Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)- approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV. Therefore, this study aims to synthesize NS5A inhibitor analogues with high potency pan-genotypic activity and high metabolic stability. Starting from an NS5A inhibitor scaffold previously identified by our research group, we made several modifications. Two series of compounds were created to test the effect of changing the length and spatial conformation (para-para vs. meta-metapositioned bis-imidazole-proline-carbamate), replacing amide groups in the linker with imidazole groups, as well as different end-cap compositions and sizes. The frontrunner inhibits genotype 1b (Con1) replicon, with an EC50 value in the picomolar range, and showed high genotypic coverage with nanomolar range EC50 values against four more genotypes. This together with its high metabolic stability (t1 ⁄2 > 120 min) makes it a potential preclinical candidate

Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors

For many inflammatory diseases, new effective drugs with fewer side effects are needed. While it appears promising to target the activation of the central pro-inflammatory transcription factor NF-κB, many previously discovered agents suffered from cytotoxicity. In this study, new alkylthiourea quinazoline derivatives were developed that selectively inhibit the activation of NF-κB in macrophage-like THP−1 cells while showing low general cytotoxicity. One of the best com pounds, 19, strongly inhibited the production of IL-6 (IC50 = 0.84 µM) and, less potently, of TNFα (IC50 = 4.0 µM); in comparison, the reference compound, caffeic acid phenethyl ester (CAPE), showed IC50s of 1.1 and 11.4 µM, respectively. Interestingly, 19 was found to block the translocation of the NF-κB dimer to the nucleus, although its release from the IκB complex was unaffected. Furthermore, 19 suppressed the phosphorylation of NF-κB-p65 at Ser468 but not at Ser536; however, 19 did not inhibit any kinase involved in NF-κB activation. The only partial suppression of p65 phosphorylation might be associated with fewer side effects. Since several compounds selectively induced cell death in activated macrophage-like THP−1 cells, they might be particularly effective in various inflam matory diseases that are exacerbated by excess activated macrophages, such as arteriosclerosis and autoimmune diseases

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Implementing a proposed methodology for integrated education

There is increasing interest in the use of blended learning in educational systems in Egypt, as one of the images used in e-learning, in addition to being a unique educational pattern complementing the traditional education process with a contemporary vision. Therefore the application of the blended learning methodology to improve the efficiency of teaching design of light metal construction, by identifying and monitoring the possibilities available and the needs of the beneficiaries, and the development of the desired goals, and seek to codify the blended of modern means and their interaction with the methods of learning, to provide an effective pattern and novelty of the patterns of design education, in line with the characteristics of students and their needs, teaching aids and content of study, and that the lowest possible costs, and in allowing control and the development of the educational process and the measurement and evaluation of performance and output periodically and to develop appropriate plans for improvement.In the sense that investment in education, the upgrading of scientific capabilities, and the transformation of education at the university, all over the world. Use modern communication mechanisms from networks and multimedia. Is it a good way, if you are the best recruit, to support the process of teaching and learning from the stage of creativity, interaction and skills development, and is also a tool to consolidateBased on the fact that the design is a human activity that combines creative thinking with practical work, and its effects appear in most products used by man on a daily basis, it represents the essence of the educational process that is employed to prepare a distinguished designer capable of innovation and development in his specialty. Is one of the important areas that reflect the previous philosophical vision, as it combines the theoretical and technical aspects, in addition to that design education is one of the most related areas of technological developments in general and information technology in particular, as well as its correlation and impact on the variable Social, cultural and economic environments, which usually have a bearing on the nature of the content and the methods of education and assessment that are being used

Proposed vision To raising the efficiency of design education method of metal construction by Using an innovative methodology for blended learning

Education is the mainstay of the progress of peoples and nations, so educational institutions seek to develop their education, and in the wake of rapid change and rapid knowledge growth, traditional teaching methods are no longer sufficient for education in the computer age and the Internet. Contemporary technological and technological developments It has become important to develop metal construction design education from traditional to modern methods that are compatible with information technology in all academic and technical aspects, Especially blended learning Method ,This development has led to the need for faculty members to acquire new skills and capabilities that enable them to employ e-learning techniques and effectively use them with traditional education in design education by developing a proposed methodology for that approach.Based on the fact that the design is a human activity that combines creative thinking with practical work, and its effects appear in most products used by man on a daily basis, it represents the essence of the educational process that is employed to prepare a distinguished designer capable of innovation and development in his specialty. Is one of the important areas that reflect the previous philosophical vision, as it combines the theoretical and technical aspects, in addition to that design education is one of the most related areas of technological developments in general and information technology in particular, as well as its correlation and impact on the variable Social, cultural and economic environments, which usually have a bearing on the nature of the content and the methods of education and assessment that are being used

Lipid peroxidation and oxidative stress in rat erythrocytes induced by aspirin and diazinon: the protective role of selenium

Objective: To investigate the adverse effect of exposure to acetylsalicylic acid (ASA), diazinon (DIA) and their combination on oxidant/antioxidant status in rat erythrocytes and the ameliorating role of selenium (Se). Methods: Rats were oral administered ASA at the maximum administration dose (1 350 mg/personal/d=2.5 mg/kg body weight/d), DIA at a dose of 20 mg/kg body weight/d and Se at a dose of 200 µg/kg body weight/d and their combinations for 28 consecutive d. Results: Administration of DIA, ASA and ASA+DIA lead to a significant increment (P≤0.05) in lipid peroxidation as evidenced by the increase in erythrocytes MDA levels by 61.8%, 20.79% and 105.62%, respectively. Co-administration of Se to treated rats modulated the augmentation of MDA levels. Administration of DIA, ASA and ASA+DIA lead to significant decreases (P≤0.05) in the activities of catalase, superoxide dismutase and glutathione peroxidase enzymes when compared to the control group. The most influence and decreases in the activities of the aforementioned enzymes were observed in the treatments of ASA+DIA by 30.53%, 43.42% and 48.31%, respectively. However, co-administration of Se mitigated the significant decreases of superoxide dismutase, catalase and glutathione peroxidase activities to by 14.47%, 15, 36% and 12.29%. Conclusions: It can be concluded that DIA and ASA induced oxidative stress and lipid peroxidation in rat erythrocytes. The results reveal the pronounced ameliorating effect of Se in DIA and ASA intoxicated rats. It is supposed that antioxidant supplementation may be beneficial for the people using ASA for longer periods and exposure to pesticides

The role of television production in improving visual communication to develop Egyptian tourism propaganda

Introduction: The television image has become important as a visual language to address the different groups in the world, due to the technological boom in the development of quality, which contributes to provide a tourist image of Egypt in a new and new quality has not been produced before and that activates the process of mass communication, Film production in terms of the cost factor has become the ultra-sharp television picture is the most representative of this kind of documentary documentaries representing tourism in the Arab Republic of EgyptThe problem of research: The problem of research is to improve the quality of the television image of the documentary films and tourist propaganda of Egypt through the technological development in digital television technologyThe importance of research: Improving the mental image of Egypt as a tourist destination by spreading the cultural awareness of Egypt at the Arab and Western levels by raising the quality of the image of the documentary films of tourist propaganda, using the modern digital technology of television image.The objective of the research: The aim of the research is to improve the quality of the image of the tourist TV films by taking advantage of the modern technological possibilities provided by the digital TV imaging system and the development in the form, dimensions, quality and colors of the digital TV picture.Research Methodology: The study follows the descriptive approach to describe the devices and the tools used in the processes of achieving high quality in the television image and the experimental methodThe most important search results• The interactive feature is the most important characteristic of the New Media on the traditional media. This stage is a coup against the traditional communication model, where the average person can reach his message to those who want it while he wants in a multi-direction rather than a higher Down only, according to the old contact form.• The need to pay attention to the development of tourism marketing methods - the most important of which is the image of the TV tourist documentary film - by raising its efficiency and quality, as well as studying the factors that control the quality of the digital display to reach the best quality of the digital TV display