Alemtuzumab treatment in real clinical practice: Experience in a multicenter cohort.

BACKGROUND: Alemtuzumab is a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), but in recent years safety-related concerns had emerged due to description of novel serious side effects not registered in CARE-MS I and CARE-MS II phase 3 studies, nor in TOPAZ extension study. Data about alemtuzumab use in real clinical practice are limited and based mainly on retrospective studies with small sample sizes. Therefore, more information about effectiveness and safety of alemtuzumab in this context is needed. METHODS: A multicenter observational prospective study to investigate effectivity and safety of alemtuzumab in a real-world setting was performed. Primary endpoints were the change in annualized relapse rate (ARR), and in disability measured by EDSS score. Secondary endpoints were the cumulative probability of confirmed 6-month disability improvement and worsening. Disability worsening and disability improvement were considered when the EDSS score was increased or decreased, respectively, in 1 point if baseline EDSS score was <5.0, or in 0.5 point if baseline EDSS score was ≥5.5, confirmed over 6 months. Other secondary endpoint was the proportion of patients who achieved NEDA-3 status (absence of clinical relapses, disability EDSS progression, and MRI disease activity as depicted by new/enlarging T2 lesions or Gadolinium enhancing T1 lesions). Adverse events also were recorded. RESULTS: A total of 195 RRMS patients (70% female) who started alemtuzumab treatment were included. Mean of follow-up was 2.38 years. Alemtuzumab significantly reduced the annualized relapse rate from baseline with risk reductions of 86%, 83.5%, and 84%, at 12, 24, and 36 months of follow-up respectively (Friedman test, p-value < 0.05 for all comparisons). Alemtuzumab also significantly reduced EDSS score over one and two years after starting alemtuzumab treatment (Friedman test, p-value<0.001 for both comparisons). A high proportion of patients presented confirmed 6-month stability or disability improvement (92%, 82%, and 79%, over 1, 2 and 3 years of follow-up respectively). The proportion of patients who retained NEDA-3 status at 12, 24 and 36 months were 61%, 49%, and 42%, respectively. Baseline characteristics associated with a lower probability of achieving NEDA-3 were younger age, sex female, high ARR, elevated number of previous treatments, and switch from a second line therapy. Infusion related reactions were the most frequent adverse event observed. The most common infections were urinary tract infections (50%), and upper respiratory tract infections (19%) over the 3 years of follow- up. Secondary thyroid autoimmunity was developed in 18.5% of patients. CONCLUSION: Alemtuzumab has demonstrated in real clinical practice high effectiveness in controlling multiple sclerosis activity, and no unexpected adverse events were observed.

Atmospheric circulation and mortality by unintentional drowning in Spain: from 1999 to 2018.

AIMS: Drowning deaths are a leading cause of unintentional deaths worldwide. Few studies have analysed the role of meteorology in drowning, and with inconclusive results. The aim of this work is to analyse the temporal and geographical distribution of deaths by accidental drowning and submersion in Spain over 20 years, and to assess the relationship between accidental drowning and main atmospheric circulation patterns. METHODS: An ecological study was performed, in which drowning and submersion mortality data from 1999 to 2018, considering demographic variables, were analysed. To study the association with atmospheric circulation we used an ERA5 reanalysis product over the whole European continent and the Climatic Research Unit Time Series (CRU TS) data set. RESULTS: The annual average rate of deaths by accidental drownings was 11.86 deaths per million of habitants in Spain. The incidence in males was four times higher than in females, and when comparing age groups, the rate in the eldest group was the highest. Unintentional drowning deaths were not equally distributed around the country; the provinces with the highest registered standardized drowning death rates were touristic waterfront provinces either in Eastern Spain or in one of the archipelagos. There was a significant relationship between accidental drowning and meteorological variables during summer months, and drowning deaths were spatially correlated with sea-level pressure over the Mediterranean basin. CONCLUSION: Although the mortality rate registered a statistically significant decreasing tendency over the studied period, our results must be taken into consideration to improve the prevention strategies in the country since most of these deaths are avoidable.

Evaluating Cr behaviour in two different polluted soils: Mechanisms and implications for soil functionality.

This work investigates the mechanisms determining Cr speciation and availability in two different soils polluted with two chromium sources (an industrial sludge, highly polluted with Cr, and Cr(VI) solution) and the influence of these parameters on the recovery of the soil functions related with biological quality and plant growth. The experiment was carried out in greenhouse conditions using 36 pots of 17 kg for the growth of Silene vulgaris for 21 months. Logistic Regression Model using Lasso estimator shows that soil organic matter (SOM) and pH control Cr availability in studied soils. In soils treated with the sludge, X ray Absorption spectroscopy showed that Cr was present as Cr(III), biological quality indicators increased and plants were able to grow. However, in soils polluted with Cr(VI), Cr availability was significantly different in the two soils. In the alkaline and poor in organic matter soil, 12% of Cr(VI) remained in the soil leading to the decrease of soil quality indicators and the total inhibition of plant growth. In the neutral soil, Cr(VI) was totally reduced to Cr(III) by soil organic matter (SOM), quality indicators were not affected and plants grown properly. Infrared Spectroscopy showed that different functional groups reacted with Cr in the two soils. This study highlights the importance to understand the mechanisms underlaying Cr redox and adsorption reactions in Cr polluted soils as they determine the potential recovery of the functions related with biological quality indicators and plant growth. The methodology proposed allows this study in complex soil samples at realistic concentrations and may be useful for risk assessment and for the planning of managing strategies in Cr polluted soils.

Risk and limits in dental practice: a Portuguese approach to medical-legal evaluation and professional liability.

Patient safety and quality of healthcare delivery systems are an objective of WHO. This study aims to present and analyse Portuguese clinical data on risk and malpractice in dental practice. Data from the Forensic Dentistry Laboratory (Faculty of Medicine, University of Coimbra) was analysed, between the years of 2013 to 2018. One hundred and seven technical reports were selected, and seventy nine files were included in the iatrogenic sequelae group. Data included the analysis of the performance of dental professionals. Sequelae were divided in descending order of occurrence:1) mandibular dysfunction (53,2%)[(42)79]; 2) neurological deficit (39,2%)[(31)79]; 3) tooth loss (6,3%)[(5)79]; and 4) opening deficit (1,3%)[(1)79].Three major areas with significant expression in the field of expert evaluations were analysed: 1) orthodontic treatment (51,9%), implant rehabilitation (29,1%), and oral surgery. Given the prevalence of malpractice, the need to assess its causes and recognise standards for its prevention is necessary.

ALLIANCE perspectives on integration of humans and the environment into the system of radiological protection.

Risks posed by the presence of radionuclides in the environment require an efficient, balanced, and adaptable assessment for protecting exposed humans and wildlife, and managing the associated radiological risk. Exposure of humans and wildlife originate from the same sources releasing radionuclides to the environment. Environmental concentrations of radionuclides serve as inputs to estimate the dose to man, fauna, and flora, with transfer processes being, in essence, similar, which calls for a common use of transport models. Dose estimates are compared with the radiological protection criteria for humans and wildlife, such as those developed by the International Commission on Radiological Protection. This indicates a similarity in the approaches for impact assessment in humans and wildlife, although some elements are different (e.g. the protection endpoint for humans is stochastic effects on individuals, whereas for wildlife, it is deterministic effects on species and ecosystems). Human and environmental assessments are consistent and complementary in terms of how they are conducted and in terms of the underlying databases (where appropriate). Not having an integrated approach may cause difficulties for operators and regulators, for communication to stakeholders, and may even hamper decision making. For optimised risk assessment and management, the impact from non-radiation contaminants and stressors should also be considered. Both in terms of the underlying philosophy and the application via appropriate tools, the European Radioecology Alliance (ALLIANCE) upholds that integration of human and ecological impact and risk assessment is recommended from several perspectives (e.g. chemical/radiological risks).

COMET strongly supported the development and implementation of medium-term topical research roadmaps consistent with the ALLIANCE Strategic Research Agenda.

The ALLIANCE6 Strategic Research Agenda (SRA) initiated by the STAR7 Network of Excellence and integrated in the research strategy implemented by the COMET consortium, defines a long-term vision of the needs for, and implementation of, research in radioecology. This reference document, reflecting views from many stakeholders groups and researchers, serves as an input to those responsible for defining EU research call topics through the ALLIANCE SRA statement delivered each year to the EJP-CONCERT8 (2015-2020). This statement highlights a focused number of priorities for funding. Research in radioecology and related sciences is justified by various drivers, such as policy changes, scientific advances and knowledge gaps, radiological risk perception by the public, and a growing awareness of interconnections between human and ecosystem health. The SRA is being complemented by topical roadmaps that have been initiated by the COMET9 EC-funded project, with the help and endorsement of the ALLIANCE. The strategy underlying roadmap development is driven by the need for improved mechanistic understanding across radioecology. By meeting this need, we can provide fit-for-purpose human and environmental impact/risk assessments in support of the protection of man and the environment in interaction with society and for the three exposure situations defined by the ICRP (i.e., planned, existing and emergency). Within the framework of the EJP-CONCERT the development of a joint roadmap is under discussion among all the European research platforms and will highlight the major research needs for the whole radiation protection field and how these are likely to be addressed by 2030.

Sustainability and integration of radioecology-position paper.

This position paper gives an overview of how the COMET project (COordination and iMplementation of a pan-European instrumenT for radioecology, a combined Collaborative Project and Coordination and Support Action under the EC/Euratom 7th Framework Programme) contributed to the integration and sustainability of radioecology in Europe via its support to and interaction with the European Radioecology ALLIANCE. COMET built upon the foundations laid by the FP7 project STAR (Strategic Network for Integrating Radioecology) Network of Excellence in radioecology. In close association with the ALLIANCE, and based on the Strategic Research Agenda (SRA), COMET developed innovative mechanisms for joint programming and implementation of radioecological research. To facilitate and foster future integration under a common federating structure, research activities developed within COMET were targeted at radioecological research needs identified in the SRA. Furthermore, COMET maintained and developed strong mechanisms for knowledge exchange, dissemination and training to enhance and maintain European capacity, competence and skills in radioecology. In the short term the work to promote radioecology will continue under the H2020 project EJP-CONCERT (European Joint Programme for the Integration of Radiation Protection Research). The EJP-CONCERT project (2015-2020) aims to develop a sustainable structure for promoting and administering joint programming and open research calls in the field of radiation protection research for Europe. In the longer term, radioecological research will be facilitated by the ALLIANCE. External funding is, however, required in order to be able to answer emerging research needs.

Phytoavailability of Cr in Silene vulgaris: The role of soil, plant genotype and bacterial rhizobiome.

Understanding the metal behavior at the soil-root interface is of utmost significance for a successful implementation of phytoremediation. In this study, we investigated the differences in chromium (Cr) uptake, chemical changes in soil solution and the shifts in rhizosphere bacterial communities of two genotypes of Silene vulgaris (SV21, SV38) with different tolerance to Cr. A greenhouse experiment was performed in two soils that differed on pH and organic matter (OM) content. An industrial sludge with high content in Cr was used as pollution source. The soil solution in the rhizosphere was sample by Rhizon Soil Moisture Samplers. The total concentration of Cr reached the highest values in soil solution samplers from calcareous soils with poor contents in OM. Plants grown in this soil also increased the Cr uptake in roots of both genotypes, but the concentration was higher in genotype SV-38 than in SV21. The clustering analysis of denaturing gradient gel electrophoresis (DGGE) of 16S rRNA fragments revealed major differences in bacterial community structure related to Cr pollution, followed by soil type and finally, plant genotype. Diversity indices based on DGGE profiles were the highest in alkaline soil, and between genotypes, values were significantly greater in SV38. Canonical correspondence analysis (CCA) showed that changes in bacterial community structure of rhizosphere were highly correlated with total Cr concentration and soil solution pH. The isolation and identification of S. vulgaris bacterial rhizosphere revealed a different composition according to soil type and plant genotype. Results suggested the potential role of Pseudomonas fluorescens on Cr mobilization and therefore, on enhanced metal bioavailability and may provide a starting point for further studies aimed at the combined use of tolerant plants and selected metal mobilizing rhizobacteria, in the microbial-assisted phytoremediation of Cr-polluted soils.

Different genotypes of Silene vulgaris (Moench) Garcke grown on chromium-contaminated soils influence root organic acid composition and rhizosphere bacterial communities.

Plant-microbe interactions are considered to be important processes determining the efficiency of phytoremediation of heavy metal-contaminated soils. However, relatively little is known about how these interactions are influenced by chromium (Cr) contamination. The effect of Cr stress on metal uptake, root organic acid composition, and rhizosphere bacterial communities was studied using two genotypes of the metallophyte Silene vulgaris, which have shown different tolerance to Cr(VI). The results indicated that root biomass and shoot biomass were not significantly influenced by Cr treatment, but metal uptake in shoots and roots was significantly impacted by the genotype. Principal component analyses (PCA) showed that variation in organic acids oxalic, citric, malic, formic, lactic, acetic, and succinic differed between genotypes. Changes in root organic acid contents in response to Cr revealed a significant increase of oxalic acid in genotype SV-21. The denaturing gradient gel electrophoresis (DGGE) cluster analysis showed that the community structure (determined by PCR-DGGE) was affected by plant genotype and, to a lesser extent, by Cr contamination, the first being the most influential factor shaping the rhizosphere microbiome. Under Cr pollution, a shift in the relative abundance of specific taxa was found and dominant phylotypes were identified as Variovorax in SV-21 and Chitinophaga niastensis, Pontibacter sp., and Ramlibacter sp. in SV-38. These results provided the basis for further studies aimed at the combined use of plants and soil microorganisms in the remediation of Cr-polluted soils.

[Fingolimod: effectiveness and safety in routine clinical practice. An observational, retrospective, multi-centre study in Galicia]. / Fingolimod: efectividad y seguridad en la practica clinica habitual. Estudio observacional, retrospectivo y multicentrico en Galicia.

INTRODUCTION: The effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) have been proven in clinical trials. Yet, due to their limitations, it is important to know how it behaves under everyday clinical practice conditions. Hence, the aim of this study is to evaluate the effectiveness and safety of fingolimod after 12 months' usage in clinical practice in Galicia. PATIENTS AND METHODS: We conducted a retrospective, multi-centre study (n = 8) of patients with RRMS who were treated with one or more doses of fingolimod, 0.5 mg/day. Effectiveness was assessed -annualised relapse rate (ARR), changes in the score on the Expanded Disability Status Scale (EDSS), percentage of patients free from relapses, free from progression of disability and free from activity in resonance- for the total number of patients and according to previous treatment. Safety was assessed based on the percentage of patients who withdrew and presented adverse side effects. RESULTS: After 12 months' use, fingolimod reduced the ARR by 87% (1.7 to 0.23; p < 0.0001) and, consequently, 81% of patients were free from relapses. The score was reduced by 9%. In all, 91% of patients were free from progression of disability and 72% were free from resonance activity. No signs of disease activity were found in 43% of the patients. Most of the benefits of fingolimod differed depending on previous treatment. About a third of the patients reported adverse side effects, but only 2% of them withdrew for this reason. CONCLUSIONS: In clinical practice, most of the results on the effectiveness of the clinical trials conducted with fingolimod were observed during the first 12 months of treatment. A better safety profile was observed than that reported in the clinical trials.

TITLE: Fingolimod: efectividad y seguridad en la practica clinica habitual. Estudio observacional, retrospectivo y multicentrico en Galicia.Introduccion. La efectividad y seguridad del fingolimod en pacientes con esclerosis multiple remitente recurrente (EMRR) se demostro en ensayos clinicos. Sin embargo, por las limitaciones de estos, es importante saber como se comporta en condiciones de practica clinica habitual. Asi, el objetivo de este estudio es evaluar la efectividad y seguridad del fingolimod despues de 12 meses de uso en la practica clinica en Galicia. Pacientes y metodos. Estudio retrospectivo y multicentrico (n = 8) de pacientes con EMRR y tratados con una o mas dosis de fingolimod, 0,5 mg/dia. Se evaluo la efectividad ­tasa anualizada de brotes (TAB), cambio en la puntuacion de la escala expandida del estado de discapacidad (EDSS), porcentaje de pacientes libres de brotes, libres de progresion de discapacidad y libres de actividad en resonancia­ para el total de pacientes y segun tratamiento previo. Se evaluo la seguridad a partir del porcentaje de pacientes que discontinuaron y que presentaron efectos adversos. Resultados. Despues de 12 meses de uso, el fingolimod redujo un 87% la TAB (de 1,7 a 0,23; p < 0,0001) y, en consecuencia, un 81% de pacientes estuvo libre de brotes. La puntuacion de la EDSS disminuyo un 9%. Un 91% de pacientes estuvo libre de progresion de discapacidad y un 72%, libre de actividad en resonancia. En el 43% de los pacientes no se evidenciaron signos de la actividad de la enfermedad. La mayoria de los beneficios del fingolimod difirieron segun el tratamiento previo. Alrededor de un tercio de los pacientes comunicaron efectos adversos, pero solo el 2% discontinuo debido a ellos. Conclusiones. La mayoria de los resultados de efectividad de los ensayos clinicos del fingolimod se observa durante los 12 primeros meses de tratamiento en la practica clinica. Se observo un mejor perfil de seguridad al comunicado en los ensayos clinicos.

Radionuclide biological half-life values for terrestrial and aquatic wildlife.

The equilibrium concentration ratio is typically the parameter used to estimate organism activity concentrations within wildlife dose assessment tools. Whilst this is assumed to be fit for purpose, there are scenarios such as accidental or irregular, fluctuating, releases from licensed facilities when this might not be the case. In such circumstances, the concentration ratio approach may under- or over-estimate radiation exposure depending upon the time since the release. To carrying out assessments for such releases, a dynamic approach is needed. The simplest and most practical option is representing the uptake and turnover processes by first-order kinetics, for which organism- and element-specific biological half-life data are required. In this paper we describe the development of a freely available international database of radionuclide biological half-life values. The database includes 1907 entries for terrestrial, freshwater, riparian and marine organisms. Biological half-life values are reported for 52 elements across a range of wildlife groups (marine = 9, freshwater = 10, terrestrial = 7 and riparian = 3 groups). Potential applications and limitations of the database are discussed.