Integrated biomarker responses in wild populations of the intertidal sea anemone Bunodosoma zamponii living under different anthropogenic pressures.

Bunodosoma zamponii is the most abundant anemone in Mar del Plata (Buenos Aires, Argentina). Given that the presence of persistent organic pollutants (organochlorine pesticides and PCBs) and the organophosphate pesticide chlorpyrifos has recently been reported in this species, two wild populations living under different anthropogenic pressures were studied and compared regarding basic aspects of their ecology and physiological response to oxidative stress. A population from an impacted site (Las Delicias, LD) and another from a reference site (Punta Cantera, PC) were monitored seasonally (spring, summer, autumn, and winter), for one year. Anemones from PC were larger and more abundant than those from LD for most sampling periods. During winter, glutathione-S-transferase and catalase activities were higher in LD. Moreover, protein content and antioxidant defenses were higher in anemones from PC during winter as well. Taking into account their ecology (size and abundance) and biomarker responses, the population from PC was comparatively healthier. Furthermore, such differences are in agreement with recent studies indicating a higher concentration of pollutants in anemones from LD (specially during the winter sampling). In this sense, considering that B. zamponii can bioaccumulate the aforementioned pollutants, its resilience to their presence, and the fact that biomarker response differed between sites, this species can be regarded as a proper sentinel species of environmental pollution. Overall, this anemone seems to be a good bioindicator to be considered in future biomonitoring and ecotoxicological studies.

Contaminant dynamics in honey bees and hive products of apiaries from environmentally contrasting Argentinean regions.

Argentina is a leading honey producer and honey bees are also critical for pollination services and wild plants. At the same time, it is a major crop producer with significant use of insecticides, posing risks to bees. Therefore, the presence of the highly toxic insecticide chlorpyrifos, and forbidden contaminants (organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs)) was investigated in honey bee, beebread, wax and honey samples in apiaries from three contrasting regions of Argentina. Chlorpyrifos was detected in all samples with higher levels during period 1 (spring) in contrast to period 2 (fall), agreeing with its season-wise use in different crops, reaching 3.05 ng/g in honey bees. A subsequent first-tier pesticide hazard analysis revealed that it was relevant to honey bee health, mainly due to the high concentrations found in wax samples from two sites, reaching 132.4 ng/g. In addition, wax was found to be the most contaminated matrix with a prevalence of OCPs (∑OCPs 58.23-172.99 ng/g). Beebread samples showed the highest concentrations and diversity of pesticide residues during period 1 (higher temperatures). A predominance of the endosulfan group was registered in most samples, consistent with its intensive past use, especially in Central Patagonia before its prohibition. Among the industrial compounds, lighter PCB congeners dominated, suggesting the importance of atmospheric transport. The spatio-temporal distribution of pesticides shows a congruence with the environmental characteristics of the areas where the fields are located (i.e., land use, type of productive activities and climatic conditions). Sustained monitoring of different pollutants in beekeeping matrices is recommended to characterize chemical risks, assess the health status of honey bee hives and the pollution levels of different agroecosystems. This knowledge will set a precedent for South America and be helpful for actions focused on the conservation of pollination services, apiculture and ecosystems in Argentina.

Occurrence of chlorpyrifos and organochlorine pesticides in a native bumblebee (Bombus pauloensis) living under different land uses in the southeastern Pampas, Argentina.

Pollinators such as Apidae bees are vital for ecosystems and food security. Unfortunately, their populations have declined due to several factors including pesticide use. Among them, the organophosphate insecticide chlorpyrifos, poses a global threat, while legacy compounds like organochlorine pesticides (OCPs) easily bioaccumulate, increasing the concern. Bombus pauloensis, a widely distributed native bee in Argentina, is used for commercial pollination; however, information regarding their health status is scarce. This study assessed chlorpyrifos and OCP levels in B. pauloensis (workers and males) and related environmental matrices living from three different land uses schemes, by means of GC-ECD and GC-MS. The ornamental horticulture field (OP) showed the highest total pesticide concentrations in workers (13.1 ng/g), flowers and soils, whereas the organic agriculture field (OA) exhibited the lowest. Chlorpyrifos was the most abundant compound, accounting for at least 20 % of pesticide load across all matrices. The food production horticulture field (FH) had the highest chlorpyrifos concentration in workers, males and soils (5.0, 4.4 and 3.3 ng/g, respectively), suggesting a local greater usage, whereas OA showed the lowest. Regarding OCPs groups, Drins and DDTs were predominant in most matrices, with FH males registering the highest levels (4.0 and 2.5 ng/g, respectively), closely followed by OP. However, metabolites' contribution indicated historical use and atmospheric inputs in all sites. Multivariate analyses confirmed the significance of site and bumblebee sex to explain pesticide composition. Males from all sites exhibited higher chlorpyrifos levels than workers and this trend was similar for some OCP groups. Overall, OA differed from FH and OP, indicating a correlation between production modes and pesticide profiles. This study demonstrates the value of B. pauloensis as a pesticide biomonitor but also offers insights into its populations' health in the area. In this sense, this information could be useful towards the preservation of this crucial pollinator.

Exposure of multidrug-resistant Klebsiella pneumoniae biofilms to 1,8-cineole leads to bacterial cell death and biomass disruption.

Klebsiella pneumoniae is a common cause of health-care associated infections. The rise of antibiotic resistance and the ability to form biofilm among K. pneumoniae strains are two key factors associated with antibiotic treatment failure. The present study investigates the antibiofilm activity of 1,8-cineole against preformed biofilms of multidrug-resistant extended-spectrum ß-lactamase-producing K. pneumoniae clinical isolates. To evaluate the antibiofilm activity, cellular viability was analyzed by colony-forming units counting and live/dead staining. In addition, biofilm biomass was evaluated by crystal violet and the biofilm matrix was stained with calcofluor white and observed by confocal laser scanning microscopy. A time- and concentration-dependent effect of the phytochemical over biofilm cell viability was observed revealing that 1% (v/v) 1,8-cineole during 1 h was the optimal treatment condition displaying a significant reduction of cell viability in the preformed biofilms (2.5-5.3 log cfu/cm2). Furthermore, confocal laser scanning microscopy after SYTO-9 and propidium iodide staining showed that 1,8-cineole was capable of killing bacteria throughout all layers of the biofilm. The compound also caused a biofilm disruption (30-62% biomass reduction determined by crystal violet staining) and a significant decrease in biofilm matrix density. Altogether, our results demonstrate that 1,8-cineole is a promising candidate as a novel antibiofilm agent against multidrug-resistant K. pneumoniae strains producing extended-spectrum ß-lactamases, given its capability to disrupt the structure and to kill cells within the biofilm.

Occurrence of polychlorinated biphenyls (PCBs) in the sea anemone Bunodosoma zamponii, sediments and seawater from the southwestern Atlantic.

Polychlorinated biphenyls (PCBs) are persistent and bioaccumulable organic compounds. The occurrence of PCBs was assessed in two populations of the intertidal sea anemone Bunodosoma zamponii living under different anthropogenic strains. One location was in vicinity to a wastewater plant (Las Delicias, LD), and the other was a preserved location chosen as a reference site (Punta Cantera, PC). Anemone populations were sampled 4 times (spring, summer, autumn and winter) throughout a year, in addition to seawater and sediment from those areas. PCB loadings ranged from 2.89 to 79.41 ng L-1 in seawater samples and from 0.07 to 6.61 ng g-1 dry weight in sediment samples. Total PCB levels ranged from 0.22 to 14.94 and 2.79 to 24.69 ng g-1 wet weight in anemones from PC and LD, respectively. PCBs concentrations in anemones from LD were significantly greater than PC during spring, summer and winter. The congeners 18 and 44 prevailed in seawater samples, 44 and 52 in sediment and 18 and 132+153 in anemones. Redundancy analysis integrated PCB levels from all matrixes and bolstered contrast between sampling sites. Seasonality was also a relevant factor since during winter PCB loading was greater in sediment and anemone samples, coincident with the rainiest season. Disparity between sites could be due to LD's proximity to the wastewater plant, effect of littoral drift direction and/or asymmetries in anemones physiological condition.

Organochlorine pesticides and chlorpyrifos in the sea anemone Bunodosoma zamponii (Actiniaria: Actiniidae) from Argentina's southeastern coast.

Temporal and spatial distribution of organochlorine pesticides (OCPs) and the organophosphate pesticide chlorpyrifos, one of the main insecticides used in Argentina, was evaluated in two populations of the sea anemone Bunodosoma zamponii living under different anthropological stressors: Las Delicias (LD) adjacent to a wastewater plant, and Punta Cantera (PC) a reference site. Pesticides were analyzed throughout the year in water, sediments and whole organisms. Chlorpyrifos represented 50% of the total pesticide found in water samples during winter. HCHs and drins were predominant in sediment samples, mainly in LD. Total pesticide concentration in anemones from LD was higher than those from PC during winter (mainly associated with HCHs, endosulfans, DDTs and chlorpyrifos levels), coincident with the main period of effluent discharge to the coast after pesticide applications and also the rainiest season. Dissimilarities among anemones populations could stem from a differential input of pesticides in each site and/or a contrasting physiological status of the populations.

PD Control Compensation Based on a Cascade Neural Network Applied to a Robot Manipulator.

A Proportional Integral Derivative (PID) controller is commonly used to carry out tasks like position tracking in the industrial robot manipulator controller; however, over time, the PID integral gain generates degradation within the controller, which then produces reduced stability and bandwidth. A proportional derivative (PD) controller has been proposed to deal with the increase in integral gain but is limited if gravity is not compensated for. In practice, the dynamic system non-linearities frequently are unknown or hard to obtain. Adaptive controllers are online schemes that are used to deal with systems that present non-linear and uncertainties dynamics. Adaptive controller use measured data of system trajectory in order to learn and compensate the uncertainties and external disturbances. However, these techniques can adopt more efficient learning methods in order to improve their performance. In this work, a nominal control law is used to achieve a sub-optimal performance, and a scheme based on a cascade neural network is implemented to act as a non-linear compensation whose task is to improve upon the performance of the nominal controller. The main contributions of this work are neural compensation based on a cascade neural networks and the function to update the weights of neural network used. The algorithm is implemented using radial basis function neural networks and a recompense function that leads longer traces for an identification problem. A two-degree-of-freedom robot manipulator is proposed to validate the proposed scheme and compare it with conventional PD control compensation.

Cell death and biomass reduction in biofilms of multidrug resistant extended spectrum ß-lactamase-producing uropathogenic Escherichia coli isolates by 1,8-cineole.

Escherichia coli is the most frequent agent of urinary tract infections in humans. The emergence of uropathogenic multidrug-resistant (MDR) E. coli strains that produce extended spectrum ß-lactamases (ESBL) has created additional problems in providing adequate treatment of urinary tract infections. We have previously reported the antimicrobial activity of 1,8-cineole, one of the main components of Rosmarinus officinalis volatile oil, against Gram negative bacteria during planktonic growth. Here, we evaluated the antibiofilm activity of 1,8-cineole against pre-formed mature biofilms of MDR ESBL-producing uropathogenic E. coli clinical strains by carrying out different technical approaches such as counting of viable cells, determination of biofilm biomass by crystal violet staining, and live/dead stain for confocal microscopy and flow cytometric analyses. The plant compound showed a concentration- and time-dependent antibiofilm activity over pre-formed biofilms. After a 1 h treatment with 1% (v/v) 1,8-cineole, a significant decrease in viable biofilm cell numbers (3-log reduction) was observed. Biofilms of antibiotic-sensitive and MDR ESBL-producing E. coli isolates were sensitive to 1,8-cineole exposure. The phytochemical treatment diminished the biofilm biomass by 48-65% for all four E. coli strain tested. Noteworthy, a significant cell death in the remaining biofilm was confirmed by confocal laser scanning microscopy after live/dead staining. In addition, the majority of the biofilm-detached cells after 1,8-cineole treatment were dead, as shown by flow cytometric assessment of live/dead-stained bacteria. Moreover, phytochemical-treated biofilms did not fully recover growth after 24 h in fresh medium. Altogether, our results support the efficacy of 1,8-cineole as a potential antimicrobial agent for the treatment of E. coli biofilm-associated infections.

Impacto en la mortalidad tras la implantación de una red de atención al infarto agudo de miocardio con elevación del segmento ST. Estudio IPHENAMIC / Impact on mortality after implementation of a network for ST-segment elevation myocardial infarction care. The IPHENAMIC study

INTRODUCCIÓN Y OBJETIVOS: Se sabe muy poco del impacto que las redes de atención del infarto agudo de miocardio con elevación del segmento ST (IAMCEST) tienen en la población. El objetivo de este estudio es averiguar si el PROGALIAM (Programa Gallego de Atención al Infarto Agudo de Miocardio) mejoró la supervivencia en la zona norte de Galicia. MÉTODOS: Se recogieron todos los eventos codificados como IAMCEST entre 2001 y 2013. Se identificó a 6.783 pacientes, divididos en 2 grupos: pre-PROGALIAM (2001-2005), 2.878 pacientes, y PROGALIAM (2006-2013), 3.905 pacientes. RESULTADOS: En la etapa pre-PROGALIAM, la mortalidad ajustada a 5 años fue superior tanto en la población total (HR=1,22; IC95%, 1,14-1,29; p < 0,001), como en cada una de las áreas (A Coruña, HR=1,12; IC95%, 1,02-1,23; p = 0,02; Lugo, HR=1,34; IC95%, 1,2-1,49; p <0,001, y Ferrol, HR=1,23; IC95%, 1,1-1,4; p = 0,001). Antes del PROGALIAM, la mortalidad a 5 años en las áreas de Lugo (HR=0,8; IC95%, 0,67-0,95; p = 0,02) y Ferrol (HR=0,75; IC95%, 0,64-0,88; p = 0,001) era superior que en A Coruña. Estas diferencias desaparecieron tras el desarrollo de la red (Lugo comparado con A Coruña, HR=0,88; IC95%, 0,72-1,06; p = 0,18; Ferrol comparado con A Coruña, HR=1,04; IC95%, 0,89-1,22; p = 0,58. CONCLUSIONES: El desarrollo del PROGALIAM en el área norte de Galicia disminuyó la mortalidad e incrementó la equidad de los pacientes con IAMCEST tanto en general como en cada una de las áreas donde se implantó

INTRODUCTION AND OBJECTIVES: Little is known about the impact of networks for ST-segment elevation myocardial infarction (STEMI) care on the population. The objective of this study was to determine whether the PROGALIAM (Programa Gallego de Atención al Infarto Agudo de Miocardio) improved survival in northern Galicia. METHODS: We collected all events coded as STEMI between 2001 and 2013. A total of 6783 patients were identified and divided into 2 groups: pre-PROGALIAM (2001-2005), with 2878 patients, and PROGALIAM (2006-2013), with 3905 patients. RESULTS: In the pre-PROGALIAM period, 5-year adjusted mortality was higher both in the total population (HR, 1.22, 95%CI, 1.14-1.29; P <.001) and in each area (A Coruña: HR, 1.12; 95%CI, 1.02-1.23; P=.02; Lugo: HR, 1.34; 95%CI, 1.2- 1.49; P <.001 and Ferrol: HR, 1.23; 95%CI, 1.1-1.4; P=.001). Before PROGALIAM, 5-year adjusted mortality was higher in the areas of Lugo (HR, 1.25; 95%CI, 1.05-1.49; P=.02) and Ferrol (HR, 1.32; 95%CI, 1.13-1.55; P=.001) than in A Coruña. These differences disappeared after the creation of the STEMI network (Lugo vs A Coruña: HR, 0.88; 95%CI, 0.72-1.06; P=.18, Ferrol vs A Coruña: HR, 1.04; 95%CI, 0.89-1.22; P=.58. CONCLUSIONS: For patients with STEMI, the creation of PROGALIAM in northern Galicia decreased mortality and increased equity in terms of survival both overall and in each of the areas where it was implemented

Impact on mortality after implementation of a network for ST-segment elevation myocardial infarction care. The IPHENAMIC study.

INTRODUCTION AND OBJECTIVES: Little is known about the impact of networks for ST-segment elevation myocardial infarction (STEMI) care on the population. The objective of this study was to determine whether the PROGALIAM (Programa Gallego de Atención al Infarto Agudo de Miocardio) improved survival in northern Galicia. METHODS: We collected all events coded as STEMI between 2001 and 2013. A total of 6783 patients were identified and divided into 2 groups: pre-PROGALIAM (2001-2005), with 2878 patients, and PROGALIAM (2006-2013), with 3905 patients. RESULTS: In the pre-PROGALIAM period, 5-year adjusted mortality was higher both in the total population (HR, 1.22, 95%CI, 1.14-1.29; P <.001) and in each area (A Coruña: HR, 1.12; 95%CI, 1.02-1.23; P=.02; Lugo: HR, 1.34; 95%CI, 1.2-1.49; P <.001 and Ferrol: HR, 1.23; 95%CI, 1.1-1.4; P=.001). Before PROGALIAM, 5-year adjusted mortality was higher in the areas of Lugo (HR, 1.25; 95%CI, 1.05-1.49; P=.02) and Ferrol (HR, 1.32; 95%CI, 1.13-1.55; P=.001) than in A Coruña. These differences disappeared after the creation of the STEMI network (Lugo vs A Coruña: HR, 0.88; 95%CI, 0.72-1.06; P=.18, Ferrol vs A Coruña: HR, 1.04; 95%CI, 0.89-1.22; P=.58. CONCLUSIONS: For patients with STEMI, the creation of PROGALIAM in northern Galicia decreased mortality and increased equity in terms of survival both overall and in each of the areas where it was implemented. This study was registered at ClinicalTrials.gov (Identifier: NCT02501070).

Does Large Vessel Size Justify Use of Bare-Metal Stents in Primary Percutaneous Coronary Intervention?

BACKGROUND: Drug-eluting stents (DES) showed improved efficacy and safety compared with bare-metal stents (BMS), and international guidelines recommend their use as first line treatment. Yet, BMS are still widely used in practice, especially in large coronary vessels. We aimed to compare efficacy and safety of second-generation DES over BMS in large coronary culprit ST-segment elevated myocardial infarction lesions. METHODS: We evaluated impact of large coronary stents (maximum size ≥3.50 mm) or smaller stents (<3.50 mm), among 1498 patients with ST-segment elevated myocardial infarction undergoing primary percutaneous coronary intervention, randomly allocated to everolimus-eluting DES or to an equivalent BMS platform in the EXAMINATION trial (Clinical Evaluation of the Xience-V Stent in Acute Myocardial Infarction Trial). Clinical events up to 5 years of follow-up were evaluated. RESULTS: Large coronary stents were used in 683 patients (45.9%). At 5-year follow-up, the crude rate of the primary end point, a composite of all-cause death, any myocardial infarction, or any revascularization, was similar among patients treated with large or smaller coronary stents. The impact of DES versus BMS implantation was consistent irrespective of the stent size both for the primary end point (Pint=0.82) and other secondary ischemic end points. Within patients treated with bigger stents, DES implantation was associated to a trend toward a reduction of target lesion (hazard ratio, 0.53; 95% CI, 0.27-1.02; P=0.05) and target vessel revascularization (hazard ratio, 0.60; 95% CI, 0.34-1.03; P=0.066). CONCLUSIONS: Our results do not support the preferential use of BMS for patients with large coronary vessels. DES may warrant improved efficacy irrespective of stent size among patients undergoing primary percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00828087.

Resistencia emergente a la mupirocina en aislados de Staphylococcus aureus resistente a meticilina en un hospital pediátrico terciario en la Argentina / Emerging mupirocin resistance in methicillin-resistant Staphylococcus aureus isolates at a tertiary care children's hospital in Argentina

En América Latina, existen escasos estudios sobre la resistencia a mupirocina y producción de biofilm en Staphylococcus aureus resistente a la meticilina (SARM). En este trabajo, se investigó la resistencia a mupirocina en SARM aislados de pacientes pediátricos con bacteremia y su capacidad para producir biofilm. Se estudió la resistencia a antibióticos por Kirby-Bauer y microdilución en caldo. Se cuantificó el biofilm bacteriano por ensayo de cristal violeta. El 2,3 % (5/217) de los aislados de SARM presentaron un alto nivel de resistencia a mupirocina con una concentración inhibitoria mínima de >512 μ/ml, además de resistencia cruzada con clindamicina, eritromicina, gentamicina y ciprofloxacina. Notablemente, dichos aislados formaron biofilm en un nivel moderado-alto. Este primer reporte en Argentina de aislados clínicos de SARM resistentes a la mupirocina es clave para seguir su evolución en el tiempo a nivel local y en la región de América Latina.

In Latin America, few studies have been done in mupirocin resistance and biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA). This study investigated mupirocin-resistance in MRSA isolates from pediatric patients with bacteremia and their ability to form biofilm. Antibiotic resistance was analyzed with the Kirby-Bauer test and the broth microdilution method. Bacterial biofilm formation was measured using the crystal violet assay. Among MRSA isolates, 2.3 % (5/217) exhibited a high level of mupirocin-resistance with a minimum inhibitory concentration of > 512 μg/mL, in addition to cross-resistance with clindamycin, erythromycin, gentamicin, and ciprofloxacin. Remarkably, biofilm formation in such isolates was moderate to high. This is the first report published in Argentina on clinical isolates of mupirocin-resistant MRSA and it is critical for following its evolution over time at a local level and in the Latin American region.

Emerging mupirocin resistance in methiciüin-resistant Staphylococcus aureus isolates at a tertiary care children's hospital in Argentina. / Resistencia emergente a la mupirocina en aislados de Staphylococcus aureus resistente a meticilina en un hospital pediátrico terciario en la Argentina.

In Latin America, few studies have been done in mupirocin resistance and biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA). This study investigated mupirocin-resistance in MRSA isolates from pediatric patients with bacteremia and their ability to form biofilm. Antibiotic resistance was analyzed with the Kirby-Bauer test and the broth microdilution method. Bacterial biofilm formation was measured using the crystal violet assay. Among MRSA isolates, 2.3 % (5/217) exhibited a high level of mupirocin-resistance with a minimum inhibitory concentration of >512 µg/mL, in addition to cross-resistance with clindamycin, erythromycin, gentamicin, and ciprofloxacin. Remarkably, biofilm formation in such isolates was moderate to high. This is the first report published in Argentina on clinical isolates of mupirocin-resistant MRSA and it is critical for following its evolution over time at a local level and in the Latin American region.

En América Latina, existen escasos estudios sobre la resistencia a mupirocina y producción de biofilm en Staphylococcus aureus resistente a la meticilina (SARM). En este trabajo, se investigó la resistencia a mupirocina en SARM aislados de pacientes pediátricos con bacteremia y su capacidad para producir biofilm. Se estudió la resistencia a antibióticos por Kirby-Bauer y microdilución en caldo. Se cuantificó el biofilm bacteriano por ensayo de cristal violeta. El 2,3 % (5/217) de los aislados de SARM presentaron un alto nivel de resistencia a mupirocina con una concentración inhibitoria mínima de > 512 µ/ml, además de resistencia cruzada con clindamicina, eritromicina, gentamicina y ciprofloxacina. Notablemente, dichos aislados formaron biofilm en un nivel moderado-alto. Este primer reporte en Argentina de aislados clínicos de SARM resistentes a la mupirocina es clave para seguir su evolución en el tiempo a nivel local y en la región de América Latina.

Cost-effectiveness of everolimus-eluting versus bare-metal stents in ST-segment elevation myocardial infarction: An analysis from the EXAMINATION randomized controlled trial.

BACKGROUND: Use of everolimus-eluting stents (EES) has proven to be clinically effective and safe in patients with ST-segment elevation myocardial infarction but it remains unclear whether it is cost-effective compared to bare-metal stents (BMS) in the long-term. We sought to assess the cost-effectiveness of EES versus BMS based on the 5-year results of the EXAMINATION trial, from a Spanish health service perspective. METHODS: Decision analysis of the use of EES versus BMS was based on the patient-level clinical outcome data of the EXAMINATION trial. The analysis adopted a lifelong time horizon, assuming that long-term survival was independent of the initial treatment strategy after the end of follow-up. Life-expectancy, health-state utility scores and unit costs were extracted from published literature and publicly available sources. Non-parametric bootstrapping was combined with probabilistic sensitivity analysis to co-assess the impact of patient-level variation and parameter uncertainty. The main outcomes were total costs and quality-adjusted life-years. The incremental cost-effectiveness ratio was expressed as cost per quality-adjusted life-years gained. Costs and effects were discounted at 3%. RESULTS: The model predicted an average survival time in patients receiving EES and BMS of 10.52 and 10.38 undiscounted years, respectively. Over the life-long time horizon, the EES strategy was €430 more costly than BMS (€8,305 vs. €7,874), but went along with incremental gains of 0.10 quality-adjusted life-years. This resulted in an average incremental cost-effectiveness ratio over all simulations of €3,948 per quality-adjusted life-years gained and was below a willingness-to-pay threshold of €25,000 per quality-adjusted life-years gained in 86.9% of simulation runs. CONCLUSIONS: Despite higher total costs relative to BMS, EES appeared to be a cost-effective therapy for ST-segment elevation myocardial infarction patients due to their incremental effectiveness. Predicted incremental cost-effectiveness ratios were below generally acceptable threshold values.

Emerging role of dynamic RNA modifications during animal development.

The central dogma of molecular biology statically says that the information flows from DNA to messenger RNA to protein. But the recent advances in mass spectrometry and high throughput technology have helped the scientists to view RNA as little more than a courier of genetic information encoded in the DNA. The dynamics of RNA modifications in coding and non-coding RNAs are just emerging as a carrier of non-genetic information, uncovering a new layer of complexity in the regulation of gene expression and protein translation. In this review, we summarize about the current knowledge of N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C) and pseudouridine (Ψ) modifications in RNA, and described how these RNA modifications are implicated in early animal development and in several human diseases.

Role of ST-Segment Resolution in Patients With ST-Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention (from the 5-Year Outcomes of the EXAMINATION [Evaluation of the Xience-V Stent in Acute Myocardial Infarction] Trial).

In patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI), lack of ST-segment resolution (STR) is associated with poor prognosis at short- and long-term follow-up. The aim of this study was to evaluate the role of STR on very long-term outcomes in patients with STEMI treated with pPCI included in the EXAMINATION (Evaluation of the Xience-V Stent in Acute Myocardial Infarction) trial. Patients were stratified according to the presence of STR < 50% and STR < 70% at the 30-minute post-pPCI electrocardiogram. Primary end point was the patient-oriented composite endpoint (POCE) of all-cause death, any myocardial infarction, or any revascularization at 5-year follow-up. Both baseline and post-PCI 30-minute electrocardiograms were available for STR assessment in 1,351 patients. Of these patients, 228 (16.9%) and 500 (37.0%) exhibited STR < 50% and STR < 70%, respectively. At 5-year follow-up, the POCE was observed more frequently in patients with STR < 50% (hazard ratio [HR] 1.556; 95% confidence interval [CI] 1.194 to 2.027; p <0.001) and in patients with STR < 70% (HR 1.460, 95% CI 1.169 to 1.824, p <0.001) compared with patients with STR > 50% and STR ≥ 70%, respectively. In both cases, this difference was mainly driven by a significant increase in the rate of all-cause death and any revascularization. After multivariable adjustment, STR < 70%, but not STR < 50%, resulted as a 5-year independent predictor of POCE (adjusted HR 1.338, 95% CI 1.008 to 1.778, p = 0.044). In conclusion, in patients with STEMI, the evaluation of 70% STR after pPCI provides independent prognostic information at 5-year follow-up and it can be used to identify patients at high risk of very long-term cardiovascular events.

Correlates of non-target vessel-related adverse events in patients with ST-segment elevation myocardial infarction: insights from five-year follow-up of the EXAMINATION trial.

AIMS: The aim of this substudy was to determine the five-year correlates of non-TV-related adverse events (AE) in STEMI patients included in the EXAMINATION trial. METHODS AND RESULTS: The EXAMINATION trial randomised 1,498 STEMI patients to bare metal or everolimus-eluting stent implantation. In this substudy, patients were analysed according to non-TV-related AE, defined as the composite of either non-TV revascularisation (non-TVR) or non-TV-related myocardial infarction (MI). At five-year follow-up, 125 patients (8.3%) exhibited 136 non-TV-related AE (124 [8.3%] non-TVR, 12 [0.8%] non-TV-related MI), accounting for 47.1% of 289 non-fatal cardiac events overall. These patients had a higher incidence of diabetes mellitus (p<0.001), arterial hypertension (p=0.032), previous MI (p=0.073), multivessel disease (p<0.001), and incomplete revascularisation (p=0.049), and a lower rate of ST-segment resolution >70% (p=0.042) as compared to the rest. At Cox analysis, previous MI (HR 1.872, 95% CI: 1.004-3.489; p=0.048), incomplete revascularisation (HR 1.746, 95% CI: 1.029-2.963; p=0.039) and diabetes (HR 1.942, 95% CI: 1.292-2.919; p=0.001) were independent correlates of non-TV-related AE. CONCLUSIONS: In STEMI patients undergoing primary percutaneous coronary intervention, previous MI, incomplete revascularisation and diabetes resulted in being independent correlates of five-year non-TV-related AE.

Impact of Body Mass Index on 5-Year Clinical Outcomes in Patients With ST-Segment Elevation Myocardial Infarction After Everolimus-Eluting or Bare-Metal Stent Implantation.

Patients with high body mass index (BMI) seem to have better outcomes after percutaneous coronary intervention than normal-weight patients. However, contrasting results have been reported on the "obesity paradox" in patients presenting with ST-elevation myocardial infarction (STEMI). The aim of our study was to investigate the impact of BMI on mortality in the population enrolled in the Evaluation of the Xience-V stent in Acute Myocardial INfArcTION (EXAMINATION) trial. The EXAMINATION trial randomized 1,498 patients with STEMI to a bare-metal stent or an everolimus-eluting stent. In this substudy patients were stratified into 3 groups according to BMI values: normal (BMI < 25 kg/m2), overweight (BMI = 25 to 29.9 kg/m2), and obese (BMI ≥ 30 kg/m2). The coprimary end points were the all-cause and cardiac deaths among the groups at the 5-year follow-up. BMI was available in 1,421 patients, divided in 401 (28.2%) normal, 702 (49.4%) overweight, and 318 (22.4%) obese. Obese patients were younger (p = 0.012) compared with the other groups, but with a worse cardiovascular risk profile. They were more frequently female (p <0.001) and with a higher rate of obesity-related co-morbidity conditions such as diabetes mellitus (p = 0.005), arterial hypertension (p <0.001), and hyperlipidemia (p = 0.001) compared with the other groups. At the 5-year follow-up, all-cause and cardiac deaths were less frequent in obese patients than in the other groups (p = 0.003 and p = 0.030, respectively). After adjustment for confounding variables, BMI was an independent predictor of all-cause death (hazard ratio 0.765, 95% confidence interval 0.599 to 0.979, p = 0.033), but not of cardiac death, without any interaction with the stent type. In conclusion, in patients with STEMI who underwent primary PCI, the long-term all-cause death rate decreased as BMI increased, confirming the obesity paradox, irrespective of the stent type.

Biodegradable Polymer Biolimus-Eluting Stents Versus Durable Polymer Everolimus-Eluting Stents in Patients With Coronary Artery Disease: Final 5-Year Report From the COMPARE II Trial (Abluminal Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent).

OBJECTIVES: This analysis investigates the 5-year outcomes of the biodegradable polymer biolimus-eluting stent (BP-BES) and durable polymer everolimus-eluting stent (DP-EES) in an all-comers population undergoing percutaneous coronary intervention. BACKGROUND: Recent 1- and 3-year results from randomized trials have indicated similar safety and efficacy outcomes of BP-BES and DP-EES. Whether benefits of the biodegradable polymer device arise over longer follow-up is unknown. Moreover, in-depth, prospective, long-term follow-up data on metallic drug-eluting stents with durable or biodegradable polymers are scarce. METHODS: The COMPARE II trial (Abluminal Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent) was a prospective, randomized, multicenter, all-comers trial in which 2,707 patients were randomly allocated (2:1) to BP-BES or DP-EES. The pre-specified endpoint at 5 years was major adverse cardiac events, a composite of cardiac death, nonfatal myocardial infarction, or target vessel revascularization. RESULTS: Five-year follow-up was available in 2,657 patients (98%). At 5 years, major adverse cardiac events occurred in 310 patients (17.3%) in the BP-BES group and 142 patients (15.6%) in the DP-EES group (p = 0.26). The rate of the combined safety endpoint all-cause death or myocardial infarction was 15.0% in the BP-BES group versus 14.8% in the DP-EES group (p = 0.90), whereas the efficacy measure target vessel revascularization was 10.6% versus 9.0% (p = 0.18), respectively. Interestingly, definite stent thrombosis rates did not differ between groups (1.5% for BP-BES vs. 0.9% for DP-EES; p = 0.17). CONCLUSIONS: The 5-year analysis comparing biodegradable polymer-coated BES and the durable polymer-coated EES confirms the initial early- and mid-term results regarding similar safety and efficacy outcomes in this all-comers percutaneous coronary intervention population.

Outcomes and predictors of success and complications for paravalvular leak closure: an analysis of the SpanisH real-wOrld paravalvular LEaks closure (HOLE) registry.

AIMS: The aim of the study was to assess the safety and efficacy of percutaneous closure of paravalvular prosthetic leak (PVL) and to identify the predictors of procedural success and early complications. METHODS AND RESULTS: A total of 514 first-attempt percutaneous PVL closure in 469 patients were included at 19 centres. Technical and procedural success was achieved in 86.6% and 73.2% of the patients, respectively. In multivariate analysis, the independent predictors for procedural success in mitral lesions were the type of device used (AMPLATZER AVP III vs. others, HR 2.68 [1.29-5.54], p=0.008) and the number of procedures performed at the centre (top quartile vs. others, HR 1.93 [1.051-3.53], p=0.03). For aortic leaks the only predictor of procedural success was the leak size (≥10 mm vs. <10 mm, HR 3.077 [1.13-8.33], p=0.027). The overall major adverse events rate (death or emergency surgery or stroke) at 30 days was 5.6%; the only predictor for combined adverse events was New York Heart Association functional Class IV (HR 4.2 [1.42-12.34], p=0.009). CONCLUSIONS: Percutaneous closure of PVL can be performed with a reasonable rate of procedural success and a low rate of major complications. The type of device used, the accumulated experience and the leak size are predictors of procedural success.