Substantial Additional Reduction Research Articles

OSSE impact analysis of airborne ocean surveys for improving upper-ocean dynamical and thermodynamical forecasts in the Gulf of Mexico

A prototype, rigorously validated ocean Observing System Simulation Experiment (OSSE) system is used to evaluate the impact of different sampling strategies for rapid-response airborne ocean profile surveys in the eastern interior Gulf of Mexico. Impacts are assessed with respect to improving ocean analyses, and forecasts initialized from those analyses, for two applications: improving oil spill forecasts and improving the ocean model response to tropical cyclone (TC) forcing. Rapid model error growth in this region requires that repeat surveys be conducted frequently in time, with separation of less than 4 days required to approach maximum error reduction in model analyses. Substantial additional error reduction in model dynamical fields is achieved by deploying deep (1000m) AXCTDs instead of shallow (400m) AXBTs. Shallow AXBTs constrain the ocean thermal field over the upper 400m nearly as well as deep AXCTDs. However, in addition to constraining ocean fields over a greater depth range, AXCTDs also measure salinity profiles and more accurately constrain upper-ocean density than AXBTs, leading to a more accurate representation of upper ocean pressure and velocity fields. Sampling AXCTD profiles over a one-half degree array compared to one degree leads to substantial additional error reduction by constraining variability with horizontal scales too small to be corrected by satellite altimetry assimilation. A 2-day lag in availability of airborne profiles does not increase errors in dynamical ocean fields, but it does increase errors in upper-ocean thermal field including Tropical Cyclone Heat Potential (TCHP), demonstrating that these profiles must be rapidly made available for assimilation to improve TC forecasts. The additional error reduction in ocean analyses achieved by assimilation of airborne surveys translates into significantly improved forecasts persisting over time intervals ranging between 1 and 2 weeks for most model variables but several weeks for TCHP. In particular, upper-ocean temperature forecasts can be significantly improved for an extended interval of time by conducting airborne profile surveys.

Effects of multiple interacting disturbances and salvage logging on forest carbon stocks

Climate change is anticipated to increase the frequency of disturbances, potentially impacting carbon stocks in terrestrial ecosystems. However, little is known about the implications of either multiple disturbances or post-disturbance forest management activities on ecosystem carbon stocks. This study quantified how forest carbon stocks responded to stand-replacing blowdown and wildfire, both individually and in combination with and without post-disturbance salvage operations, in a sub-boreal jack pine ecosystem. Individually, blowdown or fire caused similar decreases in live carbon and total ecosystem carbon. However, whereas blowdown increased carbon in down woody material and forest floor, fire increased carbon in standing snags, a difference that may have consequences for long-term carbon cycling patterns. Fire after the blowdown caused substantial additional reduction in ecosystem carbon stocks, suggesting that potential increases in multiple disturbance events may represent a challenge for sustaining ecosystem carbon stocks. Salvage logging, as examined here, decreased carbon stored in snags and down woody material but had no significant effect on total ecosystem carbon stocks.

On improved estimation for importance sampling

The standard estimator used in conjunction with importance sampling in Monte Carlo integration is unbiased but inefficient. An alternative estimator is discussed, based on the idea of a difference estimator, which is asymptotically optimal. The improved estimator uses the importance weight as a control variate, as previously studied by Hesterberg (Ph.D. Dissertation, Stanford University (1988); Technometrics 37 (1995) 185–194; Statistics and Computing 6 (1996) 147–157); it is routinely available and can deliver substantial additional variance reduction. Finite-sample performance is illustrated in a sequential testing example. Connections are made with methods from the survey-sampling literature.

Long-Term Effects of Irbesartan Treatment and Smoking on Nucleic Acid Oxidation in Patients With Type 2 Diabetes and Microalbuminuria

OBJECTIVEWe tested whether long-term treatment with the angiotensin II receptor antagonist irbesartan reduces nucleic acid oxidation in patients with type 2 diabetes and microalbuminuria.RESEARCH DESIGN AND METHODSThe Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA 2) study was a 2-year multicenter randomized double-blind trial comparing irbesartan (150 and 300 mg once daily) with placebo. We studied a subgroup of 50 patients where urine samples were available for analysis of albumin and the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo).RESULTSDuring the 2-year trial, no significant differences in 8-oxodG and 8-oxoGuo excretions between placebo and irbesartan treatment were seen. 8-oxodG and albumin excretion decreased with time (P = 0.0004 and P < 0.0001, respectively), whereas treatment-related differences were shown for albumin excretion (P = 0.0008) only, as previously reported. Important secondary findings were significant associations between changes in 8-oxodG excretion and changes in albumin excretion and glycated hemoglobin (HbA1c). During the study period, 8-oxodG excretion decreased by 3 and 26% in smokers and nonsmokers, respectively (P = 0.015), and urinary albumin excretion decreased 22% in smokers and 58% in nonsmokers (P = 0.011).CONCLUSIONSIrbesartan treatment was not significantly more effective than placebo in reducing nucleic acid oxidation. The results indicate that DNA oxidation in diabetes patients is reduced by various components in the treatment of diabetes where glycemic control seems to be important and addition of angiotensin II receptor antagonists does not lead to any substantial additional reduction. Furthermore, the reductions in DNA oxidation and albumin excretion seem to be counteracted by smoking.

Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist.

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y12 receptor antagonist that blocks ADP-induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y12 receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate greater separation between antithrombotic effects and bleeding effects with ticagrelor than with thienopyridines. Unlike the thienopyridines, ticagrelor does not require metabolic activation. It is quickly absorbed and exhibits a rapid antiplatelet effect, with higher and more consistent levels of inhibition of platelet aggregation (IPA) being maintained across the dosing interval than with clopidogrel. IPA levels decline with plasma drug levels after discontinuation of dosing. In the phase II DISPERSE-2 trial of 990 patients with non-ST-elevation acute coronary syndromes (ACS), ticagrelor treatment with 90 mg and 180 mg twice daily showed comparable rates of major and minor bleeding compared with clopidogrel 75 mg while there were numerically fewer myocardial infarctions. Ticagrelor resulted in greater IPA in clopidogrel-naïve patients and produced substantial additional reductions in platelet aggregation activity in patients pretreated with clopidogrel. Ticagrelor treatment was well tolerated in DISPERSE-2, and discontinuation rates were comparable to those observed for clopidogrel. An increased risk of mild to moderate dyspnea and mostly asymptomatic ventricular pauses were observed in phase II studies. The mechanisms for these effects are currently being investigated. The efficacy and safety of ticagrelor are being further evaluated in the phase III PLATO trial, involving approximately 18,000 patients with ACS, including both ST-elevation and non-ST-elevation ACS.

Statin and ezetimibe combination therapy in cardiovascular disease

To summarize the available data regarding the benefits of combination therapy with statins and ezetimibe in patients with cardiovascular disease. Extensive evidence, mostly in statin outcome trials, has shown that the magnitude of cardiovascular benefit is directly proportional to the degree of LDL cholesterol (LDL-C) reduction. As such, aggressive target goals for LDL-C levels have been established by guideline committees. Although statins are considered first-line agents in lipid therapy, LDL-C targets are difficult to achieve with statin therapy alone. Ezetimibe, a cholesterol absorption inhibitor, has been shown to be well tolerated and effective in lowering LDL-C. Adding ezetimibe to ongoing statin therapy leads to a substantial additional reduction in LDL-C, facilitating the achievement of target goals. The combination of ezetimibe, a cholesterol absorption inhibitor, and statins has been shown to be well tolerated and effective in lowering LDL-C and high-sensitivity C-reactive protein to target goals. Whether this greater LDL-C reduction translates into reduced cardiovascular events is the subject of ongoing clinical trials. Until such data is available, ezetimibe seems to be a reasonable choice for a second-line, lipid-lowering agent in patients on a potent statin who are not at their LDL-C goal.

Minimal Residual Disease (MRD) Kinetics after Autologous Stem Cell Transplantation for Chronic Lymphocytic Leukemia (CLL) Correlate to IgH VH Mutational Status and Predict Post Transplant Outcome: Real Time ASO-IgH PCR Results of the GCLLSG CLL3 Protocol.

The purpose of the present study was (1) to assess the quantitative impact of myeloablative therapy with autologous stem cell transplantation (SCT) on MRD levels in patients with CLL; (2) to assess the predictive value of post transplant MRD kinetics for clinical outcome; and (3) to study the influence of the IgH VH mutational status on MRD kinetics. Blood and bone marrow (BM) samples were obtained from patients from a prospective multicenter trial of the German CLL Study Group (GCLLSG CLL3 protocol) after informed consent. MRD monitoring was performed by real-time quantitative IgH PCR using allele-specific primers (ASO RQ-PCR).Results: As of July 2004, 476 blood samples from 46 patients who had an informative primer and repeated follow-up material available were analyzed by ASO RQ-PCR with a minimum sensitivity of 1E-4. In 145 cases, BM samples obtained on the same occasion were analyzed in parallel. Blood and BM showed highly significant correlating MRD values (p=.0001; slope 0.9, r<.0001), with a tendency to higher MRD levels and higher sensitivity in BM. Myeloablative treatment with SCT resulted in a strong reduction of the CLL load (median MRD level 6.6E-3 pretransplant vs. 1.0E-4 at 90–180 days post transplant; p<.0001) with no significant difference between patients with mutated and unmutated VH, respectively. Whereas MRD levels had no prognostic impact during the first 6 months after SCT, stable or decreasing MRD kinetics below 1E-4 between 6 and 12 months after SCT were strongly predictive for a favourable outcome (4-year progression-free survival (PFS) 100%). In contrast, PFS of those patients who had increasing MRD levels at this time was significantly poorer (4-year PFS 37%; p 0.02; n = 25). Patients with increasing MRD levels early post transplant almost exclusively belonged to the subgroup with unmutated VH.Conclusions: Myeloablative SCT can lead to substantial additional reduction of the tumor load in patients with CLL in remission. The cause of the dismal post transplant outcome of patients with unmutated VH is faster regrowth of the leukemic clone rather than less effective reduction of MRD levels immediately after SCT.

CETP gene variation: relation to lipid parameters and cardiovascular risk.

Over the past decade lowering of low-density lipoprotein-cholesterol levels has been established as the foundation for preventing coronary artery disease, but substantial additional risk reduction remains to be gained by modifying risk factors other than low-density lipoprotein-cholesterol. Raising high-density lipoprotein-cholesterol levels by inhibiting activity of the cholesteryl ester transfer protein (CETP) is a prime target. Research on naturally occurring variants in the CETP gene has yielded numerous insights that have been relevant for understanding lipoprotein metabolism, and crucial to the development of pharmacological CETP inhibition. This review discusses a number of recently published studies, including a haplotype analysis of the CETP promoter region confirming that the -629 C-->A variant, not the TaqIB variant, is instrumental in determining CETP activity, as previously suggested. In addition, we discuss a recent meta-analysis which confirms that the I405V and TaqIB variants are indeed associated with lower CETP activity and higher high-density lipoprotein-cholesterol levels. Also, we review two subanalyses of large randomized controlled pravastatin trials which found no evidence for a proposed pharmacogenetic interaction between the CETP TaqIB variant and pravastatin treatment. The currently available evidence suggests that several genetic variants in the CETP gene are associated with altered CETP plasma levels and activity, high-density lipoprotein-cholesterol plasma levels, low-density lipoprotein and high-density lipoprotein particle size, and perhaps the risk of coronary artery disease. No evidence exists for a pharmacogenetic interaction between the CETP TaqIB variant and pravastatin efficacy.

Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia

Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall. The efficacy and safety of adding ezetimibe to ongoing statin therapy in patients with primary hypercholesterolemia was evaluated in a randomized, double-blind, placebo-controlled study. The study group included 769 adults (aged ≥18 years) with primary hypercholesterolemia who had not achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel II goals with dietary alteration and statin monotherapy. Patients receiving a stable dose of a statin for ≥6 weeks were randomized to receive concurrent treatment with placebo (n = 390) or ezetimibe (n = 379), 10 mg/day, in addition to continuing their open-label statin for 8 weeks. The primary efficacy variable was the percent change in low-density lipoprotein (LDL) cholesterol from baseline with statin monotherapy to end point after intervention (secondary variables: high-density lipoprotein [HDL] cholesterol and triglycerides). Ongoing statin therapy plus ezetimibe led to changes of −25.1% for LDL cholesterol (HDL cholesterol +2.7%; triglycerides −14.0%) compared with LDL cholesterol −3.7% (p <0.001), HDL cholesterol +1.0% (p <0.05), and triglycerides −2.9% (p <0.001) for placebo added to ongoing statin therapy. Among patients not at LDL cholesterol goal at on-statin baseline, 71.5% receiving statin plus ezetimibe versus 18.9% receiving statin plus placebo reached goal at end point (odds ratio 23.7; p <0.001). The co-administration of statin and ezetimibe was generally well tolerated. Adding ezetimibe to ongoing statin therapy led to substantial additional reduction in LDL cholesterol levels, facilitating attainment of NCEP goals. Ezetimibe offers a new therapeutic option for patients receiving statins who require further reduction in LDL cholesterol.

Targeted poverty investments and economic growth in China

In the mid-1980s, the Chinese government launched its ambitious poor area development policy, which was centered around a series of grant, credit, and Food-for-Work programs. Ironically, for the remainder of the 1980s rural poverty remained at about 90 to 100 million, or approximately 10% of the rural population. The lack of progress cannot necessarily be blamed on ineffective poor area policies, since much of the agricultural economy was mired in a deep recession between the mid-1980s and the early 1990s. By the mid-1990s substantial additional poverty reduction had been achieved. Even in the late-1980s, farmers in many poor counties did better than the national average in terms of income growth. After accounting for the effects of macroeconomic elements, what factors can help explain the differences in performance among poor regions and between poor areas and rich ones? Can part of these differences be accounted for by poor area policies, in general, or by the way local and regional officials allocate their poor area investment funds, in particular? The overall objective of this paper is to analyze the effectiveness of Chinese poor area policy. Specifically, the paper seeks to meet three objectives. First, we want to understand the evolution of poor area policy since the mid-1980s, trying to deduce the true goals of central and regional poor area officials, as well as how these policies have been implemented in the provinces. Next, we want to understand the magnitude and scope of investment into poor areas, and examine if changes in these policies have affected the uses of the investment funds. Finally, we want to determine the effectiveness of the investment of poor area funds, analyzing which types of investments have generated growth, and which ones have not.

HYPOTENSIVE EFFECT OF ETHACRYNIC ACID.

Ethacrynic acid has been found to possess a similar antihypertensive action to the thiazide diuretics. The use of the two drugs together results in a greater fall in pressure than that obtained with either drug alone. When thiazide therapy is supplemented by ethacrynic acid and dietary restriction of sodium a substantial additional reduction in blood pressure averaging 48/18 mm. Hg was obtained.