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Introduction and objectives Microvascular obstruction (MVO) is negatively associated with cardiac structure and worse prognosis after ST-segment elevation myocardial infarction (STEMI). Epithelial cell adhesion molecule (EpCAM), involved in epithelium adhesion, is an understudied area in the MVO setting. We aimed to determine whether EpCAM is associated with the appearance of cardiac magnetic resonance (CMR)-derived MVO and long-term systolic function in reperfused STEMI. Methods We prospectively included 106 patients with a first STEMI treated with percutaneous coronary intervention, quantifying serum levels of EpCAM 24 hours postreperfusion. All patients underwent CMR imaging 1 week and 6 months post-STEMI. The independent correlation of EpCAM with MVO, systolic volume indices, and left ventricular ejection fraction was evaluated. Results The mean age of the sample was 59 ± 13 years and 76% were male. Patients were dichotomized according to median EpCAM (4.48 pg/mL). At 1-week CMR, lower EpCAM was related to extensive MVO (P = .021) and larger infarct size (P = .019). At presentation, EpCAM values were significantly associated with the presence of MVO in univariate (OR, 0.58; 95%CI, 0.38-0.88; P = .011) and multivariate logistic regression models (OR, 0.55; 95%CI, 0.35-0.87; P = .010). Although MVO tends to resolve at chronic phases, decreased EpCAM was associated with worse systolic function: reduced left ventricular ejection fraction (P = .009) and higher left ventricular end-systolic volume (P = .043). Conclusions EpCAM is associated with the occurrence of CMR-derived MVO at acute phases and long-term adverse ventricular remodeling post-STEMI.

ARPE-19 retinal pigment epithelial cells cultured in a medium containing 35 mM D-glucose led to an augmented ROS formation and release of vascular endothelial factor (VEGF)-containing exosomes compared to ARPE-19 cells cultured in a medium containing 5 mM D-glucose (standard medium). Exposing these cells to the melanocortin 5 receptor agonist (MCR5) PG-901 (10−10M), for 9 d reduced ROS generation, the number of exosomes released and their VEGF content. In contrast, incubating the cells with the melanocortin receptor MCR1 agonist BMS-470539 (10−5 M) or with the mixed MCR3/4 agonist MTII (0.30 nmol) did not produce any significant decrease in ROS levels. ARPE-19-derived VEGF-containing exosomes promoted neovascularization in human umbilical vein endothelial cells (HUVEC), an effect that was markedly reduced by PG-901 (10−10M) but not by the MCR3/4 agonist MTII (0.30 nmol) or the MCR1 agonist BMS-470539 (10−5 M). The MCR5-related action in the ARPE-19 cells was accompanied by the increased expression of two coupled factors, cytochrome p4502E1 (CYP2E1) and nuclear factor kappa b (Nf-κB). These are both involved in high glucose signalling, in ROS generation and, interestingly, were reduced by the MCR5 agonist in the ARPE-19 cells. Altogether, these data suggest that MCR5 is a modulator of the responses stimulated by glucose in ARPE-19 cells, which might possibly be translated into a modulation of the retinal pigment epithelium response to diabetes in vivo. Sin financiación 3.699 JCR (2019) Q2, 95/195 Cell Biology 1.319 SJR (2019) Q1, 318/2754 Medicine (miscellaneous); Q2, 106/300 Cell Biology, 23/87 Developmental Biology, 138/414 Molecular Biology No data IDR 2019 UEV

A novel concept for the synthesis of halogenated, conjugated dienes is disclosed: the CpTiCl2 -catalyzed coupling of keto-alkynes, in the presence of Me3 SiBr/Et3 N⋅HBr. This reaction provided five-, six-, and seven-membered carbocycles, nitrogenated heterocycles, as well as six-membered oxygenated heterocycles leading to a brominated conjugate diene. These products showed high reactivity in the Diels-Alder, Suzuki, and Sonogashira reactions, giving complex chemical structures in only three steps from the corresponding acyclic keto-alkyne. Hopefully, this strategy will pave the way towards the synthesis of bioactive natural products and new materials.

Background The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

J.A.R.N. thanks EU Feder funding, MINECO (CTQ2017-84692-R) and Junta de Andalucia (P18-RT-612). S.S. thanks the Erasmus+ (Placement) and the University of Milan for funding her stay in Granada. V.C. thanks the Italian Ministry of University and Research is acknowledged for financial support through the PRIN 2107 Program (Project 2017KKP5ZR). E.R.M. thanks UGR for a research contract. A.M. and F.A. thank Tarbiat Modares University for funding support., C2H2/CO2 separation is a highly challenging process as a consequence of their similar physicochemical properties. In this work we have explored, by static and dynamic gas sorption techniques and computational modelling, the suitability of a series of two isoreticular robust Ni(II)pyrazolatebased MOFs, bearing alkyne moieties on the ligand backbones, for C2H2/CO2 separation. The results are consistent with high adsorption capacity and selectivity of the essayed systems towards C2H2 molecules. Furthermore, a post-synthetic treatment with KOH ethanolic solution gives rise to linker vacancy defects and incorporation of extraframework potassium ions. Creation of defects is responsible for increased adsorption capacity for both gases, however, strong interactions of the cluster basic sites and extraframework potassium cations with CO2 molecules are responsible for a lowering of C2H2 over CO2 selectivity., European Commission, MINECO CTQ2017-84692-R, Junta de Andalucia P18-RT-612, Erasmus+ (Placement), University of Milan, Ministry of Education, Universities and Research (MIUR) 2017KKP5ZR, UGR, Tarbiat Modares University

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study was funded by “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” Bachground. Microvascular obstruction (MVO) is negatively associated with cardiac structure and worse prognosis after ST-segment elevation myocardial infarction (STEMI). Epithelial cell adhesion molecule (EpCAM), involved in endothelium adhesion, is an understudied area in the MVO setting. Purpose. We aimed to evaluate whether EpCAM is associated with the appearance of cardiac magnetic resonance (CMR)-derived MVO and long-term systolic function in reperfused STEMI. Methods. We prospectively included 106 patients with a first STEMI treated with primary percutaneous coronary intervention, quantifying serum levels of EpCAM 24 hours post-reperfusion. All patients underwent CMR imaging 1 week and 6 months post-STEMI. The independent correlation of EpCAM with MVO, systolic volume indices, and left ventricular ejection fraction (LVEF) was evaluated. Results. The mean age of the sample was 59 ± 13 years and 76% were male. Patients were dichotomized according to EpCAM median (4.48 pg/mL). At 1-week CMR, lower EpCAM was related to extensive MVO (p-value = 0.02) and greater infarct size (p-value = 0.02). At presentation, only EpCAM values were significantly associated with the presence of MVO in univariate (Odds Ratio [95% confidence interval] (OR [95% CI]): 0.58 [0.38-0.88], p-value = 0.01) and multivariate logistic regression models (OR [95% CI]: 0.54 [0.34-0.85], p-value = 0.007). Although MVO tends to resolve at chronic phases, decreased EpCAM was associated with worse systolic function: depressed LVEF (p-value = 0.009) and higher left ventricular end-systolic volume (p-value = 0.04). Conclusions. EpCAM is associated with occurrence of CMR-derived MVO at acute phases and long-term adverse ventricular remodeling post-STEMI. Future studies are needed to confirm EpCAM as biomarker, and eventually biotarget in STEMI pathophysiology.

Poloxamer 188 (P188) is formulated in proteinaceous therapeutics as an alternative surfactant to polysorbate because of its good chemical stability and surfactant properties, which enable interfacial protection, preventing visible and sub-visible particle formation. However, due to the nature of polymer heterogeneity and limited analytical approaches to resolve the superimposed components of P188, the impact of its quality variance on protein stability is still not well understood. In this study, we developed an analytical method to evaluate the components of P188 as a function of the length of polypropylene oxide (PPO), by maintaining polyethylene oxide (PEO) at the critical point of adsorption (CPA) to eliminate its chromatographic interference. The effectiveness of the separation was confirmed by nuclear magnetic resonance (NMR) spectroscopy and mass spectroscopy (MS) of the individual fractions corresponding to each peak. Additionally, a design of experiments (DoE) and method qualification were carried out to identify and optimize the key operation parameters, including column temperature and evaporative light scattering detector (ELSD) settings that need to be strictly controlled for reliable analytical results. In conclusion, this method is sensitive and reliable to compare the quality variance of commercial P188 and is suitable for routine quality control purposes. The application of this method could help in further understanding the Critical Material Attributes (CMA) that may affect the quality attributes of proteins in formulations.

We optimized and prospectively evaluated a simple MALDI-TOF MS-based method for direct detection of third-generation oxymino-cephalosporin resistance (3rd CephR) in Escherichia coli and Klebsiella spp. from blood cultures (BC). In addition, we assessed the performance of a lateral flow immunochromatographic assay (LFIC) for detecting extended-spectrum β-lactamases (ESBL) (NG-Test CTX-M MULTI assay) using bacterial pellets from BC. A total of 168 BCs from unique patients were included. A pre-established volume of BC flagged as positive was transferred in brain heart infusion with or without ceftriaxone (2 mg/ml). After 2-h incubation, intact bacterial pellets were used for MALDI-TOF MS testing. Identification of bacterial species (index score > 2) in the presence of CRO was considered marker of 3rd CephR. The LFIC assay was evaluated in 141 BC. Bacteremia episodes were caused by E. coli (n = 115) or Klebsiella spp. (n = 53). A total of 49 strains were 3rd CephR by broth microdilution, of which 41 were ESBL producers, seven expressed ESBL and OXA-48 type D carbapenemase, and one harbored a plasmid-mediated AmpC. The MALDI-TOF MS method yielded four very major errors (false susceptibility) and two major errors (false resistance). The overall sensitivity of the assay was 91.8% and the specificity 98.3%. Concordance between the LFIC assay and the MALDI-TOF MS method for detection of ESBL-mediated 3rd CephR was 100%. Both evaluated methods may prove useful for early adjustment of empirical therapy in patients with E. coli and Klebsiella spp. bloodstream infections. Whether their use has a beneficial impact on patient outcomes is currently under investigation.

Age related macular degeneration (AMD) is a common retina-related disease leading to blindness. Little is known on the origin of the disease, but it is well documented that oxidative stress generated in the retinal pigment epithelium and choroid neovascularization are closely involved. The study of circulating miRNAs is opening new possibilities in terms of diagnosis and therapeutics. miRNAs can travel associated to lipoproteins or inside small Extracellular Vesicles (sEVs). A number of reports indicate a significant deregulation of circulating miRNAs in AMD and experimental approaches, but it is unclear whether sEVs present a significant miRNA cargo. The present work studies miRNA expression changes in sEVs released from ARPE-19 cells under oxidative conditions (i.e. hydrogen peroxide, H2O2). H2O2 increased sEVs release from ARPE-19 cells. Moreover, 218 miRNAs could be detected in control and H2O2 induced-sEVs. Interestingly, only two of them (hsa-miR-302a and hsa-miR-122) were significantly under-expressed in H2O2-induced sEVs. Results herein suggest that the down regulation of miRNAs 302a and 122 might be related with previous studies showing sEVs-induced neovascularization after oxidative challenge in ARPE-19 cells.

© 2020 The Author(s)., [Objectives]: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters., [Methods]: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs)., [Results]: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22–0.47; p < 0.001) for tocilizumab, 0.82 (0.71–1.30; p 0.82) for IHDC, 0.61 (0.43–0.86; p 0.006) for PDC, and 1.17 (0.86–1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02–0.17; p < 0.001)., [Conclusions]: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situation., IJ has received honoraria for participating in an advisory board from Gilead Sciences, and for educational activities from ViiV. JB has received research grants from AbbVie, Gilead Sciences, Merck, and ViiV, and honoraria for being a speaker or advisory board participation from AbbVie, Gilead Sciences, Janssen, Merck, and ViiV. JRA received fees for participating in an advisory board, being a speaker, and research grant support from Viiv, Janssen, Gilead, MSD, Teva, Alexa and Serono. PR is involved as speaker or advisory board participant for Gilead Sciences, AbbVie and ViiV. JR-B, JP, JC and MY have no conflicts of interest to declare. SAM-COVID was funded by Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (COV20/01031) co-funded by European Union (ERDF/ESF, “Investing in your future”) and Fundación SEIMC/GeSIDA. In addition, Juan Berenguer, Jesús Rodríguez-Baño, Inmaculada Jarrín, Jordi Carratalá, Jerónimo Pachón, and José R Arribas received funding for research from Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades – co- financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020 through the networks: Spanish AIDS Research Network (RIS) [RD16/0025/0017 (JB), RD16/0025/0018 (JRA), RD16/0025/00XX (IJ)] and Spanish Network for Research in Infectious Diseases (REIPI)[RD16/0016/0001 (JRB), RD16/0016/0005 (JC), and RD16/0016/0009 (JP).

Jose Antonio Benavent-Oltra is funded by the University of Granada through "Plan Propio. Programa 7, Convocatoria 2019". Roberto Roman is funded by MINECO under the postdoctoral programme Juan de la Cierva-Incorporacion (IJCI2016-30007). Juan Andres Casquero-Vera is funded by MINECO under the predoctoral programme FPI (BES-2017-080015). Maria J. Granados-Munoz received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 796539. Oleg Dubovik was supported by the Labex CaPPA project, which is funded by the French National Research Agency under contract "ANR-11-LABX0005-01". This work was also supported by the Spanish Ministry of Economy and Competitiveness (projects CMT2015-66742-R, CGL2016-81092-R, CGL2017-85344-R, RTI2018-097864-B-I00 and CGL2017-90884-REDT), by the Andalusia Regional Government through project P18-RT-3820 and the Unity of Excellence "Maria de Maeztu" (project MDM-2016-0600) financed by the Spanish State Research Agency (AEI). The authors thankfully ac-knowledge the FEDER programme for the instrumentation used in this work, the University of Granada, which supported this study through the Excellence Units Program, and the Sierra Nevada National Park. We also thank Dr. Grisa Monick who provided the Aethalometer AVIO AE-33 installed on the aircraft. Thanks to AERONET and ACTRIS/AERONET Europe for the scientific and technical support. Finally, the authors would like to acknowledge the use of the GRASP inversion algorithm software (http://www.grasp-open.com, last access: 1 April 2020), in this work., The Sierra Nevada Lidar aerOsol Profiling Experiment I and II (SLOPE I and II) campaigns were intended to determine the vertical structure of aerosols by remote sensing instruments and test the various retrieval schemes for obtaining aerosol microphysical and optical properties with in situ measurements. The SLOPE I and II campaigns were developed during the summers of 2016 and 2017, respectively, combining active and passive remote sensing with in situ measurements at stations belonging to the AGORA observatory (Andalusian Global ObseRvatory of the Atmosphere) in the Granada area (Spain). In this work, we use the in situ measurements of these campaigns to evaluate aerosol properties retrieved by the GRASP code (Generalized Retrieval of Atmosphere and Surface Properties) combining lidar and sun-sky photometer measurements. We show an overview of aerosol properties retrieved by GRASP during the SLOPE I and II campaigns. In addition, we evaluate the GRASP retrievals of total aerosol volume concentration (discerning between fine and coarse modes), extinction and scattering coefficients, and for the first time we present an evaluation of the absorption coefficient. The statistical analysis of aerosol optical and microphysical properties, both column-integrated and vertically resolved, from May to July 2016 and 2017 shows a large variability in aerosol load and types. The results show a strong predominance of desert dust particles due to North African intrusions. The vertically resolved analysis denotes a decay of the atmospheric aerosols with an altitude up to 5 km a.s.l. Finally, desert dust and biomass burning events were chosen to show the high potential of GRASP to retrieve vertical profiles of aerosol properties (e.g. absorption coefficient and single scattering albedo) for different aerosol types. The aerosol properties retrieved by GRASP show good agreement with simultaneous in situ measurements (nephelometer, aethalometer, scanning mobility particle sizer, and aerodynamic particle sizer) performed at the Sierra Nevada Station (SNS) in Granada. In general, GRASP overestimates the in situ data at the SNS with a mean difference lower than 6 mu m(3) cm(-3) for volume concentration, and 11 and 2 Mm(-1)for the scattering and absorption coefficients. On the other hand, the comparison of GRASP with airborne measurements also shows an overestimation with mean absolute differences of 14 +/- 10 and 1.2 +/- 1.2 Mm(-1) for the scattering and absorption coefficients, showing a better agreement for the absorption (scattering) coefficient with higher (lower) aerosol optical depth. The potential of GRASP shown in this study will contribute to enhancing the representativeness of the aerosol vertical distribution and provide information for satellite and global model evaluation., University of Granada, MINECO under the postdoctoral programme Juan de la Cierva-Incorporacion IJCI2016-30007, MINECO under the predoctoral programme FPI BES-2017-080015, European Commission 796539, French National Research Agency (ANR) ANR-11-LABX0005-01, Spanish Ministry of Economy and Competitiveness CMT2015-66742-R CGL2016-81092-R CGL2017-85344-R RTI2018-097864-B-I00 CGL2017-90884-REDT, Andalusia Regional Government P18-RT-3820, Spanish State Research Agency (AEI) MDM-2016-0600, Excellence Units Program, Sierra Nevada National Park

OBJECTIVE To evaluate whether abutment surface and surface bio-activation have an effect on soft tissue morphogenesis. MATERIALS AND METHODS 36 patients (36 implants) were included. Abutments were randomly divided into 4 groups (n = 9): Smooth Surface-MAChined (MAC), Ultrathin Threaded Microsurface (UTM), MAC Plasma of Argon activated (Plasma-MAC), and UTM Plasma of Argon activated (Plasma-UTM). After 2 months of healing, soft tissue samples were collected and prepared for histological analysis. The margin of the peri-implant mucosa (PM), the apical extension of the barrier epithelium (aJE), and the apical location of the abutment (AM) were identified. Significances of differences among groups were tested by means of the Kruskal-Wallis test and between pairs of results by means of the Mann-Whitney test. RESULTS The mean (SD) vertical dimension of the mucosa was 2.5mm (1.0), including a connective tissue portion (CTP) of 0.8mm (0.8) in the MAC group; 3.6mm (0.2) with a CTP of 1.6mm (0.4) in the Plasma-MAC group; 3.2mm (1.0), with a CPT of 0.5mm (0.6) in the UTM; and 3.3mm (0.8), with a CPT of 0.9mm (0.7) in the Plasma-UTM group. Statistically significant differences were observed in the aJE-AM height and PM-aJE profile among the four experimental groups (p = .042 and p = .039, respectively). The Mann-Whitney test indicated differences between the Plasma-abutments and the untreated abutments both for PM-AM (p = .025) and AjE-AM (p = .021). The differences appeared more evident when the preoperative soft tissue thickness was ≤2mm. CONCLUSIONS Within its limits, the study demonstrated a favorable effect of the plasma treatment on the connective tissue portion tissues. Plasma-MAC group highlighted the best performance. This behavior appeared strictly correlated with the soft tissue thickness.

Corticosteroids reduce mortality in hospitalized patients with coronavirus disease 2019 (COVID-19), but the response seems to vary according to the level of respiratory support needed. This retrospective cohort study included COVID-19 patients with oxygen saturation (SatO2 ) in room air 0.40, the hazard ratio (HR) for death or ICU admission, between the corticosteroids and non-corticosteroids group, was 0.07 (95% CI 0.01-0.4), p = .002, and for patients requiring low-flow oxygen, the HR was 0.70 (95% CI 0.13-3.8), p = .68. Significant differences were also observed when all patients were analyzed together. A significant reduction in mortality and ICU admission frequency was observed among patients requiring high-flow oxygen or NIV, but not among those requiring low-flow oxygen. Better targeting of COVID-19 patients is needed for the beneficial use of corticosteroids.

Tedizolid has demonstrated its efficacy and safety in clinical trials; however, data concerning its tolerability in long-term treatments are scarce. The aim of the study was to assess the indications and to describe the long-term safety profile of tedizolid. A multicentric retrospective study of patients who received tedizolid for more than 6 days was conducted. Adverse events (AEs) were identified from patients' medical records and laboratory data. The World Health Organization causality categories were used to discern AEs that were probably associated with tedizolid. Eighty-one patients, treated with tedizolid 200 mg once daily for a median (interquartile range [IQR]) duration of 28 (14 to 59) days, were included; 36 (44.4%) had previously received linezolid. The most common reasons for selecting tedizolid were to avoid linezolid potential toxicities or interactions (53.1%) or due to previous linezolid-related toxicities (27.2%). The most common indications were off-label, including prosthetic joint infections, osteomyelitis, and respiratory infections (77.8%). Overall, 9/81 patients (11.1%) experienced a probably associated AE. Two patients (2.5%) developed gastrointestinal disorders, 1 (1.2%) developed anemia, and 6 developed thrombocytopenia (7.4%) after a median (IQR) duration of treatment of 26.5 (17 to 58.5) days. Four (5%) patients discontinued tedizolid due to AEs. Among 23 patients with chronic renal failure (CRF), the rate of myelotoxicity was 17.4%, and only 8.7% had to stop tedizolid; 20 out of 22 with previous linezolid-associated toxicity had no AE. Long-term tedizolid treatments had good tolerance with rates of gastrointestinal AE and hematological toxicity lower than those reported with linezolid, particularly in patients with CRF and in those with a history of linezolid-associated toxicity.

Background: The soluble guanylate cyclase (sGC) stimulator praliciguat (PRL) lowers blood pressure and improves metabolism in preclinical models. PRL is under development for diabetic nephropathy and therefore combination with antidiabetic agents such as empagliflozin (EMPA), a sodium glucose cotransporter 2 (SGLT2) inhibitor, is of interest. Here, we assessed the metabolic effects of PRL, EMPA, and their combination in SD rats with programmed hypertension and early exposure to high fat diet (HT-HF), a model with several features of metabolic syndrome - hypertension, glucose intolerance and increased adiposity. Methods: Mean arterial pressure (MAP) and abdominal fat (AF) were determined at 12 weeks of age in 4 groups of HT-HF rats that were subsequently treated for 6 weeks with vehicle control (HT-HF), PRL (10 mg/kg/day), EMPA (7.5 mg/kg/day), or PRL+EMPA. A normotensive, non-disease group on normal diet was also included. At Week 6 of treatment, an intraperitoneal glucose tolerance test (GTT) was performed, and MAP, AF, plasma leptin, and adipocyte area (AA) were measured. Results: See table. Conclusion: The sGC stimulator praliciguat in combination with the SGLT2 inhibitor empagliflozin has additive pharmacological effects in a rat programmed hypertension model. Disclosure C. Schwartzkopf: None. V. Reverte Ribó: Research Support; Self; Cyclerion. F. Rodriguez: Research Support; Self; CYCLERION. L. Oltra: Research Support; Self; Cyclerion. J. Moreno Ayuso: Research Support; Self; Cyclerion. M. Llinás: Research Support; Self; Cyclerion. A.S. Nicolas: None. C. Shea: None. M. Currie: Employee; Self; Cyclerion Therapeutics. Stock/Shareholder; Self; Cyclerion Therapeutics. J.E. Jones: None. E.S. Buys: Employee; Self; Cyclerion. Stock/Shareholder; Self; Cyclerion. J. Masferrer: None. F. Salazar aparicio: Research Support; Self; Cyclerion.

The 3X domain of hepatitis C virus has been reported to control viral replication and translation by modulating the exposure of a nucleotide segment involved in a distal base-pairing interaction with an upstream 5BSL3.2 domain. To study the mechanism of this molecular switch, we have analyzed the structure of 3X mutants that favor one of the two previously proposed conformations comprising either two or three stem–loops. Only the two-stem conformation was found to be stable and to allow the establishment of the distal contact with 5BSL3.2, and also the formation of 3X domain homodimers by means of a universally conserved palindromic sequence. Nucleotide changes disturbing the two-stem conformation resulted in poorer replication and translation levels, explaining the high degree of conservation detected for this sequence. The switch function attributed to the 3X domain does not occur as a result of a transition between two- and three-stem conformations, but likely through the sequestration of the 5BSL3.2-binding sequence by formation of 3X homodimers., We thank R. Bartenschlager (University of Heidelberg, Germany) for providing the plasmid coding for HCV replicon pFK-I389-Fluc-NS3-3′ET, and Angel Cantero-Camacho for his contribution toward the design of mutant 3′X sequences. This work was supported by Ministerio de Economía y Competitividad of Spain (BFU-2012-30770 and BFU2015-65103-R to J.G., and BFU2015-64359-P to A.B.-H.) and Universidad Católica de Valencia of Spain (PRUCV/2015/629 and 2017-114-001 to J.G., and EDUCV contract E-46-2017-0118740 to J.C.-M.).

The development of protective self-detoxifying materials is an important societal challenge to counteract risk of attacks employing highly toxic chemical warfare agents (CWAs). In this work, we have developed bifunctional zirconium metal–organic frameworks (MOFs) incorporating variable amounts of nucleophilic amino residues by means of formation of the mixed ligand [Zr6O4(OH)4(bdc)6(1–x)(bdc-NH2)6x] (UiO-66-xNH2) and [Zr6O4(OH)4(bpdc)6(1–x)(bpdc-(NH2)2)6x] (UiO-67-x(NH2)2) systems where bdc = benzene-1,4-dicarboxylate; bdc-NH2= benzene-2-amino-1,4-dicarboxylate; bpdc = 4,4′-biphenyldicarboxylate; bpdc-(NH2)2 = 2,2′-diamino-4,4′-biphenyldicarboxylate and x = 0, 0.25, 0.5, 0.75, 1. In a second step, the UiO-66-xNH2 and UiO-67-x(NH2)2 systems have been postsynthetically modified by introduction of highly basic lithium tert-butoxide (LiOtBu) on the oxohydroxometallic clusters of the mixed ligand MOFs to yield UiO-66-xNH2@LiOtBu and UiO-67-x(NH2)2@LiOtBu materials. The results show that the combination of pre ...

The development of Green Chemistry inevitably involves the development of green reagents. In this review, we highlight that Cp2TiCl is a reagent widely used in radical and organometallic chemistry, which shows, if not all, at least some of the 12 principles summarized for Green Chemistry, such as waste minimization, catalysis, safer solvents, toxicity, energy efficiency, and atom economy. Also, this complex has proved to be an ideal reagent for green C–C and C–O bond forming reactions, green reduction, isomerization, and deoxygenation reactions of several functional organic groups as we demonstrate throughout the review.

Background Hemostasis is of critical importance in endodontic surgery. Studies on bleeding control in maxillary molars are scarce. The present study compares the efficacy of two hemostatic techniques in controlling bleeding in endodontic surgery. Material and Methods A randomized two-arm pilot study involving 30 patients with peri-radicular lesions in maxillary molars (first and second molars) was carried out including the following hemostatic agents: polytetrafluoroethylene (PTFE) strips as an adjunct to epinephrine impregnated gauze (test group; n = 15) and aluminum chloride (Expasyl™) (control; n = 15). Bleeding control was independently assessed by the surgeon and by two blinded observers before and after application of the hemostatic agent, and was classified as either adequate (complete bleeding control) or inadequate (incomplete bleeding control). Results Bleeding control was similar in both groups. Simple binary logistic regression analysis failed to identify variables affecting bleeding control. Only the height of the keratinized mucosal band (≥ 2 mm) suggested a decreased risk of inadequate bleeding control of up to 89% (OR=0.11; p=0.06). Conclusions No difference in the efficacy of bleeding control was observed between PTFE strips as an adjunct to epinephrine impregnated gauze and aluminum chloride in maxillary molars. Key words:PTFE-strips, aluminum chloride, endodontic surgery, epinephrine, hemostasis, hemostatic agent, molars.

© 2020 by the authors., Plum pox virus (PPV) is the most important limiting factor for apricot (Prunus armeniaca L.) production worldwide, and development of resistant cultivars has been proven to be the best solution in the long-term. However, just like in other woody species, apricot breeding is highly time and space demanding, and this is particularly true for PPV resistance phenotyping. Therefore, marker-assisted selection (MAS) may be very helpful to speed up breeding programs. Tightly linked ParPMC1 and ParPMC2, meprin and TRAF-C homology (MATH)-domain-containing genes have been proposed as host susceptibility genes required for PPV infection. Contribution of additional genes to PPV resistance cannot be discarded, but all available studies undoubtedly show a strong correlation between ParPMC2-resistant alleles (ParPMC2res) and PPV resistance. The ParPMC2res allele was shown to carry a 5-bp deletion (ParPMC2-del) within the second exon that has been characterized as a molecular marker suitable for MAS (PMC2). Based on this finding, we propose here a method for PPV resistance selection in apricot by combining high-throughput DNA extraction of 384 samples in 2 working days and the allele-specific genotyping of PMC2 on agarose gel. Moreover, the PMC2 genotype has been determined by PCR or by using whole-genome sequences (WGS) in 175 apricot accessions. These results were complemented with phenotypic and/or genotypic data available in the literature to reach a total of 325 apricot accessions. As a whole, we conclude that this is a time-efficient, cost-effective and straightforward method for PPV resistance screening that can be highly useful for apricot breeding programs., This research was funded by the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA)-FEDER (RTA2017-00011-C03-01). Á.P.O. was funded by a fellowship cofinanced by the Generalitat Valenciana and European Social Fund (2014–2020) (DOCV 8426/19.11.2018).

International audience; Defects in diamond-like carbon coatings deposited on corrosion sensitive 100Cr6 steel have been studied. Diamond-like carbon (DLC) thin films are promising for corrosion protection due to chemical inertness and low electrical conductivity. Nevertheless, the performance of these coating is highly sensitive to the presence of uncoated areas. These defects represent the primary way of substrate degradation in aggressive environments. An in situ optical microscopy coupled to an electrochemical activation was developed to reveal micrometric growth defects and observe that they were at the origin of corrosion. A square wave voltammetry was applied to increase the sensitivity of electrochemical techniques based on the detection of the dissolution of the bare metal surface triggered by the presence of uncoated spots. This method can be utilized to quantify defect density arising from vapor deposition processes.

KAWA-RACE study group., [Background] Kawasaki disease (KD) is an acute self-limited systemic vasculitis of unknown etiology affecting mainly children less than 5 years of age. Risk factors for cardiac involvement and resistance to treatment are insufficiently studied in non-Japanese children., [Objective] This study aimed to investigate the epidemiology, clinical features and risk factors for resistance to treatment and coronary artery lesions (CAL) in KD in Spain., [Methods] Retrospective study (May 2011-June 2016) of all patients less than 16 years of age diagnosed with KD included in KAWA-RACE network (84 Spanish hospitals)., [Results] A total of 625 cases were analyzed, 63% were males, 79% under 5 year-olds and 16.8% younger than 12 months. On echocardiographic examination CAL were the most frequent findings (23%) being ectasia the most common (12%). Coronary aneurysms were diagnosed in 9.6%, reaching 20% in infants under 12 months (p 900,000 cells/mm3, maximum temperature < 39.5°C, total duration of fever > 10 days and fever before treatment ≥ 8 days as independent risk factors for developing coronary aneurysms., [Conclusions] In our population, children under 12 months develop coronary aneurysms more frequently and children with KD with anemia and leukocytosis have high risk of cardiac involvement. Adding steroids early should be considered in those patients, especially if the treatment is not started before 8 days of fever. A score applicable to non-Japanese children able to predict the risk of aneurysm development and IVIG resistance is necessary., CC received a grant from Spanish Society of Paediatric Rheumatology (SERPE), 2015.

Background Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8mg/kg loading dose, then 6mg/kg every 3weeks (q3w)] and pertuzumab (840mg loading dose, then 420mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54years; 29% had received prior trastuzumab. Median treatment duration was 16months for pertuzumab and trastuzumab and 4months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Conclusions Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. ClinicalTrials.gov NCT01572038.

Background: The present in vitro study aimed to investigate the fatigue performance of different dental fixtures in two different emergence profiles. Biological failures are frequently reported because the problem canonly be solved by replacing a failing implant with a new one. Clinicians addressed minor mechanical failures, such as bending, loosening or the fracture of screws, abutment, or the entire prosthesis, by simply replacing or fixing them. Methods: Transmucosal and submerged bone-level dental implants underwent fatigue strength tests (statical and dynamical performance) by a standardized test: UNI EN ISO 14801:2016. Two types of emergence profiles (Premium sub-crestal straight implant with a cylindrical-shaped coronal emergence or Prama one-piece cylindrical-shape implant with transmucosal convergent neck and hyperbolic geometry) were tested, and dynamic fatigue were run to failure. Data was analyzed by a suitable statistical tool. Results: The Wöhler curve of 0.38 cm Premium group c2, appeared to be significantly different from that of the 0.38 cm Prama group c3 (nonparametric one-way ANOVA χ2= 6, degree of freedom = 1, probability = 0.0043) but not from that of the 0.33 cm Premium group c1 (nonparametric one-way ANOVA χ2 = 0.62, probability = 0.4328). Fatigue performance of configuration 2 was one and a half times better than that of configuration 3. Group c3 had a better ultimate failure load (421.6 ± 12.5 N) than the other two settings i.e., c1 (324.5 ± 5.5 N) and c2 (396.3 ± 5.6) reaching almost a nonsignificant level. Conclusions: It was observed that a transmucosal implant design could provide the highest resistance to static fracture. On the other hand, an equicrestal implant design could increase dynamic endurance.

A general method for the straightforward synthesis of exocyclic allenes on five-, six-, seven-, and eight-membered oxygen heterocycles is described. A Barbier-type titanocene(III)-catalyzed cyclization of propargyl halides with a pendant carbonyl group is the key step of the process. This reaction is compatible with many functional groups, and can be smoothly carried out under neutral and mild conditions at room temperature.

We report the case of a 2-month-old girl with Dandy-Walker variant who presented with strabismus, pathologic myopia measuring -16.00 D in each eye, diffuse chorioretinal atrophy and pigment mottling in the macula of both eyes, and areas of retinal capillary nonperfusion in both eyes. The patient's brother also has Dandy-Walker variant and was found to have bilateral severe myopia, myopic fundi, tilted optic disks with peripapillary atrophy, extensive areas of white without pressure, areas of lattice degeneration, and several chronic-appearing atrophic retinal holes surrounded by pigmentation. We hypothesize that children with Dandy-Walker variant may present with refractive errors such as pathologic myopia and with diverse retinal findings, including retinal ischemia. A lower threshold for ophthalmologic examination may be considered in this population.

Introduction Bleeding control is an important aspect in endodontic surgery. Two hemostatic techniques were compared with regard to their efficacy to bleeding control in endodontic surgery. Methods A randomized, 2-arm, parallel pilot study involving 30 patients with periradicular lesions was performed including the following hemostatic agents: polytetrafluoroethylene strips as an adjunct to epinephrine-impregnated gauze (test group, n = 15) and aluminum chloride (control, n = 15). Bleeding control was independently assessed by the surgeon and 2 blinded observers before and after application of the hemostatic agent. Bleeding control was classified either as adequate (complete bleeding control) or inadequate (incomplete bleeding control). Results Hemostasis in both groups proved similar. Simple binary logistic regression analysis failed to identify variables affecting bleeding control. Only the height of the keratinized mucosa band (≥2 mm) suggested a risk reduction for an inadequate bleeding control up to 79% (odds ratio = 0.21, P > .05). Conclusions No differences in the efficacy of bleeding control were observed between polytetrafluoroethylene strips as an adjunct to epinephrine-impregnated gauze and aluminum chloride.

Dental implants can be integrated at both hard and soft tissue levels. Osseointegration is a dynamic process during its establishment and maintenance, characterized by resorption and apposition events, and the extent and degree of osseointegration is in part affected by implant surface configuration. It is marked by three distinct healing stages during endosseous implant integration: osteoconduction, “de novo” bone formation, and bone remodeling, which occur by the interaction of different bone cells: osteocytes, osteoblasts, and osteoclasts. One of the most important aspects for reaching clinical osseointegration is the primary stability during implant placement. The extent of primary anchorage is tightly related to native bone characteristics, implant design, patient characteristics, and surgical technique, respectively, where they all regulate to some extent the strain applied to mineralized tissue and directly related to bone interfacial stress and frictional force transferred, which is clinically interpreted as insertion torque. At 2 weeks there is an evident accelerated proliferation of blood vessels and mesenchymal cells embedded inside the provisional granulation tissue that stimulate the formation of an immature peri-implant primary bone or woven bone. At 4 weeks, the woven bone replacement by lamellar bone suggests an initial remodeling has begun, and it is evidenced by the presence of primary osteonic structures that elucidate the onset of woven bone remodeling toward lamellar bone configuration surrounding blood vessels. At 8 weeks, the healing chambers clearly show a “bone remodeling” process, with the presence of parallel fibered lamellar bone deposition, and there is plenty of bone formed, evidenced by the presence of primary and secondary osteonic structures. Lamellar osteons (haversian systems) outlined by cement-line boundaries are visible.

Background To determine whether saliva is a good means of evaluating concentrations of oxidative stress biomarkers, analyzing the correlation between concentrations in saliva and in follicular tissue, and to compare biomarker concentrations in patients with one asymptomatic mandibular impacted third molar (MITM) (before extraction) with a healthy control, and to determine how biomarkers are modified by extraction. Material and Methods 80 patients with one asymptomatic MITM and 80 healthy controls were included. Saliva samples were collected from all subjects (before extraction in the study group) to evaluate Myeloperoxidase (MPO) and Malondialdehyde (MDA) concentrations. Follicular tissues were obtained during surgery to measure biomarkers. One month after extraction, saliva samples were collected to assess changes of oxidative stress. Results Salivary MPO and MDA showed positive correlation with concentrations in follicular tissue (MPO: correlation coefficient=0.72, p=0.025; MDA: =0.92, p=0.001). Patients with asymptomatic MITMs showed higher salivary concentrations of oxidative stress biomarkers than healthy control subjects, with statistical significance for both MPO (p

This study evaluates the bone-healing patterns on the surface of titanium implants at the cortical and marrow compartments of bicortically-installed implants in the diaphysis and metaphysis of rabbit tibiae. In 27 New Zealand rabbits, two implants, one for each macro-design and with equal resorbable blasted media (RBM) implant surfaces, were randomly implanted in the diaphysis or metaphysis of each tibia. The flaps were sutured to allow submerged healing. The animals were sacrificed after two, four, or eight weeks, with nine weeks used for the period of healing. Ground sections were prepared and analyzed. No statistically significant differences were found between the two groups for newly formed bone in contact with the implant surface after two, four, and eight weeks of healing. Bone apposition in the marrow compartment was slightly higher in the diaphysis compared to metaphysis regions across healing stages. Despite the limitations of the present study, it can be concluded that new bone apposition was better than average in the cortical compartment as compared to the marrow compartments. Bone morphometry and density may affect bone apposition onto the implant surface. The apposition rates were slightly better at both the cortical and marrow compartments in diaphysis as compared to metaphysis sites. The new bone formation at the marrow compartment showed slightly better increasing values at diaphysis compared to metaphysis implantation sites.

BACKGROUND AND OBJECTIVE: Aggressive posterior vitreoretinopathy (APVR) manifests with a broad area of retinal avascularity, progressive neovascularization, and/or tractional retinal detachment during the neonatal period. PATIENTS AND METHODS: A multicenter, retrospective, observational, consecutive case series study was performed to evaluate the retinal findings and structural retinal outcomes in patients treated for APVR within the first 3 months of life. RESULTS: Three premature neonates with a non-retinopathy of prematurity (ROP) APVR identified during routine ROP screening exams exhibited relatively severe, rapidly progressive retinal vascular abnormalities. Immediate laser photocoagulation of the avascular retina and vitrectomy for traction retinal detachment within several days to weeks improved or stabilized the retinal anatomy in all cases. CONCLUSIONS: This series describes clinical features in APVR in premature infants and suggests that early diagnosis and intervention may mitigate the typical aggressive course and poor prognosis of this condition. [ Ophthalmic Surg Lasers Imaging Retina. 2019;50:201–207.]

A synthesis of (±)-ambrox, a compound with delicious ambergris-type scent, is presented. The key step is a highly diastereoselective titanocene(III)-catalyzed radical tandem cyclization of a farnesol derivative.

Changes induced in the surface properties of AISI 304L stainless steel when it is treated with a nanopulsed ytterbium-doped fiber laser were investigated to determine the microscale distribution of its physico-chemical properties. A Gaussian energy distribution was created with a radius of 71 μm (1/e2) at the focal point. Local investigations were carried out using transmission electron microscopy to consider the effect of overlapping individual laser impacts. The results obtained reveal that laser surface melting leads to changes in the crystallographic structure of the steel through the formation of a δ-ferritic phase. It also results in the creation of an oxide layer that increases the corrosion resistance of the steel, with the chemical composition, structure and thickness of this layer being dependent on the overlap percentage and the position along the beam radius. Measurement of the localized corrosion resistance in a 30 g L−1 NaCl solution using polarization curves found that optimal laser treatment conditions can led to an increase in the breakdown potential of more than 500 mV, which corresponds to a significant improvement in corrosion resistance.

The ability of Zn–Mg coatings (with magnesium content between 5.8 and 15.5 wt.%) to protect steel sheets has been evaluated with local electrochemical techniques (scanning vibrating electrode technique, microcapillary electrochemical cell) and rotating disk electrode, and compared with the corrosion protection afforded by a pure zinc coating. From immersion tests of coated steel cut-edges, it is observed that alloying zinc with magnesium leads to a decrease of the galvanic current between the coating and the steel surface, and to an improvement of the steel corrosion resistance after a drying period, due to the presence of magnesium in the corrosion products.