Clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital.

INTRODUCTION: The aim of this study was to assess the clinical usefulness of therapeutic drug monitoring (TDM) of voriconazole (VOR) in a university hospital. METHODS: A retrospective review was conducted on the clinical records of 52 patients treated with VOR and on whom TDM was performed. Steady-state trough plasma VOR concentration was measured at least 5 days after starting treatment. The therapeutic range of plasma VOR concentration was defined as 1-5.5µg/mL. RESULTS: The most frequent underlying conditions in the study population were lung transplant (48.1%) and hematological malignancies (26.9%). At the first TDM in each patient, VOR levels were outside the therapeutic range in 16 (30.7%) cases: <1µg/mL in 10 (19.2%) and >5.5µg/mL in 6 (11.5%). Eleven patients (21.2%) experienced severe muscle weakness and had considerable difficulty walking. All these patients were receiving concomitant treatment with corticosteroids. Age younger than 30 years (p=.005) and cystic fibrosis as the underlying disease (p=.04) were factors associated with low VOR levels. Almost all patients who had VOR concentrations >1µg/mL at the first TDM had a successful outcome (96%). CONCLUSIONS: Plasma VOR concentrations were outside the therapeutic range at the first TDM in 30% (16/52) of patients. Age younger than 30 years and cystic fibrosis were factors associated with low VOR levels. The potential interactions between corticosteroids and VOR should be highlighted, as they could be responsible for a high rate of muscle weakness observed in our patients. Prospective trials are needed to investigate VOR TDM and corticosteroid pharmacokinetics.

Germline mutations in NF1 and BRCA1 in a family with neurofibromatosis type 1 and early-onset breast cancer.

Neurofibromatosis type 1 (NF1) is a common dominant autosomal disorder caused by mutations in the NF1 gene. The main manifestations of NF1 are café-au-lait spots, neurofibromas, intertriginous freckling, Lisch nodules, and malignancy, including peripheral nerve sheath tumors, central nervous system gliomas, and a variety of other tumors not so clearly defined. The association between NF1 and breast cancer or other gynecologic malignancies seems uncommon and has been scarcely referred in the literature. We describe a family with two females affected by both NF1 and early-onset breast cancer, and a male with NF1. We evaluated whether the concomitance of both disorders could be attributed to a NF1 mutation and its supposed increased risk of breast cancer or to the concurrence of two NF1 and BRCA1/2 germline mutations. Mutation analyses identified a frameshift mutation in BRCA1 and a nonsense mutation in NF1. Our findings stress the importance of considering all phenotypic features in families with both NF1 and breast tumors. To offer a specific risk assessment and management of both conditions, NF1 and BRCA1/2 cancer predisposing genes should be analyzed.

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.

Plastic Deformation Modes of CuZr/Cu Multilayers.

We synthesized CuZr/Cu multilayers and performed nanoindentation testing to explore the dependence of plastic deformation modes on the thickness of CuZr layers. The Cu layers were 18 nm thick and the CuZr layers varied in thickness from 4 nm to 100 nm. We observed continuous plastic co-deformation in the 4 nm and 10 nm CuZr - 18 nm Cu multilayers and plastic-induced shear instability in thick CuZr layers (>20 nm). The plastic co-deformation is ascribed to the nucleation and interaction of shear transformation zones in CuZr layers at the adjacent interfaces, while the shear instability is associated with the nucleation and propagation of shear bands in CuZr layers. Shear bands are initialized in the CuZr layers due to the accumulated glide dislocations along CuZr-Cu interfaces, and propagate into adjacent Cu layers via slips on {111} plane non-parallel to the interface. Due to crystallographic constraint of the Cu layers, shear bands are approximately parallel to {111} plane in the Cu layer.

Surface softening in metal-ceramic sliding contacts: an experimental and numerical investigation.

This study investigates the tribolayer properties at the interface of ceramic/metal (i.e., WC/W) sliding contacts using various experimental approaches and classical atomistic simulations. Experimentally, nanoindentation and micropillar compression tests, as well as adhesion mapping by means of atomic force microscopy, are used to evaluate the strength of tungsten-carbon tribolayers. To capture the influence of environmental conditions, a detailed chemical and structural analysis is performed on the worn surfaces by means of XPS mapping and depth profiling along with transmission electron microscopy of the debris particles. Experimentally, the results indicate a decrease in hardness and modulus of the worn surface compared to the unworn one. Atomistic simulations of nanoindentation on deformed and undeformed specimens are used to probe the strength of the WC tribolayer and despite the fact that the simulations do not include oxygen, the simulations correlate well with the experiments on deformed and undeformed surfaces, where the difference in behavior is attributed to the bonding and structural differences of amorphous and crystalline W-C. Adhesion mapping indicates a decrease in surface adhesion, which based on chemical analysis is attributed to surface passivation.

Infection in the process of organ donation

The difference between demand and supply has led transplant organizations to look for marginal donors, including those who could transmit infections to their recipients. This potential risk must be thoroughly evaluated to optimize the use of such organs without increasing the incidence of graft dysfunction and the morbidity and mortality of the recipient. This article aims to provide a general and up-to-date overview of this issue

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Surviving the surf: the tribomechanical properties of the periostracum of Mytilus sp.

We investigated the friction and wear behavior as well as the mechanical properties of the periostracum of Mytilus sp. Tribological properties were determined with a reciprocal sliding microtribometer, while mechanical characterization was performed using a nanoindenter. Measurements were performed in dry and wet conditions. On the dry periostracum we found a low friction coefficient of 0.078±0.007 on the young parts and a higher one of 0.63±0.02 on the old parts of the shell. Under wet, saline, conditions we only observed one average coefficient of friction of 0.37±0.01. Microscopic ex situ analysis indicated that dry periostracum wore rather rapidly by plowing and fatigue, while it exhibited a high wear resistance when immersed in salt water. The Young's modulus and hardness of the periostracum were also investigated in both dry and wet conditions. Under dry conditions the Young's modulus of the periostracum was 8±3GPa, while under wet conditions it was 0.21±0.05GPa. The hardness of dry periostracum samples was 353±127MPa, whereas the hardness of wet samples was 5±2MPa. It was found that, in the wet state, viscous behavior plays a significant role in the mechanical response of the periostracum. Our results strongly indicate that the periostracum can provide an important contribution to the overall wear resistance of Mytilus sp. shell.

Clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital / / Utilidad clínica de la determinación de concentraciones plasmáticas de voriconazol en un hospital universitario

INTRODUCTION: The aim of this study was to assess the clinical usefulness of therapeutic drug monitoring (TDM) of voriconazole (VOR) in a university hospital. METHODS: A retrospective review was conducted on the clinical records of 52 patients treated with VOR and on whom TDM was performed. Steady-state trough plasma VOR concentration was measured at least 5 days after starting treatment. The therapeutic range of plasma VOR concentration was defined as 1-5.5 μg/mL. RESULTS: The most frequent underlying conditions in the study population were lung transplant (48.1%) and hematological malignancies (26.9%). At the first TDM in each patient, VOR levels were outside the therapeutic range in 16 (30.7%) cases: <1 µg/mL in 10 (19.2%) and >5.5 µg/mL in 6 (11.5%). Eleven patients (21.2%) experienced severe muscle weakness and had considerable difficulty walking. All these patients were receiving concomitant treatment with corticosteroids. Age younger than 30 years (p = .005) and cystic fibrosis as the underlying disease (p = .04) were factors associated with low VOR levels. Almost all patients who had VOR concentrations >1 µg/mL at the first TDM had a successful outcome (96%). CONCLUSIONS: Plasma VOR concentrations were outside the therapeutic range at the first TDM in 30% (16/52) of patients. Age younger than 30 years and cystic fibrosis were factors associated with low VOR levels. The potential interactions between corticosteroids and VOR should be highlighted, as they could be responsible for a high rate of muscle weakness observed in our patients. Prospective trials are needed to investigate VOR TDM and corticosteroid pharmacokinetics

INTRODUCCIÓN: Nuestro objetivo fue evaluar la utilidad clínica de la monitorización de la concentración plasmática (TMD) de voriconazol (VOR) en un hospital universitario. MÉTODOS: Revisión retrospectiva de las historias clínicas de 52 pacientes tratados con VOR en los que se realizó TDM. El intervalo terapéutico de la concentración plasmática de VOR fue definida entre 1 μg/mL y 5.5 μg/mL. RESULTADOS: Las condiciones subyacentes más frecuentes en la población de estudio fueron trasplante de pulmón (48,1%) y neoplasias hematológicas (26,9%). En la primera determinación de TMD de VOR estaban fuera del intervalo en 16 (30,7%) casos: < 1 µg/mL en 10 (19,2%) y > 5,5 µg/mL en 6 (11,5%). Once pacientes (21,2%) experimentaron debilidad muscular, éstos pacientes recibían tratamiento concomitante con corticosteroides. Los Factores asociados con bajos niveles de VOR observados fueron la edad menor a 30 años (p= 0,005) y la fibrosis quística (p = 0,04). Casi todos los pacientes que tenían concentraciones VOR > 1 µg/mL en la primera TDM tuvieron un resultado satisfactorio (96%). CONCLUSIONES: En 30% (16/52) de los pacientes, las concentraciones plasmáticas de VOR estaban fuera del intervalo terapéutico en la primera TDM. La edad menor a 30 años y la fibrosis quística fueron factores asociados con niveles bajos de VOR. Observamos una posible interacción entre corticoesteroides y voriconazol con debilidad muscular asociada en los pacientes tratados con ambos fármacos. Se necesitan estudios clínicos prospectivos en relación a las interacciones entre corticoesteroides y voriconazol

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies / Resumen ejecutivo del Documento de consenso sobre diagnóstico y manejo de pacientes con inmunodeficiencias primarias

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available

Las inmunodeficiencias primarias (IDP) son unas enfermedades raras, frecuentemente infradiagnosticadas y potencialmente fatales. Las manifestaciones clínicas de las IDP pueden ser muy graves y ocasionar secuelas que empeoran la calidad de vida de los pacientes. Tradicionalmente, el tratamiento de las IDP ha sido fundamentalmente de soporte, con excepción del trasplante de progenitores hematopoyéticos y, más recientemente, la terapia génica. El descubrimiento de nuevos mecanismos patogénicos, el desarrollo de nuevas moléculas y fármacos biológicos y los avances en el conocimiento de las bases moleculares de estas enfermedades han abierto oportunidades para el tratamiento de esta afección. El objetivo de este documento es revisar el conocimiento actual y aportar recomendaciones para el diagnóstico y el tratamiento clínico de los pacientes adultos y pediátricos con IDP basado en la evidencia científica disponible y teniendo en cuenta la actual práctica y los retos futuros. Se realizó una revisión sistemática, que justifica los niveles de evidencia para cada recomendación