Assessment of oxidative damage to proteins and DNA in urine of newborn infants by a validated UPLC-MS/MS approach

The assessment of oxidative stress is highly relevant in clinical Perinatology as it is associated to adverse outcomes in newborn infants. This study summarizes results from the validation of an Ultra Performance Liquid Chromatography-tandem Mass Spectrometry (UPLC-MS/MS) method for the simultaneous quantification of the urinary concentrations of a set of endogenous biomarkers, capable to provide a valid snapshot of the oxidative stress status applicable in human clinical trials, especially in the field of Perinatology. The set of analytes included are phenylalanine (Phe), para-tyrosine (p-Tyr), ortho-tyrosine (o-Tyr), meta-tyrosine (m-Tyr), 3-NO2-tyrosine (3NO 2-Tyr), 3-Cl-tyrosine (3Cl-Tyr), 2′-deoxyguanosine (2dG) and 8-hydroxy-2′-deoxyguanosine (8OHdG). Following the FDA-based guidelines, appropriate levels of accuracy and precision, as well as adequate levels of sensitivity with limits of detection (LODs) in the low nanomolar (nmol/L) range were confirmed after method validation. The validity of the proposed UPLC-MS/MS method was assessed by analysing urine samples from a clinical trial in extremely low birth weight (ELBW) infants randomized to be resuscitated with two different initial inspiratory fractions of oxygen

Estudio de alternativas de conexión viaria y ferroviaria entre los puertos de Sagunto y Valencia

[ES] El presente estudio tiene como objetivo trabajar sobre las alternativas que existen para conectar los puertos de València y Sagunto con infraestructuras que mejoren las conexiones ya existentes. Estas nuevas infraestructuras serán necesarias en el momento en el que esté operativa la nueva terminal de contenedores abrigada por el dique construido en la Ampliación Norte del Puerto de Valencia, que hará crecer los flujos logísticos que existen hoy en día entre el puerto y su hinterland, ya que la autovía V-30, que es el único acceso al Puerto de Valencia para vehículos pesados disponible en la actualidad, se encuentra ya muy cargada de este tipo de tráfico. Además, un hipotético acceso norte ahorraría a los vehículos ligeros el recorrido urbano que deben hacer hasta llegar al puerto y a los pesados los kilómetros suplementarios que han de recorrer obligatoriamente por el By-Pass hasta la V-30 si provienen de Sagunto o cualquier área del norte de València. Se debe destacar que es necesario que las soluciones que se adopten sean sostenibles y respetuosas con los medios urbano y agrario de gran valor cultural, ecológico y paisajístico que rodean la zona de afección de los futuros trabajos, como son los barrios marítimos y la huerta de València. El estudio contempla diferentes escenarios de tráfico viario y ferroviario para los que se obtiene la cantidad de camiones y trenes por día que deberían de utilizar el nuevo acceso norte, de forma que éste puede ser dimensionado. Para cada hipótesis de tráfico se estudia si la nueva infraestructura debe ser viaria, ferroviaria o de ambas tipologías, se proponen diferentes posibles trazados y finalmente se justifica cuál es la alternativa óptima atendiendo a criterios de sostenibilidad ambiental, funcionalidad de las infraestructuras, eficiencia económica y preservación del entorno. También se analiza la incidencia que tendría la puesta en funcionamiento de la terminal de la Ampliación Norte del Puerto de València sobre el tráfico viario y ferroviario que transcurre por las infraestructuras disponibles para el puerto en la actualidad y posteriormente se miden los efectos que provocaría el Acceso Norte para cada caso considerado sobre estas vías.[EN] The following project has as main objective to analyse the existing alternatives that could be built to connect the ports of València and Sagunt, creating infrastructures that improve the already existing connections. These new infrastructures will be needed at the moment in which the new container terminal, located at the Port of València north extension, starts being operative, since larger logistic flows will be taking place between the port and its hinterland, and the highway V-30, which is the only way in and out for heavy vehicles available for this port, is already overloaded of this kind of traffic. Moreover, an additional access to the Port of València located at its north would eliminate the urban route that light vehicles coming from the north areas from València, such as Sagunt, have to currently go through, and would save a significant amount of kilometres for heavy vehicles coming from or going to those areas of the north. It must be highlighted that it is necessary for the solutions adopted to be sustainable and that they respect the urban and agricultural surroundings because of their high ecological, cultural and landscape value. These surrounding areas are the València¿s maritime districts and València¿s countryside. The project considers different road and railroad traffic scenarios for which the amount of trucks and trains per day that should use the new north access is obtained, so that the dimensions of this new infrastructure can be determined. For each of this traffic hypothesis it is analysed what kind the new infrastructure should be: a road one, a railway one or both, different routes are suggested and finally it is explained which of the alternatives is the most efficient regarding to sustainability, economic, functional and environmental matters. The affection on the road and railroad traffic of the set in motion of the new container terminal in València¿s port is also studied in this project, as well as the effects that a new access at the north of this port would have on it.Lliso I Navarro, JM. (2020). Estudio de alternativas de conexión viaria y ferroviaria entre los puertos de Sagunto y Valencia. http://hdl.handle.net/10251/150555TFG

Synovial tissue signatures enhance clinical classification and prognostic/treatment response algorithms in early inflammatory arthritis and predict requirement for subsequent biologic therapy: results from the Pathobiology of Early Arthritis Cohort (PEAC)

Objective To establish whether synovial pathobiology improves current clinical classification and prognostic algorithms in early inflammatory arthritis and identify predictors of subsequent biological therapy requirement. Methods 200 treatment-naïve patients with early arthritis were classified as fulfilling RA1987 American College of Rheumatology (ACR) criteria (RA1987) or as undifferentiated arthritis (UA) and patients with UA further classified into those fulfilling RA2010 ACR/European League Against Rheumatism (EULAR) criteria. Treatment requirements at 12 months (Conventional Synthetic Disease Modifying Antirheumatic Drugs (csDMARDs) vs biologics vs no-csDMARDs treatment) were determined. Synovial tissue was retrieved by minimally invasive, ultrasound-guided biopsy and underwent processing for immunohistochemical (IHC) and molecular characterisation. Samples were analysed for macrophage, plasma-cell and B-cells and T-cells markers, pathotype classification (lympho-myeloid, diffuse-myeloid or pauci-immune) by IHC and gene expression profiling by Nanostring. Results 128/200 patients were classified as RA1987, 25 as RA2010 and 47 as UA. Patients classified as RA1987 criteria had significantly higher levels of disease activity, histological synovitis, degree of immune cell infiltration and differential upregulation of genes involved in B and T cell activation/function compared with RA2010 or UA, which shared similar clinical and pathobiological features. At 12-month follow-up, a significantly higher proportion of patients classified as lympho-myeloid pathotype required biological therapy. Performance of a clinical prediction model for biological therapy requirement was improved by the integration of synovial pathobiological markers from 78.8% to 89%–90%. Conclusion The capacity to refine early clinical classification criteria through synovial pathobiological markers offers the potential to predict disease outcome and stratify therapeutic intervention to patients most in need

B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure.

OBJECTIVE: To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). METHODS: Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi-IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0-9) and of CD20+ B cell infiltrate (on a scale of 0-4). B cell scores were validated by digital image analysis and B cell lineage-specific transcript analysis (RNA-Seq) in the early RA (n = 91) and TNFi-IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2). RESULTS: Semiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage-specific transcripts. B cell-rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi-IR cohort (P = 0.025). B cell-rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti-citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell-rich patients were demonstrated in both cohorts. CONCLUSION: We describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell-rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Background: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. Methods: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). Findings: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). Interpretation: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. Funding: UK Medical Research Council and Versus Arthritis

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis

Diverse values of nature for sustainability

Data availability: All the data are freely available online. The supplementary information provides links to Zenodo with specific DOIs where the data are stored for free use.Supplementary information is available online at https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-023-06406-9/MediaObjects/41586_2023_6406_MOESM1_ESM.docx . The Supplementary Information includes three parts. Part A explains how the paper is associated with the IPBES Values Assessment. Part B provides details about each of the 29 review protocols. Part C offers information about the case study of Chilika Lagoon, India, that is used in the main paper.Copyright © The Author(s) 2023. Twenty-five years since foundational publications on valuing ecosystem services for human well-being1,2, addressing the global biodiversity crisis3 still implies confronting barriers to incorporating nature’s diverse values into decision-making. These barriers include powerful interests supported by current norms and legal rules such as property rights, which determine whose values and which values of nature are acted on. A better understanding of how and why nature is (under)valued is more urgent than ever4. Notwithstanding agreements to incorporate nature’s values into actions, including the Kunming-Montreal Global Biodiversity Framework (GBF)5 and the UN Sustainable Development Goals6, predominant environmental and development policies still prioritize a subset of values, particularly those linked to markets, and ignore other ways people relate to and benefit from nature7. Arguably, a ‘values crisis’ underpins the intertwined crises of biodiversity loss and climate change8, pandemic emergence9 and socio-environmental injustices10. On the basis of more than 50,000 scientific publications, policy documents and Indigenous and local knowledge sources, the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) assessed knowledge on nature’s diverse values and valuation methods to gain insights into their role in policymaking and fuller integration into decisions7,11. Applying this evidence, combinations of values-centred approaches are proposed to improve valuation and address barriers to uptake, ultimately leveraging transformative changes towards more just (that is, fair treatment of people and nature, including inter- and intragenerational equity) and sustainable futures.We received no specific funding for this work; all authors involved in IPBES do so on a voluntary basis. The IPBES Values Assessment was made possible thanks to many generous contributions, including non-earmarked contributions to the IPBES trust fund from governments. All donors are listed on the IPBES website www.ipbes.net/donors. U.P. acknowledges BC3’s Maria de Maeztu excellence accreditation 2023–2026 (reference no. CEX2021-001201-M) provided by grant no. MCIN/AEI/10.13039/501100011033

Modelització pel mètode d'elements finits de panells de fusta contralaminada (CLT) per optimitzar el seu procés de dimensionament. Aplicació a l'edifici Saggården.

[ES] L'objectiu d'aquest Treball de Fi de Màster és desenvolupar una eina digital per al càlcul de sistemes estructurals amb panells de fusta contralaminada (CLT), ja que l'Estat de l'Art està incomplet pel que fa als mètodes de dimensionament aplicables i el sector de la construcció no disposa encara de programaris de càlcul industrial suficientment desenvolupats per verificar els panells CLT a Estat Límit Últim. A més, atès el context d'urgència climàtica, l'ús de la fusta com a material estructural pren una importància en ascens, i les eines de càlcul avançades han de tenir un paper fonamental en el desenvolupament d'aquesta indústria. El projecte es centra en edificis d'alçada considerable on els càlculs estructurals esdevenen més complexos a causa dels efectes de les càrregues horitzontals, principalment degudes al vent. El treball es divideix en tres capítols principals: modelització dels panells CLT i definició dels criteris de colapse en Estat Límit Últim, implementació del model desenvolupat mitjançant el mètode dels elements finits i validació de l'eina de càlcul dissenyada i, finalment, aplicació de l'eina de càlcul a un projecte de construcció de la consultoria Degree of Freedom. A la primera part, els panells CLT es modelitzen com a elements equivalents de placa de Reissner-Mindlin monocapa homogènia que contenen les característiques de rigidesa dels panells CLT multicapa originals, definint-se, a continuació, els quocients que proporcionen els ràtios d'utilització dels elements a Estat Límit Últim. A la segona part, el mètode de modelització per rigidesa equivalent s'implementa en dos elements placa associats a panells CLT en dos models d'elements finits, i després es realitza l'anàlisi estructural i el postprocessament dels resultats per calcular els coeficients d'utilització en Estat Límit Últim a cada punt dintegració de les plaques. L'eina de càlcul desenvolupada es valida mitjançant resultats gràfics que mostren els ràtios d'utilització obtinguts per a tots dos casos. Finalment, el programari desenvolupat es fa servir per dissenyar la secció transversal de dos nuclis d'arriostrament de CLT d'un edifici de sis plantes a Noruega. L'edifici està sotmès a càrregues de vent elevades a causa de la seva situació geogràfica.Lliso I Navarro, JM. (2024). Modélisation par éléments finis de panneaux en bois lamellé-croisé (CLT) pour l'optimisation de leur processus de dimensionnement. Universitat Politècnica de València. http://hdl.handle.net/10251/21038