Electrocardiographic biomarkers for detection of drug-induced late sodium current block

Background Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the ''CiPA'' initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. Methods and Results In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected JTpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). Conclusions Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block

Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil

Background Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology. Methods and Results Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At pre-dose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide). Conclusions T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk

Modulated Amplitude Waves in Bose-Einstein Condensates

We analyze spatio-temporal structures in the Gross-Pitaevskii equation to study the dynamics of quasi-one-dimensional Bose-Einstein condensates (BECs) with mean-field interactions. A coherent structure ansatz yields a parametrically forced nonlinear oscillator, to which we apply Lindstedt's method and multiple-scale perturbation theory to determine the dependence of the intensity of periodic orbits (``modulated amplitude waves'') on their wave number. We explore BEC band structure in detail using Hamiltonian perturbation theory and supporting numerical simulations.Comment: 5 pages, 4 figs, revtex, final form of paper, to appear in PRE (forgot to include \bibliography command in last update, so this is a correction of that; the bibliography is hence present again

Cosmic Chronometers: Constraining the Equation of State of Dark Energy. I: H(z) Measurements

We present new determinations of the cosmic expansion history from red-envelope galaxies. We have obtained for this purpose high-quality spectra with the Keck-LRIS spectrograph of red-envelope galaxies in 24 galaxy clusters in the redshift range 0.2 < z < 1.0. We complement these Keck spectra with high-quality, publicly available archival spectra from the SPICES and VVDS surveys. We improve over our previous expansion history measurements in Simon et al. (2005) by providing two new determinations of the expansion history: H(z) = 97 +- 62 km/sec/Mpc at z = 0.5 and H(z) = 90 +- 40 km/sec/Mpc at z = 0.8. We discuss the uncertainty in the expansion history determination that arises from uncertainties in the synthetic stellar-population models. We then use these new measurements in concert with cosmic-microwave-background (CMB) measurements to constrain cosmological parameters, with a special emphasis on dark-energy parameters and constraints to the curvature. In particular, we demonstrate the usefulness of direct H(z) measurements by constraining the dark- energy equation of state parameterized by w0 and wa and allowing for arbitrary curvature. Further, we also constrain, using only CMB and H(z) data, the number of relativistic degrees of freedom to be 4 +- 0.5 and their total mass to be < 0.2 eV, both at 1-sigma.Comment: Submitted to JCA

Characterizing the cavitation development and acoustic spectrum in various liquids

A bespoke cavitometer that measures acoustic spectrum and is capable of operating in a range of temperatures (up to 750 degC) was used to study the cavitation behaviour in three transparent liquids and in molten aluminium. To relate these acoustic measurements to cavitation development, the dynamics of the cavitation bubble structures was observed in three Newtonian, optically transparent liquids with significantly different physical properties: water, ethanol, and glycerine. Each liquid was treated at 20 kHz with a piezoelectric ultrasonic transducer coupled to a titanium sonotrode with a tip diameter of 40 mm. Two different transducer power levels were deployed: 50% and 100%, with the maximum power corresponding to a peak-to-peak amplitude of 17 lm. The cavitation structures and the flow patterns were filmed with a digital camera. To investigate the effect of distance from the ultrasound source on the cavitation intensity, acoustic emissions were measured with the cavitometer at two points: below the sonotrode and near the edge of the experimental vessel. The behaviour of the three tested liquids was very different, implying that their physical parameters played a decisive role in the establishment of the cavitation regime. Non dimensional analysis revealed that water shares the closest cavitation behaviour with liquid aluminium and can therefore be used as its physical analogue in cavitation studies; this similarity was also confirmed when comparing the measured acoustic spectra of water and liquid aluminium

Physics of Solar Prominences: I - Spectral Diagnostics and Non-LTE Modelling

This review paper outlines background information and covers recent advances made via the analysis of spectra and images of prominence plasma and the increased sophistication of non-LTE (ie when there is a departure from Local Thermodynamic Equilibrium) radiative transfer models. We first describe the spectral inversion techniques that have been used to infer the plasma parameters important for the general properties of the prominence plasma in both its cool core and the hotter prominence-corona transition region. We also review studies devoted to the observation of bulk motions of the prominence plasma and to the determination of prominence mass. However, a simple inversion of spectroscopic data usually fails when the lines become optically thick at certain wavelengths. Therefore, complex non-LTE models become necessary. We thus present the basics of non-LTE radiative transfer theory and the associated multi-level radiative transfer problems. The main results of one- and two-dimensional models of the prominences and their fine-structures are presented. We then discuss the energy balance in various prominence models. Finally, we outline the outstanding observational and theoretical questions, and the directions for future progress in our understanding of solar prominences.Comment: 96 pages, 37 figures, Space Science Reviews. Some figures may have a better resolution in the published version. New version reflects minor changes brought after proof editin

Are Solar Active Regions with Major Flares More Fractal, Multifractal, or Turbulent than Others?

Multiple recent investigations of solar magnetic field measurements have raised claims that the scale-free (fractal) or multiscale (multifractal) parameters inferred from the studied magnetograms may help assess the eruptive potential of solar active regions, or may even help predict major flaring activity stemming from these regions. We investigate these claims here, by testing three widely used scale-free and multiscale parameters, namely, the fractal dimension, the multifractal structure function and its inertial-range exponent, and the turbulent power spectrum and its power-law index, on a comprehensive data set of 370 timeseries of active-region magnetograms (17,733 magnetograms in total) observed by SOHO's Michelson Doppler Imager (MDI) over the entire Solar Cycle 23. We find that both flaring and non-flaring active regions exhibit significant fractality, multifractality, and non-Kolmogorov turbulence but none of the three tested parameters manages to distinguish active regions with major flares from flare-quiet ones. We also find that the multiscale parameters, but not the scale-free fractal dimension, depend sensitively on the spatial resolution and perhaps the observational characteristics of the studied magnetograms. Extending previous works, we attribute the flare-forecasting inability of fractal and multifractal parameters to i) a widespread multiscale complexity caused by a possible underlying self-organization in turbulent solar magnetic structures, flaring and non-flaring alike, and ii) a lack of correlation between the fractal properties of the photosphere and overlying layers, where solar eruptions occur. However useful for understanding solar magnetism, therefore, scale-free and multiscale measures may not be optimal tools for active-region characterization in terms of eruptive ability or, ultimately,for major solar-flare prediction.Comment: 25 pages, 7 figures, 2 tables, Solar Phys., in pres

The last stand before MAP: cosmological parameters from lensing, CMB and galaxy clustering

Cosmic shear measurements have now improved to the point where they deserve to be treated on par with CMB and galaxy clustering data for cosmological parameter analysis, using the full measured aperture mass variance curve rather than a mere phenomenological parametrization thereof. We perform a detailed 9-parameter analysis of recent lensing (RCS), CMB (up to Archeops) and galaxy clustering (2dF) data, both separately and jointly. CMB and 2dF data are consistent with a simple flat adiabatic scale-invariant model with Omega_Lambda=0.72+/-0.09, omega_cdm=0.115+/- 0.013, omega_b=0.024+/-0.003, and a hint of reionization around z~8. Lensing helps further tighten these constraints, but reveals tension regarding the power spectrum normalization: including the RCS survey results raises sigma8 significantly and forces other parameters to uncomfortable values. Indeed, sigma8 is emerging as the currently most controversial cosmological parameter, and we discuss possible resolutions of this sigma8 problem. We also comment on the disturbing fact that many recent analyses (including this one) obtain error bars smaller than the Fisher matrix bound. We produce a CMB power spectrum combining all existing experiments, and using it for a "MAP versus world" comparison next month will provide a powerful test of how realistic the error estimates have been in the cosmology community.Comment: Added references and Fisher error discussion. Combined CMB data, window and covariance matrix for January "MAP vs World" contest at http://www.hep.upenn.edu/~max/cmblsslens.html or from [email protected]

Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial

BACKGROUND: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. METHODS: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. FINDINGS: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. INTERPRETATION: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications