5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency

Clks have been shown by recent studies to be promising targets for cancer therapy, as they are considered key regulators in the process of pre-mRNA splicing, which in turn affects every aspect of tumor biology. In particular, Clk1 and -4 are overexpressed in several human tumors. Most of the potent Clk1 inhibitors reported in the literature are non-selective, mainly showing off-target activity towards Clk2, Dyrk1A and Dyrk1B. Herein, we present new 5-methoxybenzothiophene2-carboxamide derivatives with unprecedented selectivity. In particular, the introduction of a 3,5- difluoro benzyl extension to the methylated amide led to the discovery of compound 10b (cell-free IC50 = 12.7 nM), which was four times more selective for Clk1 over Clk2 than the previously published flagship compound 1b. Moreover, 10b showed an improved growth inhibitory activity with T24 cells (GI50 = 0.43 µM). Furthermore, a new binding model in the ATP pocket of Clk1 was developed based on the structure-activity relationships derived from new rigidified analogues

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

Investigation of a COVID-19 outbreak in a University Cardio-Thoracic Hospital in Cairo: exploration of the risk to healthcare workers and patients

Background: Corona virus Disease 2019 (COVID-19) pandemic has posed a challenge to health sectors all over the world. The pandemic arrived in Egypt a few weeks after Europe and Asia, with rapidly rising numbers.  Health care workers (HCWs) are front liners sustaining a major risk of acquiring the infection. Aim: In this work, we analyse an outbreak of COVID-19 in a University hospital in Cairo involving HCWs of different categories, patients and patients’ accompanying relatives. Methods: Following the reporting of the first COVID-19 confirmed case; a 55-year-old nurse at the hospital, a total of 645 healthcare workers, patients and patients' accompanying relatives were tested for SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (rRT-PCR) assay. Results: Twenty four out of 589 HCWs, 3 out of 42 patient and 4 out of 14 patients' accompanying relatives tested positive for COVID-19. No physicians, pharmacists or technicians were infected. Nursing staff and housekeeping staff were the most at risk of contracting the infection with a risk ratio of 4.99 (95%CI: 1.4-17.6) and 5.08 (95%CI: 1.4-18.4) respectively. Clustering of infected HCWs was observed in paediatrics’ ICU and in the 6th floor of the hospital. Conclusions: Nursing and housekeeping staff sustain a significantly higher risk of COVID-19 infection compared to other staff categories. The nature of their duties and the frequent unprotected contact between members of these categories may play a role in increasing their risk. &nbsp

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

Manufacture Techniques of Chitosan-Based Microcapsules to Enhance Functional Properties of Textiles

In recent years, the textile industry has been moving to novel concepts of products, which could deliver to the user, improved performances. Such smart textiles have been proven to have the potential to integrate within a commodity garment advanced feature and functional properties of different kinds. Among those functionalities, considerable interest has been played in functionalizing commodity garments in order to make them positively interact with the human body and therefore being beneficial to the user health. This kind of functionalization generally exploits biopolymers, a class of materials that possess peculiar properties such as biocompatibility and biodegradability that make them suitable for bio-functional textile production. In the context of biopolymer chitosan has been proved to be an excellent potential candidate for this kind of application given its abundant availability and its chemical properties that it positively interacts with biological tissue. Notwithstanding the high potential of chitosan-based technologies in the textile sectors, several issues limit the large-scale production of such innovative garments. In facts the morphologies of chitosan structures should be optimized in order to make them better exploit the biological activity; moreover a suitable process for the application of chitosan structures to the textile must be designed. The application process should indeed not only allow an effective and durable fixation of chitosan to textile but also comply with environmental rules concerning pollution emission and utilization of harmful substances. This chapter reviews the use of microencapsulation technique as an approach to effectively apply chitosan to the textile material while overcoming the significant limitations of finishing processes. The assembly of chitosan macromolecules into microcapsules was proved to boost the biological properties of the polymer thanks to a considerable increase in the surface area available for interactions with the living tissues. Moreover, the incorporation of different active substances into chitosan shells allows the design of multifunctional materials that effectively combine core and shell properties. Based on the kind of substances to be incorporated, several encapsulation processes have been developed. The literature evidences how the proper choices concerning encapsulation technology, chemical formulations, and process parameter allow tuning the properties and the performances of the obtained microcapsules. Furthermore, the microcapsules based finishing process have been reviewed evidencing how the microcapsules morphology can positively interact with textile substrate allowing an improvement in the durability of the treatment. The application of the chitosan shelled microcapsules was proved to be capable of imparting different functionalities to textile substrates opening possibilities for a new generation of garments with improved performances and with the potential of protecting the user from multiple harms. Lastly, a continuous interest was observed in improving the process and formulation design in order to avoid the usage of toxic substances, therefore, complying with an environmentally friendly approach

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

Role of

Chronic Obstructive Pulmonary Disease (COPD) is a major public health problem. It is the fourth leading cause of chronic morbidity and mortality worldwide. COPD is characterized by a specific pattern of inflammation involving many cells and mediators. Neopterin serves as a marker of systemic immune activation, which is of importance in the pathogenesis and progression of various diseases. Aim of the work: This study was conducted to elucidate the role of neopterin in the pathogenesis of COPD. Methods: 55 COPD patients and 20 healthy control subjects of similar age and sex were included in the study. Neopterin levels in the serum and sputum samples were measured in all subjects. Results: The mean values of neopterin in the serum (20.34 ± 4.70 nmol/l) and sputum (32.07 ± 8.14 nmol/l) samples of COPD patients were significantly higher than the mean values of neopterin in the serum and sputum samples of control subjects (6.27 ± 3.35 nmol/l and 4.13 ± 2.25 nmol/l respectively) (p < 0.001). Also, COPD patients with exacerbation had significantly higher (p < 0.001) serum and sputum neopterin levels (23.47 ± 2.56 nmol/l and 39.94 ± 5.47 nmol/l respectively) in comparison with stable COPD patients (18.69 ± 4.76 nmol/l and 27.91 ± 5.95 nmol/l respectively). There was statistically significant difference (p value < 0.05) between different COPD severity groups in the mean values of serum and sputum neopterin (nmol/l). There was statistically significant difference (p value < 0.05) in the mean values of serum and sputum neopterin between different COPD patients when they are classified according to the smoking state. Current smokers have higher mean values of serum (22.40 ± 3.04 nmol/l) and sputum (39.60 ± 7.56 nmol/l) neopterin than ex smokers (20.33 ± 4.67 nmol/l and 29.84 ± 6.33 nmol/l respectively) and nonsmokers (16.00 ± 5.3 nmol/l and 26.42 ± 6.60 nmol/l respectively). Conclusions: This study found increased neopterin serum and sputum levels among COPD patients and suggests a role for neopterin in the pathogenesis of COPD. We recommend larger studies to support our results

Investigating the effect of changing the substrate material analyzed by laser-induced breakdown spectroscopy on the antenna performance

Abstract Miniaturized microstrip antennas are efficiently utilized in MICS band wearable and implantable medical applications. However, the properties of the materials employed for antenna fabrication influence its resultant parameters and play a vital role in its performance. Rogers have been widely used as a substrate material in various antenna designs. In this work, a proof of concept study has been conducted to determine how altering the substrate used in antenna construction affects antenna performance. Using the laser-induced breakdown spectroscopy (LIBS) approach, the elements present in the two distinct substrate raw materials were compared to investigate potential effects on the antenna’s performance. Given their accessibility and widespread use, two types of Rogers’ substrates, RO 3210 and RO 4003, were selected. Furthermore, two identical antenna designs were modeled and fabricated using the two substrate materials. The reflection coefficient (S11) and other antenna parameters were determined and compared. Moreover, the recorded LIBS spectra were evaluated using principle component analysis and partial least square regression techniques. The LIBS spectra showed different copper and iron contents between the two Rogers (i.e., other dielectric properties), leading to a frequency shift. Additionally, impurities in the fabricated material increase the possible losses. Consequently, the elemental contents of the utilized Rogers control the antenna’s performance and can ensure its safety in wearable and implant applications

ABSORPTION AND FLUORESCENCE SPECTRA OF TETRAPHENYL-BUTADIENES. ENVIRONMENTAL AND STERIC EFFECTS.

Author Institution: Institute of Molecular Biophysics, Florida State University; Faculty of Science, Alexandria UniversityAbsorption and fluorescence spectra of trans 1,1,4,4-tetraphenylbutadiene (I) and trans 1,1,4,4-tetraphenyl-2-methylbutadiene (II) were measured in hydrocarbon solvent at room temperature and at $77^{\circ} K$ in rigid hydrocarbon glass. At room temperature, the first absorption band maximum of (II) lies $2280 cm^{-1}$ higher in energy compared with that of (I). This is due to the steric hindrance of the methyl group. Spectral features are interpreted in terms of potential energy curves as a function of the angle of twist around the bond that relieves steric hindrance. Absorption maxima exhibit a red shift while fluorescence maxima exhibit a large blue shift when the solution of (II) is frozen to rigid glass at $77^{\circ}K$. Thus the weak yellow fluorescence of (II) appears as an intense violet fluorescence when its solution is frozen. This is interpreted in terms of a solute-solvent rotational energy barrier in the rigid medium. Crystal fluorescence recorded at room temperature and at $77^{\circ}K$ indicate the role of an intermolecular rotational energy barrier in the crystal