A translational approach to assess the metabolomic impact of stabilized gold nanoparticles by NMR spectroscopy

[EN] Gold nanoparticles have high potential in the biomedical area, especially in disease diagnosis and treatment. The application of these nanoparticles requires the presence of stabilizers to avoid their agglomeration. Nowadays, there is a lack of reliable methods for characterising the effect of stabilised nanoparticles on biological systems. To this end, in this study, we apply an experimental approach based on nuclear magnetic resonance spectroscopy to study the effect of gold nanoparticles, stabilised with cerium oxide or chitosan, on a human cancer cell model. The results showed that both systems have a significant effect, even at non-toxic levels, on the cellular antioxidant system. However, although particles functionalised with chitosan exerted a strong effect on the aerobic respiration, nanoparticles stabilised with cerium oxide had a higher impact on the mechanisms associated with anaerobic energy production. Therefore, even though both systems contained similar gold nanoparticles, the presence of different stabilizers strongly influenced their mode of action and potential applications in biomedicine.This work was supported by the Carlos III Health Institute, the European Regional Development Fund (PI16/02064 and CP13/00252) and the Spanish Ministerio de Economia y Competitividad (SAF2014-53977-R, SAF2017-89229-R and RD12/0036/0025). In addition, JRH is a recipient of a contract from the Ministry of Health of the Carlos III Health Institute.Herance, JR.; García Gómez, H.; Guitierrez Carcedo, P.; Navalón Oltra, S.; Pineda-Lucena, A.; Palomino-Schätzlein, M. (2019). A translational approach to assess the metabolomic impact of stabilized gold nanoparticles by NMR spectroscopy. The Analyst. 144(4):1265-1274. https://doi.org/10.1039/c8an01827hS126512741444Shi, J., Kantoff, P. W., Wooster, R., & Farokhzad, O. C. (2016). Cancer nanomedicine: progress, challenges and opportunities. 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Health economics: identifying leading producers, countries relative specialization and themes

El área de investigación en economía de la salud tuvo una gran evolución a partir de la década de 1960 y está en constante crecimiento. Actualmente, el gasto en salud es un tema clave en todo el mundo. La bibliometría proporciona varios métodos para explorar el impacto y la evolución de la investigación. Así pues, el principal objetivo del presente estudio es comprender la situación actual de la investigación en materia de economía de la salud para el período 2010-2019. Se analizaron tres aspectos diferentes: la producción de los países, el índice de prioridad relativa y los temas principales. El conjunto de datos se obtuvo a partir de los documentos indizados en la base de datos Web of Science de 2010 a 2019. Se utilizó el software SciMAT para obtener el análisis temático mediante el análisis de mapas de la ciencia. Las revistas Health economics, Value in Health, Journal of Health Economics y European Journal of Health Economics son los principales productoras. Estados Unidos, Inglaterra y Alemania son los que tienen una mayor producción; los Países Bajos, Inglaterra y Australia son los que tienen el índice de prioridad relativa más alto. Los años de vida ajustados en función de la calidad y la desigualdad en materia de salud son los temas con mayor número de documentos y medidas de impacto. Este estudio es un marco útil basado en ciencia que servirá de base para futuras acciones de investigación.Health economics research area was a high evolution from the 1960s and it is constantly growing. Currently, the health expenditure is a key issue worldwide. Bibliometrics provides several methods to explore the impact and evolution of the research. Thus, the main aim of the present study is to understand the current status of the research in health economics for the period 2010-2019. Three different aspects were analyzed: countries production, relative priority index and main themes. The dataset was obtained from the documents indexed in the Web of Science database from 2010 to 2019. SciMAT software was used to obtain the thematic analysis by means of science mapping analysis. The journals Health economics, Value in Health, Journal of Health Economics, and European Journal of Health Economics are the main producers. USA, England and Germany are those with highest production; Netherlands, England and Australia are those with the highest relative priority index. Quality adjusted life years and Health inequality are the themes with the highest number of documents and impact measures. This study is a useful evidence-based framework on which to base future research actions

Renewable medium-small projects in Spain: Past and present of microgrid development

This paper reviews the on-going research studies and microgrid pilot projects focusing on the Spanish case because of its renewable energy potential with the objective set on highlights the main investigation drifts in the field such as the used technologies, control methods and operation challenges. That way, several smart grids have been commented and compared, finding that photovoltaic and wind power are the favourites energy generation technologies. Although batteries are the most widespread energy storage systems, green hydrogen has a strong presence, showing up in a third of the Spanish smart grids. Traditional control strategies are being displaced by advanced ones such as MPC or fuzzy logic due to its higher efficiency. The reader will have a clear view of the potential of renewable energy penetration in the form of smart grids in Spain, through the study of the equipment involved in the different facilities contribution and the main control strategies implemented, in a comparative analysis of the key aspect of this emerging technology.Consejería de Conocimiento, Investigación y Universidad - Junta de Andalucía PY18-RE-002

Prevalence estimation of significant fibrosis because of NASH in Spain combining transient elastography and histology

Acord transformatiu CRUE-CSICBackground & Aims: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. Methods: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. Results: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively. Conclusions: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available

Incidence and risk factors for Preeclampsia in a cohort of healthy nulliparous pregnant women: a nested case-control study

The objective of this study is to determine the incidence, socio-demographic and clinical risk factors for preeclampsia and associated maternal and perinatal adverse outcomes. This is a nested case-control derived from the multicentre cohort study Preterm SAMBA, in five different centres in Brazil, with nulliparous healthy pregnant women. Clinical data were prospectively collected, and risk factors were assessed comparatively between PE cases and controls using risk ratio (RR) (95% CI) plus multivariate analysis. Complete data were available for 1,165 participants. The incidence of preeclampsia was 7.5%. Body mass index determined at the first medical visit and diastolic blood pressure over 75 mmHg at 20 weeks of gestation were independently associated with the occurrence of preeclampsia. Women with preeclampsia sustained a higher incidence of adverse maternal outcomes, including C-section (3.5 fold), preterm birth below 34 weeks of gestation (3.9 fold) and hospital stay longer than 5 days (5.8 fold) than controls. They also had worse perinatal outcomes, including lower birthweight (a mean 379 g lower), small for gestational age babies (RR 2.45 [1.52-3.95]), 5-minute Apgar score less than 7 (RR 2.11 [1.03-4.29]), NICU admission (RR 3.34 [1.61-6.9]) and Neonatal Near Miss (3.65 [1.78-7.49]). Weight gain rate per week, obesity and diastolic blood pressure equal to or higher than 75 mmHg at 20 weeks of gestation were shown to be associated with preeclampsia. Preeclampsia also led to a higher number of C-sections and prolonged hospital admission, in addition to worse neonatal outcomes9CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ401636/2013-5Bill and Melinda Gates FoundationGates Foundation [OPP1107597]; CNPqNational Council for Scientific and Technological Development (CNPq) [401636/2013-5

Planning, Implementing, and Running a Multicentre Preterm Birth Study with Biobank Resources in Brazil: The Preterm SAMBA Study

Background. Our aim was to describe the steps in planning, implementing, and running a multicentre cohort study of maternal and perinatal health using a high-quality biobank comprised of maternal serum, plasma, and hair samples collected from five sites in Brazil. The Preterm SAMBA study, conducted by the Brazilian Network for Studies on Reproductive and Perinatal Health, was an innovative approach used to identify women at higher risk for preterm birth. It is also of great importance in the study of other maternal and perinatal complications in the context of Brazil, which is a middle-income country. Methods. We described phases of planning, implementing, and running the Preterm SAMBA study, a multicentre Brazilian cohort study of low-risk nulliparous pregnant women, to validate a set of metabolite biomarkers for preterm birth identified in an external cohort. Procedures and strategies used to plan, implement, and maintain this multicentre preterm birth study are described in detail. Barriers and experience cited in the current narrative are not usually discussed in the scientific literature or published study protocols. Results. Several barriers and strategies were identified in different phases of the Preterm SAMBA study at different levels of the study framework (steering committee; coordinating and local centres). Strategies implemented and resources used in the study are a legacy of the Brazilian Network, aimed at training collaborators in such complex settings. Conclusion. The Brazilian Network for Studies on Reproductive and Perinatal Health has gained some experience in conducting a multicentre cohort study using a resourceful biobank which may be helpful to other research groups and maternal/perinatal health networks that plan on employing a similar approach to a similar background.201

Study design for development of novel safety biomarkers of drug-induced liver injury by the translational safety biomarker pipeline (TransBioLine) consortium: a study protocol for a nested case–control study

A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative’s TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification.In a nested case–control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample size is as follows: 300 cases of DILI and 130 acute non-DILI controls. Additional cross-sectional cohorts (1 visit) are as follows: Healthy volunteers (n = 120), controls with chronic alcohol-related or non-alcoholic fatty liver disease (n = 100 each) and patients with psoriasis or rheumatoid arthritis (n = 100, 50 treated with methotrexate) are enrolled. Candidate biomarkers prioritised for evaluation include osteopontin, glutamate dehydrogenase, cytokeratin-18 (full length and caspase cleaved), macrophage-colony-stimulating factor 1 receptor and high mobility group protein B1 as well as bile acids, sphingolipids and microRNAs. The TransBioLine project is enabling biomarker discovery and validation that could improve detection, diagnostic accuracy and prognostication of DILI in premarketing clinical trials and for clinical healthcare application

New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study

Background and aims: Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol. Methods: Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot. Results: Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in sham-operated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet. Conclusions: In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.Peer reviewe

A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury

Background & Aims We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28–1.62; P = 1.2 × 10–9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10–6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10–6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI