Atorvastatin-Eluting Contact Lenses: Effects of Molecular Imprinting and Sterilization on Drug Loading and Release

Statins are receiving increasing attention in the ophthalmic field. Their activity as 3-hydroxy-3-methylglutaryl–CoA (HMG–CoA) reductase inhibitors is clinically used to regulate cholesterol levels and leads to pleiotropic effects, which may help in the management of diabetes-related ocular pathologies. This work aims to design bioinspired contact lenses (CLs) with an affinity for atorvastatin by mimicking the active site of HMG–CoA reductase. Sets of imprinted and nonimprinted 2-hydroxyethyl methacrylate (HEMA) hydrogels were synthesized, varying the contents in functional monomers that bear chemical groups that resemble those present in HMG–CoA reductase, namely, ethylene glycol phenyl ether methacrylate (EGPEM), 2-aminoethyl methacrylate hydrochloride (AEMA), and N-(3-aminopropyl) methacrylamide hydrochloride (APMA). The hydrogels were characterized in terms of suitability as CLs (solvent uptake, light transmission, mechanical properties, and biocompatibility) and capability to load and release atorvastatin. Three sterilization protocols (steam heat, gamma radiation, and high hydrostatic pressure) were implemented and their effects on hydrogel properties were evaluated. Copolymerization of AEMA and, particularly, APMA endowed the hydrogels with a high affinity for atorvastatin (up to 11 mg/g; KN/W > 200). Only high hydrostatic pressure sterilization preserved atorvastatin stability and hydrogel performance. Permeability studies through the porcine cornea and sclera tissues revealed that the amount of atorvastatin accumulated in the cornea and sclera could be effective to treat ocular surface diseasesThis project is funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions grant agreement N° 813440 (ORBITAL–Ocular Research by Integrated Training and Learning). The work was also partially supported by MINECO [SAF2017-83118-R], Agencia Estatal de Investigación (AEI) Spain, Xunta de Galicia [ED431C 2020/17], FEDER and by Fundação para a Ciência e a Tecnologia (FCT, Portugal) [UIDB/00100/2020]. M. Vivero-Lopez acknowledges Xunta de Galicia (Consellería de Cultura, Educación e Ordenación Universitaria) for a predoctoral research fellowship [ED481A-2019/120]S

In vitro–in vivo correlation of drug release profiles from medicated contact lenses using an in vitro eye blink model

There is still a paucity of information on how in vitro release profiles from drug-loaded contact lenses (CLs) recorded in 3D printed eye models correlate with in vivo profiles. This work aims to evaluate the release profiles of two drug-loaded CLs in a 3D in vitro eye blink model and compare the obtained results with the release in a vial and the drug levels in tear fluid previously obtained from an animal in vivo study. In vitro release in the eye model was tested at two different flow rates (5 and 10 µL/min) and a blink speed of 1 blink/10 s. Model CLs were loaded with two different drugs, hydrophilic pravastatin and hydrophobic resveratrol. The release of both drugs was more sustained and lower in the 3D eye model compared to the in vitro release in vials. Interestingly, both drugs presented similar release patterns in the eye model and in vivo, although the total amount of drugs released in the eye model was significantly lower, especially for resveratrol. Strong correlations between percentages of pravastatin released in the eye model and in vivo were found. These findings suggest that the current 3D printed eye blink model could be a useful tool to measure the release of ophthalmic drugs from medicated CLs. Nevertheless, physiological parameters such as the composition of the tear fluid and eyeball surface, tear flow rates, and temperature should be optimized in further studiesOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This project was funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Actions grant agreement N° 813440 (ORBITAL–Ocular Research by Integrated Training And Learning). The work was also partially supported by MCIN [PID 2020-113881RB-I00/AEI/10.13039/501100011033], Spain, Xunta de Galicia [ED431C 2020/17], FEDER, and the Hong Kong Special Administrative Region Government and InnoHK. M. Vivero-Lopez acknowledges Xunta de Galicia (Consellería de Cultura, Educación e Ordenación Universitaria) for a predoctoral research fellowship [ED481A-2019/120]. P. Garg acknowledges the support of the Collaborative Research and Training Experience (CREATE) Program awarded by the Natural Sciences and Engineering Research Council of Canada (NSERC)S

Phosphorylcholine-Based Contact Lenses for Sustained Release of Resveratrol: Design, Antioxidant and Antimicrobial Performances, and In Vivo Behavior

Design of advanced contact lenses (CLs) demands materials that are safe and comfortable for the wearers and that preserve the normal eye microbiota, avoiding chronic inflammation and biofilm development. This work aimed to combine the natural antibiofouling phosphorylcholine and the antioxidant and prebiotic resveratrol as integral components of CLs that may have the additional performance of preventing oxidative-stress related eye diseases. Different from previous uses of 2-methacryloyloxyethyl phosphorylcholine (MPC) as coating, we explored the feasibility of adding MPC at high proportions as a comonomer of 2-hydroxyethyl methacrylate (HEMA)-based hydrogels while still allowing for the loading of the hydrophobic resveratrol. Homogeneous distribution of MPC along the hydrogel depth (confirmed by Raman spectroscopy) notably increased solvent uptake and the proportion of free water while it decreased Young’s modulus. Relevantly, MPC did not hinder the uptake of resveratrol by CLs (>10 mg/g), which indeed showed network/water partition coefficients of >100. Protocols for CLs sterilization and loading of resveratrol under aseptic conditions were implemented, and the effects of tear proteins on resveratrol release rate were investigated. CLs sustained resveratrol release for more than 24 h in vitro, and sorption of albumin onto the hydrogel, although attenuated by MPC, slowed down the release. The combination of MPC and resveratrol reduced P. aeruginosa and S. aureus growth as tested in a novel hydrogel disk-agar interface biofilm growth setup. The developed CLs showed excellent anti-inflammatory properties and biocompatibility in in ovo and rabbit tests and provided higher and more prolonged levels of resveratrol in tear fluid, which favored resveratrol biodistribution in anterior and posterior eye segments compared to eye drops. Correlations between the release profiles of resveratrol in vitro and in vivo were assessed. Relevantly, the CLs preserved the antioxidant properties of resveratrol during the entire 8 h of wearing. In sum, CLs prepared with high proportion in MPC may help address safety and comfort requirements while having drug releasing capabilitiesThe authors are grateful to Mabel Loza and Cristina Val García, from BioFarma Research Group (USC GI-1685), for their help in the UPLC experiment, and to Luis Díaz-Gómez for advice in the anti-inflammatory tests. M.V.-L. acknowledges Xunta de Galicia (Consellería de Cultura, Educación e Ordenación Universitaria) for a predoctoral research fellowship [Grant ED481A-2019/120]. A.F.P.-d.-M. is an ESR of the European Union’s Horizon 2020 research and innovation program under Marie Skłodowska-Curie Actions Grant Agreement 813440 (ORBITAL-Ocular Research by Integrated Training and Learning)S

Los paisajes agrarios de la romanización en el Suroeste peninsular: balance de los últimos trabajos desarrollados desde el Instituto de Arqueología

Trabajo presentado al VI Encuentro de Arqueología del Suroeste Peninsular, celebrado en Villafranca de los Barros (Badajoz) del 4 al 6 de octubre de 2012.[ES]: El propósito de este trabajo es ofrecer una visión de síntesis sobre la labor que ha supuesto en los últimos años desde el Instituto de Arqueología la investigación sobre el fenómeno de los recintos ciclópeos de La Serena (Badajoz) y el impacto de la conquista romana en las formas de ordenación de los espacios agrarios del Suroeste peninsular. Se realiza una breve revisión de las claves de este problema histórico y de los antecedentes del trabajo presente. A continuación se exponen las diferentes líneas metodológicas desarrolladas, ofreciendo una síntesis de los conocimientos obtenidos. Finalmente se proponen algunos temas prioritarios para el desarrollo futuro de la investigación.[EN]: The aim of this paper is to give an overview of the recent activity in the Merida Institute of Archaeology regarding the study of the so called “cyclopean enclosures” of the Serena Region (Badajoz) and the impact of the Roman conquest in the agrarian landscapes of the Peninsular South-West. We make a brief review of some clues of this historical process and provide some background to understand more recent research. We will show the methodological threads we have developed, and a concise account of their main results. Finally, we suggest some key issues for future research.Los resultados mostrados en este trabajo han sido posibles gracias al soporte del Ministerio de Ciencia e Innovación a través de los proyectos del Plan Nacional “Paisaje, territorio y cambio social en el suroeste peninsular: De la protohistoria al mundo romano (HAR 20081973)” cuyo investigador responsable es Victorino Mayoral Herrera, y “Entre el Atlántico y el Mediterráneo: contraste de dinámicas en la evolución histórica del paisaje en el occidente peninsular a través de la Arqueología” (HAR 2009-10666) cuyo investigador responsable es Sebastián Celestino Pérez.Peer Reviewe

Optimization of NIR Spectral Data Management for Quality Control of Grape Bunches during On-Vine Ripening

NIR spectroscopy was used as a non-destructive technique for the assessment of chemical changes in the main internal quality properties of wine grapes (Vitis vinifera L.) during on-vine ripening and at harvest. A total of 363 samples from 25 white and red grape varieties were used to construct quality-prediction models based on reference data and on NIR spectral data obtained using a commercially-available diode-array spectrophotometer (380–1,700 nm). The feasibility of testing bunches of intact grapes was investigated and compared with the more traditional must-based method. Two regression approaches (MPLS and LOCAL algorithms) were tested for the quantification of changes in soluble solid content (SSC), reducing sugar content, pH-value, titratable acidity, tartaric acid, malic acid and potassium content. Cross-validation results indicated that NIRS technology provided excellent precision for sugar-related parameters (r2 = 0.94 for SSC and reducing sugar content) and good precision for acidity-related parameters (r2 ranging between 0.73 and 0.87) for the bunch-analysis mode assayed using MPLS regression. At validation level, comparison of LOCAL and MPLS algorithms showed that the non-linear strategy improved the predictive capacity of the models for all study parameters, with particularly good results for acidity-related parameters and potassium content

Effectiveness of a cognitive behavioral intervention in patients with medically unexplained symptoms: cluster randomized trial

BACKGROUND: Medically unexplained symptoms are an important mental health problem in primary care and generate a high cost in health services.Cognitive behavioral therapy and psychodynamic therapy have proven effective in these patients. However, there are few studies on the effectiveness of psychosocial interventions by primary health care. The project aims to determine whether a cognitive-behavioral group intervention in patients with medically unexplained symptoms, is more effective than routine clinical practice to improve the quality of life measured by the SF-12 questionary at 12 month. METHODS/DESIGN: This study involves a community based cluster randomized trial in primary healthcare centres in Madrid (Spain). The number of patients required is 242 (121 in each arm), all between 18 and 65 of age with medically unexplained symptoms that had seeked medical attention in primary care at least 10 times during the previous year. The main outcome variable is the quality of life measured by the SF-12 questionnaire on Mental Healthcare. Secondary outcome variables include number of consultations, number of drug (prescriptions) and number of days of sick leave together with other prognosis and descriptive variables. Main effectiveness will be analyzed by comparing the percentage of patients that improve at least 4 points on the SF-12 questionnaire between intervention and control groups at 12 months. All statistical tests will be performed with intention to treat. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in this analysis. DISCUSSION: This study aims to provide more insight to address medically unexplained symptoms, highly prevalent in primary care, from a quantitative methodology. It involves intervention group conducted by previously trained nursing staff to diminish the progression to the chronicity of the symptoms, improve quality of life, and reduce frequency of medical consultations. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, number NCT01484223 [http://ClinicalTrials.gov].S

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Caracterización y procedencia de los materiales geológicos utilizados en el teatro y anfiteatro de la ciudad de Mérida en época romana

Hoy en día existe la necesidad de mantener los edificios y monumentos, que forman parte del Patrimonio de la Humanidad, mediante la realización de intervenciones de restauración, muchas de ellas, con materiales diferentes a los originalmente empleados. Estos materiales, en muchas ocasiones, son incompatibles con los materiales originales utilizados en su construcción. Debemos tener en cuenta que las intervenciones de conservación de estos edificios históricos, debe realizarse de forma respetuosa, de forma que no se alteren ni la distribución ni el aspecto del edificio. Una de las formas de conseguir este objetivo es la utilización de materiales que presenten características petrofísicas y geoquímicas similares a las de los materiales originales. Esto se consigue mediante la localización de las canteras originales o de afloramientos pertenecientes a la misma formación geológica, para su posible uso en posibles casos de sustitución. Para poder localizar estas canteras es preciso utilizar una metodología basada en el conocimiento de las características petrológicas de sus materiales y en un conocimiento geológico de zona, además del conocimiento histórico y artístico de la obra. En el caso del teatro y anfiteatro romanos de Mérida, pertenecientes al Conjunto Arqueológico de Mérida, declarado Patrimonio de la Humanidad en 1993 por la UNESCO, se tiene constancia de la existencia de diversas zonas de explotación, de época romana, próximas a la ciudad. La caracterización de las rocas extraídas de estos dos monumentos, es de gran importancia, y necesaria, para resolver determinadas cuestiones arqueológicas sobre la cronología de su construcción y para determinar la relación existente entre las canteras y los monumentos, las técnicas extractivas o el proceso de construcción de estos. La metodología empleada en la presenta tesis doctoral se basa en la correlación entre los análisis mineralógicos y geoquímicos y las propiedades petrofísicas de las rocas de los monumentos, materiales graníticos y carbonáticos, y de los hormigones empleados en su construcción original, y de las rocas de las canteras para, de esta forma, determinar la procedencia del material empleado. Estas zonas de explotación han sido seleccionadas debido a, además de su cercanía a la ciudad, a la existencia de antiguas vías de comunicación, fluviales y terrestres. Con este estudio se logra cubrir el vacío existente en cuanto a la procedencia de los materiales constituyentes de estos monumentos, nunca anteriormente estudiados en profundidad desde el punto de vista de sus materiales pétreos, a pesar de la importancia de este conjunto arqueológico y monumental, así como la importancia de tener localizadas las canteras originales de procedencia de los materiales pétreos empleados en su construcció

Novedades sobre las canteras del entorno de Augusta Emerita

Trabajo presentado al Coloquio Internacional Canteras Antiguas de la Península Ibérica, celebrado en la casa de Velázquez (Madrid) del 8 al 9 de febrero de 2016.Contenidos de la presentación: -La investigación sobre las canteras de Emerita Augusta. - Novedades en la identificación de las canteras del entorno de Mérida. -Nuevas perspectivas de estudios de las canteras emeritenses: 1. Canteras y desarrollo del territorio; 2. Canteras y ciclo de producción de los edificios (caso específico de estudio: el teatro de Mérida).Peer Reviewe

Las canteras de Augusta Emerita. Identificación de los materiales y primeros datos sobre la relación con los edificios de espectáculo: el teatro romano

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