Objectives:The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy.Methods:499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed.Results:ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups.Conclusion:Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile.Trial registration number:NCT00106522.

Concentrations of seven heavy metals (Cd, Cr, Cu, Hg, Ni, Pb, and Zn) and one metalloid (As) as well as various parameters (pH, organic carbon, granulometric analysis and cation exchange capacity) were analyzed in 77 soil samples collected in the mining areas of La Zanja and Colquirrumi (Department of Cajamarca) and Julcani (Department of Huancavelica). Our study proposed geochemical baseline values for heavy metals in a natural region (La Zanja) from samples collected during the period of the environmental impact study (2006), that is, from an earlier period which occurred at the beginning of the exploitation of the current gold mine. The baseline values obtained were as follows: 8.26 mg·kg−1 for Cr; 56.97 mg·kg−1 for Ni; 22, 20 mg·kg−1 for the Cu; 47.42 mg·kg−1 for Zn; 27.50 mg·kg−1 for As; 4.36 mg·kg−1 for Cd; 4.89 mg·kg−1 for Hg, and 44.87 mg·kg−1 for Pb. Through the use of different indices of heavy metal contamination (geo-accumulation index (Igeo), improved Nemerow index (IIN) and potential ecological risk index (RI)), the degree of pollution caused by mining activities in two areas, Colquirrumi and Julcani, which have a high density of mining sites in operation, was determined. The values obtained from these indices indicated that the Colquirrumi region was the most contaminated, followed by Julcani. The area of La Zanja, despite being free of mining operations, presented slight diffuse pollution. Several positive correlations were obtained, with a high level of significance, between pH, organic carbon content, cation exchange capacity, and the Cr, Pb and Ni concentrations of the soils. The spatial distribution of the heavy metals was realized by means of the interpolation method of ordinary kriging. The results obtained and the experience gained in this work were necessary to facilitate the identification of soil contamination processes in high altitude areas of the Andes Western Cordillera (Peru) as a basis for taking appropriate measures when restoring soils, during mine closure processes, and to protect the quality of soil resources.

This paper is based on microprobe analysis (Ta, Nb, Fe, Mn, Ti, W, Sn) and Fe3+EPR spectra of cassiterite samples from 14 tin deposits from the Iberian Hercynian Massif. The interpretation of microprobe data, atomic ratios (Fe+Mn)/(Nb+Ta), and Fe3+EPR spectra reveal that the coupled substitution: 3Sn4+= (Fe,Mn)2++ 2(Nb,Ta)5+is dominant in cassiterites from pegmatites, and high-temperature quartz veins and in the dark zones of cassiterites.The mechanisms:2Sn4+= Fe3++ (Nb,Ta)5+andSn4++ O2−= Fe3++ OH−are dominant in those from medium-low temperature quartz veins and in the light zones of cassiterites.

The environmental quality of soil in the central part of the Northern Plateau of Spain has been analyzed by studying the heavy metal content of 166 samples belonging to the horizons A, B and C of 89 soil profiles. The analysis to assess the environmental risk of heavy metals in the soil was carried out by means of the spatial distribution of nine heavy metals and the use of several pollution indices. The results showed that the concentration values of heavy metals (normalxfalse¯ ± S) in the superficial soil horizons were the following: With a total of 6.71 ± 3.51 mg·kg−1, the contents of Cd is 0.08 ± 0.06 mg·kg−1, Co is 6.49 ± 3.21 mg·kg−1, Cu is 17.19 ± 10.69 mg·kg−1, Cr is 18.68 ± 12.28 mg·kg−1, Hg is 0.083 ± 0.063 mg·kg−1, Ni is 12.05 ± 6.76 mg·kg−1, Pb is 14.10 ± 11.32 mg·kg−1 and Zn is 35.31 ± 14.63 mg·kg−1. These nine metals exceed the values of the natural geological background level of Tertiary period sediments and rocks that form part of the Northern Plateau in Spain. Nemerow and Potential Ecological Risk indices were calculated, with the “improved” Nemerow index allowing pollution within the soil superficial horizons to be determined. The data obtained indicated that the majority of the soil (54.61%) showed low to moderate contamination, 22.31% showed moderate contamination and 21.54% of the samples were not contaminated. If we consider the Potential of Ecological Risk Index (RI), the largest percentage of soil samples showed low (70.79%) to moderate (25.38%) ecological risk of potential contamination, where the rest of the soil presented a considerable risk of contamination. The nine trace elements were divided into three principal components: PC1 (Cu, Cr, Ni, Co and Zn), PC2 (As and Hg) and PC3 (Cd). All metals accumulated in the soil came from parent rock, agricultural practices and the run-off of residual waters towards rivers and streams caused by industrial development and an increase in population density. Finally, cartography of the spatial distribution of the heavy metal contents in the soil of the Northern Plateau of Spain was generated using Kriging interpolation methods. Furthermore, the total heavy metal contents in three soil orders present in the area, namely Entisols, Inceptisols, and Alfisols, were analyzed. Other soil parameters, such as the organic matter content, pH, clay content and cation exchange capacity, was measured to determine their influence on and correlation with the heavy metal contents.

The authors analyse the concept of competitiveness and then apply this concept to tourist destinations. The objective is to measure tourism destination competitiveness in the regions of the Spanish Mediterranean coast to provide tourism policymakers with tools to improve destination competitiveness. Through a review of the literature, the authors identify the indicators that may explain competitiveness. They then select the variables and determine their quantitative effect on destination competitiveness in Spanish Mediterranean regions. The findings enable a better understanding of tourism destination competitiveness. Finally, the authors comment on the relationship between competitiveness and prosperity.