Evidence regarding clinical use of microvolt T-wave alternans
Stefan H. Hohnloser
Richard J. Cohen
- Background: Microvolt T-wave alternans (MTWA) testing in many studies has proven to be a highly accurate predictor of ventricular tachyarrhythmic events (VTEs) in patients with risk factors for sudden cardiac death (SCD) but without a prior history of sustained VTEs (primary prevention patients). In some recent studies involving primary prevention patients with prophylactically implanted cardioverter-defibrillators (ICDs), MTWA has not performed as well. Objective: This study examined the hypothesis that MTWA is an accurate predictor of VTEs in primary prevention patients without implanted ICDs, but not of appropriate ICD therapy in such patients with implanted ICDs. Methods: This study identified prospective clinical trials evaluating MTWA measured using the spectral analytic method in primary prevention populations and analyzed studies in which: (1) few patients had implanted ICDs and as a result none or a small fraction (≤15%) of the reported end point VTEs were appropriate ICD therapies (low ICD group), or (2) many of the patients had implanted ICDs and the majority of the reported end point VTEs were appropriate ICD therapies (high ICD group). Results: In the low ICD group comprising 3,682 patients, the hazard ratio associated with a nonnegative versus negative MTWA test was 13.6 (95% confidence interval [CI] 8.5 to 30.4) and the annual event rate among the MTWA-negative patients was 0.3% (95% CI: 0.1% to 0.5%). In contrast, in the high ICD group comprising 2,234 patients, the hazard ratio was only 1.6 (95% CI: 1.2 to 2.1) and the annual event rate among the MTWA-negative patients was elevated to 5.4% (95% CI: 4.1% to 6.7%). In support of these findings, we analyzed published data from the Multicenter Automatic Defibrillator Trial II (MADIT II) and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) trials and determined that in those trials only 32% of patients who received appropriate ICD therapy averted an SCD. Conclusion: This study found that MTWA testing using the spectral analytic method provides an accurate means of predicting VTEs in primary prevention patients without implanted ICDs; in particular, the event rate is very low among such patients with a negative MTWA test. In prospective trials of ICD therapy, the number of patients receiving appropriate ICD therapy greatly exceeds the number of patients who avert SCD as a result of ICD therapy. In trials involving patients with implanted ICDs, these excess appropriate ICD therapies seem to distribute randomly between MTWA-negative and MTWA-nonnegative patients, obscuring the predictive accuracy of MTWA for SCD. Appropriate ICD therapy is an unreliable surrogate end point for SCD. Key words: Arrhythmia; Sudden cardiac death; Cardiac arrest; ICD; T-wave alternans; Surrogate endpoint; Ventricular tachyarrhythmic event; Primary prevention
Über den Widerspruch von religiöser Hoffnung und politischer Analyse in Adam Smith Theorie des freien Marktes
- Die zentrale These des vorliegenden Aufsatzes ist es, dass es ein Adam Smith-Problem im traditionellen Sinne nicht gibt, aber sehr wohl einen Selbstwiderspruch in Adam Smith ökonomischer Theorie.
Der Aufsatz behandelt zunächst die enge systematische Verbindung von Smith ökonomischer und ethischer Theorie. Die Verbindung beruht auf der Annahme eines höchsten Wesens und einer daraus gefolgerten prästabilisierenden Harmonie Dem religiösen Vertrauen auf eine natürliche Ordnung korresponiert der Glaube an die Gerechtigkeit des Marktes. Smith weitere politische Analyse produziert allerdings einen Selbstwiderspruch. Smith zeigt auf, dass die unternehmerischen Eigeninteressen dem Allgemeininteresse der Gesellschaft widersprechen und die Unternehmer zudem virtuoser und erfolgreicher beim Durchsetzen ihrer eigenen Interessen agieren als andere Marktakteure. Dennoch hält Smith an der Annahme fest, der Markt entfalte eine harmonisierende und den allseitigen Wohlstand fördernde Wirkung. Diese Annahme mutiert bei seinen Epigonen zu einer ontologischen Gewissheit.
Integer point sets minimizing average pairwise L1 distance: What is the optimal shape of a town?
Erik D. Demaine
Sándor P. Fekete
- An n-town, n[is an element of]N , is a group of n buildings, each occupying a distinct position on a 2-dimensional integer grid. If we measure the distance between two buildings along the axis-parallel street grid, then an n-town has optimal shape if the sum of all pairwise Manhattan distances is minimized. This problem has been studied for cities, i.e., the limiting case of very large n. For cities, it is known that the optimal shape can be described by a differential equation, for which no closed-form solution is known. We show that optimal n-towns can be computed in O(n[superscript 7.5]) time. This is also practically useful, as it allows us to compute optimal solutions up to n=80.
Formation of small-scale structure in SUSY CDM
Dominik J. Schwarz
- The lightest supersymmetric particle, most likely the lightest neutralino, is one of the most prominent particle candidates for cold dark matter (CDM). We show that the primordial spectrum of density fluctuations in neutralino CDM has a sharp cut-off, induced by two different damping mechanisms. During the kinetic decoupling of neutralinos, non-equilibrium processes constitute viscosity effects, which damp or even absorb density perturbations in CDM. After the last scattering of neutralinos, free streaming induces neutralino flows from overdense to underdense regions of space. Both damping mechanisms together define a minimal mass scale for perturbations in neutralino CDM, before the inhomogeneities enter the non- linear epoch of structure formation. We find that the very first gravitationally bound neutralino clouds ought to have masses above 10-6M , which is six orders of magnitude above the mass of possible axion miniclusters.
A fast hybrid approach to air shower simulations and applications
Glennys R. Farrar
- The SENECA model, a new hybrid approach to air shower simulations, is presented. It combines the use of efficient cascade equations in the energy range where a shower can be treated as one-dimensional, with a traditional Monte Carlo method which traces individual particles. This allows one to reproduce natural fluctuations of individual showers as well as the lateral spread of low energy particles. The model is quite efficient in computation time. As an application of the new approach, the influence of the low energy hadronic models on shower properties for AUGER energies is studied. We conclude that these models have a significant impact on the tails of lateral distribution functions, and deserve therefore more attention.
Does social interaction destablise financial markets?
- With this paper, I propose a simple asset pricing model that accounts for the influence from social interaction. Investors are assumed to make up their mind about an asset’s price based on a forecasting strategy and its past profitability as well as on the contemporaneous expectations of other market participants. Empirically analysing stocks of the DAX30 index, I provide evidence that social interaction rather destabilises financial markets. Based on my results, I state that at least, it does not have a stabilising effect.
Analyst behaviour: the geography of social interaction
- An analyst who works in Germany is more likely to publish a high (low) price target regarding a DAX30 stock if other Germany based analysts are also optimistic (pessimistic) about the same stock. This finding is not biased by the fact that DAX30 companies are headquartered in Germany. In times of bull markets, price targets of analysts who regularly exchange their opinion are higher correlated compared to other analysts. This effect vanishes in a bearish market environment. This suggests that communication among analysts indeed plays an important role. However, analysts’ incentives induce them not to deviate too much from the overall average during an economic downturn.
Fluctuations of social influence: evidence from the behaviour of mutual fund managers during the economic crisis 2008/09
- In this paper, I analyse the reciprocal social influence on investment decisions within an international group of roughly 2000 mutual fund managers that invested in companies of the DAX30. Using a robust estimation procedure, I provide empirical evidence that in the average a fund manager puts 0.69% more portfolio weight on a particular stock, if other fund managers increase the corresponding position by 1%. The dynamics of this influence on portfolio weights suggest that fund managers adjust their behaviour according to the prevailing market situation and are more strongly influenced by others in times of an economic downturn. Analysing the working locations of the fund managers, I conclude that more than 90% of the magnitude of influence is due to pure observation. While this form of influence varies much in time, the magnitude of influence resulting from the exchange of opinion is more or less constant.
Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette smoke-induced pulmonary emphysema in mice and is upregulated in patients with COPD
K. C. Kent Lloyd
Harald von Melchner
- Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD is caused by chronic exposure to cigarette smoke and/or other environmental pollutants that are believed to induce reactive oxygen species (ROS) that gradually disrupt signalling pathways responsible for maintaining lung integrity. Here we identify the antioxidant protein Sestrin 2 (Sesn2) as a repressor of PDGFRβ signalling and PDGFRβ signalling as an upstream regulator of alveolar maintenance programs. In mice, the mutational inactivation of Sesn2 prevents the development of cigarette-smoke induced pulmonary emphysema by upregulating PDGFRβ expression via a selective accumulation of intracellular superoxide anions (O2-). We also show that SESN2 is overexpressed and PDGFRβ downregulated in the emphysematous lungs of patients with COPD and to a lesser extent in human lungs of habitual smokers without COPD, implicating a negative SESN2/PDGFRβ interrelationship in the pathogenesis of COPD. Taken together, our results imply that SESN2 could serve as both a biomarker and as a drug target in the clinical management of COPD.
The NO/cGMP pathway inhibits Rap1 activation in human platelets via cGMP-dependent protein kinase I
- The NO/cGMP signalling pathway strongly inhibits agonist-induced platelet aggregation. However, the molecular mechanisms involved are not completely defined.We have studied NO/cGMP effects on the activity of Rap1, an abundant guanine-nucleotidebinding protein in platelets. Rap1-GTP levels were reduced by NO-donors and activators of NO-sensitive soluble guanylyl cyclase. Four lines of evidence suggest that NO/cGMP effects are mediated by cGMP-dependent protein kinase (cGKI): (i) Rap1 inhibition correlated with cGKI activity as measured by the phosphorylation state ofVASP, an established substrate of cGKI, (ii) 8-pCPT-cGMP, a membrane permeable cGMP-analog and activator of cGKI, completely blocked Rap1 activation, (iii) Rp- 8pCPT-cGMPS, a cGKI inhibitor, reversed NO effects and (iv) expression of cGKI in cGKI-deficient megakaryocytes inhibited Rap1 activation. NO/cGMP/cGKI effects were independent of the type of stimulus used for Rap1 activation.Thrombin-,ADPand collagen-induced formation of Rap1-GTP in platelets as well as turbulence-induced Rap1 activation in megakaryocytes were inhibited. Furthermore, cGKI inhibited ADP-induced Rap1 activation induced by the G a i -coupled P2Y12 receptor alone, i.e. independently of effects on Ca2+-signalling. From these studies we conclude that NO/cGMP inhibit Rap1 activation in human platelets and that this effect is mediated by cGKI. Since Rap1 controls the function of integrin a IIbß 3 , we propose that Rap1 inhibition might play a central role in the anti-aggregatory actions of NO/cGMP.