Intramolecular rhodium-catalysed [2 + 2 + 2] cycloaddition of linear chiral N-bridged triynes: straightforward access to fused tetrahydroisoquinoline core.

A route for the preparation of merged symmetrical tetrahydroisoquinolines with central chirality through a rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition involving enantiopure triynes as substrates is described. The results show that linear triynes lacking a 3-atom tether can undergo efficient cyclisation. The N-tethered 1,7,13-triynes used in our approach were easily prepared from readily accessible chiral homopropargyl amides, the basic building blocks in our approach, which were efficiently obtained by diastereoselective addition of propargyl magnesium bromide to Ellman imines. Additional substitution at the benzene rings could be attained when substituted triynes at the terminal triple bonds were employed, giving access to more complex tetrahydroisoquinolines after the rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition. Among the different transition-metal catalysts, the Wilkinson complex (RhCl(PPh3)3) afforded higher yields in the cyclisation of linear triynes; however, triynes bearing a Br substituent at the terminal positions underwent the cyclisation more efficiently in the presence of [RhCl(CO)2]2.

Diastereoselectivity of the Addition of Propargylic Magnesium Reagents to Fluorinated Aromatic Sulfinyl Imines.

The addition of propargylmagnesium bromide to fluorinated aromatic sulfinyl imines gave homopropargyl amines with total regio- and diastereoselection. Complete reversal of diastereoselectivity can be achieved in some cases using coordinating (THF) or noncoordinating (DCM) solvents. Substituted propargylic magnesium reagents have been also tested toward fluorinated aryl sulfinyl imines affording chiral homoallenyl amines with good yields and selectivity control. DFT calculations helped to rationalize the origin of the experimental regio- and diastereoselectivities observed in each case.

Pauson-Khand reaction of fluorinated compounds.

The Pauson-Khand reaction (PKR) is one of the key methods for the construction of cyclopentenone derivatives, which can in turn undergo diverse chemical transformations to yield more complex biologically active molecules. Despite the increasing availability of fluorinated building blocks and methodologies to incorporate fluorine in compounds with biological interest, there have been few significant advances focused on the fluoro-Pauson-Khand reaction, both in the inter- and intramolecular versions. Furthermore, the use of vinyl fluorides as olefinic counterparts had been completely overlooked. In this review, we collect the advances both on the stoichiometric and catalytic intermolecular and intramolecular fluoro-Pauson-Khand reaction, with special attention to the PKR of enynes containing a fluoride moiety.

Complementary value of electron microscopy and immunohistochemistry in the diagnosis of non-small cell lung cancer: A potential role for electron microscopy in the era of targeted therapy.

With the identification of therapeutic targets for lung adenocarcinoma, it has become mandatory to distinguish it from other entities. Some cases remain classified as non-small cell lung carcinoma, not otherwise specified (NSCLC-NOS) with immunohistochemistry. Electron microscopy (EM) can be useful, allowing the identification of glandular differentiation. The aim of this study was to determine the complementary value of immunohistochemistry and EM.Forty-eight NSCLC-NOS cases were selected (PSMAR-Biobank, Barcelona, Spain). Immunohistochemistry (TTF-1, p40) was performed. Tissue was retrieved from paraffin blocks. Results were compared to the final diagnosis, derived from combination of light microscopy, immunohistochemistry, EM, molecular studies and resection specimen.Immunohistochemistry concurred with final diagnosis in 36 cases (75%, Kappa = 0.517). EM agreed with final diagnosis in 35 (72.9%, Kappa = 0.471). Immunohistochemistry had a sensitivity = 73%, specificity = 100%, positive predictive value (PPV) = 100% and negative predictive value (NPV) = 52.4% for adenocarcinoma. All adenocarcinoma cases not solved by immunohistochemistry (n = 10) were classified by EM, and vice versa. Data from EM were identical to those of immunohistochemistry: sensitivity = 73%, specificity = 100%, PPV = 100% and NPV = 52.4%. Combining both techniques, 47 cases were coincident with final diagnosis (97.9%, Kappa = 0.943).EM can provide valuable information in subtyping NSCLC-NOS, being particularly useful when immunohistochemistry is inconclusive. EM could be considered as a complementary tool for decision-making in NSCLC-NOS.

The Fluoro-Pauson-Khand Reaction in the Synthesis of Enantioenriched Nitrogenated Bicycles Bearing a Quaternary C-F Stereogenic Center.

A variety of enantioenriched fluorinated 6H-cyclopenta[c]pyridin-6-one bicycles, a scaffold present in several classes of monoterpenic alkaloids with varied biological activity, were synthesized in just five steps from simple aldehyde starting materials. The synthesis presented wide functional group tolerance and moderate to high yields and diastereoselectivities and could be carried out on a gram scale. These products were suitable for further transformations, such as hydrogenation and deprotection of the tert-butylsulfonyl protecting group.

Fluorine-Containing Drugs Approved by the FDA in 2018.

Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine-containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF3 , as well as aliphatic (CF2 ) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

Vinyl Fluorides: Competent Olefinic Counterparts in the Intramolecular Pauson-Khand Reaction.

Despite the great advances achieved in the Pauson-Khand reaction and the ever-increasing demand for fluorinated compounds, the use of vinyl fluorides as olefinic counterparts in the above-mentioned transformation had been completely overlooked. Herein, we describe, for the first time, the intramolecular Pauson-Khand reaction of enynes containing a vinyl fluoride moiety.

Norovirus shedding among food and healthcare workers exposed to the virus in outbreak settings.

BACKGROUND: Noroviruses (NoV) are highly contagious and the leading cause of nonbacterial outbreaks of gastroenteritis worldwide. Individuals who are infected asymptomatically may act as reservoirs and facilitate the transmission of NoV, but the likelihood of workers of becoming infected in outbreak settings has not been systematically studied. OBJECTIVES: We evaluated the occurrence of norovirus infections among workers exposed to the virus in different outbreak settings. STUDY DESIGN: We screened feces from food handlers and healthcare workers related with gastroenteritis outbreaks, and shedding concentrations over time were calculated from serial samples of infected individuals. Sequence analyses of the capsid P2 domain and region C were used to evaluate linkage between asymptomatic employees and outbreak cases. RESULTS: Of all employees, 59.1% were positive for NoV, and more than 70% of them were asymptomatic. Asymptomatic infections were significantly more frequent in foodborne compared to person-to-person transmitted outbreaks; and in restaurants and hotels, compared to nursing homes and healthcare institutions. Mean viral loads were similar between symptomatic and asymptomatic individuals, starting at 7.51±1.80 and 6.49±1.93 log10 genome copies/g, respectively, and decreasing to 5.28±0.76 and 4.52±1.45 log10 genome copies/g after 19days. CONCLUSIONS: The likelihood of becoming infected when a NoV outbreak occurs at the work place is high and similar between food handlers and healthcare workers, but asymptomatic infections are more frequently identified among food handlers. Since shed amounts of viruses in the absence of symptoms are also high, reinforcement of hygiene practices among workers is especially relevant to reduce the risk of virus secondary transmissions.

Gold(I)-catalysed cascade reactions in the synthesis of 2,3-fused indole derivatives.

A gold(I)-catalysed hydroaminative/arylative cascade for the efficient synthesis of a variety of indole-fused skeletons has been developed. Factors controlling the catalyst loading required in these transformations involving 1,3-unsubstituted indole intermediates have been revealed, allowing isolation of an unprecedented 1,3-dimetallated 3H-indole gold complex characterized by X-ray diffraction.

Brotes de infección por norovirus en centros geriátricos: importancia de una detección precoz / Norovirus outbreaks in geriatric centers: importance of an early detection

Fundamento y objetivos: Los brotes de gastroenteritis aguda (GEA) por norovirus (NV) son frecuentes en geriátricos. Los trastornos gastrointestinales previos y el grado de dependencia de los residentes dificultan la detección y la implementación de medidas de control. El objetivo de nuestro estudio fue conocer la incidencia de los brotes por NV en geriátricos, las vías de transmisión y los genotipos causales. Results: Se notificaron 27 brotes por NV; 5 (18,5%) en geriátricos, que afectaron a 95 personas, con una letalidad del 1,05%. El retraso en la notificación dificultó la investigación en uno de los brotes. La transmisión fue interpersonal en 4 brotes, cuya duración y tasas de ataque entre los residentes fueron mayores que en el brote de exposición común. El genotipo predominante fue el GII.4. Percentage of time within the SpO2 target range increased during automated FiO2 control (76.3% ± 9.2% vs 69.1% ± 8.2% for manual; P < .01). Prolonged episodes with SpO2 <88% of >60 seconds duration (median, 115 episodes [range, 67-240] vs 54 episodes [range, 7-184]; P < .01) and of >180 seconds duration (median, 13 episodes [range, 6-39] vs 2 episodes [range, 0-5]; P < .01) decreased significantly during the automated period. Percentage of time with SpO2 >96% decreased during automated control (6.6% ± 4.4% vs 10.4% ± 3.3%; P < .02). There was no significant difference in FiO2 exposure. The area (deviation × time) below and above the defined SctO2 threshold did not differ between the 2 periods (median, 59.7%*seconds [range, 17.2%-208.3%] for manual vs 49.0%*seconds [range, 4.3%-193.7%] for automated; P = .36). Conclusiones: Es necesario identificar los puntos críticos en los centros y establecer sistemas de alarma para prevenir y minimizar la extensión y la severidad de estos brotes (AU)

Background and objectives: Acute gastroenteritis (AGE) outbreaks of norovirus (NV) occur frequently in nursing homes. Gastrointestinal disorders and degree of dependence of residents complicate early detection and implementation of control measures. Our study's aim was to determine the incidence of NV in elderly care centers, transmission mechanisms and circulating genotypes.Patients and methods: An epidemiological study of NV outbreaks reported to the Public Health Agency of Barcelona 2010-2012 was performed. The attack rate, outbreak duration, symptomatology and identified NV genotypes were analyzed. Results: In total, 27 NV outbreaks were reported and 5 (18.5%) occurred in nursing homes (95 cases with lethality of 1.05%). The etiology of one of the five outbreaks could not be confirmed because of late notification. Four of the outbreaks were attributed to person-to-person transmission. The outbreak duration and attack rate among resident person-to-person transmission were significantly higher compared to common exposure transmission. Genotype GII.4 was predominant. Conclusions: The identification of critical points and the use of clinical alarm systems could prevent and minimize the spreading and severity of these outbreaks (AU)

[Norovirus outbreaks in geriatric centers: importance of an early detection]. / Brotes de infección por norovirus en centros geriátricos: importancia de una detección precoz.

BACKGROUND AND OBJECTIVES: Acute gastroenteritis (AGE) outbreaks of norovirus (NV) occur frequently in nursing homes. Gastrointestinal disorders and degree of dependence of residents complicate early detection and implementation of control measures. Our study's aim was to determine the incidence of NV in elderly care centers, transmission mechanisms and circulating genotypes. PATIENTS AND METHODS: An epidemiological study of NV outbreaks reported to the Public Health Agency of Barcelona 2010-2012 was performed. The attack rate, outbreak duration, symptomatology and identified NV genotypes were analyzed. RESULTS: In total, 27 NV outbreaks were reported and 5 (18.5%) occurred in nursing homes (95 cases with lethality of 1.05%). The etiology of one of the five outbreaks could not be confirmed because of late notification. Four of the outbreaks were attributed to person-to-person transmission. The outbreak duration and attack rate among resident person-to-person transmission were significantly higher compared to common exposure transmission. Genotype GII.4 was predominant. CONCLUSIONS: The identification of critical points and the use of clinical alarm systems could prevent and minimize the spreading and severity of these outbreaks.

FeCl3·6H2O-catalyzed Mukaiyama-aldol type reactions of enolizable aldehydes and acetals.

Mukaiyama-aldol type reactions of acetals derived from enolizable aldehydes with FeCl3·6H2O, an eco-friendly, low-cost, and stable catalyst, lead to ß-methoxycarbonyl compounds with nearly quantitative yields. The methodology is extended to the parent aldehydes as starting materials, leading to the corresponding aldols with lower yields, but efficiently. Different alkyl and aryl substituted acetals and aldehydes have been tested in the reaction with linear and cyclic silyl enol ethers. Reactions are carried out in an open air atmosphere, and additives are not required. Acetals can be considered activating groups of the carbonyl moiety rather than a protecting group in this type of FeCl3·6H2O-catalyzed condensation.

Molecular and clinical epidemiology of norovirus outbreaks in Spain during the emergence of GII.4 2012 variant.

BACKGROUND: Norovirus (NoV) is the most common cause of acute nonbacterial gastroenteritis outbreaks worldwide, but the impact of NoV infections in Spain remains underestimated. OBJECTIVES: This study aimed to determine the prevalence and genetic diversity of NoVs causing outbreaks of acute gastroenteritis in Northeastern Spain (Catalonia) during 2010-2012, and to compare clinical features and levels of viral shedding of the most prevalent GII.4 2012 variant with its predecessor. STUDY DESIGN: NoVs were screened and genotyped in stools from gastroenteritis outbreaks. Genetic diversity over a region covering 50% of VP1, and viral loads were analyzed in stools belonging to GII.4 2009 and 2012 variants. RESULTS: More than 50% of outbreaks were caused by genotype GII.4, although outbreaks caused by multiple strains, GII.6 and GII.1 were also prevalent. During 2012, GII.4 2012 strains clearly replaced GII.4 2009 strains. The first 2012 strain was detected in February 2011, representing the earliest isolate reported worldwide. Epidemiological features of GII.4 2012 and GII.4 2009 outbreaks were comparable, as well as levels of viral shedding in stools. Finally, analysis of the capsid gene showed a higher amino acid variability and diversification in GII.4 2012, affecting sites located at the P2 domain, but also in the shell domain. CONCLUSIONS: Clinical features of outbreaks caused by different genotypes circulating in Spain, including outbreaks caused by GII.4 2012 and GII.4 2009 strains, were comparable. Although shed at similar levels than GII.4 2009 strains, GII.4 2012 strains have clearly replaced the previous predominant strain.

Competitive gold-activation modes in terminal alkynes: an experimental and mechanistic study.

The competition between π- and dual σ,π-gold-activation modes is revealed in the gold(I)-catalyzed heterocyclization of 1-(o-ethynylaryl)urea. A noticeable effect of various ligands in gold complexes on the choice of these activation modes is described. The cationic [Au(IPr)](+) (IPr=2,6-bis(diisopropylphenyl)imidazol-2-ylidene) complex cleanly promotes the π activation of terminal alkynes, whereas [Au(PtBu3 )](+) favors intermediate σ,π species. In this experimental and mechanistic study, which includes kinetic and cross-over experiments, several σ-gold, σ,π-gold, and other gold polynuclear reaction intermediates have been isolated and identified by NMR spectroscopy, X-ray diffraction, or MALDI spectrometry. The ligand control in the simultaneous or alternative π- and σ,π-activation modes is also supported by deuterium-labeling experiments.

Switchable palladium-catalyst reaction of bromomethyl sulfoxides, CO, and N-nucleophiles: aminocarbonylation at Csp3 versus oxidative carbonylation of amines.

The palladium-catalyzed reaction of α-bromomethyl sulfoxides, carbon monoxide, and N-nucleophiles follows different reaction pathways according to the catalytic system and the reaction conditions. The Pd-xantphos catalyst affords high yields of α-sulfinyl amides by an aminocarbonylation process and is the first example of this type of transformation for a nonbenzylic sp(3)-hybridized carbon. On the other hand, the oxidative carbonylation of amines occurs with α-bromomethyl sulfoxides, carbon monoxide, and catalytic Pd(PPh(3))(4) under aerobic conditions, yielding ureas and oxalamides from either primary or secondary amines. The reaction with ambident nucleophiles such as amino alcohols was highly selective and took place exclusively at the amino group despite the presence of the alcohol functionality. In parallel to the reaction paths for simple amines, amino alcohols were converted into hydroxy sulfinyl amides when the reaction was catalyzed by Pd-xantphos, while Pd(PPh(3))(4) catalyst afforded cyclic carbamates. The alkoxycarbonylation reaction of bromomethyl sulfoxides with simple alcohols and CO leading to the corresponding sulfinyl esters is also described.

Investigación de un caso de infección neonatal por Enterobacter sakazakii asociada a un preparado en polvo para lactantes / Investigation of a neonatal case of Enterobacter sakazakii infection associated with the use of powdered infant formula

Introducción Se describe la investigación de un caso de meningitis por Enterobacter sakazakii en una unidad de prematuros con el objetivo de identificar la fuente de infección y los posibles factores contribuyentes. Material y métodos Se realizó el análisis de los posibles riesgos asociados a la infección. En las muestras del preparado en polvo de los lotes que se utilizaron en la alimentación de los neonatos se investigó la presencia de E. sakazakii y su grado de contaminación inicial. Las cepas de E. sakazakii aisladas en sangre y heces del neonato, y en las muestras del preparado en polvo se caracterizaron mediante el biotipo, antibiotipo y pulsotipo. Resultados La alimentación del neonato infectado se había realizado exclusivamente con un preparado en polvo para lactantes prematuros. E. sakazakii se detectó en una muestra abierta y otras 2 no abiertas de un único lote de los analizados. Las cepas de E. sakazakii aisladas en el preparado en polvo y las aisladas en el neonato infectado presentaron el mismo biotipo, patrón de resistencias antimicrobianas y patrón de PFGE. Como factores contribuyentes se identificaron la inadecuada reconstitución del preparado y el excesivo tiempo de conservación antes de su administración. Conclusiones La infección por E. sakazakii en el neonato de la unidad de prematuros se originó por el consumo de un preparado en polvo para lactantes prematuros contaminado durante su fabricación, como resultado de una inadecuada preparación y conservación del producto una vez reconstituido (AU)

Introduction The aim of this study was to describe the investigation of a case of meningitis in a neonatal intensive care unit in order to identify the source of infection and the associated risk factors. Material and methods An analysis was carried out on the possible risk factors associated with the infection. E. sakazakii was detected in the batch of the powdered infant formula used during the feeding of the neonate and the initial level of contamination of the microorganism was estimated. The strains of E. sakazakii previously isolated in blood and faeces of the infected neonate and those isolated in infant formula were characterised by biotype, pulsotype and antimicrobial susceptibility. ResultsE. sakazakii was detected in one opened and two unopened cases of a single batch of powdered infant formula. The E. sakazakii strains isolated in the samples of the product and those isolated in the infected neonate showed the same biochemical, antibiotic susceptibility and PFGE pattern. Conclusions The case of meningitis in the neonatal intensive care unit occurred as a result of the use of a powered infant formula contaminated with E. sakazakii at manufacturing level, and an inadequate preparation and storing of the reconstituted product were identified as risk factors (AU)

[Investigation of a neonatal case of Enterobacter sakazakii infection associated with the use of powdered infant formula]. / Investigación de un caso de infección neonatal por Enterobacter sakazakii asociada a un preparado en polvo para lactantes.

INTRODUCTION: The aim of this study was to describe the investigation of a case of meningitis in a neonatal intensive care unit in order to identify the source of infection and the associated risk factors. MATERIAL AND METHODS: An analysis was carried out on the possible risk factors associated with the infection. E. sakazakii was detected in the batch of the powdered infant formula used during the feeding of the neonate and the initial level of contamination of the microorganism was estimated. The strains of E. sakazakii previously isolated in blood and faeces of the infected neonate and those isolated in infant formula were characterised by biotype, pulsotype and antimicrobial susceptibility. RESULTS: E. sakazakii was detected in one opened and two unopened cases of a single batch of powdered infant formula. The E. sakazakii strains isolated in the samples of the product and those isolated in the infected neonate showed the same biochemical, antibiotic susceptibility and PFGE pattern. CONCLUSIONS: The case of meningitis in the neonatal intensive care unit occurred as a result of the use of a powered infant formula contaminated with E. sakazakii at manufacturing level, and an inadequate preparation and storing of the reconstituted product were identified as risk factors.

Competitive and selective Csp3-Br versus Csp2-Br bond activation in palladium-catalysed Suzuki cross-coupling: an experimental and theoretical study of the role of phosphine ligands.

Phosphine ligands have been demonstrated to have an effect on reactivity and selectivity in the competitive intramolecular palladium-catalysed Suzuki-Miyaura coupling of dibromo sulfoxide 1a possessing two different hybridised electrophilic carbons. It was found that the bromine bond to the sp(3)-hybridised carbon is selectively replaced in the presence of unhindered phosphines such as PPh(3) or xantphos. The use of hindered phosphine ligands such as P(o-tol)(3) and P(1-naphthyl)(3) reversed the selectivity, conducting the cross-coupling at the Csp(2)-Br. Identical trends were observed in external competition experiments carried out with bromomethyl sulfoxide and different substituted bromoarenes. DFT and DFT/MM calculations showed that the selectivity observed is mainly due to the different facility of the ligands to dissociate. Bisphosphine catalysts favour coupling at the sp(3) carbon, whereas monophosphine catalysts prefer the sp(2) carbon.

Osmium(III) complexes with POP pincer ligands: preparation from commercially available OsCl(3)·3H(2)O and their X-ray structures.

Complexes OsCl(3){dbf(P(i)Pr(2))(2)} [1; dbf(P(i)Pr(2))(2) = 4,6-bis(diisopropylphosphino)dibenzofuran], OsCl(3){xant(P(i)Pr(2))(2)} [2; xant(P(i)Pr(2))(2) = 9,9-dimethyl-4,5-bis(diisopropylphosphino)xanthene], and OsCl(3){xant(PPh(2))(2)} [3; xant(PPh(2))(2) = 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] have been obtained in high yield by the reaction of the corresponding diphosphine with OsCl(3)·3H(2)O. The ruthenium(III) counterparts RuCl(3){dbf(P(i)Pr(2))(2)} (4), RuCl(3){xant(P(i)Pr(2))(2)} (5), and RuCl(3){xant(PPh(2))(2)} (6) are similarly obtained from RuCl(3)·3H(2)O in moderate yields. The X-ray structures of dbf(P(i)Pr(2))(2) and complexes 1-3 are also reported.

NHC-stabilized gold(I) complexes: suitable catalysts for 6-exo-dig heterocyclization of 1-(o-ethynylaryl)ureas.

3-Substituted 1-(o-ethynylaryl)ureas 1 selectively undergo either 6-exo-dig or 5-endo-dig cyclization (to give 4-methylene-3,4-quinazolin-2-ones 2 or indoles 3, respectively) depending on the choice of the metal, ligand, and reaction conditions. The best results (up to 96% yield) in the preparation of the hydroamination products 2 are achieved with the highly bulky NHC-stabilized cationic gold(I) complex [Au(IPr)](+). Conversely, ureas bearing an internal alkyne lead to the 5-endo-dig cyclization mode regardless of the gold(I) complex employed. Whereas the nature of the substituent at N-3 does not have any influence on the regiochemistry observed, it does, in some cases, affect the efficiency of these transformations.