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This article argues that modern time discipline was a product of the eighteenth-century. Whereas other works have emphasized the integration of time through nineteenth-century railway networks, this article holds that science and the state combined to bring discipline to time well before the railway arrived. Central to this was a change in the way time was defined. During the late eighteenth- and early nineteenth centuries, in places such as Geneva, London, Berlin, and Paris, people stopped reckoning time by the sun and followed an independent standard defined by scientists. This article uses Berlin's experience with public clocks to show how this shift began within science and was completed only after city governments enforced it. It further argues that the Berlin government's role in defining time highlights a change in how knowledge was produced in late eighteenthcentury Europe. Science created new approaches to the world, but the state confirmed these approaches as knowledge. In this respect, the "discipline" in time discipline only became a fact, when science and the state defined the knowledge on which it was based. ; El presente artículo argumenta que el estudio moderno del tiempo es un producto del siglo XVIII. En tanto otros trabajos han enfatizado la integración del tiempo mediante las redes ferroviarias en el siglo XIX, este artículo sostiene que la ciencia y el estado se combinaron para dar disciplina al tiempo mucho antes que el ferrocarril llegase. El elemento fundamental del cambio se cifró en cómo se definía el tiempo. Al final del siglo XVIII e inicios del XIX, en ciudades como Ginebra, Londres, Berlín y París, las personas dejaron de calcular la hora a través de la posición del sol y siguieron un estándar definido por científicos. Este artículo usa la experiencia de Berlín con relojes públicos para demostrar como este cambio inició en la ciencia misma, y sólo se completó después que el gobierno de la ciudad lo volviera obligatorio. Se argumenta, además, que el papel desempeñado por el gobierno de Berlín en la definición del tiempo destaca un cambio en como el conocimiento científico se producía en la Europa de finales del siglo XVIII. La ciencia creó nuevas aproximaciones al mundo, pero fue el estado quien confirmó estas aproximaciones como conocimiento. A este respecto, la "disciplina" en la disciplina del tiempo sólo se convirtió en un hecho cuando ciencia y estado definieron el conocimiento en que se basaba.

El Edicto Religioso de 1788 intentó controlar la práctica religiosa, y ha sido, por esa razón, identificado como el fin de la ilustración en Prusia. Sin embargo, este artículo argumenta que el edicto no representó el fin de la ilustración, sino la extensión del absolutismo ilustrado de Federico II a la práctica religiosa. Incluso desde los tiempos de Emmanuel Kant. se ha argumentado que la ilustración en Prusia estaba apoyada en la indiferencia religiosa de Federico II. Aun así, la Prusia de Federico II también produjo una tradición de estadistas ilustrados que enfatizaba el mantener la estabilidad a través de la reforma. El Edicto Religioso se originó de esta tradición y la tornó una extensión de las políticas de reforma absolutista a la esfera religiosa. ; Prussia' s Edict on Religion of 1788 is generally understood as a conservative reaction, its promulgation on July 9th of that year marking the end of the Enlightenment in Prussia. This article argues, however, that the edict was a product of the same forces that produced the Prussian Enlightenment's most famous members. Whereas, Prussia's Enlightenment in religion and philosophy (i.e. Semler and Kant) flowered during Frederick Il's reign ( 1740- 1 786 ), other forms flourished as well. This article concentrates on what we may call the agricultura! Enlightenment, which extended across Europe during the late eighteenth century. This Enlightenment emphasized rural agricultural reform as a way of increasing productivity. Johann Christoph Woellner, the edict' s author, was Prussia' s leading agricultural reformer, during Frederick II's administration. His experiences in rural Prussia and in working for the Prussian state made him both enlightened and politically conservative. The Edict on Religion represented, therefore, not the end of the Enlightenment in Prussia, but the end of Frederickian enlightened absolutism.

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.