Podophyllic Aldehyde, a Podophyllotoxin Derivate, Elicits Different Cell Cycle Profiles Depending on the Tumor Cell Line: A Systematic Proteomic Analysis.

When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient and systematic evaluation. In the case of natural products and derived compounds, it is of special importance to investigate chemomodulation to further explore antitumoral pharmacological activities. In this work, the compound podophyllic aldehyde, a cyclolignan derived from the chemomodulation of the natural product podophyllotoxin, has been evaluated for its viability, influence on the cell cycle, and effects on intracellular signaling. We used functional proteomics characterization for the evaluation. Compared with the FDA-approved drug etoposide (another podophyllotoxin derivative), we found interesting results regarding the cytotoxicity of podophyllic aldehyde. In addition, we were able to observe the effect of mitotic arrest in the treated cells. The use of podophyllic aldehyde resulted in increased cytotoxicity in solid tumor cell lines, compared to etoposide, and blocked the cycle more successfully than etoposide. High-throughput analysis of the deregulated proteins revealed a selective antimitotic mechanism of action of podophyllic aldehyde in the HT-29 cell line, in contrast with other solid and hematological tumor lines. Also, the apoptotic profile of podophyllic aldehyde was deciphered. The cell death mechanism is activated independently of the cell cycle profile. The results of these targeted analyses have also shown a significant response to the signaling of kinases, key proteins involved in signaling cascades for cell proliferation or metastasis. Thanks to this comprehensive analysis of podophyllic aldehyde, remarkable cytotoxic, antimitotic, and other antitumoral features have been discovered that will repurpose this compound for further chemical transformations and antitumoral analysis.

Genomic and transcriptomic characterization of methylmercury detoxification in a deep ocean Alteromonas mediterranea ISS312.

Methylmercury (MeHg) is one of the most worrisome pollutants in marine systems. MeHg detoxification is mediated by merB and merA genes, responsible for the demethylation of MeHg and the reduction of inorganic mercury, respectively. Little is known about the biological capacity to detoxify this compound in marine environments, and even less the bacterial transcriptional changes during MeHg detoxification. This study provides the genomic and transcriptomic characterization of the deep ocean bacteria Alteromonas mediterranea ISS312 with capacity for MeHg degradation. Its genome sequence revealed four mer operons containing three merA gene and two merB gene copies, that could be horizontally transferred among distant related genomes by mobile genetic elements. The transcriptomic profiling in the presence of 5 µM MeHg showed that merA and merB genes are within the most expressed genes, although not all mer genes were equally transcribed. Besides, we aimed to identify functional orthologous genes that displayed expression profiles highly similar or identical to those genes within the mer operons, which could indicate they are under the same regulatory controls. We found contrasting expression profiles for each mer operon that were positively correlated with a wide array of functions mostly related to amino acid metabolism, but also to flagellar assembly or two component systems. Also, this study highlights that all merAB genes of the four operons were globally distributed across oceans layers with higher transcriptional activity in the mesopelagic deeper waters. Our study provides new insights about the transcriptional patterns related to the capacity of marine bacteria to detoxify MeHg, with important implications for the understanding of this process in marine ecosystems.

Defining a standard set of health outcomes for patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Standardizing health outcomes is challenging in clinical management, but it also holds the potential for creating a healthcare system that is both more effective and efficient. The aim of the present study is to define a standardized set of health outcomes for managing Relapsing-Remitting Multiple Sclerosis (RRMS). METHODS: The project was led and coordinated by a multidisciplinary scientific committee (SC), which included a literature review, a patient-focused group, three nominal group meetings, and two SC meetings. RESULTS: 36 outcome variables were included in the standard set: 24 clinical (including weight, smoking habit, comorbidities, disability, mobility, diagnosis of secondary progressive multiple sclerosis, relapsed-related variables, radiological variables, cognitive status and disease-related symptoms), nine treatment-related (pharmacological and non-pharmacological information), and 3 related to the impact of RRMS on the patient's life (quality of life, pregnancy desire, work-related difficulties). In addition, experts also agreed to collect 10 case-mix variables that may affect but cannot be controlled as part of the management of the condition: 4 sociodemographic (age, sex, race, and employment status) and 6 clinical (height, date of diagnosis and first episode, serological status, early symptoms, and number of relapses pre-diagnosis). CONCLUSION: The information provided through the present standard set of outcome variables can improve the management of RRMS and promote patient-centred quality care.

Unmasking the physiology of mercury detoxifying bacteria from polluted sediments.

Marine sediments polluted from anthropogenic activities can be major reservoirs of toxic mercury species. Some microorganisms in these environments have the capacity to detoxify these pollutants, by using the mer operon. In this study, we characterized microbial cultures isolated from polluted marine sediments growing under diverse environmental conditions of salinity, oxygen availability and mercury tolerance. Specific growth rates and percentage of mercury removal were measured in batch cultures for a selection of isolates. A culture affiliated with Pseudomonas putida (MERCC_1942), which contained a mer operon as well as other genes related to metal resistances, was selected as the best candidate for mercury elimination. In order to optimize mercury detoxification conditions for strain MERCC_1942 in continuous culture, three different dilution rates were tested in bioreactors until the cultures achieved steady state, and they were subsequently exposed to a mercury spike; after 24 h, strain MERCC_1942 removed up to 76% of the total mercury. Moreover, when adapted to high growth rates in bioreactors, this strain exhibited the highest specific mercury detoxification rates. Finally, an immobilization protocol using the sol-gel technology was optimized. These results highlight that some sediment bacteria show capacity to detoxify mercury and could be used for bioremediation applications.

Sequential administration of paricalcitol followed by IL-17 blockade for progressive refractory IgA nephropathy patients.

There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn's disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs). Seven r-IgAN patients were treated with at least six months of oral paricalcitol, followed by the addition of subcutaneous anti-IL-17A (secukinumab). After a mean follow-up of 28 months, proteinuria decreased by 71% (95% CI: 56-87), P < 0.001. One patient started dialysis, while the annual eGFR decline in the remaining patients [mean (95% CI)] was reduced by 4.9 mL/min/1.73 m2 (95% CI: 0.1-9.7), P = 0.046. Circulating Th1, Th17, and Treg cells remained stable, but Th2 cells decreased, modifying the Th1/Th2 ratio. Intriguingly, accumulation of circulating Th17.1 cells was observed. This novel sequential therapy appears to optimize renal advantages in patients with r-IgAN and elicit alterations in potentially pathogenic T helper cells.

Influence of the COVID-19 pandemic on patients receiving oral anticoagulants for the treatment of non-valvular atrial fibrillation.

Background: Frequent monitoring of patients declined during the COVID-19 pandemic, harming patients with chronic diseases who critically needed correct monitoring. We evaluated the impact of the COVID-19 pandemic in patients with non-valvular atrial fibrillation (NVAF) receiving treatment with vitamin K antagonists (VKA) or non-vitamin K antagonist oral anticoagulants (NOAC) in clinical practice in Spain. Methods: This observational, retrospective study analyzed prevalent patients treated with NOAC/VKA on 14/03/2019 (pre-COVID-19 period) and 14/03/2020 (COVID-19 period), who were followed up to 12 months. The study also considered incident patients who started treatment with NOAC/VKA between 15/03/2019 and 13/03/2020 (pre-COVID-19 period) and from 15/03/2020 to 13/03/2021 (COVID-19 period). Demographic characteristics, comorbidities, effectiveness, treatment patterns, and healthcare resource utilization were considered. Results: Prevalent patients amounted to 12,336 and 13,342 patients, whereas 1,612 and 1,602 incident patients were included in the pre-COVID-19 and COVID-19 periods, respectively. Prevalent patients treated with VKA had more strokes, thromboembolism, and major bleeding compared to those receiving NOAC, particularly during the COVID-19 period. NOAC patients had a 12 % lower risk of death than those on treatment with VKA (Hazard ratio = 0.88 [95 % CI: 0.81 - 0.95], p = 0.033). In addition, VKA patients were less persistent after 12 months than NOAC patients (pre-COVID-19 period: 52.1 % vs. 78.9 %, p < 0.001; COVID-19 period: 49.2 % vs. 80.3 %, p < 0.001), and required more healthcare visits and hospitalizations than those on treatment with NOAC. Conclusion: Compared to VKA, NOAC seems to have reduced the incidence of severe events and the use of healthcare resources for NVAF, particularly during the pandemic.

Recommendations for the future management of thrombocytopenia in patients with liver cirrhosis: A modified RAND/UCLA appropriateness method / Recomendaciones para el futuro manejo de la trombocitopenia en pacientes con cirrosis hepática: una versión modificada de la Metodología RAND/UCLA

Objective The lack of consensus and specific guidelines, and the introduction of new treatments in thrombocytopenia management in liver cirrhosis patients, required a series of recommendations by experts to improve knowledge on this disease. This study's aim was to improve the knowledge around thrombocytopenia in liver cirrhosis patients, in order to contribute to the generation of future evidence to improve the management of this disease. Patients and methods A modified version of the RAND/UCLA appropriateness method was used. The scientific committee, a multidisciplinary team of 7 experts in managing thrombocytopenia in liver cirrhosis patients, identified the expert panel, and participated in elaborating the questionnaire. Thirty experts from different Spanish institutions were invited to answer a 48-item questionnaire covering 6 areas on a nine-point Likert scale. Two rounds were voted. The consensus was obtained if >77.7% of panelists reached agreement or disagreement. Results A total of 48 statements were developed by the scientific committee and then voted by the experts, resulting in 28 defined as appropriate and completely necessary, relating to evidence generation (10), care circuit, (8), hemorrhagic risk assessment, decision-making and diagnostic tests (14), professionals’ role and multidisciplinary coordination (9) and patient education (7). Conclusions This is the first consensus in Spain on the management of thrombocytopenia in liver cirrhosis patients. Experts indicated several recommendations to be carried out in different areas that could help physicians make better decisions in their clinical practice (AU)

Objetivo La falta de consenso y guías específicas, y la introducción de nuevos tratamientos para el manejo de la trombocitopenia en pacientes con cirrosis hepática, requerían recomendaciones expertas para mejorar el conocimiento sobre dicha patología. El objetivo de este estudio es mejorar el conocimiento sobre la trombocitopenia en pacientes con cirrosis hepática de cara a contribuir en la generación de futuras evidencias que mejoren el manejo de esta patología. Metodología Ae utilizó una versión modificada de la metodología Delphi RAND/UCLA. El comité científico, formado por 7 expertos en el manejo de la trombocitopenia en pacientes con cirrosis hepática, identificó un panel de expertos y participó en la elaboración del cuestionario de recomendaciones. Treinta expertos de diferentes hospitales españoles fueron invitados a responder al cuestionario. Los expertos respondieron a 48 ítems divididos en 6 áreas en una escala Likert de 9 puntos. La votación tuvo lugar en 2 rondas, en las que se obtuvo consenso siempre y cuando >77,7% de los panelistas alcanzasen acuerdo o desacuerdo. Resultados Cuarenta y ocho recomendaciones fueron elaboradas por el comité científico para su votación por parte del panel de expertos. Finalmente 28 recomendaciones fueron consideradas apropiadas y completamente necesarias: 10 de ellas relativas a la generación de evidencia; 8 al circuito de cuidados; 14 a la evaluación de riesgo hemorrágico, la toma de decisiones y los test diagnósticos; 9 al papel de los profesionales y la coordinación multidisciplinar, y 7 a la educación de los pacientes. Conclusiones Se trata del primer consenso español en el manejo de la trombocitopenia en pacientes con cirrosis hepática. Los expertos definieron un amplio número de recomendaciones que podrían contribuir a la toma de decisiones clínicas y a la mejora en el manejo de estos pacientes en la práctica clínica real (AU)

Recommendations for the future management of thrombocytopenia in patients with liver cirrhosis: A modified RAND/UCLA appropriateness method.

OBJECTIVE: The lack of consensus and specific guidelines, and the introduction of new treatments in thrombocytopenia management in liver cirrhosis patients, required a series of recommendations by experts to improve knowledge on this disease. This study's aim was to improve the knowledge around thrombocytopenia in liver cirrhosis patients, in order to contribute to the generation of future evidence to improve the management of this disease. PATIENTS AND METHODS: A modified version of the RAND/UCLA appropriateness method was used. The scientific committee, a multidisciplinary team of 7 experts in managing thrombocytopenia in liver cirrhosis patients, identified the expert panel, and participated in elaborating the questionnaire. Thirty experts from different Spanish institutions were invited to answer a 48-item questionnaire covering 6 areas on a nine-point Likert scale. Two rounds were voted. The consensus was obtained if >77.7% of panelists reached agreement or disagreement. RESULTS: A total of 48 statements were developed by the scientific committee and then voted by the experts, resulting in 28 defined as appropriate and completely necessary, relating to evidence generation (10), care circuit, (8), hemorrhagic risk assessment, decision-making and diagnostic tests (14), professionals' role and multidisciplinary coordination (9) and patient education (7). CONCLUSIONS: This is the first consensus in Spain on the management of thrombocytopenia in liver cirrhosis patients. Experts indicated several recommendations to be carried out in different areas that could help physicians make better decisions in their clinical practice.

Revisiting the mercury cycle in marine sediments: A potential multifaceted role for Desulfobacterota.

Marine sediments impacted by urban and industrial pollutants are typically exposed to reducing conditions and represent major reservoirs of toxic mercury species. Mercury methylation mediated by anaerobic microorganisms is favored under such conditions, yet little is known about potential microbial mechanisms for mercury detoxification. We used culture-independent (metagenomics, metabarcoding) and culture-dependent approaches in anoxic marine sediments to identify microbial indicators of mercury pollution and analyze the distribution of genes involved in mercury reduction (merA) and demethylation (merB). While none of the isolates featured merB genes, 52 isolates, predominantly affiliated with Gammaproteobacteria, were merA positive. In contrast, merA genes detected in metagenomes were assigned to different phyla, including Desulfobacterota, Actinomycetota, Gemmatimonadota, Nitrospirota, and Pseudomonadota. This indicates a widespread capacity for mercury reduction in anoxic sediment microbiomes. Notably, merA genes were predominately identified in Desulfobacterota, a phylum previously associated only with mercury methylation. Marker genes involved in the latter process (hgcAB) were also mainly assigned to Desulfobacterota, implying a potential central and multifaceted role of this phylum in the mercury cycle. Network analysis revealed that Desulfobacterota were associated with anaerobic fermenters, methanogens and sulfur-oxidizers, indicating potential interactions between key players of the carbon, sulfur and mercury cycling in anoxic marine sediments.

Heavy Metal Tolerance of Microorganisms Isolated from Coastal Marine Sediments and Their Lead Removal Potential.

In this study, 338 microorganisms, comprising 271 bacteria and 67 fungi, were isolated from sediment samples collected from underexplored Pacific and Caribbean regions of Colombia. Screening trials were conducted on selected strains (n = 276) to assess their tolerance to cadmium (Cd2+), lead (Pb2+), and zinc (Zn2+), leading to the identification of six bacteria capable of withstanding 750 mg·L-1 of each heavy metal ion. Three promising microorganisms, identified as Enterobacter sp. INV PRT213, Pseudomonas sp. INV PRT215, and Stenotrophomonas sp. INV PRT216 were selected for lead removal experiments using LB broth medium supplemented with 400 mg·L-1 Pb2+. Among these, Pseudomonas sp. INV PRT215 exhibited significant potential, removing 49% of initial Pb2+ after 240 min of exposure (16.7 g wet biomass·L-1, pH 5, 30 °C). Infrared spectra of Pb-exposed biomass showed changes in functional groups, including carbonyl groups of amides, carboxylate, phosphate, hydroxyl, and amine groups, compared to the not-exposed control. These changes suggested interactions between the metal and functional groups in the biomass. The findings of this study highlight the potential of microorganisms derived from coastal marine environments as promising candidates for future applications in bioremediation of polluted environments contaminated with heavy metals.

Gluteoplastia de aumento con implantes intramusculares para el mejoramiento del contorno corporal / Augmentation gluteoplasty with intramuscular implants to improve the physical measurement i:en

Introducción: La región glútea ha sido considerada una de las zonas más observadas tanto en mujeres como en hombres y constituye un ícono representativo de belleza corporal. En los últimos años se ha incrementado el deseo de las féminas de aumentar esta región anatómica con implantes. Objetivo: Determinar los resultados estéticos de la gluteoplastia de aumento con implantes intramusculares. Métodos: Se realizó un estudio prospectivo, longitudinal y descriptivo de 25 mujeres que acudieron a la consulta externa del Servicio de Cirugía Plástica del Hospital Clínico-Quirúrgico Hermanos Ameijeiras, desde agosto de 2016 hasta febrero de 2019, para solicitar el aumento de su región glútea con implantes. Resultados: En la serie predominaron el grupo etario de 31 a 40 años (36,0 %) y el fototipo de piel III (88,0 %); asimismo, solo 6 pacientes presentaron complicaciones (24,0 %), entre las cuales sobresalieron el seroma (20,8 %), la asimetría (12,5 %) y la dehiscencia de la sutura (8,3 %). Se observó un aumento significativo de la proyección glútea después de la intervención (α=0,05) y los resultados fueron buenos en la mayoría de las integrantes de la muestra (84,0 %). Conclusiones: La gluteoplastia de aumento con implantes intramusculares es un procedimiento seguro y ofrece resultados estéticos favorables.

Introduction: Gluteal region has been considered one of the most observed areas either in women as in men and constitutes a representative icon of corporal beauty. In the last years the desire of women to increase this anatomical region with implants has been increased. Objective: To determine the aesthetic results of the augmentation gluteoplasty with intramuscular implants. Methods: A prospective, longitudinal and descriptive study of 25 women that went to the Plastic Surgery Service outpatient consultation of Hermanos Ameijeiras Clinical Surgical Hospital was carried out from August, 2016 to February, 2019, to request the increase of the gluteal region with implants. Results: In the series there was a prevalence of the 31 to 40 age group (36.0%) and the skin phototype III (88.0%); also only 6 patients presented complications (24.0%), among which seroma (20.8%), asymmetry (12.5%) and anastomotic dehiscence (8.3%) were notable. A significant increase of the gluteal projection after the intervention was observed (α =0.05) and the results were good in most of the members of the sample (84.0%). Conclusions: The augmentation gluteoplasty with intramuscular implants is a safe procedure and offers favorable aesthetic results.

Expanding success in the isolation of abundant marine bacteria after reduction in grazing and viral pressure and increase in nutrient availability.

Isolation of microorganisms is a useful approach to gathering knowledge about their genomic properties, physiology, and ecology, in addition to allowing the characterization of novel taxa. We performed an extensive isolation effort on samples from seawater manipulation experiments that were carried out during the four astronomical seasons in a coastal site of the northwest Mediterranean to evaluate the impact of grazing, viral mortality, resource competition reduction, and light presence/absence on bacterioplankton growth. Isolates were retrieved using two growth media, and their full 16S rRNA gene was sequenced to assess their identity and calculate their culturability across seasons and experimental conditions. A total of 1,643 isolates were obtained, mainly affiliated to the classes Gammaproteobacteria (44%), Alphaproteobacteria (26%), and Bacteroidia (17%). Isolates pertaining to class Gammaproteobacteria were the most abundant in all experiments, while Bacteroidia were preferentially enriched in the treatments with reduced grazing. Sixty-one isolates had a similarity below 97% to cultured taxa and are thus putatively novel. Comparison of isolate sequences with 16S rRNA gene amplicon sequences from the same samples showed that the percentage of reads corresponding to isolates was 21.4% within the whole data set, with dramatic increases in the summer virus-reduced (71%) and diluted (47%) treatments. In fact, we were able to isolate the top 10 abundant taxa in several experiments and from the whole data set. We also show that top-down and bottom-up controls differentially affect taxa in terms of culturability. Our results indicate that culturing marine bacteria using agar plates can be successful in certain ecological situations. IMPORTANCE Bottom-up and top-down controls greatly influence marine microbial community composition and dynamics, which in turn have effects on their culturability. We isolated a high amount of heterotrophic bacterial strains from experiments where seawater environmental conditions had been manipulated and found that decreasing grazing and viral pressure as well as rising nutrient availability are key factors increasing the success in culturing marine bacteria. Our data hint at factors influencing culturability and underpin bacterial cultures as a powerful way to discover new taxa.

An international comparative analysis and roadmap to sustainable biosimilar markets.

Background: Although biosimilar uptake has increased (at a variable pace) in many countries, there have been recent concerns about the long-term sustainability of biosimilar markets. The aim of this manuscript is to assess the sustainability of policies across the biosimilar life cycle in selected countries with a view to propose recommendations for supporting biosimilar sustainability. Methods: The study conducted a comparative analysis across 17 countries from North America, South America, Asia-Pacific, Europe and the Gulf Cooperation Council. Biosimilar policies were identified and their sustainability was assessed based on country-specific reviews of the scientific and grey literature, validation by industry experts and 23 international and local non-industry experts, and two advisory board meetings with these non-industry experts. Results: Given that European countries tend to have more experience with biosimilars and more developed policy frameworks, they generally have higher sustainability scores than the other selected countries. Existing approaches to biosimilar manufacturing and R&D, policies guaranteeing safe and high-quality biosimilars, exemption from the requirement to apply health technology assessment to biosimilars, and initiatives counteracting biosimilar misconceptions are considered sustainable. However, biosimilar contracting approaches, biosimilar education and understanding can be ameliorated in all selected countries. Also, similar policies are sometimes perceived to be sustainable in some markets, but not in others. More generally, the sustainability of the biosimilar landscape depends on the nature of the healthcare system and existing pharmaceutical market access policies, the experience with biosimilar use and policies. This suggests that a general biosimilar policy toolkit that ensures sustainability does not exist, but varies from country to country. Conclusion: This study proposes a set of elements that should underpin sustainable biosimilar policy development over time in a country. At first, biosimilar policies should guarantee the safety and quality of biosimilars, healthy levels of supply and a level of cost savings. As a country gains experience with biosimilars, policies need to optimise uptake and combat any misconceptions about biosimilars. Finally, a country should implement biosimilar policies that foster competition, expand treatment options and ensure a sustainable market environment.

Top abundant deep ocean heterotrophic bacteria can be retrieved by cultivation.

Traditional culture techniques usually retrieve a small fraction of the marine microbial diversity, which mainly belong to the so-called rare biosphere. However, this paradigm has not been fully tested at a broad scale, especially in the deep ocean. Here, we examined the fraction of heterotrophic bacterial communities in photic and deep ocean layers that could be recovered by culture-dependent techniques at a large scale. We compared 16S rRNA gene sequences from a collection of 2003 cultured heterotrophic marine bacteria with global 16S rRNA metabarcoding datasets (16S TAGs) covering surface, mesopelagic and bathypelagic ocean samples that included 16 of the 23 samples used for isolation. These global datasets represent 60 322 unique 16S amplicon sequence variants (ASVs). Our results reveal a significantly higher proportion of isolates identical to ASVs in deeper ocean layers reaching up to 28% of the 16S TAGs of the bathypelagic microbial communities, which included the isolation of 3 of the top 10 most abundant 16S ASVs in the global bathypelagic ocean, related to the genera Sulfitobacter, Halomonas and Erythrobacter. These isolates contributed differently to the prokaryotic communities across different plankton size fractions, recruiting between 38% in the free-living fraction (0.2-0.8 µm) and up to 45% in the largest particles (20-200 µm) in the bathypelagic ocean. Our findings support the hypothesis that sinking particles in the bathypelagic act as resource-rich habitats, suitable for the growth of heterotrophic bacteria with a copiotroph lifestyle that can be cultured, and that these cultivable bacteria can also thrive as free-living bacteria.

Surface Morphology and Optical Properties of Hafnium Oxide Thin Films Produced by Magnetron Sputtering.

Hafnium oxide films were deposited on sapphire and silicon (100) substrates using the DC reactive magnetron sputtering technique from a pure hafnium target at different discharge power levels. The influence of the cathode power on the chemical composition, morphology, crystallographic structure and optical properties of the films was investigated. X-ray diffraction (XRD), energy dispersive X-ray analysis (EDX) and Fourier-transform infrared spectroscopy (FTIR) were employed to determine the chemical composition and bonding structure. In all cases, the films were found to be amorphous or nanocrystalline with increased crystalline content as the sputtering power was increased, according to XRD and FTIR. In addition, EDX showed that the films were oxygen-rich. The effect of power deposition on the surface topography and morphology of the films was studied using atomic force microscopy (AFM) and scanning electron microscopy (SEM). The AFM and SEM images revealed the emergence of mound morphologies as the cathode power was increased. These features are related to blistering effects probably due to the presence of stress and its promotion within the film thickness. Finally, the optical properties showed an average transmission of 80% in the visible range, and the refractive index determined by spectral ellipsometry (SE) was found to be in the range of 1.85-1.92, close to the reported bulk value. SE was also used to study the film porosity observed by SEM, which can be related to the oxygen-rich character of the films.

Healthcare resources and costs associated with nonvalvular atrial fibrillation in Spain: apixaban versus acenocoumarol.

Aim: Healthcare resources usage and costs associated to nonvalvular atrial fibrillation (NVAF) were analyzed in Spain. Methods: This is an observational and retrospective study on patients with NVAF who started their treatment with apixaban or acenocoumarol between 1 January 2015 and 31 December 2017. Results: 2160 patients treated with apixaban were paired (1:1) with patients treated with acenocoumarol (propensity score matching). Apixaban reduced the incidence of strokes and systemic embolisms, minor and major bleedings and deaths, versus acenocoumarol. Apixaban led to reductions of 80, 55 and 43% in costs related to nursing visits, hospitalizations, and emergency visits, respectively, leading to annual cost savings of €274/patient, from the perspective of society. Conclusion: Our results suggested that apixaban is a cost-effective alternative for patients with NVAF.

Dopamine receptors D1 and D2 show prognostic significance and potential therapeutic applications for endometrial cancer patients.

OBJECTIVE: Catecholaminergic signaling has been a target for therapy in different type of cancers. In this work, we characterized the ADRß2, DRD1 and DRD2 expression in healthy tissue and endometrial tumors to evaluate their prognostic significance in endometrial cancer (EC), unraveling their possible application as an antitumor therapy. METHODS: 109 EC patients were included. The expression of the ADRß2, DRD1 and DRD2 proteins was evaluated by immunohistochemistry and univariate and multivariate analysis to assess their association with clinic-pathological and outcome variables. Finally, HEC1A and AN3CA EC cell lines were exposed to different concentrations of selective dopaminergic agents alone or in combination to study their effects on cellular viability. RESULTS: ADRß2 protein expression was not associated with clinico-pathological parameters or prognosis. DRD1 protein expression was reduced in tumors samples but showed a significant inverse association with tumor size and stage. DRD2 protein expression was significantly associated with non-endometrioid EC, high grade tumors, tumor size, worse disease-free survival (HR = 3.47 (95%CI:1.35-8.88)) and overall survival (HR = 2.98 (95%CI:1.40-6.34)). The DRD1 agonist fenoldopam showed a reduction of cellular viability in HEC1A and AN3CA cells. The exposure to domperidone, a DRD2 antagonist, significantly reduced cell viability compared to the control. Finally, DRD1 agonism and DRD2 antagonism combination induced a significant reduction in cell viability of the AN3CA cells compared to monotherapy, close to being an additive response than a synergistic effect (CI of 1.1 at 0.5% Fa). CONCLUSION: DRD1 and DRD2 expression levels showed a significant association with clinico-pathological parameters. Both the combined activation of DRD1 and blockage of DRD2 may form an innovative strategy to inhibit tumor growth in EC.

A Metagenomic and Amplicon Sequencing Combined Approach Reveals the Best Primers to Study Marine Aerobic Anoxygenic Phototrophs.

Studies based on protein-coding genes are essential to describe the diversity within bacterial functional groups. In the case of aerobic anoxygenic phototrophic (AAP) bacteria, the pufM gene has been established as the genetic marker for this particular functional group, although available primers are known to have amplification biases. We review here the existing primers for pufM gene amplification, design new ones, and evaluate their phylogenetic coverage. We then use samples from contrasting marine environments to evaluate their performance. By comparing the taxonomic composition of communities retrieved with metagenomics and with different amplicon approaches, we show that the commonly used PCR primers are biased towards the Gammaproteobacteria phylum and some Alphaproteobacteria clades. The metagenomic approach, as well as the use of other combinations of the existing and newly designed primers, show that these groups are in fact less abundant than previously observed, and that a great proportion of pufM sequences are affiliated to uncultured representatives, particularly in the open ocean. Altogether, the framework developed here becomes a better alternative for future studies based on the pufM gene and, additionally, serves as a reference for primer evaluation of other functional genes.