Clinical pharmacology of siRNA therapeutics: current status and future prospects.

INTRODUCTION: Small interfering RNA (siRNA) has emerged as a powerful tool for post-transcriptional downregulation of multiple genes for various therapies. Naked siRNA molecules are surrounded by several barriers that tackle their optimum delivery to target tissues such as limited cellular uptake, short circulation time, degradation by endonucleases, glomerular filtration, and capturing by the reticuloendothelial system (RES). AREAS COVERED: This review provides insights into studies that investigate various siRNA-based therapies, focusing on the mechanism, delivery strategies, bioavailability, pharmacokinetic, and pharmacodynamics of naked and modified siRNA molecules. The clinical pharmacology of currently approved siRNA products is also discussed. EXPERT OPINION: Few siRNA-based products have been approved recently by the Food and Drug Administration (FDA) and other regulatory agencies after approximately 20 years following its discovery due to the associated limitations. The absorption, distribution, metabolism, and excretion of siRNA therapeutics are highly restricted by several obstacles, resulting in rapid clearance of siRNA-based therapeutic products from systemic circulation before reaching the cytosol of targeted cells. The siRNA therapeutics however are very promising in many diseases, including gene therapy and SARS-COV-2 viral infection. The design of suitable delivery vehicles and developing strategies toward better pharmacokinetic parameters may solve the challenges of siRNA therapies.

Sustainable and resilient e-commerce under COVID-19 pandemic: a hybrid grey decision-making approach.

E-commerce saw a paradigm shift during COVID. Consumers turned to online shopping when pandemic lockdowns caused brick-and-mortar stores to shut for extended periods. Although the pandemic drove more buyers online, it had negative impacts that affected e-commerce performance. This study assesses both positive and negative impacts and their relative significance. The findings are then used to prioritize different strategies for e-commerce development in four vibrant Middle Eastern economies: United Arab Emirates, Saudi Arabia, Qatar, and Kuwait. The study employs a hybrid approach incorporating grey analytical hierarchy process (GAHP) and grey relational analysis (GRA). The GAHP evaluates the relative significance of impacts, whereas the GRA ranks the strategies. The study is based on the responses from 36 local e-commerce specialists. The findings revealed that the supply chain disruption was a rather significant factor, and that "expanding supplier base" was a top-ranked strategy. The study suggests that increasing market share of e-commerce will necessitate the improvement of the supply chains, including the expansion of the supply base, as well as the establishment of sustainable supply chains. In addition to that, the moment has come to implement meaningful changes, such as digital transformation of supply chains, in order to fulfil customer expectations.

Relationship of inflammatory mediators and sex-related parameters in Jordanian adult men patients with Covid-19.

Background: Recent epidemiological data suggest that Co - ro navirus disease 2019 (COVID-19) has a gender predisposition, with men being more seriously affected than women. Furthermore, older men accounting for most deaths. Therefore, this study aimed to investigate the serum testosterone, inhibin B, intrleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) levels in different age groups of Jordanian males with SARS-CoV2 infection and to evaluate the correlation of these markers in male patients with COVID-19. Methods: This study was performed on 157 selected individuals divided into two groups; COVID-19 patients and healthy controls. The participants of each group were further divided into two subgroups based on the age (20-50 years and 51-80 years age groups). The biochemical tests that were performed in this research are testosterone, inhibin-B, TNF-a, and IL-6. Results: The levels of IL-6 were significantly higher in COVID-19 patients than healthy individuals (7.63 ± 6.30 vs. 5.54 ± 2.10, P=0.006). Similarly, the difference between the levels of TNF-a in the study groups were statistically significant (P=0.001). The mean testosterone levels in COVID-19 patients and healthy controls were 1.53 ± 1.24 and 3.87 ± 1.44, respectively (P<0.001), whereas the mean inhibin B levels in COVID-19 patients (54.29 ± 7.33) were lower than in healthy controls (64.14 ± 37.66) with P = 0.011. TNF-a was significantly and positively correlated with age (r = 0.263, P=0.018) and IL-6 (r = 0.245, P=0.027). Inhibin B had a significant, but negative correlation with TNF-a (r = -0.326, P = 0.003). Conclusions: It can be concluded that most men seeking medical attention with symptomatic COVID-19 had low testosterone and inhibin B levels with increased both IL-6 and TNF-a, which are independent of age conforming the deleterious effects of SARS-CoV-2 infection on testicular function and immune response induction.

Computation of the Complications Post Covid-19 Infections Among Urban Population in Saudi Arabia

The major objective of this research analysis was to look into the intricacies that people in Saudi Arabian cities have had as a result of post Covid-19 infection. This study took place from December 1, 2021, to March 31, 2022, with a total of 1500 volunteers.The massive difference in P-esteem was obtained by using the Pearson's Chi-Square test for all surveys in order to break down the evaluation study. This research was a small step in directing such crucial preventive medicine evaluations.As a result, this study suggests that the generally positive report that the local area experienced a variety of entanglements as a result of Corona virus diseases was handled well with the necessary measures taken by medical care workers and administered by the public authority's responsive authorities.The p-esteem value for respiratory complications was 0.346% where as for the cardiac complications experience was 0.202% and the neurological complications was 0.09%.The least intricacies were recorded in the neurological complications and the maximum were due to respiratory complications.This review recommends that the in general acceptable report that thoughthe local area encountered an adaptable of entanglements post Corona virus diseases yet were handled well with the essential measures by the medical care laborers administerd by the responsive authorities of the public authority

Cognitive impairment in health care workers recovering from COVID-19 infection: a cross-sectional comparative study

Background The COVID-19 outbreak has infected people all over the world where many clinics are being constructed to diagnose and treat lingering symptoms or long COVID. Neurological and long-term cognitive consequences are very worrisome. Many of COVID-19’s neurological symptoms are likely the result of the body’s extensive immunological response to infection rather than the virus attacking the brain or nervous system directly. At the same time, the extent and type of COVID-19’s cognitive consequences are unknown. The goal of this study was to assess the cognitive functions of healthcare workers 2 weeks to 3 months after COVID-19 infection. Ninety-two healthcare workers participated in the study;32 were post-COVID-19 cases, and 60 were healthy people (the comparison group). The cognitive functions of the participants were assessed using the Addenbrooke’s Cognitive Examination (ACE-III) test, which evaluated attention, memory, language, and visuospatial skills, as well as the Arabic version of the Patient Health Questionnaire Anxiety GAD-7 and Depression Assessments PHQ-9. Results The study revealed that there was a highly significant direct correlation between post-infection with COVID-19 and scores of both anxiety and depression and an inverse correlation in the case of attention and memory. On the other hand, there is no statistical effect of post-COVID-19 on verbal fluency, language scores, and visio-spatial abilities. Using multiple linear regression, there was a powerful significant decrease effect of post-COVID-19 on memory scores controlling both anxiety and depression degrees (Beta = − 0.745, P < 0.001). Also, there was a strong negative correlation post-COVID-19 on attention scores controlling both anxiety and depression degrees (Beta = − 0.745, P < 0.001). Conclusions The study showed a strong negative effect of post-COVID-19 on the attention and memory of patients. Furthermore, both anxiety and depression scores increased significantly among the post-COVID-19 patients.

Unsupervised clustering of SARS-CoV-2 using deep convolutional autoencoder

SARS-CoV-2’s population structure might have a substantial impact on public health management and diagnostics if it can be identified. It is critical to rapidly monitor and characterize their lineages circulating globally for a more accurate diagnosis, improved care, and faster treatment. For a clearer picture of the SARS-CoV-2 population structure, clustering the sequencing data is essential. Here, deep clustering techniques were used to automatically group 29,017 different strains of SARS-CoV-2 into clusters. We aim to identify the main clusters of SARS-CoV-2 population structure based on convolutional autoencoder (CAE) trained with numerical feature vectors mapped from coronavirus Spike peptide sequences. Our clustering findings revealed that there are six large SARS-CoV-2 population clusters (C1, C2, C3, C4, C5, C6). These clusters contained 43 unique lineages in which the 29,017 publicly accessible strains were dispersed. In all the resulting six clusters, the genetic distances within the same cluster (intra-cluster distances) are less than the distances between inter-clusters (P-value 0.0019, Wilcoxon rank-sum test). This indicates substantial evidence of a connection between the cluster’s lineages. Furthermore, comparisons of the K-means and hierarchical clustering methods have been examined against the proposed deep learning clustering method. The intra-cluster genetic distances of the proposed method were smaller than those of K-means alone and hierarchical clustering methods. We used T-distributed stochastic-neighbor embedding (t-SNE) to show the outcomes of the deep learning clustering. The strains were isolated correctly between clusters in the t-SNE plot. Our results showed that the (C5) cluster exclusively includes Gamma lineage (P.1) only, suggesting that strains of P.1 in C5 are more diversified than those in the other clusters. Our study indicates that the genetic similarity between strains in the same cluster enables a better understanding of the major features of the unknown population lineages when compared to some of the more prevalent viral isolates. This information helps researchers figure out how the virus changed over time and spread to people all over the world.

Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant in Patients with Philadelphia-Negative Myeloproliferative Neoplasm: A Single Center Experience.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral agent responsible for the coronavirus disease of 2019. The disease is primarily a respiratory illness; however, multisystem involvement is not uncommon. The infection is reported to be more severe in patients with multiple comorbidities and immunocompromised patients. Patients with hematological malignancies are immunocompromised and prone to develop severe SARS-CoV-2 infection. The SARS-CoV-2 had developed several mutations that resulted in different strains with different virulence and different degree of protection by vaccination or prior infection. The Omicron variant is reported to cause mild illness; however, the effect on patients with hematological malignancies like myeloproliferative neoplasms (MPNs) is not clear. We present patients with MPNs who had infection with the Omicron variant of the SARS-CoV-2 and their outcomes. METHODS: Retrospective data from the National Center for Cancer Care and Research records from December 20, 2021, to January 30, 2022. Participants were adults over the age of 18 years with Omicron infection who had been diagnosed with Philadelphia-negative MPNs, essential thrombocythemia, polycythemia vera (PV), and primary myelofibrosis according to the 2008/2016 WHO classification for MPN. RESULTS: Twenty-two patients with Philadelphia-negative MPN had Omicron infection. All patients had a mild disease according to the WHO classification of COVID-19 severity. Most of the patients had medical comorbidities, with hypertension being the most common comorbidity. However, only one patient with PV required hospitalization. DISCUSSION/CONCLUSIONS: In patients with Philadelphia-negative MPN, the Omicron variant of SARS-CoV-2 usually results in mild infection.

Novel Antiviral and Antibacterial Durable Polyester Fabrics Printed with Selenium Nanoparticles (SeNPs).

The COVID-19 pandemic has clearly shown the importance of developing advanced protective equipment, and new antiviral fabrics for the protection and prevention of life-threatening viral diseases are needed. In this study, selenium nanoparticles (SeNPs) were combined with polyester fabrics using printing technique to obtain multifunctional properties, including combined antiviral and antibacterial activities as well as coloring. The properties of the printed polyester fabrics with SeNPs were estimated, including tensile strength and color fastness. Characterization of the SeNPs was carried out using TEM and SEM. The results of the analysis showed good uniformity and stability of the particles with sizes range from 40-60 nm and 40-80 nm for SeNPs 25 mM and 50 mM, respectively, as well as uniform coating of the SeNPs on the fabric. In addition, the SeNPs-printed polyester fabric exhibited high disinfection activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with an inhibition percentage of 87.5%. Moreover, a toxicity test of the resulting printed fabric revealed low cytotoxicity against the HFB4 cell line. In contrast, the treated fabric under study showed excellent killing potentiality against Gram-positive bacteria (Bacillus cereus) and Gram-negative bacteria (Pseudomonas aeruginosa, Salmonella typhi, and Escherichia coli). This multifunctional fabric has high potential for use in protective clothing applications by providing passive and active protection pathways.

The Impact of COVID-19 on a Large, Canadian Community Emergency Department.

INTRODUCTION: As the COVID-19 pandemic unfolded, emergency departments (EDs) across the world braced for surges in volume and demand. However, many EDs experienced decreased demand even for higher acuity illnesses. In this study we sought to examine the change in utilization at a large Canadian community ED, including changes in patient demographics and presentations, as well as structural and administrative changes made in response to the pandemic. METHODS: This retrospective observational study took place in Ontario, Canada, from March 17-June 30, 2020, during province-wide lockdowns in response to COVID-19. We used a control period of March 17-June 30 in 2018-2019. Differences between observed and expected values were calculated for total visits, Canadian Triage and Acuity Scale (CTAS) groups, and age groups using Fisher's exact test. Length of stay (LOS), physician initial assessment time (PIA), and top primary and admission diagnoses were also examined. RESULTS: Patient visits fell to 66.3% of expected volume in the exposure period (20,901 vs 31,525, P<0.0001). CTAS-1 (highest acuity) patient volumes dropped to 86.8% of expected (P = 0.1964) while CTAS-5 (lowest acuity) patient volumes dropped to 32.4% of expected (P <0.0001). Youth (0-17), adult (18-64), and senior (65+) visits all decreased to 37.4%, 71.7%, and 72.9% of expected volumes, respectively (P <0.0001). Median PIA and median ED LOS both decreased (1.1 to 0.6 hours and 3.3 to 3.0 hours, respectively). The most common primary diagnosis in both periods was "other chest pain." Viral syndromes were more prevalent in the exposure period. The top admission diagnoses were congestive heart failure in the control period (4.8%) and COVID-19 in the study period (3.5%). CONCLUSION: ED utilization changed drastically during COVID-19. Our ED responded with wide stakeholder engagement, spatial reorganization, and human resources changes informed by real-time data. Our experiences can help prepare for potential subsequent "waves" of COVID-19 and future pandemics.

It is unprecedented: trial management during the COVID-19 pandemic and beyond.

The COVID-19 pandemic has presented unique challenges for the clinical trial community, both in the rapid establishment of COVID-19 clinical trials and many existing non-COVID-19 studies either being temporarily paused (whether that is a complete pause or pause in some activities) and/or adapting their processes. Trial managers have played a key role in decision-making, undertaking risk assessments and adapting trial processes, working closely with other members of the research team. This article presents some of the ways in which trial management processes have been altered and the key role that trial managers have played. It has been born out of discussions between trial managers in the UK who are members of the UK Trial Managers' Network (UKTMN), a national network of trial management professionals managing non-commercial trials.In these unprecedented times, clinical trials have faced many uncertainties and broad-ranging challenges encompassing a range of activities including prioritising patient safety amidst the pandemic, consenting and recruiting new participants into trials, data collection and management and intervention delivery. In many cases, recruitment has been paused whilst mitigations have been put in place to continue data collection. Innovative solutions have been implemented to ensure we continue, where possible, to deliver high-quality clinical trials. Technology has provided many solutions to these challenges, and trial managers have adapted to new ways of working whilst continuing to deliver their clinical trials. Trial management groups are now faced with new uncertainties around re-starting clinical trials, and it is unclear currently how this will go, though working together with sponsors, funders and site teams is clearly a priority.Clinical trial teams have worked together to ensure their trials have adapted quickly whilst ensuring participant safety is given utmost importance. There are clear examples where the trial community have come together to share experiences and expertise, and this should continue in the future to ensure the innovative practices developed become embedded in the design and conduct of clinical trials in the future.