Background Persons with an increased bleeding tendency without abnormalities in standard hemostasis tests, are classified as having a bleeding disorder of unknown cause (BDUC). The majority is female and most common bleeding symptoms are mucocutaneous, including heavy menstrual bleeding (HMB). However, knowledge on HMB in BDUC and the impact on daily functioning is limited. Objectives Investigate the prevalence of HMB, and HMB-related quality of life (QoL) in women with BDUC, compared to women with mild bleeding disorders (MBD) and no bleeding disorder (NBD). Methods Data from women included in the Maastricht Probe-AHP study were used. HMB was defined as a score ≥1 on the menorrhagia subdomain of the ISTH-BAT. HMB-related QoL was evaluated using the Menorrhagia Multi-Attribute Scale (MMAS). Results In total, 317 women were included (BDUC n=157, MBD n=104, NBD n=56) and 144 women completed the MMAS. HMB was significantly more prevalent in BDUC and MBD (82.8% and 71.2%) compared to NBD (39.3%); p<0.001. Median total MMAS scores were lower in BDUC and MBD compared to NBD (median [IQR]: 49.8 [34.8-82.6], 54.9 [37.0-75.3], and 74.3 [IQR 46.1-100.0], p=0.249). Across all groups women with HMB had significant lower median total MMAS scores compared to women without HMB (p=0.002, p=0.001, and p=0.002). A higher ISTH-BAT menorrhagia score was associated with a lower MMAS total score. Conclusions HMB is highly prevalent among women with BDUC and HMB substantially impairs HMB-related QoL. This underscores the need for increased clinical awareness of the impact of HMB in this population, and for targeted clinical guidelines and optimized management strategies.
Background There is evidence that patients with immune thrombocytopenia (ITP) are at increased risk of thrombosis. The associations of clinical and comorbid factors with thrombosis in ITP remain unclear. Objective This study aimed to investigate the incidence rate and risk factors of arterial and venous thrombosis among primary ITP patients. Patients/Methods A retrospective cohort study was conducted, enrolling adult patients diagnosed with ITP at Qilu Hospital between January 1, 2014 and December 31, 2025. Thrombosis incidence was calculated using person-years of follow-up, and multivariable-adjusted Cox regression was used to identify independent risk factors. Sensitivity analyses were also conducted using Fine and Gray sub-distribution hazard model regression, with death as a competing event. Results Among 764 ITP patients with 3540.8 person-years of follow-up, the incidence was 5.7 (95% CI 4.9–6.5) per 100 person-years for arterial thrombosis and 2.1 (95% CI 2.1 1.6–2.6) for venous thrombosis. The median age at thrombosis onset and the interval from ITP diagnosis to the index thrombotic event were 67.5 years and 2.4 years for arterial thrombosis, 62.0 years and 1.2 years for venous thrombosis, respectively. Recent 3-month exposure to all three ITP-targeted therapies increased the risk of both arterial and venous thrombosis. Conclusion Advanced age, prior thromboembolism, comorbidities, recent exposure to ITP-targeted therapies and cardiovascular risk factors were independent risk factors for thrombosis in ITP. Thromboembolism in ITP mostly occurred in the presence of multiple thrombotic risk factors. Continuous risk assessment and optimized management are essential throughout the clinical course of ITP.
Background Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by a predominant bleeding phenotype. However, patients are also at risk of thrombotic events and may require antithrombotic therapy (AT), for which safety data remain limited. Objectives To prospectively evaluate the safety of AT in patients with HHT using standardized longitudinal assessment of bleeding outcomes. Methods We conducted a prospective observational study at a tertiary HHT referral center. Patients with a definite diagnosis of HHT and a new indication for antiplatelet or anticoagulant therapy were enrolled. The primary outcome was the incidence of hemorrhagic events, classified according to International Society on Thrombosis and Haemostasis (ISTH) criteria. Secondary outcomes included worsening of epistaxis assessed by the Epistaxis Severity Score (ESS), changes in hemoglobin levels, and transfusion requirements. Results Thirty-three patients (mean age 65.8 ± 12.9 years; 69.7% male) were included, for a total of 41 AT courses. During a mean follow-up of 21.1 ± 19.2 months, 2 major bleeding events (4.9%) occurred, both during anticoagulant therapy. Three clinically relevant non-major and one minor bleeding were recorded. Worsening of epistaxis occurred in 24.4% of treatment courses, but mean ESS values did not differ from baseline. Hemoglobin levels and transfusion requirements were not significantly affected. Conclusions In this prospective cohort, AT was associated with an acceptable safety profile in selected patients with HHT managed in a multidisciplinary setting. These findings strengthen the currently limited prospective evidence supporting individualized antithrombotic management in HHT, although larger multicenter prospective studies remain warranted.
Background Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever characterized by high mortality, thrombocytopenia, and coagulation abnormalities. Unlike other inflammatory conditions where plasma fibrinogen rises, SFTS patients exhibit normal fibrinogen levels despite evidence of consumptive coagulopathy and hepatocyte injury. Objectives To investigate whether platelets contribute to fibrinogen dysregulation and coagulopathy in SFTS. Methods We enrolled 102 SFTS patients stratified by clinical symptoms (Mild vs. Severe) and by platelet count (<50×109/L vs. 50-150×109/L). Platelet-associated SFTSV nucleoprotein (NP), activation markers (CD62P, activated GPIIb/IIIa), and fibrinogen levels were measured by flow cytometry and Western blot. In vitro infection assays using human and mouse platelets, including UV-inactivated virus controls, were performed to establish causality and assess platelet aggregation and clot turbidity. Results Patients with SFTS exhibited significant platelet activation and elevated platelet-associated fibrinogen levels despite normal plasma levels. Patients with severe thrombocytopenia (platelet count <50 × 109/L) had higher platelet-associated fibrinogen levels and more pronounced coagulopathy. Platelet fibrinogen levels correlated positively with activation markers and viral load. In vitro, live but not UV-inactivated SFTSV directly induced platelet activation, fibrinogen accumulation, and enhanced aggregation and clot formation in human and mouse platelets. Immunofluorescence revealed fibrinogen accumulated in association with platelets, with a distribution distinct from that of von Willebrand factor. Conclusions SFTSV infection drives platelet activation and fibrinogen association, potentially leading to enhanced clot formation and contributing to thrombocytopenia. This platelet-centric pathway provides a mechanistic explanation for the distinct coagulopathy of SFTS and identifies platelet fibrinogen as a potential therapeutic target.
Background In severe hemophilia A, factor VIII (FVIII) replacement is essential, but FVIII inhibitor development can be serious. Objectives This phase 3, prospective, uncontrolled, open-label, multicenter study (NCT02615691) investigated the immunogenicity, efficacy and safety of rurioctocog alfa pegol for severe hemophilia A in previously untreated patients (PUPs). Methods Patients received intravenous prophylaxis (25-50 IU/kg, up to 80 IU/kg, ≥1 dose weekly) and/or on-demand therapy (10-50 IU/kg, up to 80 IU/kg depending on bleed severity). The primary endpoint was FVIII inhibitor incidence (≥0.6 BU/mL [Nijmegen modification of Bethesda assay]) in the full analysis set (FAS; patients with ≥100 exposure-days [EDs] or who developed an inhibitor). We present final data. Results Of 146 enrolled patients, 120 received ≥1 dose; all were male and 55.8% had hemophilia A family history. Median (range) age was 9.6 (1.2-60.0) months. In the FAS (N=100), 11 patients developed FVIII inhibitors and 89 had ≥100 EDs without developing inhibitors (incidence [95% CI]: 0.110[0.056-0.188]). In post-hoc analyses, 11 patients developed inhibitors, and 101 and 96 had ≥20 and ≥50 EDs, respectively, without developing inhibitors (incidence [95% CI]: 0.098[0.050-0.169] and 0.103[0.052-0.177], respectively). Annualized bleeding rates (95% CI) were 1.7(1.2-2.4), 1.0(0.7-1.3), and 2.3(1.7-3.2) for once-weekly prophylaxis, >1× weekly prophylaxis, and on-demand therapy, respectively. Overall, 109/120 (90.8%) patients had 745 adverse events; serious adverse events occurred in 47 (39.2%) patients. Conclusions These data demonstrate low incidence of FVIII inhibitors among PUPs receiving rurioctocog alfa pegol for severe hemophilia A. Efficacy and safety results were similar to prior reports in previously treated patients.
Introduction Sexual function can be negatively affected in individuals with congenital bleeding disorders (CBDs). Patient Reported Outcome Measures (PROMs) can provide insight into patients’ experiences and help address sexual function and sexual satisfaction in clinical care. This study evaluates the measurement properties of a selection of PROMIS® Sexual Function and Satisfaction (PROMIS SexFS) measures in adults with CBDs, and describes outcomes. Methods In this cross-sectional multicenter study, men with hemophilia and women with hemophilia or von Willebrand disease were invited to participate. Six screener items and 12 measures from the PROMIS SexFS, and disease-specific items on sexual function and satisfaction were completed. Reliability was evaluated using standard error of T-scores. Internal consistency was evaluated using item-total correlation. Known-group validity was examined by testing predefined hypotheses. Feasibility was evaluated using percentage of lowest and highest scores, and relevance was evaluated qualitatively. Lastly, PROMIS T-scores were compared with reference data from the Dutch general population using independent samples t-test. Results Data from 231 patients (mean age = 44 years, range 18-81 years; 54% male) were collected. For all measures, > 78% met the reliability criterion. Internal consistency and feasibility were sufficient, and known-group validity was supported. Compared with reference data, patients reported greater orgasm pleasure (d = 0.23) and more interest in sexual activity (d = 0.19). Males reported better erectile function (d = 0.26), while females reported more vaginal discomfort with sexual activity (d = 0.48). Conclusion The Dutch PROMIS SexFS measures showed sufficient reliability and validity for assessing sexual function and satisfaction in individuals with CBDs. It can inform research and support clinical discussions.
Background and Objectives The immune system is increasingly recognized as a contributor to thrombus formation and outcomes in acute ischemic stroke (AIS). We aimed to characterize immune cell composition in thrombi retrieved during endovascular thrombectomy and evaluate its association with thrombus morphology, stroke etiology, and clinical outcomes. Methods Thrombi from 56 patients in the MR CLEAN-NO IV study were analyzed histologically for immune cell densities. Outcomes included thrombus volume, 90-day functional outcome (modified Rankin Scale ≥3), National Institutes of Health Stroke Scale (NIHSS) at 24h and 7d, mortality, successful recanalization, final infarct volume, and procedure variables. Results Median age was 69 years, 33.9% female, median baseline NIHSS 17, and 51.8% received intravenous thrombolysis. Immune cell expression was not associated with thrombus morphology. However, cardioembolic (CE) thrombi exhibited higher CD68+ cell density compared with large artery atherosclerosis (p=0.016) and cryptogenic thrombi (p=0.034). In CE thrombi, CD19+ and Congo Red+ cell densities were positively correlated with thrombus volume (linear regression β=37.98, 95% CI [12.63-63.33], p=0.020; β=54.05, 95% CI [-17.69-90.32], p=0.023, respectively). Furthermore, higher CD3+ and Congo Red+ cell densities were independently associated with favorable 90-day functional outcome (OR=0.37, 95% CI [0.17-0.72], p=0.006; OR=0.28, 95% CI [0.08-0.70], p=0.020, respectively). Conclusion Immune cell composition within retrieved thrombi may vary depending on stroke etiology and might be relevant for treatment strategy and clinical recovery. The exploratory results of this study suggest a possible role for immunothrombosis in AIS. However, further validation in larger-sample, adjusted analyses is needed before any clinical significance can be derived.
Venous thromboembolism (VTE) in children has historically been considered uncommon; however, it is increasingly recognized in hospitalized pediatric populations, and its incidence has risen over the past few decades. This can be attributed to several factors, including greater awareness of the condition, improved survival rates for children with chronic and complex medical conditions, increased use of supportive care (such as central venous catheters), and advancements in diagnostic imaging. Acquired conditions, such as infections, malignancies, cardiovascular diseases, and inflammatory bowel disease, are recognized as risk factors for VTE. Among these, the presence of a central venous catheter remains the most significant and common risk factor for pediatric VTE. In this review, we present and illustrate the pathophysiology and current treatment options for VTE in the pediatric population.
Introduction Venous thromboembolism (VTE) risk assessment (VTERA) tools can be used to guide clinical decisions on postpartum thromboprophylaxis. However, the appropriateness of these decisions depends on the accuracy of the data input into VTERA tools. Objectives The primary objective was to assess whether the accuracy of postpartum VTE risk assessments differed between the study years (2019–2025), across nine predefined risk factors. The secondary objectives included evaluating the accuracy of all risk factors, and thromboprophylaxis recommendations, in a 2025 sample. Methods In this retrospective observational study, the accuracy of data entered into a postpartum VTERA tool was assessed, through comparison to electronic health record (EHR) data. Differences in accuracy across study years (2019–2025), for nine structured risk factors, were evaluated using Poisson regression.For the primary analysis, all deliveries and bookings, with a matched VTE risk assessment between January 2019 and August 2025 were included. For the secondary analysis, 283 patients from 2025 were manually reviewed, to assess all 23 risk factors and thromboprophylaxis recommendations. Results Primary analysis included 47 489 deliveries and bookings, with a matched risk assessment. BMI was the risk factor with the lowest accuracy overall (94.3%), and remained the lowest across each year. Compared with 2019, postpartum VTE risk factor recording was significantly more accurate in 2020, 2021, 2022, 2023, 2024 and 2025.Secondary analysis showed that 6.0% of risk assessments produced inaccurate thromboprophylaxis recommendations, regarding indication and duration, and 4.9% yielded inaccurate dose recommendations. Conclusions Future research must focus on enhancing the accuracy of VTE risk assessments. This may involve auto-population of VTERA tools using EHR data.
Background:Venous thromboembolism (VTE) recurrence on anticoagulation (ROA) and anticoagulant failure (ACF) are frequently described but poorly defined. Objectives:To determine the incidence and causes of ROA and ACF in patients with VTE. The secondary aim was to describe the management of these cases, including anticoagulation selection and dosing strategies. Methods:Patients with acute VTE enrolled in the Mayo Clinic VTE Registry from 2013 to 2022 were included. Charts of patients with VTE recurrence despite anticoagulation were reviewed. ROA was defined as any new thrombotic event in patients prescribed and recently taking anticoagulants. ACF was defined as ROA in the absence of modifiable risk factors. Results:Of the 4980 patients included, 150 (3.0%) ROA events occurred in 130 patients. Altered absorption (n = 40, 26.7%), medication dosing (n = 35, 23.3%), and recent interruption of therapy (n = 37, 24.7%) were frequently documented reasons for ROA events. Malignancy was present in 107 (71.3%) patients, with 47 (43.9%) having metastatic malignancy. ROA was attributed to a modifiable cause in 75 (50.0%) patients. In 26 (17.3%) patients, there were no identifiable reasons for failure, and these were labeled as ACF. After a recurrent VTE event, 92 (61.3%) patients were transitioned to an alternative anticoagulant, with the most frequent being enoxaparin. However, 27 (18.0%) patients remained on the same medication at an increased dose, and 27 (18.0%) did not have any change in therapy. There were 4 (2.7%) patients with unclear management strategies. Conclusion:ROA can affect 3% of patients with VTE. Nearly half of ROA events are preventable with careful review of medications and patient characteristics. When not modifiable, the most used strategy for managing patients with ACF is to transition to another anticoagulant, usually enoxaparin. Our practice strategy for evaluating and managing ROA is outlined.
Background:Circulating cell-free DNA levels increase in the circulation during inflammation and thrombosis. During immunothrombosis, neutrophil extracellular traps provide long DNA fibers with prothrombotic properties. Von Willebrand factor (VWF) has been reported to interact with DNA via its A1 domain; however, the consequences of this interaction and its regulation by the adjacent A2 domain remain poorly understood. Objectives:Using recombinant VWF domain constructs, we aimed to characterize VWF-A1-DNA interactions and to determine whether the VWF-A2 domain modulates A1-DNA binding and its impact on platelet adhesion under flow. Methods:VWF-A1-DNA interactions were examined using atomic force microscopy, magnetic tweezers, ELISAs, and microfluidic flow assays. Both recombinant A1 and mammalian-expressed A1A2 constructs were employed to assess physiological relevance. Results:VWF-A1 bound to DNA and induced concentration-dependent DNA compaction. DNA binding to VWF-A1 significantly impaired platelet adhesion under flow conditions. In contrast, the A2 domain inhibited VWF-A1-DNA binding, as shown using both isolated A2 and A1A2 constructs, and mitigated DNA's inhibitory effect on A1-mediated platelet adhesion. Conclusion:These findings suggest that, within recombinant VWF domain constructs, VWF-A1 compacts DNA and that the A2 domain negatively regulates A1-DNA interactions while preserving A1-mediated platelet binding under flow. Although further validation in native multimeric VWF and physiologically relevant models is required, these results provide new insights into how the A2 domain differentially regulates VWF-A1 interactions with DNA and platelets.
Background Altered fibrin clot architecture is a distinct signature in cardiovascular diseases. To determine the origin and importance of these alterations, a fundamental understanding of normal plasma clotting mechanisms is essential. While biochemical and structural aspects of fibrin formation are individually well documented, their mechanistic link lacks a quantitative description. Objectives This study addresses two questions: How does fibrin architecture vary with [TF] in normal plasma, and can a simple mechanistic relationship between fibrin structure and thrombin generation be extracted? Methods The structuring of clots formed in TF-triggered normal pooled plasma and IIa-triggered fibrinogen were compared by varying the triggers concentrations. Architecture was quantified using confocal microscopy (pore size) and fibrinography (nanostructure). Thrombin kinetics were monitored using thrombinography. Results Although purified and plasma clots appeared morphologically identical, their ultrastructural parameters showed fundamentally different sensitivities to trigger concentrations. In purified systems, a 100-fold [IIa] increase induced a 30-fold decrease in protofibril number (Nfinal) and a 5-fold change in pore size. Conversely, plasma clots exhibited remarkable robustness: a 40-fold increase in [TF] resulted in only a 2-fold change in Nfinal, with little pore size evolution. Crucially, by applying inverted purified data to plasma structural data, we predicted thrombin concentrations during the exponential growth phase of plasma CAT curves. Conclusions Our findings show that the unique functional shape of the thrombin burst, rather than the trigger concentration, governs plasma fibrin architecture. This inherent robustness supports the existence of a 'normal' clot structure and the potential of fibrinography as a robust structural biomarker candidate.
Background:Inappropriate dosing occurs in up to 20% of direct oral anticoagulant (DOAC) prescriptions and is associated with bleeding, hospitalization, and death. Understanding why DOAC dosing errors arise after the initial prescribing period and how clinicians decide to adjust doses may help improve future antithrombotic stewardship efforts. Objectives:This study aimed to describe responses by clinicians to asynchronous electronic health record notifications regarding inappropriate DOAC prescriptions that develop after the initial prescribing period. Methods:As part of a larger randomized trial to improve evidence-based DOAC prescribing, we conducted a manual chart review to assess reasons for inappropriate DOAC prescriptions, clinician response, and reasons for not changing DOAC prescriptions. Results:Most apixaban prescribing errors occurred in patients aged 80 years or older (87.8%). Overall, dose changes occurred after 32.7% of notifications. Notifications to increase the dose of apixaban resulted in fewer dose changes (16.8%) than those to reduce the dose of apixaban (52%), increase the dose of rivaroxaban (43.2%), or decrease the dose of rivaroxaban (43.6%). The original DOAC prescribers were less likely than pharmacists to document a reason for not making a dose change (46.1% vs 90.5%). Renal function, weight, and bleeding-related reasons were commonly cited as reasons not to make a dose change. Conclusion:Various patient factors differentially influenced the likelihood that a clinician would change an inappropriate DOAC prescription. These factors can be used to tailor electronic health record-based notifications to reduce the burden on prescribers while maximizing the impact on patient safety by increasing evidence-based prescribing.
Background Early prophylaxis reduces the risk of joint damage in children with haemophilia A (CwHA). Long-term comparative data on bleeding outcomes and joint health in CwHA under primary prophylaxis (PP) and secondary prophylaxis (SP) remain limited. Methods This prospective cohort study enrolled previously untreated or minimally treated (<5 exposure days [ED]) CwHA (factor VIII <0.02 IU/mL). Patients were followed until 75 EDs or inhibitor development. Annual bleeding rate (ABR) and annual joint bleeding rate (AjBR) were evaluated before and after prophylaxis initiation. Joint status was assessed once, at median patient age of 8.4 years, using the Haemophilia Early Arthropathy Detection with Ultrasound and the Haemophilia Joint Health Score. Results Forty-three children were included (PP, n=23; SP, n=20). Children receiving PP were younger at diagnosis and prophylaxis initiation. Before prophylaxis initiation, PP was associated with higher median ABR (8.5 vs 5.3; p=0.014) and lower AjBR (0.6 vs 2.0; p=0.006) vs SP, respectively. After prophylaxis initiation, ABR declined in both groups, with a greater reduction in SP (p=0.016), while AjBR was comparable between the groups. Multivariable analysis showed that earlier diagnosis of HA and younger age at first joint bleeding were associated with a more severe bleeding phenotype. Ultrasound of 252 joints showed mild synovial hypertrophy in 35.7%; bone damage was uncommon and observed exclusively in SP. Conclusions In this study, CwHA receiving PP appeared to have a more severe bleeding phenotype compared with those on SP. However, this requires confirmation in future studies. Long-term joint outcomes were generally mild.
Background Emicizumab has been in clinical use for less than 10 years. Real-world experience is still needed to guide its use for optimal safety, efficacy, and resource efficiency. Recent data suggest that conventional weight-based dosing may be excessive for many patients. More data on the correlation between bleeding events and plasma emicizumab levels will help to clarify optimal dosing regimens. Methods We conducted an observational study in a large cohort of adult and pediatric patients with severe hemophilia A without inhibitors to determine the rate of bleeding events during emicizumab prophylaxis, and the correlation between plasma emicizumab levels and bleeding rates. Results Among 73 patients followed for a mean of 69.0 weeks, 47.9% had zero treated bleeds and 80.8% had zero spontaneous bleeds. The mean and median annualized treated bleed rates (ABR) were 1.12 and 0.57, and annualized joint bleed rates (AJBR) 0.51 and 0. Mean FVIII concentrate used to treat bleeds was 63.0 IU/kg/year per patient (median 23.1). Steady-state plasma emicizumab levels did not correlate with total or spontaneous ABR and AJBR, or with patient age at enrolment, body weight, or BMI. Dose capping at 150 mg/week did not result in lower emicizumab levels in 9 patients with body weight >100 kg. Conclusions Emicizumab provided highly effective prophylaxis in severe hemophilia A patients across the age spectrum. The lack of correlation of bleed outcomes with plasma emicizumab concentration suggests that minimal effective drug concentrations should be reconsidered. Studies to rationalize and personalize therapy should be explored.
Objective To characterize the clinical features, maternal outcomes, and neonatal outcomes across different strata of platelet counts in pregnant women with severe thrombocytopenia. Design Retrospective cohort study. Setting A single tertiary care center in South China. Participants 175 pregnant women with a platelet count ≤30 × 109/L. Methods We conducted a retrospective analysis of 175 cases over an 8-year period. Etiologies, maternal characteristics, and maternal-neonatal outcomes were compared across three platelet count strata: ≤10, >10 to ≤20×109/L, and >20 to ≤30×109/L. Statistical analyses included t-tests, the Kruskal-Wallis H test, chi-square tests, and ANOVA. Main Outcome Measures Maternal and neonatal outcomes. Results Primary immune thrombocytopenia (ITP) was the predominant etiology (62.3%, 109/175). The incidence of postpartum hemorrhage was highest in the ≤10×109/L group (12.5%), compared with the >10 to ≤20×109/L (4.8%) and >20 to ≤30×109/L (3.6%) groups. Preterm birth was also most common in the ≤10×109/L group (58.9%), versus the >10 to ≤20×109/L (27.0%) and >20 to ≤30×109/L (23.2%) groups. The rates of neonatal thrombocytopenia were 33.9%, 23.8%, and 14.3% in the three groups, respectively. The overall rate of neonatal intracranial hemorrhage was 3.4% (6/175). Conclusions Primary ITP is the leading cause of severe thrombocytopenia in pregnancy. A lower platelet count, particularly ≤10×109/L, is associated with an increased risk of preterm birth and postpartum hemorrhage. Neonatal intracranial hemorrhage is a rare complication. Severe thrombocytopenia may correlate with preterm delivery but no statistical difference in the incidence of neonatal thrombocytopenia was observed across the maternal platelet strata.Funding: This work was supported by the Guangzhou Fundamental Research Project Jointly Funded by School (Institution) (High-Level University) [No. 202102010131].
