High-Density Lipoprotein Cholesterol and Particle Concentrations, Carotid Atherosclerosis, and Coronary Events MESA (Multi-Ethnic Study of Atherosclerosis)

ObjectivesThe purpose of this study was to evaluate independent associations of high-density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary heart disease (CHD).BackgroundHDL-C is inversely related to CHD, and also to triglycerides, low-density lipoprotein particles (LDL-P), and related metabolic risk. HDL-P associations with CHD may be partially independent of these factors.MethodsIn a multiethnic study of 5,598 men and women ages 45 to 84 years old, without baseline CHD, excluding subjects on lipid-lowering medications, triglycerides >400 mg/dl, or missing values, we evaluated associations of HDL-C and nuclear magnetic resonance spectroscopy-measured HDL-P with cIMT and incident CHD (myocardial infarction, CHD death, and angina, n = 227 events; mean 6.0 years follow-up). All models were adjusted for age, sex, ethnicity, hypertension, and smoking.ResultsHDL-C and HDL-P correlated with each other (ρ = 0.69) and LDL-P (ρ = −0.38, −0.25, respectively, p < 0.05 for all). For (1 SD) higher HDL-C (15 mg/dl) or HDL-P (6.64 μmol/l), cIMT differences were − 26.1 (95% confidence interval [CI]: −34.7 to −17.4) μm and −30.1 (95% CI: −38.8 to − 21.4) μm, and CHD hazard ratios were 0.74 (95% CI: 0.63 to 0.88) and 0.70 (95% CI: 0.59 to 0.82), respectively. Adjusted for each other and LDL-P, HDL-C was no longer associated with cIMT (2.3; 95% CI: − 9.5 to 14.2 μm) or CHD (0.97; 95% CI: 0.77 to 1.22), but HDL-P remained independently associated with cIMT (−22.2; 95% CI: − 33.8 to −10.6 μm) and CHD (0.75; 95% CI: 0.61 to 0.93). Interactions by sex, ethnicity, diabetes, and high-sensitivity C-reactive protein were not significant.ConclusionsAdjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL-related risk

Interpretation of the Coronary Artery Calcium Score in Combination With Conventional Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis (MESA)

The coronary artery calcium (CAC) score predicts coronary heart disease (CHD) events, but methods for interpreting the score in combination with conventional CHD risk factors have not been established

Utility of Nontraditional Risk Markers in Atherosclerotic Cardiovascular Disease Risk Assessment

AbstractBackgroundThe improvement in discrimination gained by adding nontraditional cardiovascular risk markers cited in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines to the atherosclerotic cardiovascular disease (ASCVD) risk estimator (pooled cohort equation [PCE]) is untested.ObjectivesThis study assessed the predictive accuracy and improvement in reclassification gained by the addition of the coronary artery calcium (CAC) score, the ankle–brachial index (ABI), high-sensitivity C-reactive protein (hsCRP) levels, and family history (FH) of ASCVD to the PCE in participants of MESA (Multi-Ethnic Study of Atherosclerosis).MethodsThe PCE was calibrated (cPCE) and used for this analysis. The Cox proportional hazards survival model, Harrell’s C statistics, and net reclassification improvement analyses were used. ASCVD was defined as myocardial infarction, coronary heart disease–related death, or fatal or nonfatal stroke.ResultsOf 6,814 MESA participants not prescribed statins at baseline, 5,185 had complete data and were included in this analysis. Their mean age was 61 years; 53.1% were women, 9.8% had diabetes, and 13.6% were current smokers. After 10 years of follow-up, 320 (6.2%) ASCVD events occurred. CAC score, ABI, and FH were independent predictors of ASCVD events in the multivariable Cox models. CAC score modestly improved the Harrell’s C statistic (0.74 vs. 0.76; p = 0.04); ABI, hsCRP levels, and FH produced no improvement in Harrell’s C statistic when added to the cPCE.ConclusionsCAC score, ABI, and FH were independent predictors of ASCVD events. CAC score modestly improved the discriminative ability of the cPCE compared with other nontraditional risk markers

Identification of Allele-Specific RNAi Effectors Targeting Genetic Forms of Parkinson's Disease

Parkinson's disease (PD) is a progressive neurological disorder affecting an estimated 5–10 million people worldwide. Recent evidence has implicated several genes that directly cause or increase susceptibility to PD. As well as advancing understanding of the genetic aetiology of PD these findings suggest new ways to modify the disease course, in some cases through genetic manipulation. Here we generated a ‘walk-through’ series of RNA Pol III-expressed shRNAs targeting both the α-synuclein A30P and LRRK2 G2019S PD-associated mutations. Allele-specific discrimination of the α-synuclein A30P mutation was achieved with alignments at position 10, 13 and 14 in two model systems, including a heterozygous model mimicking the disease setting, whilst 5′RACE was used to confirm stated alignments. Discrimination of the most common PD-linked LRRK2 G2019S mutation was assessed in hemizygous dual-luciferase assays and showed that alignment of the mutation opposite position 4 of the antisense species produced robust discrimination of alleles at all time points studied. Discrimination at this position was subsequently confirmed using siRNAs, where up to 10-fold discrimination was seen. The results suggest that RNAi-mediated silencing of PD-associated autosomal dominant genes could be a novel therapeutic approach for the treatment of the relevant clinical cases of PD in future

The Impact of Phenotypic and Genotypic G6PD Deficiency on Risk of Plasmodium vivax Infection: A Case-Control Study amongst Afghan Refugees in Pakistan

Analyses of a case-control study among Afghan refugees in Pakistan find that a G6PD (glucose-6-phosphate dehydrogenase) “Mediterranean” type deficiency confers substantial protection against Plasmodium vivax malaria

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit