Characteristics, outcome, duration of hospitalization, and cycle threshold of patients with COVID-19 referred to four hospitals in Babol City: a multicenter retrospective observational study on the fourth, fifth, and sixth waves.

BACKGROUND: The aim of the present study was to compare the epidemiological patterns of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections, hospitalizations, deaths, and duration of hospitalization during the fourth, fifth and sixth epidemic waves of coronavirus disease 2019 (COVID-19) in Iran. METHODS: A multicenter retrospective observational study was conducted on hospitalized patients in four hospitals in the Babol district of northern Iran. The study periods were during the fourth, fifth, and sixth waves of the epidemic in Iran, (March 2021 to March 2022). A total of 13,312 patients with suspected COVID-19 were included. Patient demographics, medical history, length of hospital stay, and clinical outcomes were obtained from the hospital information system. Data on the cycle threshold (Ct) and SARS-CoV2 variant were collected for SARS-CoV2-positive cases. RESULTS: The highest number of hospitalized patients was reported during the fifth (Delta) wave (5231; 39.3%), while the lowest number of hospitalized patients was reported during the sixth (Omicron) wave (2143; 16.1%). In total, 6459 (48.5%) out of 13,312 hospitalized patients with suspected COVID-19 had a positive rRT-PCR result. The fifth (Delta) wave had the highest number of SARS-CoV2 rRT-PCR-positive hospitalized patients (3573, 55.3%), while the sixth (Omicron) wave had the lowest number (835, 12.9%). Moreover, 238 (3.7%) patients with laboratory-confirmed COVID-19 died. The hospital mortality rate was 6.8% in the fourth (Alpha) wave, which reduced to 2.7 and 3.5% in the fifth (Delta) and sixth (Omicron) waves, respectively (p < 0.001). CONCLUSIONS: This is the most comprehensive study evaluating the epidemiologic characteristics of laboratory-confirmed SARS-CoV2 cases in Iran during the Alpha, Delta, and Omicron waves. The highest number of SARS-CoV2-positive hospitalized patients was in the fifth wave of COVID-19 (dominance of the Delta variant), while the sixth wave (dominance of the Omicron variant) had the lowest number. Comorbidities were similar, and cardiovascular disease, diabetes, kidney disease, and hypertension were the main risk factors in all waves.

The relationship between long non-coding RNAs and Wnt/ß-catenin signaling pathway in the pathogenesis of Alzheimer's disease.

Long non-coding RNAs (lncRNAs) cannot be coded to proteins; however, they can display important functions in several aspects of cell biology. Their abnormal expression is verified in various disorders, including neurodegenerative diseases, especially Alzheimer's disease (AD). By acting as a cell cycle suppressor or promotor, lncRNAs mediate some signaling pathways, which in turn lead to exacerbation or improvement of AD. Wnt/ß-catenin signaling pathway, as an important pathway in the pathogenesis of AD, can extremely be affected by lncRNAs. This pathway participates in various biological processes, such as embryogenesis and tissue homeostasis, and is involved in expanding the central nervous system, such as synaptogenesis, plasticity, and hippocampal neurogenesis. lncRNAs can regulate the expression of Wnt pathway target genes by interacting with various components of this pathway. This article discusses lncRNAs and their associated mechanisms in the alteration of Wnt/ß-catenin signaling, which can be regarded as a new aspect of diagnosing and treating AD.

COVID-19: A trigger of autoimmune diseases.

The SARS-coronavirus-2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19), has spread worldwide and caused a global health emergency. SARS-CoV-2 is a coronaviridae virus that infects target cells by interacting with the plasma membrane-expressed angiotensin-converting enzyme 2 (ACE2) via the S1 component of the S protein. Effective host immune response to SARS-CoV-2 infection, which includes both innate and adaptive immunity, is critical for virus management and elimination. The intensity and outcome of COVID-19 may be related to an overabundance of pro-inflammatory cytokines, which results in a "cytokine storm" and acute respiratory distress syndrome. After SARS-CoV-2 infection, the immune system's hyperactivity and production of autoantibodies may result in autoimmune diseases such as autoimmune hemolytic anemia, autoimmune thrombocytopenia, Guillain-Barré syndrome, vasculitis, multiple sclerosis, pro-thrombotic state, and diffuse coagulopathy, as well as certain autoinflammatory conditions such as Kawasaki disease in children. We have reviewed the association between COVID-19 and autoimmune disorders in this article.

One-year prevalence and the association between SARS-CoV-2 cycle threshold, comorbidity and outcomes in population of Babol, North of Iran (2020-2021).

Background: The present study aimed to investigate the one-year prevalence of SARS-CoV-2, common comorbidities and demographic information among negative- and positive rRT-PCR in health care workers (HCW), hospitalized and outpatients. Also, the association between SARS-CoV-2 cycle threshold (Ct) and the outcomes of patients were analyzed in Babol, northern Iran. Methods: This large retrospective cross-sectional study was performed between March 2020 and March 2021. The records of 19232 hospitalized, outpatients and HCW suspected to COVID-19 were collected from teaching hospitals in the North of Iran. Results: Out of the 19232 suspected to COVID-19 patients, 7251 (37.7%) had a positive rRT-PCR result; 652 (9%), 4599 (63.4%) and 2000 (27.6%) of those were categorized as HCW, hospitalized and outpatients, respectively. Moreover, between the hospitalized and the outpatient group, 10.2 and 0.8% cases died, whereas no death cases were reported in the HCW. Furthermore, it seems that death rate was significantly different between the three groups of Ct value, the highest mortality in those with Ct between 21 and 30 (group B=7.6%) and the lowest in the group with the highest Ct (between 31 and 40 = 5.5%) (p<0.001). Conclusion: In summary, 37.7% of cases were positive for SARS-CoV-2; of which, 63.4, 27.6 and 9% were hospitalized, outpatients and HCW, respectively. With regard to the mortality rate in hospitalized patients and the significant association with Ct under 20 and 30, it seems that the early detection and the initial quantification of SARS-CoV-2 in the first week of the conflict and therapeutic considerations to reduce the relative load can reduce the mortality rate.

A Large Retrospective Study of Epidemiological Characteristics of COVID-19 Patients in the North of Iran: Association between SARS-CoV-2 RT-PCR Ct Values with Demographic Data.

Objectives: To avoid worsening from mild, moderate, and severe diseases and to reduce mortality, it is necessary to identify the subpopulation that is more vulnerable to the development of COVID-19 unfavorable consequences. This study aims to investigate the demographic information, prevalence rates of common comorbidities among negative and positive real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) patients, and the association between SARS-CoV-2 cycle threshold (Ct) at hospital admission, demographic data, and outcomes of the patients in a large population in Northern Iran. Methods: This large retrospective cross-sectional study was performed from 7 March to 20 December 2020. Demographic data, including gender, age, underlying diseases, clinical outcomes, and Ct values, were obtained from 8,318 cases suspected of COVID-19, who were admitted to four teaching hospitals affiliated to Babol University of Medical Sciences (MUBABOL), in the north of Iran. Results: Since 7 March 2020, the data were collected from 8,318 cases suspected of COVID-19 (48.5% female and 51.5% male) with a mean age of 53 ± 25.3 years. Among 8,318 suspected COVID-19 patients, 3,250 (39.1%) had a positive rRT-PCR result; 1,632 (50.2%) patients were male and 335 (10.3%) patients died during their hospital stay. The distribution of positive rRT-PCR revealed that most patients (464 (75.7%)) had a Ct between 21 and 30 (Group B). Conclusion: Elderly patients, lower Ct, patients having at least one comorbidity, and male cases were significantly associated with increased risk for COVID-19-related mortality. Moreover, mortality was significantly higher in patients with diabetes, kidney disease, and respiratory disease.

Design of a new multi-epitope peptide vaccine for non-small cell Lung cancer via vaccinology methods: an in silico study.

Lung cancer is the most common type of tumor worldwide. Non-small-cell lung carcinoma (NSCLC) is considered any epithelial cell-related lung cancer, which includes more than 85% of all lung cancer cases. NSCLC is less responsive to chemotherapy than SCLC. Therefore, the need for other treatments has become more pronounced and immunotherapy has gained increasing attention as a promising therapy in recent years. The current study aimed to design a multi-epitope peptide vaccine targeting main cancer/testis antigens of SP17, AKAP4, and PTTG1, which have a major function in tumor cell proliferation invasion. The protein vaccine was constructed using the rigorous immunoinformatics analysis and investigation of several immune system parameters, considering B cell epitopes and CD4 and CD8 induced epitopes as the most important cells to respond to cancer cells. Inverse translation and optimization of codons were performed to have the designed protein's cloning as well as expression potential in E.coli. Physicochemical, antigenic, and allergenic features were assessed to confirm the safety and immunogenicity of the vaccine. The secondary and tertiary structures were predicted. Finally, intrinsic disorder and 3D model refinement and validation were performed to eliminate structural problems. The designed construct had a stable structure that could be an antigen and stimulate the immune system and not be an allergen. The built model 3D structure was valid and stable. Further investigations are needed to approve the safety and immunogenic property of this new vaccine for NSCLC before it can be used in patients.

Association of VLA4, 5, 6 and PSGL1 expression levels with engraftment in autologous HPSC transplantation in multiple myeloma patients.

The most promising therapy for leukemia is hematopoietic stem cell transplantation. Engraftment of HPSCs mainly depends on some factors such as adhesion molecules, including VLAs. This study tried to delineate the relationship between HPSCs engraftment and expression level of PSGL1 and VLA4, 5, and 6 genes in candidate MM patients for autologous bone marrow transplantation. Firstly, the CD 34+ HPSCs were collected from multiple myeloma (MM) patients after five days of G-CSF therapy through apheresis processes. Then, the patients were categorized into two groups of good and bad prognosis depending on engraftment time (Less or more than 18 days). Followingly, the expression of PSGL1 and VLA4, VLA5, and VLA6 genes were assessed by the qRT-PCR technique in each patient. Finally, the correlation between the genes and engraftment time was investigated to determine the prognostic role of each gene on HPSCs transplantation. Our findings demonstrated that there is a significant correlation between VLA4 (P=< 0.0001) and 5 (P = 0.005) levels and HPSCs engraftment time. As the higher levels of VLA4 and 5, the shorter time HPSCs engraftment occurs. In contrast, there was no significant correlation between VLA6 (P = 0.2) and PSGL1 (P = 0.3) genes levels and engraftment time. So that, the patients with a good prognosis had a higher level of VLA4 and VLA5, but no relation was found between VLA6 and PSGL1. It is concluded that VLA4 and VLA5 expression could be considered a significant prognostic factor for HPSC transplantation.

Pathophysiological roles of chronic low-grade inflammation mediators in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common hormonal imbalance disease in reproductive-aged women. Its basic characteristics are ovulatory dysfunction and ovarian overproduction of androgens that lead to severe symptoms such as insulin resistance, hirsutism, infertility, and acne. Notwithstanding the disease burden, its underlying mechanisms remain unknown, and no causal therapeutic exists. In recent years, further studies showed that inflammation processes are involved in ovulation and play a key role in ovarian follicular dynamics. Visceral adipose tissue can cause inflammatory response and maintenance of the inflammation state in adipocytes by augmented production of inflammatory cytokines, monocyte chemoattractant proteins, and recruitment of the immune cell. Therefore, the PCOS can be related to a low-grade inflammation state and inflammatory markers. Investigating the inflammatory processes and mediators that contribute to the commencement and development of PCOS can be a critical step for better understanding the pathophysiology of the disease and its treatment through inhibition or control of related pathways. In the present review, we discuss the pathophysiological roles of chronic low-grade inflammation mediators including inflammasome-related cytokines, interleukin-1ß (IL-1ß), and IL-18 in PCOS development.

Development of a conserved chimeric vaccine based on helper T-cell and CTL epitopes for induction of strong immune response against Schistosoma mansoni using immunoinformatics approaches.

Currently, three recombinant antigens based vaccines are under clinical trials against Schistosomiasis, but there is no vaccine available for prophylaxis or therapeutic. This study was conducted to construct a multi-epitope based vaccine against Schistosoma mansoni via utilizing Sm14, Sm21.7, Sm23, Sm29, Smp80, Sm-CB and SM-TSP-2 antigens. Helper T lymphocyte (HTL), cytotoxic T lymphocyte (CTL) and IFN-γ epitopes were predicted. Furthermore, Pan HLA DR-binding epitope was added to the vaccine. Moreover, 50S ribosomal protein L7/L12 of Mycobacterium tuberculosis as a novel TLR4 agonist was applied. The TAT peptide was added to the vaccine to augment intracellular delivery. The selected epitopes were linked together through appropriate linkers and chimeric vaccine was constructed with 617 amino acids with molecular weight of 65.43 kDa. Physico-chemical properties revealed a soluble protein with antigenic and non-allergic properties. Further analyses validated the stability of the construct that was able to interact with TLR4. Immunoinformatics analysis demonstrated the strong potential of constructed vaccine to stimulate T and B-cell mediated immune responses. In summary, obtained data indicated that the proposed vaccine can properly induce both T and B cells immune responses and could possibly be utilized for prophylactic or therapeutic aims in response to infection caused by S. mansoni.

The importance of miRNAs and epigenetics in acute lymphoblastic leukemia prognosis.

Acute lymphoblastic leukemia (ALL), one of the most common malignant human disorders, originates in different important genetic lesions in T-cell or B-cell progenitors. ALL is a malignant lymphoid progenitor with peak prevalence in children (2-5 years). The rate of survival when one is suffering from ALL depends on various agents including the age of the patient, responses to anti-leukemic therapy, and cell biology. miRNAs and epigenetics are important regulatory factors in the expression of genes. miRNAs are noncoding RNA with inhibitory effectors on specific mRNA. Patterns of DNA methylation are profoundly changed in ALL by epigenetic mechanisms. The deciphering of miRNA and the epigenetic pathogenesis in ALL could revolutionize response to the therapy and outcome, and create an enormous promise for novel approaches to reduce the toxic side-effects of intensive leukemia. Hence, pathogenetic miRNAs and epigenetics leading to the initiation and the progression of ALL are summarized in this review.

Association of TNF-α but not IL-1ß levels with the presence of Helicobacter pylori infection increased the risk of peptic ulcer development.

Peptic ulcer is a lesion in the mucosa of the digestive tract affecting many people all around the world. Recent investigations have indicated that produced inflammatory cytokines such as TNF-α and IL-1ß in response to gastric infection by Helicobacter pylori play an important role in the development of peptic ulcer. With regard to the significance of these cytokines in peptic ulcer development and the high prevalence of this disease in the developing countries, this study aimed to investigate the association of TNF-α and IL-1ß with peptic ulcer in the presence of H. pylori. This case-control study enrolled 61 patients with peptic ulcer disease (PUD) as cases and 59 people without peptic ulcer (NPUD) as controls. Blood samples and endoscopic biopsies were collected. H. pylori infection was confirmed by using rapid urease test (RUT), specific IgG measurement and histopathological examination. Then, IL-1ß and TNF-α levels were evaluated using enzyme linked immunosorbent assay (ELISA). The seropositivity of H. pylori was 62.5% in the studied population, while by considering RUT and histopathological examination along with specific-IgG antibody, H. pylori infection decreased to 56.7%. In addition, H. pylori infection was significantly (OR = 0.37; 95% CI = 0.17-0.82; P = .02) associated with peptic ulcer development. The TNF-α level in PUD and infected H. pylori subjects was significantly higher than that of control and un-infected H. pylori individuals. However, no significant difference of IL1ß level was observed between PUD and control groups as well as between H. pylori infected and un-infected individuals. Interestingly, IL-1ß level in PUD patients without H. pylori infection was significantly higher than infected ones. Moreover, a significant correlation between specific-IgG antibody with TNF-α level was observed. Taken together, our results showed that increased level of TNF-α could probably play pivotal role in pathogenesis of peptic ulcer in the presence of H. pylori infection. These findings also highlighted the importance of IL-1ß in the absence of H. pylori infection in peptic ulcer development.

TLR2 Arg677Trp but not TLR2 -196 to -174 ins/del and Arg753Gln polymorphism alter the risk of peptic ulcer in north of Iran.

BACKGROUND: Most polymorphisms that occur in TLR-2 are associated with gastrointestinal disorders such as peptic ulcer disease (PUD). Hence, in current study, association between TLR2-196 to -174 ins/del, Arg753Gln and Arg677Trp polymorphisms and risk of PUD development in north of Iran was evaluated. METHODS: This case-control study included 50 patients with PUD as cases and 50 people without peptic ulcer as control group. Blood and endoscopic biopsies were collected. Helicobacter pylori infection was screened by rapid urease test, specific IgG measurement and specific PCR for glmM gene. Then, TLR2-196 to -174 ins/del polymorphism was assessed by using allele-specific PCR. The Arg753Gln and Arg677Trp polymorphism in TLR2 gene were analyzed by the PCR-restriction fragment length polymorphism (RFLP). RESULTS: There was no significant difference in the allele and genotype frequencies of polymorphisms in the TLR2-196 to -174 ins/ins and Arg753Gln genes between controls and patients, respectively. However, an association with increased risk for PUD was observed for polymorphism TLR-2 Arg677Trp (odds ratio [OR] = 7.9; 95% confidence interval [CI] = 0.94-67.5). Further analysis showed that H. pylori infection was associated with a significant difference in genotype and allele frequencies of TLR2-196 to -174 ins/ins and Arg753Gln polymorphism, respectively. Furthermore, there was no association between variant haplotypes and PUD development in H. pylori infected subjects. However, no association was detected between gender and genotypic frequencies of all polymorphisms in TLR2. CONCLUSION: Our findings showed that TLR2 Arg677Trp polymorphism and H. pylori infection may play crucial roles in peptic ulcer development respectively in north of Iran.

Association of Helicobacter pylori infection with Toll-like receptor-4 Thr399Ile polymorphism increased the risk of peptic ulcer development in North of Iran.

Toll-like receptor-4 (TLR4) polymorphisms may influence host immune response against Helicobacter pylori (H. pylori). This study aimed to investigate whether TLR4 polymorphisms are associated with H. pylori susceptibility and risk of peptic ulcer development or not. The TLR4 + 3725 G/C polymorphism was studied using polymerase chain reaction with confronting two-pair primers (PCR-CTPP). In addition, TLR4 Asp299Gly and Thr399Ile polymorphisms were evaluated by PCR-restriction fragment length polymorphism (RFLP). There was no significant difference in TLR4 + 3725 G/C and Asp299Gly genotype frequencies between non-peptic ulcer (NPUD) and peptic ulcer (PUD) individuals in the context of peptic ulcer development and susceptibility to infection with H. pylori. Nevertheless, a significant association with increased risk for PUD development was observed for polymorphism TLR4 Thr399Ile [odds ratio (OR) = 4.2; 95% confidence interval (CI) = 1.35-13.26; p = 0.01]. Correspondingly, TLR4 Thr399Ile polymorphism was associated with H. pylori susceptibility (OR = 0.27; 95% CI = 0.08-0.88; p = 0.04). In addition, TLR4 Thr399Ile polymorphism increased 4.2-fold, the risk of peptic ulcer development in individuals infected by H. pylori carrying CT + TT genotype. Our results showed that TLR4 Thr399Ile polymorphism along with H. pylori infection may play critical roles in peptic ulcer development in North of Iran.

Development of an epitope-based vaccine inhibiting immune cells rolling and migration against atherosclerosis using in silico approaches.

Atherosclerosis is a chronic inflammatory disease characterized by formation of pro-oxidative lipids in large and medium-sized vessels. Over the years, many treatments and drugs have entered the market to improve atherosclerosis and autoantigen-mediated active immunization is currently considered as a beneficial method. Therefore, this study was conducted to design a novel epitope-based vaccine against atherosclerosis employing CD99, CD81 and CD99L2 antigens. In this way, structural vaccinology approaches were used to design a novel multi-epitope vaccine against atherosclerosis. Six epitopes were predicted from CD99, CD81 and CD99L2 proteins. In addition, helper epitopes selected from Tetanus toxin fragment C (TTFrC)ion were applied to induce CD4+ helper T lymphocytes (HTLs) responses. Moreover, cholera toxin B (CTB) was employed as an adjuvant. Finally, EAAAK AND GPGPG sequences as linkers were considered to make a linkage between favorite peptide sequences. A multi-epitope construction was designed based on the predicted epitopes which was 270 residues in length. Further immunoinformatic analyses were carried out to assess physicochemical properties, secondary and tertiary structures, stability, intrinsic protein disorder, solubility, and allergenicity of this chimeric protein. Based on the obtained results, a soluble, and non-allergic protein with a molecular weight of 28.7kDa was designed. Further analyses revealed that the chimeric protein is a stable protein and the predicted epitopes indicated strong potential to induce B-cell and T-cell mediated immune response. Our immunoinformatic analyses revealed that the modeled multi-epitope vaccine had appropriate properties,which can properly stimulate the immune responses of both T and B cells.