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A selective direct arylation of the different Csp2-H bonds of imidazo[2,1-b]thiazole with (hetero) aryl halides can be achieved simply by switching from a palladium catalyst system to the use of stoichiometric amounts of copper. The observed selectivity, also rationalized by DFT calculations, can be explained by a change in the mechanistic pathways between electrophilic palladation and base-promoted C-H metalation.
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The synthesis of ruthenium-complexes with cyclic (amino)(barrelene)carbenes (namely CABCs) as ligands is reported. Isolated in moderate to good yields, these new complexes showed impressive thermal stability at 110 °C over several days. Good catalytic performances were demonstrated in various ring-closing metathesis (RCM), macrocyclic-RCM, ring-closing enyne metathesis (RCEYM), cross-metathesis (CM), and ring-opening cross metathesis (ROCM) reactions.
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This note discusses the application of a Minisci-type reaction for the direct alkylation of azoles with carboxylic acids as radical precursors. Different reaction conditions were investigated to achieve high yield of the desired products, focusing on acid strength and solvent screening. Moreover, the reactivity of imidazoles with various carboxylic acids was investigated, showing good yield for most cases. The study reveals the potential of this approach for late-stage functionalization in drug discovery.
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Orellanic syndrome is caused by fungi of the Cortinarius orellanus and speciosissimus (Europe) species, Cortinarius fluorescens (South America), and Cortinarius rainierensis (North America). Orellanic syndrome is characterized by initially nonspecific symptoms such as muscle and abdominal pain, and a metallic taste sensation in the mouth. After a few days, more specific symptoms appear, such as intense thirst, headache, chills without fever, and anorexia, followed by a phase of polyuria and then of oligoanuria. Renal failure occurs in 70% of cases and is often irreversible. The clinical case involves a 52-year-old man who developed acute renal failure from Orellanic syndrome, necessitating hemodialysis.
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Lesión Renal Aguda , Intoxicación por Setas , Masculino , Humanos , Persona de Mediana Edad , Intoxicación por Setas/complicaciones , Intoxicación por Setas/diagnóstico , Lesión Renal Aguda/etiología , Diálisis Renal/efectos adversos , Síndrome , Europa (Continente)RESUMEN
Harvesting sunlight to drive carbon dioxide (CO2) valorisation represents an ideal concept to support a sustainable and carbon-neutral economy. While the photochemical reduction of CO2 to carbon monoxide (CO) has emerged as a hot research topic, the full CO2-to-CO conversion remains an often-overlooked criterion that prevents a productive and direct valorisation of CO into high-value-added chemicals. Herein, we report a photocatalytic process that unlocks full and fast CO2-to-CO conversion (<10 min) and its straightforward valorisation into human health related field of radiochemistry with carbon isotopes. Guided by reaction-model-based kinetic simulations to rationalize reaction optimisations, this manifold opens new opportunities for the direct access to 11C- and 14C-labeled pharmaceuticals from their primary isotopic sources [11C]CO2 and [14C]CO2.
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The versatility of olefin metathesis is evident from its successful applications ranging from natural product synthesis to the valorization of renewable feedstocks. On the other side, flow chemistry has recently gained particular interest among the synthetic community, offering valuable alternatives to classic batch chemistry and paving the way to the development of new transformations. The application of continuous-flow methods to olefin metathesis represents one of the most promising evolutions in the field at the interface of industrially relevant synthesis and reactor engineering, significantly improving some of the typical problems such as undesired self-reactions and ethylene-mediated catalyst deactivation. This Minireview aims to provide a brief survey covering the major aspects of those techniques which we hope may be of interest for the chemical community as well as those interested in catalysis, continuous processing, enabling technologies and reactor design.
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Productos Biológicos , Rutenio , Alquenos , CatálisisRESUMEN
Domperidone and metoclopramide are widely prescribed antiemetic drugs with distinct neurological side effects. The impact of P-glycoprotein (P-gp)-mediated efflux at the blood−brain barrier (BBB) on brain exposure and BBB permeation was compared in vitro and in vivo using positron emission tomography (PET) imaging in rats with the radiolabeled analogs [11C]domperidone and [11C]metoclopramide. In P-gp-overexpressing cells, the IC50 of tariquidar, a potent P-gp inhibitor, was drastically different using [11C]domperidone (221 nM [198−248 nM]) or [11C]metoclopramide (4 nM [2−8 nM]) as the substrate. Complete P-gp inhibition led to a 1.8-fold higher increase in the cellular uptake of [11C]domperidone compared with [11C]metoclopramide (p < 0.0001). Brain PET imaging revealed that the baseline brain exposure (AUCbrain) of [11C]metoclopramide was 2.4-fold higher compared with [11C]domperidone (p < 0.001), consistent with a 1.8-fold higher BBB penetration (AUCbrain/AUCplasma). The maximal increase in the brain exposure (2.9-fold, p < 0.0001) and BBB penetration (2.9-fold, p < 0.0001) of [11C]metoclopramide was achieved using 8 mg/kg of tariquidar. In comparison, neither 8 nor 15 mg/kg of tariquidar increased the brain exposure of [11C]domperidone (p > 0.05). Domperidone is an avid P-gp substrate that was in vitro compared with metoclopramide. Domperidone benefits from a lower brain exposure and a limited risk for P-gp-mediated drug−drug interaction involving P-gp inhibition at the BBB.
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Synergistic catalysis offers the unique possibility of simultaneous activation of both the nucleophile and the electrophile in a reaction. A requirement for this strategy is the stability of the active species towards the reaction conditions and the two concerted catalytic cycles. Since the beginning of the century, aminocatalysis has been established as a platform for the stereoselective activation of carbonyl compounds through HOMO-raising or LUMO-lowering. The burgeoning era of aminocatalysis has been driven by a deep understanding of these activation and stereoinduction modes, thanks to the introduction of versatile and privileged chiral amines. The aim of this review is to cover recent developments in synergistic strategies involving aminocatalysis in combination with organo-, metal-, photo-, and electro-catalysis, focusing on the evolution of privileged aminocatalysts architectures.
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Aminas , CatálisisRESUMEN
Carbon isotope labeling is a traceless technology, which allows tracking the fate of organic compounds either in the environment or in living organisms. This article reports on a general approach to label urea derivatives with all carbon isotopes, including 14C and 11C, based on a Staudinger aza-Wittig sequence. It provides access to all aliphatic/aromatic urea combinations.
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Dióxido de Carbono/química , Radioisótopos de Carbono/química , Marcaje Isotópico/métodos , Urea/químicaRESUMEN
OBJECTIVES: To assess ductal size correlated to spontaneous closure, pharmacological or surgical treatment; to index ductal diameter to body weight and body surface area; to evaluate the morbidities. STUDY DESIGN: Retrospective study on preterms ≤32 weeks, birth weight ≤1500 g, extremely low birth weight (ELBW) and very low birth weight (VLBW). Inclusion criteria: patent ductus arteriosus (PDA) with a diameter ≥1 millimeter (mm) at 72 h from birth; need for ibuprofen treatment on the basis of a hemodynamically significant ductus arteriosus (HsPDA). RESULTS: One hundred infants with the diagnosis of PDA have been included. We observed a prevalence of spontaneous closure in 34% of newborns (41.3% VLBW versus 26.7% ELBW). The percentage of response to a single course of ibuprofen was of 62% (68.5% ELBW versus 54.3% VLBW). The mean of absolute ductal diameter was of 2.26 ± 0.62 mm in ELBW and 2.18 ± 0.42 mm in VLBW. The indexing of ductus size to body weight demonstrated a higher value in ELBW than VLBW (2.76 ± 0.97 mm/kg versus 1.84 ± 0.40 mm/kg). CONCLUSIONS: Our results confirmed that HsPDA can develop in presence of a ductus >1.5 mm as absolute value or >1.4 mm/kg as indexed to body weight. In ELBW infants the ductal size indexed for body weight and body surface area could be more predictive of spontaneous closure or need for pharmacological treatment compared to the absolute value of ductal size. A strong association between HsPDA and short- or long-term morbidities was confirmed particularly in ELBW.
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Conducto Arterioso Permeable , Recien Nacido Prematuro , Superficie Corporal , Conducto Arterioso Permeable/epidemiología , Humanos , Ibuprofeno , Recien Nacido con Peso al Nacer Extremadamente Bajo , Recién Nacido , Morbilidad , Estudios RetrospectivosRESUMEN
BACKGROUND: Preterm neonates are likely to require red blood cell (RBC) transfusion, and extremely low birth weight infants almost invariably receive multiple transfusions. Transfusion-reduction strategies can reduce transfusion rates, and might diminish certain adverse outcomes associated with transfusions. MATERIALS AND METHODS: In a single centre, we retrospectively evaluated RBC transfusion rates among preterm infants ≤32 weeks' gestational age (GA), over a 6-year period before and after adopting national transfusion-reduction strategies. We compared demographic data, adverse events, and outcomes between transfused vs not-transfused neonates. Univariate logistic regression was used to evaluate associations between dichotomous outcomes and number of transfusions, and day of first transfusion. Multivariate logistic regression evaluated the correlation between dichotomous outcomes and transfusion as an independent risk factor. RESULTS: During the 6 years studied, 181 infants born at ≤32 weeks' GA were admitted to our Neonatal Intensive Care Unit of whom 80 (44%) received at least one RBC transfusion. The transfusion rate tended downwards after adopting transfusion-reduction strategies, reaching 31% in 2018. The reduction was largely due to a marked fall in transfusions of neonates born at 29-32 weeks' GA (p<0.001). The number of transfusions received correlated with odds of having intraventricular haemorrhage (IVH) (OR=1.9; 95% CI: 1.3-2.7; p=0.0001) and the duration of oxygen supplementation (rho=0.51; 95% CI: 0.33-0.66; p≤0.0001). In multivariate logistic regression analysis, transfusion was an independent risk factor for IVH (adjusted OR=7.38; 95% CI: 2.24-24.30; p=0.0001). DISCUSSION: The application of national, standardised transfusion-reduction strategies was associated with a lower transfusion rate in neonates born at 29-32 weeks' GA, but was less effective among neonates ≤28 weeks, in whom transfusions appeared to be an independent risk factor for severe IVH.
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Transfusión de Eritrocitos , Nacimiento Prematuro/terapia , Transfusión de Eritrocitos/efectos adversos , Femenino , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro , Masculino , Nacimiento Prematuro/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: The importance of lung recruitment before surfactant administration has been shown in animal studies. Well designed trials in preterm infants are absent. We aimed to examine whether the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (intubate-recruit-surfactant-extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with no recruitment manoeuvre (ie, intubate-surfactant-extubate [IN-SUR-E]). METHODS: We did a randomised, unblinded, controlled trial in 35 tertiary neonatal intensive care units in Italy. Spontaneously breathing extremely preterm neonates (24â+â0 to 27â+â6 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 h of life were randomly assigned (1:1) with a minimisation algorithm to IN-REC-SUR-E or IN-SUR-E using an interactive web-based electronic system, stratified by clinical site and gestational age. The primary outcome was the need for mechanical ventilation in the first 72 h of life. Analyses were done in intention-to-treat and per-protocol populations, with a log-binomial regression model correcting for stratification factors to estimate adjusted relative risk (RR). This study is registered with ClinicalTrials.gov, NCT02482766. FINDINGS: Of 556 infants assessed for eligibility, 218 infants were recruited from Nov 12, 2015, to Sept 23, 2018, and included in the intention-to-treat analysis. The requirement for mechanical ventilation during the first 72 h of life was reduced in the IN-REC-SUR-E group (43 [40%] of 107) compared with the IN-SUR-E group (60 [54%] of 111; adjusted RR 0·75, 95% CI 0·57-0·98; p=0·037), with a number needed to treat of 7·2 (95% CI 3·7-135·0). The addition of the recruitment manoeuvre did not adversely affect the safety outcomes of in-hospital mortality (19 [19%] of 101 in the IN-REC-SUR-E group vs 37 [33%] of 111 in the IN-SUR-E group), pneumothorax (four [4%] of 101 vs seven [6%] of 111), or grade 3 or worse intraventricular haemorrhage (12 [12%] of 101 vs 17 [15%] of 111). INTERPRETATION: A lung recruitment manoeuvre just before surfactant administration improved the efficacy of surfactant treatment in extremely preterm neonates compared with the standard IN-SUR-E technique, without increasing the risk of adverse neonatal outcomes. The reduced need for mechanical ventilation during the first 72 h of life might facilitate implementation of a non-invasive respiratory support strategy. FUNDING: None.
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Extubación Traqueal/métodos , Cuidados Críticos/métodos , Intubación Intratraqueal/métodos , Surfactantes Pulmonares/uso terapéutico , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Femenino , Humanos , Recien Nacido Extremadamente Prematuro , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Italia , Pulmón/fisiopatología , Masculino , Respiración Artificial/estadística & datos numéricos , Resultado del TratamientoRESUMEN
A general procedure for the late-stage [11C], [13C] and [14C]carbon isotope labeling of cyclic carbamates is reported. This protocol allows the incorporation of carbon dioxide, the primary source of carbon-14 and carbon-11 radioisotopes, in a direct, cost-effective and sustainable manner. A disconnection/reconnection strategy, involving ring opening/isotopic closure, was also implemented.
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Pediatricians have observed a significant decrease in in-person child health visits during the COVID-19 pandemic. In the post lockdown period, the coronavirus trend remains positive in Italy but fears of a second wave have recently grown in Italy due to active hotbeds of contagion. The pandemic may negatively affect the care of pediatric patients and overall children welfare as it may present with severe signs and symptoms or it may complicate. The Italian Pediatric Society recommend to separate well visits from sick ones, to educate families and to promote hygienic strategies to provide an adequate pediatric assistance in case of a second pandemic wave.
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Betacoronavirus , Protección a la Infancia , Infecciones por Coronavirus/epidemiología , Transmisión de Enfermedad Infecciosa/prevención & control , Pandemias , Neumonía Viral/epidemiología , Guías de Práctica Clínica como Asunto , Sociedades Médicas , COVID-19 , Niño , Infecciones por Coronavirus/transmisión , Humanos , Italia/epidemiología , Pediatría , Neumonía Viral/transmisión , SARS-CoV-2RESUMEN
Facial masks may be one of the most cost-effective strategies to prevent the diffusion of COVID 19 infection. Nevertheless, fake news are spreading, alerting parents on dangerous side effects in children, such as hypercapnia, hypoxia, gut dysbiosis and immune system weakness. Aim of the Italian Pediatric Society statement is to face misconception towards the use of face masks and to spread scientific trustable information.
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Betacoronavirus , Consenso , Infecciones por Coronavirus/transmisión , Transmisión de Enfermedad Infecciosa/prevención & control , Control de Infecciones/organización & administración , Máscaras/provisión & distribución , Neumonía Viral/transmisión , COVID-19 , Niño , Infecciones por Coronavirus/epidemiología , Diseño de Equipo , Humanos , Máscaras/normas , Pandemias , Neumonía Viral/epidemiología , SARS-CoV-2RESUMEN
C-H activation has emerged as one of the most efficient tools for the formation of carbon-carbon and carbon-heteroatom bonds, avoiding the use of prefunctionalized materials. In spite of tremendous progress in the field, stoichiometric quantities of toxic and/or costly chemical redox reagents, such as silver(I) or copper(II) salts, are largely required for oxidative C-H activations. Recently, electrosynthesis has experienced a remarkable renaissance that enables the use of storable, safe and waste-free electric current as a redox equivalent. While major recent momentum was gained in electrocatalyzed C-H activations by 4d and 5d metals, user-friendly and inexpensive nickela-electrocatalysis has until recently proven elusive for oxidative C-H activations. Herein, the early developments of nickela-electrocatalyzed reductive cross-electrophile couplings as well as net-redox-neutral cross-couplings are first introduced. The focus of this Minireview is, however, the recent emergence of nickel-catalyzed electrooxidative C-H activations until April 2020.
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A transition-metal-free carbon isotope exchange procedure on phenyl acetic acids is described. Utilizing the universal precursor CO2 , this protocol allows the carbon isotope to be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with carbon isotopes [14 C] and [13 C]. A proof of concept with [11 C] was also obtained with low molar activity valuable for distribution studies.
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Manganaelectro-catalyzed azidation of otherwise inert C(sp3)-H bonds was accomplished using most user-friendly sodium azide as the nitrogen-source. The operationally simple, resource-economic C-H azidation strategy was characterized by mild reaction conditions, no directing group, traceless electrons as the sole redox-reagent, Earth-abundant manganese as the catalyst, high functional-group compatibility and high chemoselectivity, setting the stage for late-stage azidation of bioactive compounds. Detailed mechanistic studies by experiment, spectrophotometry and cyclic voltammetry provided strong support for metal-catalyzed aliphatic radical formation, along with subsequent azidyl radical transfer within a manganese(iii/iv) manifold.
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BACKGROUND: The only pharmacologic prophylaxis against respiratory syncytial virus (RSV) infection in preterm infants is the humanized monoclonal antibody palivizumab. After the 2014 modification of the American Academy of Pediatrics (AAP) recommendations, the Italian Medicines Agency (AIFA) limited the financial coverage for palivizumab prescriptions to otherwise healthy preterm infants with < 29 weeks of gestational age (wGA) aged < 12 months at the beginning of the 2016-2017 RSV season. However, due to the effect on disease severity and hospitalizations following this limitation, shown by several Italian clinical studies, in November 2017 AIFA reinstated the financial coverage for these infants. In this systematic review, we critically summarize the data that show the importance of palivizumab prophylaxis. METHODS: Data from six Italian pediatric institutes and the Italian Network of Pediatric Intensive Care Units (TIPNet) were retrieved from the literature and considered. The epidemiologic information for infants 29-36 wGA, aged < 12 months and admitted for viral-induced acute lower respiratory tract infection were retrospectively reviewed. RSV-associated hospitalizations were compared between the season with running limitation, i.e. 2016-2017, versus 2 seasons before (2014-2015 and 2015-2016) and one season after (2017-2018) the AIFA limitation. RESULTS: During the 2016-2017 RSV epidemic season, when the AIFA limited the financial coverage of palivizumab prophylaxis based on the 2014 AAP recommendation, the study reports on a higher incidences of RSV bronchiolitis and greater respiratory function impairment. During this season, we also found an increase in hospitalizations and admissions to the Pediatric Intensive Care Units and longer hospital stays, incurring higher healthcare costs. During the 2016-2017 epidemic season, an overall increase in the number of RSV bronchiolitis cases was also observed in infants born full term, suggesting that the decreased prophylaxis in preterm infants may have caused a wider infection diffusion in groups of infants not considered to be at risk. CONCLUSIONS: The Italian results support the use of palivizumab prophylaxis for otherwise healthy preterm (29-36 wGA) infants aged < 6 months at the beginning of the RSV season.