Association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Egyptian children and adolescents.

BACKGROUND: Given the sparse data on the renin-angiotensin system (RAS) and its biological effector molecules ACE1 and ACE2 in pediatric COVID-19 cases, we investigated whether the ACE1 insertion/deletion (I/D) polymorphism could be a genetic marker for susceptibility to COVID-19 in Egyptian children and adolescents. METHODS: This was a case-control study included four hundred sixty patients diagnosed with COVID-19, and 460 well-matched healthy control children and adolescents. The I/D polymorphism (rs1799752) in the ACE1 gene was genotyped by polymerase chain reaction (PCR), meanwhile the ACE serum concentrations were assessed by ELISA. RESULTS: The ACE1 D/D genotype and Deletion allele were significantly more represented in patients with COVID-19 compared to the control group (55% vs. 28%; OR = 2.4; [95% CI: 1.46-3.95]; for the DD genotype; P = 0.002) and (68% vs. 52.5%; OR: 1.93; [95% CI: 1.49-2.5] for the D allele; P = 0.032). The presence of ACE1 D/D genotype was an independent risk factor for severe COVID-19 among studied patients (adjusted OR: 2.6; [95% CI: 1.6-9.7]; P < 0.001. CONCLUSIONS: The ACE1 insertion/deletion polymorphism may confer susceptibility to SARS-CoV-2 infection in Egyptian children and adolescents. IMPACT: Recent studies suggested a crucial role of renin-angiotensin system and its biological effector molecules ACE1 and ACE2 in the pathogenesis and progression of COVID-19. To our knowledge, ours is the first study to investigate the association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Caucasian children and adolescents. The presence of the ACE1 D/D genotype or ACE1 Deletion allele may confer susceptibility to SARS-CoV-2 infection and being associated with higher ACE serum levels; may constitute independent risk factors for severe COVID-19. The ACE1 I/D genotyping help design further clinical trials reconsidering RAS-pathway antagonists to achieve more efficient targeted therapies.

Vitamin D deficiency and vitamin D receptor FokI polymorphism as risk factors for COVID-19.

BACKGROUND: Given the sparse data on vitamin D status in pediatric COVID-19, we investigated whether vitamin D deficiency could be a risk factor for susceptibility to COVID-19 in Egyptian children and adolescents. We also investigated whether vitamin D receptor (VDR) FokI polymorphism could be a genetic marker for COVID-19 susceptibility. METHODS: One hundred and eighty patients diagnosed to have COVID-19 and 200 matched control children and adolescents were recruited. Patients were laboratory confirmed as SARS-CoV-2 positive by real-time RT-PCR. All participants were genotyped for VDR Fok1 polymorphism by RT-PCR. Vitamin D status was defined as sufficient for serum 25(OH) D at least 30 ng/mL, insufficient at 21-29 ng/mL, deficient at <20 ng/mL. RESULTS: Ninety-four patients (52%) had low vitamin D levels with 74 (41%) being deficient and 20 (11%) had vitamin D insufficiency. Vitamin D deficiency was associated with 2.6-fold increased risk for COVID-19 (OR = 2.6; [95% CI 1.96-4.9]; P = 0.002. The FokI FF genotype was significantly more represented in patients compared to control group (OR = 4.05; [95% CI: 1.95-8.55]; P < 0.001). CONCLUSIONS: Vitamin D deficiency and VDR Fok I polymorphism may constitute independent risk factors for susceptibility to COVID-19 in Egyptian children and adolescents. IMPACT: Vitamin D deficiency could be a modifiable risk factor for COVID-19 in children and adolescents because of its immune-modulatory action. To our knowledge, ours is the first such study to investigate the VDR Fok I polymorphism in Caucasian children and adolescents with COVID-19. Vitamin D deficiency and the VDR Fok I polymorphism may constitute independent risk factors for susceptibility to COVID-19 in Egyptian children and adolescents. Clinical trials should be urgently conducted to test for causality and to evaluate the efficacy of vitamin D supplementation for prophylaxis and treatment of COVID-19 taking into account the VDR polymorphisms.

Optimal Timing of Thyroid Hormone Replacement During Ramadan Fasting: A Randomized Controlled Trial in Patients with Prior Total Thyroidectomy.

Background: Fasting during Ramadan may be challenging for patients on levothyroxine (LT4), as the drug has a narrow therapeutic index and is administered on an empty stomach. The majority of Muslims who fast in Ramadan have two meals per day, iftar immediately after sunset and suhoor just before dawn. This study aimed at evaluating the impact of LT4 timing during Ramadan on thyrotropin (TSH) levels in patients who underwent total thyroidectomy to determine the best timing for intake and identify the predictors of TSH level changes. Methods: We conducted a parallel, double-blind, randomized controlled trial on Saudi patients diagnosed with hypothyroidism who underwent total thyroidectomy. Patients were required to have stable thyroid function for 6 months before the study period and fast ≥20 days of Ramadan. Participants were randomized to one of three times for LT4 administration: Group A, 30 minutes pre-iftar (n = 48); Group B, 3 hours post-iftar (n = 47); or Group C, 1 hour pre-suhoor (n = 47). The number of participants in the final analysis (excluding patients who dropped out) was as follows: Group A, (n = 31); Group B, (n = 34); and Group C, (n = 22). The changes in TSH and free thyroxine (fT4) levels two weeks before and after Ramadan were compared. Factors associated with a change in TSH levels were examined through multivariable analysis. Results: The TSH levels significantly increased in Group B (1.7 ± 1.8 mU/L vs. 3.1 ± 3.9 mU/L, p = 0.003) and Group C (2 ± 1.7 mU/L vs. 5.5 ± 10 mU/L, p = 0.011), but not Group A (1.8 ± 1.6 mU/L vs. 3.3 ± 4.2 mU/L, p = 0.158). The change in fT4 levels was comparable among the groups: Group A, 16.5 ± 2.7 mcg/dL vs. 15.9 ± 3.2 mcg/dL, p = 0.144; Group B, 15.8 ± 3.8 mcg/dL vs. 16.3 ± 3.6 mcg/dL, p = 0.620; and Group C, 17.5 ± 2.8 mcg/dL vs. 17.3 ± 3.9 mcg/dL, p = 0.770. In multivariable linear regression analysis, the following variables were significantly independently associated with TSH level change: age, weight gain, and the number of nonadherence days to LT4, where ß = -0.2, p = 0.026; ß = + 0.2, p = 0.026; and ß = + 0.5, p < 0.0001, respectively. Conclusions: Fasting patients who took LT4 pre-iftar did not experience significant changes in TSH, whereas those who took LT4 post-iftar or pre-suhoor did. The TSH changes during Ramadan may be associated with age (inverse association), weight gain, and the number of non-adherence to LT4 days. Trial Registration: SCTR Application no. 21122002.

Alveolar Ridge Augmentation Around Exposed Mandibular Dental Implant With Histomorphometric Analysis.

INTRODUCTION: Alveolar ridge augmentation either before or during implant placement is a predictable procedure under certain conditions. A major complication during the healing phase is incision line opening and membrane exposure, which may result in reduced bone gain and reduced implant survival. This case report describes alveolar bone regeneration around three dental implants despite membrane exposure that developed during healing post-surgically. CASE PRESENTATION: A 72-year-old female presented requesting dental implants to replace tooth numbers 18, 19, and 20. A cone-beam computed tomography (CBCT) scan showed loss of horizontal and vertical ridge dimensions. All implants were placed with a variable degree of implant thread exposure on their buccal surfaces, ranging from 3 to 4.5 mm. Simultaneous bone grafting was performed using freeze dried bone allograft and deproteinized bovine bone mineral that was covered by a d-PTFE membrane that was secured with tacking screws. Primary closure was obtained, and flaps were sutured. Three weeks post-surgically, membrane exposure occurred. Exposure was monitored and patient was instructed to follow strict oral hygiene instructions around the exposed membrane. Membrane exposure gradually increased without infection and was removed at 16 weeks. Membrane removal revealed dense fibrous tissues covering all implant surfaces. At the second stage surgery, new bone was seen covering all the implants coronal to the cover screws. A trephine core biopsy specimen revealed significant new bone formation and connective tissue around any residual grafted bone. CONCLUSION: d-PTFE membrane exposure does not necessarily lead to adverse healing outcomes for alveolar ridge augmentation if handled properly with close patient follow-up.

IgY antibodies for the immunoprophylaxis and therapy of respiratory infections.

Emergence of drug resistance among the causative organisms for respiratory tract infections represents a critical challenge to the global health care community. Further, although vaccination can prevent disease, vaccine development is impeded by several factors. Therefore, novel approaches to treat and manage respiratory infections are urgently needed. Passive immunization represents a possible alternative to meet this need. Immunoglobulin Y antibodies (IgYs) from the yolk of chicken eggs have previously been used against bacterial and viral infections in human and animals. Their advantages include lack of reaction with mammalian Fc receptors, low production cost, and ease of extraction. Compared to mammalian IgGs, they have higher target specificity and greater binding avidity. They also possess remarkable pathogen-neutralizing activity in the respiratory tract and lungs. In this review, we provide an overview of avian IgYs and describe their potential therapeutic applications for the prevention and treatment of respiratory infections.

Predictive and prognostic significance of CD8+ tumor-infiltrating lymphocytes in patients with luminal B/HER 2 negative breast cancer treated with neoadjuvant chemotherapy.

The immunobiology of breast cancer (BC) subtypes, including luminal cancer, remains unclear. Cluster of differentiation (CD)8+ tumor-infiltrating lymphocytes (TIL) are essential components of tumor-specific cellular adaptive immunity. However, only few studies have addressed the significance of cluster of differentiation 8+(CD8+) TIL in patients with luminal BC. The present study aimed to evaluate the predictive and prognostic significance of CD8+ TIL in patients with luminal B/human epidermal growth factor receptor 2 (HER 2)-negative BC treated with anthracycline-based neoadjuvant chemotherapy (NC). A total of 31 patients who underwent breast-conserving surgery or mastectomy post-NC were enrolled. Immunostaining for CD8+ TIL was performed using rabbit monoclonal antibodies against human CD8+. Intra- and peritumoral CD8+ TIL expression levels were classified into high and low, based on the median value of each. CD8+ TIL expression data were demonstrated to be correlated with disease-free survival (DFS) and overall survival (OS), using Kaplan-Meier and Cox's proportional hazards regression tests. The results revealed that, among all clinicopathological characteristics, only pathological complete response (pCR) was significantly correlated with intratumoral CD8+ TIL expression (P=0.016). A total of 9/16 patients (56%) with high intratumoral CD8+ TIL expression achieved pCR, in contrast with 2 out of 15 patients (13.3%) with low expression (P=0.016). High expression of intratumoral CD8+ TIL was significantly associated with OS (log-rank test, P=0.023). Multivariate Cox regression analysis revealed that intratumoral expression of CD8+ TIL was an independent prognostic factor for OS [hazard ratio (HR)=2.82; 95% confidence interval (CI)=0.911-4.833, P=0.007], but not for DFS (HR=1.11; 95% CI=0.282-2.078; P=0.508). In conclusion, the results of the present study suggested that high intratumoral CD8+ TIL expression was significantly predictive of pCR post-NC, and represented an independent prognostic factor for improved OS. In contrast, low intratumoral CD8+ TIL expression was a strong predictor of lack of pCR to NC, as well as an independent prognostic factor for poor OS. Assessment of the immune response in conjunction with the usual parameters may aid in the further stratification of patients with luminal B/HER 2-negative BC regarding the prediction of pCR post-NC and overall prognosis.

Synthesis and biological evaluation of 2-oxonicotinonitriles and 2-oxonicotinonitrile based nucleoside analogues.

Drug resistance and emergence of new pathogens highlight the need for developing new therapeutic agents. We focused on 2-oxonicotinonitrile (2-ONN) as derivative of the natural product 2-pyridinone.(1) Herein, we describe the synthesis of 2-ONNs bearing two aryl groups, which we coupled with organohalides, including three glycosyl bromides, to prepare the nucleoside analogues. Coupling occurred mostly at the 2-ONN ring nitrogen to give the aimed targets, and in a few cases, it happened at the 2-oxo position giving O-alkylation products. Free 2-ONNs and their acetylated nucleosides were tested against a number of viruses. The nucleoside analogue 2a(Ac) showed good anti SARS-CoV and anti influenza A (H5N1) activities. Additionally, 7b had good activity against Gram positive bacterium, Bacillis subtilis.