BACKGROUND & AIMS: Evidence relating dietary sodium and blood pressure comes from a variety of sourcesanimal experiments, observational epidemiologic studies, migration studies, and randomized controlled trials. In this review, we examine new findings in each of these areas published during 1995 and 1996. Results from both observational epidemiologic studies and randomized controlled trials demonstrated a dose-response association between dietary sodium and blood pressure in humans. The relationship of dietary sodium to blood pressure was modified by age, race, body weight, and initial level of blood pressure. On average, a 100-mmol decrease in urinary sodium was associated with a reduction of approximately 3 mm Hg in systolic and a 2 mm Hg in diastolic blood pressure. In a general population, this blood pressure reduction would substantially reduce the societal burden of cardiovascular and renal diseases.

背景与目标： 有关饮食钠和血压的证据来自各种来源的动物实验，观察性流行病学研究，迁移研究和随机对照试验。在这篇综述中，我们研究了1995年和1996发表的每个领域的新发现。观察性流行病学研究和随机对照试验的结果表明，饮食钠与人类血压之间存在剂量反应关联。饮食钠与血压的关系因年龄，种族，体重和血压的初始水平而改变。平均而言，尿钠降低100 mmol与收缩压降低约3毫米Hg和舒张压降低2毫米Hg相关。在一般人群中，这种血压降低将大大减轻心血管和肾脏疾病的社会负担。

BACKGROUND & AIMS: :Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease. Autoantibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4+ T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co-stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG. The effect of CD28 blockade on lupus nephritis onset, survival, production of anti-ds DNA antibodies and costimulatory molecules was evaluated. CD28 blockade prevented the development of lupus nephritis and prolonged survival during the 3-month treatment and 12 weeks after. Furthermore, the production of anti-ds DNA autoAbs was decreased. Lastly, the protective effect of CD28 blockade was associated with increased intrarenal expression of the immunoregulatory molecule, Indoleamine 2, 3-dioxygenase, of the co-inhibitory receptor programmed cell-Death - 1 (PD-1) and of its ligand programmed death ligand - 1 (PDL-1).In conclusion, CD28 blockade prevented the development of lupus nephritis in NZB/NZW F1 mice. This immunomodulatory strategy is a promising candidate for SLE therapy in humans.

背景与目标： 系统性红斑狼疮 (SLE) 是一种慢性全身性炎症性疾病。抗狼疮标志双链DNA (ds DNA) 的自身抗体 (autoAbs) 是通过自身反应性b细胞和CD4 T细胞之间的相互作用产生和维持的。该相互作用由CD28/CD80-86/CTLA-4轴控制。在这里，我们研究了在SLE的鼠模型中，选择性阻断CD28-CD80/86共刺激相互作用是否可以缓解狼疮性肾炎的发展。为此，用anti-CD28 Fab' 片段或对照Fab'-IgG处理NZB/nzwf1小鼠3个月。评估了CD28阻断对狼疮性肾炎发作，存活，抗ds DNA抗体和共刺激分子产生的影响。CD28阻断可防止狼疮性肾炎的发展，并在3个月的治疗和12周后延长生存期。此外，抗ds DNA autoAbs的产生减少了。最后，CD28阻断的保护作用与免疫调节分子吲哚胺2,3-双加氧酶，共抑制性受体程序性细胞死亡-1 (PD-1) 及其配体程序性死亡配体-1 (PDL-1) 的肾内表达增加有关。总之，CD28阻断阻止了NZB/NZW F1小鼠狼疮性肾炎的发展。这种免疫调节策略是人类SLE治疗的有希望的候选者。

BACKGROUND & AIMS: :Thrombosis is the main cause of failure of small-diameter synthetic vascular grafts when used for by-pass procedures. The development of bioresorbable vascular scaffolds with localized and sustained intra-luminal antithrombotic drug release could be considered a desirable improvement towards a valuable solution for this relevant clinical need. For this aim, we present the fabrication and characterization of aspirin-loaded electrospun poly(ε-caprolactone) tubular scaffolds as a vascular drug-delivery graft. Three different drug concentrations were considered (i.e., 1, 5 or 10 % w/w). Although a fibrous structure was clearly observed for all the collected scaffolds, aspirin content was directly implied in the final microstructure leading to a bimodal fiber diameter distribution and fused fibers at crossing-points (5 or 10 % w/w). Mechanical response highlighted a direct relationship for modulus and stress at break with the aspirin content, while the elongation at break was not remarkably different for the investigated cases. The temporal drug release was strongly dependent from the amount of loaded aspirin, reaching a steady state release after about 50 h. Finally, the adhesion assay confirmed the capability of the electrospun scaffolds to reduce platelet adhesion/aggregation onto aspirin loaded polymeric fibers. Aspirin-loaded electrospun tubular scaffold could represent a feasible candidate to develop a novel bioresorbable drug-releasing graft for small-diameter vessel replacements.

背景与目标： : 血栓形成是用于旁路手术时小直径合成血管移植物失败的主要原因。开发具有局部和持续的腔内抗血栓药物释放的生物可吸收血管支架可被认为是针对此相关临床需求的有价值解决方案的理想改进。为此，我们介绍了负载阿司匹林的电纺聚 (ε-己内酯) 管状支架作为血管药物递送移植物的制备和表征。考虑三种不同的药物浓度 (即1、5或10% w/w)。尽管对于所有收集的支架都清楚地观察到纤维结构，但在最终微结构中直接隐含阿司匹林含量，导致双峰纤维直径分布和在交叉点处的融合纤维 (5或10% w/w)。机械响应强调了模量和断裂应力与阿司匹林含量的直接关系，而断裂伸长率在所研究的情况下没有显着差异。暂时的药物释放强烈依赖于阿司匹林的载量，约50小时后达到稳定状态释放。最后，粘附试验证实了电纺支架减少血小板粘附/聚集在阿司匹林负载的聚合物纤维上的能力。阿司匹林负载的电纺管状支架可能是开发用于小直径血管置换的新型生物可吸收药物释放移植物的可行候选者。

BACKGROUND & AIMS: :Hereditary cancer due to pathological mutations in the mismatch repair gene family is now known as Lynch syndrome and affects at least 1 in 1,000 people, resulting in a 30-50% cancer risk most often involving the colorectum and endometrium. Annual or biennial colonoscopy reduces cancer deaths and many offer gynaecological surveillance, but most other associated cancers are not amenable to early detection. As microsatellite instability testing and tumour immunohistochemistry become routine, case finding will improve. Our recent demonstration that 600 mg aspirin per day for at least 2 years reduces the cancer burden by 63% after a 3-year lag period reinforces the need to identify gene carriers and introduce them to chemoprevention. CaPP3 will test different doses of aspirin in at least 3,000 gene carriers to determine whether low-dose aspirin is as effective.

背景与目标： : 由于错配修复基因家族的病理突变引起的遗传性癌症现在被称为Lynch综合征，至少1,000人中有1人受到影响，导致30-50% 的癌症风险最常涉及结直肠和子宫内膜。每年或两年一次的结肠镜检查可减少癌症死亡，并且许多提供妇科监测，但大多数其他相关癌症不适合早期发现。随着微卫星不稳定性测试和肿瘤免疫组织化学成为常规，病例发现将得到改善。我们最近的证明，每天600毫克阿司匹林持续至少2年，在3年的滞后期后，癌症负担减轻了63%，这加强了鉴定基因携带者并将其引入化学预防的必要性。CaPP3将在至少3,000基因携带者中测试不同剂量的阿司匹林，以确定低剂量阿司匹林是否同样有效。

BACKGROUND & AIMS: BACKGROUND:Clinicians are encouraged to use guidelines to assist in providing evidence-based secondary prevention to patients with coronary heart disease. However, the expanding number of publications providing guidance about exercise training may confuse cardiac rehabilitation clinicians. We therefore sought to explore the number, scope, publication characteristics, methodological quality, and clinical usefulness of published exercise-based cardiac rehabilitation guidance. METHODS:We included publications recommending physical activity, exercise or cardiac rehabilitation for patients with coronary heart disease. These included systematically developed clinical practice guidelines, as well as other publications intended to support clinician decision making, such as position papers or consensus statements. Publications were obtained via electronic searches of preventive cardiology societies, guideline databases and PubMed, to November 2016. Publication characteristics were extracted, and two independent assessors evaluated quality using the 23-item Appraisal of Guidelines Research and Evaluation II (AGREE) tool. RESULTS:Fifty-four international publications from 1994 to 2016 were identified. Most were found on preventive cardiology association websites (n = 35; 65%) and were freely accessible (n = 50; 93%). Thirty (56%) publications contained only broad recommendations for physical activity and cardiac rehabilitation referral, while 24 (44%) contained the necessary detailed exercise training recommendations. Many were labelled as "guidelines", however publications with other titles (e.g. scientific statements) were common (n = 24; 44%). This latter group of publications contained a significantly greater proportion of detailed exercise training recommendations than clinical guidelines (p = 0.017). Wide variation in quality also existed, with 'applicability' the worst scoring AGREE II domain for clinical guidelines (mean score 53%) and 'rigour of development' rated lowest for other guidance types (mean score 33%). CONCLUSIONS:While a large number of guidance documents provide recommendations for exercise-based cardiac rehabilitation, most have limitations in either methodological quality or clinical usefulness. The lack of rigorously developed guidelines which also contain necessary detail about exercise training remains a substantial problem for clinicians.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Surface contamination in hospitals is involved in the transmission of pathogens in a proportion of healthcare-associated infections. Admission to a room previously occupied by a patient colonized or infected with certain nosocomial pathogens increases the risk of acquisition by subsequent occupants; thus, there is a need to improve terminal disinfection of these patient rooms. Conventional disinfection methods may be limited by reliance on the operator to ensure appropriate selection, formulation, distribution and contact time of the agent. These problems can be reduced by the use of 'no-touch' automated room disinfection (NTD) systems. AIM:To summarize published data related to NTD systems. METHODS:Pubmed searches for relevant articles. FINDINGS:A number of NTD systems have emerged, which remove or reduce reliance on the operator to ensure distribution, contact time and process repeatability, and aim to improve the level of disinfection and thus mitigate the increased risk from the prior room occupant. Available NTD systems include hydrogen peroxide (H(2)O(2)) vapour systems, aerosolized hydrogen peroxide (aHP) and ultraviolet radiation. These systems have important differences in their active agent, delivery mechanism, efficacy, process time and ease of use. Typically, there is a trade-off between time and effectiveness among NTD systems. The choice of NTD system should be influenced by the intended application, the evidence base for effectiveness, practicalities of implementation and cost constraints. CONCLUSION:NTD systems are gaining acceptance as a useful tool for infection prevention and control.

背景与目标：

BACKGROUND & AIMS: :Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but poses a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD defined by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC), 610 women participating in the Kronos Early Estrogen Prevention Study (KEEPS), a clinical trial of MHT to prevent progression of CVD, were genotyped for 13,229 single nucleotide polymorphisms (SNPs) within 764 genes from anticoagulant, procoagulant, fibrinolytic, or innate immunity pathways. According to linear regression, proportion of European ancestry correlated negatively, but age at enrollment and pulse pressure correlated positively with CIMT. Adjusting for these variables, two SNPs, one on chromosome 2 for MAP4K4 gene (rs2236935, β = 0.037, P value = 2.36 × 10(-06)) and one on chromosome 5 for IL5 gene (rs739318, β = 0.051, P value = 5.02 × 10(-05)), associated positively with CIMT; two SNPs on chromosome 17 for CCL5 (rs4796119, β = -0.043, P value = 3.59 × 10(-05); rs2291299, β = -0.032, P value = 5.59 × 10(-05)) correlated negatively with CIMT; only rs2236935 remained significant after correcting for multiple testing. Using logistic regression, when we adjusted for waist circumference, two SNPs (rs11465886, IRAK2, chromosome 3, OR = 3.91, P value = 1.10 × 10(-04); and rs17751769, SERPINA1, chromosome 14, OR = 1.96, P value = 2.42 × 10(-04)) associated positively with a CAC score of >0 Agatston unit; one SNP (rs630014, ABO, OR = 0.51, P value = 2.51 × 10(-04)) associated negatively; none remained significant after correcting for multiple testing. Whether these SNPs associate with CIMT and CAC in women randomized to MHT remains to be determined.

背景与目标： : 更年期激素治疗 (MHT) 可能会限制心血管疾病 (CVD) 的进展，但会带来血栓形成的风险。为了测试与颈动脉内膜中层厚度 (CIMT) 和冠状动脉钙化 (CAC) 定义的亚临床CVD相关的靶向候选基因变异，610参加Kronos早期雌激素预防研究 (KEEPS) 的妇女，MHT预防CVD进展的临床试验，在抗凝剂，促凝剂，纤溶或先天免疫途径的764基因内对13,229单核苷酸多态性 (snp) 进行基因分型。根据线性回归，欧洲血统的比例呈负相关，但入学年龄和脉压与CIMT呈正相关。调整这些变量，两个snp，一个在2号染色体上的MAP4K4基因 (rs2236935，β = 0.037，p值 = 2.36 × 10(-06))，一个在5号染色体上的IL5基因 (rs739318，β = 0.051，p值 = 5.02 × 10(-05))，与CIMT呈正相关; CCL5 17号染色体上的两个snp (rs4796119，β = -0.043，p值 = 3.59 × 10(-05); rs2291299，β = -0.032，p值 = 5.59 × 10(-05)) 与CIMT呈负相关; 校正多重测试后，只有rs2236935仍然显著。使用逻辑回归，当我们调整腰围时，两个snp (rs11465886，IRAK2，3号染色体，OR = 3.91，p值 = 1.10 × 10(-04); 和rs17751769，SERPINA1，14号染色体，OR = 1.96，p值 = 2.42 × 10(-04)) 与> 0 Agatston单位的CAC评分呈正相关; 1个SNP (rs630014，ABO，OR = 0.51，p值 = 2.51 × 10(-04)) 呈负相关; 校正多重测试后无显著。这些snp是否与CIMT和CAC相关，在随机分配到MHT的女性中仍有待确定。

BACKGROUND & AIMS: :Although low-dose acetylsalicylic acid (ASA) is recommended for prevention of cardiovascular events in at-risk patients, its long-term use can be associated with the risk of peptic ulcer and upper gastrointestinal (GI) symptoms that may impact treatment compliance. This prespecified secondary analysis of the OBERON study (NCT00441727) determined the efficacy of esomeprazole for prevention/resolution of low-dose ASA-associated upper GI symptoms. A post hoc analysis of predictors of symptom prevention/resolution was also conducted. Helicobacter pylori-negative patients taking low-dose ASA (75-325 mg) for cardiovascular protection who had ≥1 upper GI risk factor were eligible. The patients were randomized to once-daily esomeprazole 40 mg, 20 mg, or placebo, for 26 weeks; 2303 patients (mean age 67.6 years; 36% aged >70 years) were evaluable for upper GI symptoms. The proportion of patients with dyspeptic or reflux symptoms (self-reported Reflux Disease Questionnaire) was significantly lower (P < 0.0001) in those treated with esomeprazole versus in those treated with placebo. Treatment with esomeprazole (P < 0.0001), age >70 years (P < 0.01), and the absence of upper GI symptoms at baseline (P < 0.0001) were all factors associated with prevention/resolution of upper GI symptoms. Together, these analyses demonstrate that esomeprazole is effective in preventing and resolving patient-reported upper GI symptoms in low-dose ASA users at increased GI risk.

背景与目标： : 尽管低剂量乙酰水杨酸 (ASA) 被推荐用于预防高危患者的心血管事件，但长期使用可能与消化性溃疡和上消化道 (GI) 症状的风险有关，这可能会影响治疗依从性。这项预先设定的OBERON研究 (NCT00441727) 的二次分析确定了埃索美拉唑预防/缓解低剂量ASA相关上消化道症状的疗效。还对症状预防/解决的预测因素进行了事后分析。幽门螺杆菌阴性患者服用低剂量ASA (75-325 mg) 进行心血管保护，且上消化道危险因素 ≥ 1。患者被随机分配至每日一次埃索美拉唑40 mg、20 mg或安慰剂，持续26周; 2303患者 (平均年龄67.6岁; 36% 年龄> 70岁) 可评估上消化道症状。与安慰剂组相比，使用埃索美拉唑治疗的患者有消化不良或反流症状 (自我报告的反流疾病问卷) 的比例显著降低 (P <0.0001)。埃索美拉唑治疗 (P < 0.0001) 、年龄> 70岁 (P < 0.01) 和基线时没有上消化道症状 (P < 0.0001) 都是与预防/缓解上消化道症状相关的因素。总之，这些分析表明，埃索美拉唑可有效预防和解决患者报告的上消化道症状，在胃肠道风险增加的低剂量ASA使用者中。

BACKGROUND & AIMS: :The regulations pertaining to the obligation of continuation of health surveillance of workers formerly exposed to asbestos are also examined from the point of view of clinical epidemiological usefulness. The outcomes of some types of campaigns of health surveillance of formerly exposed workers organized by the SSN (National Health Service) are also examined.

背景与目标： : 还从临床流行病学有用性的角度研究了与继续对以前接触石棉的工人进行健康监测的义务有关的法规。还检查了SSN (国家卫生局) 组织的某些类型的健康监测运动的结果。

BACKGROUND & AIMS: BACKGROUND:Low utilization of effective coronary heart disease (CHD) prevention strategies may be due to many factors, but chief among them is the lack of patient involvement in prevention decisions. We undertook this study to test the effectiveness of an individually-tailored, computerized decision aid about CHD on patients' discussions with their doctor and their plans for CHD prevention. METHODS:We conducted a pilot randomized trial in a convenience sample of adults with no previous history of cardiovascular disease to test the effectiveness of an individually-tailored, computerized decision aid about CHD prevention against a risk factor list that patients could present to their doctor. RESULTS:We enrolled 75 adults. Mean age was 53. 59% were female, 73% white, and 23% African-American. 66% had some college education. 43% had a 10-year CHD risk of 0-5%, 25% a risk of 6-10%, 24% a risk of 11-20%, and 5% a risk of > 20%. 78% had at least one option to reduce their CHD risk, but only 45% accurately identified the strategies best supported by evidence. 41 patients received the decision aid, 34 received usual care. In unadjusted analysis, the decision aid increased the proportion of patients who discussed CHD risk reduction with their doctor from 24% to 40% (absolute difference 16%; 95% CI -4% to +37%) and increased the proportion who had a specific plan to reduce their risk from 24% to 37% (absolute difference 13%; 95% CI -7% to +34%). In pre-post testing, the decision aid also appeared to increase the proportion of patients with plans to intervene on their CHD risk (absolute increase ranging from 21% to 47% for planned medication use and 5% to 16% for planned behavioral interventions). CONCLUSION:Our study confirms patients' limited knowledge about their CHD risk and effective risk reduction options and provides preliminary evidence that an individually-tailored decision aid about CHD prevention might be expected to increase patients' discussions about CHD prevention with their doctor and their plans for CHD risk reduction. These findings should be replicated in studies with a larger sample size and patients at overall higher risk of CHD.

背景与目标：

BACKGROUND & AIMS: :Cholera is a substantial health burden on the developing world and is endemic in Africa, Asia, South America, and Central America. The exact scale of the problem is uncertain because of limitations in existing surveillance systems, differences in reporting procedures, and failure to report cholera to WHO; official figures are likely to greatly underestimate the true prevalence of the disease. We have identified, through extensive literature searches, additional outbreaks of cholera to those reported to WHO, many of which originated from the Indian subcontinent and southeast Asia. Such underestimation of cholera can have important implications for decisions on provision of health interventions for indigenous populations, and on risk assessments for travellers. Furthermore, until recently, it has not been possible to implement public-health interventions in low-income countries to eliminate disease, and the prevention of cholera in travellers has been limited to restrictive guidelines. However, a vaccine against cholera is now available that has proven efficacy and tolerability in mass vaccination campaigns in low-income countries, and among travellers.

背景与目标： : 霍乱是发展中国家的沉重健康负担，在非洲，亚洲，南美和中美洲很流行。由于现有监测系统的局限性，报告程序的差异以及未能向世卫组织报告霍乱，问题的确切规模尚不确定; 官方数字可能大大低估了该疾病的真实患病率。通过广泛的文献检索，我们发现了向世卫组织报告的霍乱疫情，其中许多霍乱疫情来自印度次大陆和东南亚。对霍乱的这种低估可能对决定为土著居民提供健康干预措施以及对旅行者的风险评估产生重要影响。此外，直到最近，还无法在低收入国家实施公共卫生干预措施来消除疾病，旅行者霍乱的预防仅限于限制性准则。然而，现在已经有了一种霍乱疫苗，该疫苗在低收入国家和旅行者的群体接种运动中被证明是有效和耐受性的。

BACKGROUND & AIMS: :The objective of this study was to answer the question of whether a double instead of triple embryo transfer strategy in patients over 38 years would substantially reduce the number of multiple pregnancies while maintaining the chance of a term live birth at an acceptable level. A randomized controlled two-centre trial was performed. Forty-five patients, 38 years or older, were randomized. Double embryo transfer over a maximum of four cycles (DET group) or triple embryo transfer over a maximum of three cycles (TET group) was performed. The cumulative term live birth rate was 47.3% after four cycles in the DET group and 40.5% after three cycles in the TET group. The difference between the DET and the TET group was 6.8% in favour of the DET group (95% CI -25 to 38). The multiple pregnancy rates in the DET and TET group were 0% (95% CI 0 to 24) and 30% (95% CI 7 to 65) respectively (P = 0.05). In the DET patients, the mean number of treatment cycles was 2.9 compared with 2.1 in the TET group (P = 0.01). In women of 38 years and older, double embryo transfer after IVF may result in similar cumulative term live birth rates compared with triple embryo transfer, provided that a higher number of treatment cycles is accepted.

背景与目标： : 这项研究的目的是回答以下问题: 在38岁以上的患者中采用双重而不是三重胚胎移植策略是否会大大减少多胎妊娠的数量，同时将足月活产的机会保持在可接受的水平。进行了一项随机对照的两中心试验。45名38岁或以上的患者被随机分组。进行了最多四个周期的双胚胎移植 (DET组) 或最多三个周期的三胚胎移植 (TET组)。在DET组中，在四个周期后47.3% 累积足月活产率，在TET组中，在三个周期后40.5%。DET和TET组之间的差异6.8% 有利于DET组 (95% CI -25至38)。DET组和TET组的多次妊娠率分别为0% (95% CI 0 ~ 24) 和30% (95% CI 7 ~ 65) (P = 0.05)。在DET患者中，平均治疗周期数与TET组的2.1相比2.9 (P = 0.01)。在38岁及以上的女性中，如果接受更多的治疗周期，IVF后的双胚胎移植可能会导致与三胚胎移植相似的累积足月活产率。

BACKGROUND & AIMS: :The aim of the study was to use in silico and in vitro techniques to evaluate whether a triple formulation of antiretroviral drugs (tenofovir, darunavir, and dapivirine) interacted with P-glycoprotein (P-gp) or exhibited any other permeability-altering drug-drug interactions in the colorectal mucosa. Potential drug interactions with P-gp were screened initially using molecular docking, followed by molecular dynamics simulations to analyze the identified drug-transporter interaction more mechanistically. The transport of tenofovir, darunavir, and dapivirine was investigated in the Caco-2 cell models and colorectal tissue, and their apparent permeability coefficient (Papp), efflux ratio (ER), and the effect of transporter inhibitors were evaluated. In silico, dapivirine and darunavir showed strong affinity for P-gp with similar free energy of binding; dapivirine exhibiting a ΔGPB value -38.24 kcal/mol, darunavir a ΔGPB value -36.84 kcal/mol. The rank order of permeability of the compounds in vitro was tenofovir < darunavir < dapivirine. The Papp for tenofovir in Caco-2 cell monolayers was 0.10 ± 0.02 × 10-6 cm/s, ER = 1. For dapivirine, Papp was 32.2 ± 3.7 × 10-6 cm/s, but the ER = 1.3 was lower than anticipated based on the in silico findings. Neither tenofovir nor dapivirine transport was influenced by P-gp inhibitors. The absorptive permeability of darunavir (Papp = 6.4 ± 0.9 × 10-6 cm/s) was concentration dependent with ER = 6.3, which was reduced by verapamil to 1.2. Administration of the drugs in combination did not alter their permeability compared to administration as single agents. In conclusion, in silico modeling, cell culture, and tissue-based assays showed that tenofovir does not interact with P-gp and is poorly permeable, consistent with a paracellular transport mechanism. In silico modeling predicted that darunavir and dapivirine were P-gp substrates, but only darunavir showed P-gp-dependent permeability in the biological models, illustrating that in silico modeling requires experimental validation. When administered in combination, the disposition of the proposed triple-therapy antiretroviral drugs in the colorectal mucosa will depend on their distinctly different permeability, but was not interdependent.

背景与目标： : 该研究的目的是使用计算机和体外技术来评估抗逆转录病毒药物的三重制剂 (替诺福韦，达罗纳韦和达比韦林) 是否与P-糖蛋白 (P-gp) 相互作用或表现出任何其他渗透性改变的药物-大肠粘膜中的药物相互作用。最初使用分子对接筛选与P-gp的潜在药物相互作用，然后进行分子动力学模拟，以更机械地分析已鉴定的药物-转运蛋白相互作用。在Caco-2细胞模型和结直肠组织中研究了替诺福韦，达鲁纳韦和达比韦林的转运，并评估了它们的表观渗透系数 (Papp)，流出比 (ER) 和转运蛋白抑制剂的作用。在计算机中，达皮韦林和达卢纳韦对P-gp表现出很强的亲和力，具有相似的结合自由能; 达皮韦林表现出 Δ gpb值-38.24 kcal/mol，达卢纳韦a Δ gpb值-36.84 kcal/mol。化合物体外通透性的等级顺序为替诺福韦 <达瑞那韦 <达瑞韦林。替诺福韦在Caco-2细胞单层中的Papp为0.10 ± 0.02 × 10-6厘米/s，ER = 1。对于dapivirine，Papp为32.2 ± 3.7 × 10-6厘米/s，但ER = 1.3低于基于计算机研究结果的预期。替诺福韦和达比韦林的转运均不受P-gp抑制剂的影响。darunavir的吸收渗透率 (Papp = 6.4 ± 0.9 × 10-6厘米/s) 与ER = 6.3有关，维拉帕米将其降低至1.2。与作为单一药物施用相比，联合施用药物不会改变其渗透性。总之，在计算机模拟，细胞培养和基于组织的测定中，替诺福韦不与P-gp相互作用，渗透性差，与细胞旁转运机制一致。在计算机模拟中预测darunavir和dapivirine是P-gp底物，但只有darunavir在生物模型中显示出P-gp依赖性渗透性，这说明在计算机模拟中需要实验验证。当联合给药时，拟议的三联疗法抗逆转录病毒药物在大肠粘膜中的配置将取决于它们明显不同的渗透性，但不是相互依存的。

BACKGROUND & AIMS: :Epilepsy prevention is one of the great unmet needs in epilepsy. Approximately 15% of all epilepsy is caused by an acute acquired CNS insult such as traumatic brain injury (TBI), stroke or encephalitis. There is a latent period between the insult and epilepsy onset that presents an opportunity to intervene with preventive treatment that is unique in neurology. Yet no phase 3 epilepsy prevention studies, and only 2 phase 2 studies have been initiated in the last 16years. Current prevailing opinion is that the research community is not ready for clinical preventive epilepsy studies, and that animal models should first be refined and biomarkers of epileptogenesis and of epilepsy discovered before clinical studies are embarked upon. We review data to suggest that there is basis to do epilepsy prevention studies now with the current knowledge and available drugs, and that those studies are feasible with currently available tools. We suggest that a different approach is needed from the past in order to maximize chances of success, minimize the cost, and set up platform for future preventive treatment development. That approach should include close coordination of preclinical and clinical development programs in a combined PTE prevention strategy, consideration of polytherapy, and simultaneous, combined clinical development of preventive treatment and of biomarker discovery. We argue that the currently favored approach of eschewing clinical studies until biomarkers are available will delay the discovery of epilepsy prevention treatment by at least 10 years and significantly increase the cost of such discovery.

背景与目标： : 癫痫预防是癫痫病中巨大的未满足的需求之一。大约15% 的癫痫是由急性获得性CNS损伤引起的，例如创伤性脑损伤 (TBI)，中风或脑炎。在侮辱和癫痫发作之间有一个潜伏期，这为干预神经科独特的预防性治疗提供了机会。然而，在过去的16年中，尚未进行3期癫痫预防研究，并且仅启动了2期研究。目前的普遍观点是，研究界还没有准备好进行临床预防性癫痫研究，应该首先完善动物模型，并在开始临床研究之前发现癫痫发生和癫痫的生物标志物。我们回顾了数据，以表明现在有基础可以利用当前的知识和可用的药物进行癫痫预防研究，并且使用当前可用的工具进行这些研究是可行的。我们建议需要一种与过去不同的方法，以最大程度地提高成功机会，最大程度地降低成本，并为将来的预防性治疗开发建立平台。该方法应包括在联合PTE预防策略中密切协调临床前和临床开发计划，考虑多治疗以及预防性治疗和生物标志物发现的同时，联合临床开发。我们认为，在生物标志物可用之前，目前最受欢迎的避免临床研究的方法将使癫痫预防治疗的发现延迟至少10年，并显着增加这种发现的成本。

BACKGROUND & AIMS: :The recognition that human papillomavirus (HPV) infection is the central, necessary cause of cervical cancer paved the way to new fronts of prevention via improved screening methods and HPV vaccination. Much has been learned in all fronts, from the molecular basis of our understanding of how HPV causes disease to the health economics of preventive strategies at the individual and population levels. Progress in other areas of cancer control has yet to show the same multi- and trans-disciplinary gains seen in research on HPV-associated malignancies, which is one of the unequivocal success stories in disease prevention. Yet, as an embarrassment of riches, much more research is needed to fill the gaps in knowledge that remain before we are able to reap the benefits from the knowledge translation from all fronts. Public health research on setting-specific implementation of HPV-based preventive strategies and more concerted advocacy to counter barriers facing the adoption of these strategies are likely to yield major dividends in reducing the burden of HPV-associated diseases. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

背景与目标： : 认识到人乳头瘤病毒 (HPV) 感染是宫颈癌的主要必要原因，通过改进筛查方法和HPV疫苗接种，为预防的新领域铺平了道路。从我们对HPV如何引起疾病的理解的分子基础到个人和人群水平的预防策略的健康经济学，在各个方面都学到了很多东西。癌症控制的其他领域的进展尚未显示出与HPV相关的恶性肿瘤研究中相同的多学科和跨学科收益，这是疾病预防中明确的成功案例之一。然而，作为财富的尴尬，需要更多的研究来填补知识的空白，这些空白在我们能够从各个方面获得知识翻译的好处之前仍然存在。针对特定环境实施基于HPV的预防策略的公共卫生研究以及采取这些策略所面临的障碍的更协调一致的倡导，可能会在减轻HPV相关疾病的负担方面产生重大好处。本文是2012年《HPV感染及相关疾病的综合控制》疫苗第30卷第5期补充的部分内容。