Self-assembled coumarin- and 5-fluorouracil-PEG micelles as multifunctional drug delivery systems

The copper(I)-catalyzed azide/alkyne cycloaddition is recognized as one of the most successful click reactions to access self-assembling amphiphilic polymer-drug conjugates (PDCs). In this way, poor water-soluble drugs can be linked covalently to hydrophilic poly(ethylene glycol) (PEG) to obtain PEGylated drug micelles that can be used as versatile carriers for the delivery of diverse therapeutic agents. In this work, two novel amphiphilic PDCs that combine PEG with privileged scaffolds well-known for their anticancer properties, such as coumarin and 5-fluorouracil, have been synthesized and characterized. These conjugates were able to self-assemble into micelles at relatively high critical micellar concentration, probably due to the large portion of hydrophilic PEG. The micelles allowed to load other anticancer drugs (paclitaxel, curcumin, and gemcitabine), providing a unique opportunity to develop promising co-delivery carriers for synergistic cancer therapy. The Korsmeyer-Peppas mathematical model was used for describing the in vitro kinetics of drug release from the micelles. Similar sustained and controlled drug release profiles were obtained for paclitaxel and curcumin in both conjugates, which was attributed to the excellent stability driven by the strong interaction between polymeric conjugates and drugs in the micelle core. In contrast, the high instability observed for the gemcitabine-loaded micelles provided an initial uncontrolled burst release of drug. A preliminary in vitro cytotoxicity study of the micelles against human pancreatic cancer cells PANC-1 and BxPC-3 was also carried out, demonstrating that both coumarin and 5-fluorouracil retain their anticancer properties after conjugation with PEG.La cicloadición de azida/alquino catalizada por cobre (I) se reconoce como una de las reacciones de clic más exitosas para acceder a conjugados de polímero-fármaco anfifílicos (PDC) autoensamblados. De esta manera, los fármacos poco solubles en agua se pueden unir covalentemente al poli(etilenglicol) (PEG) hidrofílico para obtener micelas de fármacos PEGilados que se pueden utilizar como vehículos versátiles para la administración de diversos agentes terapéuticos. En este trabajo, dos PDC anfifílicos novedosos que combinan PEG con andamios privilegiados conocidos por sus propiedades anticancerígenas, como la cumarina .y 5-fluorouracilo, han sido sintetizados y caracterizados. Estos conjugados pudieron autoensamblarse en micelas a una concentración micelar crítica relativamente alta, probablemente debido a la gran porción de PEG hidrofílico. Las micelas permitieron cargar otros medicamentos contra el cáncer (paclitaxel, curcumina y gemcitabina), lo que brinda una oportunidad única para desarrollar portadores de administración conjunta prometedores para la terapia sinérgica contra el cáncer. Se utilizó el modelo matemático de Korsmeyer-Peppas para describir la cinética in vitro de la liberación del fármaco desde las micelas. Se obtuvieron perfiles similares de liberación sostenida y controlada del fármaco para paclitaxel.y curcumina en ambos conjugados, lo que se atribuyó a la excelente estabilidad impulsada por la fuerte interacción entre los conjugados poliméricos y los fármacos en el núcleo de la micela. Por el contrario, la alta inestabilidad observada para las micelas cargadas con gemcitabina proporcionó una liberación inicial descontrolada del fármaco. También se llevó a cabo un estudio preliminar de citotoxicidad in vitro de las micelas contra las células de cáncer de páncreas humano PANC-1 y BxPC-3, demostrando que tanto la cumarina como el 5-fluorouracilo conservan sus propiedades anticancerígenas después de la conjugación con PEG

Generación de dolinas en medios aluviales con modelos analógicos

La formación de cavidades y su posterior colapso genera distintos tipos de dolinas en superficie. La evaluación de los riesgos asociados al karst aluvial o cubierto varía respecto la percepción habitual por encontrarse su origen desde varios a decenas de metros de profundidad. Las dolinas no son estáticas; en su desarrollo influye tanto la continuidad del proceso de disolución como la estabilización del terreno aluvial afectado. Estos procesos pueden requerir amplios periodos de tiempo para su estabilización. En este trabajo se propone la realización de una serie de modelos de propagación de cavidades dentro de un material no cementado para que sean realizados por estudiantes en el aula. En estos modelos se evalúan las dimensiones de la cavidad en el subsuelo, la variación del comportamiento del aluvial a partir de cambios de sus propiedades y la estabilización dinámica de dichas evidencias. En este trabajo se propone además la utilización de distintas técnicas de investigación del fenómeno y la obtención de conclusiones a partir de un caso práctico que puede resolverse con ayuda de los resultados obtenidos en los ensayos. Este ejercicio consiste en la determinación de la influencia de las propiedades del material aluvial en la propagación de cavidades, y en la comparación de los resultados que pueden obtenerse en función del carácter estático-instantáneo y dinámico-estable¿de estos fenómenos. Como aspecto transversal a los conceptos adquiridos durante la realización de la actividad, se fomenta también la discusión y evaluación de datos con pensamiento crítico y la aplicación del método científico a partir de los datos obtenidos en laboratorio

Influencia antrópica vs. natural en el origen del riesgo kárstico del entorno de la ciudad de Zaragoza.

La correlación lógica entre el incremento de la disponibilidad hídrica y el incremento de los procesos kársticos se generaliza al punto de aplicarse en contextos donde los materiales solubles se encuentran siempre localizados bajo el nivel freático. El análisis del espesor saturado en el entorno de aguas arriba de la ciudad de Zaragoza, donde existe un amplio desarrollo de estructuras de karst aluvial evaporítico, se evalúa para determinar si el regadío, las pérdidas de agua de conducciones o acequias pueden incrementar los procesos kársticos. Los datos evaluados permiten identificar que estos aportes extraordinarios pueden favorecer los procesos de consolidación superficial en contextos con actividad de subsidencia previa pero no incrementar el proceso de karstificación. La subsaturación general de las aguas del Ebro se explica en este modelo a través del aislamiento del substrato de la entrada de aguas del acuífero del Ebro, que con una dinámica compleja, puede presentar condiciones de confinamiento. The logic correlation between the increase of water availability and the increase of karst solution can be generalized at contexts where the soluble materials are located below the water level. Alluvial saturated thickness upwards of Zaragoza city, where wide areas are submitted to a mantled karstic evaporitic process, is evaluated in order to decipher if irrigation, pipe or channel leaks can increase karstic processes. Evaluated data permits to identify that not ordinary supplies, can favor surficial settlement processes at previous subsidence areas, but not to increase the karstic solution process. The general subsaturated Ebro water level is explained in this model by the presence of a hidrogeological barrier that confines the substratum aquifer excluding in many cases, and at a complex hidrogeological context, the water entry at the evaporitic substratum and precluding their influence to solution processes. Key-words: Mantled karst, subsidence, hydrogeology, sinkhole, evaporite karst

Impact of an Antimicrobial Stewardship Program on the Incidence of Carbapenem Resistant Gram-Negative Bacilli: An Interrupted Time-Series Analysis

This article belongs to the Section Antibiotics Use and Antimicrobial Stewardship.Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a critical public health threat, and carbapenem use contributes to their spread. Antimicrobial stewardship programs (ASPs) have proven successful in reducing antimicrobial use. However, evidence on the impact of carbapenem resistance remains unclear. We evaluated the impact of a multifaceted ASP on carbapenem use and incidence of CR-GNB in a high-endemic hospital. An interrupted time-series analysis was conducted one year before and two years after starting the ASP to assess carbapenem consumption, CR-GNB incidence, death rates of sentinel events, and other variables potentially related to CR-GNB incidence. An intense reduction in carbapenem consumption occurred after starting the intervention and was sustained two years later (relative effect −83.51%; 95% CI −87.23 to −79.79). The incidence density of CR-GNB decreased by −0.915 cases per 1000 occupied bed days (95% CI −1.743 to −0.087). This effect was especially marked in CR-Klebsiella pneumoniae and CR-Escherichia coli, reversing the pre-intervention upward trend and leading to a relative reduction of −91.15% (95% CI −105.53 to −76.76) and −89.93% (95% CI −107.03 to −72.83), respectively, two years after starting the program. Death rates did not change. This ASP contributed to decreasing CR-GNB incidence through a sustained reduction in antibiotic use without increasing mortality rates.This research was funded by the Plan Nacional de I + D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0008; RD16/0016/0009) co-financed by European Development Regional Fund ‘A way to achieve Europe’ and Operative program intelligent Growth 2014–2020, which did not participate in the development of the program or the analysis of its results

Costs and benefits of automation for astronomical facilities

The Observatorio Astrof\'isico de Javalambre (OAJ{\dag}1) in Spain is a young astronomical facility, conceived and developed from the beginning as a fully automated observatory with the main goal of optimizing the processes in the scientific and general operation of the Observatory. The OAJ has been particularly conceived for carrying out large sky surveys with two unprecedented telescopes of unusually large fields of view (FoV): the JST/T250, a 2.55m telescope of 3deg field of view, and the JAST/T80, an 83cm telescope of 2deg field of view. The most immediate objective of the two telescopes for the next years is carrying out two unique photometric surveys of several thousands square degrees, J-PAS{\dag}2 and J-PLUS{\dag}3, each of them with a wide range of scientific applications, like e.g. large structure cosmology and Dark Energy, galaxy evolution, supernovae, Milky Way structure, exoplanets, among many others. To do that, JST and JAST are equipped with panoramic cameras under development within the J-PAS collaboration, JPCam and T80Cam respectively, which make use of large format (~ 10k x 10k) CCDs covering the entire focal plane. This paper describes in detail, from operations point of view, a comparison between the detailed cost of the global automation of the Observatory and the standard automation cost for astronomical facilities, in reference to the total investment and highlighting all benefits obtained from this approach and difficulties encountered. The paper also describes the engineering development of the overall facilities and infrastructures for the fully automated observatory and a global overview of current status, pinpointing lessons learned in order to boost observatory operations performance, achieving scientific targets, maintaining quality requirements, but also minimizing operation cost and human resources.Comment: Global Observatory Control System GOC

Predictive Power of the "Trigger Tool" for the detection of adverse events in general surgery: a multicenter observational validation study

Background In spite of the global implementation of standardized surgical safety checklists and evidence-based practices, general surgery remains associated with a high residual risk of preventable perioperative complications and adverse events. This study was designed to validate the hypothesis that a new “Trigger Tool” represents a sensitive predictor of adverse events in general surgery. Methods An observational multicenter validation study was performed among 31 hospitals in Spain. The previously described “Trigger Tool” based on 40 specific triggers was applied to validate the predictive power of predicting adverse events in the perioperative care of surgical patients. A prediction model was used by means of a binary logistic regression analysis. Results The prevalence of adverse events among a total of 1,132 surgical cases included in this study was 31.53%. The “Trigger Tool” had a sensitivity and specificity of 86.27% and 79.55% respectively for predicting these adverse events. A total of 12 selected triggers of overall 40 triggers were identified for optimizing the predictive power of the “Trigger Tool”. Conclusions The “Trigger Tool” has a high predictive capacity for predicting adverse events in surgical procedures. We recommend a revision of the original 40 triggers to 12 selected triggers to optimize the predictive power of this tool, which will have to be validated in future studies

COVID-19 outbreaks in a transmission control scenario: challenges posed by social and leisure activities, and for workers in vulnerable conditions, Spain, early summer 2020

Severe acute respiratory syndrome coronavirus 2 community-wide transmission declined in Spain by early May 2020, being replaced by outbreaks and sporadic cases. From mid-June to 2 August, excluding single household outbreaks, 673 outbreaks were notified nationally, 551 active (>6,200 cases) at the time. More than half of these outbreaks and cases coincided with: (i) social (family/friends’ gatherings or leisure venues) and (ii) occupational (mainly involving workers in vulnerable conditions) settings. Control measures were accordingly applied

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Variation in Antiosteoporotic Drug Prescribing and Spending Across Spain. A Population-Based Ecological Cross-Sectional Study

Introduction: Evidence has shown that utilization of antiosteoporotic medications does not correspond with risk, and studies on other therapies have shown that adequacy of pharmaceutical prescribing might vary between regions. Nevertheless, very few studies have addressed the variability in osteoporotic drug consumption. We aimed to describe variations in pharmaceutical utilization and spending on osteoporotic drugs between Health Areas (HA) in Spain.Methods: Population-based cross-sectional ecological study of expenditure and utilization of the five therapeutic groups marketed for osteoporosis treatment in Spain in 2009. Small area variation analysis (SAVA) methods were used. The units of analysis were the 168 HA of 13 Spanish regions, including 7.2 million women aged 50 years and older. The main outcomes were the defined daily dose (DDD) per 1000 inhabitants and day (DDD/1000/Day) dispensed according to the pharmaceutical claims reimbursed, and the expenditure on antiosteoporotics at retail price per woman ≥50 years old and per year.Results: The average osteoporosis drug consumption was 116.8 DDD/1000W/Day, ranging from 78.5 to 158.7 DDD/1000W/Day between the HAs in the 5th and 95th percentiles. Seventy-five percent of the antiosteoporotics consumed was bisphosphonates, followed by raloxifene, strontium ranelate, calcitonins, and parathyroid hormones including teriparatide. Regarding variability by therapeutic groups, biphosphonates showed the lowest variation, while calcitonins and parathyroid hormones showed the highest variation. The annual expenditure on antiosteoporotics was €426.5 million, translating into an expenditure of €59.2 for each woman ≥50 years old and varying between €38.1 and €83.3 between HAs in the 5th and 95th percentiles. Biphosphonates, despite accounting for 79% of utilization, only represented 63% of total expenditure, while parathyroid hormones with only 1.6% of utilization accounted for 15% of the pharmaceutical spending.Conclusion: This study highlights a marked geographical variation in the prescription of antiosteoporotics, being more pronounced in the case of costly drugs such as parathyroid hormones. The differences in rates of prescribing explained almost all of the variance in drug spending, suggesting that the difference in prescription volume between territories, and not the price of the drugs, is the main source of variation in this setting. Data on geographical variation of prescription can help guide policy proposals for targeting areas with inadequate antiosteoporotic drug use