SAP，10种不同措施）的一部分，同时记录了来自同一只动物的数据（n = 4）使用经过认证的设备和遥测系统。在60天内评估了可靠性。
结果：智商和OQ均成功完成。电子数据管理已成功执行。温度和压力的离体评估显示出高度相关性（R（2）> 0.99），但与这种变送器模型一样，压力变化不大，正如预期的那样。对于体育活动，相关系数在具有较高活动计数的情况下很好到极好，但是比较结果表明，在动物活动水平较低的情况下，遥测系统的灵敏度有限。使用遥测软件进行的ECG间隔测量被认为至少等同于手动测量，但是在读取ECG方面存在一些限制。两种SAP测量方法之间的比较显示了足够的精度（R（2）= 0.969），但没有精度。
讨论：参考监视方法对于确保正确的测试系统验证很重要。为了评估测试系统的精度和准确性，使用参考方法和遥测系统进行监视非常重要。计算机分析可能缺乏分析形态异常的心电图复合物的能力。这加强了在遥测植入之前进行ECG评估以及在所有时间点以标准速度（例如50 mm / s）进行ECG追踪视觉评估的需求。