Comparative Genomic Analysis of Human Fungal Pathogens Causing Paracoccidioidomycosis

Paracoccidioides is a fungal pathogen and the cause of paracoccidioidomycosis, a health-threatening human systemic mycosis endemic to Latin America. Infection by Paracoccidioides, a dimorphic fungus in the order Onygenales, is coupled with a thermally regulated transition from a soil-dwelling filamentous form to a yeast-like pathogenic form. To better understand the genetic basis of growth and pathogenicity in Paracoccidioides, we sequenced the genomes of two strains of Paracoccidioides brasiliensis (Pb03 and Pb18) and one strain of Paracoccidioides lutzii (Pb01). These genomes range in size from 29.1 Mb to 32.9 Mb and encode 7,610 to 8,130 genes. To enable genetic studies, we mapped 94% of the P. brasiliensis Pb18 assembly onto five chromosomes. We characterized gene family content across Onygenales and related fungi, and within Paracoccidioides we found expansions of the fungal-specific kinase family FunK1. Additionally, the Onygenales have lost many genes involved in carbohydrate metabolism and fewer genes involved in protein metabolism, resulting in a higher ratio of proteases to carbohydrate active enzymes in the Onygenales than their relatives. To determine if gene content correlated with growth on different substrates, we screened the non-pathogenic onygenale Uncinocarpus reesii, which has orthologs for 91% of Paracoccidioides metabolic genes, for growth on 190 carbon sources. U. reesii showed growth on a limited range of carbohydrates, primarily basic plant sugars and cell wall components; this suggests that Onygenales, including dimorphic fungi, can degrade cellulosic plant material in the soil. In addition, U. reesii grew on gelatin and a wide range of dipeptides and amino acids, indicating a preference for proteinaceous growth substrates over carbohydrates, which may enable these fungi to also degrade animal biomass. These capabilities for degrading plant and animal substrates suggest a duality in lifestyle that could enable pathogenic species of Onygenales to transfer from soil to animal hosts.National Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health. Department of Health and Human Services (contract HHSN266200400001C)National Institutes of Health. Department of Health and Human Services(contract HHSN2722009000018C)Brazil. National Council for Scientific and Technological Developmen

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

A fifth species of the genus Euparkerella (Griffths, 1959), the advertisement calls of E. robusta Izecksohn, 1988 and E. tridactyla Izecksohn, 1988, and a key for the Euparkerella species (Anura: Brachycephaloidea: Craugastoridae)

Hepp, Fábio, De Carvalho-E-Silva, Sergio P., Telles De Carvalho-E-Silva, Ana M. P., Folly, Manuella (2015): A fifth species of the genus Euparkerella (Griffths, 1959), the advertisement calls of E. robusta Izecksohn, 1988 and E. tridactyla Izecksohn, 1988, and a key for the Euparkerella species (Anura: Brachycephaloidea: Craugastoridae). Zootaxa 3973 (2): 251-270, DOI: http://dx.doi.org/10.11646/zootaxa.3973.2.

Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial

Carvalho, Lucas Pedreira de. Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Pesquisa Clínica. Salvador, BA, Brasil. a Postgraduate Program in Medicine and Health, b Psychiatry Service, University Hospital, Universidade Federal da Bahia, Salvador, c LiNC—Laboratório Interdisciplinar de Neurociências Clínicas, d Depatment of Anesthesiology, e PRODAF—Programa de Transtornos Afetivos, Universidade Federal de São Paulo, São Paulo, f Postgraduate Program in Psychology, Institute of Psychology, g Immunology Service, Universidade Federal da Bahial, h Clinical Research Laboratory (LAPEC), Gonçalo Moniz Institute, Fiocruz-Bahia, Salvador, Brazil, i McGill Group for Suicide Studies, Douglas Mental Health University Institute & Department of Psychiatry, McGill University, Montreal, Canada, j Center for Research and Clinical Trials Sinapse-Bairral, Instituto Bairral de Psiquiatria, Itapira, Brazil.Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2018-12-21T16:28:46Z No. of bitstreams: 1 Melo FSC Comparative_study_of_esketamine_and_racemic.64.pdf: 212500 bytes, checksum: 350198044d38100f8cc9dd703451de7c (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2018-12-21T16:45:26Z (GMT) No. of bitstreams: 1 Melo FSC Comparative_study_of_esketamine_and_racemic.64.pdf: 212500 bytes, checksum: 350198044d38100f8cc9dd703451de7c (MD5)Made available in DSpace on 2018-12-21T16:45:26Z (GMT). No. of bitstreams: 1 Melo FSC Comparative_study_of_esketamine_and_racemic.64.pdf: 212500 bytes, checksum: 350198044d38100f8cc9dd703451de7c (MD5) Previous issue date: 2018Allergan and Lundbeck and research fees from Janssen Pharmaceutical during the last 12 months. ALTL has received consulting fees from Janssen Pharmaceutical, Daiichi Sankyo Brasil, Cristalia Produtos Químicos e Farmacêuticos, Libbs Farmacêutica and SanofiAventis and has received research fees from Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche and Forum Pharmaceuticals during the last 12 months.Múltipla - ver em NotasThe use of ketamine as an option in the treatment of depressive disorder is growing rapidly, supported by numerous clinical trials attesting its efficacy and safety. Esketamine, the S (+) enantiomer of ketamine, is the most widely used form in the anesthetic environment in some countries, and new studies have shown that it may also be effective in depression and with better tolerability. However, no study so far has directly compared esketamine with racemic ketamine. Here we propose a protocol of a clinical trial to evaluate esketamine as a noninferior medicationMethods/design: This study protocol is for a randomized, controlled, double-blind noninferiority clinical trial. Subjects will be 18 years or older, with major depression characterized as treatment-resistant. Participants will receive a single infusion of either esketamine (0.25mg/kg) or ketamine (0.5 mg/kg) over 40 minutes. The primary outcome will be the difference in remission rates between the 2 treatment arms at 24 and 72hours after drug infusion. Secondary outcomes will include other timepoints, measurements of cognition, dissociation, and blood biomarkers. Discussion: A head-to-head study is the best way to evaluate whether the esketamine is in fact comparable to the racemic ketamine in terms of both efficacy and safety, and, if positive, it would be an initial step to increase the access to that type of treatment worldwide. Ethics and dissemination: The study was approved by the local Institutional Review Board (University Hospital Professor Edgard Santos—Federal University of Bahia—Number: 46657415.0.0000.0049). Subjects will only participate after voluntarily agreeing and signing the Informed Consent Form. The study findings will be published in peer-reviewed journals and presented at national and international conferences. Trial registration: This trial has been registered in the Japan Primary Registries Network (JPRN): UMIN000032355, which is affiliated with the World Health Organization. when compared to ketamine in the treatment of patients with treatment-resistant depression