COMMEnTOPEn 2 Scientific Data | (2020) 7:136 | https://doi.), an effort to build a comprehensive, standardized knowledge repository of SARS-CoV-2 virus-host interaction mechanisms, guided by input from domain experts and based on published work. This knowledge, available in the vast body of existing literature 1,2 and the fast-growing number of new SARS-CoV-2 publications, needs rigorous and efficient organization in both human and machine-readable formats.This endeavour is an open collaboration between clinical researchers, life scientists, pathway curators, computational biologists and data scientists. Currently, 162 contributors from 25 countries around the world are participating in the project, including partners from Reactome 3 , WikiPathways 4 , IMEx Consortium 5 , Pathway Commons 6 , DisGeNET 7 , ELIXIR 8 , and the Disease Maps Community 9 . With this effort, we aim for long-term community-based development of high-quality models and knowledge bases, linked to data repositories.The COVID-19 Disease Map will be a platform for visual exploration and computational analyses of molecular processes involved in SARS-CoV-2 entry, replication, and host-pathogen interactions, as well as immune response, host cell recovery and repair mechanisms. The map will support the research community and improve our understanding of this disease to facilitate the development of efficient diagnostics and therapies. Figure 1 illustrates the initial scope and layout of the map and its life cycle.At the time this Comment went to press, the COVID-19 Disease Map contains pathways of (i) the virus replication cycle and its transcription mechanisms; (ii) SARS-CoV-2 impact on ACE2-regulated pulmonary blood pressure, apoptosis, Cul2-mediated ubiquitination, heme catabolism, Interferon 2 and PAMP signalling, and endoplasmic reticulum stress; (iii) SARS-CoV-2 proteins Nsp4, Nsp6, Nsp14 and Orf3a. Moreover, the map incorporates the COVID-19 collection of WikiPathway diagrams 10 and a pre-published genome-scale metabolic model of human alveolar macrophages with SARS-CoV-2 11 . All these contributed open-access resources are referenced at https://fairdomhub.org/projects/190#models.By combining diagrammatic representation of COVID-19 mechanisms with underlying models, the map fulfils a dual role. First, it is a graphical, interactive representation of disease-relevant molecular mechanisms linking different knowledge bases. Second, it is a computational resource of reviewed content for graph-based analyses 12 and disease modelling 13 . Thus, it provides a platform for domain experts, such as clinicians, virologists, and immunologists, to collaborate with data scientists and computational biologists for a rigorous model building, accurate data interpretation and drug repositioning. It offers a shared mental map to understand gender, age, and other susceptibility features of the host, disease progression, defence mechanisms, and response to treatment. Finally, it can be used together with the maps of other human diseases to study comorbidities.In...

WHAT'S KNOWN ON THIS SUBJECT: Although still off-label for newborns, the use of inhibitors of gastric acid secretion continues to increase. Acid-suppressive drugs could facilitate the onset of infections in adults and children. Evidence for efficacy is weak in newborns, particularly if preterm. WHAT THIS STUDY ADDS:This is the first prospective study demonstrating an association between the use of ranitidine and infections, necrotizing enterocolitis, and fatal outcome in very low birth weight newborns. Caution is advocated in using ranitidine in newborns.abstract BACKGROUND AND OBJECTIVES: Gastric acidity is a major nonimmune defense mechanism against infections. The objective of this study was to investigate whether ranitidine treatment in very low birth weight (VLBW) infants is associated with an increased risk of infections, necrotizing enterocolitis (NEC), and fatal outcome. METHODS:Newborns with birth weight between 401 and 1500 g or gestational age between 24 and 32 weeks, consecutively observed in neonatal intensive care units, were enrolled in a multicenter prospective observational study. The rates of infectious diseases, NEC, and death in enrolled subjects exposed or not to ranitidine were recorded. RESULTS:We evaluated 274 VLBW infants: 91 had taken ranitidine and 183 had not. The main clinical and demographic characteristics did not differ between the 2 groups. Thirty-four (37.4%) of the 91 children exposed to ranitidine and 18 (9.8%) of the 183 not exposed to ranitidine had contracted infections (odds ratio 5.5, 95% confidence interval 2.9-10.4, P , .001). The risk of NEC was 6.6-fold higher in ranitidine-treated VLBW infants (95% confidence interval 1.7-25.0, P = .003) than in control subjects. Mortality rate was significantly higher in newborns receiving ranitidine (9.9% vs 1.6%, P = .003).CONCLUSIONS: Ranitidine therapy is associated with an increased risk of infections, NEC, and fatal outcome in VLBW infants. Caution is advocated in the use of this drug in neonatal age. Infections are a common cause of morbidity and mortality in premature infants. 1 Gastric juice is a major nonimmune defense mechanism against infections. 2 Treatment with inhibitors of gastric acid secretion leads to insufficient elimination of several ingested pathogens. [3][4][5][6][7][8][9][10][11] Many studies show that these drugs facilitate the onset of infections in adults [3][4][5][6][7]12 and children, as we recently demonstrated. 10 There is evidence of an increased risk of infections and necrotizing enterocolitis (NEC) related to the use of histamine-2 receptor (H2-R) blockers and proton pump inhibitors in neonates. [13][14][15] These medications, like many others administered in neonatology, have not been approved by the US Food and Drug Administration for use in this population and are prescribed in an off-label manner because of the perceived safety and potential benefit demonstrated for older populations. Despite these aspects, the use of these drugs has progressively increased. 12,16 In the NICU, the most common i...

Background Drug survival analysis of biologic agents in psoriasis is of extreme importance, as it allows not only the evaluation of objective clinical outcomes (such as effectiveness and safety) but also of factors that are associated with patients' adherence to treatment. The aim of this study was to evaluate and compare the drug survival of the most recent biologic agents approved for the treatment of moderate-to-severe psoriasis-ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and risankizumab-and to identify clinical predictors that can influence the drug survival of these drugs. Methods This retrospective multicentric cohort study from 16 dermatology centers in Portugal,

Abstract Background Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. Objectives To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. Methods Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method. Results We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure. Conclusions We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.

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