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

Laboratory findings in COVID-19 - alterations of hematological, immunological, biochemical, hormonal and other lab panels: a narrative review

Up to the present date, according to the official reports of the World Health Organization (WHO), 205,338,159 patients have been confirmed with the coronavirus disease (COVID-19) and 4,333,094 have died as a consequence of this infectious disorder. The majority of COVID-19 patients will develop hematological, biochemical, immunological, hormonal and other complex alterations of their laboratory data which may be diagnosed using different biomarkers. In this paper, we review the alterations of the hematology, immunology, biochemistry, hormonal and other laboratory panels discovered in the subjects diagnosed with SARS-CoV-2 infection, based on the available data in the literature

Microcystic adnexal carcinoma: A focused review and updates

Microcystic adnexal carcinoma (MAC) is an uncommon, locally aggressive, malignant cutaneous tumor with pilar and eccrine differentiation. In this article we describe the clinical presentation, pathologic hallmarks, and the use of new adjunct diagnostic devices, to optimize diagnosis, management and treatment options

STUDY OF GENETIC RELATIONSHIP BETWEEN SOME OLIVE VARIETIES IN GELLIN GENE BANK

Olive tree (Olea europaea L.) is one of the most important fruit trees, there is a lot of varieties with the possibility of mislabeling, homogenouses and synonyms, which makes major troubles when having plant material for propagation and breeding programs. In this search, 12 olive varieties (Mawi Istanbuli, Khilkhali Khishen, Dan, Mniekri, Adkam, Doaibli, Jlot, Khilkhali Saghir, Karamani Modabal,       Mawi abo Shokeh, Sourani, and Abo Shokeh),  cultivated in ACSAD Gene bank in Gellin, were characterized by ISSR molecular markers to determine the relationship between these varieties. Depending on quantitive traits the results indicated that these varieties are so close to each other's, ranged from 60% and 85%. It was noticed that Mneikri was apart from the other varieties in its traits, (polymorphic rate was 92.94%)

Serum Calprotectin in Rheumatoid Arthritis: A Promising Diagnostic Marker, How Far Is It Related to Activity and Sonographic Findings?

Background: In the past 2 decades, there has been increasing interest in calprotectin. It is released and detected in serum and body fluids as a potentially useful clinical inflammatory marker. The protein has been described in synovial tissue in rheumatoid arthritis (RA) patients, specifically in the lining layer adjacent to the cartilage–pannus junction, which is the primary site of cartilage destruction and bone erosion. Assessment of inflammatory activity in RA is of pivotal importance for the optimal treatment. Our aim in this study is to measure the serum calprotectin levels in RA patients and to assess its association—if there is any—with disease activity score and radiological findings using the musculoskeletal ultrasound. Patients and methods: In our case control study, we included 44 RA patients (Group I) and 20 age- and sex-matched healthy volunteers who served as the control group (Group II). Both groups were subjected to full history taking and thorough clinical examination. Assessment of RA disease activity state was done for all RA patients using the Disease Activity Score 28. Laboratory investigations included the measurement of complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anticitrullinated peptide antibodies, kidney, liver functions; serum calprotectin levels were determined using enzyme-linked immunosorbent assay and radiological joint assessment was done using musculoskeletal ultrasound score. Results: There was a statistically significant elevation of serum calprotectin levels among RA patients when compared with healthy controls. Statistically significant correlations were also found between serum calprotectin and the ultrasound grading score, Disease Activity Score 28, and erythrocyte sedimentation rate, which reflect the degree of inflammatory activity in the affected joints in RA patients. Moreover, the study yielded a significant correlation between serum calprotectin levels and rheumatoid autoantibodies (rheumatoid factor and anticitrullinated peptide antibodies), which are strong predictors of the aggressiveness of the disease. Serum calprotectin at a cutoff level of 93.9 μg/dL had 88.6% sensitivity and 100% specificity for diagnosis of RA. Conclusion: Calprotectin was found to have high association with laboratory and ultrasonography markers of inflammation in RA patients, so it is recommended for use as a marker of inflammatory activity in RA patients especially for the follow-up of patients on biological therapy to assess its efficacy

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-meta-positioned 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 (t½ > 120 min) makes it a potential preclinical candidate

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population