Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Taxation of E-Commerce: Persistent Problems and Recent Developments

E-commerce on the Internet will create new demands on taxation. In the field of income and business taxation there exists a large potential for profit-shifting into low-tax countries, especially concerning transfers of immaterial goods and transfer pricing. In the long run, this can lead to a severe revenue shortfall. Turnover taxation/VAT raise problems if foreign suppliers sell electronic products or services to final consumers online. VAT should be charged in the country where the consumption takes place, which is currently not the case. Otherwise, distortions of competition and unjust effects of taxation will become more comprehensive. This requires special technical solutions and closer international co-operation among taxation authorities. As a basic principle, e-commerce should not enjoy tax privileges. Rather, it should compete against the traditional economy on the basis of its specific advantages, which, on the other hand, should not be impeded by undue taxation procedures. Zusammenfassung Besteuerung des E-Commerce: Anhaltende Probleme und neuere Entwicklungen E-Commerce über das Internet bedeutet neue Herausforderungen für die Besteuerung. Im Bereich der Einkommens- und Unternehmensbesteuerung entsteht ein großes Potential zur Verlagerung von Einkünften in Niedrigsteuerländer, insbesondere durch Gestaltung von Verrechnungspreisen und durch Übertragung von immateriellen Wirtschaftsgütern. Längerfristig sind dadurch erhebliche Steuerausfälle zu befürchten. Bei der Umsatzsteuer (Mehrwertsteuer) entstehen Probleme, wenn ausländische Anbieter an inländische Endverbraucher elektronische Produkte oder Dienstleistungen online verkaufen. Die Mehrwertsteuer sollte in dem Land erhoben werden, wo der Verbrauch stattfindet, was gegenwärtig nicht der Fall ist, andernfalls drohen Wettbewerbsverfälschungen und ungerechte Steuerbelastungen. Dies erfordert besondere technische Lösungen sowie eine verstärkte internationale Kooperation der Finanzbehörden. Grundsätzlich sollte der e-commerce nicht steuerlich privilegiert werden, sondern sich aufgrund seiner spezifischen Wettbewerbsvorteile durchsetzen, andererseits sollte er aber auch nicht durch aufwendige steuertechnische Anforderungen behindert werden

Co-operative Compliance and the OECD's International Compliance and Assurance Programme

A study into CC of several jurisdictions in relation to the ICAP programm

Co-operative Compliance and the OECD's International Compliance and Assurance Programme

A study into CC of several jurisdictions in relation to the ICAP programm