ABSTRACT There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an antifungal drug derived from natural sources (i.e., amphotericin B) and two other drugs developed synthetically (i.e., flucytosine and fluconazole). Despite treatment, the mortality rates associated with fungal cryptococcosis are high. Amphotericin B and flucytosine are toxic, require intravenous administration, and are usually unavailable in low-income countries because of their high cost. However, fluconazole is cost-effective, widely available, and harmless with regard to its side effects. However, fluconazole is a fungistatic agent that has contributed considerably to the increase in fungal resistance and frequent relapses in patients with cryptococcal meningitis. Therefore, there is an unquestionable need to identify new alternatives or adjuvants to conventional drugs for the treatment of cryptococcosis. A potential antifungal agent should be able to kill cryptococci and “bypass” the virulence mechanism of the yeast. Furthermore, it should have fungicidal action, low toxicity, high selectivity, easily penetrate the central nervous system, and widely available. In this review, we describe cryptococcosis, its conventional therapy, and failures arising from the use of drugs traditionally considered to be the reference standard. Additionally, we present the approaches used for the discovery of new drugs to counteract cryptococcosis, ranging from the conventional screening of natural products to the inclusion of structural modifications to optimize anticryptococcal activity, as well as drug repositioning and combined therapies.

Abstract Background: Low-dose alteplase (LrtPA) has been shown not to be inferior to the standard-dose (SrtPA) with respect to death/disability. Objective: We aim to evaluate the percentage of patients treated with LrtPA at our center after the ENCHANTED trial and the factors associated with the use of this dosage. Methods: Prospective study in consecutive patients with an acute stroke admitted between June 2016 and November 2018. Results: 160 patients were treated with intravenous thrombolysis, 50% female; mean age 65.4±18.5 years. Of these, 48 patients (30%) received LrtPA. In univariate analysis, LrtPA was associated with patient's age (p=0.000), previous modified Rankin scale scores (mRS) (p<0.000), hypertension (p=0.076), diabetes mellitus (p=0.021), hypercholesterolemia (p=0.19), smoking (p=0.06), atrial fibrillation (p=0.10), history of coronary artery disease (p=0.06), previous treatment with antiplatelet agents (p<0.000), admission International Normalized Ratio-INR (p=0.18), platelet count (p=0.045), leukoaraiosis on neuroimaging (p<0.003), contraindications for thrombolytic treatment (p=0.000) and endovascular treatment (p=0.027). Previous relevant bleedings were determinants for treatment with LrtPA. Final diagnosis on discharge of stroke mimic was significant (p=0.02) for treatment with SrtPA. In multivariate analysis, mRS (OR: 2.21; 95%CI 1.37‒14.19), previous antiplatelet therapy (OR: 11.41; 95%CI 3.98‒32.70), contraindications for thrombolysis (OR: 56.10; 95%CI 8.81‒357.80), leukoaraiosis (OR: 4.41; 95%CI 1.37‒14.10) and diagnosis of SM (OR: 0.22; 95%CI 0.10‒0.40) remained independently associated. Conclusions: Following the ENCHANTED trial, LrtPA was restricted to 30% of our patients. The criteria that clinicians apply are based mostly on clinical variables that may increase the risk of brain or systemic hemorrhage or exclude the patient from treatment with lytic drugs.

RESUMEN Introducción: Dosis reducidas de trombolitico (LrtPA) podrían no ser inferiores en muerte/discapacidad. Objetivo: Evaluar el porcentaje de pacientes tratados con LrtPA en nuestro centro después del ensayo ENCHANTED, y los factores asociados con el uso de esta dosis. Métodos: Estudio prospectivo de pacientes consecutivos con infarto cerebral ingresados entre junio de 2016 y noviembre de 2018. Resultados: 160 pacientes fueron tratados con trombólisis intravenosa, 50% mujeres; edad media 65,4±18,5 años. 48 casos (30%) recibieron LrtPA. En el análisis univariado, LrtPA se asoció con la edad del paciente (p=0,000), escala de Rankin modificadas (mRS) (p<0,000), hipertensión arterial (p=0,076), diabetes mellitus (p=0,021), hipercolesterolemia (p=0,19), tabaquismo (p=0,06), fibrilación auricular (p=0,10), antecedentes de enfermedad coronaria (p=0,06), tratamiento previo con antiplaquetarios (p<0,000), International Normalized Ratio-INR (p=0,18), recuento de plaquetario (p=0,045), leucoaraiosis en neuroimagen (p<0,003), contraindicaciones para el tratamiento trombolítico (p=0,000) y tratamiento endovascular (p=0,027). Las hemorragias previas relevantes fueron determinantes para el tratamiento con LrtPA. El diagnóstico al alta de imitador de accidente cerebrovascular fue significativo (p=0,02) para el tratamiento con dosis estándar. El análisis multivariado demostró que mRS (OR: 2,21; IC95% 1,37‒14,19), tratamiento antiplaquetario previo (OR: 11,41; IC95% 3,98‒32,7), contraindicaciones para trombólisis (OR: 56,1; IC95% 8,81‒357,8), leucoaraiosis (OR: 4,41; IC95% 1,37‒14,1) y un diagnóstico de imitador de accidente cerebrovascular (OR: 0,22; IC95% 0,1‒0,40) fueron asociados con la dosis recibida. Conclusiones: LrtPA está restringido al 30% de nuestros pacientes. Los criterios para tomar esta decisión se basan en variables que podrían aumentar el riesgo de hemorragia cerebral/sistémica o excluir al paciente del tratamiento con fármacos líticos.

Resumen En este artículo se estudia la correspondencia entre una teoría de campos en el espacio de De Sitter en D-dimensiones y una teoría dual conforme en un espacio euclidiano en (D - 1)-dimensiones. En particular, se investiga la forma en la que se establece esta correspondencia para un sistema compuesto por un campo escalar y un campo vectorial acoplados propagándose en el espacio de De Sitter. Se analizan algunas condiciones necesarias (pero no suficientes) en las cuales la simetría conforme se preserva en la teoría dual en (D - 1)-dimensiones y hace posible el establecimiento de la correspondencia. La discusión presentada aquí se enmarca en el contexto de la cosmología inflacionaria, así que los resultados obtenidos plantean algunas posibilidades relevantes de aplicación en el cálculo de funciones de correlación de los campos y de la perturbación de ¡a curvatura primordial Z en modelos inflacionarios que incluyen campos escalares y vectoriales acoplados.

Abstract In this paper, we study the correspondence between a field theory in de Sitter space in D-dimensions and a dual conformal field theory in a euclidean space in (D-1)-dimensions. In particular, we investigate the form in which this correspondence is established for a system of interacting scalar and a vector fields propagating in de Sitter space. We analyze some necessary (but not sufficient) conditions for which conformal symmetry is preserved in the dual theory in (D - 1)-dimensions, making possible the establishment of the correspondence. The discussion that we address in this paper is framed on the context of inflationary cosmology. Thusly, the results obtained here pose some relevant possibilities of application to the calculation of the fields’s correlation functions and of the primordial curvature perturbation Z, in inflationary models including coupled scalar and vector fields.

Resumen Neste artigo, é estudada a correspondencia entre uma teoria de campos no espaço de De Sitter em D-dimensões e uma teoria dual conforme num espaço euclidiano em (D - 1)-dimensões. Em particular, é pesquisado o caminho no qual se estabelece esta correspondência para um sistema de interação composto dum campo escalar e um vetorial, propagando-se no espaço de De Sitter. São analisadas algumas condições necessárias (mas não suficientes) para as quais a simetria conforme é preservada na teoria dual em (D-l)-dimensões, fazendo viável o estabelecimento da correspondência. A discussão apresentada aqui, está situada no contexto da cosmologia inflacionária. Portanto, os resultados obtidos representam algumas possibilidades relevantes para sua aplicacão no cálculo de funções de correlação dos campos e da perturbação da curvatura primordial Ç em modelos inflacionários incluindo campos acoplados escalares e vetoriais.

Este estudo investiga a relação entre firmas de auditoria e suas capacidades para mitigar earnings management. Nesse contexto, analisa-se se as companhias abertas auditadas pelas consideradas Big Four (Deloitte Touche Tohmatsu, Ernst & Young, KPMG e PricewaterhouseCoopers) e demais firmas de auditoria possuem diferença, estatisticamente significante, nos accruals discricionários. A amostra total consiste em 1.414 observações para o período de 1999 até 2005, 'segregada em 897 observações das companhias auditadas pelas Big Four e 517 de companhias auditadas pelas demais firmas. As informações foram obtidas pelos softwares Economática e Divulgação Externa, sendo o último disponibilizado pela BOVESPA e do qual foram extraídas informações sobre auditoria. Foi utilizado o modelo KS com técnica de variáveis instrumentais e testes não paramétricos para analisar a diferença entre os dois agrupamentos de auditoria. Os resultados dos testes estatísticos indicam que as empresas auditadas pelas Big Four possuem menor grau de accruals discricionários em relação às demais, sugerindo a capacidade para mitigar práticas de earnings management. Verifica-se, também, a pouca quantidade de estudos e, principalmente, pesquisas empíricas sobre auditoria no Brasil.

This paper investigates the relations between auditing firms and their ability to mitigate earnings management. In this context, we analyze if discretionary accruals of publicly-traded companies audited by the "Big Four" (Deloitte Touche Tohmatsu, Ernst & Young, KPMG and PricewaterhouseCoopers) and other auditing firms are statistically different. The final sample consists of 1,414 observations collected from the 1999-2005 period: 897 observations for publicly-traded companies audited by the "Big Four" and 517 representing other publicly-traded companies audited by other firms. The information content in the database was obtained from Economatica software and "Divulgação Externa" available at the BOVESPA website to obtain information from auditing firms. We used KS model with instruments and non-parametric tests to verify the difference in discretionary accruals between these groups of firms. The results indicate that companies audited by the "Big Four" have a lower level of discretionary accruals than companies audited by other auditing firms, suggesting the capacity to mitigate earnings management. Additionally, we verified that there is little research in this subject in Brazil.