Novel 1,3,4-oxadiazole derivatives of naproxen targeting EGFR: Synthesis, molecular docking studies, and cytotoxic evaluation.

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.

Synthesis, In Silico Prediction, and In Vitro Evaluation of Anti-tumor Activities of Novel 4'-Hydroxybiphenyl-4-carboxylic Acid Derivatives as EGFR Allosteric Site Inhibitors.

INTRODUCTION: Allosteric inhibition of EGFR Tyrosine Kinase (TK) is currently among the most attractive approaches for designing and developing anti-cancer drugs to avoid chemoresistance exhibited by clinically approved ATP-competitive inhibitors. The current work aimed to synthesize new biphenyl-containing derivatives that were predicted to act as EGFR TK allosteric site inhibitors based on molecular docking studies. METHOD: A new series of 4'-hydroxybiphenyl-4-carboxylic acid derivatives, including hydrazine-1-carbothioamide (S3-S6) and 1,2,4-triazole (S7-S10) derivatives, were synthesized and characterized using IR, 1HNMR, 13CNMR, and HR-mass spectroscopy. Compound S4 had a relatively high pharmacophore-fit score, indicating that it may have biological activity similar to the EGFR allosteric inhibitor reference, and it scored a relatively low ΔG against EGFR TK allosteric site, indicating a high likelihood of drug-receptor complex formation. Compound S4 was cytotoxic to the three cancer cell lines tested, particularly HCT-116 colorectal cancer cells, with an IC50 value comparable to Erlotinib. Compound S4 induced the intrinsic apoptotic pathway in HCT-116 cells by arresting them in the G2/M phase. RESULT: All of the new derivatives, including S4, met the in silico requirements for EGFR allosteric inhibitory activity. CONCLUSION: Compound S4 is a promising EGFR tyrosine kinase allosteric inhibitor that warrants further research.

New Carbothioamide and Carboxamide Derivatives of 3-Phenoxybenzoic Acid as Potent VEGFR-2 Inhibitors: Synthesis, Molecular Docking, and Cytotoxicity Assessment.

INTRODUCTION/BACKGROUND: Because of the well-established link between angiogenesis and tumor development, the use of antiangiogenic therapeutics, such as those targeting VEGFR-2, presents a promising approach to cancer treatment. In the current study, a set of five hydrazine-1-- carbothioamide (compounds 3a-e) and three hydrazine-1-carboxamide derivatives (compounds 4a-c) were successfully synthesized from 3-phenoxybenzoic acid. These compounds were specially created as antiproliferative agents with the goal of targeting cancer cells by inhibiting VEGFR-2 tyrosine kinase. MATERIALS AND METHODS: The new derivatives were synthesized by conventional organic methods, and their structure was versified by IR, 1HNMR, 13CNMR, and mass spectroscopy. In silico investigation was carried out to identify the compounds' target, molecular similarity, ADMET, and toxicity profile. The cytotoxic activity of the prepared compounds was evaluated in vitro against three human cancer cell lines (DLD1 colorectal adenocarcinoma, HeLa cervical cancer, and HepG2 hepatocellular carcinoma). The effects of the leading compound on cell cycle progression and apoptosis induction were investigated by flow cytometry, and the specific apoptotic pathway triggered by the treatment was evaluated by RT-PCR and immunoblotting. Finally, the inhibitory activities of the new compounds against VEGFR-2 was measured. RESULTS: The designed derivatives exhibited comparable binding positions and interactions to the VEGFR-2 binding site to that of sorafenib (a standard VEGFR-2 tyrosine kinase inhibitor), as determined by molecular docking analysis. Compound 4b was the most cytotoxic compound, achieving the lowest IC50 against HeLa cells. Compound 4b, a strong representative of the synthesized series, induced cell cycle arrest at the G2/M phase, increased the proportion of necrotic and apoptotic HeLa cells, and activated caspase 3. The EC50 value of compound 4b against VEGFR-2 kinase activity was comparable to sorafenib's. CONCLUSION: Overall, the findings suggest that compound 4b has a promising future as a starting point for the development of new anticancer drugs.

Using a Disposable Flexible Fiberoptic Scope as a Bougie for Difficult Intubation.

In this case report, we describe two difficult intubations in which an endotracheal tube was threaded over a fiberoptic bronchoscope that was acting as a bougie. Our patients initially presented with limited neck extension, narrow mouth opening, and restricted view of the glottic region. A fiberoptic bronchoscope was guided through while the patient was oxygenated through a laryngeal mask. After the scope provided an unrestricted view of the vocal cords, the digital module was removed by cutting the fiberoptic thread, and an endotracheal tube was passed through. After proper confirmation of the endotracheal tube position, the intubation was deemed successful and thereby, we share our experience with the novel technique. This technique may potentially improve critical patient outcomes whether in trauma or an unexpectedly difficult intubation.

Synthesis, docking study, and antitumor evaluation of benzamides and oxadiazole derivatives of 3-phenoxybenzoic acid as VEGFR-2 inhibitors.

Current chemotherapeutic agents have several limitations, including lack of selectivity, the development of undesirable side effects, and chemoresistance. As a result, there is an unmet need for the development of novel small molecules with minimal side effects and the ability to specifically target tumor cells. A new series of 3-phenoxybenzoic acid derivatives, including 1,3,4-oxadiazole derivatives (4a-d) and benzamides derivatives (5a-e) were synthesized; their chemical structures were confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectra; and various physicochemical properties were determined. The antiproliferative activities of the new derivatives were evaluated by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Three compounds (4b, 4c, and 4d) exhibited cytotoxicity against two of the three cell lines tested, five compounds (3, 4a, 5a, 5b, and 5e) were toxic to one cell line, while two compounds (5c and 5d) were not cytotoxic to any of the three cell lines tested in the current study. Based on docking scores, MTT assay findings, and vascular endothelial growth factor receptor 2 (VEGFR-2) kinase activity data, Compound 4d was selected for further biological investigation. Flow cytometry was used to determine the mode of cell death (apoptosis vs. necrosis) and the effect on cell cycle progression. Compound 4d arrested HepG2 hepatocellular carcinoma cells in the G2/M phase and activated both the intrinsic and extrinsic apoptosis pathways. In conclusion, Compound 4d has shown promising results for future research as a potent VEGFR-2 tyrosine kinase inhibitor.

Characterization of residual debris on packaged hip arthroplasty stems demonstrates the dominance of less than 10 µm sized particulate: Updated USP788 guidelines for orthopedic implants.

Past evaluation of particle contamination on packaged implants has typically been conducted using US Pharmacopeia (USP) 788, a 1970s pharmaceutical guideline created to evaluate contaminant particles in injectable fluids and syringes. Our objective was to reestablish relevant acceptance criteria for residual orthopedic and other implant debris, including smaller particles (i.e., <10 µm in diameter). Packaged total hip arthroplasty (THA) titanium (Ti6Al4V)-alloy femoral stems were used (hydroxyapatite [HA]-coated and non-coated stems). Short-term ultrasonication and longer-term 24-hour soak/agitation methods were used to elute surface-bound contaminant particles, and released particles were analyzed via scanning electron microscopy, energy-dispersive x-ray analysis, image analysis, and particle characterization. For HA-coated THA-stems, >99% of eluted particles were calcium phosphate. For plain non-coated THA-stems, >99% of eluted particles were titanium-alloy-based. The number-based median size of particles in both groups was approximately 1.5 µm in diameter despite being composed of different materials. The total volume of particulate removed from HA-coated stems was 0.037 mm3 (671 × 103 particles total), which was approximately >50-fold more volume than that on plain non-coated stems at 0.0006 mm3 (89 × 103 particles total). Only non-coated THA stems passed reestablished USP788 acceptance criteria, compared by using equivalent total volumes of contaminant particulate within new and legacy guideline ranges of >10 and >25 µm ECD, that is, <1.0 × 107 particles for <1 µm diameter in size, <600,000 for <1-10 µm, <6000 for 10-25 µm and <600 for >25 µm. These results fill a knowledge gap on how much residual debris can be expected to exist on packaged implants and can be used as a basis for updating acceptance criteria (i.e., termed USP788-Implant [USP788-I]). Residual implant particulate assessment is critical given the increasing implant complexity and new manufacturing techniques (e.g., additive manufacturing).

Dietary flaxseed cake influences on performance, quality, and sensory attributes of eggs, serum, and egg trace minerals of laying hens.

Nowadays, there is a global shortage in feed supply for animal nutrition; however, there are a considerable amount of agro-industrial co- and by-products that may offer a reasonable solution. Flaxseed cake (FSC) is a by-product of flaxseed for oil extraction rich in n-3 α-linolenic acid (ALA). Thus, the dietary inclusion of FSC on laying performance, egg quality, and serum and egg trace elements (Se, Zn, and Fe) was evaluated using Hisex White hens. The hens were distributed to three equal experimental treatments and provided diets including 0%, 5%, or 10% FSC from 48 to 58 weeks of age. Findings clarified that up to 10% FSC in the laying hen diet had no detrimental effect on laying rate, egg mass, and feed utilization. It was found that FSC resulted in a valuable source of protein, energy, macro- (Ca and P), micro- (Se, Zn and Fe) elements, and essential amino acids, with arginine being the highest. Dietary FSC did not negatively influence the egg quality traits, as well as egg sensory attributes. Including 5% or 10% FSC in diet did not significantly affect serum total protein and renal function in terms of creatinine, uric acid, and uric acid-to-creatinine ratio. Different FSC levels did not influence the chemical composition of eggs and trace elements in serum and eggs. It could be concluded that FSC is a valuable feedstuff that can provide a good source of energy, protein, amino acids, and macro- and micro-elements for hens' nutrition. The inclusion of up to 10% of FSC in hens diet did not adversely influence egg laying performance, egg quality of both fresh and stored eggs, sensory attributes, and nutritional composition, as well as Se, Zn, and Fe in serum and eggs due to balanced nutrient profile of FSC.

New Indole-6-Carboxylic Acid Derivatives as Multi-Target Antiproliferative Agents: Synthesis, in Silico Studies, and Cytotoxicity Evaluation.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are commonly overexpressed in cancers making them appealing targets for cancer therapeutics. Two groups of indole-6-carboxylic acid derivatives, hydrazone derivatives targeting EGFR and oxadiazole derivatives targeting VEGFR-2, were synthesized and characterized using FT-IR, 1 H-NMR, 13 CNMR, and HR-MS techniques. Binding patterns to potential molecular targets were studied using molecular docking and compared to standard EGFR and VEGFR-2 inhibitors. The newly synthesized compounds were cytotoxic to the three cancer cell lines tested (HCT-116, HeLa, and HT-29 cell lines) as evaluated by the MTT assay. Compound 3 b (EGFR-targeting) and compound 6 e (VEGFR-2-targeting) possessed the highest antiproliferation activity, were cancer-selective, arrested cancer cells in the G2/M phase, induced the extrinsic apoptosis pathway, and had the highest EGFR/VEGFR-2 enzyme inhibitory activity, respectively. The structure-activity relationships of the new compounds showed that the presence of an aryl or heteroaryl fragment attached to a linker is required for the anti-tumor activity. In conclusion, the findings of the current study suggest that compounds 3 b and 6 e are promising cytotoxic agents that act by inhibiting EGFR and VEGFR-2 tyrosine kinases, respectively.

Do internship students do well in a clinical environment? A qualitative naturistic study.

Background: The internship year marks the culmination of the nursing program across all Saudi universities, bridging theoretical learning and practical application. The significance of the internship year lies in the application of skills acquired during the preceding years of study. Understanding interns' experiences, identifying influences, and sharing their recommendations for best practices become crucial. Objective: This study aimed to explore the experiences of internship students and address the challenges they encountered in a clinical environment. Methods: A qualitative naturistic descriptive approach was employed, involving 20 purposively selected participants from internship students in two regions in Saudi Arabia. Data were collected in January 2023 through semi-structured interviews, focus group discussions, and observation. A conventional content analysis approach was used for data analysis. Results: Four major themes were generated: 1) Transferring Shock, 2) Self-Learning, 3) Supportive Environments, and 4) Factors Facilitating Learning. Transferring Shock comprised two subthemes: feeling lost and feeling left out. Conclusion: Internship students acknowledged the utility of orientation and mentorship programs in advancing the practical skills of new nurses and enhancing patient safety. The findings also indicated that those with prior preparation and robust communication skills reported a positive experience. Consequently, integrating communication courses into the nursing education curriculum could be beneficial. Establishing a supportive learning environment for nursing interns is imperative to address challenges and ensure the delivery of safe and effective patient care.

Corrigendum: The impact of multi-enzyme fortification on growth performance, intestinal morphology, nutrient digestibility, and meat quality of broiler chickens fed a standard or low-density diet.

[This corrects the article DOI: 10.3389/fvets.2022.1012462.].

Synthesis of bee venom loaded chitosan nanoparticles for anti-MERS-COV and multi-drug resistance bacteria.

This study aims to fully exploit the natural compound; bee venom (BV) as a substance that can kill and inhibit the growth of microbes and viruses. For this target, BV was loaded onto a safe, natural, and economically inexpensive polymer; chitosan (Ch) in its nano-size form prepared using ionic gelation method in the presence of chemical crosslinking agent (sodium tripolyphosphate; TPP). The findings illustrated that chitosan nanoparticles (ChNPs) were prepared thru this method and exhibited spherical shape and average hydrodynamic size of 202 nm with a polydispersity index (PDI = 0.44). However, the size was increased to 221 nm with PDI (0.37) when chitosan nanoparticles were loaded with BV (ChNC). In addition, the particles of BV appeared as a core and chitosan nanoparticles as a shell implying the successful preparation of nanocomposite (ChNC). Encapsulation of BV into ChNPs with significantly small size distribution and good stability that protect these formed nanocomposites from agglomeration. The cytopathic effect (CPE) inhibition assay was used to identify potential antivirals for Middle East respiratory syndrome coronavirus (MERS-CoV). The response of the dose study was designed to influence the range of effectiveness for the chosen antiviral, i.e., the 50 % inhibitory concentration (IC50), as well as the range of cytotoxicity (CC50). However, our results indicated that crude BV had mild anti-MERS-COV with selective index (SI = 4.6), followed by ChNPs that exhibited moderate anti-MERS-COV with SI = 8.6. Meanwhile. The nanocomposite of ChNC displayed a promising anti-MERS-COV with SI = 12.1. Additionally, the synthesized nanocomposite (ChNC) had greater antimicrobial activity against both Gram-positive and Gram-negative bacteria when compared with ChNPs, BV or the utilized model drug.

c-ANCA-associated vasculitis with predominant CNS demyelination after COVID-19.

COVID-19 infection may trigger the presentation or exacerbation of autoimmune diseases. c-Antineutrophil cytoplasmic antibody (c-ANCA)-associated vasculitis after COVID-19 mainly involves the kidneys and lungs, and is rarely reported. We describe the case of a 13-year-old girl with a history of chronic immunologic thrombocytopenic purpura who presented with transverse myelitis and central nervous system demyelination, and was subsequently diagnosed with c-ANCA-associated vasculitis following COVID-19. The patient's condition improved after pulse therapy with methylprednisolone and rituximab. To our knowledge, this is the first reported pediatric case of ANCA-associated vasculitis with predominant central nervous system involvement after COVID-19 infection.

The impact of multi-enzyme fortification on growth performance, intestinal morphology, nutrient digestibility, and meat quality of broiler chickens fed a standard or low-density diet.

This research aimed to study the impact of supplementation of three multi-enzyme levels (0, 0.1, and 0.2% of feed) and two levels of dietary treatments [standard diet (SD) and low-density diet (LDD)] on growth performance, carcass traits, digestibility, and meat quality of broilers from 1 to 38 days of age. A total of 216 1-day-old Arbor Acres broiler chicks were randomly assigned to a factorial experiment (2 × 3) comprising six dietary treatments, each with six replicates and each replicate with six chickens. The results showed that the LDD significantly reduced body weight gain by 5.0%, compared with the SD. Multi-enzymes significantly improved body weight gain and the production index (PI) relative to the SD. The feed conversion ratio was significantly enhanced with increased multi-enzymes from 1 to 21 days. A significant relation between the multi-enzyme concentration and type of dietary treatment was observed in body weight gain and feed conversion ratio from 1 to 21 days of age. Nitrogen-free extract digestibility was significantly increased by using the SD diet compared with using the LDD. Multi-enzyme supplementation improved the digestibility of dry matter, crude protein, crude fiber, and nitrogen-free extract in the LDD. A significant relationship was found between the multi-enzyme concentration and type of dietary treatment on the pancreas, liver, and intestinal length percentages. The meat dry matter concentration was significantly higher in the LDD group than in the SD group. The low-density diet significantly reduced the total revenue compared with the SD, whereas broilers fed the SD recorded significantly higher total revenue and economic efficiency than those fed the LDD. The low-density diet significantly increased economic efficiency compared with the SD. Multi-enzymes significantly increased the total revenue, net revenue, and economic efficiency than the standard set. In conclusion, using multi-enzymes in broiler diets improved body weight gain. The LDD with multi-enzymes showed enhanced body weight gain compared with the SD without multi-enzymes.

Prostate-Specific Antigen Monitoring Using Nano Zinc(II) Metal-Organic Framework-Based Optical Biosensor.

BACKGROUND: The prostate-specific antigen (PSA) is an important cancer biomarker that is commonly utilized in the diagnosis of prostate cancer. The development of a PSA determination technique that is rapid, simple, and inexpensive, in addition to highly accurate, sensitive, and selective, remains a formidable obstacle. METHODS: In this study, we developed a practical biosensor based on Zn(II) metal-organic framework nanoparticles (Zn-MOFs-NPs). Many spectroscopic and microanalytical tools are used to determine the structure, morphology, and physicochemical properties of the prepared MOF. RESULTS: According to the results, Zn-MOFs-NPs are sensitive to PSA, selective to an extremely greater extent, and stable in terms of chemical composition. Furthermore, the Zn-MOFs-NPs did not exhibit any interferences from other common analytes that might cause interference. The detection limit for PSA was calculated and was 0.145 fg/mL throughout a wide linear concentration range (0.1 fg/mL-20 pg/mL). CONCLUSIONS: Zn-MOFs-NPs were successfully used as a growing biosensor for the monitoring and measurement of PSA in biological real samples.

Primary retrograde urinary drainage using image and endoscopy guidance via urostomies.

AIM: To report the technical success of image and endoscopy-guided retrograde trans-urostomy urinary drainage as a primary catheter placement method performed by interventional radiology (IR). MATERIALS AND METHODS: Nine patients (15 attempted drain placements) with ureteric obstruction following radical cystectomy and urostomy creation were included. The patients were referred to IR for urinary drainage. All patients underwent primary image and endoscopy-guided retrograde trans-urostomy urinary drainage. RESULTS: Primary image and endoscopy-guided retrograde trans-urostomy urinary drainage was successful in 13/15 (86.6%) attempts. The proposed technique had a limited complication rate omitting the percutaneous nephrostomy access step. CONCLUSION: Primary image and endoscopy guided retrograde trans-urostomy urinary drainage should be considered before percutaneous nephrostomy in all patients with a urostomy.

Antioxidant Status, Blood Constituents and Immune Response of Broiler Chickens Fed Two Types of Diets with or without Different Concentrations of Active Yeast.

Probiotics, such as active yeasts, are widely used to enhance poultry production and reduce feeding costs. This study aimed to investigate the antioxidant and immune responses of broilers to different concentrations of active Saccharomyces cerevisiae (SC) when supplemented to two types of diets. A total of 216 1-day-old Arbor Acres unsexed chicks were used in a factorial design, involving two feeds (regular- versus low-density diet) and three concentrations of SC (0%, 0.02% and 0.04%). The results revealed that the low-density diet reduced the body weight and production index of broilers. The addition of SC improved the production index more than the control diet. Total antioxidant capacity (TAC), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and eosinophils were significantly higher in response to the regular-density diet than the low-density diet; however, phagocytic activity (PA), lymphocyte and lysozyme activity (LYS) were lower. Saccharomyces cerevisiae reduced ALT, AST, malondialdehyde (MAD) and TAC more than the standard set, but improved packed cell volume (PCV), hemoglobin (Hgb), red blood cells (RBCs), lymphocytes, monocytes, heterophils, phagocytic index (PI) and the immune response to Newcastle disease virus (NDV) and avian influenza (AI). In conclusion, supplementation of a regular- or low-density diet with SC at a concentration of 0.02% or 0.04% improved the antioxidant parameters, immune status and production index of broilers against stress and infectious agents.

Setup for pressurizing thin films through the superconductor-insulator transition.

We describe an experimental setup designed for transport measurement of thin disordered superconducting films as a function of pressure up to several GPa. We use a specially designed single screw diamond anvil cell that allows the gradual increase of high pressure at cryogenic temperatures. By depositing amorphous films of disordered superconducting indium oxide directly on the diamond, we avoid the effect of pressure-induced structural changes in the substrate. Using this technique, we are able to drive thin films through a pressure tuned superconductor-insulator transition.

Chloroquine and Hydroxychloroquine for the Prevention and Treatment of COVID-19: A Fiction, Hope or Hype? An Updated Review.

In December 2019, the novel coronavirus disease pandemic (COVID-19) that began in China had infected so far more than 109,217,366 million individuals worldwide and accounted for more than 2,413,912 fatalities. With the dawn of this novel coronavirus (SARS-CoV-2), there was a requirement to select potential therapies that might effectively kill the virus, accelerate the recovery, or decrease the case fatality rate. Besides the currently available antiviral medications for human immunodeficiency virus (HIV) and hepatitis C virus (HCV), the chloroquine/hydroxychloroquine (CQ/HCQ) regimen with or without azithromycin has been repurposed in China and was recommended by the National Health Commission, China in mid-February 2020. By this time, the selection of this regimen was based on its efficacy against the previous SARS-CoV-1 virus and its potential to inhibit viral replication of the SARS-CoV-2 in vitro. There was a shortage of robust clinical proof about the effectiveness of this regimen against the novel SARS-CoV-2. Therefore, extensive research effort has been made by several researchers worldwide to investigate whether this regimen is safe and effective for the management of COVID-19. In this review, we provided a comprehensive overview of the CQ/HCQ regimen, summarizing data from in vitro studies and clinical trials for the protection against or the treatment of SARS-CoV-2. Despite the initial promising results from the in vitro studies and the widespread use of CQ/HCQ in clinical settings during the 1st wave of COVID-19, current data from well-designed randomized controlled trials showed no evidence of benefit from CQ/HCQ supplementation for the treatment or prophylaxis against SARS-CoV-2 infection. Particularly, the two largest randomized controlled trials to date (RECOVERY and WHO SOLIDARITY trials), both confirmed that CQ/HCQ regimen does not provide any clinical benefit for COVID-19 patients. Therefore, we do not recommend the use of this regimen in COVID-19 patients outside the context of clinical trials.

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study.

BACKGROUND: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10-8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. RESULTS: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-ß signalling and Th17 cell differentiation. CONCLUSIONS: Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

COVID-19: pathogenesis, advances in treatment and vaccine development and environmental impact-an updated review.

Diseases negatively impact the environment, causing many health risks and the spread of pollution and hazards. A novel coronavirus, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has led to a recent respiratory syndrome epidemic in humans. In December 2019, the sudden emergence of this new coronavirus and the subsequent severe disease it causes created a serious global health threat and hazards. This is in contrast to the two aforementioned coronaviruses, SARS-CoV-2 (in 2002) and middle east respiratory syndrome coronavirus MERS-CoV (in 2012), which were much more easily contained. The World Health Organization (WHO) dubbed this contagious respiratory disease an "epidemic outbreak" in March 2020. More than 80 companies and research institutions worldwide are working together, in cooperation with many governmental agencies, to develop an effective vaccine. To date, six authorized vaccines have been registered. Up till now, no approved drugs and drug scientists are racing from development to clinical trials to find new drugs for COVID-19. Wild animals, such as snakes, bats, and pangolins are the main sources of coronaviruses, as determined by the sequence homology between MERS-CoV and viruses in these animals. Human infection is caused by inhalation of respiratory droplets. To date, the only available treatment protocol for COVID-19 is based on the prevalent clinical signs. This review aims to summarize the current information regarding the origin, evolution, genomic organization, epidemiology, and molecular and cellular characteristics of SARS-CoV-2 as well as the diagnostic and treatment approaches for COVID-19 and its impact on global health, environment, and economy.