Cardiac resynchronization therapy-defibrillator improves long-term survival compared with cardiac resynchronization therapy-pacemaker in patients with a class IA indication for cardiac resynchronization therapy: Data from the Contak Italian Registry

Aims In candidates for cardiac resynchronization therapy (CRT), the choice between pacemaker (CRT-P) and defibrillator (CRT-D) implantation is still debated. We compared the long-term prognosis of patients who received CRT-D or CRT-P according to class IA recommendations of the European Society of Cardiology (ESC) and who were enrolled in a multicentre prospective registry. Methods and results A total of 620 heart failure patients underwent successful implantation of a CRT device and were enrolled in the Contak Italian Registry. This analysis included 266 patients who received a CRT-D and 108 who received a CRT-P according to class IA ESC indications. Their survival status was verified after a median follow-up of 55 months. During follow-up, 73 CRT-D and 44 CRT-P patients died (rate 6.6 vs. 10.4%/year; log-rank test, P = 0.020). Patients receiving CRT-P were predominantly older, female, had no history of life-threatening ventricular arrhythmias, and more frequently presented non-ischaemic aetiology of heart failure, longer QRS durations, and worse renal function. However, the only independent predictor of death from any cause was the use of CRT-P (hazard ratio, 1.97; 95% confidence interval, 1.21–3.16; P = 0.007). Conclusion The implantation of CRT-D, rather than CRT-P, may be preferable in patients presenting with current class IA ESC indications for CRT. Indeed, CRT-D resulted in greater long-term survival and was independently associated with a better prognosis

Atributos do solo e produtividade do milho cultivado em sucessão a plantas de cobertura de inverno

The aim of this study was to evaluate the effect of different winter cover plants on soil physical and chemical attributes and corn crop productivity. The experiment was carried out for three crops, from 2011 to 2014. The treatments were winter cover crops vetch, black oat, blue lupin, wild radish, ryegrass and field pea cultivated alone and intercropped with black oat + vetch, black oat + wild radish + vetch, black oat + wild radish, and a control treatment, without the use of cover crops (fallow). The experimental design consisted of random blocks with three repetitions. Chemical and physical soil parameters were evaluated, as well as yield of dry plant biomass of the cover crops and yield of corn cultivated in sucession. The greatest production of dry mass for field pea was obtained in the 2011/2012 crop and for the treatments with black oat + vetch and black oat + wild radish + vetch, in 2012/2013 and 2013/2014. Corn grain yield was higher in the treatments utilizing Fabaceae species and intercropping in the 2011/2012 crop. In the 2012/2013 and 2013/2014 crops, the greatest yield of corn grains was found in the treatments with black oat + vetch + wild radish and blue lupin as cover crops. Growing cover crops for three consecutive years resulted in increase in the organic matter contents and availability of phosphorus and potassium in the soil.O objetivo deste trabalho foi avaliar o efeito de diferentes plantas de cobertura de inverno na fertilidade do solo e produtividade da cultura do milho. O experimento foi conduzido por três safras agrícolas, de 2011 a 2014. Os tratamentos utilizados foram as plantas de coberturas de inverno ervilhaca, aveia preta, tremoço azul, nabo forrageiro, azevém e ervilha forrageira cultivadas isoladamente, além dos consórcios aveia preta com ervilhaca, aveia preta com nabo forrageiro e ervilhaca, aveia preta com nabo forrageiro e uma parcela controle, sem uso de plantas de cobertura (Pousio). O delineamento experimental foi de blocos ao acaso com três repetições. Em três safras agrícolas foram avaliados os atributos químicos e físicos do solo, o rendimento de massa seca da parte aérea das plantas de cobertura e o rendimento de grãos do milho cultivado em sucessão. A ervilha forrageira produziu mais matéria seca na safra 2011/2012, enquanto os consórcios aveia + ervilhaca e aveia + nabo + ervilhaca produziram mais nas safras de 2012/2013 e 2013/2014. O rendimento de grãos de milho foi maior em sucessão a fabáceas e consórcios na safra 2011/2012 e em sucessão a aveia + ervilhaca + nabo e tremoço nas safras 2012/2013 e 2013/2014. O cultivo de plantas de cobertura por três anos consecutivos resultou em incremento nos teores de matéria orgânica e na disponibilidade de fósforo e potássio no solo

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

A multi-element psychosocial intervention for early psychosis (GET UP PIANO TRIAL) conducted in a catchment area of 10 million inhabitants: study protocol for a pragmatic cluster randomized controlled trial

Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

COMPUTATIONAL CHEMISTRY: a useful art to support asymmetric organic synthesis and organometallic chemistry

Il presente lavoro di tesi, a conclusione dei tre anni di Dottorato di Ricerca, riporta i quattro argomenti che più significativamente hanno caratterizzato questo percorso. L’elaborato inizia con un primo capitolo riguardante lo studio computazionale delle ragioni che portano ad un inatteso output stereochimico durante la reazione di desimmetrizzazione di un composto meso. Prosegue con il lavoro svolto presso l’Università di Oxford, utilizzando il Machine Learning per indirizzare il design di nuovi catalizzatori organici. Il terzo capitolo mira a comprendere il meccanismo di scambio di leganti su derivati titanocenici, che verranno poi opportunamente funzionalizzati tramite chimica bioortogonale per scopi di imaging e come possibili antitumorali. Infine, un altro studio meccanicistico su catalizzatori Fe-porfirinici ha permesso di evidenziare i piccoli dettagli che regolano il processo di ciclopropanazione e come l’intorno chimico a ridosso del centro metallico possa ridurre ulteriormente le energie di attivazione dei processi in una sorta di comportamento simil-enzimatico.This thesis, as a conclusion of the three years of the Ph.D. course, reports the four topics that most significantly characterized the research. The first chapter concerns the computational study of the reasons behind the unexpected stereochemical output during the desymmetrization reaction of a meso-compound. Then, it continues with the research done at the University of Oxford, using Machine Learning to guide the design of new organic catalysts. The third chapter aims to understand the mechanism of ligand exchange on titanocene derivatives, which will then be suitably functionalized by bioorthogonal chemistry for imaging purposes and as possible anticancer agents. Finally, another mechanistic study on Fe-porphyrin catalysts has allowed to highlight the small details that regulate the cyclopropanation process and how the catalyst environment close to the metal center can further reduce the activation energies of the processes in a sort of enzyme-like behavior

Oxo-Rhenium-Mediated Allylation of Furanoside Derivatives: A Computational Study on the Mechanism and the Stereoselectivity

: Properly substituted tetrahydrofuran (THF) rings are important building blocks in the synthesis of many natural metabolites. Having reliable procedures to control the stereoselectivity at the THF core while decorating it with different substituents is a fundamental requirement to achieve and fulfill the complexity of nature. We recently reported a new chemical approach to control the stereochemistry in the alkylation and arylation of furanoside derivatives by using a rhenium(V) complex to form an intermediate oxo-carbenium species able to react with proper soft nucleophiles. Here, we describe theoretical calculations, performed at the DFT B3LYP level, to disclose the important mechanistic features which regulate the entire catalytic cycle of the reaction of mono- and disubstituted furanosides with allyltrimethylsilane catalyzed by Re(O)Cl3(OPPh3)(Me2S). Moreover, the key factors governing the allylation step were investigated, confirming that the stereoselectivity, which is independent of the anomeric configuration of starting acetal, mainly arises from the orientation of the substituent at C-4, with only marginal contribution of the substituent at C-5. Finally, puckering Cremer-Pople parameters were used to take trace of the structural modifications throughout the catalytic cycle

PythiaCHEM : a user-friendly machine learning toolkit for chemistry

Machine learning (ML) is currently transforming the field of chemistry by offering unparalleled efficiency in addressing complex challenges. Despite the progress made, a notable gap persists in the availability of user-friendly tools tailored to chemical problems involving small and sparse datasets. Here, we introduce PythiaCHEM, an ML toolkit designed to develop data-driven predictive ML models. It enables the use of various descriptors and ML frameworks for regression and classification tasks in an automated, flexible, and accessible manner through Jupyter Notebooks, making it easy to customize for specific tasks. We showcase the capabilities and versatility of PythiaCHEM in two distinct chemistry tasks: first, the evaluation of the transmembrane chloride anion transport activity of synthetic anion transporters, and second, the prediction of enantioselectivity in the Strecker synthesis of a-amino acids. Our results highlight the utility of PythiaCHEM as a powerful and user-friendly framework for developing predictive ML models applicable in different domains of chemistry

NLRP3 monomer functional dynamics: From the effects of allosteric binding to implications for drug design

The protein NLRP3 and its complexes are associated with an array of inflammatory pathologies, among which neurodegenerative, autoimmune, and metabolic diseases. Targeting the NLRP3 inflammasome represents a promising strategy for easing the symptoms of pathologic neuroinflammation. When the inflammasome is activated, NLRP3 undergoes a conformational change triggering the production of pro-inflammatory cytokines IL-1β and IL-18, as well as cell death by pyroptosis. NLRP3 nucleotide-binding and oligomerization (NACHT) domain plays a crucial role in this function by binding and hydrolysing ATP and is primarily responsible, together with conformational transitions involving the PYD domain, for the complex-assembly process. Allosteric ligands proved able to induce NLRP3 inhibition. Herein, we examine the origins of allosteric inhibition of NLRP3. Through the use of molecular dynamics (MD) simulations and advanced analysis methods, we provide molecular-level insights into how allosteric binding affects protein structure and dynamics, remodelling of the conformational ensembles populated by the protein, with key reverberations on how NLRP3 is preorganized for assembly and ultimately function. The data are used to develop a Machine Learning model to define the protein as Active or Inactive, only based on the analysis of its internal dynamics. We propose this model as a novel tool to select allosteric ligands