BRCA2 Polymorphisms and Breast Cancer Susceptibility: a Multi-Tools Bioinformatics Approach.

BACKGROUND/AIMS: The main focus of this investigation is to identify deleterious single nucleotide polymorphisms (SNPs) located in the BRCA2 gene through in silico approach, thereby,providing an understanding of potential consequences regarding the susceptibility to breast cancer. METHODS: The GenomAD database was used to identify SNPs. To determine the potential adverse consequences, our study employed various prediction tools, including SIFT, PolyPhen, PredictSNP, SNAP2, PhD-SNP, and ClinVar. The pathogenicity associated with the deleterious snSNPs was evaluated bu MutPred and Fathmm. Additionally, I-Mutant and MuPro were used to assess the stability, followed by conservation and protein-protein interaction analysis using robust computational tools. The 3D structure of BRCA2 protein was generated by SwissModel, followed by validation using PROCHECK and Errat. RESULTS: The GenomAD database was used to identify a total of 7, 921 SNPs, including 1940 missense SNPs. A set of 69 SNPs predicted by consensus to be damaging across all platforms was identified. Mutpred and Fathmm identified 48 and 38 SNPs, respectively to be associated with cancer. While I- Mutant and MuPro assays suggested 22 SNPs to decrease protein stability. Additionally, these 22 SNPs reside within highly conserved regions of the BRCA2 protein. Domain analysis, utilizing InterPro, pinpointed 18 deleterious mutations within crucial DNA binding domains and one in the BRC repeat region. CONCLUSION: This study establishes a foundation for future experimental validations and the creation of breast cancer-targeted treatment approaches.

Prescription patterns of quetiapine for multiple drug abuse, depression, and psychosis: A retrospective study.

Background: Quetiapine is an atypical antipsychotic prescribed for schizophrenia, bipolar disorder, multiple drug abuse (MDA), generalized anxiety disorder, severe depression, dementia, and mood disorders. Prescription of quetiapine varies according to use, with side effects increasingly reported with higher doses. Many previous case reports highlighted the misuse of the drug. Here we studied the prescribing patterns of quetiapine in multiple drug abuse (MDA), depression, and psychosis patients in the Madinah region in Saudi Arabia. Methods: This is a retrospective single-center study carried out in the main referral hospital for mental health in Madinah, Saudi Arabia for the period December 2020 till December 2021. Results: A total of 158 patients were included in this study. The mean age of the patients was 30.5 ± 10.1 years. Male presented for 89.9 % of the patients. In terms of quetiapine indications, 46.2 % of patients used it for MDA, 29.7 % for psychosis, and 24.1 for depression. For all patients, quetiapine was used with a mean daily dose of 285.2 ± 222 mg and for a mean duration of 13.9 ± 15.4 weeks. Quetiapine was prescribed with a mean of 2.1 ± 2.2 prescriptions. Comparison between different indications shows that quetiapine was more frequently prescribed for MDA (p < 0.001). The MDA patients were significantly younger than in other groups (p = 0.001). All patients who received quetiapine for MDA were males. However, MDA patients received a smaller dose of quetiapine than other indications (p < 0.001). There were no significant differences between groups in terms of the number of prescriptions, duration, and whether the patient was on other medications or not. These results have been confirmed by regression analysis, where male and younger ages represented a significant contributing factor to MDA compared to psychosis, 95 % CI: 8 x107 (8 x107 - 8 x107) and 0.943 (0.900---0.987), respectively. Conclusion: Quetiapine was prescribed more frequently in MDA patients and younger individuals. Low dose was predominant in those patients, indicating a probability of drug abuse.

Safety of Tocilizumab in COVID-19 Patients and Benefit of Single-Dose: The Largest Retrospective Observational Study.

Severe acute respiratory coronavirus-2 (SARS-CoV-2) still presents a public threat and puts extra strain on healthcare facilities. Without an effective antiviral drug, all available treatment options are considered supportive. Tocilizumab as a treatment option has to date shown variable results. In this retrospective study, we aimed to assess predictors of mortality of COVID-19 patients (n = 300) on tocilizumab and the clinical effectiveness of this drug. The results showed that ICU admission OR = 64.6 (95% CI: 8.2, 507.4); age of the patient OR = 1.1 (95% CI: 1.0, 1.1); and number of tocilizumab doses administered by the patient OR(two doses) = 4.0 (95% CI: 1.5, 10.9), OR(three doses) = 1.5 (95% CI: 0.5, 5.1), and OR(four doses or more) = 7.2 (95% CI: 2.0, 25.5) presented strong correlation factors that may be linked to COVID-19 mortality. Furthermore, our study showed the beneficial effects of early administration of tocilizumab OR = 1.2 (95% CI: 1.1, 1.4) and longer hospital length of stay OR = 0.974 (95% CI: 0.9, 1.0) in reducing COVID-19 mortalities. High blood D-dimer concentration OR = 1.1 (95% CI: 1.0, 1.2) and reciprocal blood phosphate concentration OR = 0.008 (95% CI: 0.0, 1.2) were correlated to high mortality under SARS-CoV-2 infection. The short-term effect of a single dose of tocilizumab was a significant increase in blood BUN and liver enzymes (ALT, AST, and LDH) above their normal ranges. Furthermore, it significantly reduced CRP blood concentration, but not to normal levels (13.90 to 1.40 mg/dL, p < 0.001). Assessing the effect of different doses of tocilizumab (in terms of the number of doses, total mg, and total mg/kg administered by the patients) indicated that administering more than one dose may lead to increases in ICU length of stay and hospital length of stay of up to 14 and 22 days after the last dose of tocilizumab (6 to 14, p = 0.06, and 10 to 22, p < 0.001), with no improvement in 28- and 90-day mortality, as confirmed by Kaplan−Meier analysis. There were also clear correlations and trends between the number of doses of tocilizumab and increased blood CO2, MCV, RDW, and D-dimer concentrations and between number of doses of tocilizumab and decreased CRP, AST, and hemoglobin concentrations. Microbiology analysis showed a significant increase in the incidence of infection after tocilizumab administration (28 to 119, p < 0.001) with a median time of incidence within 6 days of the first dose of tocilizumab. A significant correlation was also found between the number of tocilizumab doses and the number of incidences of infections after tocilizumab administration r (298) = 0.396, p = 1.028 × 10−12. Based on these results and depending on the pharmacokinetic parameters of the drug, we recommend single-dose administration of tocilizumab as the optimal dosage for COVID-19 patients who do not have active bacterial infection or liver diseases, to be administered as soon as the patient is admitted to the hospital.

Dose-dependent atorvastatin associated with angioedema.

PURPOSE: To describe a case of angioedema associated with increasing the dose of HMG-CoA reductase inhibitor (atorvastatin) from 20 to 40 mg daily in a patient previously stable on angiotensin II receptor blocker (losartan) and calcium channel blocker (amlodipine) as antihypertensive agents. SUMMARY: A 79-year-old woman with no known drug allergies and a history of multiple clinical conditions presented to the emergency department with facial and periorbital swelling, edema of the lower extremities, shortness of breath, and generalized itching and skin rash, that started 2 days after increasing her atorvastatin dose from 20 to 40 mg daily. She was concurrently on losartan 50 mg and amlodipine 5 mg daily for the management of hypertension. Atorvastatin was discontinued, and the symptoms resolved during hospitalization. CONCLUSION: While atorvastatin use is not commonly associated with angioedema, the prescriber should be mindful of this possible adverse effect, especially when increasing the dose, or when prescribing together with medications known to cause angioedema (e.g., angiotensin II receptor blockers and calcium channel blockers), which may increase the risk of this adverse event.

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses.

The pathogenesis of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still not fully unraveled. Though preventive vaccines and treatment methods are out on the market, a specific cure for the disease has not been discovered. Recent investigations and research studies primarily focus on the immunopathology of the disease. A healthy immune system responds immediately after viral entry, causing immediate viral annihilation and recovery. However, an impaired immune system causes extensive systemic damage due to an unregulated immune response characterized by the hypersecretion of chemokines and cytokines. The elevated levels of cytokine or hypercytokinemia leads to acute respiratory distress syndrome (ARDS) along with multiple organ damage. Moreover, the immune response against SARS-CoV-2 has been linked with race, gender, and age; hence, this viral infection's outcome differs among the patients. Many therapeutic strategies focusing on immunomodulation have been tested out to assuage the cytokine storm in patients with severe COVID-19. A thorough understanding of the diverse signaling pathways triggered by the SARS-CoV-2 virus is essential before contemplating relief measures. This present review explains the interrelationships of hyperinflammatory response or cytokine storm with organ damage and the disease severity. Furthermore, we have thrown light on the diverse mechanisms and risk factors that influence pathogenesis and the molecular pathways that lead to severe SARS-CoV-2 infection and multiple organ damage. Recognition of altered pathways of a dysregulated immune system can be a loophole to identify potential target markers. Identifying biomarkers in the dysregulated pathway can aid in better clinical management for patients with severe COVID-19 disease. A special focus has also been given to potent inhibitors of proinflammatory cytokines, immunomodulatory and immunotherapeutic options to ameliorate cytokine storm and inflammatory responses in patients affected with COVID-19.

Airborne transmission of SARS-CoV-2 is the dominant route of transmission: droplets and aerosols.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic worldwide. On a daily basis the number of deaths associated with COVID-19 is rapidly increasing. The main transmission route of SARS-CoV-2 is through the air (airborne transmission). This review details the airborne transmission of SARS-CoV-2, the aerodynamics, and different modes of transmission (e.g. droplets, droplet nuclei, and aerosol particles). SARS-CoV-2 can be transmitted by an infected person during activities such as expiration, coughing, sneezing, and talking. During such activities and some medical procedures, aerosols and droplets contaminated with SARS-CoV-2 particles are formed. Depending on their sizes and the environmental conditions, such particles stay viable in the air for varying time periods and can cause infection in a susceptible host. Very few studies have been conducted to establish the mechanism or the aerodynamics of virus-loaded particles and droplets in causing infection. In this review we discuss the various forms in which SARS-CoV-2 virus particles can be transmitted in air and cause infections.

Genome composition and genetic characterization of SARS-CoV-2.

SARS-CoV-2 is a type of Betacoronaviruses responsible for COVID-19 pandemic disease, with more than 1.745 million fatalities globally as of December-2020. Genetically, it is considered the second largest genome of all RNA viruses with a 5' cap and 3' poly-A tail. Phylogenetic analyses of coronaviruses reveal that SARS-CoV-2 is genetically closely related to the Bat-SARS Like-Corona virus (Bat-SL-Cov) with 96% whole-genome identity. SARS-CoV-2 genome consists of 15 ORFs coded into 29 proteins. At the 5' terminal of the genome, we have ORF1ab and ORF1a, which encode the 1ab and 1a polypeptides that are proteolytically cleaved into 16 different nonstructural proteins (NSPs). The 3' terminal of the genome represents four structural (spike, envelope, matrix, and nucleocapsid) and nine accessory (3a, 3b, 6, 7a, 7b, 8b, 9a, 9b, and orf10) proteins. As the number of COVID-19 patients increases dramatically worldwide, there is an urgent need to find a quick and sensitive diagnostic tool for controlling the outbreak of SARS-CoV-2 in the community. Today, molecular testing methods utilizing viral genetic material (e.g., PCR) represent the crucial diagnostic tool for the SARS-CoV-2 virus despite its low sensitivity in the early stage of viral infection. This review summarizes the genome composition and genetic characterization of the SARS-CoV-2.

Structural and operational redesigning of patient-centered ambulatory care pharmacy services and its effectiveness during the COVID-19 pandemic.

BACKGROUND: The newly emerged coronavirus pandemic (COVID-19) has collapsed the entire global health care system. Due to these settings, a lot of strategic changes are adopted by healthcare facilities to ensure continuity in patient-centered services. OBJECTIVE: This study aims to evaluate the effectiveness of structural and operational changes made in ambulatory care pharmacy services during the COVID-19 pandemic. METHODS: A retrospective comparative study was conducted to evaluate the impact and effectiveness of patient-centered interventions and consequent access to medication management care within Johns Hopkins Aramco Health Care ambulatory care pharmacy services during the COVID-19 pandemic by comparing patient-centered key performance indicators before and during COVID-19 pandemic for a total of 4 months. RESULTS: As a result of the structural and operational changes made in patient-centered ambulatory care pharmacy services during the COVID-19 pandemic, a 48% prescriptions requests and 90% prescriptions fills are increased through online health portal application. A three-fold increase in the pharmacy call center utilization resulted in around 10% abandoned calls. In the number of physical visits to ambulatory care pharmacies, a 37% reduction was also noted. The decrease in staff schedule efficiency and an increase in average prescription waiting time were also noticed. The prescription collection through remote area pick up locations, and medication home delivery services were successful during COVID-19 pandemic as supported by statistical data. CONCLUSION: The access to ambulatory care pharmacy services during COVID-19 pandemic has been successfully maintained via medication home delivery, remote area pickup locations, pharmacy call-center consultations and refill requests, online health portal application services, and other measures, while reducing the number of physical visits to the JHAH hospital/clinic to ensure compliance with infection control and prevention measures.

Recent advances in vaccine and immunotherapy for COVID-19.

The COVID-19 pandemic caused by SARS-CoV-2 has resulted in millions of cases and hundreds of thousands of deaths. Beyond there being no available antiviral therapy, stimulating protective immunity by vaccines is the best option for managing future infections. Development of a vaccine for a novel virus is a challenging effort that may take several years to accomplish. This mini-review summarizes the immunopathological responses to SARS-CoV-2 infection and discusses advances in the development of vaccines and immunotherapeutics for COVID-19.