Bioequivalence risk assessment of oral formulations containing racemic ibuprofen through a chiral physiologically based pharmacokinetic model of ibuprofen enantiomers.

The characterization of the time course of ibuprofen enantiomers can be useful in the selection of the most sensitive analyte in bioequivalence studies. Physiologically based pharmacokinetic (PBPK) modelling and simulation represents the most efficient methodology to virtually assess bioequivalence outcomes. In this work, we aim to develop and verify a PBPK model for ibuprofen enantiomers administered as a racemic mixture with different immediate release dosage forms to anticipate bioequivalence outcomes based on different particle size distributions. A PBPK model incorporating stereoselectivity and non-linearity in plasma protein binding and metabolism as well as R-to-S unidirectional inversion has been developed in Simcyp®. A dataset composed of 11 Phase I clinical trials with 54 scenarios (27 per enantiomer) and 14,452 observations (7129 for R-ibuprofen and 7323 for S-ibuprofen) was used. Prediction errors for AUC0-t and Cmax for both enantiomers fell within the 0.8-1.25 range in 50/54 (93 %) and 42/54 (78 %) of scenarios, respectively. Outstanding model performance, with 10/10 (100 %) of Cmax and 9/10 (90 %) of AUC0-t within the 0.9-1.1 range, was demonstrated for oral suspensions, which strongly supported its use for bioequivalence risk assessment. The deterministic bioequivalence risk assessment has revealed R-ibuprofen as the most sensitive analyte to detect differences in particle size distribution for oral suspensions containing 400 mg of racemic ibuprofen, suggesting that achiral bioanalytical methods would increase type II error and declare non-bioequivalence for formulations that are bioequivalent for the eutomer.

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

International Association for the Study of Lung Cancer Study of Reproducibility in Assessment of Pathologic Response in Resected Lung Cancers After Neoadjuvant Therapy.

INTRODUCTION: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria. METHODS: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable tumor, necrosis, and stroma. For each slide, tumor bed area was measured microscopically, and pre-embedded formulas calculated unweighted and weighted major pathologic response (MPR) averages to reflect variable tumor bed proportion. RESULTS: Unanimous agreement among pathologists for MPR was observed in 68 patients (81%), and inter-rater agreement (IRA) was 0.84 (95% confidence interval [CI]: 0.76-0.92) and 0.86 (95% CI: 0.79-0.93) for unweighted and weighted averages, respectively. Overall, unweighted and weighted methods did not reveal significant differences in the classification of MPR. The highest concordance by both methods was observed for cases with more than 95% viable tumor (IRA = 0.98, 95% CI: 0.96-1) and 0% viable tumor (IRA = 0.94, 95% CI: 0.89-0.98). The most common reasons for discrepancies included interpretations of tumor bed, presence of prominent stromal inflammation, distinction between reactive and neoplastic pneumocytes, and assessment of invasive mucinous adenocarcinoma. CONCLUSIONS: Our study revealed excellent reliability in cases with no residual viable tumor and good reliability for MPR with the IASLC recommended less than or equal to 10% cutoff for viable tumor after neoadjuvant therapy.

Assessment of the potential value of plasma Torque Teno virus DNA load monitoring to predict cytomegalovirus DNAemia in patients with hematological malignancies treated with small molecule inhibitors: A proof-of-concept study.

It is unknown whether Torque Teno virus (TTV) DNA load monitoring could anticipate the development of infectious events in hematological patients undergoing treatment with small molecular targeting agents. We characterized the kinetics of plasma TTV DNA in patients treated with ibrutinib or ruxolitinib and assessed whether TTV DNA load monitoring could predict the occurrence of Cytomegalovirus (CMV) DNAemia or the magnitude of CMV-specific T-cell responses. Multicenter, retrospective, observational study, recruiting 20 patients treated with ibrutinib and 21 with ruxolitinib. Plasma TTV and CMV DNA loads were quantified by real-time PCR at baseline and days +15, +30, +45, +60, +75, +90, +120, +150, and +180 after treatment inception. Enumeration of CMV-specific interferon-γ (IFN-γ)-producing CD8+ and CD4+ T-cells in whole blood was performed by flow cytometry. Median TTV DNA load in ibrutinib-treated patients increased significantly (p = 0.025) from baseline (median: 5.76 log10 copies/mL) to day +120 (median: 7.83 log10 copies/mL). A moderate inverse correlation (Rho = -0.46; p < 0.001) was found between TTV DNA load and absolute lymphocyte count. In ruxolitinib-treated patients, TTV DNA load quantified at baseline was not significantly different from that measured after treatment inception (p ≥ 0.12). TTV DNA load was not predictive of the subsequent occurrence of CMV DNAemia in either patient group. No correlation was observed between TTV DNA loads and CMV-specific IFN-γ-producing CD8+ and CD4+ T-cell counts in either patient group. The data did not support the hypothesis that TTV DNA load monitoring in hematological patients treated with ibrutinib or ruxolitinib could be useful to predict either the occurrence of CMV DNAemia or the level of CMV-specific T-cell reconstitution; nevertheless, due to the small sample size, further studies involving larger cohorts are warranted to elucidate this issue.

Reflexiones de las 4 funciones de enfermería e impactos en América Latina / Reflections on the 4 nursing functions and impacts in Latin America / Reflexões sobre as 4 funções e impactos da enfermagem na América Latina

La enfermería reconocida como disciplina profesional cuenta con conocimientos dirigidos al cuidado de la vida humana, su desarrollo la ha diferenciado de otras disciplinas dándole visibilidad particular desde cuatro funciones: gestión, enseñanza, investigación y atención clínica. Para lo cual se generó una reflexión sobre los impactos positivos y negativos del evolucionar de enfermería en América Latina ante estas funciones, desde la gestión se evidencia avances importantes desde el liderazgo gremial y organizacional, pero retrocesos en el escalamiento político, e institucional. Existe brecha de la formación profesional en comparación a otras regiones, aun así, el crecimiento de programas educativos ha dado la posibilidad de la profesionalización, pero debate el reto de la calidad, la disparidad formativa y la oferta centrada en el paradigma clínico. En el campo investigativo se resalta la creación de programas doctorales y post graduales que amplían la generación de conocimiento, pero también se evidencian barreras en la transferencia y visibilidad colectiva del conocimiento. En el área clínica espacio con mayor abordaje de las acciones formativas y laborales del profesional, cuenta con grandes retos en su crecimiento, organización, escalamiento, seguridad y precariedad laboral. En esa perspectiva la comunidad U-Nursing LatAm se ha integrado para aportar a la región en estos retos. Finalmente se concluye que la mayoría de los desafíos son relacionados con las habilidades sociales y blandas que deben potencializarse en el plano personal y colectivo. Todas las situaciones requieren tener una valoración directa de las posibilidades de fortalecer y mejorar la enfermería desde cada país de la región, teniendo en cuenta las cuatro funciones.

Structural assessment of pre-flexion in silicone implants for arthroplasty of the first metatarsophalangeal joint.

The development of numerical models to analyze pathologies and implants related to the first metatarsophalangeal joint of the foot remains an issue for attention. The structural effects of implants pre-flexion have been discarded in several finite elements analyses due to complexities to achieve these positions. This work aims to evaluate if the pre-flexion stress state should be included or could be discarded when only flexion is applied in two different silicone commercial implants, Swanson and Tornier, during a gait cycle. Finite element models were created for silicone implants. Both models were discretized using high-order finite elements. The hyperelasticity constitutive material model of Arruda-Boyce was used, based on experimental data; its behavior was compared with linear elastic models reported and used frequently assuming small and large deformations and applying to the Swanson and Tornier implants a flexion angle of 64°, which corresponds to in vivo measurements reported after implantation. Comparison between models, regarding hyperelastic model, showed mean variations of up to 32.5% for stresses and 14.01% for bending moment in Swanson implant, while for Tornier implant mean variations of 29.73% and 632.55% was obtained for stress and bending moment respectively. The maximum stress value obtained for the hyperelastic model in the Swanson implant reached a value of 22.82% of the tensile strength of the implant material while in the Tornier implant reached a value of 25.92%, the above values were evaluated at a flexion angle of 64°. The results suggest considering in finite element analyses not only the stress state generated to achieve critical flexion position in pleflexed implants models but also the hyperelastic material behavior of silicone for implants to avoid dismissing the non-linear structural behavior of hyperelastic materials.

The economic burden of newly diagnosed epilepsy in Spain.

OBJECTIVE: The aim of this study was to determine the hospital burden and economic impact of epilepsy in adults in Spain and identify characteristics associated with higher direct medical costs. METHOD: Patients newly diagnosed with epilepsy at the outpatient epilepsy unit of a tertiary hospital in Spain in 2012 were included. Sociodemographic and clinical data and use of health resources were collected retrospectively from electronic medical records from the time of diagnosis to the end of follow-up (2019). Direct costs (in 2012 Euro) were estimated and linear regression models built to explore predictors of higher costs. RESULTS: We studied 110 patients with newly diagnosed epilepsy. Their mean (SD) age was 52.6 (19.6) years and 53.6% were men. Eighty-nine patients (80.9%) had focal epilepsy and 45 (40.9%) had an unknown etiology. At 6 months, 79.1% of patients were classified as responders and 17.6% as having drug-resistant epilepsy. The mean direct cost in the first year of epilepsy diagnosis was €3816.06, 49.7% of which was due to hospital admissions. The mean annual cost per patient was €2584.17, 51.4% of which was due to anti-seizure medications (ASMs). Focal epilepsy and poor response in the first 6 months of treatment predicted higher annual costs, while focal epilepsy and pre-existing comorbidities predicted higher costs in the first year. CONCLUSIONS: The direct cost of newly diagnosed epilepsy in adults in our area is €2584 per patient/year. Anti-seizure medication use is the main cost driver. Focal epilepsy, comorbidities, and poor response to ASMs are independent predictors of higher costs.

Patients and general practitioners assessment of the main outcomes employed in the acute and preventive treatment of migraine: a cross sectional study.

BACKGROUND: We aim to describe and compare patients and general practitioners' opinions about the different variables related to acute and preventive treatment for migraine. PATIENTS AND METHODS: An observational descriptive study was performed. Patients with episodic migraine and general practitioners, from our healthcare area, were invited to answer a survey about the different variables related to migraine treatment. They were asked for their opinions on the different variables, and to consider the desired efficacy in percentage terms and the desired action times of treatment. RESULTS: Fifty-five patients and fifty-five general practitioners were selected. Effectiveness was considered the most important variable for symptomatic and preventive treatment. Cost was considered the least important variable. Patients desired percentage of efficacy was 84.0% (±16.7%) for symptomatic treatment and 79.9% (±17.1%) for preventive treatment. General practitioners desired percentage of efficacy was 75.0% (±14.0) for symptomatic treatment and 70.4% (±14.3) for preventive treatment. For symptomatic treatment the desired action time for pain cessation was selected as 27.5 min (±13.8) for patients and 24.0 min (±18.3) for GPs. For preventive treatment the desired action time for effect was 7.1 days (±4.5) for patients and 13.9 days (±8.9) for general practitioners. CONCLUSION: The most important endpoints were, for acute: effectiveness, a short action time and a persistent effect. For prophylactic: effectiveness, sustained effect and tolerability. Both patients and general practitioners agreed on the most and least preferred endpoints. Desired percentage of efficacy was above 75% for both symptomatic and preventive treatment; and the desired action time was below 30 min for acute treatment and 2 weeks for preventive treatment.

Monte Carlo simulation of the effect of magnetic fields on brachytherapy dose distributions in lung tissue material.

The aim of this work was to use TOPAS Monte Carlo simulations to model the effect of magnetic fields on dose distributions in brachytherapy lung treatments, under ideal and clinical conditions. Idealistic studies were modeled consisting of either a monoenergetic electron source of 432 keV, or a polyenergetic electron source using the spectrum of secondary electrons produced by 192Ir gamma-ray irradiation. The electron source was positioned in the center of a homogeneous, lung tissue phantom (ρ = 0.26 g/cm3). Conversely, the clinical study was simulated using the VariSource VS2000 192Ir source in a patient with a lung tumor. Three contoured volumes were considered: the tumor, the planning tumor volume (PTV), and the lung. In all studies, dose distributions were calculated in the presence or absence of a constant magnetic field of 3T. Also, TG-43 parameters were calculated for the VariSource and compared with published data from EGS-brachy (EGSnrc) and PENELOPE. The magnetic field affected the dose distributions in the idealistic studies. For the monoenergetic and poly-energetic studies, the radial distance of the 10% iso-dose line was reduced in the presence of the magnetic field by 64.9% and 24.6%, respectively. For the clinical study, the magnetic field caused differences of 10% on average in the patient dose distributions. Nevertheless, differences in dose-volume histograms were below 2%. Finally, for TG-43 parameters, the dose-rate constant from TOPAS differed by 0.09% ± 0.33% and 0.18% ± 0.33% with respect to EGS-brachy and PENELOPE, respectively. The geometry and anisotropy functions differed within 1.2% ± 1.1%, and within 0.0% ± 0.3%, respectively. The Lorentz forces inside a 3T magnetic resonance machine during 192Ir brachytherapy treatment of the lung are not large enough to affect the tumor dose distributions significantly, as expected. Nevertheless, large local differences were found in the lung tissue. Applications of this effect are therefore limited by the fact that meaningful differences appeared only in regions containing air, which is not abundant inside the human.

Beam characterisation studies of the 62 MeV proton therapy beamline at the Clatterbridge Cancer Centre.

The Clatterbridge Cancer Centre (CCC) in the United Kingdom is the world's first hospital proton beam therapy facility, providing treatment for ocular cancers since 1989. A 62 MeV beam of protons is produced by a Scanditronix cyclotron and transported through a passive delivery system. In addition to the long history of clinical use, the facility supports a wide programme of experimental work and as such, an accurate and reliable simulation model of the treatment beamline is highly valuable. However, as the facility has seen several changes to the accelerator and beamline over the years, a comprehensive study of the CCC beam dynamics is needed to firstly examine the beam optics. An extensive analysis was required to overcome facility related constraints to determine fundamental beamline parameters and define an optical lattice written with the Methodical Accelerator Design (MAD-X) and the particle tracking Beam Delivery Simulation (BDSIM) code. An optimised case is presented and simulated results of the optical functions, beam distribution, losses and the transverse rms beam sizes along the beamline are discussed. Corresponding optical and beam information was used in TOPAS to simulate transverse beam profiles and compared to EBT3 film measurements. We provide an overview of the magnetic components, beam transport, cyclotron, beam and treatment related parameters necessary for the development of a present day optical model of the facility. This work represents the first comprehensive study of the CCC facility to date, as a basis to determine input beam parameters to accurately simulate and completely characterise the beamline.

Development of a bioeconomy monitoring framework for the European Union: An integrative and collaborative approach.

The EU Bioeconomy Strategy, updated in 2018, in its Action Plan pledges an EU-wide, internationally coherent monitoring system to track economic, environmental and social progress towards a sustainable bioeconomy. This paper presents the approach taken by the European Commission's (EC) Joint Research Centre (JRC) to develop such a system. To accomplish this, we capitalise on (1) the experiences of existing indicator frameworks; (2) stakeholder knowledge and expectations; and (3) national experiences and expertise. This approach is taken to ensure coherence with other bioeconomy-related European monitoring frameworks, the usefulness for decision-making and consistency with national and international initiatives to monitor the bioeconomy. We develop a conceptual framework, based on the definition of a sustainable bioeconomy as stated in the Strategy, for a holistic analysis of the trends in the bioeconomy sectors, following the three pillars of sustainability (economy, society and environment). From this conceptual framework, we derive an implementation framework that aims to highlight the synergies and trade-offs across the five objectives of the Bioeconomy Strategy in a coherent way. The EU Bioeconomy Monitoring System will be publicly available on the web platform of the EC Knowledge Centre for Bioeconomy.

Preconditioning with levosimendan reduces postoperative low cardiac output in moderate-severe systolic dysfunction patients who will undergo elective coronary artery bypass graft surgery: a cost-effective strategy.

BACKGROUND: Patients with moderate-severe systolic dysfunction undergoing coronary artery bypass graft have a higher incidence of postoperative low cardiac output. Preconditioning with levosimendan may be a useful strategy to prevent this complication. In this context, design cost-effective strategies like preconditioning with levosimendan may become necessary. METHODS: In a sequential assignment of patients with Left Ventricle Ejection Fraction less than 40%, two strategies were compared in terms of cost-effectiveness: standard care (n = 41) versus preconditioning with Levosimendan (n = 13). The adverse effects studied included: postoperative new-onset atrial fibrillation, low cardiac output, renal failure and prolonged mechanical ventilation. The costs were evaluated using deterministic and probabilistic sensitivity analysis, and Monte Carlo simulations were performed. RESULTS: Preconditioning with levosimendan in moderate to severe systolic dysfunction (Left Ventricle Ejection Fraction < 40%), was associated with a lower incidence of postoperative low cardiac output in elective coronary artery bypass graft surgery 2(15.4%) vs 25(61%) (P < 0.01) and lesser intensive care unit length of stay 2(1-4) vs 4(3-6) days (P = 0.03). Average cost on levosimendan group was 14,792€ while the average cost per patient without levosimendan was 17,007€. Patients with no complications represented 53.8% of the total in the levosimendan arm, as compared to 31.7% in the non-levosimendan arm. In all Montecarlo simulations for sensitivity analysis, use of levosimendan was less expensive and more effective. CONCLUSIONS: Preconditioning with levosimendan, is a cost-effective strategy preventing postoperative low cardiac output in patients with moderate-severe left ventricular systolic dysfunction undergoing elective coronary artery bypass graft surgery.

Preparation of a radiobiology beam line at the 18 MeV proton cyclotron facility at CNA.

Proton therapy has gained interest in recent years due to its excellent clinical outcomes. However, the lack of accurate biological data, especially in the Bragg peak region of clinical beams, makes it difficult to implement biophysically optimized treatment plans in clinical practice. In this context, low energy proton accelerator facilities provide the perfect environment to collect good radiobiological data, as they can produce high LET beams with narrow energy distributions. This study presents the radiobiology beam line that has been designed at the 18 MeV proton cyclotron facility at the National Centre of Accelerators (CNA, Seville, Spain), to perform irradiations of mono-layer cell cultures. To ensure that all the cells receive the same dose with a suitable dose rate, low beam intensities and broad and homogeneous beam profiles are necessary. To do so, at the CNA an unfocused beam has been used, broadened with a 500 µm thick aluminium scattering foil. Homogeneous dose profiles, with deviations lower than 10% have been obtained over a circular surface of 35 mm diameter for an incident average energy of 12.8 MeV. Further, a Monte Carlo simulation of the beam line has been developed with Geant4, and benchmarked towards experimental measurements, with differences generally below 1%. Once validated, the code has been used, together with an ionization chamber, for dosimetry studies, to characterize the beam and monitor the dose. Finally, cultures of Human Bone Osteosarcoma cells (U2OS) have been successfully irradiated at the radiobiology beam line, investigating the effects of radiation in terms of DNA damage induction.

The Neighborhood as a Unit of Change for Health: Early Findings from the East Harlem Neighborhood Health Action Center.

Place-based approaches have been promoted as one way to reduce health inequities by addressing community-level factors that shape health, such as housing quality, healthcare systems, the built environment, and social capital. In 2016-2017, the NYC Health Department's Center for Health Equity launched three Neighborhood Health Action Centers (Action Centers), which use a place-based approach to improve health in neighborhoods with disproportionate burdens of premature mortality. We describe this approach and the genesis of the Action Centers. We then describe the East Harlem Action Center, which was the first to open, and share findings from qualitative interviews with the East Harlem Action Center's Governance Council, a group comprised of Action Center staff and co-located partners and programs which supports Action Center coordination. Interviewees felt that collaboration, being responsive to community needs, and being community based were essential elements of the Action Center. Interviewees recognized the complex dynamic of a large city agency serving as the host for the Action Center while simultaneously aiming to establish more equitable relationships with partners. Governance Council members' expectations and hopes for the East Harlem Action Center were consistent with the overall vision and model for the Action Centers, which may facilitate implementation.

Comparison and cost analysis of three protocols for mobilization and apheresis of haematopoietic progenitor cells.

INTRODUCTION: Autologous bone marrow transplantation is a component of the malignant hemopathy therapy. The preferred mobilization and collection method is apheresis. The aim of this study is to compare three protocols analyzing the effect of plerixafor, higher dose of G-CSF and large volume leukapheresis (LVL). MATERIALS AND METHODS: A retrospective cohort study including 119 patients referred for mobilization. Three protocols were compared: (a) G-CSF 10 µg/kg/day subcutaneous (sc) × 4 days mobilizing 1 to 1.5 blood volumes. (b) G-CSF 10 µg/kg/day sc × 4 days + plerixafor 0.24 mg/kg/day sc preventively or as a rescue agent mobilizing 1 to 1.5 blood volumes. (c) G-CSF 20 µg/kg/day sc × 4 days ± plerixafor 0.24 mg/kg/day sc preventively or as a rescue agent mobilizing 3 to 4 blood volumes. RESULTS: The average number of days of apheresis was reduced to 1.37 with protocol 3. The average cost per patient was reduced by 67% compared with protocol 2 and increased by only 5% compared with protocol 1, reducing the failure rate to 0%. CONCLUSION: Adding preemptive or rescue plerixafor (protocol 2) to G-CSF 10 µg/kg/day alone (protocol 1) did not improve the days of apheresis nor the number of CD34+ cells collected but had higher cost and failure rate. Using LVL, plerixafor and G-CSF 20 µg/kg/day (protocol 3) decreased the number of sessions to 1.37, reduced the failure rate to 0% and led to a significant increase in the number of CD34+ cells collected without toxicity and with a similar cost to protocol 1.

Ecosystem-based management planning across aquatic realms at the Ria de Aveiro Natura 2000 territory.

Ria de Aveiro represents a coastal territory, in which its natural capital, mostly classified under a Natura 2000 network of protected areas, is of paramount importance for the regional and national economy, supporting harbour activities and maritime traffic, agriculture, commercial fisheries, aquaculture, manufacturing, tourism, sports and recreational activities. Current and foreseen changes connected to human activities, namely land and water uses and potential conflicts, in frame of environmental policies, sustainable economic development and human well-being require the implementation of ecosystem-based management (EBM) planning processes considering the connectivity across marine, transitional, freshwater, and terrestrial domains. The main objective is to elaborate on the co-development of the EBM planning process across the three water domains, all characterized by high biodiversity and by the wide range of services provided by ecosystems and their abiotic components, for the mitigation of impacts from the management plan under implementation. The approach used follows a stepwise procedure in frame of resilience principles, considering the analysis of the relationship between the social and ecological components and on how these can be connected through risk assessment and a spatial multi-criteria analysis based on the delivery of ecosystem services. Stakeholders' perception matched the ecosystem services provisioning risk assessment and supported the planning EBM response that consist in saltmarshes and seagrasses meadows restoration programs. Compliance of the proposed measures is achievable regarding policies (policy targets and policy instruments) and feasibility (scientific and technological knowledge and financial resources). The EBM response can support the Vouga estuary management plan and regional smart specialization (RIS3 Centro).

Social equity shapes zone-selection: Balancing aquatic biodiversity conservation and ecosystem services delivery in the transboundary Danube River Basin.

Freshwater biodiversity is declining, despite national and international efforts to manage and protect freshwater ecosystems. Ecosystem-based management (EBM) has been proposed as an approach that could more efficiently and adaptively balance ecological and societal needs. However, this raises the question of how social and ecological objectives can be included in an integrated management plan. Here, we present a generic model-coupling framework tailored to address this question for freshwater ecosystems, using three components: biodiversity, ecosystem services (ESS), and a spatial prioritisation that aims to balance the spatial representation of biodiversity and ESS supply and demand. We illustrate this model-coupling approach within the Danube River Basin using the spatially explicit, potential distribution of (i) 85 fish species as a surrogate for biodiversity as modelled using hierarchical Bayesian models, and (ii) four estimated ESS layers produced by the Artificial Intelligence for Ecosystem Services (ARIES) platform (with ESS supply defined as carbon storage and flood regulation, and demand specified as recreation and water use). These are then used for (iii) a joint spatial prioritisation of biodiversity and ESS employing Marxan with Zones, laying out the spatial representation of multiple management zones. Given the transboundary setting of the Danube River Basin, we also run comparative analyses including the country-level purchasing power parity (PPP)-adjusted gross domestic product (GDP) and each country's percent cover of the total basin area as potential cost factors, illustrating a scheme for balancing the share of establishing specific zones among countries. We demonstrate how emphasizing various biodiversity or ESS targets in an EBM model-coupling framework can be used to cost-effectively test various spatially explicit management options across a multi-national case study. We further discuss possible limitations, future developments, and requirements for effectively managing a balance between biodiversity and ESS supply and demand in freshwater ecosystems.

Cost-effective restoration and conservation planning in Green and Blue Infrastructure designs. A case study on the Intercontinental Biosphere Reserve of the Mediterranean: Andalusia (Spain) - Morocco.

Green and Blue Infrastructure (GBI) is a network designed and planned to deliver a wide range of ecosystem services and to protect biodiversity. Existing GBI designs lacked a systematic method to allocate restoration zones. This study proposes a novel approach for systematically selecting cost-effective areas for restoration on the basis of biodiversity, ecosystem services, and ecosystem condition to give an optimal spatial design of GBI. The approach was tested at a regional scale, in a transboundary setting encompassing the Intercontinental Biosphere Reserve of the Mediterranean in Andalusia (Spain) - Morocco (IBRM), across three aquatic ecosystems: freshwater, coastal and marine. We applied Marxan with Zones to stakeholder-defined scenarios of GBI in the IBRM. Specifically, we aimed to identify management zones within the GBl that addressed different conservation, restoration and exploitation objectives. Although almost all conservation targets were achieved, our results highlighted that the proportion of conservation features (i.e., biodiversity, ecosystem services) that would be compromised in the GBl, and the proportion of provisioning services that would be lost due to conservation (i.e., incidental representation) are potentially large, indicating that the probability of conflicts between conservation and exploitation goals in the area is high. The implementation of restoration zones improved connectivity across the GBI, and also achieved European and global policy targets. Our approach may help guide future applications of GBI to implement the flexible conservation management that aquatic environments require, considering many areas at different spatial scales, across multiple ecosystems, and in transboundary contexts.

Cardiovascular risk assessment in prediabetic patients in a hypertensive population: The role of cystatin C.

BACKGROUND: The aim of our study was to determine whether prediabetes increases cardiovascular (CV) risk compared to the non-prediabetic patients in our hypertensive population. Once this was achieved, the objective was to identify relevant CV prognostic features among prediabetic individuals. METHODS: We included hypertensive 1652 patients. The primary outcome was a composite of incident CV events: cardiovascular death, stroke, heart failure and myocardial infarction. We performed a Cox proportional hazard regression to assess the CV risk of prediabetic patients compared to non-prediabetic and to produce a survival model in the prediabetic cohort. RESULTS: The risk of developing a CV event was higher in the prediabetic cohort than in the non-prediabetic cohort, with a hazard ratio (HR) = 1.61, 95% CI 1.01-2.54, p = 0.04. Our Cox proportional hazard model selected age (HR = 1.04, 95% CI 1.02-1.07, p < 0.001) and cystatin C (HR = 2.4, 95% CI 1.26-4.22, p = 0.01) as the most relevant prognostic features in our prediabetic patients. CONCLUSIONS: Prediabetes was associated with an increased risk of CV events, when compared with the non-prediabetic patients. Age and cystatin C were found as significant risk factors for CV events in the prediabetic cohort.

Global Geriatric Assessment and In-Hospital Bleeding Risk in Elderly Patients with Acute Coronary Syndromes: Insights from the LONGEVO-SCA Registry.

BACKGROUND: Bleeding risk scores have shown a limited predictive ability in elderly patients with acute coronary syndromes (ACS). No study explored the role of a comprehensive geriatric assessment to predict in-hospital bleeding in this clinical setting. METHODS: The prospective multicentre LONGEVO-SCA registry included 532 unselected patients with non-ST segment elevation ACS (NSTEACS) aged 80 years or older. Comorbidity (Charlson index), frailty (FRAIL scale), disability (Barthel index and Lawton-Brody index), cognitive status (Pfeiffer test) and nutritional risk (mini nutritional assessment-short form test) were assessed during hospitalization. CRUSADE score was prospectively calculated for each patient. In-hospital major bleeding was defined by the CRUSADE classification. The association between geriatric syndromes and in-hospital major bleeding was assessed by logistic regression method and the area under the receiver operating characteristic curves (AUC). RESULTS: Mean age was 84.3 years (SD 4.1), 61.7% male. Most patients had increased troponin levels (84%). Mean CRUSADE bleeding score was 41 (SD 13). A total of 416 patients (78%) underwent an invasive strategy, and major bleeding was observed in 37 cases (7%). The ability of the CRUSADE score for predicting major bleeding was modest (AUC 0.64). From all aging-related variables, only comorbidity (Charlson index) was independently associated with major bleeding (per point, odds ratio: 1.23, p = 0.021). The addition of comorbidity to CRUSADE score slightly improved the ability for predicting major bleeding (AUC: 0.68). CONCLUSION: Comorbidity was associated with major bleeding in very elderly patients with NSTEACS. The contribution of frailty, disability or nutritional risk for predicting in-hospital major bleeding was marginal.