Antifungal screening and in silico mechanistic studies of an in-house azole library

Systemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis, however non-albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first-choice antifungal drugs for candidiasis, however they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in-house azole library of 65 compounds to identify hit matter followed by a molecular modelling study for their CYP51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies 12 and 13 have the necessary binding characteristics for effective inhibition of CYP51. Finally, molecular dynamics (MD) simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 was stable demonstrating excellent binding. This article is protected by copyright. All rights reserved

Global mortality and readmission rates following COPD exacerbation-related hospitalisation: a meta-analysis of 65 945 individual patients

\ua9 2024, European Respiratory Society. All rights reserved.Background Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods A systematic review was performed identifying studies that reported in-hospital mortality, postdischarge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisation

Variación fenotípica en poblaciones de veza (Vicia sativa ssp.) del centro de Turquía, sembradas en otoño y primavera

In central Turkey, common vetch (Vicia sativa ssp. sativa) is traditionally grown in spring. Frequent droughts cause crop failures. Autumn sowing can give higher yields, but then winter plant death is a major problem. The objective of this research was to explore and quantify variation available in V. sativa ssp. germplasm for winter hardiness, yield and adaptability. Eleven plant characters were evaluated in 164 vetch populations in autumn and spring sowings over two years, and their inter-relationships were analyzed. Mean winter death was 27% and was greater in the second, colder year, though the magnitude of the coefficient-of-variation was similar in both years (27 and 28%). Autumn-sown plants produced more standing biomass (17%) than spring-sown plants. Winter death was strongly related to other characters, particularly in the colder year. Principle component analysis proved to be efficient at simplifying the results by classifying the eleven variables into three main groups on the basis of seed size, maturity and winter hardiness. There is wide, exploitable phenotypic variation, and enhanced adaptation for autumn sowing could be achieved by selecting for large seeds and early maturity combined with reasonable winter survival.La veza (Vicia sativa ssp. sativa) crece tradicionalmente en el centro de Turquía y las cosechas sufren pérdidas importantes en las frecuentes temporadas de sequía en primavera. La siembra en el otoño puede conducir a rendimientos más altos, pero las plantas pueden sufrir una mortandad elevada en el invierno, lo que representa un problema mayor. El objetivo de nuestra investigación fue explorar y cuantificar la variación para el vigor, el rendimiento y la adaptabilidad en una colección de germoplasma de V. sativa ssp. Se analizaron once caracteres vegetativos y sus inter-relaciones en 164 poblaciones de haba en siembras de otoño y primavera durante dos años. La mortalidad media en invierno fue un 27% superior en el segundo año, aunque la magnitud del coeficiente de variación fue similar en ambos años (27% y 28%). Las plantas sembradas en otoño produjeron más biomasa (17%) que las de primavera. La mortalidad registrada en invierno estuvo fuertemente relacionada con otros caracteres, particularmente con el índice de heladas anual. El análisis de componentes principales demostró su eficiencia para la simplificación y clasificación de las once variables en tres grupos principales sobre la base del tamaño de la muestra, madurez y resistencia al frío. Existe una amplia variación aprovechable y se demuestra la posibilidad de incrementar la adaptación en la siembra de otoño, con una razonable supervivencia en invierno, mediante la selección de plantas con semillas de mayor tamaño y madurez temprana

Physiologic determinants of prolonged mechanical ventilation in patients after major surgery

Purpose: The aim of the study was to evaluate the physiologic determinants of ventilator dependency in patients who underwent major surgery. Materials and Methods: In this observational study, 43 stable tracheostomized patients undergoing prolonged ventilation (>14 days) were evaluated. Diaphragmatic muscle function was assessed invasively by the tension-time index of the diaphragm (TTdi), an indicator of diaphragm endurance time. The TTdi was calculated as transdiaphragmatic pressure/maximum transdiaphragmatic pressure × inspiratory time/total respiratory time and was recorded either when weaning from mechanical ventilation had finally been successful (n = 28 patients) or at the end of the fifth week in those patients in whom weaning failed (FW) (n = 15). Furthermore, the characteristics of survivors (n = 33) were compared with those of nonsurvivors (n = 10). Results: Successfully weaned patients had a lower breathing frequency/tidal volume or rapid shallow breathing index compared with FW patients (93.9 ± 45.5 vs 142.4 ± 60.3, respectively; P < .005). The TTdi was significantly higher in FW than in successfully weaned patients (0.107 ± 0.050 vs 0.148 ± 0.059; P < .023) and in nonsurvivors than in survivors (0.106 ± 0.046 vs 0.174 ± 0.058, P < .0001, respectively). A transdiaphragmatic pressure/maximum transdiaphragmatic pressure ratio of more than 40% was an independent predictor of mortality, whereas an increased frequency/tidal volume ratio and TTdi were independent predictors of weaning failure. Conclusions: Difficult-to-wean patients after major surgery have overall a limited diaphragm endurance time, in particular, FW breathe very close to the fatigue threshold, and they adopt a rapid shallow breathing respiratory pattern to avoid crossing this threshol