Targeting dihydroceramide desaturase 1 (Des1): Syntheses of ceramide analogues with a rigid scaffold, inhibitory assays, and AlphaFold2-assisted structural insights reveal cyclopropenone PR280 as a potent inhibitor.

Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of PR280 as a better Des 1 inhibitor in vitro (IC50 = 700 nM) than GT11 and XM462, the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of GT11.

[Influence of leadership style on knowledge management and hospital efficiency]. / Influencia del liderazgo en gestión del conocimiento y eficiencia hospitalaria.

OBJECTIVE: To analyse the effect of leadership style on knowledge management in hospitals and hospital efficiency based on the opinion of experts in hospital management, applying fuzzy cognitive maps (FCM). METHOD: FCM are relational models that can be used to graphically represent expert opinion and knowledge to infer cause-effect relationships between different concepts. The use of FCM as a simulation tool allows the evaluation of possible scenarios based on different leadership styles in hospitals. RESULTS: In the resulting augmented matrix, standardized effects range from 0.02 to 0.84, with the highest value representing the strongest relationship between knowledge exploitation and hospital efficiency. From the viewpoint of experts, knowledge creation within the hospital also influences hospital efficiency. Regarding variables reflecting leadership characteristics, positive effects have been identified, though with varying intensities, between authority, benevolence, and charisma, both in terms of knowledge creation and exploitation, as well as hospital efficiency. The transformational leadership style is associated with coefficients having higher values for knowledge management and hospital efficiency. CONCLUSIONS: Experts suggest that hospitals with authoritarian leadership styles would exhibit lower levels of knowledge creation and management, as well as lower hospital efficiency. On the other hand, they associate hospitals managed with a paternalistic leadership style with better values in both knowledge creation and exploitation, as well as hospital efficiency, compared to the authoritarian leadership style. Finally, they attribute the highest levels in aspects related to knowledge management and hospital efficiency to the transformational leadership style.

Influencia del liderazgo en gestión del conocimiento y eficiencia hospitalaria / Influence of leadership style on knowledge management and hospital efficiency

Objetivo: Analizar el efecto del estilo de liderazgo sobre la gestión del conocimiento y la eficiencia hospitalaria aplicando para ello mapas cognitivos difusos (MCD). Método: Los MCD son modelos relacionales que se pueden utilizar para representar gráficamente la opinión y el conocimiento de un grupo de personas expertas e inferir las relaciones causa-efecto que hay entre distintos conceptos. La utilización de MCD como herramienta de simulación permite evaluar posibles escenarios basados en distintos estilos de liderazgo en los hospitales. Resultados: En la matriz aumentada resultante, los efectos estandarizados varían de 0,02 a 0,84, representando el valor más alto la relación entre explotación del conocimiento y eficiencia hospitalaria. Para las personas expertas, la creación de conocimiento en el hospital también influye en la eficiencia hospitalaria. Se han identificado efectos positivos, aunque con distinta intensidad, de la autoridad, la benevolencia y el carisma del líder en la creación y la explotación del conocimiento y en la eficiencia hospitalaria. El liderazgo transformacional se asocia a los valores más altos de gestión de conocimiento y eficiencia hospitalaria. Conclusiones: El estilo de liderazgo autoritario parece ofrecer niveles más bajos de creación y gestión de conocimiento, así como una menor eficiencia hospitalaria. Se asocian al estilo de liderazgo paternalista mejores valores tanto en la creación y la explotación de conocimiento como en la eficiencia hospitalaria, en comparación con el estilo de liderazgo autoritario. Por último, se atribuyen al liderazgo transformacional las mayores cotas en los aspectos relacionados con gestión del conocimiento y eficiencia hospitalaria.(AU)

Objective: To analyse the effect of leadership style on knowledge management in hospitals and hospital efficiency based on the opinion of experts in hospital management, applying fuzzy cognitive maps (FCM). Method: FCM are relational models that can be used to graphically represent expert opinion and knowledge to infer cause–effect relationships between different concepts. The use of FCM as a simulation tool allows the evaluation of possible scenarios based on different leadership styles in hospitals. Results: In the resulting augmented matrix, standardized effects range from 0.02 to 0.84, with the highest value representing the strongest relationship between knowledge exploitation and hospital efficiency. From the viewpoint of experts, knowledge creation within the hospital also influences hospital efficiency. Regarding variables reflecting leadership characteristics, positive effects have been identified, though with varying intensities, between authority, benevolence, and charisma, both in terms of knowledge creation and exploitation, as well as hospital efficiency. The transformational leadership style is associated with coefficients having higher values for knowledge management and hospital efficiency. Conclusions: Experts suggest that hospitals with authoritarian leadership styles would exhibit lower levels of knowledge creation and management, as well as lower hospital efficiency. On the other hand, they associate hospitals managed with a paternalistic leadership style with better values in both knowledge creation and exploitation, as well as hospital efficiency, compared to the authoritarian leadership style. Finally, they attribute the highest levels in aspects related to knowledge management and hospital efficiency to the transformational leadership style.(AU)

Association between histological diaphragm atrophy and ultrasound diaphragm expiratory thickness in ventilated patients.

BACKGROUND: Diaphragm fiber atrophy has been evidenced after short periods of mechanical ventilation (MV) and related to critical illness-associated diaphragm weakness. Atrophy is described as a decrease in diaphragm fiber cross-sectional area (CSA) in human diaphragm biopsy, but human samples are still difficult to obtain in clinics. In recent years, ultrasound has become a useful tool in intensive care to evaluate diaphragm anatomy. The present study aimed to evaluate the ability of diaphragm expiratory thickness (Tdi) measured by ultrasound to predict diaphragm atrophy, defined by a decrease in diaphragm fiber CSA obtained through diaphragm biopsy (the gold standard technique) in ventilated patients. METHODS: Diaphragm biopsies and diaphragm ultrasound were performed in ventilated donors and in control subjects. Demographic variables, comorbidities, severity on admission, treatment, laboratory test results and evolution variables were evaluated. Immunohistochemical analysis to determine CSA and ultrasound measurements of Tdi at end-expiration were performed, and median values of the control group were used as thresholds to determine agreement between them in further analysis. Sensitivity, specificity, and positive and negative predictive values of an ultrasound Tdi cutoff for detecting histologic atrophy were calculated. Agreement between two ultrasound observers was also assessed. RESULTS: Thirty-five ventilated organ donors and 5 ventilated controls were included, without differences in basic characteristics. CSA and Tdi were lower in donors than in controls. All donors presented lower CSA, but only 74% lower Tdi regarding control group thresholds. The cut-off value for lower diaphragm expiratory thickness (Tdi < 1.7 mm) presented a sensitivity of 73%, a specificity of 67%, a positive predictive value of 96% and a negative predictive value of 17% for determining the presence of diaphragm atrophy (CSA < 2851 µm2). CONCLUSIONS: Diaphragm atrophy and thickness reduction is associated to MV. While a lower Tdi in diaphragm ultrasound is a good tool for diagnosing atrophy, normal or increased Tdi cannot rule atrophy out showing that both parameters should not be considered as synonymous.

Revealing 2-dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as sphingosine kinase 2 inhibitors: Some hints on the structural basis for selective inhibition.

Sphingosine kinase (SphK), which catalyzes the transfer of phosphate from ATP to sphingosine (Sph) generating sphingosine-1-phosphate (S1P) has emerged as therapeutic target since the discovery of connections of S1P with cancer progress. So far, most effort has focused on the development of inhibitors of SphK1, and selective inhibitors of SphK2 have been much less explored. Here, we describe the syntheses of new sphingosine derivatives bearing a tetrasubstituted carbon atom at C-2, dimethylhydrazino or azo moieties in the polar head, and alkane, alkene or alkyne moieties as linkers between the polar ahead and the fatty tail. In vitro inhibitory assays based on a time resolved fluorescence energy transfer (TR-FRET) have revealed the hydrazino and alkynyl moieties as the best combination for the design of selective SphK2 inhibitors (19a and 19b). Docking studies showed that compounds 19a-b have the optimal binding to SphK2 through the exploitation of polar but also hydrophobic interactions of their head group with the head of the enzyme binding pocket, while also producing full contact of the fatty tail with the hydrophobic pocket of the enzyme. By contrast, this elongation causes loss of contact surface with the shorter hydrophobic toe of the SphK1 isoform, thus accounting for the SphK2-biased selectivity of these compounds. Cell viability assays of the most promising candidates 19a-b have shown that 19a is not cytotoxic to human endothelial cells at 30 µM.

Training for professionals and other health workers as regard as hospital management of COVID-19 / Artículo original

RESUMEN Fundamento: Cuba ha desplegado una estrategia nacional para la prevención y control contra la COVID-19; entre sus elementos se destaca la capacitación a profesionales y otros trabajadores del sector de la salud. Objetivo: mostrar el diseño y puesta en práctica de un curso de superación para la capacitación de profesionales y otros trabajadores sobre el abordaje hospitalario contra la COVID-19. Métodos: se realizó un estudio descriptivo transversal, entre marzo-mayo de 2020 en el Hospital Militar Universitario "Manuel Fajardo Rivero", de Santa Clara, Villa Clara. Se emplearon métodos teóricos: análisis-síntesis e inductivo-deductivo; empíricos: análisis documental, grupo nominal y el criterio de especialistas para la valoración del producto diseñado. Resultados: la capacitación se efectuó mediante el curso diseñado en la modalidad presencial con una semana de duración; consta de seis temas y está concebido según necesidades específicas de aprendizaje dependiendo de la actividad laboral de los trabajadores. Se aplicaron varios principios didácticos y diferentes modalidades evaluativas para comprobar la aprehensión de los contenidos, y se potencializó la simulación como estrategia didáctica. Conclusiones: el curso diseñado cumple los requerimientos didácticos, es pertinente, factible y tiene un adecuado tratamiento científico y metodológico en sus temas según el criterio de los especialistas consultados; su ejecución posibilitó medir el nivel de apropiación de conocimientos y habilidades para la atención a pacientes Su impacto positivo se ha demostrado cuando después de más de 60 días de trabajo ininterrumpido en el hospital no se ha reportado contagio entre sus trabajadores.

ABSTRACT Background: Cuba has developed a national strategy to prevent and control COVID-19; training for professionals and other workers from the healthcare sector are among the key elements included in it. Objective: to present the design and implementation of a training course for professionals and other workers about the hospital management of COVID-19. Methods: from March to May 2020 a cross-sectional descriptive study was conducted at the "Manuel Fajardo Rivero" University Military Hospital, Santa Clara, Villa Clara. Theoretical methods were used: analysis-synthesis and inductive-deductive methods; empirical methods: documentary analysis, nominal group and expert judgement for evaluating the product design. Results: training was carried out according to a face to face learning course, for a week; it was divided into six topics and it was conceived according to specific learning needs depending on the labour peformed by workers. Several didactic principles and different types of evaluation were applied to check the content understanding, and simulation as didactic strategy, was enhanced. Conclusions: the course was designed to meet the didactic requirements, it is pertinent, feasible and it was designed taking into account an adequate scientific and methodological treatment for each topic according to expert judgement. Knowledge understanding and professional skills when working with patients were meaured after being implemented this course. The positive impact of it is evident since no contagion has been reported among workers in the hospital, for a continuous period of more than 60 days.

Impact of adrenomedullin levels on clinical risk stratification and outcome in subarachnoid haemorrhage.

PURPOSE: To use classification tree analysis to identify risk factors for nonsurvival in a neurological patients with subarachnoid haemorrhage (SAH) and to propose a clinical model for predicting of mortality. METHODS: Prospective study of SAH admitted to a Critical Care Department and Stroke Unit over a 2-year period. Middle region of pro-ADM plasma levels (MR-proADM) was measured in EDTA plasma within the first 24 hours of hospital admission using the automatic immunofluorescence test. A regression tree was made to identify prognostic models for the development of mortality at 90 days. RESULTS: Ninety patients were included. The mean MR-proADM plasma value in the samples analysed was 0.78 ± 0.41 nmol/L. MR-proADM plasma levels were significantly associated with mortality at 90 days (1.05 ± 0.51 nmol/L vs 0.64 ± 0.25 nmol/L; P < .001). Regression tree analysis provided an algorithm based on the combined use of clinical variables and one biomarker allowing accurate mortality discrimination of three distinct subgroups with high risk of 90-day mortality ranged from 75% to 100% (AUC 0.9; 95% CI 0.83-0.98). CONCLUSIONS: The study established a model (APACHE II, MR-proADM and Hunt&Hess) to predict fatal outcomes in patients with SAH. The proposed decision-making algorithm may help identify patients with a high risk of mortality.

[PAPPS Cancer Expert Group. Cancer Prevention Recommendations. 2020 PAPPS update]. / Grupos de Expertos de Cáncer del PAPPS. Recomendaciones de Prevención del Cáncer. Actualización PAPPS 2020.

Cancer is a major cause of morbidity and mortality. Tobacco use, unhealthy diet, and physical inactivity are some of the lifestyle risk factors that have led to an increase in cancer. This article updates the evidence, and includes recommendations for prevention strategies for each of the cancers with the highest incidence. These are based on the reduction of risk factors (primary prevention) and early diagnosis of cancer through screening and early detection of signs and symptoms, in medium-risk and high-risk populations.

Enantioselective Synthesis of 3-Heterosubstituted-2-amino-1-ols by Sequential Metal-Free Diene Aziridination/Kinetic Resolution.

A general protocol for the enantioselective synthesis of 3-heterosubstituted-2-amino-1-ols was developed based on metal- free intramolecular regio- and stereoselective diene aziridination and regioselective opening. Kinetic resolution of the resulting (1'-NR1 R2 and 1'-SR)-4-oxazolidinones was performed using ABCs organocatalysts, expanding the application of this methodology.

Criptococosis miocárdica fulminante en un paciente con infección por el virus de la inmunodeficiencia humana / Fulminant myocardial cryptococcosis in an human immunodeficiency virus infected patient

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Fluorinated triazole-containing sphingosine analogues. Syntheses and in vitro evaluation as SPHK inhibitors.

Sphingosine analogues with a rigid triazole moiety in the aliphatic chain and systematic modifications in the polar head and different degrees of fluorination at the terminus of the alkylic chain were synthesized from a common alkynyl aziridine key synthon. This key synthon was obtained by enantioselective organocatalyzed aziridination and it was subsequently ring opened in a regioselective manner in acidic medium. Up to 16 sphingosine analogues were prepared in a straightforward manner. The in vitro activity of the obtained products as SPHK1 and SPHK2 inhibitors was evaluated, displaying comparable activity to that of DMS.

Enantioselective Synthesis of Aminodiols by Sequential Rhodium-Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine-Based Catalysis.

Regio- and stereoselective oxyamination of dienes through a tandem rhodium-catalysed aziridination-nucleophilic opening affords racemic oxazolidinone derivatives, which undergo a kinetic resolution acylation process with amidine-based catalysts (ABCs) to achieve s values of up to 117. This protocol was applied to the enantioselective synthesis of sphingosine.

Highly reactive 2-deoxy-2-iodo-d-allo and d-gulo pyranosyl sulfoxide donors ensure ß-stereoselective glycosylations with steroidal aglycones.

The preparation of well-defined d-xylo and d-ribo glycosides represents a synthetic challenge due to the limited configurational availability of starting materials and the laborious synthesis of homogeneous 2-deoxy-ß-glycosidic linkages, in particular that of the sugar-steroid motif, which represents the "stereoselective determining step" of the overall synthesis. Herein we describe the use of 2-deoxy-2-iodo-glycopyranosyl sulfoxides accessible from widely available d-xylose and d-ribose monosaccharides as privileged glycosyl donors that permit activation at very low temperature. This ensures a precise kinetic control for a complete 1,2-trans stereoselective glycosylation of particularly challenging steroidal aglycones.

Palladium-catalyzed allylic amination: a powerful tool for the enantioselective synthesis of acyclic nucleoside phosphonates.

Acyclic nucleoside phosphonates have been prepared in a straightforward manner and in high yields by an enantioselective palladium-catalyzed allylic substitution involving nucleic bases as nucleophiles followed by cross-metathesis reaction with diethyl allylphosphonate.

Chemical Access to d-Sarmentose Units Enables the Total Synthesis of Cardenolide Monoglycoside N-1 from Nerium oleander.

Herein we present a chemical approach for the ready preparation of d-sarmentosyl donors enabling the first total synthesis and structure validation of cardenolide N-1, a challenging 2,6-dideoxy-3-O-methyl-ß-d-xylo-hexopyranoside extracted from Nerium oleander twigs that displays anti-inflammatory properties and cell growth inhibitory activity against tumor cells. The strategy highlights the synthetic value of the sequential methodology developed in our group for the synthesis of 2-deoxyglycosides. Key steps include Wittig-Horner olefination of a d-xylofuranose precursor, [I+]-induced 6-endo cyclization, and 1,2-trans stereoselective glycosylation.

Enantioselective Formal Synthesis of Nectrisine Using a Palladium-Catalyzed Asymmetric Allylic Amination and Cross-Metathesis as Key Steps.

A formal enantioselective synthesis of nectrisine, a potent α-glucosidase inhibitor, was carried out starting from butadiene monoepoxide through a synthetic sequence involving enantioselective allylic substitution, cross-metathesis, dihydroxylation, and cyclization.

Conformationally-locked N-glycosides: exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease.

Pyranoid-type glycomimetics having a cis-1,2-fused glucopyranose-2-alkylsulfanyl-1,3-oxazoline (Glc-PSO) structure exhibit an unprecedented specificity as inhibitors of mammalian ß-glucosidase. Notably, their inhibitory potency against human ß-glucocerebrosidase (GCase) was found to be strongly dependent on the nature of aglycone-type moieties attached at the sulfur atom. In the particular case of ω-substituted hexadecyl chains, an amazing influence of the terminal group was observed. A comparative study on a series of Glc-PSO derivatives suggests that hydrogen bond acceptor functionalities, e.g. fluoro or methyloxycarbonyl, significantly stabilize the Glc-PSO:GCase complex. The S-(16-fluorohexadecyl)-PSO glycomimetic turned out to be a more potent GCase competitive inhibitor than ambroxol, a non glycomimetic drug currently in pilot trials as a pharmacological chaperone for Gaucher disease. Moreover, the inhibition constant increased by one order of magnitude when shifting from neutral (pH 7) to acidic (pH 5) media, a favorable characteristic for a chaperone candidate. Indeed, the fluoro-PSO derivative also proved superior to ambroxol in mutant GCase activity enhancement assays in N370S/N370S Gaucher fibroblasts. The results presented here represent a proof of concept of the potential of exploiting long-range non-glycone interactions for the optimization of glycosidase inhibitors with chaperone activity.

Rhodium-catalyzed regio- and stereoselective oxyamination of dienes via tandem aziridination/ring-opening of dienyl carbamates.

The reaction of dienyl carbamates with PhI(OR)2 in the presence of rhodium catalysts affords vinyl aziridines which are in situ regio- and stereoselectively opened to afford oxyamination products resulting from a selective S(N)2 (Rh2(OAc)4/PhI(OPiv)2) or S(N)2' (Rh2(OPiv)4/PhI(OAc)2) opening. The scope and limitations of this tandem process are described.

Syntheses of a novel fluorinated trisphosphinoborate ligand and its copper and silver complexes. Catalytic activity toward nitrene transfer reactions.

A novel fluorinated ligand, the anionic PhB(CH2P(p-CF3C6H4)2)3 (PhBP3 (p-CF3Ph)), has been synthesized and characterized, as well as its corresponding thallium, copper, and silver derivatives. The presence of fluorine atoms in the ligand structure induced the desired effect of enhancing electrophilic character at the metal center, without promoting substantial changes in the ligand skeleton compared with the parent ligand PhB(CH2PPh2)3(-) (PhBP3). Olefin aziridination and C-H amidation reactions have been induced with those complexes as catalyst precursors. The copper derivative catalyzed the olefin aziridination of an array of olefins bearing either electron-donating or electron-withdrawing groups. The silver analogue was found to promote the C-H amidation of a series of substrates in moderate to high yields.