Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections.

BACKGROUND: Recommended oral voriconazole (VRC) doses are lower than intravenous doses. Because plasma concentrations impact efficacy and safety of therapy, optimizing individual drug exposure may improve these outcomes. METHODS: A population pharmacokinetic analysis (NONMEM) was performed on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended VRC doses. RESULTS: A 1-compartment model with first-order absorption and elimination best fitted the data. VRC clearance was 5.2 L/h, the volume of distribution was 92 L, the absorption rate constant was 1.1 hour(-1), and oral bioavailability was 0.63. Severe cholestasis decreased VRC elimination by 52%. A large interpatient variability was observed on clearance (coefficient of variation [CV], 40%) and bioavailability (CV 84%), and an interoccasion variability was observed on bioavailability (CV, 93%). Lack of response to therapy occurred in 12 of 55 patients (22%), and grade 3 neurotoxicity occurred in 5 of 55 patients (9%). A logistic multivariate regression analysis revealed an independent association between VRC trough concentrations and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (<15% probability of neurotoxicity). Population-based simulations with the recommended 200 mg oral or 300 mg intravenous twice-daily regimens predicted probabilities of 49% and 87%, respectively, for achievement of 1.5 mg/L and of 8% and 37%, respectively, for achievement of 4.5 mg/L. With 300-400 mg twice-daily oral doses and 200-300 mg twice-daily intravenous doses, the predicted probabilities of achieving the lower target concentration were 68%-78% for the oral regimen and 70%-87% for the intravenous regimen, and the predicted probabilities of achieving the upper target concentration were 19%-29% for the oral regimen and 18%-37% for the intravenous regimen. CONCLUSIONS: Higher oral than intravenous VRC doses, followed by individualized adjustments based on measured plasma concentrations, improve achievement of the therapeutic target that maximizes the probability of therapeutic response and minimizes the probability of neurotoxicity. These findings challenge dose recommendations for VRC.

The regional employment impacts of renewable energy expenditures: The case for modelling

One aspect of the case for policy support for renewable energy developments is the wider economic benefits that are expected to be generated. Within Scotland, as with other regions of the UK, there is a focus on encouraging domestically‐based renewable technologies. In this paper, we use a regional computable general equilibrium framework to model the impact on the Scottish economy of expenditures relating to marine energy installations. The results illustrate the potential for (considerable) ‘legacy’ effects after expenditures cease. In identifying the specific sectoral expenditures with the largest impact on (lifetime) regional employment, this approach offers important policy guidance.

The regional employment impacts of renewable energy expenditures: The case for modelling

One aspect of the case for policy support for renewable energy developments is the wider economic benefits that are expected to be generated. Within Scotland, as with other regions of the UK, there is a focus on encouraging domestically‐based renewable technologies. In this paper, we use a regional computable general equilibrium framework to model the impact on the Scottish economy of expenditures relating to marine energy installations. The results illustrate the potential for (considerable) ‘legacy’ effects after expenditures cease. In identifying the specific sectoral expenditures with the largest impact on (lifetime) regional employment, this approach offers important policy guidance.

An adapted model of ex vivo vein perfusion: the key to understand vessel wall remodeling

Objective: Saphenous vein graft bypass remains the salvage option when¦endovascular procedure has failed or was contraindicated due to extensive¦occlusive lesions. However, pathological wall remodeling leading leading to¦graft failure is one of the most limiting factors of this therapy. Therefore, the¦understanding of this remodeling process of human vein is essential to the design¦of future effective therapeutics and it requires an adapted model of ex-vivo vein¦perfusion.¦Methods: We have developed an ex vivo vein support system (EVVSS), which¦uses standardized and controlled hemodynamic parameters for the pulsatile¦perfusion of saphenous vein segments. The morphological and molecular¦parameters involved in the remodeling process under an arterial shear stress¦associated to low (7 mm Hg) or high (70 mm Hg) pressure conditions can be¦analyzed.¦Results: Histomorphometric analysis showed that the vein segments perfused¦during 7 days under high pressure undergo a significant neointima development¦compared to veins exposed to low pressure conditions. The application of an¦arterial shear stress in the vein under low pressure induced an elevation of the¦MMP-2 and MMP-9 expression, activity and transcription. The application of¦higher pressure is associated to increased MMP2 expression and transcription¦and MMP9 transcription. TIMP1 expression and transcription were initiated by¦the application of an arterial shear stress but not modified by the modification¦of the pressure. However, TIMP2 expression was increased under high¦pressure conditions but its transcription was inhibited by arterial shear stress,¦independently of the pressure. The values of transcription and expression of¦PAI-1 were not modified by high pressure. Eph-B4 transcription and expression¦were significantly decreased under arterial shear stress.¦Conclusion: These data show that our EVVSS is a valuable setting to study¦ex vivo remodeling of human saphenous veins submitted to arterial conditions.¦The intimal hyperplasia as well as MMP 2, 9 and TIMP 2 seem to be influenced¦by the pressure.

The regional economic impacts of biofuels: A review of multisectoral modelling techniques and evaluation of applications

The regional economic impact of biofuel production depends upon a number of interrelated factors: the specific biofuels feedstock and production technology employed; the sector’s embeddedness to the rest of the economy, through its demand for local resources; the extent to which new activity is created. These issues can be analysed using multisectoral economic models. Some studies have used (fixed price) Input-Output (IO) and Social Accounting Matrix (SAM) modelling frameworks, whilst a nascent Computable General Equilibrium (CGE) literature has also begun to examine the regional (and national) impact of biofuel development. This paper reviews, compares and evaluates these approaches for modelling the regional economic impacts of biofuels.

Forward Looking and Myopic Regional Computable General Equilibrium Models. How Significant is the Distinction?

We present a stylized intertemporal forward-looking model able that accommodates key regional economic features, an area where the literature is not well developed. The main difference, from the standard applications, is the role of saving and its implication for the balance of payments. Though maintaining dynamic forward-looking behaviour for agents, the rate of private saving is exogenously determined and so no neoclassical financial adjustment is needed. Also, we focus on the similarities and the differences between myopic and forward-looking models, highlighting the divergences among the main adjustment equations and the resulting simulation outcomes.

The regional economic impacts of biofuels: A review of multisectoral modelling techniques and evaluation of applications

The regional economic impact of biofuel production depends upon a number of interrelated factors: the specific biofuels feedstock and production technology employed; the sector’s embeddedness to the rest of the economy, through its demand for local resources; the extent to which new activity is created. These issues can be analysed using multisectoral economic models. Some studies have used (fixed price) Input-Output (IO) and Social Accounting Matrix (SAM) modelling frameworks, whilst a nascent Computable General Equilibrium (CGE) literature has also begun to examine the regional (and national) impact of biofuel development. This paper reviews, compares and evaluates these approaches for modelling the regional economic impacts of biofuels.

FDI, Trade Costs and Regional Asymmetries

We set up a trade model where three countries compete for an exogenous number of firms. Our innovation lies in the geography of the model. Of the three countries, one is the hub through which all trade takes place. First, we establish the natural geography of the region, which is given by the equilibrium distribution of industrial activity in the absence of taxes or subsidies. We then examine the implications for corporate taxes when the countries compete with each other to attract firms. We find that, even when all countries are the same size, the centrality of the hub gives it an advantage in tax setting, such that its equilibrium tax can be larger than that of the spokes and yet it still attracts a disproportionate share of industry. Thus geographic advantage in tax competition has a second dimension, centrality in addition to size.

How much does a single graduation cohort from further education colleges contribute to an open regional economy?

Econometric analysis has been inconclusive in determining the contribution that increased skills have on macroeconomic performance whilst conventional growth accounting approaches to the same problem rest on restrictive assumptions. We propose an alternative micro-to-macro method which combines elements of growth accounting and numerical general equilibrium modelling. The usefulness of this approach for applied education policy analysis is demonstrated by evaluating the macroeconomic impact on the Scottish economy of a single graduation cohort from further education colleges. We find the macroeconomic impact to be significant. From a policy point of view this supports a revival of interest in the conventional teaching role of education institutions.

El Nuevo acuerdo de financiación regional: un análisis de urgencia

El pasado 15 de julio el Consejo de Política Fiscal y Financiera (CPPF) aprobó un nuevo acuerdo de financiación para las comunidades autónomas de régimen común. El documento en el que se recoge el acuerdo no es precisamente un prodigio de claridad expositiva y describe además un modelo complejo. Como resultado de ambos factores, las descripciones del nuevo sistema que han aparecido en la prensa reciente y en el material "informativo" distribuido por algunas administraciones resultan bastante confusas y no reflejan correctamente, a mi entender, el funcionamiento del modelo o su previsible incidencia sobre la distribución territorial de los recursos públicos. Con el fin de facilitar un debate más informado sobre el tema, en este trabajo se intenta clarificar el funcionamiento del nuevo modelo, ofreciendo una descripción sistemática del mismo, un análisis de sus propiedades dinámicas y una primera estimación de sus resultados iniciales. Por otra parte, en el trabajo se realiza también una valoración crítica del nuevo sistema y se identifican ciertos aspectos del mismo que pueden ser problemáticos. Algunos de ellos son de carácter técnico y podrían corregirse durante el proceso de elaboración de la normativa en la que ha de plasmarse el nuevo acuerdo sin alterar la esencia de éste.

El Nuevo acuerdo de financiación regional: un análisis de urgencia ADENDA

This note contains some addenda to a recent paper (de la Fuente, 2009) that analyzed the new Spanish system of regional financing on the basis of the agreement between the central and regional Governments reached last July. The note updates my previous discussion after examining the bill that has been recently sent to Parliament by the Government and identifies some technical problems of the Government's proposal.

Inter-regional redistribution through infrastructure investment: tactical or programmatic?

In this paper we analyze the effects of both tactical and programmatic politics on the inter-regional allocation of infrastructure investment. We use a panel of data for the Spanish electoral districts during the period 1964-2004 to estimate an equation where investment depends both on economic and political variables. The results show that tactical politics do matter since, after controlling for economic traits, the districts with more ‘Political power’ still receive more investment. These districts are those where the incumbents’ Vote margin of victory/ defeat in the past election is low, where the Marginal seat price is low, where there is Partisan alignment between the executives at the central and regional layers of government, and where there are Pivotal regional parties which are influential in the formation of the central executive. However, the results also show that programmatic politics matter, since inter-regional redistribution (measured as the elasticity of investment to per capita income) is shown to increase with the arrival of the Democracy and EU Funds, with Left governments, and to decrease the higher is the correlation between a measure of ‘Political power’ and per capita income.

Human capital spillovers, productivity and regional convergence in Spain

This paper analyses the differential impact of human capital, in terms of different levels of schooling, on regional productivity and convergence. The potential existence of geographical spillovers of human capital is also considered by applying spatial panel data techniques. The empirical analysis of Spanish provinces between 1980 and 2007 confirms the positive impact of human capital on regional productivity and convergence, but reveals no evidence of any positive geographical spillovers of human capital. In fact, in some specifications the spatial lag presented by tertiary studies has a negative effect on the variables under consideration.

Renal perfusion evaluation with contrast-enhanced ultrasonography.

BACKGROUND: Contrast-enhanced ultrasonography (CEUS) is a novel imaging technique that is safe and applicable on the bedside. Recent developments seem to enable CEUS to quantify organ perfusion. We performed an exploratory study to determine the ability of CEUS to detect changes in renal perfusion and to correlate them with effective renal plasma flow. METHODS: CEUS with destruction-refilling sequences was studied in 10 healthy subjects, at baseline and during infusion of angiotensin II (AngII) at low (1 ng/kg/min) and high dose (3 ng/kg/min) and 1 h after oral captopril (50 mg). Perfusion index (PI) was obtained and compared with the effective renal plasma flow (ERPF) obtained by parallel para-aminohippurate (PAH) clearance. RESULTS: Median PI decreased from 188.6 (baseline) to 100.4 with low-dose AngII (-47%; P < 0.02) and to 66.1 with high-dose AngII (-65%; P < 0.01) but increased to 254.7 with captopril (+35%; P > 0.2). These changes parallelled those observed with ERPF, which changed from a median of 672.1 mL/min (baseline) to 572.3 (low-dose AngII, -15%, P < 0.05) and to 427.2 (high-dose AngII, -36%, P < 0.001) and finally 697.1 (captopril, +4%, P < 0.02). CONCLUSIONS: This study demonstrates that CEUS is able to detect changes in human renal cortical microcirculation as induced by AngII infusion and/or captopril administration. The changes in perfusion indices parallel those in ERPF as obtained by PAH clearance.