Reduced graphene oxide supported piperazine in aminocatalysis

Reduced graphene oxide (rGO) has been used as a support for piperazine to provide heterogeneous bifunctional organocatalyst (rGO-NH) that is able to efficiently promotvintage organic transformations such as Knoevenagel, Michael and aldol reactions. The obtained results suggest a significant role of the support in the course of these reactionsWe thank the Spanish Government (CTQ-2012-35957) and CAM (AVANCAT CS2009/PPQ-1634) for financial support. E.R. thanks the Spanish Ministry for a predoctoral fellowship (FPU/AP-2010-0807). R.S. thanks the Spanish Ministry of Science for a postdoctoral contract (PTQ-11-04601

The Acidity of a Carbon Nucleophile Dictates Enantioselectivity and Reactivity in Michael Additions to Aromatic and Aliphatic Enals via Iminium Activation

The Michael addition of activated methylenes to β-substituted α,β-unsaturated aldehydes (enals) via iminium catalysis takes place following reactivity and enantioselectivity patterns which depend on the electronic nature of the substituent in the β position (β-aryl or β-alkyl). Application of the same reaction conditions to both families of enals may result in erratic levels of asymmetric induction in the reactions of β-aryl enals or low reactivity with β-alkyl enals. A systematic analysis of this behavior using phenylacetic acid derivatives as case studies has led us to find a general trend: the different problems found for β-aryl and β-alkyl enals depend on the acidity of the nucleophile, and the outcome of the reaction for both types of enals can be improved substantially by careful choice of catalyst, solvent, and additive. Furthermore, this study has allowed us to understand subtle aspects of this transformation and has enabled the formulation of a general and reliable protocol to obtain high yields and enantioselectivities consistently, regardless of the acidity of the nucleophile and the nature of the substituent (aromatic or aliphatic) at the β positionWe thank CTQ-2009-12168, CAM (AVANCAT CS2009/PPQ-1634), UAM-CAM (CCG10-UAM/PPQ-5769), CTQ-2012-35957, CTQ2015-63997-C2-1-P, CTQ2016-78779-R and FOTOCARBON-CAM S2013/MIT-2841 for financial support. S.D. thanks the Comunidad Autónoma de Madrid (CAM), and E.R. and S.M. thank MICINN, for predoctoral fellowships. P.M. thanks MICINN for a Ramón y Cajal contract and the EU for a Marie Curie grant (CIG: HYPERCAT-30422

The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever

Background Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Methods Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. Results The incidence of NF among the groups was reduced (64%, 44%, and 24%; P2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05). Conclusions G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial

The case of a southern European glacier disappearing under recent warming that survived Roman and Medieval warm periods

Mountain glaciers have generally experienced an accelerated retreat over the last three decades as a rapid response to current global warming. However, the response to previous warm periods in the Holocene is not well-described for glaciers of the of southern Europe mountain ranges, such as the Pyrenees. The situation during the Medieval Climate Anomaly (900-1300 CE) is particularly relevant since it is not certain whether the glaciers just experienced significant ice loss or whether they actually disappeared. We present here the first chronological study of a glacier located in the Central Pyrenees (N Spain), the Monte Perdido Glacier (MPG), carried out by different radiochronological techniques and their comparison with geochemical proxies with neighboring paleoclimate records. The result of the chronological model proves that the glacier endured during the Roman Period and the Medieval Climate Anomaly. The lack of ice from last 600 years indicates that the ice formed during the Little Ice Age has melted away. The analyses of the content of several metals of anthropogenic origin, such as Zn, Se, Cd, Hg, Pb, appear in low amounts in MPG ice, which further supports our age model in which the record from the industrial period is lost. This study confirms the exceptional warming of the last decades in the context of last two millennia. We demonstrate that we are facing an unprecedented retreat of the 55 Pyrenean glaciers which survival is compromised beyond a few decades

The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever

Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. The incidence of NF among the groups was reduced (64%, 44%, and 24%; P2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age �60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05. G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial

Analysis of the common genetic component of large-vessel vasculitides through a meta- Immunochip strategy

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P?=?7.54E-07; ORGCA?=?1.19, ORTAK?=?1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA?=?5.52E-04, ORGCA?=?1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Síntesis y reacciones de Diels-Alder. Asimétrica de 1-sulfinildienos

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química Orgánica, 4-12-199