Angiotensin-Converting Enzyme-2 (ACE-2) with Interferon-Induced Transmembrane Protein-3 (IFITM-3) Genetic Variants and Interleukin-6 as Severity and Risk Predictors among COVID-19 Egyptian Population.

Introduction: The host genetic background is a crucial factor that underlies the interindividual variability of COVID-19 fatality and outcomes. Angiotensin-converting enzyme-2 (ACE-2) and interferon-induced transmembrane protein-3 (IFITM-3) have a key role in viral cell entrance and priming. The evoked immune response will also provide a predictive prognosis for COVID-19 infection. This study aimed to explore the association between ACE-2 and IFITM-3 genotypes and their corresponding allele frequencies with disease severity indices in the Egyptian COVID-19 population. The serum level of interleukin-6, as a biomarker of hyperinflammatory response, and cytokine storm, was correlated with disease progression, single nucleotide polymorphisms (SNPs) of the selected receptors, and treatment response. Methodology. We enrolled 900 COVID-19-confirmed cases and 100 healthy controls. Genomic DNA was extracted from 200 subjects (160 patients selected based on clinical and laboratory data and 40 healthy controls). The ACE-2 rs2285666 and IFITM-3 rs12252 SNPs were genotyped using the TaqMan probe allelic discrimination assay, and the serum IL-6 level was determined by ELISA. Logistic regression analysis was applied to analyze the association between ACE-2 and IFITM-3 genetic variants, IL-6 profile, and COVID-19 severity. Results: The identified genotypes and their alleles were significantly correlated with COVID-19 clinical deterioration as follows: ACE2 rs2285666 CT + TT, odds ratio (95% confidence interval): 12.136 (2.784-52.896) and IFITM-3 rs12252 AG + GG: 17.276 (3.673-81.249), both p < 0.001. Compared to the controls, the heterozygous and mutant genotypes for both SNPs were considerable risk factors for increased susceptibility to COVID-19. IL-6 levels were significantly correlated with disease progression (p < 0.001). Conclusion: ACE-2 and IFITM-3 genetic variants are potential predictors of COVID-19 severity, critical outcomes, and post-COVID-19 complications. Together, these SNPs and serum IL-6 levels explain a large proportion of the variability in the severity of COVID-19 infection and its consequences among Egyptian subjects.

Safety and efficacy of the combination of cryotherapy and photodynamic modalities with imiquimod in patients with actinic keratosis: a systematic review and meta-analysis.

INTRODUCTION: Actinic keratosis (AK) is an intraepithelial tumor that, in most cases, arises in chronically sun-exposed areas. The combination of cryotherapy and photodynamic modalities with imiquimod has been proven to be a potential therapeutic option for AKs. However, there is no comprehensive systematic study that discussed this concept in literature taking into consideration both efficacy and safety. EVIDENCE ACQUISITION: We performed a comprehensive search of the literature for studies assessing the efficacy and toxicity of the combinatorial tripartite regimen, consisting of cryotherapy and photodynamic modalities with imiquimod in AK. Metanalysis was performed using comprehensive meta-analysis version 3.0. EVIDENCE SYNTHESIS: After the screening of 1031 studies, five studies were included. Two trials compared the effect of imiquimod/cryotherapy versus cryotherapy alone or versus cryotherapy/vehicle. Our meta-analysis indicated that imiquimod/cryotherapy effectively induces complete clinical clearance in patients with AKs (OR: 6.26; 95%CI: 1.56-24.1; P=0.01). Moreover, another two studies, which were not meta-analyzed, indicated a substantial clinical clearance in the number of AK lesions in the imiquimod plus photodynamic therapy arm as compared to 5% imiquimod or PDT alone. No serious systemic adverse events were reported in all the treatment arms. CONCLUSIONS: Combined PDT or cryotherapy with imiquimod is more effective in the complete recovery of AK than treatment with imiquimod alone.

Dupilumab therapy in atopic dermatitis is safe during COVID-19 infection era: A systematic review and meta-analysis of 1611 patients.

The aim of this meta-analysis is to evaluate the safety of dupilumab use in the management of atopic dermatitis (AD) during the current pandemic regarding the risk and the hazards of COVID-19 infection. Seven databases (Google Scholar, Web of Science, Scopus, Virtual Health Library, PubMed, System for Information on Gray Literature in Europe, and The New York Academy of Medicine) were searched for eligible studies from inception until November 24, 2021. The quality of evidence was rated using the National Institute of Health and the Joanna Briggs Institute Critical Appraisal tool. Meta-analysis was performed when the outcome is presented ≥2 studies. A total of 12 papers including 1611 AD patients were included in the study. The prevalence of COVID-19 in AD treated with dupilumab was 3.2% (95% confidence interval [CI]: 1.7-5.8). COVID-19 symptoms were reported by five patients who were presented with one or more of the following symptoms (fatigue, loss of taste and smell, runny nose, conjunctivitis, gastrointestinal symptoms, fever, cough, and dyspnea). Only three cases of COVID-19 were hospitalized with a prevalence of 4.5%, while no patients with COVID-19 died. Dupilumab is safe regarding the risk and the hazards of COVID-19 in AD patients. Thus, based on these results continuation of dupilumab in AD patients is recommended, since dupilumab seems to be safe and crucial for a better disease outcome.

Melanoma and hypertension: is there an association? A USA population-based study.

BACKGROUND: Melanoma is one of the three major types of skin cancer. In this study we aimed to investigate the association between melanoma and hypertension comorbidity. METHODS: We performed a population-based study using NHANES database during the period 1999-2004. Data were analyzed using SPSS version 24. RESULTS: Data for 12,446 individuals of which 146 had a diagnosis for melanoma were extracted. Melanoma group were older than the no melanoma group as 51% of the melanoma group were 60 years or elder; however 53.6% of the no melanoma group falls below 30 years old. Melanoma group had higher frequency of hypertension (37%) compared to the no melanoma group (22.5%). Logistic regression revealed that melanoma patients had higher odds of hypertension prevalence using the unadjusted model (odds ratio (OR): 2.03, 95% confidence interval (CI): 1.45-2.84, P<0.001). However, after controlling of all potential confounding factors the significance was lost (OR: 0.89, 95% CI: 0.61-1.3, P=0.54). CONCLUSIONS: There may be a possible association of melanoma with hypertension comorbidity. With the limitations we faced, we encourage further research to confirm the association of melanoma and hypertension comorbidity.

Brief in vitro IL-12 conditioning of CD8 + T Cells for anticancer adoptive T cell therapy.

Cancer immunotherapy represents a potential treatment approach through non-specific and specific enhancement of the immune responses. Adoptive cell therapy (ACT) is a potential modality of immunotherapy that depends on harvesting T cells from the tumor-bearing host, activating them in vitro and infusing them back to the same host. Several cytokines, in particular IL-2, IL-7 and IL-15, have been used to enhance survival T cells in vitro. Although effective, conditioning of T cells in vitro with these cytokines requires long-term culture which results in the loss of expression of their trafficking receptors mainly CD62L. It also results in exhaustion of the activated T cells and reduction in their functions upon adoptive transfer in vivo. Our recent studies and those of other groups showed that brief (3 days) conditioning of CD8+ T cells by IL-12 in vitro can result in enhancing function of tumor-reactive CD8+ T cells. Adoptive transfer of these IL-12-conditioned CD8+ T cells into tumor-bearing mice, preconditioned with cyclophosphamide, 1 day before ACT, induced tumor eradication that was associated with generation of tumor-specific memory response. In this review, we summarize studies that indicated to the superiority of IL-12 as a potential cytokine for conditioning T cells for ACT. In addition, we discuss some of the cellular and molecular mechanisms that govern how IL-12 programs CD8+ T cells to enhance their functionality especially in vitro and its implication in combination with other ACT modalities, opening a avenue for the clinical application of this cytokine.

Efficacy of retinoids alone or in combination with other remedies in the management of warts: A systematic review and network meta-analysis.

The use of combined systemic retinoids and intralesional immunotherapy in the management of warts is still debatable without straightforward evidence. Through network meta-analysis, the current study evaluated the efficacy and safety of systemic retinoids alone or combined with other remedies in the treatment of warts. We searched six literature databases for clinical trials that compared systemic retinoids to local treatments or placebo in wart management. Outcomes were calculated as odds ratios (OR) with 95% confidence-interval. We used the R software to perform conventional and network meta-analyses (with a frequentist approach). Network meta-analysis of eight trials showed that oral acitretin plus intralesional Candida Ag (OR = 367.71), INF-α plus oral isotretinoin (OR = 223.77), oral acitretin (OR = 117), Candida Ag (OR = 91.93), oral isotretinoin (OR = 62.26) and topical isotretinoin (OR = 17.69) had higher complete recovery rates than placebo. Regarding the P-score, oral acitretin plus intralesional Candida Ag had the highest efficacy in achieving complete response (P-score = 0.88), followed by INF-α plus oral isotretinoin (P-score = 0.79), then oral acitretin (P-score = 0.60). Variable baseline characteristics and lack of data on some outcomes. The current study shows the efficacy for systemic retinoids in the treatment of warts, especially reluctant or recurrent types. Moreover, combinations of systemic retinoids with intralesional immunotherapy yield higher rates of complete clearance with lower recurrence.

WITHDRAWN: The effect of anti IL-2/IL-2 complex versus stand-alone low dose of IL-2 on imiquimod induced psoriasis like skin inflammation model.

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Telemedicine approach for psoriasis management, time for application? A systematic review of published studies.

Psoriasis is a common chronic inflammatory skin condition. It has a chronic course with multiple evolving relapses and patients require long-term treatment and follow-up. Teledermatology was introduced for diagnosis, treatment and follow-up of chronic diseases. Thus, we performed a systematic review for collecting the evidence regarding the efficacy of telemedicine in psoriasis management. Out of 287 records, we included seven studies (four of which were randomized controlled trials). We found that telemedicine alone or combined with usual care had the same or higher efficacy of psoriasis management compared to usual care or control group. We recommend further studies for assessing the pros and cons of this intervention which can replace conventional strategies especially in pandemic times.

Treatment options for autoimmune bullous dermatoses other than systemic steroids: A systematic review and network meta-analysis.

Autoimmune blistering diseases can eventually cause life-threatening complications if left untreated. Although there is no cure for these bullous diseases; their therapy is based on suppressing the immune system to cease the de novo formation of the generated antibodies. The current study aimed to assess the safety and efficacy of using standing alone alternative therapies beyond systemic steroids for management of autoimmune bullous diseases. We searched six literature databases for both randomized and quasi-randomized clinical trials that assessed the efficacy of drugs other than systemic steroids in autoimmune bullous diseases. Outcomes were calculated as odds ratios with 95% confidence-interval. We used the R software to perform conventional and network meta-analyses with a frequentist approach. The network ranking order for 629 bullous pemphigoid patients, from the best to the worst was, clobetasol propionate cream (40 mg; (P-score = .87), clobetasol propionate cream (10-30 mg; P-score = .77), nicotinamide plus tetracycline (P-score = .56), steroids (P-score = .29) and doxycycline (P-score = .01). Limitations of this study are the small sample of the included studies except for blister trial and lack of randomization in most trials. To conclude, Combined doxycycline and nicotinamides are safer and more effective option for extensive bullous pemphigoid patients than the usual use of systemic steroids. For limited disease, topical corticosteroid (40 mg/d) use provides a safer and better response modality than the other proposed treatments.

Intralesional immunotherapy for the treatment of warts: A network meta-analysis.

BACKGROUND: Without clear evidence, selecting among the existing immunotherapeutic options for warts remains challenging. OBJECTIVE: Through network meta-analyses, we aimed to evaluate the comparative efficacy of different intralesional immunotherapeutic modalities. METHODS: We included randomized controlled trials comparing intralesional immunotherapeutic modalities to cryotherapy, placebo, or imiquimod. All outcomes were presented as odds ratios (ORs) with 95% confidence intervals. Both conventional and network meta-analyses (with a frequentist approach) were conducted on R software. The P-score was used to rank different treatments. RESULTS: Network meta-analysis of 17 randomized controlled trials (1676 patients) showed that PPD (purified protein derivative vaccine, OR 39.56), MMR (measles, mumps, rubella vaccine, OR 17.46) and interferon ß (OR 15.55) had the highest efficacy in terms of complete recovery at the primary site compared with placebo. Regarding complete recovery at the distant site, autoinoculation (OR 79.95), PPD (OR 42.95), and MMR (OR 15.39) were all statistically superior to placebo. According to the P-score, MMR was more effective than other modalities in reducing the recurrence rate at the same site. LIMITATIONS: Relatively small sample size in some comparisons and variability in baseline characteristics. CONCLUSION: PPD and MMR were the most effective in achieving complete primary and distant recovery (along with autoinoculation for distant recovery) and reducing the recurrence rate at the same site compared with cryotherapy and other immunotherapeutic modalities.

Ginsenoside Rk1 bioactivity: a systematic review.

Ginsenoside Rk1 (G-Rk1) is a unique component created by processing the ginseng plant (mainly Sung Ginseng (SG)) at high temperatures. The aim of our study was to systematically review the pharmacological effects of G-Rk1. We utilized and manually searched eight databases to select in vivo and in vitro original studies that provided information about biological, pharmaceutical effects of G-Rk1 and were published up to July 2017 with no restriction on language or study design. Out of the 156 papers identified, we retrieved 28 eligible papers in the first skimming phase of research. Several articles largely described the G-Rk1 anti-cancer activity investigating "cell viability", "cell proliferation inhibition", "apoptotic activity", and "effects of G-Rk1 on G1 phase and autophagy in tumor cells" either alone or in combination with G-Rg5. Others proved that it has antiplatelet aggregation activities, anti-inflammatory effects, anti-insulin resistance, nephroprotective effect, antimicrobial effect, cognitive function enhancement, lipid accumulation reduction and prevents osteoporosis. In conclusion, G-Rk1 has a significant anti-tumor effect on liver cancer, melanoma, lung cancer, cervical cancer, colon cancer, pancreatic cancer, gastric cancer, and breast adenocarcinoma against in vitro cell lines. In vivo experiments are further warranted to confirm these effects.

T-Regulatory Cell Subsets in Children with Type 1 Diabetes Mellitus: Relation to Control of the Disease.

BACKGROUND: Type 1 diabetes mellitus is described as a chronic metabolic disorder characterized by aggressive immune &#946;-cell destruction. There are a number of varied immune mechanisms for sustaining self-tolerance in opposition to the autoimmune disorders. A recessive tolerance is accomplished by thymic gland via a negative assortment of different clones, while a dominant tolerance is accomplished by the regulatory T cells (Treg) in the periphery. Treg (CD4+ CD25+FOXP3+) are subsets of T cells which have an essential role in maintaining tolerance. OBJECTIVE: To evaluate peripheral Treg (CD4+; CD25+; FOXP3+) in children cohort with T1DM. METHODS: This study included 64 children diagnosed with T1DM and 35 age- and sex-matched healthy children as controls. All children were clinically evaluated and subjected to assessment of complete blood count (CBC), glycated hemoglobin, surface and cytoplasmic detection of Treg by flow cytometry. RESULTS: This study showed that the frequency of Treg (CD4+; CD25+; FOXP3+) was significantly lower in diabetic children than with normal controls (P<0.001). There was a significant (P <0.001) reduction in the Treg (CD4+; CD25+; FOXP3+) in T1DM children with uncontrolled (Hemoglobin A1c>7%) as compared to those with controlled (Hemoglobin A1c<7%) disease. CONCLUSION: Diminished Treg in T1DM proved that auto-reactivation of T-cell as a result of the breakdown of immune tolerance takes part in the elaboration of autoimmune disorders as T1DM. Treg may be used in immunotherapy, thus preventing T1DM development due to its pivotal role in immune tolerance.

Progressive cutaneous Cryptococcosis complicated with meningitis in a myasthenia gravis patient on long-term immunosuppressive therapy - a case report.

BACKGROUND: Cryptococcosis is an opportunistic infection caused by the encapsulated yeast Cryptococcus neoformans and most remarkably manifests in HIV-infected individuals, especially in the settings of very low CD4 count. Development of cryptococcosis in HIV-uninfected individuals is exceedingly rare and usually signifies a marked immunodeficiency. Cryptococcosis in association with myasthenia gravis or thymoma has been previously documented in only very few cases in the literature. CASE PRESENTATION: We reported a complicated case of severe cutaneous cryptococcosis in a 39-year-old Vietnamese male patient with myasthenia gravis on long-term immunosuppressive therapy. The patient presented with a five month history of recurrent and progressive skin lesions that later on progressed into cryptococcal meningitis. CONCLUSION: Through this case, we aimed to emphasize the importance of including cutaneous cryptococcosis in the differential diagnosis of cutaneous lesions in patients on chronic immunosuppressive therapy. The cutaneous manifestations of cryptococcosis can be the first clue for a disseminated disease, which makes early recognition crucial and life-saving.