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INTRODUCTION: Missing age presents a significant challenge when evaluating individual case safety reports (ICSRs) in the FDA Adverse Event Reporting System (FAERS). When age is missing in an ICSR’s structured field, it may be in the report’s free-text narrative. OBJECTIVES: This study aimed to evaluate the performance and assess the potential impact of a rule-based natural language processing (NLP) tool that utilizes a text string search to identify patients’ numerical age from unstructured narratives. METHODS: Using FAERS ICSRs from 2002 to 2018, we evaluated the annual proportion of ICSRs with age missing in the structured field before and after NLP application. Reviewers manually identified patients’ age from ICSR narratives (gold standard) from a random sample of 1500 ICSRs. The gold standard was compared to the NLP-identified age. RESULTS: During the study period, the percentage of ICSRs missing age in the structured field increased from 21.9 to 43.8%. The NLP tool performed well among the random sample: sensitivity 98.5%, specificity 92.9%, positive predictive value (PPV) 94.9%, and F-measure 96.7%. It also performed well for the subset of ICSRs missing age in the structured field; when applied to these cases, NLP identified age for an additional one million ICSRs (10% of the total number of ICSRs from 2002 to 2018) and decreased the percentage of ICSRs missing age to 27% overall. CONCLUSIONS: NLP has potential utility to extract patients’ age from ICSR narratives. Use of this tool would enhance pharmacovigilance and research using FAERS data.

PURPOSE Erythropoiesis-stimulating agents (ESAs), indicated for treating some patients with chemotherapy-induced anemia (CIA), may increase the risk of tumor progression and mortality. FDA required a Risk Evaluation and Mitigation Strategy (REMS) to mitigate these risks. We assessed REMS impact on ESA administration and red blood cell (RBC) transfusion as surrogate metrics for REMS effectiveness. METHODS Retrospective cohort study including data from January 1, 2006 to December 31, 2018 for beneficiaries ≥65 years enrolled in Centers for Medicare & Medicaid Services (CMS) Medicare Parts A/B with a cancer diagnosis; patients with other indications for ESA use were excluded. Study time was divided into five periods demarcated by issuance of CMS National Coverage Determination (NCD) (Pre-NCD, Pre-REMS) and REMS milestones (Grace Period, REMS, post-REMS). Study outcomes were monthly proportion of chemotherapy episodes (CTEs) with concomitant ESA administration, with post-CTE ESA administration, and with RBC transfusions. RESULTS Of 1 778 855 beneficiaries treated with CT, 308742 received concomitant ESA for CIA. The proportion of CTEs with concomitant and post-CTE ESA administration decreased Pre-REMS (9.0 percentage points [pp] and 3.5 pp, respectively). There were no significant post-REMS changes in the proportion of CTEs with concomitant (0.0 pp) and post-CTE ESA administration (0.1 pp). Fluctuation in RBC transfusions was

BACKGROUND: A previous FDA study reported a favorable benefit risk for apixaban compared with warfarin for stroke prevention in older non-valvular atrial fibrillation (NVAF) patients (≥ 65 years). However, it remains unclear whether this favorable benefit risk persists in other populations including younger users. We examined if a similar benefit risk was observed in the Sentinel System and if it varied by age group. OBJECTIVE: To examine the risk of ischemic stroke, gastrointestinal (GI) bleeding, and intracranial hemorrhage (ICH) in apixaban users compared with warfarin users in Sentinel Distributed Database (SDD). DESIGN AND PARTICIPANTS: A retrospective new user cohort study was conducted among patients, 21 years and older initiating apixaban and warfarin for NVAF, between December 28, 2012, and June 30, 2018, in the SDD. MAIN MEASURES: Cox proportional hazard regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (95% CI) for each outcome (ischemic stroke, GI bleeding, and ICH) in propensity score matched apixaban users compared with the warfarin users. Subgroup analyses by age (21–64, 65–74, and 75+ years) were conducted. KEY RESULTS: After matching, 55.3% and 58.4% (n = 55,038) of the apixaban and warfarin users were included in the main analysis. GI bleeding was the most common outcome. The HR (95% CI) for GI bleeding, ICH, and ischemic stroke in apixaban users compared with warfarin users were 0.57 (0.50–0.66), 0.53 (0.40–0.70), and 0.56 (0.45–0.71) respectively. The reduced risk of these outcomes in apixaban compared with warfarin users persisted across age groups. CONCLUSION: In NVAF patients of all ages initiating either apixaban or warfarin for stroke prevention in the Sentinel System, apixaban was associated with a decreased risk of GI bleeding, ICH, and ischemic stroke compared with warfarin. Among patients less than 65 years of age, apixaban use was associated with a decreased risk of GI bleeding and ischemic stroke. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-020-06180-8) contains supplementary material, which is available to authorized users.

Objectives: This study aimed to explore the levels and associations among depressive symptoms, perceived stress, and proinflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α) in treatment-naïve patients with breast cancer. Methods: A cross-sectional study with one case and two control groups. Patients with breast cancer, matched patients with depression, and matched healthy women completed questionnaires and blood collection between May 2015 and March 2017. Data were analyzed using the general linear model and linear regression model. Results: The severity of depressive symptoms and perceived stress among patients with breast cancer was significantly higher than that in healthy controls and lower than those in patients with depression. Interleukin-1β was lower in patients with breast cancer than the other two groups. Perceived stress was independently and positively associated with depressive symptoms in patients with breast cancer. There were no significant associations between cytokines and depressive symptoms. Conclusion: Women with breast cancer experienced increased perceived stress prior to anticancer treatment, which was a strong contributor to severe symptoms of depression. Results emphasize the need to screen and identify patients with high perceived stress shortly after the disclosure of the diagnosis of breast cancer. Further research in larger sample is needed to investigate the relationship between proinflammatory cytokines and depressive symptoms.

Purpose To identify and analyze postmarketing cases of complex sleep behaviors (CSBs) resulting in serious injuries, including death, associated with eszopiclone, zaleplon, or zolpidem (Z-drugs). Methods Retrospective analysis of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 16 December 1992 through 27 February 2018 and medical literature using PubMed and EMBASE. We used random sampling and descriptive statistics. Results We identified 66 cases that met inclusion and exclusion criteria, four of which were identified in the medical literature. Twenty cases reported death and 46 cases reported serious injuries in association with CSBs occurring after the use of a Z-drug. Fatal cases described events, such as carbon monoxide poisoning, drowning, falls, hypothermia, motor vehicle collisions, and apparent completed suicide. Nonfatal cases resulting in serious injuries described events, such as accidental overdoses, falls, gunshot wounds, hypothermia, third-degree burns, and self-injuries or suicide attempts. Twenty-two cases reported a previous episode of a CSB while taking a Z-drug prior to the event reported in this case series. Conclusions The FAERS and medical literature cases support the need for increased awareness of the consequences that may occur because of CSBs associated with the use of Z-drugs. Therefore, to protect public health, regulatory actions were taken, including adding a Boxed Warning, a Contraindication in patients who have experienced a prior episode of a CSB with a Z-drug, and updating the existing Warnings and Precautions. An FDA Drug Safety Communication was also disseminated to alert healthcare professionals and the public of this potential risk.

There have been reports of clinically relevant uterine bleeding events among women of reproductive age exposed to rivaroxaban. The aim of this study was to compare the risk of severe abnormal uterine bleeding (SAUB) resulting in transfusion or surgical intervention among women on rivaroxaban versus apixaban, dabigatran and warfarin. We conducted a retrospective cohort study in the FDA’s Sentinel System (10/2010–09/2015) among females aged 18+ years with venous thromboembolism (VTE), or atrial flutter/fibrillation (AF) who newly initiated a direct oral anticoagulant (DOAC; rivaroxaban, apixaban, dabigatran) or warfarin. We followed women from dispensing date until the earliest of transfusion or surgery following vaginal bleeding, disenrollment, exposure or study end date, or recorded death. We estimated hazard ratios (HRs) using Cox proportional hazards regression via propensity score stratification. Four pairwise comparisons were conducted for each intervention. Overall, there was an increased risk of surgical intervention with rivaroxaban when compared with dabigatran (HR 1.19; 95% CI 1.03–1.38), apixaban (1.23; 1.04–1.47), and warfarin (1.34; 1.22–1.47). No difference in risk for surgical intervention was observed for dabigatran–apixaban comparisons. Increased risk of transfusion was observed for rivaroxaban compared with dabigatran (1.49; 1.03–2.17) only. For patients with no gynecological history, rivaroxaban was associated with risk of surgical intervention compared with dabigatran (1.22; 1.05–1.42), apixaban (1.25; 1.04–1.49), and warfarin (1.36; 1.23–1.50). Our study found increased SAUB risk with rivaroxaban use compared with other DOACs or warfarin. Increased risk with rivaroxaban was present among women without underlying gynecological conditions. Women on anticoagulant therapy should be aware of a risk of SAUB.

OBJECTIVE We aimed to provide information through 2015 about use in the United States of estrogen products, including orally and vaginally administered products, in postmenopausal women. METHODS We used prescription claims for US commercial health insurance to calculate, in women 50 years of age or older (n = 12,007,364), the age-standardized and age-specific annual prevalence of estrogen use, by formulation and route of administration, for the period 2006 through 2015. RESULTS The age-standardized annual prevalence of a prescription claim for oral estrogens declined over time, from 83 per 1,000 women in 2007 to 42 per 1,000 women in 2015. The age-standardized annual prevalence of a prescription claim for vaginal estrogens peaked in 2011, at 42 per 1,000 women, before declining to 35 per 1,000 women in 2015. The age-standardized annual prevalence of a prescription claim for transdermal estrogen fluctuated between 15 and 17 per 1,000 women. In age groups under 65 years of age, annual prevalence rates for vaginal rings and inserts declined over the latter half of the study period. CONCLUSIONS Analyses of US prescription claims data between 2006 and 2015 for women 50 years of age or older showed declining use of oral estrogen generally and vaginally administered estrogen products specifically in age groups less than 65 years of age.

Purpose The US Food and Drug Administration's Sentinel system developed tools for sequential surveillance. Methods In patients with non-valvular atrial fibrillation, we sequentially compared outcomes for new users of rivaroxaban versus warfarin, employing propensity score matching and Cox regression. A total of 36 173 rivaroxaban and 79 520 warfarin initiators were variable-ratio matched within 2 monitoring periods. Results Statistically significant signals were observed for ischemic stroke (IS) (first period) and intracranial hemorrhage (ICH) (second period) favoring rivaroxaban, and gastrointestinal bleeding (GIB) (second period) favoring warfarin. In follow-up analyses using primary position diagnoses from inpatient encounters for increased definition specificity, the hazard ratios (HR) for rivaroxaban vs warfarin new users were 0.61 (0.47, 0.79) for IS, 1.47 (1.29, 1.67) for GIB, and 0.71 (0.50, 1.01) for ICH. For GIB, the HR varied by age

Purpose Population-based prescription opioid abuse studies in which one drug is compared to another, or drugs are compared across time, often account for the availability of those drugs in the community. The objective of this investigation is to assess consistency in the relative abuse ratios (RARs) across different approaches for adjusting for drug availability. Methods For the years 2004 through 2010, RARs for each of four prescription opioids (hydrocodone, oxycodone, hydromorphone, and morphine) were calculated using negative binomial regression. Measures of abuse (outcome) were misuse/abuse-related emergency department visits obtained from the Drug Abuse Warning Network. Measures of drug availability (offsets) were drug utilization estimates obtained from IMS Health. Separate regression models were run using each of five measures of drug utilization: unique patients (URDD), prescriptions dispensed (RX), tablets dispensed (TD), kilograms (KGs) sold, and morphine-equivalents (MEs) of kilograms sold. These results were compared for consistency. Results Aside from oxycodone-combination products, across molecules, RARs adjusted by RXs, TDs, and URDDs were generally similar to each other while RARs adjusted by KGs and MEs were different. For example, compared to hydrocodone, oxycodone had statistically significantly increased RARs of 3.6 (95%CI: 2.0–6.5), 3.5 (95%CI: 1.9–6.4), and 2.7 (95%CI: 1.5–5.0) when adjusted by URDDs, RXs, and TDs, respectively, but not when adjusted by KGs or MEs. Conclusions Different drug utilization adjustment approaches may yield inconsistent RAR estimates in population-based prescription opioid abuse analyses. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Depressive symptoms are common among kidney transplantation recipients. Previous studies have reported that fatigue and rumination are risk factors for depressive symptoms. To date, the underlying mechanisms of fatigue, rumination, and depressive symptoms among kidney transplantation recipients remain unclear. This study aimed to assess the prevalence of depressive symptoms and investigate whether rumination mediates the association between fatigue and depressive symptoms among kidney transplantation recipients.Cross-sectional study.The study of 207 kidney transplantation recipients with an average age of 44.5 years was conducted from January 2017-July 2017. Sociodemographic and clinical characteristics, fatigue, rumination, and depressive symptoms data were collected. For the descriptive analysis, Pearson correlations and mediation analysis based on the PROCESS macro were used.The prevalence of depressive symptoms among kidney transplantation recipients was 21.7%. Rumination mediated the association between fatigue and depressive symptoms and the indirect effect was 0.19 (95% confidence interval: 0.10-0.28).Depressive symptoms were highly prevalent among kidney transplantation recipients. Rumination exerts a mediating role between fatigue and depressive symptoms.This study alerts physicians and nurses for the importance of considering the mental health of these patients and contributes to the development of effective depression management interventions.目的: 抑郁症状在肾移植接受者中非常常见。以往研究表明疲倦和反刍性沉思是患上抑郁症状的危险因素。迄今为止,肾移植者的疲倦、反刍性沉思和抑郁症状的潜在机制仍不清楚。此研究旨在评估抑郁症状的患病率,并探讨反刍性沉思是否能介导疲倦和抑郁症状之间的关系。 设计: 横断面研究 方法: 自2017年1月至2017年7月,我们对对207名平均年龄为44.5岁的肾脏移植者进行了研究,并且收集了社会人口统计学和临床特征,疲劳,反刍性沉思和抑郁症状数据。对于描述性分析,我们使用了Pearson相关系数以及基于PROCESS宏的中介分析。 结果: 肾移植者中,抑郁症状的患病率为21.7%。反刍性沉思对疲倦和抑郁症状之间的关系起到了中介作用,间接效应为0.19(95%置信区间:0.10-0.28)。 结论: 抑郁症状在肾移植者中非常普遍。反刍性沉思在疲倦和抑郁症状之间起到了中介作用。 影响: 本研究提醒医生和护士考虑这类患者心理健康的重要性,并有助于制定有效的抑郁症治疗干预措施。.

Observational studies provide a core resource in assessing post-market drug safety and effectiveness. Propensity scores are a predominant method for confounding adjustment to achieve unbiased estimation of average treatment effects in observational data. However, the use of propensity score methods has been limited to comparing two treatment groups, while medical situations frequently present with multiple treatment options. Inverse probability of treatment weighting (IPTW) is a popular propensity score adjustment method, but its performance degrades with decreased positivity leading to extreme weights, a problem that can be amplified with multiple treatment groups. Meanwhile, regression on a spline of the propensity score has shown favorable performance compared to other propensity score methods in recent studies involving two treatments. This project utilizes a simulation study to compare IPTW and propensity score splines as adjustment methods in a three-treatment setting. We test a variety of spline methods, including natural cubic splines with varying numbers of interior knots, and thin-plate regression splines. We vary several parameters across simulations, including the degree of propensity score overlap among treatment groups, treatment prevalence, outcome prevalence, and true marginal relative risk. We assess methods based on their bias, root mean squared error, and coverage of the true marginal relative risk across simulations. We find that all methods perform similarly well when there is good propensity score distribution overlap. However, with even moderate decrease in overlap or low outcome prevalence, IPTW produces more biased estimates and higher variance than propensity score splines. Low treatment prevalence or unequal treatment prevalences across groups also worsens IPTW performance. Overall, a natural cubic spline with a relatively small number of interior knots provides good performance across a range of simulations.

Background— The comparative safety of dabigatran versus warfarin for treatment of nonvalvular atrial fibrillation in general practice settings has not been established. Methods and Results— We formed new-user cohorts of propensity score–matched elderly patients enrolled in Medicare who initiated dabigatran or warfarin for treatment of nonvalvular atrial fibrillation between October 2010 and December 2012. Among 134 414 patients with 37 587 person-years of follow-up, there were 2715 primary outcome events. The hazard ratios (95% confidence intervals) comparing dabigatran with warfarin (reference) were as follows: ischemic stroke, 0.80 (0.67–0.96); intracranial hemorrhage, 0.34 (0.26–0.46); major gastrointestinal bleeding, 1.28 (1.14–1.44); acute myocardial infarction, 0.92 (0.78–1.08); and death, 0.86 (0.77–0.96). In the subgroup treated with dabigatran 75 mg twice daily, there was no difference in risk compared with warfarin for any outcome except intracranial hemorrhage, in which case dabigatran risk was reduced. Most patients treated with dabigatran 75 mg twice daily appeared not to have severe renal impairment, the intended population for this dose. In the dabigatran 150-mg twice daily subgroup, the magnitude of effect for each outcome was greater than in the combined-dose analysis. Conclusions— In general practice settings, dabigatran was associated with reduced risk of ischemic stroke, intracranial hemorrhage, and death and increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with nonvalvular atrial fibrillation. These associations were most pronounced in patients treated with dabigatran 150 mg twice daily, whereas the association of 75 mg twice daily with study outcomes was indistinguishable from warfarin except for a lower risk of intracranial hemorrhage with dabigatran.

OBJECTIVE The cardiovascular safety of saxagliptin, a dipeptidyl-peptidase 4 inhibitor, compared with other antihyperglycemic treatments is not well understood. We prospectively examined the association between saxagliptin use and acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS We identified patients aged ≥18 years, starting from the approval date of saxagliptin in 2009 and continuing through August 2014, using data from 18 Mini-Sentinel data partners. We conducted seven sequential assessments comparing saxagliptin separately with sitagliptin, pioglitazone, second-generation sulfonylureas, and long-acting insulin, using disease risk score (DRS) stratification and propensity score (PS) matching to adjust for potential confounders. Sequential testing kept the overall chance of a false-positive signal below 0.05 (one-sided) for each pairwise comparison. RESULTS We identified 82,264 saxagliptin users and more than 1.5 times as many users of each comparator. At the end of surveillance, the DRS-stratified hazard ratios (HRs) (95% CI) were 1.08 (0.90–1.28) in the comparison with sitagliptin, 1.11 (0.87–1.42) with pioglitazone, 0.79 (0.64–0.98) with sulfonylureas, and 0.57 (0.46–0.70) with long-acting insulin. The corresponding PS-matched HRs were similar. Only one interim analysis of 168 analyses met criteria for a safety signal: the PS-matched saxagliptin-pioglitazone comparison from the fifth sequential analysis, which yielded an HR of 1.63 (1.12–2.37). This association diminished in subsequent analyses. CONCLUSIONS We did not find a higher AMI risk in saxagliptin users compared with users of other selected antihyperglycemic agents during the first 5 years after U.S. Food and Drug Administration approval of the drug.

Nonvitamin K antagonist oral anticoagulants (NOACs) are alternatives to warfarin in patients with nonvalvular atrial fibrillation. Randomized trials compared NOACs with warfarin, but none have compared individual NOACs against each other for safety and effectiveness.We performed a retrospective new-user cohort study of patients with nonvalvular atrial fibrillation enrolled in US Medicare who initiated warfarin (n = 183,318), or a standard dose of dabigatran (150 mg twice daily; n = 86,198), rivaroxaban (20 mg once daily; n = 106,389), or apixaban (5 mg twice daily; n = 73,039) between October 2010 and September 2015. Propensity score-adjusted Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the outcomes of thromboembolic stroke, intracranial hemorrhage, major extracranial bleeding, and all-cause mortality, comparing each NOAC with warfarin, and with each other NOAC.Compared with warfarin, each NOAC was associated with reduced risks of thromboembolic stroke (20%-29% reduction; P = .002 [dabigatran], P0.001 [rivaroxaban, apixaban]), intracranial hemorrhage (35%-62% reduction; P0.001 [each NOAC]), and mortality (19%-34% reduction; P.001 [each NOAC]). The NOACs were similar for thromboembolic stroke but rivaroxaban was associated with increased risks of intracranial hemorrhage (vs dabigatran: HR = 1.71; 95% CI, 1.35-2.17), major extracranial bleeding (vs dabigatran: HR = 1.32; 95% CI, 1.21-1.45; vs apixaban: HR = 2.70; 95% CI, 2.38-3.05), and death (vs dabigatran: HR = 1.12; 95% CI, 1.01-1.24; vs apixaban: HR = 1.23; 95% CI, 1.09-1.38). Dabigatran was associated with reduced risk of intracranial hemorrhage (HR = 0.70; 95% CI ,0.53-0.94) and increased risk of major extracranial bleeding (HR = 2.04; 95% CI, 1.78-2.32) compared with apixaban.Among patients treated with standard-dose NOAC for nonvalvular atrial fibrillation and warfarin users with similar baseline characteristics, dabigatran, rivaroxaban, and apixaban were associated with a more favorable benefit-harm profile than warfarin. Among NOAC users, dabigatran and apixaban were associated with a more favorable benefit-harm profile than rivaroxaban.

A single nucleotide polymorphism, � 160C/A, has been identified in the promoter region of the E-cadherin gene and has been shown to alter its transcriptional activity. To assess susceptibility of � 160A allele carriers to seven types of cancers, the authors conducted a comprehensive meta-analysis, up to November 2006, of 26 case-control studies comprising 7,042 cases and 7,011 controls. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analyses were also performed, which showed that � 160A allele carriers, compared with noncarriers, had about a 17–19% increased risk of several invasive/ metastatic tumors. Analyses of various types of cancers revealed that, in Europeans, the � 160AA homozygote was associated with an increased risk of urothelial cancer, carriers of � 160A were at increased risk of lung and prostate cancers, and carriers of � 160A with gastric cancer were found to suffer a significantly increased risk, whereas their Asian counterparts seemed to be tolerant. No evidence was found that the � 160A allele predisposed its carriers to breast, colorectal, or esophageal cancers. These findings indicate that � 160A of the E-cadherin gene is emerging as a low-penetrance tumor susceptibility allele for the development of gastric, lung, prostate, and urothelial cancers.

Condor provides high throughput computing by leveraging idle-cycles on off-the-shelf desktop machines. It also supports flocking, a mechanism for sharing resources among Condor pools. Since Condor pools distributed over a wide area can have dynamically changing availability and sharing preferences, the current flocking mechanism based on static configurations can limit the potential of sharing resources across Condor pools. This paper presents a technique for resource discovery in distributed Condor pools using peer-to-peer mechanisms that are self-organizing, fault-tolerant, scalable, and locality-aware. Locality-awareness guarantees that applications are not shipped across long distances when nearby resources are available. Measurements using a synthetic job trace show that self-organized flocking reduces the maximum job wait time in queue for a heavily loaded pool by a factor of 10 compared to without flocking. Simulations of 1000 Condor pools are also presented and the results confirm that our technique discovers and utilizes nearby resources in the physical network.

Background Dabigatran (150 mg twice daily) has been associated with lower rates of stroke than warfarin in trials of atrial fibrillation, but large-scale evaluations in clinical practice are limited. Objective To compare incidence of stroke, bleeding, and myocardial infarction in patients receiving dabigatran versus warfarin in practice. Design Retrospective cohort. Setting National U.S. Food and Drug Administration Sentinel network. Patients Adults with atrial fibrillation initiating dabigatran or warfarin therapy between November 2010 and May 2014. Measurements Ischemic stroke, intracranial hemorrhage, extracranial bleeding, and myocardial infarction identified from hospital claims among propensity score-matched patients starting treatment with dabigatran or warfarin. Results Among 25 289 patients starting dabigatran therapy and 25 289 propensity score-matched patients starting warfarin therapy, those receiving dabigatran did not have significantly different rates of ischemic stroke (0.80 vs. 0.94 events per 100 person-years; hazard ratio [HR], 0.92 [95% CI, 0.65 to 1.28]) or extracranial hemorrhage (2.12 vs. 2.63 events per 100 person-years; HR, 0.89 [CI, 0.72 to 1.09]) but were less likely to have intracranial bleeding (0.39 vs. 0.77 events per 100 person-years; HR, 0.51 [CI, 0.33 to 0.79]) and more likely to have myocardial infarction (0.77 vs. 0.43 events per 100 person-years; HR, 1.88 [CI, 1.22 to 2.90]). However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition (HR range, 1.13 [CI, 0.78 to 1.64] to 1.43 [CI, 0.99 to 2.08]). Older patients and those with kidney disease had higher gastrointestinal bleeding rates with dabigatran. Limitation Inability to examine outcomes by dabigatran dose (unacceptable covariate balance between matched patients) or quality of warfarin anticoagulation (few patients receiving warfarin had available international normalized ratio values). Conclusion In matched adults with atrial fibrillation treated in practice, the incidences of stroke and bleeding with dabigatran versus warfarin were consistent with those seen in trials. The possible relationship between dabigatran and myocardial infarction warrants further investigation. Primary funding source U.S. Food and Drug Administration.

An increased risk of depressive symptoms has been associated with the transition to menopause, but the risk of depressive symptoms in the early postmenopausal years has not been well characterized.To identify within-woman changes in depressive symptoms during a 14-year period around menopause, determine associations of a history of depression with the pattern of depressive symptoms, and evaluate the rate of change in reproductive hormones as predictors of depressive symptoms following menopause.A randomly identified, population-based sample in Philadelphia County, Pennsylvania, of 203 late-reproductive-age women who were premenopausal at baseline and reached natural menopause.Center for Epidemiologic Studies Depression Scale.The prevalence of high scores on the Center for Epidemiologic Studies Depression Scale decreased from 10 years before to 8 years after the final menstrual period (FMP), with a decrease of approximately 15% of baseline per year (odds ratio, 0.85; 95% CI, 0.81-0.89; P .001). Relative to the FMP, the risk of depressive symptoms was higher in the years before and lower in the years after the FMP. Among women with a history of depression, the likelihood of depressive symptoms was more than 13 times greater overall and 8 times greater after menopause compared with women with no depression history. Among women who first experienced depressive symptoms approaching menopause, the risk of depressive symptoms declined after the FMP, with a significantly lower risk the second year after menopause. The risk of depressive symptoms after menopause decreased by 35% for each unit (SD) increase before the FMP in the log rate of change of follicle-stimulating hormone (odds ratio, 0.65; 95% CI, 0.46-0.91; P = .01).The FMP was pivotal in the overall pattern of decreasing depressive symptoms in midlife women, with higher risk before and lower risk after the FMP. A history of depression strongly increased the risk both before and after menopause. Women who had no history of depression before the menopause transition had a low risk of depressive symptoms 2 or more years after the FMP.

The main trend of the agriculture development is Precision Agriculture, so more and more agriculture decision support system about Precision Agriculture appear. In this paper, we study how to use GIS(Geography Information System), Data mining and Web technologies to apply to the agricultural expert decision system. With the researching background of Hebei expert system for farming soil variable rate fertilization, the GIS-based agriculture expert system according to the foreign advanced experience was put forward, which can meet situation of our country, and the key technologies to implement this system are described in detail.

To investigate the frequency and clinical significance of RET rearrangement in Chinese patients with papillary thyroid carcinoma (PTC) and discuss the role of RET rearrangement in therapeutic decision-making after the performance of level VI lymph node dissection and the 2002 AJCC staging system.RET/PTC-1 and RET/PTC-3 were detected in 126 PTCs using reverse transcription-polymerase chain reaction (RT-PCR) and direct sequencing.RET rearrangement was detected in 18 cases of PTC. The patient group aged20 years had the highest frequency (3/6) of RET rearrangement among the age groups (20 years, 20-40 years andor = 40 years; P=0.03). RET/PTC-1 positive patients were more likely to suffer from Hashimoto's thyroiditis simultaneously (P=0.02) while RET/PTC-3 positive patients had a higher frequency of extrathyroidal extension (P0.01) and advanced T classification (P0.01). RET rearrangement (OR=8.70, 95% CI 1.69-44.81), male (OR=3.88, 95% CI 1.41-10.69), age (OR=0.96, 95% CI 0.93-0.99), multifocality (OR=3.54, 95% CI 1.33-9.41) and advanced T classification (OR=7.32, 95% CI 2.91-18.40) were all identified as risk factors of level II-V lymph node involvement in the multivariate analysis.The frequency of RET rearrangement in Chinese patients is low and age related. RET/PTC-1 and RET/PTC-3 are associated with different clinical pathological characteristics but not with lymph node involvement. The RET/PTC positive patients should receive more attention to lateral neck in the management of PTC.

Internet distance prediction gives pair-wise latency information with limited measurements. Recent studies have revealed that the quality of existing prediction mechanisms from the application perspective is short of satisfactory. In this paper, we explore the root causes and remedies for this problem. Our experience with different landmark selection schemes shows that although selecting nearby landmarks can increase the prediction accuracy for short distances, it can cause the prediction accuracy for longer distances to degrade. Such uneven prediction quality significantly impacts application performance. Instead of trying to select the landmark nodes in some "intelligent" fashion, we propose a hierarchical prediction approach with straightforward landmark selection. Hierarchical prediction utilizes multiple coordinate sets at multiple distance scales, with the "right" scale being chosen for prediction each time. Experiments with Internet measurement datasets show that this hierarchical approach is extremely promising for increasing the accuracy of network distance prediction.

Publish/Subscribe (pub/sub) is an important paradigm for distributed content delivery. Traditionally, there have been two approaches to supporting pub/sub service: subject-based and content-based. Content-based pub/sub allows fine-grained expressiveness, and thus is a more attractive solution for content dissemination. However, the performance of a content-based pub/sub network is bounded by the expensive matching cost of content messages. In this paper, we propose a hybrid approach capable of minimizing both the matching and forwarding overhead within the pub/sub network and the delay experienced by clients receiving the content. The hybrid approach aims to eliminate redundant matching and forwarding inside the pub/sub network. In particular, it identifies a number of virtual groups by exploring common subscription interests among clients, and messages for each virtual group are only matched once at the group entry point. In addition, for each virtual group, the content delivery tree embedded in the underlying pub/sub network can benefit from shortcutting forwarding-only paths. Simulations have shown that the hybrid approach is highly effective in improving the service efficiency and quality of a content-based pub/sub system

Structured peer-to-peer (p2p) overlay networks like CAN, Chord, Pastry and Tapestry [3, 6, 5, 9] provide a self-organizing substrate for large-scale peer-to-peer applications. These systems provide efficient, fault-tolerant routing, object location and load balancing within a self-organization overlay network. In this paper, we show how redundant information that is collected as part of the normal overlay maintenance protocol can be exploited to improve the performance of routing, in terms of both the number of routing hops and routing delay penalty. We use Pastry as a concrete example to describe the set of optimizations and to evaluate their improvement in routing performance via a large scale simulation using a realistic network topology model. We then discuss how these optimizations can be applied to other structured p2p overlays.

Multicast avoids sending repeated packets over the same network links and thus offers the promise of supporting multimedia streaming over wide-area networks. Previously, two opposite multicast schemes -- forward-path forwarding and reverse-path forwarding -- have been proposed on top of structured peer-to-peer (p2p) overlay networks. This paper presents Borg, a new scalable application-level multicast system built on top of p2p overlay networks. Borg is a hybrid protocol that exploits the asymmetry in p2p routing and leverages the reverse-path multicast scheme for its low link stress on the physical networks. Borg has been implemented on top of Pastry, a generic, structured p2p routing substrate. Simulation results based on a realistic network topology model shows that Borg induces significantly lower routing delay penalty than both forward-path and reverse-path multicast schemes while retaining the low link stress of the reverse-path multicast scheme.

This paper advocates implementing anycast in peer-to-peer (p2p) overlay networks. We argue that anycast in p2p overlays (exemplified by Pastry, Tapestry, Chord, CAN) combines the advantages of IP anycast and existing application-layer anycast services. We show that anycast can leverage the locality-awareness embedded in existing p2p overlays. The locality-awareness of the p2p routing substrates can be extended to support anycast and anycast is achieved as the result of the enhanced locality-aware routing. We have implemented anycast in Pastry, and experiments confirm that with high probability, a message addressed to an anycast group is routed to the closest node in the group according to the proximity metric. We also evaluate the performance of anycast using a realistic failure trace and the results show that our implementation of anycast is resilient to node failures.

In this paper, we consider large-scale high-bandwidth on-demand media streaming in a dynamic and heterogeneous environment. We present MetaStream, a scalable and distributed content discovery protocol that enables clients across the Internet to self-organize into a topology-aware overlay network, in which they can “cache and relay” a stream among nearby peers. We present the design and implementation of MetaStream and show experimental results obtained in a large-scale emulated environment. Our evaluation shows that MetaStream distributes relaying load among the clients in a topology-aware manner, imposing low link cost to the underlying network and low streaming load on the media server. MetaStream is also highly resilient to node or network failures and is capable of quickly recovering the streaming quality at clients even at high failure rates.