Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights

This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Chlorhexidine versus povidone–iodine skin antisepsis before upper limb surgery (CIPHUR) : an international multicentre prospective cohort study

Introduction Surgical site infection (SSI) is the most common and costly complication of surgery. International guidelines recommend topical alcoholic chlorhexidine (CHX) before surgery. However, upper limb surgeons continue to use other antiseptics, citing a lack of applicable evidence, and concerns related to open wounds and tourniquets. This study aimed to evaluate the safety and effectiveness of different topical antiseptics before upper limb surgery. Methods This international multicentre prospective cohort study recruited consecutive adults and children who underwent surgery distal to the shoulder joint. The intervention was use of CHX or povidone–iodine (PVI) antiseptics in either aqueous or alcoholic form. The primary outcome was SSI within 90 days. Mixed-effects time-to-event models were used to estimate the risk (hazard ratio (HR)) of SSI for patients undergoing elective and emergency upper limb surgery. Results A total of 2454 patients were included. The overall risk of SSI was 3.5 per cent. For elective upper limb surgery (1018 patients), alcoholic CHX appeared to be the most effective antiseptic, reducing the risk of SSI by 70 per cent (adjusted HR 0.30, 95 per cent c.i. 0.11 to 0.84), when compared with aqueous PVI. Concerning emergency upper limb surgery (1436 patients), aqueous PVI appeared to be the least effective antiseptic for preventing SSI; however, there was uncertainty in the estimates. No adverse events were reported. Conclusion The findings align with the global evidence base and international guidance, suggesting that alcoholic CHX should be used for skin antisepsis before clean (elective upper limb) surgery. For emergency (contaminated or dirty) upper limb surgery, the findings of this study were unclear and contradict the available evidence, concluding that further research is necessary

Synthèse asymétrique d’analogues tripeptidiques de l’asunaprévir basés sur une oxaproline et leur évaluation biologique

L’’ infection par le virus de l’ hépatite C (HCV) est considérée comme un des défis majeurs de santé publique en Egypte où la prévalence du virus de 10 % est la plus élevée au monde selon l’EHIS (Enquête sur les Problèmes de Santé en Egypte). Dans les récents développements thérapeutiques de nouveaux médicaments anti-HCV, une gamme d’inhibiteurs de protéase actifs a déjà été approuvée dans le traitement de l’HCV dans plusieurs pays (asunaprévir, paritaprévir, grazoprévir). Ces membres de la famille “prévir” ont en commun une structure tripeptidique équipée d’une unité 4-hétéroarylproline centrale. Notre travail de thèse s’est donné comme objectif de préparer deux nouvelles séries d’analogues potentiellement actifs comme anti-HCV. Ceux-ci impliquent le remplacement isostérique du cycle de la proline par un cycle isoxazolidine et l’introduction d’un groupe en position 4 de type heteroaryloxy- ou -CH2-. Les précurseurs des oxaprolines ont été synthétisés de novo avec une stratégie par cycloaddition 1,3-dipolaire (1,3-DC) impliquant une carboxynitrone et une vinyloxy/ allyl quinoline. L’unité oxaproline obtenue a été deprotégée séquentiellement (groupes N- et CO2H) et couplée jusqu’à l’obtention des tripeptides visés. Notre travail inclut deux domaines de la recherche méthodologique en chimie organique : (i) l’accès à des isoxazolidines très fonctionnelles par 1,3-DC avec la difficulté du diastéréocontrôle avec des aldonitrones et la sensibilité en milieu acide de ces composés et (ii) la synthèse et le couplage de dérivés d’acides aminés optiquement actifs non-naturels et difficile à faire. Des tests biochimiques et cellulaires ont été effectués sur les analogues formés.Hepatitis C virus (HCV) infection is considered the most challenging public health problem in Egypt where the prevalence is the highest in the world. Recent survey known as the Egyptian Health Issues Survey (EHIS) reported a prevalence of 10% HCV infection. In the recent therapeutical development of new anti-HCV drugs, a variety of active protease inhibitors have been already approved for treatment of HCV in some countries (asunaprevir, paritaprevir, grazoprevir). These members of the "previr" family display a common structure based on a tripeptide featuring a central 4-heteroarylproline unit. Our PhD work involves the attempts to prepare two new series of anti-protease analogues as novel anti-HCV agents. These analogues involve isosteric replacement of proline ring by isoxazolidine ring and introduction of either a heteroaryloxy or a heteroaryl-CH2- appendage at the C4 position. The oxaproline precursors have been de novo synthetized using an asymmetric 1,3-dipolar cycloaddition (1,3-DC) strategy, that involves the reaction between a vinyloxy / allyl quinoline and a carbalkoxynitrone. The obtained oxaproline unit have been subjected to sequential deprotection of N- and CO2H groups, and amide couplings to afford the target tripeptide analogues. Our work includes two domains of methodologic research in organic chemistry: (i) the access of highly functional isoxazolidines by 1,3-DC with the difficulty of diastereocontrol with aldonitrones and the acid sensitivity of these compounds (ii) the synthesis and the coupling of optically active non-natural and «difficult to make» amino acid derivatives. Both biochemical and cell-based assays have been done for the formed analogues

Estudio del espectro de infrarrojo y la relajación vibracional de péptidos en disolución acuosa= Study of the IR spectrum and the vibrational relaxation of peptides in water solution

En la presente tesis presentamos un estudio teórico del espectro infrarrojo y de la relajación vibracional de péptidos modelo disueltos en agua. Los péptidos son descritos utilizando campos de fuerza estándar de Mecánica Molecular y también Hamiltonianos electrónicos semiempíricos. El analisis de los ujos de energía vibracional intra e intermoleculares se realiza utilizando los Modos Normales Instantáneos. Así mismo se propone una nueva metodología para trazar su identidad durante la dinámica de relajación. Los tiempos de relajación obtenidos en nuestras simulaciones se encuentran en un acuerdo excelente con las medidas experimentales. También se describe la importancia relativa de los diferentes caminos de relajación, la velocidad de transferencia de energía hacia el disolvente y los cambios conformacionales de los péptidos. Palabras clave: Transferencia de energía, procesos de relajación, espectroscopía molecular, péptidos. Abstract In this thesis we present a theoretical study of the IR spectrum and the vibrational relaxation of model peptides solved in water. The peptides are described using standard Molecular Mechanics and Semiempirical Hamiltonian force elds. The analysis of the intra e intermolecular vibrational energy ows is carried out using the Instantaneous Normal Modes. A new methodology is proposed to track their identity during the relaxation dynamics. The relaxation lifetimes derived from our simulations are shown to be in excellent agreement with the experimental measurements. The relative importance of the di erent relaxation pathways, the rate of the energy transfer into the solvent and the conformational changes of the peptides are also described. Keywords: Energy transfer, relaxation processes, molecular spectroscopy, peptides

Parametric study on moment redistribution of fiber reinforced concrete continuous beams with basalt FRP bars

The state of Qatar is suffering from its harsh environment and coastal conditions which stand for most of the year. As a result, steel-reinforced concrete structures are subjected to rapid corrosion and deterioration. Therefore, there is a necessity to replace the conventional steel reinforcement by fiber-reinforced polymers (FRP) bars. Apart from FRP bars corrosion resistance, their strength to weight ratio is higher than steel reinforcement which made the FRP bars a viable alternative to steel reinforcement. Continuous concrete beams are commonly-used elements in structures such as parking garages and overpasses. In such structures, forces could be distributed between the critical sections after cracking. This phenomenon is called moment redistribution. It reduces the congested rebars in connections and enhances the ductility of the members. However, the linear-elastic behaviour of FRP materials makes the ability of continuous beams to redistribute loads and moments questionable. This study aims to investigate the capability of moment redistribution of basalt fiber reinforced concrete (BFRC) continuous beams reinforced with basalt FRP (BFRP) bars. Eleven reinforced concrete (RC) continuous beams of 200 x 300 x 4000 mm were tested up to failure under five-point loading. The main investigated parameters were the reinforcement ratio (0.6rb, 1.0rb, 1.8rb and 2.8rb; where rb is the balanced reinforcement ratio), stirrups spacing (80 and 120 mm) and volume fractions of Basalt-macro fibers (BMF) (0.75 and 1.5%). A parametric study was then conducted using a validated finite element (FE) model to extend the investigated parameters that may affect the moment redistribution of RC continuous beams. It was concluded that moment redistribution occurs in beams that have at least a ratio of bottom to top reinforcement of 0.

Understanding Chemistry and Unique NMR Characters of Novel Amide and Ester Leflunomide Analogues

A series of diverse substituted 5-methyl-isoxazole-4-carboxylic acid amides, imide and esters in which the benzene ring is mono or disubstituted was prepared. Spectroscopic and conformational examination was investigated and a new insight involving steric interference and interesting downfield deviation due to additional diamagnetic anisotropic effect of the amidic carbonyl group and the methine protons in 2,6-diisopropyl-aryl derivative (2) as conformationaly restricted analogues Leflunomide was discussed. Individual substituent electronic effects through π resonance of p-substituents and most stable conformation of compound (2) are discussed

Learning deep domain-agnostic features from synthetic renders for industrial visual inspection

International audienceDeep learning has resulted in a huge advancement in computer vision. However, deep models require an enormous amount of manually annotated data, which is a laborious and time-consuming task. Large amounts of images demand the availability of target objects for acquisition. This is a kind of luxury we usually do not have in the context of automatic inspection of complex mechanical assemblies, such as in the aircraft industry. We focus on using deep convolutional neural networks (CNN) for automatic industrial inspection of mechanical assemblies, where training images are limited and hard to collect. Computer-aided design model (CAD) is a standard way to describe mechanical assemblies; for each assembly part we have a three-dimensional CAD model with the real dimensions and geometrical properties. Therefore, rendering of CAD models to generate synthetic training data is an attractive approach that comes with perfect annotations. Our ultimate goal is to obtain a deep CNN model trained on synthetic renders and deployed to recognize the presence of target objects in never-before-seen real images collected by commercial RGB cameras. Different approaches are adopted to close the domain gap between synthetic and real images. First, the domain randomization technique is applied to generate synthetic data for training. Second, domain invariant features are utilized while training, allowing to use the trained model directly in the target domain. Finally, we propose a way to learn better representative features using augmented autoencoders, getting performance close to our baseline models trained with real images