ABSTARCT Objective: The tick-borne encephalitis virus (TBEV), a flavivirus transmitted by Ixodes spp. ticks, can cause a clinical picture characterized by nonspecific symptoms, as well as more specific conditions such as encephalitis and myelitis. Most patients admitted and followed with a preliminary diagnosis of Crimean-Congo hemorrhagic fever (CCHF) are from regions with a risk of tick exposure. The aim of this study is to determine the epidemiology of TBEV. Material and Method: A total of 272 adult patients admitted with a preliminary diagnosis of CCHF between April and September 2021 in the Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, XXX University, were included in the study. The diagnosis of CCHF was defined using the criteria established by the CCHF Scientific Committee of the Turkish Ministry of Health. To determine the seroprevalence of TBE, TBEV-IgG antibodies were investigated in patient serum samples using the ELISA method (Anti-TBE Virus ELISA (IgG), Euroimmun, Germany). The results were evaluated by calculating the ratio of the extinction value of the patient sample to the extinction value of calibrator 2. Ratios below 0.8 were considered negative, between 0.8 and 1.1 were considered borderline, and greater than 1.1 were considered positive. Patients with no detected antibodies against TBEV in their serum samples were considered seronegative. Results: The mean age of the 272 patients included in the study was 49.46 ± 17.48 years (Range: 18-98 years), with 181 (66.5%) being male. All patients' TBEV antibody levels were evaluated as negative. The provinces of residence of the patients were Sivas, Giresun, Tokat, Yozgat, and Erzincan. A history of tick exposure was found in 204 (75%) of the patients, with 143 (79%) of male patients and 61 (67%) of female patients reporting tick exposure. Conclusion: In this study, the absence of antibodies against TBEV indirectly demonstrated the absence of TBEV in the tick population. However, no study has been conducted to detect the presence of TBEV in the tick population in Sivas province, and our study is the first to address this issue. Nevertheless, further seroepidemiological studies are required.

Jingmen tick virus (JMTV) is a single-stranded RNA virus transmitted to humans through tick bites and classified within the Flaviviridae family. It has been detected in various arthropods and mammals. JMTV causes an acute febrile illness with symptoms such as skin lesions, fatigue, headache, nausea, and vomiting; however, limited research exists on its clinical impact and pathogenesis in humans. This study aims to report the first detection and molecular characterization of JMTV in patients with Crimean-Congo Hemorrhagic Fever (CCHF) in Türkiye. During the 2022 outbreak, serum samples from 206 hospitalized CCHF-suspected patients were retrospectively analyzed. JMTV was identified in 3 (1.5%) cases using nested PCR. The nucleotide similarity within the three JMTV sequences was found to be between 98.0% and 99.0%. Phylogenetic analysis showed 82-98% similarity with previously identified JMTV isolates in Türkiye. This study presents the first detection and molecular characterization of JMTV in humans in Türkiye. Clinicians should consider JMTV in patients with a history of tick bites, especially in CCHF-endemic regions.

Crimean-Congo Haemorrhagic Fever Virus (CCHFV) is spread by infected ticks or direct contact with blood, tissues and fluids from infected patients or livestock. Infection with CCHFV causes severe haemorrhagic fever in humans which is fatal in up to 83 % of cases. CCHFV is listed as a priority pathogen by the World Health Organization (WHO) and there are currently no widely-approved vaccines. Defining a serological correlate of protection against CCHFV infection would support the development of vaccines by providing a ‘target threshold’ for pre-clinical and clinical immunogenicity studies to achieve in subjects and potentially obviate the need for in vivo protection studies. We therefore sought to establish titratable protection against CCHFV using pooled human convalescent plasma, in a mouse model. Convalescent plasma collected from seven individuals with a known previous CCHFV virus infection were characterised using binding antibody and neutralisation assays. All plasma recognised nucleoprotein and the Gc glycoprotein, but some had a lower Gn glycoprotein response by ELISA. Pooled plasma and two individual donations from convalescent donors were administered intraperitoneally to A129 mice 24 h prior to intradermal challenge with CCHFV (strain IbAr10200). A partial protective effect was observed with all three convalescent plasmas characterised by longer survival post-challenge and reduced clinical score. These protective responses were titratable. Further characterisation of the serological reactivities within these samples will establish their value as reference materials to support assay harmonisation and accelerate vaccine development for CCHFV.

Climate change and population densities accelerated transmission of highly pathogenic viruses to humans, including the Crimean-Congo haemorrhagic fever virus (CCHFV). Here we report that the Low Density Lipoprotein Receptor (LDLR) is a critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in cell culture and blood vessel organoids. The interaction between CCHFV and LDLR is highly specific, with other members of the LDLR protein family failing to bind to or neutralize the virus. Biosensor experiments demonstrate that LDLR specifically binds the surface glycoproteins of CCHFV. Importantly, mice lacking LDLR exhibit a delay in CCHFV-induced disease. Furthermore, we identified the presence of Apolipoprotein E (ApoE) on CCHFV particles. Our findings highlight the essential role of LDLR in CCHFV infection, irrespective of ApoE presence, when the virus is produced in tick cells. This discovery holds profound implications for the development of future therapies against CCHFV.

Background: Little is known about the possible association of vitamin D receptor (VDR) gene polymorphisms in obese patients with chronic kidney disease on dialysis (CKD-G5D). Therefore, we aimed to investigate VDR gene TaqI, ApaI, and FokI single-nucleotide polymorphisms (SNPs) in overweight/obese CKD-G5D patients. Methods: Seventy-one normal-weight and 68 overweight/obese CKD-G5D patients were included in the study. The polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping. Demographic and laboratory data were obtained from the medical records of patients. Results: For all 3 SNPs, no significant association was found between normal-weight and overweight/obese patients ( P > .05). High-density lipoprotein (HDL) concentrations were lower, but triglyceride (TG) and glucose levels were higher in overweight/obese patients compared to normal-weight patients ( P < .001 for HDL and TG and P = .023 for glucose). In overweight/obese patients, individuals with the TaqI CC genotype had higher (PTH) levels than those with TC and TT genotypes (CC = 717.1 +/- 616.4, TC = 342.7 +/- 360.8, and TT = 310.2 +/- 323.4 pg/mL; P = .028). Similarly, patients with the ApaI genotype (627.3 +/- 653.0 mg/dL) had higher TG levels than those with the AA and AC genotypes (CC = 627.3 +/- 653.0, AA = 223.3 +/- 156.6, AC = 193.1 +/- 85.4; P < .001). Overweight/obese patients with the FokI TT genotype had higher glucose concentrations than those with the CC and CT genotypes (CC = 183.4 +/- 128.4 mg/dL, TT = 151.9 +/- 66.1 mg/dL, and CT = 107.6 +/- 41.9 mg/dL; P = .008). Conclusion: Our study suggests that VDR TaqI, ApaI, and FokI polymorphisms are not associated with obesity in CKD-G5D patients. However, they might increase the risk of secondary hyperparathyroidism, dyslipidemia, and hyperglycemia.

Crimean-Congo haemorrhagic fever (CCHF) is the most prevalent human tick-borne viral disease, with a reported case fatality rate of 30 % or higher. The virus contains a tri-segmented, negative-sense RNA genome consisting of the small (S), medium (M) and large (L) segments encoding respectively the nucleoprotein (NP), the glycoproteins precursor (GPC) and the viral RNA-dependent RNA polymerase (RDRP). CCHFV is one of the most genetically diverse arboviruses, with seven distinct lineages named after the region they were first reported in and based on S segment phylogenetic analysis.Due to the high genetic divergence of the virus, a single targeted tiling PCR strategy to enrich for viral nucleic acids prior to sequencing is difficult to develop, and previously we have developed and validated a tiling PCR enrichment method for the Europe 1 genetic lineage.We have developed a targeted, probe hybridisation capture method and validated its performance on clinical as well as cell-cultured material of CCHFV from different genetic lineages, including Europe 1, Europe 2, Africa 2 and Africa 3. The method produced over 95 % reference coverages with at least 10x sequencing depth. While we were only able to recover a single complete genome sequence from the tested Europe 1 clinical samples with the capture hybridisation protocol, the data provides evidence of its applicability to different CCHFV genetic lineages.CCHFV is an important tick-borne human pathogen with wide geographical distribution. Environmental as well as anthropogenic factors are causing increased CCHFV transmission. Development of strategies to recover CCHFV sequences from genetically diverse lineages of the virus is of paramount importance to monitor the presence of the virus in new areas, and in public health responses for CCHFV molecular surveillance to rapidly detect, diagnose and characterise currently circulating strains.

Crimean-Congo haemorrhagic fever (CCHF) is the most widespread tick-borne viral haemorrhagic fever affecting humans, and yet a licensed drug against the virus (CCHFV) is still not available. While several studies have suggested the efficacy of ribavirin against CCHFV, current literature remains inconclusive. In this study, we have utilised next-generation sequencing to investigate the mutagenic effect of ribavirin on the CCHFV genome during clinical disease. Samples collected from CCHF patients receiving ribavirin treatment or supportive care only at Sivas Cumhuriyet University Hospital, Turkey, were analysed. By comparing the frequency of mutations in each group, we found little evidence of an overall mutagenic effect. This suggests that ribavirin, administered at the acute stages of CCHFV infection (at the World Health Organization-recommended dose) is unable to induce lethal mutagenesis that would cause an extinction event in the CCHFV population and reduce viremia.

Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection. The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.

Toll-like receptors (TLRs) recognize infectious agents and play an important role in the innate immune system. Studies have suggested that TLR single nucleotide polymorphisms (SNPs) are associated with poor antiviral responses against SARS-CoV-2. Therefore, we aimed to investigate the relationship of TLR7 and TLR8 (SNPs) with COVID-19 disease prognosis. A total of 120 COVID-19 patients, 40 outpatients, 40 clinical ward patients and 40 intensive care unit (ICU) patients were included in the study. TLR7 (rs179009), TLR8-129 C/G (rs3764879) and TLR8 Met1Val (rs3764880) SNPs were genotyped using the PCR-RFLP method. In female patients, individuals carrying AG genotype and G allele for TLR8 Met1Val SNP were found at a higher frequency in patients hospitalized in the ICU than in patients followed in the clinical ward (p < 0.05). In terms of the other two SNPs, no significant difference was found between the groups in females. Furthermore, in male patients, A allele of TLR7 rs179009 SNP was at a higher frequency in patients who have at least one comorbidity than in patients who have no comorbidity (p < 0.05). Our results suggest that TLR8 Met1Val SNP is important in the COVID-19 disease severity in females. Furthermore, TLR7 rs179009 SNP is important in male patients in the presence of comorbid diseases.

The pathogenesis and host-viral interactions of the Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches including biological network analysis in elucidating the complex host-viral response, allow for interrogating the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) and untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host’s metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and was in agreement with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at system-level and during progressive replication. Significance Statement A combination of multi-modal systems-wide host-immune response and in vitro temporal analysis identified molecular re-arrangement in CCEM and fingerprinting the interferon-mediated antiviral mechanism during CCHFV-infection. Using the newly gained insights, we then modulated the key pathways of CCEM by drugs and inhibited the productive CCHFV-replication in in vitro infection models. Our study thus provides a comprehensive, system-level picture of the regulation of cellular and metabolic pathways during productive CCHFV-infection for the first time that aids in identifying novel therapeutic targets and treatment strategies.

Objectives: In this study, it was aimed to investigate the effects of neurodynamic mobilization (NM) technique on inflammation biomarkers, and pain, pressure pain threshold, range of motion, muscle strength, and functional status in delayed onset muscle soreness. Materials-Methods:In the study, 32 healthy sedentary male volunteers were randomly divided into two groups as NM (n = 16) and placebo-NM (n = 16).After the initial evaluation of the individuals, femoral nerve NM and placebo NM techniques were administered three sets a day with ten repetitions for three days a week for three weeks.Then, a delayed muscle pain induction protocol was started for the quadriceps femoris muscle was initiated.Initial assessments were repeated immediately after the onset of delayed muscle pain and at hours 24, 48, and 72.Serum inflammation (IL-6, IL-10, IL-1 beta, TNF-alpha, and C reactive protein) biomarkers, pain (rest and activity), pressure pain threshold, range of motion, muscle strength (QF, hamstring eccentric/concentric) and performance (one-leg jump, vertical jump) parameters were measured. Results:In the interaction of time by the group, in IL-6 level (η²: 0.162), activity pain intensity (η²: 0.165-0.110),pressure pain thresholds (η²: 0.219-0.162),active knee flexion range of motion (η²: 0.097), and one leg forward jump distance (η²: 0.156), statistically significant differences were detected with varying effect size levels (p <0.05).Individuals in the NM group had higher recovery rates at IL-6, IL-10, IL1-β, TNF-α, pain intensity, and QF eccentric muscle strength levels. Conclusions:It is thought that the NM technique can be applied as a preventive treatment method in reducing and controlling the symptoms caused by delayed onset muscle soreness.

The pathogenesis and host-viral interactions of the Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and is not well evaluated. To understand the host immune responses against CCHFV, we have performed a global transcriptomic analysis of peripheral blood mononuclear cells from a longitudinal cohort of CCHF patients who survived the infection and temporal untargeted proteomics analysis of CCHFV infected Huh7 cells. Our results indicate that during the acute phase of CCHFV infection, the host's metabolic reprogramming towards central carbon metabolism including glycolysis and glutaminolysis occurs that favours the virus replication as blocking these pathways in vitro inhibits CCHFV cellular replication. Furthermore, CCHFV replication was inhibited by blocking Akt with MK-2206 suggesting a regulatory role of PI3K/Akt/mTOR pathways. We also show activation of key interferon stimulating genes during infection, suggesting a role for type I and II interferon-mediated antiviral mechanisms. Targeting immune-metabolic pathways could be attractive therapeutic intervention for CCHFV.

Crimean-Congo hemorrhagic fever (CCHF) is a thick-borne viral zoonotic disease. The pathogenesis and the reasons why cases have a mild or severe course in CCHF have not yet been explained. In this study, we investigated the relationship between promoter -2518 A/G single-nucleotide polymorphism (SNP) of the MCP-1 gene and the clinical course of CCHF. The MCP-1-2518 A/G SNP (rs1024611) frequency was examined in 128 virologically/serologically confirmed CCHF patients and 181 healthy controls by using the PCR-RFLP method. When CCHF patients and controls were compared, no significant difference was found between genotype distributions and allele frequencies of the -2518 A/G SNP of MCP-1 gene (P > .05). Compared to the AA genotype, both AG (P = .016; OR = 2.57) and GG genotype (P = .039; OR = 3.43) were found with significantly higher frequencies in mild/moderate cases than in severe cases. Compared to the AG + GG genotype, AA showed a significant risk for severe CCHF (60.0% vs 38.4%, P = .02; OR = 2.41). In contrast, the AG genotype showed a significant protective effect against severe disease compared to AA + GG genotype (29.1% vs 47.9%, P = .013; OR = 2.58). Compared to mild/moderate cases, the A allele was found to be significantly higher in severe cases (0.745 vs 0.623, P = .039; OR = 1.77). However, no significant relationship was found between fatal and nonfatal cases in terms of genotype or allele frequencies (P > .05). In conclusion, both -2518 AA genotype and A allele of MCP-1 were associated with disease severity, and the AG genotype had a protective effect against a severe disease course in CCHF patients.

OBJECTIVESThe aim of the present study was to investigate the presence of GJB2, GJB3, and GJB6 gene mutations in non-syndromic sensorineural hearing loss (NSHL) cases living in Sivas region, to provide appropriate genetic counseling for cases who were found to have mutation, and to contribute to decrease the frequency of mutant allele in the next generation and plan treatment and rehabilitation with early diagnosis.MATERIALS AND METHODSThe study included 53 unrelated cases that were diagnosed with congenital NSHL between June 2009 and March 2010. Multiplex ligation-dependent probe amplification method was used for genotyping of GJB2, GJB3, and GJB6 gene mutations.RESULTSHeterozygous 35delG variant was determined in 1.9% (n=1) of cases, homozygous 35delG in 15.1% (n=8), heterozygous IVS1+1G>A mutation in 1.9% (n=1), compound heterozygous in 3.8% (n=2), and homozygous IVS1+1G>A variant in 3.8% (n=2). None of the cases had mutation in GJB3 and GJB6 genes. Mutated allele frequencies in the present study were found to be 17.9% for 35delG and 6.6% for IVS1+1G>A.CONCLUSIONThe present study showed that 35delG mutation is the most common variant in the Sivas region, and that IVS1+1G>A mutation should be investigated in hearing loss. Another result of the present study was that genetic analyzes would allow early diagnosis of hearing impairments particularly when infants whose parents have consanguinity do not pass the newborn hearing screening.

Aim: Although several associations were found between Dicer rs3742330 single nucleotide polymorphism (SNP) and development and prognosis of some epithelial cancers, relationship between the SNP rs3742330 and endometrial cancer (EC) has not yet been studied. We aimed to investigate the prognostic role of rs3742330 SNP of Dicer gene in EC patients. Subjects and Methods: A total of 80 EC patients and 80 control subjects included in the study. Real-time polymerase chain reaction and the allele discrimination technique was used for genotyping of rs3742330 SNP. Results: There was no significant difference between EC patients and control subjects with regard to the genotype and allele frequencies for Dicer rs3742330 SNP (P > 0.05). Despite Dicer rs3742330 SNP had no prognostic value in terms of stage, grade, lymphovascular invasion, myometrial invasion, tumor size, and histopathology; malignant peritoneal cytology has been detected higher in the patients bearing AA genotype compare with AG genotype (P = 0.023). Higher recurrence rate and shorter time to recurrence were found in patients bearing AG and GG genotype compare with AA genotype (P = 0.009). Conclusion: Dicer rs3742330 AG and GG genotypes may have the potential to be used as a predictor of poor prognosis in the management of EC case.

Purpose: We investigated the influence of the vitamin D receptor gene Taql (rs731236), Apal (rs7975232), and Fokl (rs2228570) polymorphisms in arteriovenous fistula failure in hemodialysis patients. Methods: This study was carried out with 54 patients who experienced two or more fistula failures in the late period after arteriovenous fistula operation and 58 control patients with no history of arteriovenous fistula failure in 3years or longer. The polymerase chain reaction-restriction fragment length polymorphism method was used to determine the vitamin D receptor Taql, Fokl, and Apal polymorphisms. Results: For vitamin D receptor gene Taql and Fokl polymorphisms, no significant association was found between the two groups (p>0.05). However, a statistically significant association was determined for Apal polymorphism between the two groups (p = 0.02). In patients, Apal AA, AC, and CC genotype frequencies were found as 21 (38.9%), 32 (59.3%), and I (1.8%), respectively. However, genotype frequencies of AA, AC, and CC in the control group were 29 (50%), 22 (37.9%), and 7 (12.1%), respectively. In all three polymorphisms, no significant difference was found between the two groups in terms of allele frequencies (p>0.05). Conclusion: Vitamin D receptor Apal AC genotype may be a possible cardiovascular risk factor for the development of arteriovenous fistula failure.