A model-based study of workload influence on computing system dependability.

Whereas the concepts of system reliability and availability originated from concerns with structural integrity, e.g., a system's capacity to perform, the contemporary view of system dependability (reliability, availability) is user-oriented. More precisely, with respect to a user's specification of desired service, dependability refers to a system's ability to deliver that service. Further, such specifications typically require that services be delivered only in response to corresponding workload demands. Hence, dependability can often be qualified as a system's "ability to serve when called on to serve." This view, together with the fact that fault tolerance mechanisms are usually workload sensitive, imply that workload considerations are generally an integral part of dependability evaluation. We take a model-based approach to establish basic quantitative relationships between a system's workload and its dependability. We start by examining various forms of user specifications and then propose a general framework for dependability evaluation which, based on a discrete event system formalism, incorporates an external event model to account for the effects of workload. This general approach is then used to characterize fault recovery and investigate how workload can affect key recovery parameters, including coverage and recovery time. To gain further insight to the nature of workload influence on dependability, we study two specific types of systems. The first are systems with transient faults where workload can have either positive or negative effects depending on the fault situation. We develop both an analytical model employing Markov renewal process and a simulation model employing stochastic activity networks to derive relationships between dependability measures and parameters characterizing workload, fault and system fault tolerance. The second type of systems are systems with intermittent use where, adopting a high level workload model, we examine dependability measures in terms of both the fault-related parameters and workload-related parameters. Comparisons are made with traditional structure-based formulations of reliability and availability. In particular, it is shown how dependability measures such as mean time to failure and reliability are influenced the extent of intermittent use. The effects of intermittent use are particularly significant in the case of infrequent use, i.e., when active utilization is small.Ph.D.Electrical Engineering: SystemsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105815/1/9208690.pdfDescription of 9208690.pdf : Restricted to UM users only

Sensitive detection and monitoring of senescence-associated secretory phenotype by SASP-RAP assay.

Senescence-associated secretory phenotype (SASP) is characterized by abundant secretion of various proteins in senescent cells and implicated in tumor progression and inflammatory responses. However, the profile of secreted proteins in SASP is different from cell type to cell type, and currently, universal markers for SASP have not been reported. In the present investigation, we show that SASP-responsive alkaline phosphatase (SASP-RAP) serves as a sensitive, general and convenient marker for SASP. Etoposide-treated cells exhibited a senescent phenotype characterized by senile morphology, positive staining for senescence-associated β-galactosidase, growth arrest and induction of p53 and p21(WAF1/CIP1). In SASP-RAP-transfected cells, exposure to etoposide increased secretion of SASP-RAP time-dependently. The kinetics of secretion was closely correlated with that of activation of the p21(WAF1/CIP1) promoter and the p16(INK4a) promoter. The enhanced secretion of SASP-RAP by senescence was also observed in cells treated with other senescence inducers such as trichostatin A, doxorubicin and 4-phenylbutylic acid. The induction of SASP-RAP by senescence was similarly observed in natural replicative senescence. To confirm selectivity of the SASP-RAP response, cells were treated with senescence-related and -unrelated stimuli (IL-1β, LPS, TNF-α and TGF-β), and induction of senescence markers and activity of SASP-RAP were evaluated in parallel. Unlike etoposide, senescence-unrelated stimuli did not induce p53 and p21(WAF1/CIP1), and it was correlated with lack of induction of SASP-RAP. In contrast, senescence-unrelated stimuli up-regulated conventional indicators for SASP, e.g., MMP-3, IL-6 and TIMP, without induction of senescence. SASP-RAP thus serves as a selective, convenient and general marker for detection and monitoring of SASP during cellular senescence

Response of SEAP (SASP-RAP) to etoposide-induced senescence.

<p>(A–C) NRK-52E cells were transfected with pSV40-SEAP (A, B) or pCMV-SEAP (C) and treated with etoposide for indicated time periods. Culture medium was changed with fresh 1% FBS, incubated for 8 h before sampling and subjected to chemiluminescent assay (A). SEAP (SASP-RAP) activity was normalized by the level of viable cells estimated by formazan assay, and relative values are shown in (B) and (C). (D, E) Cells transfected with p21^WAF1/CIP1-Luc (D) or p16^INK4a-Luc (E) were treated with etoposide for indicated time periods and subjected to luciferase assay and formazan assay. The values were normalized by the level of viable cells. Assays were performed in quadruplicate. Data are expressed as means ± SE, and asterisks indicate statistically significant differences (<i>p</i><0.05). (F, G) NRK-52E cells were stably transfected with a pSV40-SEAP. Established NRK/SV-SEAP cells were treated with etoposide for up to 72 h (F) or 7 days (G) and subjected to Northern blot analysis (F) and chemiluminescent assay (G) of SEAP. (H) Cells were transfected with pSV40-SEAP, treated with etoposide in the presence of indicated inhibitors [Akti-1/2 (Akti), 10 µM; PD98059 (PD), 50 µM; SB203580 (SB), 25 µM; SP600125 (SP), 10 µM; DHMEQ (DH), 5 µg/ml] for 3 days and subjected to chemiluminescent assay. NS, not statistically significant.</p

A review and comparison of methods for recreating individual patient data from published Kaplan-Meier survival curves for economic evaluations: a simulation study.

In general, the individual patient-level data (IPD) collected in clinical trials are not available to independent researchers to conduct economic evaluations; researchers only have access to published survival curves and summary statistics. Thus, methods that use published survival curves and summary statistics to reproduce statistics for economic evaluations are essential. Four methods have been identified: two traditional methods 1) least squares method, 2) graphical method; and two recently proposed methods by 3) Hoyle and Henley, 4) Guyot et al. The four methods were first individually reviewed and subsequently assessed regarding their abilities to estimate mean survival through a simulation study.A number of different scenarios were developed that comprised combinations of various sample sizes, censoring rates and parametric survival distributions. One thousand simulated survival datasets were generated for each scenario, and all methods were applied to actual IPD. The uncertainty in the estimate of mean survival time was also captured.All methods provided accurate estimates of the mean survival time when the sample size was 500 and a Weibull distribution was used. When the sample size was 100 and the Weibull distribution was used, the Guyot et al. method was almost as accurate as the Hoyle and Henley method; however, more biases were identified in the traditional methods. When a lognormal distribution was used, the Guyot et al. method generated noticeably less bias and a more accurate uncertainty compared with the Hoyle and Henley method.The traditional methods should not be preferred because of their remarkable overestimation. When the Weibull distribution was used for a fitted model, the Guyot et al. method was almost as accurate as the Hoyle and Henley method. However, if the lognormal distribution was used, the Guyot et al. method was less biased compared with the Hoyle and Henley method

Response of SASP-RAP to senescence under different cellular contexts.

<p>(A) NRK-52E cells were treated with 4 mM 4-PBA, 20 ng/ml trichostatin A (Tri A) and 100 nM doxorubicin (Doxo) for 3 days and subjected to phase-contrast microscopy. Quantitative assessment of senescent morphology is shown in the right graph. (B) Cells were transfected with pSV40-SEAP and treated with 4-PBA, trichostatin A or doxorubicin at indicated concentrations for 3 days and subjected to chemiluminescent assay. (C) MEF were treated with 1 µg/ml etoposide for 3 days and subjected to phase-contrast microscopy and SA-β-gal staining. (D) MEF were transfected with pSV40-SEAP and exposed to 1–5 µg/ml etoposide for 3 days, and culture media were subjected to chemiluminescent assay. (E) Normal human mesangial cells (NHMC) at passage 8 (P8) and passage 13 (P13) were co-transfected with pSV40-SEAP and pEGFP-N1, treated with 1 µg/ml etoposide for 3 days and subjected to phase-contrast microscopy and SA-β-gal staining (E) and chemiluminescent assay (F). In (F), SASP-RAP activity was normalized by both transfection efficiency (percentages of EGFP-positive cells) and viable cell number, and the resultant values are shown. In reporter assays, assays were performed in quadruplicate, and data are expressed as means ± SE. Asterisks indicate statistically significant differences (<i>p</i><0.05).</p

CRIMINAL PROCEDURE IN FRANCE

<p>The values of .6, 1 and 2 represent the shape values of the Weibull distribution and .76, .42 and .26 represent the censoring rates.</p

Effect of statin treatment on mortality in elderly patients with type 2 diabetes mellitus patients: a retrospective cohort study

Abstract Background The effects of statins on the reduction of mortality in individuals aged 75 years or older remain controversial. We conducted this study to investigate whether there is an association between statin therapy and mortality in patients with type 2 diabetes mellitus (T2DM) who are over the age of 75 years. Methods The present study used data from the Staged Diabetes Targeting Management Study, which began in 2005. A total of 518 T2DM patients older than 75 years were included. Cox regression analyses were used to evaluate the association between statins and specific causes of death in patients with T2DM. Results After a follow-up period of 6.09 years (interquartile range 3.94–8.81 years), 111 out of 518 patients died. The results of Cox regression analyses showed that there was no significant association between statin use and all-cause mortality (HR 0.75; 95% CI 0.47, 1.19) after adjustment for all potential confounders. Subgroup analysis indicated that statins had no association with the risk of all-cause mortality or deaths caused by ischemic cardiovascular diseases in T2DM patients with or without coronary heart disease. Conclusions Our study found no significant association between all-cause mortality and statin use in T2DM patients over the age of 75 years. More evidence is needed to support the use of statins in the elderly T2DM patients

The results of uncertainty regarding the estimate of mean survival time.

<p>The uncertainty was captured in the following situations: Weibull distribution: A. γ = 0.6, censoring rate = 0.76; B. γ = 1, censoring rate = 0.76; C. γ = 1, censoring rate = 0.26, and lognormal distribution: D. σ = 2, censoring rate = 0.26.</p

Simulation results for the five methods: 500 patients per trial.

<p>The values of .6, 1 and 2 represent the shape values of the Weibull distribution and .76, .42 and .26 represent the censoring rates.</p