Quantitative monitoring of tamoxifen in human plasma extended to 40 metabolites using liquid-chromatography high-resolution mass spectrometry: new investigation capabilities for clinical pharmacology.

Liquid-chromatography (LC) high-resolution (HR) mass spectrometry (MS) analysis can record HR full scans, a technique of detection that shows comparable selectivity and sensitivity to ion transitions (SRM) performed with triple-quadrupole (TQ)-MS but that allows de facto determination of "all" ions including drug metabolites. This could be of potential utility in in vivo drug metabolism and pharmacovigilance studies in order to have a more comprehensive insight in drug biotransformation profile differences in patients. This simultaneous quantitative and qualitative (Quan/Qual) approach has been tested with 20 patients chronically treated with tamoxifen (TAM). The absolute quantification of TAM and three metabolites in plasma was realized using HR- and TQ-MS and compared. The same LC-HR-MS analysis allowed the identification and relative quantification of 37 additional TAM metabolites. A number of new metabolites were detected in patients' plasma including metabolites identified as didemethyl-trihydroxy-TAM-glucoside and didemethyl-tetrahydroxy-TAM-glucoside conjugates corresponding to TAM with six and seven biotransformation steps, respectively. Multivariate analysis allowed relevant patterns of metabolites and ratios to be associated with TAM administration and CYP2D6 genotype. Two hydroxylated metabolites, α-OH-TAM and 4'-OH-TAM, were newly identified as putative CYP2D6 substrates. The relative quantification was precise (<20 %), and the semiquantitative estimation suggests that metabolite levels are non-negligible. Metabolites could play an important role in drug toxicity, but their impact on drug-related side effects has been partially neglected due to the tremendous effort needed with previous MS technologies. Using present HR-MS, this situation should evolve with the straightforward determination of drug metabolites, enlarging the possibilities in studying inter- and intra-patients drug metabolism variability and related effects.

A reflection about the social and technological aspects in flood risk management - the case of the Italian Civil Protection

The right of a person to be protected from natural hazards is a characteristic of the social and economical development of the society. This paper is a contribution to the reflection about the role of Civil Protection organizations in a modern society. The paper is based in the inaugural conference made by the authors on the 9th Plinius Conference on Mediterranean Storms. Two major issues are considered. The first one is sociological; the Civil Protection organizations and the responsible administration of the land use planning should be perceived as reliable as possible, in order to get consensus on the restrictions they pose, temporary or definitely, on the individual free use of the territory as well as in the entire warning system. The second one is technological: in order to be reliable they have to issue timely alert and warning to the population at large, but such alarms should be as "true" as possible. With this aim, the paper summarizes the historical evolution of the risk assessment, starting from the original concept of "hazard", introducing the concepts of "scenario of event" and "scenario of risk" and ending with a discussion about the uncertainties and limits of the most advanced and efficient tools to predict, to forecast and to observe the ground effects affecting people and their properties. The discussion is centred in the case of heavy rains and flood events in the North-West of Mediterranean Region.

Complementarity between human capital and trade in regional technological progress

The effect of openness and trade orientation on economic growth remains a highly contentious issue in the literature. Trade facilitates the spread of knowledge and the adoption of more advanced and efficient technologies, which hastens total factor productivity (TFP) growth and, hence, per capita income. New technologies that spread through trade require a sufficiently skilled labour force to adapt them to the domestic productive environment. Thus, openness and human capital accumulation will lead to TFP growth and the greater the complementarity between both variables, the higher the TFP growth. This paper discusses the implications of these assumptions and tests their empirical validity, using a pool of data for manufacturing industry in Spanish regions in a period in which both the stock of human capital and openness experienced a notable increase.

Thermal modeling and management in ultrathin chip stack technology

This paper presents a thermal modeling for power management of a new three-dimensional (3-D) thinned dies stacking process. Besides the high concentration of power dissipating sources, which is the direct consequence of the very interesting integration efficiency increase, this new ultra-compact packaging technology can suffer of the poor thermal conductivity (about 700 times smaller than silicon one) of the benzocyclobutene (BCB) used as both adhesive and planarization layers in each level of the stack. Thermal simulation was conducted using three-dimensional (3-D) FEM tool to analyze the specific behaviors in such stacked structure and to optimize the design rules. This study first describes the heat transfer limitation through the vertical path by examining particularly the case of the high dissipating sources under small area. First results of characterization in transient regime by means of dedicated test device mounted in single level structure are presented. For the design optimization, the thermal draining capabilities of a copper grid or full copper plate embedded in the intermediate layer of stacked structure are evaluated as a function of the technological parameters and the physical properties. It is shown an interest for the transverse heat extraction under the buffer devices dissipating most the power and generally localized in the peripheral zone, and for the temperature uniformization, by heat spreading mechanism, in the localized regions where the attachment of the thin die is altered. Finally, all conclusions of this analysis are used for the quantitative projections of the thermal performance of a first demonstrator based on a three-levels stacking structure for space application.

Technological Change and Immigration

We develop a simple model where two technologies are available to produce the same good, and we study under what conditions both will be used. We use the model to analyze the consequences of the simultaneous use of two different technologies for the economic variables and economic growth. Finally, we explore how migrations of factors affect the technological change and the performance of the economy.

Complementarity between human capital and trade in regional technological progress

The effect of openness and trade orientation on economic growth remains a highly contentious issue in the literature. Trade facilitates the spread of knowledge and the adoption of more advanced and efficient technologies, which hastens total factor productivity (TFP) growth and, hence, per capita income. New technologies that spread through trade require a sufficiently skilled labour force to adapt them to the domestic productive environment. Thus, openness and human capital accumulation will lead to TFP growth and the greater the complementarity between both variables, the higher the TFP growth. This paper discusses the implications of these assumptions and tests their empirical validity, using a pool of data for manufacturing industry in Spanish regions in a period in which both the stock of human capital and openness experienced a notable increase.

Technological Change and Immigration

We develop a simple model where two technologies are available to produce the same good, and we study under what conditions both will be used. We use the model to analyze the consequences of the simultaneous use of two different technologies for the economic variables and economic growth. Finally, we explore how migrations of factors affect the technological change and the performance of the economy.

Demonstration of Load Rating Capabilities through Physical Load Testing: Sioux County Bridge Case Study, RB32-013, 2013

The objective of this work, Pilot Project - Demonstration of Capabilities and Benefits of Bridge Load Rating through Physical Testing, was to demonstrate the capabilities for load testing and rating bridges in Iowa, study the economic benefit of performing such testing, and perform outreach to local, state, and national engineers on the topic of bridge load testing and rating. This report documents one of three bridges inspected, load tested, and load rated as part of the project, the Sioux County Bridge (FHWA #308730), including testing procedures and performance of the bridge under static loading along with the calculated load rating from the field-calibrated analytical model. Two parallel reports document the testing and load rating of the Ida County Bridge (FHWA #186070) and the Johnson County Bridge (FHWA #205750). A tech brief provides overall information about the project.

Demonstration of Load Rating Capabilities through Physical Load Testing: Ida County Bridge Case Study, RB32-013, 2013

The objective of this work, Pilot Project - Demonstration of Capabilities and Benefits of Bridge Load Rating through Physical Testing, was to demonstrate the capabilities for load testing and rating bridges in Iowa, study the economic benefit of performing such testing, and perform outreach to local, state, and national engineers on the topic of bridge load testing and rating. This report documents one of three bridges inspected, load tested, and load rated as part of the project, the Ida County Bridge (FHWA #186070), including testing procedures and performance of the bridge under static loading along with the calculated load rating from the field-calibrated analytical model. Two parallel reports document the testing and load rating of the Sioux County Bridge (FHWA #308730) and the Johnson County Bridge (FHWA #205750). A tech brief provides overall information about the project.

Demonstration of Load Rating Capabilities through Physical Load Testing: Johnson County Bridge Case Study, RB32-013, 2013

The objective of this work, Pilot Project - Demonstration of Capabilities and Benefits of Bridge Load Rating through Physical Testing, was to demonstrate the capabilities for load testing and rating bridges in Iowa, study the economic benefit of performing such testing, and perform outreach to local, state, and national engineers on the topic of bridge load testing and rating. This report documents one of three bridges inspected, load tested, and load rated as part of the project, the Johnson County Bridge (FHWA #205750), including testing procedures and performance of the bridge under static loading along with the calculated load rating from the field-calibrated analytical model. Two parallel reports document the testing and load rating of the Sioux County Bridge (FHWA #308730) and the Ida County Bridge (FHWA #186070). A tech brief provides overall information about the project.

Pilot Project - Demonstration of Load Rating Capabilities through Physical Load Testing: Tech Transfer Summary, RB32-013, 2013

This project demonstrated the capabilities for load testing bridges in Iowa, developed and presented a webinar to local and state engineers, and produced a spreadsheet and benefit evaluation matrix that others can use to preliminarily assess where bridge testing may be economically feasible given truck traffic and detour lengths.

Demonstration of Load Rating Capabilities through Physical Load Testing (4 vol), RB32-013, 2013

The objective of this work, Pilot Project - Demonstration of Capabilities and Benefits of Bridge Load Rating through Physical Testing, was to demonstrate the capabilities for load testing and rating bridges in Iowa, study the economic benefit of performing such testing, and perform outreach to local, state, and national engineers on the topic of bridge load testing and rating. The three final reports document one each of three bridges inspected, load tested, and load rated as part of the project. The bridges include the Sioux County Bridge (FHWA #308730), the Ida County Bridge (FHWA #186070), and the Johnson County Bridge (FHWA #205750). Actions included testing procedures and performance of the bridge under static loading along with the calculated load rating from the field-calibrated analytical model. A Tech Transfer Summary provides overall information about the project.

Technological, biopharmaceutical and pharmacokinetic advances: new formulations of application on the skin and oral mucosa

Currently a growing interest to improve the pharmacological therapy exists, not only by the production and the appearance of new drugs, but guaranteeing that the uses of those which already exist, become more effective. In fact, the conventional pharmaceutical formulations of different drugs present a few secondary effects due to oral administration. In order to avoid these undesired side effects, the purpose of current therapeutic is the development and research of formulations as an alternative to others routes of administration. Therefore, in spite of the undoubtedly complete parenteral absorption, the transdermal and transbuccal routes appear to be a rather attractive alternative to provide an efficient absorption. In this chapter a new technological, biopharmaceutical and pharmacokinetic approach of strategies for application on skin and buccal mucosa are reported. In the future new transdermal drug delivery systems will emerge to be more effective, equipped with an improved aesthetic appearance, better adherence and greater diffusion. But to reach these aims, it is necessary previous knowledge of histology and physiology of skin, and factors involved in the penetration of drugs through it.