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.
Ultrasound-guided intramural inoculation of orthotopic bladder cancer xenografts: a novel high-precision approach
Kilian M. Gust
Alan I. So
Joachim W. Thüroff
Peter C. Black
- Orthotopic bladder cancer xenografts are essential for testing novel therapies and molecular manipulations of cell lines in vivo. Current xenografts rely on tumor cell inoculation by intravesical instillation or direct injection into the bladder wall. Instillation is limited by the lack of cell lines that are tumorigenic when delivered in this manner. The invasive model inflicts morbidity on the mice by the need for laparotomy and mobilization of the bladder. Furthermore this procedure is complex and time-consuming. Three bladder cancer cell lines (UM-UC1, UM-UC3, UM-UC13) were inoculated into 50 athymic nude mice by percutaneous injection under ultrasound guidance. PBS was first injected between the muscle wall and the mucosa to separate these layers, and tumor cells were subsequently injected into this space. Bioluminescence and ultrasound were used to monitor tumor growth. Contrast-enhanced ultrasound was used to study changes in tumor perfusion after systemic gemcitabine/cisplatin treatment. To demonstrate proof of principle that therapeutic agents can be injected into established xenografts under ultrasound guidance, oncolytic virus (VSV) was injected into UM-UC3 tumors. Xenograft tissue was harvested for immunohistochemistry after 23–37 days. Percutaneous injection of tumor cells into the bladder wall was performed efficiently (mean time: 5.7 min) and without complications in all 50 animals. Ultrasound and bioluminescence confirmed presence of tumor in the anterior bladder wall in all animals 3 days later. The average tumor volumes increased steadily over the study period. UM-UC13 tumors showed a marked decrease in volume and perfusion after chemotherapy. Immunohistochemical staining for VSV-G demonstrated virus uptake in all UM-UC3 tumors after intratumoral injection. We have developed a novel method for creating orthotopic bladder cancer xenograft in a minimally invasive fashion. In our hands this has replaced the traditional model requiring laparotomy, because this model is more time efficient, more precise and associated with less morbidity for the mice.
Neural networks for impact parameter determination
Steffen A. Bass
Joachim A. Maruhn
- Abstract: An accurate impact parameter determination in a heavy ion collision is crucial for almost all further analysis. The capabilities of an artificial neural network are investigated to that respect. A novel input generation for the network is proposed, namely the transverse and longitudinal momentum distribution of all outgoing (or actually detectable) particles. The neural network approach yields an improvement in performance of a factor of two as compared to classical techniques. To achieve this improvement simple network architectures and a 5 × 5 input grid in (pt, pz) space are suffcient.