BACKGROUND & AIMS: :A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 +/- 0.5 microM with respect to the inhibition of calcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cells expressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led to a 6-fold increase in activity (7m, IC50 = 0.9 +/- 0.2 microM). Among the carboxamides synthesized, one of the most active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 +/- 0.02 microM). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic study of one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomers can be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR. Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenyl moiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate [3H]IP accumulation in CHO cells expressing or not expressing the CaSR.

背景与目标： ：结构活性关系（SAR）研究主要在N1-芳基磺酰基-N2- [1-（1-（萘基）乙基]-反式1,2-二氨基环己烷的N1位置进行的钙敏感受体（CaSR）。该系列中活性最高的化合物是4-（三氟甲氧基）苯磺酰基衍生物7e，在抑制中国仓鼠中钙诱导的tri化肌醇磷酸酯（[3H] IP）积累方面，其IC50为5.4 /-0.5 microM。表达CaSR的卵巢（CHO）细胞。该化合物的磺酰胺键被羧酰胺取代导致活性增加了6倍（7m，IC50 = 0.9 /-0.2 microM）。在合成的羧酰胺中，活性最高的化合物之一是4-氯苯基羧酰胺（1S，2S，1'R）-7n（Calhex 231，IC50 = 0.33 /-0.02 microM）。 （1S，2S，1'R）-7n的绝对构型是通过对化合物7d的一种非对映异构体进行X射线晶体学研究得出的。 （1S，2S，1'R）-异构体的立体化学偏好可以基于CaSR钙解结合口袋的三维模型来合理化。除去C-1'甲基或用2-萘基或联苯部分取代1-萘基导致明显的钙解活性损失。化合物7e，7m和Calhex 231不会刺激表达或不表达CaSR的CHO细胞中的[3H] IP积累。

BACKGROUND & AIMS: :Reports on the efficacy of physical activity intervention trials usually only include discussion of the primary outcomes. However, assessing factors such as participant retention, adherence and compliance can assist in the accurate interpretation of the overall impact of a program in terms of reach and appeal. A quasi-randomised trial was carried out to assess and compare retention and adherence rates, and compliance with, a twice weekly resistance training program provided either individually at home or in a group format. Retirement villages (n=6) were assigned to either 'Have A Try' (HAT, home-based) or 'Come Have A Try' (CHAT, group-based); both programs included nine strength and two balance exercises. The program involved a 20-week Intervention Phase a 24-week Maintenance Phase and a 20-week On-going Maintenance Phase. One hundred and nineteen participants (mean age 80+/-6 years) were recruited (HAT=38, CHAT=81). There was no difference in retention rates at the end of the Intervention Phase, but significantly more HAT than CHAT participants had dropped out of the study (p<0.01) after the Maintenance Phase and the On-going Maintenance Phase. During the Intervention Phase, over half the HAT and CHAT participants completed > or =75% of the prescribed activity sessions, but adherence was significantly greater in CHAT than HAT during the Maintenance Phase (p<0.01). Participants in CHAT were significantly more compliant than HAT participants (p<0.05). Both home- and group-based formats were successful over the short-term, but, in retirement villages, the group program had better adherence and compliance in the longer-term.

背景与目标： ：有关体育锻炼干预试验功效的报告通常仅包括对主要结局的讨论。但是，评估参与者的保留，遵守和遵守等因素可以帮助准确地解释计划在影响力和吸引力方面的总体影响。进行了一项半随机试验，以评估和比较保留率和依从率，以及是否遵守每周两次的在家中或以小组形式提供的每周两次阻力训练计划。退休村（n = 6）被分配为“尝试一下”（HAT，基于家庭）或“来一下尝试”（CHAT，基于组）；这两个程序都包括九项力量和两项平衡练习。该计划包括20周的干预阶段，24周的维护阶段和20周的持续维护阶段。招募了119名参与者（平均年龄80 / -6岁）（HAT = 38，CHAT = 81）。在干预阶段结束时，保留率没有差异，但是在维护阶段和正在进行的维护阶段之后，HAT的退出人数比CHAT参与者退出研究的次数多（p <0.01）。在干预阶段，超过一半的HAT和CHAT参与者完成了规定活动的>或= 75％，但是在维持阶段，CHAT中的依从性明显高​​于HAT（p <0.01）。与CHAT参与者相比，CHAT参与者的依从性更高（p <0.05）。以家庭为基础和以团体为基础的形式在短期内都是成功的，但是在退休村，从长期来看，团体计划具有更好的遵守性和合规性。

BACKGROUND & AIMS: Recently, 65-kDa glutamic acid decarboxylase (GAD 65) antibodies (GADA) have been introduced as autoimmune markers in blood to confirm the diagnosis of insulin-dependent diabetes mellitus (IDDM). In this study, to evaluate two new assays that use 125I-labeled GAD 65, we assayed samples from 100 children with recent onset of diabetes and 100 control children, the results were compared with those of a [35S]GADA assay and with results for islet cell antibodies (ICA), the conventional autoimmune marker. Receiver operating characteristic (ROC) curve analysis showed one of the new assays (from RSR) to be more sensitive (P = 0.01) than the comparison ([35S]GADA) assay, whereas the second new assay (from Elias) was less sensitive (P < 0.001). The GADA frequency at 97.5% specificity was greatest in the comparison assay63 of 100 vs 41 of 100 (P < 0.01) and 53 of 100 (P = 0.16) in the RSR and Elias assays, respectively. Almost all GADA-positive patients had ICA, but one-third of the ICA-positive patients was GADA-negative. Accordingly, adding GADA analysis results to ICA testing increased the frequency of detection of autoimmune markers only slightly (from 81% to 85%). In conclusion, at 97.5% specificity the [35S]GADA assay seemed to be more efficient than the 125I assays, although the difference was significant only for the Elias 125I assay. Antigen-specific antibodies other than GADA may explain the difference in GADA and ICA frequencies.

背景与目标： 最近，已引入65 kDa的谷氨酸脱羧酶（GAD 65）抗体（GADA）作为血液中的自身免疫标记，以证实对胰岛素依赖型糖尿病（IDDM）的诊断。在这项研究中，为了评估使用125I标记的GAD 65的两种新检测方法，我们检测了100例最近患糖尿病的儿童和100例对照儿童的样品，将结果与[35S] GADA检测的结果进行了比较，并得出了胰岛细胞抗体（ICA），传统的自身免疫标记。接收者工作特征（ROC）曲线分析显示，一种新的测定法（来自RSR）比比较（[35S] GADA）灵敏度更高（P = 0.01），而第二种新的测定法（来自Elias）灵敏度较低（P <0.001）。在RSR和Elias分析中，分别为100和41（100（P <0.01））和53（100（P = 0.16））的比较分析63中，在97.5％特异性下的GADA频率最高。几乎所有GADA阳性患者都患有ICA，但是ICA阳性患者中有三分之一是GADA阴性。因此，将GADA分析结果添加到ICA测试中，仅略微增加了自身免疫标记物的检测频率（从81％到85％）。结论是，[35S] GADA分析的特异性为97.5％，似乎比125I分析更有效，尽管这种差异仅对Elias 125I分析有意义。 GADA以外的抗原特异性抗体可以解释GADA和ICA频率的差异。

BACKGROUND & AIMS: :Parents play an important role in the sexual health of their adolescent children. Based on previous research, formative research, and theories of behavioral change, we developed Talking Parents, Healthy Teens, an intervention designed to help parents improve communication with their adolescent children, promote healthy adolescent sexual development, and reduce adolescent sexual risk behaviors. We conduct the parenting program at worksites to facilitate recruitment and retention of participants. The program consists of 8 weekly 1-hour sessions during the lunch hour. In this article, we review the literature that identifies parental influences on adolescent sexual behavior, summarize our formative research, present the theoretical framework we used to develop Talking Parents, Healthy Teens, describe the program's components and intervention strategies, and offer recommendations based on our experiences developing the program. By targeting parents at their worksites, this program represents an innovative approach to promoting adolescent sexual health. This article is intended to be helpful to health educators and clinicians designing programs for parents, employers implementing health-related programs, and researchers who may consider designing and evaluating such worksite-based programs.

背景与目标： ：父母在青春期儿童的性健康中起着重要作用。基于以前的研究，形成性研究和行为改变的理论，我们开发了“会说话的父母，健康的青少年”，旨在帮助父母改善与青春期孩子的沟通，促进健康的青少年性发育并减少青少年性风险行为的干预措施。我们在工作场所实施育儿计划，以促进参与者的招募和保留。该计划在午餐时间包括8个每周的1小时课程。在本文中，我们回顾了确定父母对青少年性行为的影响的文献，总结了我们的形成性研究，介绍了我们用于发展会说话的父母，健康的青少年的理论框架，描述了该计划的组成部分和干预策略，并根据我们的建议提供了建议开发该程序的经验。通过针对父母的工作场所，该计划代表了一种促进青少年性健康的创新方法。本文旨在为健康教育者和临床医生为父母设计程序，实施与健康相关的程序的雇主以及可能考虑设计和评估基于工作场所的程序的研究人员提供帮助。

BACKGROUND & AIMS: :In the present pilot study, the feasibility of a site-of-care cervicovaginal self-sampling methodology for HPV-based screening was tested in 346 women residing in underserved rural areas of Northern Greece. These women provided self-collected cervicovaginal sample along with a study questionnaire. Following molecular testing, using the cobas® HPV Test, Roche®, HPV positive women, were referred to colposcopy and upon abnormal findings, to biopsy and treatment. Participation rate was 100%. Regular pap-test examination was reported for 17.1%. Among hrHPV testing, 11.9% were positive and colposcopy/biopsy revealed 2 CIN3 cases. Non-compliance was the most prevalent reason for no previous attendance. Most women reported non-difficulty and non-discomfort in self-sampling (77.6% and 82.4%, respectively). They would choose self-sampling over clinician-sampling (86.2%), and should self-sampling being available, they would test themselves more regularly (92.3%). In conclusion, self-sampling is feasible and well-accepted for HPV-based screening, and could increase population coverage in underserved areas, helping towards successful prevention.

背景与目标： ：在本项初步研究中，对希腊北部农村地区服务不足的346名妇女进行了基于宫颈癌阴道自我采样方法的HPV筛查的可行性的测试。这些妇女提供了自己收集的宫颈阴道样本以及研究问卷。在进行分子测试后，使用cobas®HPV测试，将Roche®，HPV阳性女性进行阴道镜检查，并在发现异常后进行活检和治疗。参与率为100％。定期进行子宫颈抹片检查的报道为17.1％。在hrHPV测试中，有11.9％呈阳性，阴道镜检查/活检显示有2例CIN3病例。不遵守是没有参加会议的最普遍原因。大多数妇女在自我抽样中报告没有困难和不舒服（分别为77.6％和82.4％）。他们将选择自采样而不是临床医生采样（86.2％），并且如果可以使用自采样，他们将更定期地进行自我测试（92.3％）。总之，对于基于HPV的筛查，自我抽样是可行的并且被广泛接受，并且可以扩大服务不足地区的人口覆盖率，有助于成功进行预防。

BACKGROUND & AIMS: :The advance of mitral valve repair techniques through tissue engineering is impeded by the lack of information regarding the cellular and extracellular components of the mitral valve. The present study aims to expand our understanding of the mitral valve structure by analysing the synthesis of extracellular matrix (ECM) proteins and the expression of nitric oxide synthase (NOS). Valvular endothelial cells (VECs) and valvular interstitial cells (VICs) were isolated from porcine mitral valves. Immunochemical staining of ECM components, including type I, II, III, IV and V collagen, laminin, fibronectin, elastin and chondroitin sulphate (CS), was performed on both mitral valve tissue and cell cultures. Reverse transcription polymerase chain reaction and immunochemistry were used to analyse NOS expression in native valve and in culture. Both VECs and VICs synthesised the basement membrane components, laminin and type IV collagen both in vivo and in vitro, amongst other fibrous ECM proteins. Synthesis of type I collagen and CS was absent in VEC cultures. Each cell type had a characteristic profile of NOS expression. VECs synthesised endothelial NOS both in vivo and in vitro, with a minority of VICs expressing neuronal NOS in vitro. The present study reports newly recognised aspects of the mitral valve structure and the in vitro behaviour of mitral valve cell populations based on ECM synthesis and NOS expression. The presented profiles can be used as base tools for the generation of data necessary for the selection of ideal cell sources and for the design of appropriate scaffolds for the development of effective tissue-engineered mitral valves.

背景与目标： ：由于缺乏有关二尖瓣细胞和细胞外成分的信息，阻碍了通过组织工程进行的二尖瓣修复技术的发展。本研究旨在通过分析细胞外基质（ECM）蛋白的合成和一氧化氮合酶（NOS）的表达来扩大我们对二尖瓣结构的了解。从猪二尖瓣分离出瓣膜内皮细胞（VEC）和瓣膜间质细胞（VIC）。对二尖瓣组织和细胞培养物进行ECM成分的免疫化学染色，包括I，II，III，IV和V型胶原，层粘连蛋白，纤连蛋白，弹性蛋白和软骨素硫酸盐（CS）。逆转录聚合酶链反应和免疫化学用于分析天然瓣膜和培养物中的NOS表达。 VEC和VIC都在体内和体外合成了基底膜成分，层粘连蛋白和IV型胶原蛋白，以及其他纤维状ECM蛋白。在VEC培养物中不存在I型胶原蛋白和CS的合成。每种细胞类型均具有NOS表达的特征谱。 VEC在体内和体外合成内皮NOS，少数VIC在体外表达神经元NOS。本研究报告了基于ECM合成和NOS表达的二尖瓣结构和二尖瓣细胞群体的体外行为的新认识的方面。提出的配置文件可以用作基础工具，以生成选择理想细胞来源所需的数据，以及设计适当的支架以开发有效的组织工程性二尖瓣。

BACKGROUND & AIMS: :In some randomized (drug versus placebo) clinical trials, the estimand of interest is the between-treatment difference in population means of a clinical endpoint that is free from the confounding effects of "rescue" medication (e.g., HbA1c change from baseline at 24 weeks that would be observed without rescue medication regardless of whether or when the assigned treatment was discontinued). In such settings, a missing data problem arises if some patients prematurely discontinue from the trial or initiate rescue medication while in the trial, the latter necessitating the discarding of post-rescue data. We caution that the commonly used mixed-effects model repeated measures analysis with the embedded missing at random assumption can deliver an exaggerated estimate of the aforementioned estimand of interest. This happens, in part, due to implicit imputation of an overly optimistic mean for "dropouts" (i.e., patients with missing endpoint data of interest) in the drug arm. We propose an alternative approach in which the missing mean for the drug arm dropouts is explicitly replaced with either the estimated mean of the entire endpoint distribution under placebo (primary analysis) or a sequence of increasingly more conservative means within a tipping point framework (sensitivity analysis); patient-level imputation is not required. A supplemental "dropout = failure" analysis is considered in which a common poor outcome is imputed for all dropouts followed by a between-treatment comparison using quantile regression. All analyses address the same estimand and can adjust for baseline covariates. Three examples and simulation results are used to support our recommendations.

背景与目标： ：在一些随机的（药物与安慰剂）临床试验中，关注的估计是临床终点的人群均值之间的治疗差异，而不受“拯救”药物的混杂影响（例如，HbA1c在24岁时偏离基线）不论是否或何时终止指定的治疗，都无需救援药物即可观察到的数周时间）。在这种情况下，如果某些患者在试验期间过早中断试验或开始抢救药物，则会出现数据丢失的问题，后者需要丢弃救援后的数据。我们提醒您，通常使用的混合效应模型重复测量分析会在随机假设的情况下出现嵌入缺失，从而可能对上述感兴趣的估计值进行夸大的估计。之所以会发生这种情况，部分原因是由于对药物部门中的“辍学”（即患者缺少目标终点数据缺失的患者）过于乐观的平均值的隐式估算。我们提出了另一种方法，即用安慰剂（主要分析）下整个终点分布的估计均值（主要分析）或临界点框架内一系列越来越保守的均值（敏感性分析）明确替换掉药物臂退出的均值）;不需要患者级别的估算。考虑进行补充的“辍学=失败”分析，在该分析中，对所有辍学的普遍不良结果进行了归因，然后使用分位数回归进行了治疗之间的比较。所有分析都针对相同的估计值，并且可以针对基线协变量进行调整。使用三个示例和仿真结果来支持我们的建议。

BACKGROUND & AIMS: BACKGROUND:The Nutrition Embedded Evaluation Programme Impact Evaluation (NEEP-IE) study is a cluster randomised controlled trial designed to evaluate the impact of a childcare centre-based integrated nutritional and agricultural intervention on the diets, nutrition and development of young children in Malawi. The intervention includes activities to improve nutritious food production and training/behaviour-change communication to improve food intake, care and hygiene practices. This paper presents the rationale and study design for this randomised control trial. METHODS:Sixty community-based childcare centres (CBCCs) in rural communities around Zomba district, Malawi, were randomised to either (1) a control group where children were attending CBCCs supported by Save the Children's Early Childhood Health and Development (ECD) programme, or (2) an intervention group where nutritional and agricultural support activities were provided alongside the routine provision of the Save the Children's ECD programme. Primary outcomes at child level include dietary intake (measured through 24-h recall), whilst secondary outcomes include child development (Malawi Development Assessment Tool (MDAT)) and nutritional status (anthropometric measurements). At household level, primary outcomes include smallholder farmer production output and crop-mix (recall of last production season). Intermediate outcomes along theorised agricultural and nutritional pathways were measured. During this trial, we will follow a mixed-methods approach and undertake child-, household-, CBCC- and market-level surveys and assessments as well as in-depth interviews and focus group discussions with project stakeholders. DISCUSSION:Assessing the simultaneous impact of preschool meals on diets, nutrition, child development and agriculture is a complex undertaking. This study is the first to explicitly examine, from a food systems perspective, the impact of a preschool meals programme on dietary choices, alongside outcomes in the nutritional, child development and agricultural domains. The findings of this evaluation will provide evidence to support policymakers in the scale-up of national programmes. TRIAL REGISTRATION:ISRCTN registry, ID: ISRCTN96497560 . Registered on 21 September 2016.

背景与目标： 背景：营养嵌入式评估计划影响评估（NEEP-IE）研究是一项集群随机对照试验，旨在评估基于托儿所的营养和农业综合干预对马拉维幼儿饮食，营养和发育的影响。干预措施包括改善营养食品生产的活动和培训/行为改变交流，以改善食物摄入，护理和卫生习惯。本文介绍了该随机对照试验的原理和研究设计。
方法：将马拉维Zomba地区周边农村社区的60个社区托儿中心（CBCC）随机分为（1）对照组，在该组中，儿童参加了由Save the Children's Early Childhood Health and Development（ECD）计划支持的CBCC，或（2）一个干预小组，在该小组的日常服务之外，还提供了营养和农业支持活动。儿童一级的主要结局包括饮食摄入量（通过24小时召回来衡量），而次级一级的结局包括儿童发育（马拉维发育评估工具（MDAT））和营养状况（人体测量）。在家庭一级，主要成果包括小农户的农产品产量和作物结构（回顾上个生产季节）。测量了沿理论化的农业和营养途径的中间结果。在此试验期间，我们将采用混合方法，并进行儿童，家庭，CBCC和市场级别的调查和评估，以及与项目利益相关者的深入访谈和焦点小组讨论。
讨论：评估学龄前膳食对饮食，营养，儿童发育和农业的同时影响是一项复杂的工作。这项研究是第一个从食品系统的角度明确检查学龄前儿童饮食计划对饮食选择以及营养，儿童发育和农业领域的成果的影响的研究。评估的结果将为支持决策者扩大国家计划提供证据。
试用注册：ISRCTN注册，ID：ISRCTN96497560。 2016年9月21日注册。