Genomic alterations and molecular subtypes of gastric cancers in Asians

Gastric cancer(GC) is a highly heterogenic disease,and it is the second leading cause of cancer death in the world.Common chemotherapies are not very effective for GC,which often presents as an advanced or metastatic disease at diagnosis.Treatment options are limited,and the prognosis for advanced GCs is poor.The landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs,including studies that focused exclusively on GCs in Asians.These studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of GCs.An analysis of gene expression data by the Asian Cancer Research Group(ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical development.In this article,we review the ACRG GC project.We also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs.

Efficacy and safety of on demand tadalafil in the treatment of East and Southeast Asian men with erectile dysfunction:a randomized double-blind,parallel,placebo-controlled clinical study

Aim： To assess the efficacy and safety of tadalafil in comparison to a placebo, when taken on demand for 12 weeks by East/Southeast Asian men with erectile dysfunction （ED）, Methods： This multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted at 17 centers across East and Southeast Asia between August 2002 and February 2003. Men more than 18 years of age with mild to severe ED of various etiologies were randomized to receive a placebo or 20 mg of tadalafil taken as needed （maximum once daily）. Efficacy assessments included the International Index of Erectile Function, the Sexual Encounter Profile diary and Global Assessment Questions. Results： Tadalafil significantly improved erectile function as compared to the placebo （P 〈 0.001）. At the endpoint, the patients receiving 20 mg of tadalafil reported a greater mean per patient percentage of successful intercourse attempts （Sexual Encounter Profile question 3： 70.9% compared to 33.5% in the placebo） and a greater proportion of improved erections （Global Assessment Question： 86.2% compared to 30.1%）. Most （≥3%） treatment emergent adverse events were mild or moderate. The most common treatment emergent adverse events were headache, back pain, dizziness and dyspepsia. Conclusion： Tadalafil was an effective and well-tolerated treatment for ED in East and Southeast Asian men.

Safety and efficacy of pemetrexed in gynecologic cancers: A systematic literature review

Gynecologic cancers represent a significant problem worldwide. Advanced, recurrent gynecologic cancers are often refractory to chemo-therapy, so new treatment regimens are needed. Pemetrexed is a third-generation, multi-targeted antifolate that has been approved for use in non-squamous non-small cell lung cancer and malignant pleural mesothelioma in both the United States and European Union. This paper reviews the safety and efficacy of pemetrexed in gynecologic cancers, which were defined as maligancies of the ovaries (including fallopian tubes and primary peritoneum), uterine endometrium, and uterine cervix. A search of English-language literature via PubMed and American Society of Clinical Oncology proceedings was performed from database inception to June 2012. Thirteen clinical trials involving the use of pemetrexed (alone and in combination with other agents) in gynecologic cancers were identified. These were phase I and phase II trials;there were 9 studies in ovarian cancer, 1 study in endometrial cancer, and 3 studies in cervical cancer. Pemetrexed with vitamin supplementation was tolerable in all clinical trials and had activity in ovarian and cervical cancers. Therefore, it may be reasonable to further explore the use of pemetrexed in ovarian and cervical malignancies.

Primary tumor location and survival in colorectal cancer: A retrospective cohort study

BACKGROUND Primary tumor location is a prognostic factor for metastatic colorectal cancer(m CRC).Post hoc analyses of m CRC clinical trials,including FIRE-3,CALGB/SWOG 80405,suggest that primary tumor location is also predictive of survival benefit with cetuximab or bevacizumab in combination with 5-fluorouracil-based chemotherapy.AIM Evaluate prognostic/predictive roles of primary tumor location in real-world m CRC patients treated with cetuximab or bevacizumab plus 5-fluorouracil-based chemotherapy.METHODS This retrospective cohort study selected patients with KRAS wild-type m CRC who initiated first-line therapy with cetuximab or bevacizumab in combination with 5-fluorouracil/leucovorin/irinotecan(FOLFIRI)or 5-fluorouracil/leucovorin/oxaliplatin(FOLFOX)between January 2013 and April 2017 from the Flatiron Health electronic health record-derived database of de-identified patientlevel data in the United States.Primary tumor location was abstracted from patients’charts.Left-sided primary tumor location(LPTL)was defined as tumors that originated in the splenic flexure,descending colon,sigmoid colon,or rectum;right-sided primary tumor location(RPTL)was defined as tumors that originated from the appendix,cecum,ascending colon,hepatic flexure,or transverse colon.Propensity score matching was used to balance the baseline demographic and clinical characteristics between patients treated with cetuximab and patientstreated with bevacizumab.Kaplan-Meier and Cox regression methods were used for survival analyses.RESULTS A total of 1312 patients met the selection criteria.Of 248 cetuximab plus FOLFIRI or FOLFOX patients,164 had LPTL and 84 had RPTL;of 1064 bevacizumab plus FOLFIRI or FOLFOX patients,679 had LPTL and 385 had RPTL.Cetuximab LPTL and RPTL patients were more likely to receive FOLFIRI vs bevacizumab patients(LPTL:64.0%vs 24.3%;RPTL:76.2%vs 24.9%,P<0.001).Stage at initial diagnosis was different between cetuximab RPTL vs bevacizumab RPTL patients(P<0.001);cetuximab RPTL patients were more likely to have stage III disease(44.0%vs 22.6%),while bevacizumab RPTL patients were more likely to have stage IV disease(65.7%vs 48.8%).Cetuximab RPTL patients were more likely to have a documented history of adjuvant chemotherapy vs bevacizumab RPTL patients(47.6%vs 22.3%,P<0.001).In the propensity score-matched sample,median overall survival(OS)was 29.7 mo(95%CI:26.9-35.2)for LPTL patients vs 18.3 mo(95%CI:15.8-21.3)for RPTL patients(P<0.001).Median OS was 29.7 mo(95%CI:27.4-NA)for cetuximab LPTL patients vs 29.1 mo(95%CI:26.6-35.6)for bevacizumab LPTL patients(HR=0.87;95%CI:0.63-1.19;P=0.378)and 17.0 mo(95%CI:12.0-32.6)for cetuximab RPTL patients vs 18.8 mo(95%CI:15.8-22.3)for bevacizumab RPTL patients(HR=1.00;95%CI:0.68-1.46;P=0.996).The interaction of treatment and primary tumor location was not significant in the Cox regression.CONCLUSION In this real-world m CRC cohort,the prognostic role of primary tumor location was substantiated,but not the predictive role for treatment with cetuximab vs bevacizumab in combination with 5-fluorouracil-based chemotherapy.

Adjunctive pharmacotherapy and treatment patterns among initiators of SSRI therapy for major depressive disorder: A cohort study using a primary care database

Objective: Adjunctive therapy is often used for treatment of major depressive disorder (MDD) following an inadequate response to an antidepressant. However, there is little information regarding its practice within primary care in the United Kingdom (UK). Objectives of the study were to examine incidence and predictors of adjunctive pharmacotherapy among patients with MDD treated with selective serotonin reuptake inhibitors (SSRIs) by UK general practitioners (GPs). Methods: The General Practice Research Database was used to identify 15,274 MDD patients prescribed first-line treatment with SSRIs from 2006-2008 (latest patient follow-up towards end of 2010). Treatment trajectories were identified and classified as adjunctive therapy, combination therapy, drug switches, dose increases, and restart of therapy. Incidence and predictors of adjunctive therapy were assessed, and healthcare resource utilization was evaluated. Results: Overall incidence of adjunctive therapy was 3.07/100 person years (95% CI 2.90-3.25). Patients prescribed adjunctive therapy were more likely to be female (IRR 1.15, p = 0.03), of higher age (IRRs 1.51-2.60, p ≤ 0.001), and had a greater depression severity score (IRR 1.02, p = 0.003). Presence of irritable bowel syndrome (IRR 1.53, p = 0.001), and an increasing Charlson Comorbidity Index (IRR 1.15, p = 0.01) were associated with a higher incidence of adjunctive therapy. MDD-related general practitioner consultations among patients who received adjunctive therapy was lower compared with patients receiving other treatment interventions (IRRs 0.79 - 0.87, p ≤ 0.001). Conclusions: Adjunctive therapy is infrequently utilized relative to other treatment options for management of MDD among patients who are inadequate responders to their SSRI treatments in UK primary care;however some groups are more likely to receive adjunctive therapy than others.

Safety and Tolerability of Edivoxetine for Long-Term Treatment of Major Depressive Disorder in Adult Patients

This 12-month open-label, but dose-blinded extension phase, evaluated the safety and tolerability of flexibly-dosed edivoxetine (6, 9, 12 or 18 mg once daily) in patients (N = 397) with major depressive disorder, who completed the 10-week randomized, double-blind, placebo-controlled acute phase of the study.All patients were treated with edivoxetine during the extension phase. The mean age of the patients was 45 years, and most were white females. Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), laboratory and vital sign measures, and suicidality. Within-group t-tests based on a 2-sided significance level of 0.05 and 95% confidence levels were used to assess whether changes from baseline were statistically significant from zero. The overall completion rate was 54%. Adverse event was the most common (14.4%) reason for discontinuation, which included blood pressure increased (1.3%), heart rate increased (1.3%), anxiety (1.0%), and tachycardia (1.0%). At least 1 TEAE was reported by 72.3% of patients, of which headache (10.8%) and hyperhidrosis (10.1%) were the most common;2.8% of patients had ≥1 serious adverse events, and there were no completed suicides. No clinically relevant changes were observed in most laboratory measures. Potentially clinically significant changes in ALT values occurred in 1.8% of patients, and either normalized or had decreased by the last assessment. Mean increases in blood pressure and pulse were consistent with those observed in the acute phase and appeared to reach a plateau within 3 to 5 months of treatment. In conclusion, safety and tolerability findings during this long-term extension phase evaluation of edivoxetine were consistent with its norepinephrine reuptake inhibition profile.

Apoptosis is not an invariable component of in vitro models of cortical cerebral ischaemia

Characterising the mechanisms of cell death following focal cerebral ischaemia has been hampered by a lack of an in vitro assay emulating both the apoptotic and necrotic features observed in vivo. The present study systematically characterised oxygen-glucose-deprivation (OGD) in primary rat cortical neurones to establish a reproducible model with components of both cell-death endpoints. OGD induced a time-dependent reduction in cell viability, with 80% cell death occurring 24 h after 3 h exposure to 0% O2 and 0.5 mM glucose. Indicative of a necrotic component to OGDinduced cell death, N-methyl-D-aspartate (NMDA) receptor inhibition with MK-801 attenuated neuronal loss by 60%.The lack of protection by the caspase inhibitors DEVD-CHO and z-VAD-fmk suggested that under these conditions neurones did not die by an apoptotic mechanism. Moderating the severity of the insult by decreasing OGD exposure to 60 min did not reduce the amount of necrosis, but did induce a small degree of apoptosis (a slight reduction in cell death was observed in the presence of 10 μtM DEVD-CHO). In separate experiments purported to enhance the apoptotic component, cells were gradually deprived of O2, exposed to 4% O2 (as opposed to 0%) during the OGD period, or maintained in serum-containing media throughout. While NMDA receptor antagonism significantly reduced cortical cell death under all conditions, a caspase-inhibitor sensitive component of cell death was not uncovered. These studies suggest that OGD of cultured cortical cells models the excitotoxic, but not the apoptotic component of cell death observed in vivo.

意大利临床实践中的PDE5抑制剂治疗模式：“勃起功能障碍观测研究”的纵向数据

“勃起功能障碍观测研究”（Erectile Dysfunction Observational Study,EDOS）是一项为期6个月的多中心前瞻性研究，研究对象包括被要求开始接受治疗或改变治疗方式的ED病人。本研究旨在分析ED的治疗模式，并比较不同治疗模式的疗效。研究对象为到医院看病并诊断需要进行ED治疗的患者。他们接受ED治疗，并在治疗开始时、治疗3个月、6个月时回答来自IIEF（International Index of Erectile Function），EDITS（Erectile Dysfunction Inventory of Treatment Satisfaction），SF-PAIRS（Short Form of the Psychological and Interpersonal Relationship Scale）／nq卷的问题。医生可以给病人开出市场上现有的任何疗法，并可以在治疗过程中任何时间改变疗法。在完成为期6个月的分析的1338名病人中，有624人（47％）改变了疗法，714人（53％）一直接受最初诊断的疗法，其中接受治疗的病人持续接受一种疗法的比率显著高于接受西地那非或伐地那非治疗的病人。其它影响这一比率的变量包括性欲低下和ED。各种PDE-5抑制剂在效力、病人满意度、自信心、自发性等方面无显著差异。接受他达拉非治疗的病人的SF—PAIRS“时间相关”项的分数显著优于接受其它治疗的病人。结果显示现有的三种PDE-5抑制剂的临床实践和临床实验结果相似，但病人如果要终止或改变用药，他达拉非的风险较低。

Discontinuation of antidepressant therapy among patients with major depressive disorder

Objective: Patients with major depressive disorder (MDD) often discontinue antidepressant therapy pre- maturely risking relapse, despite United Kingdom (UK) guidelines recommending therapy for up to at least six months after remission. More information is needed on the patterns of antidepressant discontinuation in UK primary care. Objectives of the study were to assess the patterns, incidence and predictors of therapy discontinuation among MDD patients initiating treatment with selective serotonin reuptake inhibitors (SSRIs). Methods: This was a retrospective cohort study using general practices registered with the General Practice Research Database (GPRD). 15,274 patients with MDD receiving a first ever prescription (index) for an SSRI between 2006-2008 were identified in GPRD. Discontinuation (including temporary gaps) and cessation of antidepressant therapy were examined over follow-up. Predictors of incidence of discontinuation in the six months after index were assessed. Results: Incidence of discontinuation of antidepressant therapy over follow-up was 80.05 per 100 person years (95% CI 78.94 - 81.17). At six months after index 42% of patients had discontinued and 33% had ceased therapy altogether. Lower discontinuation of index SSRI therapy in the first six months after initiation was associated with higher age, higher body mass index (BMI), and comorbid irritable bowel syndrome. Higher discontinuation was associated with paroxetine or fluoxetine at index, and a more recent index calendar year. Conclusions: There is a significant risk of discontinuation of antidepressant therapy in the 6 months after initiation of treatment for MDD. This finding requires awareness by the general practitioner (GP) to ensure implementation of optimal treatment regimens, and minimization of therapy non-compliance among MDD patients.

Long-Term, Open-Label, Safety Study of Edivoxetine as Adjunctive Treatment for Adult Patients with Major Depressive Disorder Who Were Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment in Japan

Edivoxetine is a highly selective norepinephrine reuptake inhibitor (NRI) that has been investigated in short-term studies as adjunctive therapy to?selective serotonin reuptake inhibitor antidepressants (SSRIs) in patients with major depressive disorder (MDD) who were partial responders to their SSRIs. This 52-week open-label study investigated the safety and tolerability of longer-term treatment with adjunctive edivoxetine in patients with MDD in Japan, who had completed one of two placebo-controlled acute studies of edivoxetine as adjunctive therapy to SSRIs. All patients continued on their stable dose of SSRI. Two hundred eighty-eight patients were enrolled and assessed for up to 1 year using standard safety and tolerability measures. Of these, 195 patients previously received only placebo in the parent study and, therefore, were first exposed to edivoxetine in this study. Approximately 46% of patients completed the study. The most frequently cited (>5%) reasons for discontinuation were sponsor decision (19.4%, which included patients discontinued due to early study termination), adverse event (17.4%) and subject decision (8.7%). Adverse events leading to discontinuation in more than 2 patients (>1%) were palpitations, vomiting, hepatic function abnormal, hypertension, nausea, and tachycardia. Treatment-emergent elevations in diastolic blood pressure and pulse were at least twice that reported in the literature for non-Asian patients. Twenty percent of patients had sustained elevations in pulse. Treatment-emergent changes in laboratory measures were small and not clinically meaningful. Assessment across all safety measures in this study indicated that the safety profile of edivoxetine was consistent with that expected for a selective NRI.

Second-line treatment of advanced hepatocellular carcinoma:Time for more individualized treatment options?

Hepatocellular carcinoma(HCC)is the most frequently diagnosed primary tumor of the liver and is usually detected as advanced disease.It is an aggressive disease that often progresses rapidly when it fails to respond to treatment.As such,patients have limited opportunities to try different subsequent-line treatment regimens.In the last 5 years,the number of agents and/or regimens available for the treatment of advanced HCC has significantly increased,which has made treatment choices for this patient population increasingly complex.In the secondline setting,several phase III trials of regorafenib(RESORCE),ramucirumab(REACH/REACH-2),and cabozantinib(CELESTIAL)have demonstrated clinically meaningful survival benefits in patients with the disease.However,the median overall survival of patients with advanced HCC remains unchanged at approximately 12 mo from the start of systemic second-line therapy,with a limited duration of response.Evidence from the REACH/REACH-2 trials demonstrated for the first time that baseline alpha-fetoprotein(AFP)levels can be used as an identification factor to select those who are likely to benefit the most from ramucirumab treatment.Ramucirumab is both well tolerated and efficacious and has a clinically acceptable safety profile.Therefore,it should be considered an option for patients with AFP levels≥400 ng/mL.

雷洛昔芬对患有骨质疏松症的绝经后女性不良心血管事件的影响

The impact of selective estrogen receptor modulators on cardiovascular disease outcomes in postmenopausal women remains unclear. This analysis assessed the effect of raloxifene on the incidence of cardiovascular adverse events in postmenopausal women followed for ≤ 8 years as participants in a 4- year osteoporosis treatment trial and a subsequent 4- year follow- up trial. The Continuing Outcomes Relevant to Evista(CORE) trial, designed to determine the effect of raloxifene on the incidence of invasive breast cancer, was a 4- year follow- up study to the 4- year Multiple Outcomes of Raloxifene Evaluation(MORE)- osteoporosis treatment trial. Of the 7,705 participants originally enrolled in MORE, 4,011 were enrolled in CORE and thus participated in both trials(MORE- CORE participants). The incidence of serious cardiovascular(i.e., coronary and cerebrovascular) adverse events during 8 years, confirmed by external adjudication in the 2 trials, was compared between treatment groups using Cox proportional hazards models. The 8- year incidence of serious cardiovascular adverse events did not differ significantly between the raloxifene(5.5% ) and placebo(4.7% ) groups(hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.86 to 1.56). Similar results were obtained when coronary(HR 1.22, 95% CI 0.82 to 1.83) or cerebrovascular(HR 1.19, 95% CI 0.78 to 1.84) events were analyzed separately, and when cardiovascular events were analyzed in the 459 MORE- CORE participants who were at increased risk of cardiovascular events by previously established criteria(HR 1.03, 95% CI 0.58 to 1.82). In conclusion, we found no evidence of a beneficial or harmful effect of raloxifene on the incidence of cardiovascular events overall, or coronary or cerebrovascular events, in postmenopausal osteoporotic women at relatively low risk of cardiovascular events.

关于度洛西汀治疗妇女压力性尿失禁安全性的整合分析

Objective: The objective was to characterize the safety of duloxetine for treatment of stress urinary incontinence (SUI)- in women, using an integrated database generated from four published placebo-controlled clinical trials. Methods: The database included 1913 women randomized to duloxetine (N = 958) or placebo (N = 955), exa-mining adverse events (AEs), serious adverse events (SAEs), vital signs, electrocardiograms, and laboratory analytes. AEs occurring initially or worsening during the double-blind treatment period were considered treatment-emergent (TEAE). Differences between duloxetinetreated and placebo-treated groups were compared statistically. Results: Common TEAEs included: nausea (23.2% ), dry mouth (13.4% ), fatigue (12.7% ), insomnia (12.6% ), constipation (11.0% ), headache (9.7% ), dizziness (9.5% ), somnolence (6.8% ), and diarrhea (5.1% ). Most TEAEs that emerged early were mild to moderate, rarely worsened, and resolved quickly. Overall AE discontinuation rates were 20.5% for duloxetine and 3.9% for placebo (P < .001). Most discontinuations (83% ) occurred within the first month of treatment. SAEs were uncommon and did not differ between treatments. Statistically significant, but clinically unimportant mean increases in heart rate (2.4 bpm) and systolic and diastolic blood pressure (≤ 2 mmHg) occurred. No arrhythmogenic potential was observed and any rare, transient, asymptomatic increases in hepatocellular enzymes normalized. Conclusions: Duloxetine was safe and tolerable, although transient AEs were not uncommon.

强效高选择性PPAR-α激动剂对致动脉粥样硬化性血脂紊乱或高胆固醇血症患者的影响—两项随机对照试验

背景：贝特类药物是一种较弱的过氧化体增殖物激活型受体仪（peroxisome proliferators-activated receptor-α，PPAR-α）激动剂。目前尚无有关效果更强、选择性更高的相关制剂的报道。 目的：研究PPAR-α激动剂LY518674的安全性和疗效。设计、地点及参试者：开展两项多中心、随机、双盲、安慰剂对照研究，其中一项针对高甘油三酯及低HDL-C血症患者（致动脉粥样硬化陛血脂紊乱），另一项针对高LDL-C患者（即高胆固醇血症）。2005年8月至2006年8月，参与血脂紊乱研究的研究人员在美国医疗中心随机入选309例患者，参与高胆固醇血症研究的研究人员入选304例患者。干预：在血脂紊乱研究中，患者服用安慰剂、非诺贝特（200mg）或LY518674（10μg、25μg、50μg或100μg），共12周。在高胆固醇血症研究中，患者首先服用安慰剂或阿托伐他汀（10mg或40mg）4周，然后服用安慰剂或LY518674（10μg或50μg）12周。主要观测指标：血脂紊乱研究的观测指标为HDL-C和甘油三酯变化的百分比，高胆固醇血症研究的观测指标为LDL-C变化的百分比。 结果：血脂紊乱研究显示，LY518674（25μg）和非诺贝特分别使HDL—C水平增加5．9mg／dL和5．5mg／dL（15．8％和14．4％）（与安慰剂相比P值均≤0．001，组间比较P：0．79）。更高剂量的LY518674对HDL．C水平的影响不大。LY518674可使甘油三酯水平降低97．3～114．5rag／dE（34．9％～41．7％），与非诺贝特效果相似。LY518674可使LDL—C水平呈剂量依赖性升高，100μg LY518674可使LDL—C升高20．4mg／dL（19．5％），而非诺贝特仅使LDL-C升高0．3mg／dL（2．3％）。非诺贝特和LY518674（50μg和100μg）均可增加血清肌酐值（与安慰剂相比P≤0．001），分别有38％和37．3％的患者肌酐值超出正常范围。非诺贝特还可增加磷酸肌酸激酶水平（与安慰剂相比P=0．004），LY518674则无此反应。高胆固醇血症研究显示，LY518674（10μg或50μg）可使LDL—C降低21．4～26．0mg／dL（13．2％～15．8％），使甘油三酯降低约37％，使HDL-C升高6．3～6．7mg／dL（12．5％～15．0％）。当与阿托伐他汀合用时，LY518674可使HDL．C变化-0．7～6．2mg／dL（-0．6％～11．9％），使甘油三酯显著降低，但对LDL—C无明显的进一步降低作用。 结论：在血脂紊乱患者中，LY518674和非诺贝特可降低甘油三酯水平，升高HDL-C水平，但同时也增加血清肌酐水平。与非诺贝特不同，LY518674还可升高LDL-C水平。在高胆固醇血症患者中，LY518674可降低甘油三酯水平，升高HDL-C水平，但与阿托伐他汀合用时并不能进一步降低LDL—C水平。非诺贝特和LY518674的安全陛均需进一步观察。

Log-rank and stratified log-rank tests

In randomized clinical trials with right-censored time-to-event outcomes,the popular log-rank test without adjusting for baseline covariates is asymptotically valid for treatment effect under simple randomization of treatments but is too conservative under covariate-adaptive random-ization.The stratified log-rank test,which adjusts baseline covariates in the test procedure by stratification,is asymptotically valid regardless of what treatment randomization is applied.In the literature,however,under simple randomization there is no affirmative conclusion about whether the stratified log-rank test is asymptotically more powerful than the unstratified log-rank test.In this article we show when the stratified and unstratified log-rank tests aim for the same null hypothesis and that,under simple randomization,the stratified log-rank test is asymp-totically more powerful than the unstratified log-rank test in the region of alternative hypothesis that is specified by a Cox proportional hazards model.We also provide some discussion about why we do not have an affirmative conclusion in general.

首次妊娠及分娩12年后发生压力性尿失禁的风险

OBJECTIVE: To estimate the impact of onset of stress urinary incontinence in first pregnancy or postpartum period, for the risk of symptoms 12 years after the first delivery. METHODS: In a longitudinal cohort study, 241 women answered validated questions about stress urinary incontinence after first delivery and 12 years later. RESULTS: Twelve years after first delivery the prevalence of stress urinary incontinence was 42% (102 of 241). The 12- year incidence was 30% (44 of 146). The prevalence of stress urinary incontinence 12 years after first pregnancy and delivery was significantly higher (P < .01) in women with onset during first pregnancy (56% , 37 of 66) and in women with onset shortly after delivery (78% , 14 of 18) compared with those without initial symptoms (30% , 44 of 146). In 70 women who had onset of symptoms during first pregnancy or shortly after the delivery but remission 3 months postpartum, a total of 40 (57% ) had stress urinary incontinence 12 years later. In 11 women with onset of symptoms during the first pregnancy or shortly after delivery but no remission 3 months postpartum, a total of 10 (91% ) had stress urinary incontinence 12 years later. Cesarean during first delivery was significantly associated with a lower risk of incontinence. Other obstetric factors were not significantly associated with the risk of incontinence 12 years later. Patients who were overweight before their first pregnancy were at increased risk. CONCLUSION: Onset of stress urinary incontinence during first pregnancy or puerperal period carries an increased risk of long-lasting symptoms.

Bioconjugated Silica Nanoparticles: Development and Applications

Advanced bioanalysis,including accurate quantitation,has driven the need to understand biology and medicine at the molecular level.Bioconjugated silica nanoparticles have the potential to address this emerging challenge.Particularly intriguing diagnostic and therapeutic applications in cancer and infectious disease as well as uses in gene and drug delivery,have also been found for silica nanoparticles.In this review,we describe the synthesis,bioconjugation,and applications of silica nanoparticles in different bioanalysis formats,such as selective tagging,barcoding,and separation of a wide range of biomedically important targets.Overall,we envisage that further development of these nanoparticles will provide a variety of advanced tools for molecular biology,genomics,proteomics and medicine.

A randomized clinical trial investigating treatment choice in Chinese men receiving sildenafil citrate and tadalafil for treating erectile dysfunction

Sildenafil and tadalafil are efficacious and well tolerated in Chinese men with erectile dysfunction （ED）. Recent study results indicate that men with ED in China who were naive to phosphodiesterase inhibitor type 5 （PDE5） therapy prefer tadalafil 20-mg （on-demand） versus sildenafil 100-mg （on-demand）. Differences in psychosocial outcomes may help to explain treatment preference in favor of tadalafih This open-label, randomized, crossover study compared psychosocial outcomes and drug attribute choices between tadalafil and sildenafil in Chinese men with ED na＇（ve to PDE5 inhibitor therapy. Eligible patients were randomized to sequential 20-mg tadalafU/lOO-mg sildenafil （n = 190） or 100-mg sildenafil/20-mg tadalafil （n = 193） for 8 weeks each and were asked which treatment they preferred to take for the 8-week extension phase. Psychosocial outcomes were assessed using the Psychological and Interpersonal Relationship Scale （PAIRS）, Drug Attributes Questionnaire （DRAQ）, and Sexual Life Quality Questionnaire （SLQQ）. When taking tadalafil versus sildenafil, men had a higher mean endpoint score on the PAIRS Spontaneity Domain （tadalafil = 2.86 vs sildenafil = 2.72; P 〈 0.001）, and a lower mean endpoint score on the Time Concerns Domain （tadalafil = 2.41 vs sildenafil = 2.55; P 〈 0.001）. A numerical increase in the Sexual Self-Confidence Domain was observed when taking tadalafil versus sildenafil （tadalafil -- 2.76 vs sildenafil = 2.72; P= 0.102）. The most frequently chosen drug attributes explaining treatment preference were able to get an erection long after having drug, and ability to get an erection every time. SLQQ results were comparable between treatment groups. These psychosocial outcomes may explain why more Chinese men preferred tadalafil versus sildenafil for the treatment of ED in this clinical trial.

Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis: a multi-center, randomized, placebo-controlled clinical trial

Background Raloxifene has been approved for prevention and treatment of postmenopausal osteoporosis in Caucasian women. It also has some positive effects on serum lipids in Caucasians. The objective of this study was to determine the effect of raloxifene hydrochloride on lumbar spine and total hip bone mineral density (BMD), bone metabolism, and serum lipids in Chinese postmenopausal women with osteoporosis.Methods This was a multi-center, randomized, double-blind, placebo-controlled clinical trial in which 204 postmenopausal Chinese women with osteoporosis were assigned to receive raloxifene (60 mg) or placebo treatment daily for 12 months. BMD, serum bone metabolism markers, and serum lipids were measured before and after drug administration. BMD was measured by Dual-Energy X-Ray Absorptiometry (DEXA) and bone metabolism markers were analyzed by one-step enzyme-linked immunosorbent assay. Serum lipids were measured by enzymatic analysis.Results At the end of the 12-month study, lumbar spine BMD increased in both groups with a mean increase of (3.3±4.8) % in the raloxifene group and (1.0±4.9) % in the placebo group (P<0.001). There was a mean increase in total hip BMD of (1.4±4.8) % in the raloxifene group and a mean decrease of (0.9±5.0) % in the placebo group (P<0.001). No subject in the raloxifene group had a new vertebral fracture and 5 placebo subjects had new fractures (P>0.05). In the raloxifene group, the median decreases in the biochemical markers of bone metabolism serum osteocalcin and C-telopeptide were 41.7% and 61.5%, respectively. These changes were statistically significant compared with those in the placebo group (10.6% and 35.6%, P<0.001, respectively). Both total cholesterol and low-density lipoprotein cholesterol decreased significantly in the raloxifene group compared with those in the placebo group (P<0.001, respectively) and there was no significant effect of raloxifene on high-density lipoprotein cholesterol and triglycerides compared with placebo. Conclusions Raloxifene 60 mg/d for 12 months significantly increases lumbar spine and total hip BMD, significantly decreases bone turnover, and has favourable effects on serum lipids in Chinese postmenopausal women with osteoporosis.

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.