Statins for acutely hospitalized patients: randomized controlled trials are long overdue

From the earliest studies of statins for control of plasma cholesterol, observations have been made that the reductions in mortality observed occurred in a manner seemingly independent from what could be anticipated from cholesterol lowering alone. Over the last decade, the pleiotropic effects of statins have been increasingly elucidated. Perhaps most intriguing are the effects statins appear to have on the immune system, especially the modulation of diffuse or systemic inflammation. There is a growing body of observational literature suggesting that statins can actually reduce hospital mortality through mechanisms far beyond those that can be explained by reductions in cardiovascular events

Multilevel RTS in proton irradiated CMOS image sensors manufactured in a deep submicron technology

A new automated method able to detect multilevel random telegraph signals (RTS) in pixel arrays and to extract their main characteristics is presented. The proposed method is applied to several proton irradiated pixel arrays manufactured using a 0.18um CMOS process dedicated to imaging. Despite the large proton energy range and the large fluence range used, similar exponential RTS amplitude distributions are observed. A mean maximum amplitude independent of displacement damage dose is extracted from these distributions and the number of RTS defects appears to scale well with total nonionizing energy loss. These conclusions allow the prediction of RTS amplitude distributions. The effect of electric field on RTS amplitude is also studied and no significant relation between applied bias and RTS amplitude is observed

High Frequency Ultrasonics

A high frequency 250 MHz A-scan system has been used for flaw detection. We have been able to detect 25-500 ~m defects of different types (C, Si, SIC, BN, Fe, WC) in a Si3N4 plate. Since it is difficult to determine the defect type and size from the amplitude of the backscattered signal , we have carried out Fourier transforms of the backscattered signal to obtain reflectivity as a function of frequency, and used that information to characterize the size and type of defect. Our ea~ly experiments have been with voids in glass and Si 3N4 and we are able to predict the size of the defects we detect

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

INTRODUCTION: Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. METHODS: In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. RESULTS: Seventy patients received AZD9773 (n=47) or placebo (n=23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. CONCLUSIONS: The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies

Dust Emission from Evolved and Unevolved HII Regions in the Large Magellanic Cloud

We present a study of the dust properties of 12 classical and superbubble HII regions in the Large Magellanic Cloud. We use infrared photometry from Spitzer (8, 24, 70, and 160 \mum bands), obtained as part of the Surveying the Agents of a Galaxy's Evolution (SAGE) program, along with archival spectroscopic classifications of the ionizing stars to examine the role of stellar sources on dust heating and processing. Our infrared observations show surprisingly little correlation between the emission properties of the dust and the effective temperatures or bolometric magnitudes of stars in the HII regions, suggesting that the HII region evolutionary timescale is not on the order of the dust processing timescale. We find that the infrared emission of superbubbles and classical HII regions shows little differentiation between the two classes, despite the significant differences in age and morphology. We do detect a correlation of the 24 \mum emission from hot dust with the ratio of 70 to 160 \mum flux. This correlation can be modeled as a trend in the temperature of a minority hot dust component, while a majority of the dust remains significantly cooler.Comment: 15 pages, 5 figures. Accepted to Ap

The Dust-to-Gas Ratio in the Small Magellanic Cloud Tail

The Tail region of the Small Magellanic Cloud (SMC) was imaged using the MIPS instrument on the Spitzer Space Telescope as part of the SAGE-SMC Spitzer Legacy. Diffuse infrared emission from dust was detected in all the MIPS bands. The Tail gas-to-dust ratio was measured to be 1200 +/- 350 using the MIPS observations combined with existing IRAS and HI observations. This gas-to-dust ratio is higher than the expected 500-800 from the known Tail metallicity indicating possible destruction of dust grains. Two cluster regions in the Tail were resolved into multiple sources in the MIPS observations and local gas-to-dust ratios were measured to be ~440 and ~250 suggests dust formation and/or significant amounts of ionized gas in these regions. These results support the interpretation that the SMC Tail is a tidal tail recently stripped from the SMC that includes gas, dust, and young stars.Comment: 6 pages, 3 figures, ApJ Letters, in press, (version with full resolution figures at http://www.stsci.edu/~kgordon/papers/PS_files/sage-smc_taildust_v1.62.pdf

Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome

INTRODUCTION: Protein C, because of its central role in hemostasis, plays an integral role in the host response to infection. Protein C depletion, resulting from increased consumption, degradation, and/or decreased synthesis, is characteristic of sepsis and has been shown to predict morbidity and mortality. The objective of this study was to determine whether early directional changes in protein C levels correlate with outcome. METHODS: Patients in the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) clinical trial were assessed and categorized by baseline protein C (n = 1574). Deficiency was categorized as: severe deficiency, protein C levels ≤ 40% of normal protein C activity (n = 615, 39% of patients); deficient, protein C levels 41–80% of normal protein C activity (n = 764, 48.5% of patients); and normal, >80% of normal protein C activity (n = 195, 12.4% of patients). Logistic regression analysis of 28-day mortality for placebo patients was used to investigate whether baseline and day 1 protein C levels were independent risk factors for mortality. The impact of treatment with drotrecogin alfa (activated) (DrotAA) was also assessed. RESULTS: Protein C levels at baseline and day 1 were independent risk factors in placebo patients. If baseline protein C levels of severely deficient placebo patients remained ≤ 40% at day 1 their odds of death increased (odds ratio = 2.75, P < 0.0001), while if levels improved to >40% by day 1 their risk of death decreased (odds ratio = 0.43, P = 0.03). If baseline protein C levels of placebo patients were >40% but decreased by ≥ 10% on day 1, their risk of death increased (odds ratio = 1.87, P = 0.02). DrotAA treatment improved protein C levels by day 1 compared with placebo (P = 0.008) and reduced the risk of death in severely deficient (≤ 40%) patients at baseline. Treatment also decreased the number of severely protein C deficient (= 40%) patients and decreased the number of deficient (41–80%) patients and normal (>80%) patients who had a ≥ 10% decrease in protein C levels by day 1. CONCLUSION: Baseline protein C levels were an independent predictor of sepsis outcome. Day 1 changes in protein C, regardless of baseline levels, were also predictive of outcome. The association of DrotAA treatment, increased protein C levels, and improved survival may partially explain the mechanism of action

Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis

INTRODUCTION: Drotrecogin alfa (activated; recombinant activated protein C) was shown to reduce 28-day all-cause mortality in patients with severe sepsis and to have an acceptable safety profile in 1690 patients studied in the F1K-MC-EVAD (PROWESS) trial. We analyzed all available data on the safety of treatment with drotrecogin alfa (activated) in 2786 adult patients with severe sepsis enrolled in all phase 2 and 3 clinical trials, and in an estimated 3991 patients receiving the drug in commercial use. PATIENTS AND METHOD: Mortality and safety analyses were performed on all available data from adult severe sepsis patients enrolled in seven clinical trials as of 12 April 2002. Trial-specific safety data and spontaneously reported serious adverse events from commercial use were extracted from a pharmacovigilance database. RESULTS: The 28-day mortality rate for all adult patients who received active treatment in all clinical trials was 25.3% (704/2786). Serious bleeding events during the infusion period and 28-day study period occurred in 2.8% (79/2786) and 5.3% (148/2786) of patients, respectively. Of bleeding events during the infusion period, 43% (34/79) were procedure-related. Fatal serious bleeding events during the infusion period occurred in 0.4% (12/2786) of cases. Intracranial hemorrhage (ICH) events during the infusion period and 28-day study period occurred in 0.6% (16/2786) and 1.1% (32/2786) of patients, respectively. Ten out of the 16 ICH events occurring during the study drug infusion period were associated with severe thrombocytopenia (≤ 30,000/mm(3)) and/or meningitis. Serious bleeding and ICH events spontaneously reported from commercial use (n = 3991) occurred in 0.9% and 0.2% of patients, respectively. CONCLUSION: Drotrecogin alfa (activated) significantly reduces mortality in severe sepsis. The efficacy and safety profiles of drotrecogin alfa (activated) have remained consistent over the conduct of multiple clinical trials. The most important serious adverse event associated with drotrecogin alfa (activated) treatment is bleeding. Additional clinical experience indicates that invasive procedures are associated with a substantial percentage of serious bleeding events, particularly those occurring at the start of infusion of the drug. Severe thrombocytopenia (for all serious bleeding events, including ICH) and meningitis (for ICH only) may be risk factors for serious bleeding. However, patients with severe thrombocytopenia and/or meningitis may be at greater risk for bleeding or ICH in the absence of drug therapy