Use of virtual reality exercises in disaster preparedness training: A scoping review.

Background: The scope and number of disasters have increased over the years. This has called for more robust disaster preparedness training and plans. The use of virtual reality exercises in addition to tabletop exercises is considered a new approach to the preparation of disaster preparedness plans. Virtual reality exercises are being developed to either replace or complement current traditional approaches to disaster preparedness training. Objectives: To review and summarize the current existing literature regarding the effectiveness, advantages and limitations of using virtual reality exercises in disaster preparedness as a complementary/replacement mechanism for real-time drills and tabletop exercises. Methods: In this scoping review, we searched PubMed, Cochrane, EMBASE, PLOS, and Google Scholar for research publications involving virtual reality exercises in disaster training from 2008 to 2022 using "AND" and "OR" operators for the keywords "disaster," "preparedness," "virtual reality," and "tabletop." From a total of 333 articles that resulted in our search and were then evaluated by the authors, 55 articles were finally included in this review. Results: Virtual reality exercises are found to be better in the formulation of disaster preparedness plans compared to tabletop exercises. Virtual reality exercises can be used as the primary means of creating a real-life-like experience in disaster preparedness training and proved at least as better complementary to tabletop exercises. Virtual reality exercises have many advantages over traditional real-life or tabletop exercises and are more cost-effective, but some drawbacks are still identified. Conclusion: The advantages of virtual reality exercises are remarkable and underline their benefits and uses versus costs. We highly encourage decision-makers and institutions dealing in disaster preparedness to adopt using virtual reality exercises in training for disaster preparedness.

Targeting Ligand Independent Tropism of siRNA-LNP by Small Molecules for Directed Therapy of Liver or Myeloid Immune Cells.

Hepatic clearance of lipid nanoparticles (LNP) with encapsulated nucleic acids restricts their therapeutic applicability. Therefore, tools for regulating hepatic clearance are of high interest for nucleic acid delivery. To this end, this work employs wild-type (WT) and low-density lipoprotein receptor (Ldlr)-/- mice pretreated with either a leukotriene B4 receptor inhibitor (BLT1i) or a high-density lipoprotein receptor inhibitor (HDLRi) prior to the injection of siRNA-LNP. This work is able to demonstrate significantly increased hepatic uptake of siRNA-LNP by the BLT1i in Ldlr-/- mice by in vivo imaging and discover an induction of specific uptake-related proteins. Irrespective of the inhibitors and Ldlr deficiency, the siRNA-LNP induced RNA-binding and transport-related proteins in liver, including haptoglobin (HP) that is also identified as most upregulated serum protein. This work observes a downregulation of proteins functioning in hepatic detoxification and of serum opsonins. Most strikingly, the HDLRi reduces hepatic uptake and increases siRNA accumulation in spleen and myeloid immune cells of blood and liver. RNA sequencing demonstrates leukocyte recruitment by the siRNA-LNP and the HDLRi through induction of chemokine ligands in liver tissue. The data provide insights into key mechanisms of siRNA-LNP biodistribution and indicate that the HDLRi has potential for extrahepatic and leukocyte targeting.

Assessment of early kidney injury caused by asymptomatic bacteriuria in children with type 1 diabetes.

INTRODUCTION: Infection is one of the most frequent causes of morbidity and mortality in diabetic patients. Some microorganisms become more virulent in a high glucose concentration. Diabetics are more likely to have asymptomatic and symptomatic bacteriuria. NGAL is secreted in high concentrations into the blood and urine within two hours of AKI. OBJECTIVES: The aim of the study is early detection of UTI in type1diabetic children through screening of their urine samples, and measurement of NGAL urinary levels in cases with asymptomatic bacteriuria for early detection of AKI to prevent serious complications. PATIENTS AND METHODS: One thousand twenty-two known diabetic children on regular follow up in endocrine outpatient clinic at Minia Children University hospital were screened for UTI. From them only 52 diabetic children were diagnosed as asymptomatic bacteriuria (group I), 52 diabetic children with normal urine analysis (group II) and 52 apparently healthy children, age and sex matched, served as controls (group III). CBC, Renal function test, HbA1c, hs- CRP, Albumin/creatinine ratio, urine examination, urine culture, GFR and urinary NGAL were done to all children. RESULTS: Thirty-seven females (71.2%) had asymptomatic bacteriuria, Hs CRP and urinary NGAL were significantly higher, while GFR was significantly lower in diabetic children with bacteriuria than the other two groups. For diabetic children with bacteriuria, (AUC) for NGAL was 1 with optimal cutoff value of > 44.1 (Sensitivity 100% and Specificity 100%) while AUC for hsCRP was 0.887 with optimal cutoff value of > 1 (Sensitivity 82.69% and Specificity 90.38%). CONCLUSION: Routine urine analysis should be done for all diabetic children even if they are asymptomatic. NGAL and hsCRP are non-invasive methods that could detect early renal injury in these patients thus, early, and proper management of UTI should be started to prevent renal injury.

Harnessing ROS-Induced Oxidative Stress for Halting Colorectal Cancer via Thiazolidinedione-Based SOD Inhibitors.

Based on the "canonical" view of reactive oxygen species' (ROS) contribution to carcinogenesis, ROS induce oxidative stress and promote various tumor progression events. However, tumor cells also need to defend themselves against oxidative damage. This "heresy" was supported by several recent studies underlining the role of cellular antioxidant capacity in promoting metastasis and resistance to chemotherapy. Accordingly, harnessing the ROS-induced oxidative stress via selective suppression of the cancer antioxidant defense machinery has been launched as an innovative anticancer strategy. Within this approach, pharmacological inhibition of superoxide dismutases (SODs), the first-line defense antioxidant enzymes for cancer cells, selectively kills tumor cells and circumvents their acquired resistance. Various SOD inhibitors have been introduced, of which some were tolerated in clinical trials. However, the hit SOD inhibitors belong to diverse chemical classes and lack comprehensive structure-activity relationships (SAR). Herein, we probe the potential of newly synthesized benzylidene thiazolidinedione derivatives to inhibit SOD in colorectal cancer with special emphasis on their effects on correlated antioxidant enzymes aldehyde dehydrogenase 1 (ALDH1) and glutathione peroxidase (GPx). This may possibly bring a new dawn for utilizing thiazolidinediones (TZDs) in cancer therapy through SOD inhibition mechanisms. The preliminary 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that all of the evaluated TZDs exhibited excellent safety profiles on normal human cells, recording an EC100 of up to 47.5-folds higher than that of doxorubicin. Compounds 3c, 6a, and 6e (IC50 = 4.4-4.7 µM) were superior to doxorubicin and other derivatives against Caco-2 colorectal cancer cells within their safe doses. The hit anticancer agents inhibited SOD (IC50 = 97.2-228.8 µM). Then, they were selected for further in-depth evaluation on the cellular level. The anticancer IC50 doses of 3c, 6a, and 6e diminished the antioxidant activities of SOD (by 29.7, 70.1, and 33.3%, respectively), ALDH1A (by 85.92, 95.84, and 86.48%, respectively), and GPX (by 50.17, 87.03, and 53.28%, respectively) in the treated Caco-2 cells, elevating the Caco-2 cellular content of ROS by 21.42, 7.863, and 8.986-folds, respectively. Docking simulations were conducted to display their possible binding modes and essential structural features. Also, their physicochemical parameters and pharmacokinetic profiles formulating drug-likeness were computed.

Neutrophil Respiratory Burst: an immunological indicator of post stroke infection.

Stroke is long known to be followed by a series of immunosuppressive events, and infections might be a cause of death after an acute insult of stroke. The aim of our work was to assess the percentage of neutrophils showing spontaneous oxidative burst in patients with acute ischemic stroke. The study included 30 patients with acute cerebral infarction subjected to the following: magnetic resonance imaging of the brain immediately on admission, and blood sampling on day one of admission (baseline) and after 3 days of admission. Blood samples were used for the assessment of: differential leucocyte count and percentage of neutrophils showing spontaneous oxidative burst, performed by flow cytometry. Thirty age and gender matched controls were also recruited. Neutrophil respiratory burst percentage was significantly lower in stroke patients in comparison to controls (P < 0.001), and stroke patients had significantly lower neutrophil respiratory burst percent on day 3 of admission compared to the baseline (P < 0.001). Stroke-induced immune alterations including impairment of the first-line defense performed by neutrophils against bacteria. The hypothesis that these changes enhance susceptibility to acquired infections is supported by our observation that oxidative burst in neutrophils was more impaired in patients with stroke who exhibited subsequent stroke-associated infections.

Low frequency of CD4+CD25highFOXP3+ T regulatory cells in Egyptian patients with chronic spontaneous urticaria.

Chronic urticaria is a prevalent disabling dermatological disease. About 90%, are considered idiopathic and referred to as chronic spontaneous urticaria (CSU), and nearly half of them are likely to have autoimmune mechanisms. Regulatory T cells play a substantial role to prevent autoimmune diseases. Subsets of Tregs expressing the CD4+CD25high and forkhead-box-P3 (FOXP3) transcription factor, crucial for their development and function, are best characterized in maintenance of self-tolerance. The objective of this study was the analysis of peripheral CD4+CD25highFOXP3+(T regs) frequency in chronic spontaneous urticaria; and its possible association with autologous serum skin test (ASST). Fifty chronic spontaneous urticaria patients (25 with positive ASST and 25 with negative ASST) and 20 healthy controls were enrolled in this study. The frequency of CD4+CD25highFOXP3+ (T regs) was analyzed by flow cytometry. A Significant decrease in peripheral blood CD4+CD25highFOXP3+ T regs% was detected in CSU patients in comparison to healthy individuals (median [IQR], 1.47% [0.71-3.12] vs 1.79% [1.15-4.00]; P = 0.05). When ASST positive patients were compared with ASST negative patients, no significant difference was found in percentage of T regs, (P=0.112). In conclusion our data provided further insights into CSU pathogenesis. Reduced frequency of CD4+CD25highFOXP3+(Tregs) in patients with urticaria, support the notion that CSU is an immune mediated disease and may help researchers to develop a novel immunotherapy strategy.

Celastrol augments sensitivity of NLRP3 to CP-456773 by modulating HSP-90 and inducing autophagy in dextran sodium sulphate-induced colitis in rats.

NLRP3, one of the HSP-90 clients, has been defined as a critical component of IBD. In a rat model of DSS-induced colitis, we investigated the anti-inflammatory potential of the combined therapy with CP-456773 (CP), an NLRP3 inhibitor, and celastrol (CSR), an NF-κB inhibitor. Our results revealed that the CSR/CP combined therapy (CCCT) attenuated colon shortening, DAI and MDI in addition to improvement of the colonic histological picture. Moreover, the CCCT increased the antioxidant defense machinery of the colonic tissue and decreased MPO activity. Furthermore, the inflammation markers such as TNF-α and IL-6 were downregulated. These effects might be attributed to the inhibitory effect of CSR on the priming step of the NLRP3 inflammasome activation by interrupting NF-κB signalling and inhibition of HSP-90 (at the protein and mRNA levels) along with inhibitory effect of CP on the expression of the NLRP3. These latter effects resulted in decreased tissue expression and activity of the caspase-1 and repressing the subsequent release of the active forms of IL-1ß and IL-18, hence, the pyroptosis process is restrained. Additionally, the CCCT resulted in inducing autophagy by AMPK/mTOR-dependent mechanisms leading to the accumulation of BECN1 protein and a significant decrease in the levels of p62 SQSTM1. The inhibitory effect on HSP-90 in conjunction with induction of autophagy suggest increased autophagic degradation of NLRP3. This novel approach provides a basis for the clinical application of this combination in IBD treatment and might also be promising for the pharmacological intervention of other NLRP3 inflammasome-dependent inflammatory conditions.

Evaluation of Botulinum Toxin Type A Injection in the Treatment of Localized Chronic Pruritus.

BACKGROUND: Botulinum toxin is a neurotoxin produced by the bacterium Clostridium botulinum that causes a flaccid muscle paralysis. It is currently used for aesthetic procedures and to treat focal hyperhidrosis. The botulinum toxin has also been used experimentally in many other dermatological conditions with positive results. OBJECTIVE: We sought to evaluate the efficacy and safety of intradermal injection of botulinum toxin A in the treatment of localized recalcitrant chronic pruritus in lichen simplex, inverse psoriasis, post-burn itching, lichen planus (hypertrophic), and postherpetic neuralgia. METHODS: This was a clinical trial study of 32 patients (12 with lichen simplex chronicus [LSC], 4 with inverse psoriasis, 4 with post-burning itch, 4 with lichen planus, 4 with hypertrophic lichen planus, and 4 with post-herpetic neuralgia). We used 2 to 3mL of unpreserved saline to dilute each vial (50 units) of botulinum toxin A. This led to a final concentration of 2 to 2.5U/0.1cc; injections were typically made into the dermis. RESULTS: The ages of patients in the group studied ranged from 13 to 85 years, with a mean of 37.38 years, and 59.4 percent were female. There were statistical reductions in visual analog scale in all the studied cases. CONCLUSION: Botulinum toxin A appears to be a safe and effective therapy for the improvement of localized recalcitrant itching in LSC, inverse psoriasis, burns, hypertrophic lichen planus, lichen planus, and symptoms of postherpetic neuralgia.

α-Mannosyl-Functionalized Cationic Nanohydrogel Particles for Targeted Gene Knockdown in Immunosuppressive Macrophages.

Immunosuppressive M2 macrophages govern the immunophathogenic micromilieu in many severe diseases including cancer or fibrosis, thus, their re-polarization through RNA interference is a promising concept to support combinatorial therapies. For targeted siRNA delivery, however, safe and stable carriers are required that manage cell specific transport to M2 macrophages. Here, siRNA-loaded cationic nanogels are reported with α-mannosyl decorated surfaces that target and modify M2 macrophages selectively. Via amphiphilic precursor block copolymers bearing one single α-mannosyl moiety at their chain end mannosylated cationic nanohydrogel particles (ManNP) were obtained of 20 nm diameter determined by dynamic light scattering and cryogenic electron transmission microscopy. α-Mannosyl surface modification is confirmed by agglutination with concanavalin A. SiRNA-loaded ManNP preferentially targets the overexpressed mannose receptor CD206 on M2 macrophages, as shown by in vitro cell uptake studies in M2 polarized primary macrophages. This specificity is confirmed, since ManNP uptake could be reduced by blocking of CD206 with mannan. Effective ManNP-guided siRNA delivery is confirmed by sequence-specific gene knockdown of CSF-1R in M2-type macrophages exclusively, while the expression levels in M1-polarized macrophages is not affected. In conclusion, α-mannosyl-functionalized ManNPs are promising universal siRNA carriers for targeted immunomodulatory treatment of immunosuppressive macrophages.

Aspergillus terreus Meningitis in Immunocompetent Patient: A Case Report.

We present a description of a rare but dangerous case of fungal meningitis caused by Aspergillus terreus in an immunocompetent patient with a history of sinus disease.

IL28B rs 12979860 predicts response to treatment in Egyptian hepatitis C virus genotype 4 patients and alpha fetoprotein increases its predictive strength.

To assess the role of IL28B rs 12979860 polymorphism in predicting response to treatment in genotype 4 (G4) Egyptian patients, and to evaluate the role of alpha fetoprotein (AFP) in increasing the predictive strength of IL28B rs 12979860 polymorphism to predict response to treatment. One hundred thirty 7 HCV patients were genotyped for IL28B rs 12979860 by polymerase chain reaction--restriction fragment length polymorphism technique. The presence of the C allele of IL28B rs 12979860 was associated with response to treatment, while the T allele was associated with failure of response to treatment. AFP is associated with IL28B rs 12979860 SNP genotypes at cut off 2.68 and 4.5 ng/mL individually. Response rate was 1.3 and 1.6, 3 times higher in CC, CT, and TT respectively in patients below AFP 4.5 ng/mL than in patients above it. IL28B rs 12979860 polymorphism is strongly associated with treatment induced response to treatment. AFP (cut off 4.5 mg/mL) increases the predictive power of IL28B in response to treatment.

Association of IL28B polymorphism with fibrosis, liver inflammation, gender respective natural history of hepatitis C virus in Egyptian patients with genotype 4.

The polymorphism of interleukin 28B (IL28B) rs12979860 is associated with spontaneous and treatment-induced clearance in hepatitis C virus (HCV) genotype 4 (G4). However, there is no information on its interaction with gender, moreover its association with intrahepatic inflammation in North Africans is not studied and its association with fibrosis in North Africans (especially Egyptians) is controversial. This study aims to explore the association between the minor allele of the IL28B rs12979860 polymorphism with gender, fibrosis and necroinflammation in Egyptian G4 HCV patients. IL28B rs12979860 was genotyped in 224 individuals, including 100 healthy controls and 124 consecutive patients with chronic HCV. Results showed (1) IL28B rs12979860 minor alleles associated with susceptibity to chronic HCV mainly in men not women, (2) no association between IL28B rs12979860 with fibrosis and necroinflammation activity, (3) the IL28B rs12979860 TT genotype associated with severe fibrosis in women only and with the necroinflammation activity in men using a recessive model. In conclusion, the IL28B rs12979860 polymorphism is not associated with fibrosis and liver inflammation in Egyptian HCV G4. Nonetheless, the TT genotype of IL28B rs12979860 polymorphism affects the natural history of each gender independently.

Impact of IL12B gene rs 3212227 polymorphism on fibrosis, liver inflammation, and response to treatment in genotype 4 Egyptian hepatitis C patients.

INTRODUCTION: Hepatitis C virus (HCV) infection affects almost 3% of the world's population with the highest prevalence in Egypt (15%). The standard therapy; pegylated interferon (PEG-IFN) and ribavirin, is effective in only 60% of Egyptian patients; moreover it is costly, prolonged, and has severe side effects, so prediction of response is essential to reduce burden of unfavorable treatment. Several viral and host factors have been proved to affect response to the treatment PEG-IFN and ribavirin; the strongest of them is polymorphisms near IL28B; nonetheless, nonresponse in patients with favorable IL28B is still unexplained, which implies the importance of studying other immunological factors that may correlate with response. Interleukin 12 (IL-12) is one of the most important proinflammatory cytokine presented with the initiation of immune response, determining Th1 and Th2 differentiation. A functional single nucleotide polymorphism (A/C) at the 3' untranslated region (3'UTR) at position 1188 (NCBI SNP database no 3212227) was reported to be associated with responding more efficiently to antiviral combination therapy in HCV genotype 1 infected patients. The present study aims to evaluate association between this polymorphism with fibrosis stages, necroinflammation activity, response to the combined therapy, and gender in Egyptian HCV genotype 4. MATERIAL AND METHODS: A total of 133 Egyptian chronic HCV (CHCV) patients were treated with IFN/RBV and were followed up. IL12B 1188 A/C genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PRC-RFLP) analysis. RESULTS: A nonsignificant trend for higher sustained virological response (SVR) was observed in patients homozygote for IL12B 1188 A/C SNP CC genotype (69% SVR versus 30.8% NR) only but not in AC and AA genotypes. No association was detected between IL12B 1188 A/C polymorphism and less severe fibrosis or less liver activity. By stratification of response according to gender genotype, a significant difference in response between males and females was seen among AA genotype carriers only due to high number of non responder females. CONCLUSION: IL12B CC genotype appears to have some influence on SVR achievement but not on severe fibrosis and severe necroinflamation activity. Females carrying A/A genotype of IL12B 1188 A/C SNP achieve less SVR than those carrying AC and CC genotypes.

Interleukin-12B gene polymorphism frequencies in Egyptians and sex-related susceptibility to hepatitis C infection.

Hepatitis C virus (HCV) infection is a major health problem worldwide. Egypt is the country with the highest HCV infection epidemic in the world. Interleukin (IL)-12 is a cytokine that has been shown to have a potent role as an antiviral cytokine. IL-12 is a heterodimer of the polypeptides p35 and p40. IL-12 B, the gene encoding IL-12 p40, is polymorphic, and a functional single-nucleotide polymorphism (SNP) of the 3'-untranslated region at position rs3212227 was associated with apparent resistance to HCV. The genotype distribution of this polymorphism differs by race. This study is sought to identify the genotype distribution of the IL-12 SNP rs3212227 polymorphism in Egyptians and to assess its role in susceptibility to chronic HCV infection alone or in a sex-dependent way. The study included 238 subjects: 100 healthy controls and 138 patients with HCV infection. The IL-12 SNP rs3212227 was genotyped by the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Results showed a genotype frequency of 46%, 39%, and 15% for AA, AC, and CC IL-12 genotypes, respectively. No significant result (P=0.5) was shown in the differential distribution of the IL-12 SNP genotypes between controls and patients with HCV infection. Nonetheless, this difference in the IL-12 genotype distribution was significant (0.005) when it was stratified according to sex; moreover, the C allele distribution in men and women differed with a statistically high significance (P=0.0001) in controls versus HCV patients. In conclusion, the IL-12 SNP rs3212227 polymorphism confers a susceptibility to HCV infection in a sex-dependent way in Egyptians.