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Vanadium bis-phosphine imido and oxo chloride alkylidenes have been extensively applied in the ring-closing metathesis of various acyclic olefins. However, their reactions involving ethylene have shown limited productivity due to rapid decomposition. The primary degradation pathway involving V bis-phosphine imido complexes is β-H elimination at an unsubstituted metallacyclobutane. In contrast, β-H elimination is disfavored for V oxo species, but bimolecular decomposition precludes its high productivity. Herein, we present the synthesis of V imido NHC complexes that are the most productive V catalysts toward various terminal olefins in ring-closing metathesis reactions. Experimental and computational studies suggest that β-H elimination and bimolecular decomposition are disfavored for V imido NHC complexes.

The interaction between the T‐lymphocyte costimulatory molecule ICOS and its ligand (ICOS‐L) is needed for efficient immune responses, but expression levels are tightly controlled, as altered expression of ICOS or ICOS‐L may lead to immunodeficiency, or favor autoimmune diseases and tumor growth. Using cells of mouse B cell lymphoma (M12.C3) and melanoma (B16), or hamster CHO cells transfected with various forms of mouse ICOS‐L, and ICOS+T cell lines, we show that, within minutes, ICOS induces significant downmodulation of surface ICOS‐L that is largely mediated by endocytosis and trans‐endocytosis. So, after interaction with ICOS+cells, ICOS‐L was found inside permeabilized cells, or in cell lysates, with significant transfer of ICOS from ICOS+T cells to ICOS‐L‐expressing cells, and simultaneous loss of surface ICOS by the T cells. Data from cells expressing ICOS‐L mutants show that conserved, functionally important residues in the cytoplasmic domain of mouse ICOS‐L (Arg300, Ser307and Tyr308), or removal of ICOS‐L cytoplasmic tail have minor effect on its internalization. Internalization was dependent on temperature, and was partially dependent on actin polymerization, the GTPase dynamin, protein kinase C, or the integrity of lipid rafts. In fact, a fraction of ICOS‐L was detected in lipid rafts. On the other hand, proteinase inhibitors had negligible effects on early modulation of ICOS‐L from the cell surface. Our data add a new mechanism of control of ICOS‐L expression to the regulation of ICOS‐dependent responses. ICOS‐induced downmodulation of ICOS‐L involving endocytosis and trans‐endocytosis controls ICOS‐L levels and can regulate immune responses that are dependent on ICOS costimulation

Presentamos el caso de una mujer hondureña de 27 años sin antecedentes médicos de interés que presentó múltiples áreas de desprendimientos de retina (DR) exudativos y una mejor agudeza visual corregida de 1,3logMAR en ambos ojos. Fue diagnosticada de síndrome de Vogt-Koyanagi-Harada incompleto y tratada con prednisolona intravenosa (1g/24h) durante 3 días, tal y como recomienda la evidencia publicada, junto con micofenolato de mofetilo (2g/24h). Durante el descenso paulatino de corticoesteroides, los DR recidivaron, por lo que se reintrodujeron las megadosis de 1g/24h de corticoesteroides intravenosos durante 6 días hasta la resolución completa de los DR y se añadieron ciclosporina (100mg/24h), triamcinolona subtenoniana (40mg/mL) e inyecciones intravítreas mensuales de ranibizumab en ambos ojos, con un adecuado control de la inflamación coroidea que se tradujo en la remisión de los síntomas y signos.

V imido alkylidenes have been applied for the ring-opening metathesis polymerization involving cyclic olefins. However, those complexes found limited application in reactions with acyclic terminal olefins due to instability toward ethylene. Experimental and theoretical studies show that the β-hydride elimination from unsubstituted metallacyclobutene is the primary decomposition pathway in those systems. Herein, we report the synthesis of the first catalytically active V oxo alkylidene, VO(CHSiMe3)(PEt3)2Cl, which exhibits the highest reported productivity with various terminal olefins in ring-closing metathesis reactions among known V catalysts. Presented DFT studies indicate that β-hydride elimination is significantly disfavored for V oxo species.

Establecer recomendaciones de consenso sobre normas de buena práctica clínica en la atención a los pacientes al final de la vida.

A low CD4/CD8 ratio during antiretroviral therapy (ART) identifies people with heightened immunosenescence and increased risk of mortality. We aimed to assess the effects of integrase strand transfer inhibitor (INSTI)-based, protease inhibitor-based, or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART on long-term CD4/CD8 ratio recovery.

Because nitric oxide could play an important role in the pathogenesis of migraine (suggested by experimental, neuropathological, biochemical, and pharmacological data), and a recent meta-analysis showed an association between the single-nucleotide polymorphism (SNP) rs2070744 in the endothelial nitric oxide synthase (eNOSor NOS3)gene (chromosome 7q36.1) and the risk for migraine in Caucasians, we attempted to replicate the possible association between this SNP and the and the risk for migraine in the Caucasian Spanish population. The frequencies for the NOS3rs2070744 genotypes and allelic variants were assessed in 283 migraine patients and 287 healthy controls with a TaqMan-based qPCR Assay. The putative influence on genotype frequency of age at onset of migraine attacks, gender, family history of migraine, absence or presence of aura, and triggering of migraine attacks by ethanol, were also analyzed. The frequencies of NOS3rs2070744 genotypes and allelic variants were not associated with the risk for migraine (OR [95%] CI for the minor allele = 0.91 [0.72–1.15]) and were not influenced by age at onset of migraine, gender, presence of aura, or triggering of migraine attacks by ethanol. NOS3rs2070744CC genotypes were significantly more frequent in patients with a family history of migraine. NOS3rs2070744 SNP is not associated with the risk for migraine in Caucasian Spanish people although it might be related to family history.

A new technique for measurement of glufosinate (GLU), glyphosate (GLY) and its metabolite aminomethylphosphonic acid (AMPA) using liquid chromatography with tandem mass spectrometry with a triple quadrupole (LC-QqQ-MS/MS) is proposed for the analysis of vegetables, agricultural soil and irrigation water. An ion-pair liquid–liquid microextraction (IP-LLME) procedure using 9-fluorenylmethyl chloroformate as the derivatizing reagent, methyl isobutyl ketone as the extraction solvent and hexadecyltrimethylammonium bromide as the ion-pair reagent was performed for preconcentration purposes, because the herbicides are present at very low concentrations. Limits of quantification (LOQs) of 0.5 ng mL−1, 2.5 μg kg−1and 1.6 μg kg−1were obtained for water, vegetables and soil, respectively. Repeatability and reproducibility were calculated using the relative standard deviation, and values ranged between 6 and 11%, depending on the analyte. Enrichment factors were 62, 60 and 85 for GLY, GLU and AMPA, respectively.

Liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) with a triple quadrupole (QqQ) is proposed for determining the vitamin K homologues, phylloquinone (PK), menaquinone-4 (MK) and menadione (MD), in vegetables. The analytes were isolated from the samples (1–1.5 g) by ultrasound assisted extraction using acetonitrile (2 mL), and the liquids were submitted to microwave assisted cloud point extraction with Triton X-45. The enrichment factors were between 20 and 50, depending on the vitamin homologue in question. The analytes were determined by LC-ESI-QqQ-MS/MS in the multiple reaction monitoring (MRM) mode, providing unequivocal identification and quantification, with limits of detection of 0.8, 1.0, and 16 ng/g for MK, PK, and MD, respectively. Recovery assays for samples spiked at two concentration levels, between 40 and 600 ng/g depending on the compound, provided recoveries in the 90–114% range. Only PK was detected in the samples analyzed, at concentrations in the 90–2350 ng/g range.

Agriculture is an activity closely related to nature, but at the same time can be the source of negative and permanent environmental effects. In this work we have evaluated the combination of solarization and ozonation techniques for the elimination of six amide pesticides (boscalid, chlorantraniliprole, cyflufenamid, fluopyram, napropamide, and propyzamide) in soil. Initial experiments were performed with four different soils in order to assess the efficiency of this methodology in laboratory conditions. The influence of soil temperature and ozone dosage was also investigated. Different treatments were conducted under controlled conditions, with pots placed inside a greenhouse during the summer season. After 50 days since the beginning of the trials, higher degradation percentages were observed in ozonized soils, in particular when ozone is applied at 10 cm depth. Results exhibit that the utilisation of ozone, along with solarization, represents a valid method for degrading residues of the studied pesticides and suggests that this combined technology could be a promising tool for remediating pesticide polluted soils.

ABSTRACTWe test whether European countries or US states who experienced their first death from COVID-19 at a later date have fewer deaths from COVID  60 and 100 days after the start of the pandemic in their borders. Our sample consists of 29 European countries associated with the European Union and 50 U.S. states and we control for a number of demographic, economic and health-policy related factors that are likely to influence mortality. We find that late starting countries or states registered fewer deaths from COVID-19. Countries/states’ differential reliance on partial or complete lockdown policies helps explain an areas' advantage of being a late starter.

Stomatal cell lineage is an archetypal example of asymmetric cell division (ACD), which is necessary for plant survival1–4. In Arabidopsis thaliana, the GLYCOGEN SYNTHASE KINASE3 (GSK3)/SHAGGY-like kinase BRASSINOSTEROID INSENSITIVE 2 (BIN2) phosphorylates both the mitogen-activated protein kinase (MAPK) signalling module5,6and its downstream target, the transcription factor SPEECHLESS (SPCH)7, to promote and restrict ACDs, respectively, in the same stomatal lineage cell. However, the mechanisms that balance these mutually exclusive activities remain unclear. Here we identify the plant-specific protein POLAR as a stomatal lineage scaffold for a subset of GSK3-like kinases that confines them to the cytosol and subsequently transiently polarizes them within the cell, together with BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL), before ACD. As a result, MAPK signalling is attenuated, enabling SPCH to drive ACD in the nucleus. Moreover, POLAR turnover requires phosphorylation on specific residues, mediated by GSK3. Our study reveals a mechanism by which the scaffolding protein POLAR ensures GSK3 substrate specificity, and could serve as a paradigm for understanding regulation of GSK3 in plants.

Analizar la incidencia y los resultados visuales de cada uno de los subtipos de lesión neovascular en pacientes con degeneración macular asociada la edad (DMAE).

The possible role of gammaaminobutyric acid (GABA) in the pathophysiology of restless legs syndrome (RLS) is suggested by the symptomatic improvement achieved with GABAergic drugs. Thalamic GABA levels have shown positive correlation with periodic limb movements indices and with RLS severity. We tried to investigate the possible association between the most common single nucleotide polymorphisms (SNPs) in the GABA receptors(GABR) genes rho1, 2, and 3(GABRR1, GABRR2, GABRR3), alpha4(GABRA4), epsilon(GABRE), and theta(GABRQ) with the risk of developing RLS. We studied the genotype and allelic variant frequencies of the most common SNPs in the GABRR1(rs12200969, rs1186902), GABRR2(rs282129), GABRR3(rs832032), GABRA4(rs2229940), GABRE(rs1139916), and GABRQ(rs3810651) genes in 205 RLS patients and 230 age- and gender-matched healthy controls using specific TaqMan assays. The frequencies of the GABRR3rs832032TT genotype and the allelic variant GABRR3rs832032T were significantly higher in RLS patients than in controls (odds ratio [95% confidence intervals] 7.08[1.48–46.44] and 1.66[1.16–2.37], respectively), although only the higher frequency of the rs832032T allele remained as significant after multiple comparison analysis, both in the whole series and in the female gender. The frequencies of the other genotypes of allelic variants did not differ significantly between RLS patients and controls. RLS patients carrying the GABRA4rs2229940TT genotype showed a significantly younger age at onset of RLS symptoms than those with the other two genotypes. These results suggest association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4rs2229940 on the age of onset of RLS.

We report the case of a patient who developed keloid scarring associated with Mammostat-induced skin trauma during reduction mammoplasty. A 32-year-old patient consulted for breast hypertrophy and developed from the fourth postoperative month significant keloid scars on skin shears caused by dermal stretching techniques used during de-epithelialization. The Mammostat-related scars were keloid, while those found on old skin incisions were only enlarged and slightly hypertrophic. We followed up this patient for 7 years. During this time, she received the following local treatments: scar kneading, silicone dressings, intralesional injections of corticosteroids, and potent dermocorticosteroids. After balancing the benefit/risk ratio of a possible revision surgery for resection and plasty of her keloid scars, we opted for therapeutic abstention. In patients at high risk of keloids, we recommend a soft de-epithelialization causing no skin shear, performed by manual tensioning of the dermis.

ABSTRACTIn nuclear safety field, neutronic and thermalhydraulic codes performance is an important issue. New capabilities implementation, as well as models and tools improvements are a significant part of the community effort in looking for better nuclear power plants (NPP) designs. A procedure to analyze the PWR response to local deviations on neutronic or thermalhydraulic parameters is being developed. This procedure includes the simulation of Incoreand Excoreneutron flux detectors signals. A control rod drop real plant transient is used to validate the used codes and their new capabilities. Cross-section data are obtained by means of the SIMTAB methodology. Detailed thermalhydraulic models were developed: RELAP5 and TRACE models simulate three different azimuthal zones. Besides, TRACE model is performed with a fully three-dimensional core, thus, the cross-flow can be obtained. A Cartesian vessel represents the fuel assemblies and a cylindrical vessel the bypass and downcomer. Simulated detectors signals are obtained and compared with the real data collected during a control rod drop trial at a PWR NPP and also with data obtained with SIMULATE-3K code.

To assess the prevalence of vitreoretinal interface abnormalities in a general population of healthy adults ≥45 years of age.

Conocer el porcentaje de recuperación funcional, según estrategia pro re nata(PRN) con inyecciones intravítreas con ranibizumab en pacientes con degeneración macular asociada a la edad (DMAE).

Purpose To evaluate the association between subfoveal choroidal thickness and the visual outcome in eyes with type 1 choroidal neovascularization (CNV) due to neovascular age-related macular degeneration (nAMD).Methods This was a retrospective, longitudinal, cross-sectional study including patients diagnosed with nAMD type 1 lesions managed with intravitreal injections of ranibizumab in a PRN strategy during 24 months. Retrospective chart review of patients with type 1 CNV recording the visual acuity, number of intravitreal injections, multimodal imaging data, and follow-up period was performed. Subfoveal choroidal thickness was measured using enhanced depth imaging scans obtained with spectral-domain optical coherence tomography.Results Twenty-five eyes of 21 patients were included. The mean baseline logMAR best-corrected visual acuity was 0.52 (+0.35) (median 0.5; range 0.1-1; interquartile range (IQR) 0.3-0.8) and improved to 0.39 (+0.39) (median 0.4; range 0.1-1; IQR 0.2-0.5) by the end of the follow-up (p = 0.038). Subfoveal choroidal thickness was 202.8 (+60.3) μm (median 218; range 81-285; IQR 146-258). Statistical mixed effects model demonstrated an association between rate of improvement of visual acuity with subfoveal choroidal thickness after 24 months (p<0.001) (95% confidence interval 0.0002-0.0001 logMAR month μm); higher thickness values were correlated with better visual acuity.Conclusions Thicker subfoveal choroid was associated with better visual outcomes in patients with type 1 CNV due to nAMD following a strict PRN regimen with intravitreal ranibizumab at 24 months of follow-up.

Presentar la relevancia clínica de la clasificación anatómica de la forma neovascular de degeneración macular asociada a la edad (DMAE).

The application of pesticides is a common practice for pest control. Either its excessive use or by performing improper farming practices, the occurrence of residual levels of these compounds in soil has become a global issue due to their negative impacts on environment and human health. This work was aimed to assess the effectiveness of ozonation technique for the remediation of soils polluted with boscalid, chlorantraniliprole, flonicamid and metribuzin residues at field conditions and the impact of its application on microorganism activity of the soil. Trial was conducted in plots located in a greenhouse, exposing polluted soil to different treatments during the winter season. Four different treatments were applied: S (soil covered with polyethylene film), SOD (film covering and deep-ozonation), SOSD (film covering and superficial-deep-ozonation) and C (no treatment, control). Better degradation efficiency was found for SOSD treatment (dual ozone application), where remaining percentages ranged from 13.2 % to 33.1 %. The main transformation products (TPs) were monitored through the remediation experiment, showing residual levels of six intermediates in all treatments. Further, the overall activity of the soil microbial community was evaluated through basal respiration, with SOSD showing the greatest microbial activity. The results suggest that ozonation could be proposed as an alternative technical approach for the remediation of pesticide polluted soils.

ABSTRACTTemporal trends of serotypes from invasive pneumococcal disease (IPD) in Spain from 1979 to September 2007 under antibiotic and vaccine pressure were analyzed. A significant trend in pneumococcal conjugate 7-valent vaccine (PCV7) serotypes (except serotype 4) was found, whereby the prevalence increased from the early 1980s and decreased in the 2000s for all but serotype 23F, which began decreasing in the late 1980s. Among the major non-PCV7 serotypes, a significant decrease was observed for serotypes 1, 5, and 7F in the 1980s. From the late 1990s, serotypes 1, 5, 6A, 7F, and 19A increased significantly, while serotypes 3 and 8 showed similar but nonsignificant trends over time. The incidence of IPD cases was 10.7/100,000 for the period 1996 to 2006, with reporting coverage ranging from 18% to 43%. A significant decrease in IPD incidence due to PCV7 serotypes was observed, while the incidence of non-PCV7 serotypes increased, with the consequence that there was no clear pattern in the overall incidence of IPD. Penicillin nonsusceptibility was correlated with the proportion of PCV7 serotypes. Erythromycin nonsusceptibility increased in association with long-half-life macrolide consumption and then decreased in 2004 to 2007. The increase in PCV7 serotypes and antibiotic nonsusceptibility related to antibiotic consumption in the 1980s and 1990s was reversed in the 2000s, probably as a result of PCV7 immunization. The decrease in IPD incidence due to PCV7 serotypes was mirrored by an increase in that of non-PCV7 serotypes. The impact of various preventive/therapeutic strategies on pneumococcal evolution is serotype dependent, and the dynamics remain unpredictable.

Purpose: To evaluate the prevalence of different optical coherence tomography (OCT) findings in European patients with high myopia.Methods: Cross-sectional study conducted in the Macula Unit of the University and Polytechnic Hospital La Fe (Valencia, Spain). A total of 134 myopic eyes of 69 patients (16 males and 53 females) were included. All patients underwent a spectral domain OCT examination at least once. The presence of tractional and atrophic myopic maculopathy and choroidal neovascularization (CNV) was evaluated through OCT scans.Results: The prevalence of tractional myopic maculopathy was found in 53.7% of the eyes. Within this group, 9.7% had foveal retinoschisis, 23.9% extrafoveal retinoschisis, 31.3% internal limiting membrane rigidity, 24.6% epiretinal membrane, and none had vitreomacular traction. The most prevalent OCT finding was chorioretinal atrophy, present in 79.1% of the eyes. Choroidal neovascularization was present in 61.9% of the eyes. There was a trend toward higher prevalence of CNV in eyes with patchy atrophy with foveal involvement compared to those without foveal involvement (81.8% vs 65.5%; P= .103).Conclusion: The prevalence of CNV was quite high, especially in patients with patchy atrophy with foveal involvement.

La internacionalización de la educación médica es un tema relevante cuya importancia va en aumento con el paso de los años en un mundo cada vez más globalizado. Sorprende, sin embargo, que exista confusión sobre el significado del término «internacionalización» y que se utilice de manera diferente en educación superior y esto se detecta especialmente en los procesos de evaluación de la calidad y acreditación de titulaciones.

El objetivo de este estudio es analizar la efectividad, seguridad y costes de aflibercept en el tratamiento de la degeneración macular relacionada con la edad (DMAE) refractaria al ranibizumab.

La promoción de la excelencia en educación universitaria es un tópico de reciente interés. Algunas enseñanzas de grado y máster, como Ingeniería e Informática, tienen definido su modelo de excelencia internacional, y alcanzar los estándares establecidos supone la obtención de un sello de reconocimiento. La ausencia de mecanismos de reconocimiento de la excelencia en el ámbito de la educación médica a nivel mundial, mediante revisión por pares del mismo ámbito profesional, ha motivado por parte de la Association for Medical Education in Europe(AMEE) la puesta en marcha de diversas acciones para promover la excelencia educativa a nivel internacional en la formación de médicos, odontólogos y veterinarios en facultades de Medicina y Ciencias de la Salud.