Rationale and design of the PRAETORIAN-COVID trial:A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome–coronavirus-2 (SARS-CoV-2)–infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II–mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. Methods: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2–infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2–infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally

The structure of the PanD/PanZ protein complex reveals negative feedback regulation of pantothenate biosynthesis by coenzyme A.

Coenzyme A (CoA) is an ubiquitous and essential cofactor, synthesized from the precursor pantothenate. Vitamin biosynthetic pathways are normally tightly regulated, including the pathway from pantothenate to CoA. However, no regulation of pantothenate biosynthesis has been identified. We have recently described an additional component in the pantothenate biosynthetic pathway, PanZ, which promotes the activation of the zymogen, PanD, to form aspartate ?-decarboxylase (ADC) in a CoA-dependent manner. Here we report the structure of PanZ in complex with PanD, which reveals the structural basis for the CoA dependence of this interaction and activation. In addition, we show that PanZ acts as a CoA-dependent inhibitor of ADC catalysis. This inhibitory effect can effectively regulate the biosynthetic pathway to pantothenate, and thereby also regulate CoA biosynthesis. This represents a previously unobserved mode of metabolic regulation whereby a cofactor-utilizing protein negatively regulates the biosynthesis of the same cofactor

A duration model for phonetic units in isolated Dutch words

this paper was done as part of the ESPRIT project POLYGLOT. The aim of the project is to develop a multi-lingual Speech-to-Text and Text-to-Speech system. Part of the work comprises the adaptation of a large vocabulary isolated word speech recognition (IWSR) system, originally developed for Italian (Billi et al., 1989), to a number of other European languages, including Dutch. The IWSR system runs on a MS-DOS PC that uses one or two special purpose plug-in boards. The speech is picked up by a table-mounted microphone and A/D-converted with a sampling frequency of 16 kHz and a 12 bit resolution. For each 10 ms frame 20 LPC Cepstrum coefficients are calculated, which are used to calculate the acoustic distance to a set of stored prototypes. A prototype represents a phonetic unit, and because these phonetic units are not always phonemes we will use the terms prototype and phonetic unit throughout this article. The resulting lattice of prototype labels is then submitted to a dynamic programming procedure that outputs the most likely string of prototype labels. To calculate the optimal path in the lattice, the dynamic programming algorithm uses the acoustic distances (which are stored in the lattice) and statistics on prototype frequency, prototype-pair frequency, and the duration of prototypes. The prototype string is then used for fast lexical access, to retrieve the most likely word candidates. In a later stage of the recognition process, called Fine Phonetic Analysis (FPA), a top-down algorithm is used to find the best candidate. For FPA the statistics on the duration of prototypes is also required (Billi et al., 1989). The statistics on prototype frequency and prototype-pair frequency can be derived from large text corpora with tools that were developed in a previous ES..