Characteristics of Hospitalized COVID-19 Patients in a Major Referral Center in Shiraz, Iran.

Background: Several countries, including Iran, have been affected by the novel Coronavirus Disease 2019 (COVID-19) pandemic since December 2019. The aim of this study was to provide a comprehensive report on COVID-19 patients in Shiraz, Southern Iran. Materials and Methods: This study was performed on 311 hospitalized patients with COVID-19. The data on demographic, clinical, and paraclinical features were analyzed. Results: The median age of the patients was 58 years, with 42.1% of the patients being above 60 years of age. Upon admission, fever was detected in 28.2% of critically ill patients. At least one underlying disease or risk factor was also present in 75.6% of the patients. Shortness of breath was the most common clinical symptom (66.2%), dry cough (53.7%), and muscle pain (40.5%) was the second and third. Sneezing (0.3%), rhinorrhea (0.7%), and sore throat (3.09%) were observed only in non-critically ill patients. In addition, 26.9% of all patients had lymphocytopenia, 25.8% had raised C-reactive protein, and 79.9% had abnormal creatinine levels. Finally, death occurred in 39 patients (12.5%). Conclusions: Noncritically ill patients were younger than critically ill patients. The most common risk factors for getting critically ill were surgery, hypertension, diabetes mellitus, chronic heart disease, asthma, and chronic renal disease.

Recent advances in the roles of exosomal microRNAs (exomiRs) in hematologic neoplasms: pathogenesis, diagnosis, and treatment.

In clinical diagnosis, the capability of exosomes to serve as biomarkers is one of the most important biological functions of exosomes. The superior stability of exosome biomarkers makes them superior to those isolated from traditional samples such as serum and urine. Almost all body fluids contain exosomes, which contain proteins, nucleic acids, and lipids. Several molecular components of exosomes, including exosome proteins and microRNAs (miRNAs), are promising diagnostic biomarkers. These exosomes may carry genetic information by containing messenger RNA (mRNA) and miRNA. The miRNAs are small noncoding RNAs that regulate protein-coding genes by acting as translational repressors. It has been shown that miRNAs are mis-expressed in a range of conditions, including hematologic neoplasms. Additionally, miRNAs found within exosomes have been linked with specific diseases, including hematologic neoplasms. Numerous studies suggest that circulating exosomes contain miRNAs similar to those found in parental cancer cells. Exosomes contain miRNAs that are released by almost all kinds of cells. MiRNAs are packaged into exosomes and delivered to recipient cells, and manipulate its function. It has been recognized that exosomes are new therapeutic targets for immunotherapy and biomedicine of cancers. The current review discusses the current evidence around exosomal miRNAs involved in the pathogenesis, diagnosis, and treatment of hematologic neoplasms. Video Abstract.

The reproduction rate of severe acute respiratory syndrome coronavirus 2 different variants recently circulated in human: a narrative review.

SARS-COV-2 is responsible for the current worldwide pandemic, which started on December 2019 in Wuhan, China. On March 2020 World Health Organization announced COVID-19 as the new pandemic. Some SARS-COV-2 variants have increased transmissibility, cause more severe disease (e.g., increased hospitalizations or deaths), are resistant to antibodies produced by the previous infection or vaccination, and there is more difficulty in treatment and diagnosis of them. World Health Organization considered them as SARS-CoV-2 variants of concern. The introductory reproduction rate (R0) is an epidemiologic index of the transmissibility of the virus, defined as the average number of persons infected by the virus after known contact with an infectious person in a susceptible population. An R0 > 1 means that the virus is spreading exponentially, and R0 < 1, means that the outbreak is subsiding. In various studies, the estimated R and VOC growth rates were reported to be greater than the ancestral strains. However, it was also a low level of concordance between the estimated Rt of the same variant in different studies. It is because the R of a variant not only dependent on the biological and intrinsic factors of the virus but also several parameters can affect the R0, including the duration of contagiousness and the likelihood of infection per contact. Evaluation of changes in SARS-CoV-2 has shown that the rate of human-to-human transmission of this virus has increased. Like other viruses with non-human sources which succeeded in surviving in the human population, SARS-CoV-2 has gradually adapted to the human population, and its ability to transmit from human to human has increased. Of course, due to the continuous changes in this virus, it is crucial to survey the rate of transmission of the virus over time.

Reinfection and reactivation of SARS-CoV-2.

As the cases of SARS-CoV-2 infection escalates, the essence of in-depth knowledge around acquired immunity and emergence of reinfection and reactivation have to be captured. While being a rare phenomenon, reinfection occurs as the result of diminishing protection conferred by antibodies, especially IgG. Reactivation is more concerned with the role of various elements including shedding lingering viral RNA for a prolonged time and incomplete resolution of infection along with the insight of dormant viral exosomes' role. The concept of testing positive after two consecutive negative results requires proper discrimination of reinfection from reactivation. In this review, we summarized the current evidence for possible mechanisms leading to viral reactivation or test re-positivity. We also pointed out risk factors associated with both reinfection and reactivation.

Molecular variants of SARS-CoV-2: antigenic properties and current vaccine efficacy.

An ongoing pandemic of newly emerged SARS-CoV-2 has puzzled many scientists and health care policymakers around the globe. The appearance of the virus was accompanied by several distinct antigenic changes, specifically spike protein which is a key element for host cell entry of virus and major target of currently developing vaccines. Some of these mutations enable the virus to attach to receptors more firmly and easily. Moreover, a growing number of trials are demonstrating higher transmissibility and, in some of them, potentially more serious forms of illness related to novel variants. Some of these lineages, especially the Beta variant of concern, were reported to diminish the neutralizing activity of monoclonal and polyclonal antibodies present in both convalescent and vaccine sera. This could imply that these independently emerged variants could make antiviral strategies prone to serious threats. The rapid changes in the mutational profile of new clades, especially escape mutations, suggest the convergent evolution of the virus due to immune pressure. Nevertheless, great international efforts have been dedicated to producing efficacious vaccines with cutting-edge technologies. Despite the partial decrease in vaccines efficacy against worrisome clades, most current vaccines are still effective at preventing mild to severe forms of disease and hospital admission or death due to coronavirus disease 2019 (COVID-19). Here, we summarize existing evidence about newly emerged variants of SARS-CoV-2 and, notably, how well vaccines work against targeting new variants and modifications of highly flexible mRNA vaccines that might be required in the future.

Renin-Angiotensin-Aldosterone Axis Inhibition Improves Outcome of Diabetic Patients with Chronic Hypertension and COVID-19: An Iranian Perspective.

Background: Safe use of drugs such as angiotensin-converting enzyme 2 (ACE2) inhibitors and angiotensin receptor blockers (ARBs) in COVID diabetic patients needs comprehensive studies. This study addressed this issue from the Iranian perspective. Materials and Methods: Admitted COVID-19 patients were divided into four groups in this historical cohort study. Group 1 included 740 non-diabetic, non-hypertensive patients. Group 2 included 132 non-hypertensive diabetic patients. Group 3 included 154 non-diabetic hypertensive patients. Group 4 included 183 diabetic patients who were under ACE inhibitors or ARBs. Death, intensive care unit (ICU) admission, and length of hospitalization were compared between the groups. Results: After considering associated factors such as age, gender, dyslipidemia, cardiovascular diseases, rheumatoid arthritis (RA), chronic kidney disease (CKD), history of surgery, and corticosteroid use, diabetic patients (group 2) were associated with increased mortality (CI 95%, OR 1.93 [1.11-3.33]). Presence of diabetes (group 2) and hypertension were associated with an increased need for ICU admission (CI 95%, OR 1.69 [1.04-2.76]; CI 95%, OR 1.71 [1.08-2.71], respectively). Group 4 patients although having a similar rate of ICU admission with group 2 and 3 patients, had significantly better ICU survival. Conclusions: The current study suggests that ACE inhibitors and ARBs are associated with decreased mortality, ICU admission, and better ICU survival in the diabetic subgroup of hypertensive patients.

A multicenter retrospective study of clinical features, laboratory characteristics, and outcomes of 166 hospitalized children with coronavirus disease 2019 (COVID-19): A preliminary report from Iranian Network for Research in Viral Diseases (INRVD).

BACKGROUND: The objectives of this study were to analyze the clinical features and laboratory profiles and risk factors associated with critical illness of children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: One hundred and sixty-six coronavirus disease 2019 (COVID-19) Iranian pediatric patients were recruited through a collaborative research network between March and May 2020. Demographics, clinical, laboratory, and radiological results were obtained from patient files. RESULTS: Of 166 patients, 102 (61%) and 64 (39%) were males and females, respectively. Ninety-six (57.8%) and 70 (42.2%), had moderate and severe conditions, respectively. Thirty (18%) of patients died. The common symptoms were fever (73%), cough (54%), and shortness of breath, headache decrease in neutrophil and platelet counts; increase values in lactate dehydrogenase, decrease in the blood pH and HCO3 were significantly associated with the disease severity. 54% and 56% of patients showed abnormal radiographic appearance in Chest X-ray and in chest computed tomography scan, respectively. Sixty-one (36.7%) of patients were referred to intensive care unit (ICU). The coexistence of comorbidity was the main factor associated with ICU admission, shock, arrhythmia, acute kidney injury, acute respiratory distress syndrome, acute cardiac injury, and death. CONCLUSIONS: We describe a higher than previously recognized rate of COVID-19 mortality in Iranian pediatric patients. Epidemiological factors, such as the relatively high case fatality rate in the country and the presence of underlying diseases were the main factors for the high death rate.

Host factors: Implications in immunopathogenesis of COVID-19.

Coronavirus disease 2019 (COVID-19) is a viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is more serious in people with underlying diseases, but the cause of healthy people with progressive disease is largely unknown. Host genetic factors such as ACE2 variants, IFITM-3, HLA, TMRSS2, and furin polymorphisms appear to be one of the agents involved in the progression of the COVID-19 and outcome of the disease. This review discusses the general characteristics of SARS-CoV-2, including viral features, receptors, cell entry, clinical findings, and the main human genetic factors that may contribute to the pathogenesis of COVID-19 and get the patients' situation more complex. Further knowledge in this context may help to find a way to prevent and treat this viral pneumonia.

Relative frequency of hepatitis B virus, human papilloma virus, Epstein-Barr virus, and herpes simplex viruses in the semen of fertile and infertile men in Shiraz, Iran: A cross-sectional study.

BACKGROUND: About 8-12% of couples on reproductive age suffers from infertility worldwide. Since 1993, the role of genital tract infections by microbes, including viruses that can infect the sperm, in human infertility has been proposed. OBJECTIVE: To investigate the frequency of hepatitis B virus (HBV), human papilloma virus (HPV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV) infection in the semen of fertile and infertile men referred to the Mother and Child Hospital, Shiraz, Iran. MATERIALS AND METHODS: In this cross-sectional study, 350 men including 200 infertile and 150 fertile men were included. All semen samples were allowed to liquefy, followed by the assessment of sperm parameters. DNA was extracted using a DNA extraction kit (CinaGene, Tehran, Iran) according to the manufacturer's instructions. Detection of HBV, HPV, EBV, and HSV1/2 was done by the PCR method. RESULTS: The mean age of the participants was 36 ± 7 yr. Molecular results showed that 16 samples (8%) of infertile men and 5 (3.3%) of fertile men were positive for HBV, which was not statistically significant (p = 0.069). Only one sample of the fertile participants was positive for HPV. None of the semen samples of the infertile or fertile groups was positive for the presence of EBV or HSV1/2. CONCLUSION: The results of this study indicated that HBV, HPV, EBV, and HSV might not be involved in men's infertility. Further studies are recommended for clarifying the role of these viruses in infertility.

Detection of human papillomavirus (HPV) DNA in benign laryngeal lesions and role of cigarette smoking as an inducing factor.

The association of human papillomavirus (HPV) in laryngeal malignancies is largely known. This study evaluated the association between HPV and benign laryngeal lesions and also the role of smoking and alcohol consumption in increasing the prevalence of HPV in such benign lesions. Seventy-eight specimens of benign laryngeal lesions including 26 polyps, 26 dysplasia, and 26 other lesions such as nodules and cysts were enrolled in this study. Polymerase chain reaction (PCR) technique was used to detect HPV DNA in the tissues. The role of smoking and alcohol consumption in the prevalence of HPV was also evaluated through appropriate statistical tests. This study showed that the prevalence of HPV in benign laryngeal lesions was not statistically significant. The Cohen's effect size for comparing polyps vs. other lesions was nearly 0.7, indicating that HPV prevalence in laryngeal polyps may be clinically meaningful. Another finding in our study is the role of smoking in increasing the HPV prevalence in laryngeal polyps (P = 0.034). In benign laryngeal polyps, HPV prevalence may be clinically important. Smoking acts as a co-factor to induce HPV infection in laryngeal polyps in our study.

The Prevalence of Hepatitis B Virus Markers among Students of Shiraz University of Medical Sciences.

BACKGROUND: Protection against hepatitis B virus (HBV) is based on the presence of antibodies against hepatitis B surface antigen (HBsAg). Vaccination of newborns is the most effective means of prevention. This study aimed to evaluate the frequency of anti-HBs antibody (anti-HBsAb), anti-HB core Ab (anti-HBcAb), HBsAg, and HBV DNA among university students in Fars province, Southern Iran. MATERIALS AND METHODS: In this cross-sectional study, 272 students of Shiraz University of Medical Sciences, were enrolled. Venous blood (5 mL) was collected from each participant and centrifuged; the sera were stored at -20°C until use. Anti-HBsAb, Anti-HBcAb, and HBsAg were measured using a commercial enzyme-linked immunosorbent assay kit. HBV DNA load was also measured by a real-time polymerase chain reaction. RESULTS: The mean age of the participants was 19 ± 1 years. There were 171 (62.9%) females and 101 (37.1%) males. Anti-HBsAb at a protective level (>10 mIU/mL) were detected in the sera of 104 (38.5%) of the cases. Of the anti-HBsAb seropositive participants, 82 were female and 22 were male; the difference between the gender and seropositivity to anti-HBsAb was statistically significant (P = 0.001, odds ratio: 3.3, 95% confidence interval = 1.89-5.79). Anti-HBcAb was detected in only one participant that was negative for both HBsAg and HBV DNA. CONCLUSION: Findings of the current study show that more than half of the students do not have a protective level of anti-HBsAb and might be susceptible to HBV infection, indicating the necessity of checking the level of anti-HBsAb as well as a booster dose in high-risk groups.

Various interferon (IFN)-inducible transmembrane (IFITM) proteins for COVID-19, is there a role for the combination of mycophenolic acid and interferon?

Various interferon (IFN)-inducible transmembrane (IFITM) proteins are known to be expressed in human tissues though only IFITM 1-3 are inducible by IFN. Numerous studies have shown that activation of IFITM3 could suppress infection by influenza and coronaviruses such as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). In view of the potential application of IFITM proteins' induction to target SARS-CoV-2 infection that causes COVID-19, this article layout insights into the known antiviral mechanisms and therapeutic agents related to IFITM. Blocking viral entry through various mechanisms and the potential application of the FDA approved immunosuppressant agent, mycophenolic acid, as inducer of IFITM3 are among those discussed.

Comparison of ISG15, IL28B and USP18 mRNA levels in peripheral blood mononuclear cells of chronic hepatitis B virus infected patients and healthy individuals.

AIM: The purpose of this study was to evaluate the expression level of Interferon-stimulated Gene 15 (ISG15), Interleukin28B (IL28B) or IFN-lambda-3 and Ubiquitin specific peptidase 18 (USP18) genes in Peripheral Blood Mononuclear Cells (PBMCs) of patients with chronic active and inactive hepatitis B in comparison with healthy individuals. BACKGROUND: Despite the presence of the vaccine for hepatitis B virus (HBV), it remains a public health challenge. The effort to uncover the immune genes attributed to infection outcome is going through. METHODS: This Cross-sectional study was conducted on hepatitis B infected patients that were admitted to the Clinic of Liver diseases, Shiraz, January-November 2016. Patients were divided into two groups including active and inactive chronic regarding relevant World Gastroenterology Organization Global Guideline. They were mono-infected with HBV, and HCV or HIV co-infection was excluded from the study. Gene expression analysis was performed on fresh PBMCs samples with the help of Real-time PCR method. RESULTS: Interleukin 28B gene expression showed no statistically significant difference between the three studied groups (P>0.05). The expression level of ISG15 was significantly higher in the healthy control group compared to active (P= 0.0068) and inactive chronic subjects (P<0.0001). Similarly, USP18 expression level in the control group was also significantly higher compared to the active (P= 0.0228) and inactive chronic patients (P=0. 0226). CONCLUSION: The results of this study showed that the expression level of ISG15 and USP18 but not IL28B were higher in healthy individuals than in those infected with HBV. This difference expression may highlight the role of ISG15 and USP18 in the immune-related mechanism of HBV infection.

No detection of EBV, BKV and JCV in breast cancer tissue samples in Iran.

OBJECTIVE: The most common cancer amongst women is breast cancer. Reports on the role of EBV, BKV, and JCV in the development of breast cancer are controversial. Hence, the aim of this study was to determine the frequency of EBV, BKV, and JCV in malignant breast tumors in comparison with benign ones. RESULTS: A total of 300 breast biopsy tissues were included, of which 150 were malignant and 150 benign. After deparaffinization, tissues were subjected to DNA extraction. ß-globin gene was amplified by PCR to evaluate the quality of extracted DNA. In house PCRs assay was performed to detect EBV, JCV, and BKV genome fragment. The mean age of malignant and benign groups was 45.0 ± 9.4 and 35.2 ± 12.1 years old. Out of 150 malignant samples, 146 were ductal, two lobular and two samples both invasive ductal and lobular carcinoma. In the benign group, 96, 52 and two samples were fibroadenoma, fibrocystic, and adenosis types, respectively. Genomic DNA fragment of EBV, BKV, and JCV was not found in any of the malignant and benign breast tissues. CONCLUSION: According to our finding, there is the possibility that EBV, BKV, and JCV are not involved in breast cancer pathogenesis.

Association of PD-1 gene with outcome of hepatitis C virus infection.

Primary hepatitis C virus infection might be spontaneously cleared or become chronic. Polymorphisms in immune regulatory genes might influence the outcome. The aim of this study was to determine the frequency of genotypes and alleles of PD-1.3 and PD-1.5 gene loci in HCV infected patients and their association with the disease outcome. In this study 167 patients with chronic hepatic C and 42 individuals whose infection was spontaneously cleared, and a healthy control group comprising of 300 participants were included. The presence of chronic or spontaneously cleared infection amongst the participants was determined in advance by serologic and molecular methods. Genomic DNA was extracted using salting out method. PD-1 gene polymorphisms assay was performed using PCR-RFLP method. The frequency of alleles of PD-1.3 gene locus was significantly higher in the spontaneously cleared HCV infected group (P = 0.03) as well as the healthy control group (P = 0.04) in comparison to the chronic infected participants. In the case of PD-1.5 locus, there was no association between the frequency of inherited genotype or alleles and HCV infection outcome amongst the three groups. Haplotype analysis showed no statistically significant differences in the frequencies of different haplotypes between the three studied groups. Our finding collectively inferred that individuals with A allele at PD-1.3 locus might clear HCV infection more frequently than those with T allele. Instead, polymorphisms at PD-1.5 locus as well as haplotypes emerged from PD-1.3 G/A and PD-1.5 C/T might not be significant in the HCV infection outcome.

The pattern of IL-24/mda-7 and its cognate receptors expression following activation of human hepatic stellate cells.

Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrosis. Interleukin (IL)-24/melanoma differentiation-associated gene-7 (mda-7) has attracted attention in the pathophysiology of some diseases, while its role in activation/suppression of human HSCs is still unclear. It is important to elucidate whether the expression levels of the IL-24/mda-7 protein and its receptors in HSC cells are changed following activation. LX-2 cells, a human hepatic stellate cell line were activated by a combination of leptin and serum starvation. The activation state was evaluated through measuring the mRNA expression of profibrotic molecules, collagen-I, TIMP metalloproteinase inhibitor-1 and transforming growth factor-ß. The expression of IL-24/mda-7 was assessed in mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and ELISA methods, respectively. Hence, the amount of IL-22R1 and IL-20R2 subunit expression was also compared in activated and normal LX-2 cells by RT-qPCR. The expression level of IL-24/mda-7 and its cognate receptors was detectable both in the normal and activated LX-2 cell line. Furthermore, in activated LX-2, a significant increase of IL24 expression either on IL-22R1 and IL-20R2 subunits was also noticeable in comparison to normal cells. The activation state of LX-2 cells caused significant changes of IL-24/mda-7 and its receptors expression. In addition, the elevation in IL-24/mda-7 during LX-2 cell activation, suggested that IL-24/mda-7 and its cognate receptors serve a possible role in the development of the fibrosis process. Therefore, IL-24/mda-7 and relevant signaling pathways may be employed as a target for fibrosis treatment.

Analysis of TLR7, SOCS1 and ISG15 immune genes expression in the peripheral blood of responder and non-responder patients with chronic Hepatitis C.

AIM: To evaluate the baseline expression of the immune genes in PBMCs of responder and non-responder patients with chronic Hepatitis C. BACKGROUND: Although the contribution of peripheral blood mononuclear cell (PBMC) gene expression in treatment outcome of hepatitis C virus (HCV) infection is supposed, it has remained to be distinctly delineated. The baseline expression of the immune genes inside PBMCs may reflect the responsiveness status following IFN treatment. METHODS: Totally, 22 chronic HCV encompasses 10 responders and 12 non-responsive cases enrolled randomly regarding medical records. The PBMCs from the peripheral blood samples were isolated and then incubated for 6 hours in the culture media. The baseline expression of TLR7, SOCS1 and ISG15 was measured by Real time PCR. RESULTS: The gene expression pattern in PBMCs of both groups showed a similar trend. The expression of SOCS1 and TLR7 genes showed higher levels in non-responder group (P>0.05). The result of ISG15 showed a higher but non-significant expression in the responder group (P>0.05). CONCLUSION: The similar pattern of TLR7, SOCS1 and ISG15 expression in the responder and non-responder patients indicated their poor discriminating and predictive value in PBMCs sample.