Vitamin D enhances type I IFN signaling in COVID-19 patients

The ability of Vitamin D (VitD) to modulate antiviral responses through induction of antimicrobial peptide is well established. However, the effect of VitD on host responses to SARS-CoV-2 is not well investigated. We here report the ability of VitD to enhance host IFN-alpha/beta (a/β) signaling both in vitro and among severe COVID-19 patients treated with VitD. Blood and saliva specimens were obtained from severe COVID-19 patients treated (43 patients), or not (37 patients), with vitD, during their stay in intensive care unit. Patients were followed up to 29 days following admission, and patient survival outcomes were collected. Higher activity levels of RIG-1/MDA-5 and JAK-STAT signaling pathways were observed with significantly higher gene and protein levels of antiviral interferon stimulating genes (ISGs) such as MX-1 and ISG-15; both in vitro, following treatment of PBMCs with vitD, and in whole blood and saliva specimens of VitD treated patients. Moreover, VitD treated patients had lower risk of all-cause mortality by day 29 compared to untreated patients (adjusted hazard ratio, 0.37, 95% confidence interval of 0.14–0.94; P = 0.038). The herein uncovered regulatory role of VitD on type I IFNs suggests the importance of insuring a normal level of VitD for the prevention and probably treatment of SARS-CoV-2 infection. Additional mechanistic studies, however, are needed to fully elucidate the antiviral effects of VitD particularly in the setting of COVID-19 infection

Vitamin D modulates systemic inflammation in patients with severe COVID-19

Aims The ability of vitamin D (VitD) to modulate immune responses in the clinical setting of COVID-19 infection is not well investigated. This study aimed to evaluate the ability of VitD to attenuate inflammatory responses in patients with severe COVID-19. Materials and methods Blood samples and nasopharyngeal swabs were obtained from patients with severe COVID-19 who had been treated (20 patients), or not (25 patients), with VitD, during their stay in the intensive care unit. Western blotting was used to evaluate the expressions of STAT3, JNK and AKT signaling pathways and ELISA was used to measure levels of IL-6, IL-17, and IL-1β in blood of these patients. Key findings Reduced levels of STAT3, JNK and AKT pathways and lower levels of proinflammatory cytokines such as IL-6, IL-17, and IL-1β were observed in VitD treated patients (50,000 IU of cholecalciferol weekly for 3 weeks), and in vitro following treatment of poly I:C stimulated PBMCs with VitD (50 nM of calcitriol). Moreover, lower circulatory levels of these proinflammatory cytokines following treatment with VitD were associated with lower serum levels of COVID-19-related severity markers such as D-dimer and C-reactive proteins (

Multiple inborn errors of type I IFN immunity in a 33-year-old male with a fatal case of COVID-19

The host genetic inborn errors of immunity (IEIs) have been shown to contribute to susceptibility to life-threatening coronavirus disease 2019 (COVID-19), as it had been associated previously with other viral infections. Most genetic association studies have described IEIs as a monogenic defect, while there have been no reports of patients with multiple inherited immune deficiencies. This is a complex case of IEIs predisposing to severe viral infections in an unvaccinated 33-year-old male patient. The patient was admitted with no respiratory symptoms, showed a SARS-CoV-2 PCR positive test on the second day of admission, started developing progressive lung consolidation within three days of hospitalization, and was moved from non-invasive to mechanical ventilation within 12 days of hospitalization. Impaired production of type I IFN was detected in patient PBMCs treated with poly(I:C), at both mRNA and protein levels. Whole exome sequencing revealed three mutations across type I IFN production pathway, which were predicted to be loss-of-function (pLOF). The three mutations were predicted to predispose to severe viral infections: monoallelic R488X TLR3, monoallelic His684Arg TLR3, and biallelic Val363Met IRF3. Functional analysis confirmed that all these mutations dysregulated the type I IFN pathway. Evaluation of TLR3 and IRF3 IFN-β1 luciferase reporter activity showed a hypomorphic suppression of function. TOPO TA cloning was used to ascertain the positioning of both TLR3 variants, indicating that both variants were on the same allele. We have described a unique complex IEI patient with multiple mutations, particularly along type I IFN production pathway

Implications for COVID-19: A systematic review with meta analysis of nurses experiences of working in acute care hospital settings during a respiratory pandemic

Aim: To carry out systematic review and meta-analysis of experiences of nurses working during respiratory infection pandemic in hospitals providing management of the acute conditions. Background:  The major portion of the health professionals working as the main frontline workers in COVID -19 pandemics and other respiratory pandemics are constituted by nurses. In recent literature there has been evaluation of the increased risk among health workers. But very few studies have been put forward which have provided data especially regarding risk among the nurses irrespective of the other health activists and analysed the experience of nurses regarding their involvement in the pandemic. Review Results: The systematic and meta-analysis contained reports from 15 qualitative research including 397 nurses. The study was primarily phenomenological in nature. The majority of the nurses were female and between the ages of twenty to fifty years. The review and meta-analysis included 136 findings of the study, 111 of which were unambiguous and 25 of which were convincing. The nursing teams offered high-quality care despite facing significant emotional, social and physical consequences, and lack of responsiveness of formalised managerial reaction

Unveiling the potential application of intraoperative brain smear for brain tumor diagnosis in low-middle-income countries: A comprehensive systematic review

Background: Immediate intraoperative histopathological examination of tumor tissue is indispensable for a neurosurgeon to track surgical resection. A brain smear is a simple, rapid, and cost-effective technique, particularly important in the diagnosis of brain tumors. The study aims to determine the effectiveness of intraoperative brain smear in the diagnosis of brain tumors in low- and middle-income countries (LMICs), while also evaluating its sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy.Methods: A comprehensive search of the literature was conducted using PubMed, Scopus, and Google Scholar. The retrieved articles were independently screened by two reviewers. The data was extracted, processed, and organized using Microsoft Excel.Results: A total of 59 out of 553 articles screened were included in the final analysis. The sensitivity and specificity of the intraoperative smear of brain tumors were found to be over 90% in most studies. The PPV was consistently above 90% in 11 studies, reaching 100% in one study and the NPV varied, ranging from 63% to 100%, and the accuracy was found to be \u3e80% in most studies. One recurrent theme in the majority of the included studies was that an intraoperative brain smear is a cost-effective, quick, accessible, and accurate method of diagnosing brain tumors, requiring minimal training and infrastructure.Conclusion: Intraoperative brain smear is a simple, rapid, cost-effective, and highly sensitive diagnostic modality for brain tumors. It can be a viable and accessible alternative to more traditional methods such as frozen sections and can be incorporated into neurosurgical practice in LMICs as a reliable and efficient diagnostic tool

Epidemiological and Clinical Characteristics of Streptococcus pneumoniae Infections in a Tertiary Care Center in Bahrain (2010-2014)

Objective: To describe the epidemiology of invasive and non-invasive pneumococcal disease during a 5-year period in a major hospital in Bahrain.   Design and Setting: Retrospective study of cases of pneumococcal diseases among patient ≥ 14 years old during a five-year period (2010-2014), who attended Salmaniya Medical Complex, Bahrain.   Patients and Methods: Laboratory data was obtained on Streptococcus pneumoniae isolates. Patients ≥14 years old of age, both inpatient and outpatient with cultures positive for Streptococcus pneumoniae were included. Only samples from blood, cerebrospinal fluid (CSF), pleural fluid, sputum, deep tracheal aspirate (DTA), bronchial wash, eye discharge and middle ear fluid were included. Demographics and clinical records from medical files were then reviewed.   Results: A total of 130 culture samples met the inclusion criteria and were analyzed. One-hundred twenty-six patients with pneumococcal disease were identified; with 65% being non-invasive and 35% being invasive pneumococcal disease. Overall, non-bacteremic Pneumonia was the most frequent manifestation, followed by bacteremia. Pneumococcal disease was more common among male patients (62.7%). Mean age was 57.67 (15-95 years). The most common comorbidities were hypertension, Diabetes Mellitus followed by cardiovascular disease. Twenty-seven patients received mechanical ventilation during their admission, 13 patients were admitted to the intensive care unit, and 6 patients developed para-pneumonic effusion as a complication. In-hospital Mortality rate was 13.5%.     Conclusion:  This study supports the current literature where pneumococcal infection is more prevalent in elderly and those with comorbidities. Mortality was related to age, certain chronic medical illness, admission to intensive care unit and need for mechanical ventilation

Determinants of healthcare workers perceptions, acceptance and choice of COVID-19 vaccines: a cross-sectional study from the United Arab Emirates

Acceptance of COVID-19 vaccine among health-care workers (HCWs) is crucial for controlling the pandemic and ensuring HCW and patient safety. Information on the acceptance of different COVID-19 vaccines is lacking. Despite the United Arab Emirates (UAE) having vaccinated most of its population, vaccine acceptance still raises concerns. This study explores COVID-19 vaccine acceptance, vaccine choice, and associated factors among HCWs in the UAE. An online national cross-sectional study was conducted among 517 HCWs. Acceptance and choice of COVID-19 vaccines were assessed, and logistic regression analysis identified predictors for vaccine acceptance. More than half (58%) of HCWs were willing to take the vaccine and give it to their family. Reasons for taking the vaccine were concerns for families contracting COVID-19 (67%) and social responsibility (64%). Reasons for refusals included concerns with side-effects (61%). Most HCWs knew of the Pfizer (79%) and Sinopharm (57%) vaccines; however, acceptance was higher for Pfizer (35%) and AstraZeneca (21%) vaccines. Being male and being influenza vaccinated predicted willingness to take the vaccine (aOR: 2.34; 95% CI:1.34–4.08; p ≤ 0.001) and (aOR: 2.13; 95% CI: 1.29–3.51; p ≤ 0.001), respectively. HCWs who expressed concerns with inadequate safety data were less likely to take the vaccine (aOR: 0.17; 95% CI: 0.10–0.30; p ≤ 0.001). Additionally, side effects, perception of risk, and level of trust of company and country of manufacture predicted acceptance and choice of vaccines. Effective vaccine policy campaigns to improve acceptance should target HCW’s knowledge and awareness of perceived risks of COVID-19, safety data, social responsibility, and individual preferences for vaccine choice

Thymoquinone Potentiates the Effect of Phenytoin against Electroshock-Induced Convulsions in Rats by Reducing the Hyperactivation of m-TOR Pathway and Neuroinflammation: Evidence from In Vivo, In Vitro and Computational Studies

Epilepsy is a chronic neurodegenerative disease characterized by multiple seizures, hereto 35% of patients remain poor responders. Phenytoin (PHT; 20 and 40 mg/kg) and thymoquinone (THQ; 40 and 80 mg/kg) were given alone and as a low dose combination for 14 days (p.o), prior to challenge with maximal electroshock (MES; 180 mA, 220 V, 0.2 s). Apart from observing convulsions, hippocampal mTOR, IL-1β, IL-6 and TNF-α levels were measured. Hippocampal histomorphological analysis was also conducted. In vitro cell line studies and molecular docking studies were run in parallel. The results revealed the synergistic potential of the novel duo-drug combination regimen: PHT (20 mg/kg) and THQ (40 mg/kg) against MES-induced convulsions. MES amplified signaling through mTOR, and inflated the levels of proinflammatory markers (IL-1β, IL-6 and TNF-α), which was significantly averted (p < 0.001) with the said drug combination. The computational studies revealed that PHT and THQ cooperatively bind the active site on Akt (upstream target of m-TOR) and establish a good network of intermolecular interactions, which indicates the sequential inhibition of PI3K/Akt/m-TOR signaling with the combination. The combination also increased cell viability by 242.81% compared to 85.66% viability from the the toxic control. The results suggest that the PHT and THQ in combination possesses excellent anticonvulsant and neuroprotective effects

Increased blood immune regulatory cells in severe COVID-19 with autoantibodies to type I interferons

Abstract The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. While regulatory T (Treg) and B (Breg) cells, as the main elements of immune homeostasis, contribute to the control of hyperinflammation during COVID-19 infection, we hypothesized change in their levels in relation to disease severity and the presence of autoantibodies (auto-Abs) to type I IFNs. Cytometric analysis of blood of 62 COVID-19 patients with different severities revealed an increased proportion of conventional (cTreg; CD25+FoxP3+) and unconventional (uTreg; CD25-FoxP3+) Tregs, as well as the LAG3+ immune suppressive form of cTreg/uTreg, in the blood of severe COVID-19 cases compared to the milder, non-hospitalized cases. The increase in blood levels of cTreg/uTreg, but not LAG3+ cTreg/uTreg subtypes, was even higher among patients with severe COVID-19 and auto-Abs to type I IFNs. Regarding Bregs, compared to the milder, non-hospitalized cases, the proportion of IL-35+ and IL-10+ Bregs was elevated in the blood of severe COVID-19 patients, and to a higher extent in those with auto-Abs to type I IFNs. Moreover, blood levels of cTreg, LAG3+ cTreg/uTreg, and IL-35+ and IL-10+ Breg subtypes were associated with lower blood levels of proinflammatory cytokines such as IL-6, IL-17, TNFα, and IL-1β. Interestingly, patients who were treated with either tocilizumab and/or a high dose of Vitamin D had higher blood levels of these regulatory cells and better control of the proinflammatory cytokines. These observations suggest that perturbations in the levels of immunomodulatory Tregs and Bregs occur in COVID-19, especially in the presence of auto-Abs to type I IFNs

GRADE-ADOLOPMENT of clinical practice guidelines and creation of clinical pathways for the primary care management of chronic respiratory conditions in Pakistan

Abstract Introduction In Pakistan, chronic respiratory conditions contribute a large burden of morbidity and mortality. A major reason for this is the lack of availability of local evidence-based clinical practice guidelines (EBCPGs) in Pakistan, particularly at the primary care level. Thus, we developed EBCPGs and created clinical diagnosis and referral pathways for the primary care management of chronic respiratory conditions in Pakistan. Methods The source guidelines were selected by two local expert pulmonologists after a thorough literature review on PubMed and Google Scholar from 2010 to December 2021. The source guidelines covered idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disorders, and bronchiectasis. The GRADE-ADOLOPMENT process consists of three key elements: adoption (using recommendations as is or with minor changes), adaptation (effective context-specific changes to recommendations) or additions (including new recommendations to fill a gap in the EBCPG). We employed the GRADE-ADOLOPMENT process to adopt, adapt, adopt with minor changes, or exclude recommendations from a source guideline. Additional recommendations were added to the clinical pathways based on a best-evidence review process. Results 46 recommendations were excluded mainly due to the unavailability of recommended management in Pakistan and scope beyond the practice of general physicians. Clinical diagnosis and referral pathways were designed for the four chronic respiratory conditions, explicitly delineating the role of primary care practitioners in the diagnosis, basic management, and timely referral of patients. Across the four conditions, 18 recommendations were added (seven for IPF, three for bronchiectasis, four for COPD, and four for asthma). Conclusion The widespread use of the newly created EBCPGs and clinical pathways in the primary healthcare system of Pakistan can help alleviate the morbidity and mortality related to chronic respiratory conditions disease in the country