Synthesis, characterization, antimicrobial activity and molecular docking studies of combined pyrazol-barbituric acid pharmacophores

Purpose: To synthesize, and determine the antibacterial activity and binding mode of new pyrazolbarbituric acid derivatives in a search for new antimicrobial agents.Methods: One-pot multi-component reaction of aldehyde derivatives, barbituric acid and 3-methyl-1- phenyl-1H-pyrazol-5(4H)-one in the presence of NHEt2 to afford Michael adduct was carried out. The reaction was carried out in water and afforded new heterocycles in a one-step fashion, with expedient work-up and high yield without extraction and purification steps. The synthesized compounds were evaluated for antimicrobial activity using agar disc diffusion. Molecular docking approach via MOE-Dock program was applied to predict the binding interactions of some of the new pyrazol-barbituric acid derivatives against six different target proteins downloaded from Protein Data Bank.Results: A series of pyrazole-barbituric acid derivatives were successfully synthesized and characterized. The synthesized compounds showed moderate to very good antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC29212, as well as also antifungal activity against Candida albicans ATCC 10400Conclusion: A series of pyrazole-barbituric acid derivatives has been synthesized and some of them display antimicrobial activities.Keywords: Pyrazole, Barbituric acid, Pyrazole-barbituric acid derivatives, Antimicrobial activity, Molecular dockin

Ticarcillin degradation product thiophene acetic acid is a novel auxin analog that promotes organogenesis in tomato

Efficient regeneration of transgenic plants from explants after transformation is one of the crucial steps in developing genetically modified plants with desirable traits. Identification of novel plant growth regulators and developmental regulators will assist to enhance organogenesis in culture. In this study, we observed enhanced shoot regeneration from tomato cotyledon explants in culture media containing timentin, an antibiotic frequently used to prevent Agrobacterium overgrowth after transformation. Comparative transcriptome analysis of explants grown in the presence and absence of timentin revealed several genes previously reported to play important roles in plant growth and development, including Auxin Response Factors (ARFs), GRF Interacting Factors (GIFs), Flowering Locus T (SP5G), Small auxin up-regulated RNAs (SAUR) etc. Some of the differentially expressed genes were validated by quantitative real-time PCR. We showed that ticarcillin, the main component of timentin, degrades into thiophene acetic acid (TAA) over time. TAA was detected in plant tissue grown in media containing timentin. Our results showed that TAA is indeed a plant growth regulator that promotes root organogenesis from tomato cotyledons in a manner similar to the well-known auxins, indole-3-acetic acid (IAA) and indole-3-butyric acid (IBA). In combination with the cytokinin 6-benzylaminopurine (BAP), TAA was shown to promote shoot organogenesis from tomato cotyledon in a concentration-dependent manner. To the best of our knowledge, the present study reports for the first time demonstrating the function of TAA as a growth regulator in a plant species. Our work will pave the way for future studies involving different combinations of TAA with other plant hormones which may play an important role in in vitro organogenesis of recalcitrant species. Moreover, the differentially expressed genes and long noncoding RNAs identified in our transcriptome studies may serve as contender genes for studying molecular mechanisms of shoot organogenesis

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

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Experimental Preparation and Numerical Simulation of High Thermal Conductive Cu/CNTs Nanocomposites

Due to the rapid growth of high performance electronics devices accompanied by overheating problem, heat dissipater nanocomposites material having ultra-high thermal conductivity and low coefficient of thermal expansion was proposed. In this work, a nanocomposite material made of copper (Cu) reinforced by multi-walled carbon nanotubes (CNTs) up to 10 vol. % was prepared and their thermal behaviour was measured experimentally and evaluated using numerical simulation. In order to numerically predict the thermal behaviour of Cu/CNTs composites, three different prediction methods were performed. The results showed that rules of mixture method records the highest thermal conductivity for all predicted composites. In contrast, the prediction model which takes into account the influence of the interface thermal resistance between CNTs and copper particles, has shown the lowest thermal conductivity which considered as the closest results to the experimental measurement. The experimentally measured thermal conductivities showed remarkable increase after adding 5 vol.% CNTs and higher than the thermal conductivities predicted via Nan models, indicating that the improved fabrication technique of powder injection molding that has been used to produced Cu/CNTs nanocomposites has overcome the challenges assumed in the mathematical models

Mitigative potential of kaempferide against polyethylene microplastics induced testicular damage by activating Nrf-2/Keap-1 pathway

Polyethylene microplastics (PE-MPs) are one of the environmental contaminants that instigate oxidative stress (OS) in various organs of the body, including testes. Kaempferide (KFD) is a plant-derived natural flavonol with potential neuroprotective, hepatoprotective, anti-cancer, anti-oxidant and anti-inflammatory properties. Therefore, the present study was designed to evaluate the alleviative effects of KFD against PE-MPs-prompted testicular toxicity in rats. Fourty eight adult male albino rats were randomly distributed into 4 groups: control, PE-MPs-administered (1.5 mgkg-1), PE-MPs (1.5 mgkg-1) + KFD (20 mgkg-1) co-treated and KFD (20 mgkg-1) only treated group. PE-MPs intoxication significantly (P < 0.05) lowered the expression of Nrf-2 and anti-oxidant enzymes, while increasing the expression of Keap-1. The activities of anti-oxidants i.e., catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), hemeoxygene-1 (HO-1) and glutathione peroxidase (GPx) were reduced, besides malondialdehyde (MDA) and reactive oxygen species (ROS) contents were increased significantly (P < 0.05) following the PE-MPs exposure. Moreover, PE-MPs exposure significantly (P < 0.05) reduced the sperm motility, viability and count, whereas considerably (P < 0.05) increased the dead sperm number and sperm structural anomalies. Furthermore, PE-MPs remarkably (P < 0.05) decreased steroidogenic enzymes and Bcl-2 expression, while increasing the expression of Caspase-3 and Bax. PE-MPs exposure significantly (P < 0.05) reduced the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone, whereas inflammatory indices were increased. PE-MPs exposure also induced significant histopathological damages in the testes. Nevertheless, KFD supplementation significantly (P < 0.05) abrogated all the damages induced by PE-MPs. The findings of our study demonstrated that KFD could significantly attenuate PE-MPs-instigated OS and testicular toxicity, due to its anti-oxidant, anti-inflammatory, androgenic and anti-apoptotic potential