Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility

Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional‐UMVUE and contrast it with other estimates, including naïve estimators, the well‐studied unconditional‐UMVUE and the mean and median Whitehead‐adjusted estimators. The conditional‐UMVUE appears to be a very good choice. Copyright © 2008 John Wiley & Sons, Ltd.     

Graves甲亢多种治疗方法对Graves眼病影响的系统评价

目的 通过榆索、分析文献系统评价131I、手术、抗甲状腺药物(ATD)治疗Graves病(GD)对Graves眼病(GO)的影响.方法 检索了MEDIJNE(1966年-2006年3月)、EMBASE(1984-2005年)、The Cochrane Library(2006年第1期)、中国生物医学文献光盘数据库(EBMdisc,1978年1月-2006年4月)和中国学术期刊全文数据库(CNKI,1994-2006年)所收录的有关不同GD治疗方法对GO影响的文献,同时从参考文献中追溯文献.对纳入研究的方法学质量进行评价,根据是否采取预防甲状腺功能低下(简称甲低)发生的措施对纳入研究进行亚组分析,结果采用RevMan4.2软件进行统计学分析.结果 最终纳入随机对照研究5项,非随机对照研究2项,病例对照研究1项,共1625例患者.Meta分析显示:如GD治疗后早期未采取措施预防甲低,131I与手术治疗、131I与ATD治疗GD在诱发或加重GO以及减轻GO症状方面莘异有统计学意义[检验值分别为2.31,5.97,3.70,5.55;P均＜0.05];如GD治疗后早期采取措施预防甲低,手术与ATD治疗GD在诱发或加重GO以及减轻GO症状方面差异无统计学意义(检验值分别为0.27,0.99;P均＞0.05),尚无研究涉及131I治疗GD后早期采取甲低预防措施时131I对GO的影响.结论 若未及时采取甲低预防措施,131I较ATD、手术治疗GD更容易诱发或加重GO,减轻GO的症状却不如后两者,对于治疗前已有活动性GO的患者,应慎用131I.     

低剂量奥沙利铂并氟脲嘧啶对晚期复发直肠癌放疗增敏作用的临床观察

目的：观察奥沙利铂（L-OHP）并5-氟脲嘧啶、甲酰四氢叶酸钙（5-Fu／LV）配合放疗治疗晚期复发直肠癌患者的增效作用与毒性反应。方法：23例无法手术的晚期复发直肠癌患者进行盆腔放疗，在放疗的第1、5同前一天开始给予L-OHP30mg／m。静滴0．5h，LV100mg／m^2和5-Fu375mg／m^2静滴4h，连用4d。25例单纯放疗者为对照组。结果：放疗结束时，观察组局部症状缓解率较对照组高，尤其对会阴区下坠疼的改善明显（P〈0．05），且转移症状亦有所缓解。两组有效率分别为78．3％、48％（P〈0．05），完全缓解分别为8．7％、4．0％。主要毒副反应是消化道反应、神经毒性、静脉炎，骨髓抑制。结论：利用低剂量L-OHP并5-Fu／LV的增敏作用配合放疗治疗晚期、复发直肠癌可提高近期疗效，改善症状，尤其对于伴远外转移者，为理想、安全的治疗手段。     

RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to alphavbeta3-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to couple RGD-peptides and RGD-mimetics to liposomes, polymers, peptides, small molecule drugs and radiotracers. Some of these products show impressive results in preclinical animal models and a RGD targeted radiotracer has already successfully been tested in humans for the visualization of alphavbeta3-integrin, which demonstrates the feasibility of this approach. This review will summarize the structural requirements for RGD-peptides and RGD-mimetics as ligands for alphavbeta3. We will show how they have been introduced in the various types of constructs by chemical and recombinant techniques. The importance of multivalent RGD-constructs for high affinity binding and internalization will be highlighted. Furthermore the in vitro and in vivo efficacy of RGD-targeted therapeutics and diagnostics reported in recent years will be reviewed.     

中美中学生对由父母原因引起的考试焦虑认知研究

目的：比较中国和美国的中学生对由父母原因引起的考试焦虑的认知情况。方法：采用“失败结果预期（FOE）”问卷中的由父母原因引起的考试焦虑12项，测量中美两国公立学校14、15岁的1215名中学生对考试焦虑原因的认知。结果：1．相似认知：两国学生在由父母原因引起的考试焦虑方面有类似的认知，包括父母会担心自己能否进入高一级学校、会让父母烦恼等。2．跨文化的差异：表现为中国学生更多是因为父母责备、辜负了父母期望或会让父母生气而导致考试焦虑；而美国学生更多是由于父母认为他们不能面对生活中的挑战而产生焦虑。3．性别差异：表现在美国的女中学生在7个项目上、中国的男中学生在2个项目上分别比本国异性有更大程度的焦虑（P〈0．05）。结论：中美中学生对由父母原因引起的考试焦虑方面有类似的认知，但存在文化差异和性别差异。     

乳腺癌新辅助化疗后动态增强MRI表现与病理反应性相关性研究

目的探讨乳腺癌新辅助化疗后动态增强MRI（DCE—MRI）表现的形态学和时间信号强度曲线（TIC）类型与病理学反应性的关系。方法45例乳腺癌患者经新辅助化疗结束后行乳腺DCE—MR检查及手术治疗。应用AW4．2图像工作站观察残余肿瘤强化的形态和TIC类型（共3型）。由病理科医师对乳腺癌化疗后手术标本的病理反应性进行评估，分为1～5级，5级为病理完全缓解，4级和5级为组织学显著反应。分析病理反应性级别与DCE—MRI残余强化的TIC类型、形态的关系，统计方法采用精确概率法。结果45例中病理反应性5级7例，4级16例，3级16例，1和2级共6例。20例I型曲线中组织学显著反应者占70．0％（14／20），而6例Ⅲ型曲线均为组织学反应不显著者。TIC类型在不同的病理反应级别分布差异有统计学意义（P=0．001）。组织学显著反应且有残余强化者共18例，其中非肿块性强化11例。残余强化的肿块（非肿块）形态表现在不同病理反应性分级中分布差异有统计学意义（P=0．012）。结论乳腺癌新辅助化疗后DCE—MRI的形态及血液动力学表现特点与化疗后病理反应性相关。非肿块性强化和I型TIC与组织学显著反应有关。     

Assessment of anti-inflammatory activity of Poria cocos in sodium lauryl sulphate-induced irritant contact dermatitis

OBJECTIVE: In the present study, we evaluated the anti-inflammatory activity of Poria cocos (PoCo) on experimentally induced irritant contact dermatitis (ICD) in a repeated sodium lauryl sulphate (SLS) irritation model. METHODS: The anti-irritative effect of PoCo was evaluated with a visual score and quantified by non-invasive bioengineering methods, namely chromametry and transepidermal water loss. Three concentrations of PoCo in base cream DAC (amphiphilic emollient; German pharmacopoeia) were tested in a 4-day repetitive irritation test using SLS. RESULTS: A statistically significant anti-inflammatory activity was observed for PoCo by all three methods when applied in parallel to the induction period of ICD. Application of PoCo after induction of ICD once a day for 5 days, starting just at the end of 4 days, was without any effect. CONCLUSION: An anti-inflammatory efficacy of PoCo on the elicitation phase of the ICD induced by repeated SLS test could be observed and quantified by three independent, non-invasive biophysical assessment parameters. This effect can be explained by its influence on pro-inflammatory enzymes, namely phospholipase A2.     

Neuropsychological test for the detection of dementia in elderly individuals: the Nishimura Dementia Test

Background: Progression of the core and accessory symptoms of dementia can be slowed if drug therapies and psychosocial interventions are administered at an early stage. The aim of this study was to develop and standardize a neuropsychological test for the elderly that can detect dementia at an early stage with high sensitivity and can evaluate a wide range of severities of dementia based on assessments of various cognitive functions. Methods: A preliminary test consisting of 23 items and the Nishimura Mental State Scale for the Elderly (NM Scale), which evaluates the mental functions of elderly individuals by observing their actual behaviors in daily life, were administered to 448 elderly subjects. After applying Hayashi’s quantification theory type I to the results, we revised the preliminary test to construct a neuropsychological test for the elderly, which we named the Nishimura Dementia Test (ND Test), and standardized it. Then, we examined its validity and test–retest reliability. Results: Among the 448 subjects, there was a strong correlation between the ND Test scores and NM Scale scores. The ND Test showed a good general agreement rate for the discrimination of the severity of dementia, and good sensitivity and specificity of discrimination of dementia when compared with the actual NM Scale. Using different groups of elderly subjects, the ND Test showed validity and test–retest reliability, and the ND Test scores showed strong correlations with the Revised Hasegawa Dementia Scale scores and the Mini‐Mental State Examination scores. Conclusions: The ND Test is based on assessment of a variety of cognitive functions and can evaluate a wide range of severities of dementia with good validity and reliability.     

HIV抗体快速检测试剂的临床评估

目的:通过对HIV抗体快速检测试剂的临床评估,为HIV检测试剂的临床应用提供参考.方法:对快速试剂的使用性能进行比较,并采用美国输血协会(AABB)血清盘、临床样品血清盘、特性血清盘(阳性样品盘)、稀释系列血清盘评估快速试剂的敏感性和特异性.结果:三种快速试剂在检测AABB血清盘时,敏感性分别是86.4%、86.4%、100%,特异性皆为100%;三种快速试剂在检测临床样品血清盘时,敏感性分别是88.6%、91.4%、97.1%,特异性皆为100%.快速试剂具有很高的阳性预期值,对于低危人群(感染率很低人群)也具有很高的阴性预期值.快速试剂检测弱阳性的样品(酶联试剂s/co比值小于6～8的样品)存在漏检.快速试剂与ELISA参考试剂在分析灵敏度方面相差3个以上倍比稀释度.结论:快速试剂具有较好的使用特性,非常适用于样本量较少的实验室及对低危人群的HIV筛查,在对高危人群筛查时,可能有弱阳性样品漏检,同时快速试剂在分析灵敏度方面有待提高.