Showing papers in "Balkan Medical Journal in 2022"

Must-have Qualities of Clinical Research on Artificial Intelligence and Machine Learning

Abstract: In the field of computer science, known as artificial intelligence, algorithms imitate reasoning tasks that are typically performed by humans. The techniques that allow machines to learn and get better at tasks such as recognition and prediction, which form the basis of clinical practice, are referred to as machine learning, which is a subfield of artificial intelligence. The number of artificial intelligence-and machine learnings-related publications in clinical journals has grown exponentially, driven by recent developments in computation and the accessibility of simple tools. However, clinicians are often not included in data science teams, which may limit the clinical relevance, explanability, workflow compatibility, and quality improvement of artificial intelligence solutions. Thus, this results in the language barrier between clinicians and artificial intelligence developers. Healthcare practitioners sometimes lack a basic understanding of artificial intelligence research because the approach is difficult for non-specialists to understand. Furthermore, many editors and reviewers of medical publications might not be familiar with the fundamental ideas behind these technologies, which may prevent journals from publishing high-quality artificial intelligence studies or, worse still, could allow for the publication of low-quality works. In this review, we aim to improve readers’ artificial intelligence literacy and critical thinking. As a result, we concentrated on what we consider the 10 most important qualities of artificial intelligence research: valid scientific purpose, high-quality data set, robust reference standard, robust input, no information leakage, optimal bias-variance tradeoff, proper model evaluation, proven clinical utility, transparent reporting, and open science. Before designing a study, one should have defined a sound scientific purpose. Then, it should be backed by a high-quality data set, robust input, and a solid reference standard. The artificial intelligence development pipeline should prevent information leakage. For the models, optimal bias-variance tradeoff should be achieved, and generalizability assessment must be adequately performed. The clinical value of the final models must also be established. After the study, thought should be given to transparency in publishing the process and results as well as open science for sharing data, code, and models. We hope this work may improve the artificial intelligence literacy and mindset of the readers.

Clinical and Genetic Survey for Charcot-Marie-Tooth Neuropathy Based on the Findings in Turkey, a Country with a High Rate of Consanguineous Marriages

Abstract: Inherited peripheral neuropathies (IPNs) are a heterogeneous group of disorders of the peripheral nervous system. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease, which constitutes an interesting research focus for neurologists and human geneticists alike. Most cases with CMT manifest with a slowly progressive symmetric distal weakness in the lower limbs that usually begin in the first to the third decade that causes atrophy and foot drop. Deep tendon reflexes are usually absent or reduced. A proven and efficient CMT therapy is yet available and may require different molecules and approaches due to its high clinical and genetic heterogeneity. Several ongoing clinical trials are promising and are mostly focused on the most frequent form, namely CMT Type 1A (CMT1A). Approximately, 60% of patients with CMT can be genetically diagnosed using the most advanced mutation screening techniques that cover approximately 100 IPN genes. Turkey has a 25% consanguineous marriage rate, and nearly 60% genetic diagnosis rate can still be reached when SH3 Domain and Tetratricopeptide Repeat Domain 2, Ganglioside-induced Differentiation-Associated Protein 1, and Histidine Triad Nucleotide Binding Protein 1 genes are also screened along with Myelin Protein Zero and Gap Junction Protein Beta-1 after exclusion of CMT1A duplication in families with probable recessive inheritance. The genetic diagnosis rates in different regions worldwide implicate that the most recent sequencing techniques should be more commonly used for both diagnosis and identification of further CMT genes. Herein, presented our 30 years of experience on genetic diagnosis and management strategies in CMT neuropathy in Turkey and review clinical and genetic features of this group of disorders.

The Clinicopathological Characteristics of Pure and Mixed Invasive Micropapillary Breast Carcinomas: A Single Center Experience

Abstract: Background: Invasive micropapillary carcinoma (IMPC) is a rare tumor of the breast. IMPC can be classified as a pure or mixed type based on the extent of micropapillary differentiation. Aims: To evaluate the prognostic importance of the IMPC component in breast cancer through retrospective comparison of the clinicopathological characteristics and clinical outcomes of pure and mixed IMPC patients. Study Design: The data of 147 (2.2%) patients with IMPC among 6648 patients histopathologically diagnosed with invasive breast cancer between January 2000-2022 were retrospectively reviewed. The patients were assigned to two groups: pure IMPC and mixed IMPC. Methods: The clinicopathological features such as age at diagnosis, histological type, grade, size, and components of mixed carcinoma, the numbers of metastatic lymph nodes, presence of lymph vascular invasion, hormone receptor, and the Her-2 status of the tumor, T, N, M stages, and the survival rates were reviewed. The clinicopathologic features, patterns of failures, and survival rates were coded and compared between pure and mixed IMPC patients. Results: A total of 45 patients (30.6%) had pure and 102 patients (69.4%) had mixed IMPC. The median follow-up time was 46 months (3-178). The progesterone receptor positivity rate was significantly lower in the pure group than in the mixed group (66.7% vs. 83.3%, p: 0.024). In the pure and mixed groups, respectively, the 5-year overall survival was 90% and 91% (p: 0.839); progression-free survival was 70% and 77% (p: 0.537); locoregional recurrence-free survival was 86% and 95% (p: 0.043); 5-year distant metastasis-free survival was 88% and 83% (p: 0.066), and the locoregional recurrence rate was 10.3% and 2% (p: 0.052). Conclusion: Compared to the mixed IMPC, pure IMPC appears to have a more aggressive behavior with lower locoregional recurrence-free survival and more locoregional recurrences. This may be due to the low progesterone receptor positivity rate.

Biomimetic Nanosystems for the Synergistic Delivery of miR-144/451a for Oral Squamous Cell Carcinoma

Abstract: Background: The miR-144/451a cluster acts as a tumor suppressor in various tumors by synergistically inhibiting the proliferation, migration, and invasion of oral squamous cell carcinoma (OSCC). Aims: To achieve the synergistic delivery of the miR-144/451a cluster for OSCC treatment by constructing chitosan nanoparticles (CAs) camouflaged with macrophage membranes. Study Design: A cell-culture study. Methods: CAs were prepared using the ionic cross-linking method, and biomimetic nanoparticles coloaded with the miR-144/451a cluster (miR-144-source of macrophage-derived exosomes [MEXO]/CA-miR-451a) were prepared using the uptake–efflux method. The MEXO was detected by a bicinchoninic acid assay. The as-prepared biomimetic nanoparticles were then characterized to determine their protective effects on microRNAs (miRNAs). Moreover, the influence of the miR-144-MEXO/CA-miR-451a nanoparticles on the proliferation, migration, and invasion of OSCCs was evaluated. Finally, the effects of the biomimetic system on the expression of calcium-binding protein 39 (CAB39) and migration inhibitory factor (MIF) were detected using the real-time polymerase chain reaction and Western blot. Results: After coating the CAs with MEXO, their particle size increased from 113.1 ± 3.4 nm to 143.2 ± 14 nm, and their surface potential decreased from 26.34 ± 0.4 mV to −10.3 ± 1.6 mV. The expression of the MEXO marker protein was also observed on the biomimetic nanoparticles’ surface. The system can protect miRNAs from RNase A degradation. Compared with the CAs cotransfected with free miR-144/451a cluster, CAs that are coloaded with miR-144-MEXO/CA-miR-451a nanoparticles substantially reduced the viability (p < 0.001), migration (p = 0.023), and invasion (p = 0.004) of OSCC. These findings revealed the successful construction of biomimetic nanoparticles coloaded with the miR-144/451a cluster. CAB39 and MIF expression in OSCC treated with miR-144-MEXO/CA-miR-451a nanoparticles have significantly decreased compared with the miR-144/451a group (p < 0.05). Thus, the nanoparticles can effectively improve the inhibitory effects of the miR-144/451a cluster on OSCC. Conclusion: This study provided a new idea for the application of gene cotransfection to tumor treatment.

Podcasting as a Learning Tool in Medical Education: Prior to and During the Pandemic Period

Abstract: Podcasting as a Learning Tool in Medical Education: Before and During the Pandemic Period Podcasts have seen significant growth as a medium for medical education over the last 15 years. The COVID-19 pandemic altered the way in which medical education is delivered to learners, including medical students, resident physicians, fellows, and practicing clinicians in the form of continuing medical education. A literature search using Google Scholar, PubMed, and NCBI was conducted to analyze and discuss how podcasts are utilized in medical education-both before and during the pandemic-and how this form of asynchronous education may influence clinical decision-making and patient outcomes. Finally, this review discusses how learners’ habits while using podcasts may affect the way in which the information is internalized and the future of using podcasts to supplement medical education.

Neuroinflammation in Parkinson’s Disease and its Treatment Opportunities

Abstract: Parkinson’s disease (PD) is a complex, chronic, and progressive neurodegenerative disease that is characterized by irreversible dopaminergic neuronal loss in the substantia nigra. Alpha-synuclein is normally a synaptic protein that plays a key role in PD due to pathological accumulation as oligomers or fibrils. Clustered alpha-synuclein binds to the Toll-like receptors and activates the microglia, which initiates a process that continues with pro-inflammatory cytokine production and secretion. Pro-inflammatory cytokine overproduction and secretion induce cell death and accelerate PD progression. Microglia are found in a resting state in physiological conditions. Microglia became activated by stimulating Toll-like receptors on it under pathological conditions, such as alpha-synuclein aggregation, environmental toxins, or oxidative stress. The interaction between Toll-like receptors and its downstream pathway triggers an activation series, leads to nuclear factor-kappa B activation, initiates the inflammasome formation, and increases cytokine levels. This consecutive inflammatory process leads to dopaminergic cell damage and cell death. Microglia become overactive in response to chronic inflammation, which is observed in PD and causes excessive cytotoxic factor production, such as reactive oxidase, nitric oxide, and tumor necrosis factor-alpha. This inflammatory process contributes to the exacerbation of pathology by triggering neuronal damage or death. Current treatments, such as dopaminergic agonists, anticholinergics, or monoamine oxidase inhibitors alleviate PD symptoms, but they can not stop the disease progression. Finding a radical treatment option or stopping the progression is essential when considering that PD is the second most reported neurodegenerative disorder. Many cytokines are released during inflammation, and they can start the phagocytic process, which caused the degradation of infected cells along with healthy ones. Therefore, targeting the pathological mechanisms, such as microglial activation, mitochondrial dysfunction, and oxidative stress, that should be involved in the treatment program is important. Neuroinflammation is one of the key factors involved in PD pathogenesis as well as alpha-synuclein accumulation, synaptic dysfunction, or dopaminergic neuronal loss, especially in the substantia nigra. Therefore, evaluating the therapeutic efficiency of the mechanisms is important, such as microglial activation and nuclear factor-kappa B pathway or inflammasome formation inhibition, and cytokine release interruption against neuroinflammation may create new treatment possibilities for PD. This study examined the pathological relation between PD and neuroinflammation, and targeting neuroinflammation as an opportunity for PD treatments, such as Toll-like receptor antagonists, NOD-like receptor family pyrin domain containing-3 inflammasome inhibitors, cytokine inhibitors, peroxisome proliferator-activated receptor-γ agonists, reactive oxygen species inhibitors, and nonsteroidal anti-inflammatory drugs.

Anti-SARS-CoV-2 IgG and Neutralizing Antibody Levels in Patients with Past COVID-19 Infection: A Longitudinal Study

Abstract: Background: Monitoring the longevity of immunoglobulin G (IgG) responses following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections is vital to understanding the role of antibodies in preventing infection. Aims: To determine the quantitative IgG responses specific to the Spike-S1 (S1) receptor-binding domain (S1/RBD) region of the virus in serum samples taken between 4 weeks and 7 months after polymerase chain reaction (PCR) positivity in patients who are diagnosed with coronavirus disease-2019 (COVID-19). Study Design: A longitudinal study. Methods: This study included 113 patients with a clinical and molecular diagnosis of COVID-19. The first and second serum samples were taken 1 and 7 months, respectively, after the PCR positivity. S1/RBD-specific IgG antibody response was assayed using anti-SARS-CoV- 2 QuantiVac ELISA (IgG) kit (Euroimmun, Lübeck, Germany). The neutralizing antibodies were investigated in 57 patients whose IgG test results were above the cut-off value. Results: In 57 patients with SARS-CoV-2 IgG, the anti-SARS-CoV-2 IgG quantitative antibody levels significantly decreased after 7 months (Z = −2.197, p = 0.028). A correlation was detected between the anti-SARS-CoV-2 IgG and nAb percent inhibition (IH%) levels detected in 1 month (rs = 0.496, p < 0.001), but without significant correlation in serum samples taken on 7 months. The nAb IH% levels of the first and second were compared for COVID-19 severity and revealed no statistical difference (p = 0.256). In the second serum sample, the nAb IH%s of patients with moderate COVID-19 showed a statistically significant difference from patients with mild COVID-19 (p = 0.018), but without significant differences between severe and moderate or mild COVID-19. Conclusion: SARS-CoV-2 quantitative IgG antibody titers are significantly reduced at long-term follow-up (> 6 months). Due to the limited information on seroconversion, comprehensive studies should be conducted for long-term follow-up of the immune response against SARS-CoV-2.

Efficacy of Noble Metal–alloy Endotracheal Tubes in Ventilator-associated Pneumonia Prevention: a Randomized Clinical Trial

Abstract: Background: Endotracheal tube (ETT) is an important risk factor for the development of Ventilator-associated pneumonia (VAP), as it acts as a reservoir for infectious microorganisms and bypasses the host’s defenses. One of the preventive measures for VAP is endotracheal tube composition. It has been reported that biofilm formation is reduced by using ETTs coated with pure silver or silver compounds. However, noble metal-alloy ETTs have not been adequately studied. Aims: To evaluate the efficacy of noble metal alloy ETT (coated Bactiguard Infection Protection ETTs) in preventing VAP compared to standard non-coated ETTs in patients requiring ≥ 48 hours of mechanical ventilation and presenting for coma due to drug intoxication. Study Design: Randomized controlled study. Methods: Participants were randomized using sealed envelopes with a concealed 1:1 allocation to either the intervention group or the control group. The intervention group used a noble metal–alloy ETT, while the control group received standard ETT. The primary outcomes were the incidence of VAP (per ventilated patients) and the duration of mechanical ventilation. Results: Initially, a total of 188 patients were assessed for eligibility, and the final allocation group consisted of 180 patients, who were subsequently randomized into the intervention group (n = 97) and control group (n = 83). The incidence of VAP in the intervention and control groups was 27.83% and 43.16% (P = 0.03), and the VAP ratio per 1000 ventilation days was 51.26/1000 and 83.38/1000 (P = 0.01), respectively. The mean durations of mechanical ventilation were 3.2 ± 0.78 in the intervention group and 5.03 ± 1.88 in the control group (P = 0.22). There was no statistically significant difference between groups in terms of mortality and duration of hospital stay. Conclusion: Noble metal-alloy ETT reduces the incidence of VAP, ventilation days, and ICU stay for patients in mechanical ventilation.

Hemophagocytic Lymphohistiocytosis

Abstract: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive life-threatening disease that consists of uncontrolled activated lymphocytes and macrophages that secrete excessive cytokines. Symptoms and laboratory findings of HLH include prolonged fever, cytopenia, hepatosplenomegaly, liver dysfunction, hypertriglyceridemia, hyperferritinemia, increased soluble interleukin-2 receptor, low fibrinogen, and neurological problems. HLH has two forms: primary (familial autosomal recessive) or secondary (related to infections, malignancy, autoimmune and metabolic disorders, transplantations, chimeric antigen receptor T-cell therapies, etc.) form. As underlying conditions in HLH varied, clinical findings are nonspecific and disease diagnosis is challenging. Furthermore, patients diagnosed with primary HLH can have a secondary triggering agent, such as infection. Thus, there is no clear-cut distinction between these two forms. Abnormal immune response and a low number or absence of natural killer cells and cytotoxic T-lymphocytes are hallmarks of HLH. Despite the early and aggressive treatment, HLH is a deadly disease. Urgent immunosuppressive therapy is necessary to control hyperinflammation. Hematopoietic stem cell transplantation is a curative treatment in familial forms. Targeted therapy with emapalumab was also recently reported to be effective.

Cytomegalovirus Reactivation in Critically-ill COVID-19 Patients

Abstract: COVID-19 is an ongoing global pandemic that causes significant morbidity and mortality. Although severe pneumonia and acute respiratory distress syndrome (ARDS) are seen in the foreground, it causes widespread diseases, involving multiple organ systems in severe cases. Various immunosuppressive agents, such as corticosteroids and interleukin antagonists, are used in the treatment of COVID-19. Thus, immune paralysis due to severe COVID-19, sepsis, and drugs used for its treatment cause secondary bacterial/ fungal infections and viral reactivation.1

The Predictive Values of Respiratory Rate Oxygenation Index and Chest Computed Tomography Severity Score for High-Flow Nasal Oxygen Failure in Critically Ill Patients with Coronavirus Disease-2019

Abstract: Background: The prediction of high-flow nasal oxygen (HFNO) failure in patients with coronavirus disease-2019 (COVID-19) having acute respiratory failure (ARF) may prevent delayed intubation and decrease mortality. Aims: To define the related risk factors to HFNO failure and hospital mortality. Study Design: Retrospective cohort study. Methods: To this study, 85 critically ill patients (≥18 years) with COVID-19 related acute kidney injury who were treated with HFNO were enrolled. Treatment success was defined as the de-escalation of the oxygenation support to the conventional oxygen therapies. HFNO therapy failure was determined as the need for invasive mechanical ventilation or death. The patients were divided into HFNO-failure (HFNO-F) and HFNO-success (HFNO-S) groups. Electronic medical records and laboratory data were screened for all patients. Respiratory rate oxygenation (ROX) index on the first hour and chest computed tomography (CT) severity score were calculated. Factors related to HFNO therapy failure and mortality were defined. Results: This study assessed 85 patients (median age 67 years, 69.4% male) who were divided into two groups as HFNO success (n = 33) and HFNO failure (n = 52). The respiratory rate oxygenation (ROX) was measured at 1 hour and the computed tomography (CT) score indicated HFNO failure and intubation, with an area under the receiver operating characteristic of 0.695 for the ROX index and 0.628 for the CT score. A ROX index of <3.81 and a CT score of >15 in the first hour of therapy were the predictors of HFNO failure and intubation. Age, Acute Physiology and Chronic Health Evaluation II score, arterial blood gas findings “(i.e., partial pressure of oxygen [PaO2], PaO2 [fraction of inspired oxygen]/SO2 [oxygen saturation] ratio)”, and D-dimer levels were also associated with HFNO failure; however, based on logistic regression analysis, a calculated ROX on the first hour of therapy of <3.81 (odds ratio [OR] = 4.78, 95% confidence interval [CI] = 1.75–13.02, P = 0.001) and a chest CT score of >15 (OR = 2.83, 95% CI = 1.01–7.88, P = <0.001) were the only independent risk factors. In logistic regression analysis, a ROX calculated on the first hour of therapy of <3.81 (OR = 4.78, [95% CI = 1.75–13.02], P = 0.001) and a chest CT score of >15 (OR 2.83, 95% CI = 1.01–7.88, P = <0.001) were the independent risk factors for the HFNO failure. The intensive care unit and hospital mortality rates were 80.2% and 82.7%, respectively, in the HFNO failure group. Conclusion: The early prediction of HFNO therapy failure is essential considering the high mortality rate in patients with HFNO therapy failure. Using the ROX index and the chest CT severity score combined with the other clinical parameters may reduce mortality. Additionally, multi-centre observational studies are needed to define the predictive value of ROX and chest CT score not only for COVID-19 but also other causes of ARF.

COL3A1 Overexpression Associates with Poor Prognosis and Cisplatin Resistance in Lung Cancer

Abstract: Background: Collagen type III alpha 1 chain (COL3A1) is reported to mediate drug resistance in various cancers, and public database analysis indicated its overexpression in lung cancer. Aims: To investigate the effects of COL3A1 on modulating cisplatin (DDP) resistance in lung carcinoma. Study Design: A cell study. Methods: Gene Expression Omnibus datasets were used to determine the differentially expressed genes between H460 and H460/DDP cell lines using bioinformatics analysis. COL3A1 expression and its clinical value in lung cancer prognosis were analyzed using GEPIA and UALCAN databases. Its roles in modulating the growth, viability, apoptosis, and drug resistance were also assessed in vitro. Results: In H460/DDP cells, the CLO3A1 was among the up-regulated genes compared to H460 cells.COL3A1 overexpression and its association with poor survival in patients with adenocarcinoma were detected by public database analysis. In A549 and H1299 cells, COL3A1 overexpression was associated with increased cell growth and clone formation but decreased cell apoptosis, whereas its reduced expression led to decreased cell growth and clone formation and increased cell apoptosis. Conclusion: COL3A1 is upregulated in lung cancer cells with DDP resistance, and its downregulation sensitizes the cells to DDP.

Unilateral Axillary Lymphadenopathy after the Inactivated SARS-COV-2 (CoronaVac) Vaccine: Ultrasonographic Imaging

Abstract: Background: Currently, unilateral clinical and subclinical axillary adenopathy cases associated with the Pfizer-BioNTech and Moderna vaccines are increasingly reported. However, only one study on axillary adenopathy due to the CoronaVac vaccine is published. Aims: To present the incidence, severity, and ultrasonographic findings of axillary adenopathy that developed in healthcare professionals in Turkey after they were vaccinated with CoronaVac against coronavirus disease-19. Study Design: A prospective study. Methods: In Turkey, the first dose of the CoronaVac vaccine for coronavirus disease-19 was administered to healthcare professionals on January 14, 2021, and the second dose on February 11, 2021. This study covered the period from January 21, 2021 (1 week after the first dose), and April 15, 2021 (9 weeks after the second dose). Individuals who had a history of COVID-19 more than 3 weeks after vaccine doses, systemic disease, and diagnosis and treatment history of breast cancer were excluded. The axillary lymph nodes of the vaccinated and contralateral arms were evaluated in 101 volunteer healthcare professionals using axillary ultrasonography. Results: A significant difference was found in the cortical thicknesses of the lymph nodes between the vaccinated and contralateral axilla after both the first (*p < 0.01) and second (*p < 0.01) doses. Accordingly, the rates of subclinical lymphatic hyperplasia on the vaccinated side were 25.7% (n = 26/101) after the first and 31.1% (n = 28/90) after the second dose. Lymph nodes with pathological appearance based on a reduced echogenic hilum with marked cortical thickening were found only in 2.2%. Among the 39 cases in which antibodies (immunoglobulin G and immunoglobulin M) were measured, the antibody level was classified as <10 and ≥10. No statistically significant difference was found in the cortical thickness of the axillary lymph nodes between patients with high antibody levels (≥10) and those with low antibody levels (<10) (p > 0.05). Conclusion: In this study, clinical signs of axillary lymph node hyperplasia were not detected after vaccination with CoronaVac. Mild and diffuse thickening of the CoronaVac vaccine-induced lymph nodes was more common than pathological and palpable lymph nodes.

A Challenging Diagnosis: A Case of Multisystem Inflammatory Syndrome Following COVID-19 Vaccination

Abstract: AOSD was differentials differential , the presence of proteinuria and pulmonary edema due to cardiac failure were atypical. Moreover, macrophage activation syndrome was based on normal BME findings. the of vaccinated patients undergoing vaccination, clinical identified among them which is termed as MIS-V in nomenclature. Based on limited experiences, the sole or combined administration of steroids, intravenous immunoglobulin, and IL-1 inhibitors might be beneficial in controlling systemic inflammation. In all clinicians should be cognizant of this novel clinical entity and its importance, highlighting the need for an extensive investigation.

Eltrombopag for the Treatment of Poor Graft Function Following Haematopoietic Cell Transplantation: Real-Life Data

Abstract: Background: Eltrombopag has an off-label indication for haematopoietic cell transplantation in patients experiencing delayed thrombocyte recovery and/or thrombocytopaenia. Aims: To present our centre’s experience of using this agent not only for post- haematopoietic cell transplantation thrombocytopaenia but also for poor graft functioning in the post-haematopoietic cell transplantation setting. Study Design: Retrospective cross-sectional study. Methods: Thirty-nine patients who had persistent cytopaenia following haematopoietic cell transplantation and treated with eltrombopag at our centre between October 2011 and December 2021 were retrospectively identified. During this period, 9 (23.1%) and 30 (76.9%) patients who underwent allogeneic transplantations, respectively, received eltrombopag. Results: The female-to-male ratio was 12:27, and the median transplant age was 49 (18-70) years. Eight (20.5%) patients had isolated thrombocytopaenia, 19 (49.4%) had bi-lineage cytopaenia and 12 (30.1%) had pancytopaenia. Patients received a median of 50 mg/day (25-150 mg/day) of eltrombopagfor a median duration of 82 (24-386) days. Nine (23.1%) patients had autologous haematopoietic cell transplantation, and 30 (76.9%) had allogeneic haematopoietic cell transplantation (14 unrelated, 9 sibling and 7 haploidentical). The median donor age was 32 (20-67) years. The median follow-up was 16.4 (1.8-84.3) months. The median pre-treatment platelet count was 11x109/l (1-23), which increased to 41x109/l (6-150). The median platelet count increment was 29.5x109/l (p = 0.001). The pre-treatment median neutrophil count was 1.19x109/l (0.39-5.1), which increased to 2.35 x109/l (0.1-5.33) (p = 0.05), and the pre-treatment median haemoglobin was 8.3 (6.2-14) g/dl, which increased to 10 (6.2-14) g/dl (p = 0.001) with eltrombopag. No eltrombopag-related hepatotoxicity occurred; however, 1 (2.6%) patient failed to continue treatment because of two consecutive episodes of deep venous thrombosis. Six (15.4%) patients were unresponsive to eltrombopag and dependent on blood product transfusions. After a median time of 82 days, 61.5% of the patients discontinued eltrombopag successfully. Conclusion: The results confirmed that eltrombopag could provide a rapid, sustained response in patients with poor graft functioning after haematopoietic cell transplantation. This finding is essential given the high rate of non-relapse mortality caused by poor graft functioning after haematopoietic cell transplantation.

Preoperative Risk Factors for Predicting Postoperative Human Serum Albumin Infusion after Hip Fracture Surgery: Development and Validation of a Nomogram

Abstract: Background: As one of the adverse events after hip fracture surgery, hypoalbuminemia is usually treated using human serum albumin infusion. However, the application of human serum albumin may cause complications such as postsurgical infection and increased mortality. Aims: To examine the preoperative risk factors of human serum albumin infusion after hip fracture surgery, establish a nomogram prediction model, and verify its accuracy. Study Design: A retrospective cross-sectional study. Methods: Eligible patients who underwent hip fracture surgery were divided into the infusion and non-infusion groups according to whether human serum albumin was infused or not. All patients were divided randomly into a training set and a testing set in line with the ratio of 7:3. In the training set, independent risk factors of postoperative human serum albumin infusion were determined by univariate logistic regression analysis, LASSO regression, and multivariate logistic regression analysis. Then, a nomogram model was established. Furthermore, the receiver operating characteristic curve and calibration curve were plotted, and decision curve analysis was performed for the training and testing sets to assess the predictability, discriminative ability, and clinical usefulness of the model. Results: This study included a total of 1,339 eligible patients, 141 of whom were injected with human serum albumin postoperatively. Altogether, the training set incorporated 939 patients, and the testing set included 400 patients. Multivariate logistic analysis indicated five independent risk factors, including chronic lung disease (odds ratio, 95% confidence interval, 2.618, 1.413-4.849, p = 0.002), (albumin; odds ratio, 95% confidence interval, 0.842, 0.787-0.900, p < 0.001), prothrombin time (odds ratio, 95% confidence interval, 1.252, 1.071-1.463, p = 0.005), red blood cells (odds ratio, 95% confidence interval, 0.370, 0.228-0.602, p < 0.001), and type of anesthesia (odds ratio, 95% confidence interval, 0.553, 0.327-0.937, p = 0.028). Fracture type, a clinically significant factor, was also considered. Finally, the nomogram model was built based on these seven predictors. The areas under the curve of the nomogram were 0.854 (95% confidence interval, 0.811-0.898) and 0.767 (95% confidence interval, 0.686-0.847) in the training and testing sets separately. As shown in the calibration curve, the predicted result was consistent with the observed one. The decision curve analysis indicated that the nomogram has good clinical value. Conclusion: Low preoperative serum albumin levels, low preoperative red blood cell counts, prolonged preoperative prothrombin time, history of chronic lung disease, and general anesthesia were independent risk factors for postoperative human serum albumin infusion. Besides, the fracture type, clinically significant factor, was also included. The nomogram that combined these six predictors could accurately predict the risk of postoperative human serum albumin infusion.

Inhibiting miR-182-3p Alleviates Gestational Diabetes Mellitus by Improving Insulin Resistance in Skeletal Muscle

Abstract: Background: Gestational diabetes mellitus (GDM) is one of the most common metabolic diseases occurring during pregnancy. MiR-182-3p participates in a variety of physiological processes such as cell proliferation, apoptosis, differentiation, and migration5, but its role in GDM is largely unknown. Aims: To investigate the relationship between miRNA-182-3p and GDM and explore a potential therapeutic strategy for GDM. Study Design: Animal experimentation. Methods: To evaluate the effect of miRNA182-3p in GDM, mice were separated as negative control (NC), miRNA-182-3p mimic or miRNA-182-3p inhibitor, and miRNAs were administered intraperitoneally. Additionally, miRNA-182-3p mimic or miRNA-182-3p inhibitor was transfected into C2C12 cells to evaluate glucose metabolism and insulin-related pathways. Results: The miR-182-3p mimic accelerated GDM, which was effectively reversed by the inhibitor in GDM mice (P = 0.005, miR- 182-3p inhibitor vs. mimic). Insulin receptor 1 (INSR1) was predicted to be the direct target gene of miR-182-3p using online tools. In addition, the miR-182-3p mimic inhibited INSR1 expression and insulin-related pathways in vivo and in vitro, which were all reversed by the miRNA82-3p inhibitor. Furthermore, the miR-182-3p mimic impaired glucose uptake and consumption by inhibiting translocation of glucose transporter type 4 (GLUT4) toward the C2C12 cell membrane (P = 0.007 vs. control), while the inhibitor accelerated these processes (P = 0.032 vs. control; P = 0.005, miRNA-182-3p inhibitor vs. mimic). Conclusion: Inhibiting miR-182-3p effectively alleviated the development of GDM through INSR1, suggesting a potential therapeutic strategy for GDM.

Is Seizure an Adverse Effect of Salbutamol in the Pediatric Population?

Abstract: Background: Although studies on epileptic seizures occurring during acute asthma attacks are limited, there is widespread belief among families and physicians that salbutamol causes seizures. Aims: To investigate whether salbutamol triggers seizures in patients with epilepsy and asthma. Study Design: A retrospective cohort study. Methods: Epilepsy and asthma in patients aged 2-18 years who were admitted to the pediatric emergency department because of asthma attacks between January 2016 and December 2016 in a university hospital were evaluated retrospectively. The inclusion criteria were age 2–18 years, previous diagnosis of epilepsy and asthma, and admission to the pediatric emergency department due to asthma attacks. Results: 276 medical records were evaluated. The seizure group had a longer period of diagnosis for epilepsy than the seizure absent group in the pediatric emergency department (5.4 years and 3.1, respectively). According to the logistic regression analysis, the duration of seizures in the emergency department, duration of asthma diagnosis, duration of epilepsy diagnosis, uncontrolled asthma, and severity of asthma attack in the pediatric emergency department have significantly increased the possibility of having a seizure during an asthma attack in our study population. Conclusion: This study shows that patients using salbutamol have a lower risk of epileptic seizures than those who do not use salbutamol. This result should be verified by studies containing a large number of patients.

Umbilical Cord-derived Mesenchymal Stem Cells with Surfactant Protein B Alleviates Inflammatory Response in Acute Respiratory Distress Syndrome by Regulating Macrophage Polarization

Abstract: Background: Acute respiratory distress syndrome (ARDS) is a severe disorder that is related to a high mortality. Mesenchymal stem cells (MSCs) have shown strong effects in relieving lung injury. Aims: To determine the role of umbilical cord-derived MSCs (UC-MSCs) together with surfactant protein B (SP-B) in ARDS. Study Design: Animal experimentation. Methods: Immunophenotypic characteristics of UC-MSCs were identified. BALB/c mice were intratracheally administrated with lipopolysaccharide (LPS) and received UC-MSCs or UC-MSCs transfected with SP-B (UC-MSCs-SP-B). Pathological changes and lung injury degrees after transplantation were assessed by histological and biochemical analyses. Inflammatory chemokine and cytokine production in the bronchoalveolar lavage fluid (BALF) was measured using enzyme-linked immunoassay. Flow cytometry was used to examine macrophage phenotypes and differentiation of T-helper 17 (Th17) and T-regulatory (Treg) in the BALF. Results: Our results showed that isolated UC-MSCs possessed multilineage differentiation potential. SP-B transfection into UC-MSCs strengthened the effects of UC-MSCs on lung function repair in LPS-induced ARDS. UC-MSCs and UC-MSCs-SP-B attenuated cellular infiltration. Additionally, UC-MSCs and UC-MSCs-SP-B inhibited the inflammatory response by promoting M2-like polarization, as well as reduced Th17 differentiation and promoted Treg differentiation. Conclusion: UC-MSCs in combination with SP-B, alleviates inflammatory reaction in ARDS by regulating macrophage polarization.

Antibiotic use and Influencing Factors Among Hospitalized Patients with COVID-19: A Multicenter Point-Prevalence Study from Turkey

Abstract: Background: Broad-spectrum empirical antimicrobials are frequently prescribed for patients with coronavirus disease 2019 (COVID-19) despite the lack of evidence for bacterial coinfection. Aims: We aimed to cross-sectionally determine the frequency of antibiotics use, type of antibiotics prescribed, and the factors influencing antibiotics use in hospitalized patients with COVID-19 confirmed by polymerase chain reaction. Study Design: The study was a national, multicenter, retrospective, and single-day point prevalence study. Methods: This was a national, multicenter, retrospective, and single-day point-prevalence study, conducted in the 24-h period between 00:00 and 24:00 on November 18, 2020, during the start of the second COVID-19 peak in Turkey. Results: A total of 1500 patients hospitalized with a diagnosis of COVID-19 were included in the study. The mean age ± standard deviation of the patients was 65.0 ± 15.5, and 56.2% (n = 843) of these patients were men. Of these hospitalized patients, 11.9% (n = 178) were undergoing invasive mechanical ventilation or ECMO. It was observed that 1118 (74.5%) patients were receiving antibiotics, of which 416 (37.2%) were prescribed a combination of antibiotics. In total, 71.2% of the patients had neither a clinical diagnosis nor microbiological evidence for prescribing antibiotics. In the multivariate logistic regression analysis, hospitalization in a state hospital (p < 0.001), requiring any supplemental oxygen (p = 0.005), presence of moderate/diffuse lung involvement (p < 0.001), C-reactive protein > 10 ULT coefficient (p < 0.001), lymphocyte count < 800 (p = 0.007), and clinical diagnosis and/or confirmation by culture (p < 0.001) were found to be independent factors associated with increased antibiotic use. Conclusion: The necessity of empirical antibiotics use in patients with COVID-19 should be reconsidered according to their clinical, imaging, and laboratory findings.

A Rare Cause of Acute Abdomen: Torsion of Subserous Uterine Fibroid in a Postmenopausal Woman

Abstract: Uterine fibroids, the most common tumors in reproductive-aged women, are found in 20%-30% of women aged ≥ 30 years.1 However, they rarely become symptomatic after menopause, and emergency operation is usually unnecessary.2 Herein, we report a rare case of uterine fibroid torsion in a 60-year-old postmenopausal woman. The patient presented to an emergency department with a history of intermittent diffuse lower abdominal pain that started 3 days earlier. Previously, she had no episodes of vomiting, diarrhea, or vaginal bleeding. Upon examination, she was afebrile and tachycardiac (103 beats/min) and had diffuse lower abdominal tenderness with peritoneal signs. Laboratory testing revealed a white blood cell count of 9.6 (normal 3.5-9.1) x 109/l and a C-reactive protein level of 117 (normal 0-3) mg/l. Peritonitis was suspected, and pelvic and abdominal contrast-enhanced computed tomography (CT) showed a mass cranial to the uterus with a dark fan sign but no sign of appendicitis or other bowel etiologies (Figure 1a-c). Emergency transvaginal ultrasonography revealed a pelvic mass suggestive of a uterine fibroid (Figure 1d). Pelvic magnetic resonance imaging also suggested a uterine fibroid (Figure 1e) and confirmed bilateral intact ovaries, excluding the possibility of ovarian torsion. Signs of peritonitis and imaging findings indicated uterine fibroid torsion. Interoperative examination confirmed the diagnosis of necrotic pedunculated subserous uterine fibroid twisted by 360° with slight bleeding (Figure 2a). Given the prominent intrapelvic inflammation and strong edematous change to the uterus, hysterectomy was avoided to minimize the risk of unnecessary complications due to heavy bleeding. Necrotic fibroid myomectomy was successfully performed, and no postoperative complications were observed. Histology confirmed a benign necrotic leiomyoma with no sign of malignancy (Figure 2b). 1Department of Obstetrics and Gynecology, Suwa Central Hospital, Nagano, Japan 2Department of Medical Education Studies, International Research Center for Medical Education, Graduate School of Medicine The University of Tokyo, Tokyo, Japan 3Department of Internal Medicine, Suwa Central Hospital, Chino, Nagano, Japan So Yamashita1 , Hirohisa Fujikawa2,3 , Toru Yoshizawa1 A Rare Cause of Acute Abdomen: Torsion of Subserous Uterine Fibroid in a Postmenopausal Woman

Serum Expression Levels of Certain miRNAs in Predicting Diagnosis, Prognosis, and Response to Chemotherapy in Malignant Pleural Mesothelioma

Abstract: Background: miRNAs are involved in tumor pathogenesis and can therefore be determined in the primary tumor, plasma and serum, and body fluids. As in various cancers, their role in the diagnosis, prognosis, and treatment of patients with malignant pleural mesothelioma (MPM) may be important. Aims: To analyze the predictive value of miR-16-5p, miR-29c-3p, miR-31-5p, miR-125a-5p, miR-320a, miR-484 and miR-532-5p expressions for diagnosis, prognosis and response to treatment in patients with MPM. Study Design: Prospective case-control study. Methods: In the first phase of the study, blood samples were collected from 101 MPM patients before chemotherapy and from 24 healthy donors (HDs). In the second phase, the blood samples were collected from 74 MPM patients who had received chemotherapy when the best overall response and disease recurrence were determined. A quantitative real-time polymerase chain reaction was undertaken to detect the miRNA expression levels. The miRNA expression profiles of MPM patients were compared with those of HDs. The associations between the expression levels of miRNAs and prognosis and response to treatment were then evaluated. Results: All miRNAs, except miR-31-5p, were expressed differently in MPM relative to that in HDs. The expression level of miR-16-5p decreased when compared with that of HDs, and the expression levels of miR-29c-3p, miR-125a-5p, miR-320a, miR-484, and miR-532-5p increased when compared with that of HDs. The sensitivity and specificity values of miR-29c-3p, miR-125a-5p, miR-320a, miR-484, and miR-532-5p for discriminating MPM from HDs were 85.9% and 59.1%, 95.1% and 62.5%, 87.1% and 79.2%, 82.2% and 58.3%, and 69.3% and 82.6%, respectively. After adjusting for the histological subtype, stage, and treatment, the miR-29c-3p, miR-125a-5p, and miR-484 were associated with longer survival. The miRNA expression levels did not change longitudinally for the determination of chemotherapy response and recurrence. Conclusion: miRNAs may be useful in diagnosing patients with MPM and provides helpful information in determining the prognosis of patients.

Deacetylated-poly-N-acetylglucosamine-folic Acid as a Nanocarrier for Delivering miR-196a Inhibitor to Anticancer Activity

Abstract: Background: MiR-196a is particularly noticeable in the development of liver cancer. However, the rapid degradation by ribonuclease (RNase) imposes a limit on the miRNA gene therapy applications. Aims: To design a novel gene-targeting nano system for liver cancer treatment. Study Design: Cell culture study and animal experimentation. Methods: Deacetylated (DEAC)-poly-N-acetylglucosamine (PNAG)-folic acid (FA) was prepared via ethyl (dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide reaction, and miR-196a inhibitor (miR-196a I)/DEAC-PNAG-FA was prepared through self-assembly. The characterization and nucleic acid protection of the self-assembly system were also determined. The biological function and related mechanism of the prepared system were studied at cellular and molecular levels. Mice were established as a xenotransplantation model to evaluate the anticancer capacity of miR-196a I/DEAC-PNAG-FA in vivo. Results: The morphology of miR-196a I/DEAC-PNAG-FA was uniform, and its particle size was approximately 70–100 nm. A nanocarrier with an N/P ratio of 200:1 can maximize the nucleic acid carrying capacity of the self-assembly system. The nanosystem can protect miRNA from RNase degradation and could be internalized rapidly within 4 h. The self-assembly system significantly enhanced the apoptosis-inducing effect of miR-196a I on HepG2 cells (P = 0.003). Molecular biological analyses confirmed that the apoptosis-inducing effect of the nanosystem was due to the inhibition of miR-196a gene expression in HepG2 cells, which upregulate the expression of pro-apoptotic proteins FOXO1 (P < 0.001), Bax (P < 0.001), Ki67 (P < 0.001), and proliferating cell nuclear antigen (P < 0.001), and inhibit the expression of apoptosis inhibitory protein Bcl-2 (P < 0.001). Moreover, compared with free miR-196a inhibitor or miR-196a I/DEAC-PNAG, miR-196a I/DEAC-PNAG-FA can more effectively inhibit tumor growth in vivo (P = 0.026). Conclusion: The newly prepared self-assembly targeting system can effectively induce apoptosis and abrogate tumor growth, which may open a new approach for liver cancer treatment.

Hypoxia-induced Circular RNA hsa_circ_0006508 Promotes the Warburg Effect in Colorectal Cancer Cells

Abstract: Background: The hypoxia-induced Warburg effect promotes colorectal cancer malignancy with altered circular RNA (circRNA) expression. Aims: To investigate the association with the Warburg effect in colorectal cancer and whether has_circ_0006508 can be induced by hypoxia. Study Design: In vitro cell lines and human-sample study. Methods: The biological functions of circ_0006508 and miR-1272 in the viability, colony formation, and glycolysis under hypoxic conditions were determined by loss-of-function and gain-of-function experiments. The chromatin immunoprecipitation assay was used to demonstrate the direct binding between circ_0006508 promoters and hypoxia-inducible factor 1α (HIF-1α). Transcription activity was subjected to the Luciferase reporter assay. The correlation of circ_0006508 and miR-1272 with overall survival was determined with the Kaplan-Meier analysis. Results: Upregulated circ_0006508 and downregulated miR-1272 were observed in colorectal cancer samples, which was associated with the TNM stage and overall survival. Functional assays demonstrated that the hypoxia-induced upregulated circ_0006508 and downregulated miR-1272 promoted the viability and Warburg effect of colorectal cancer in vitro. Mechanistically, HIF-1α-induced circ_0006508 could directly sponge miR-1272, which played a suppressive role in glycolysis. Conclusion: Circ_0006508-mediated miR-1272 inhibition could promote the malignant behaviors of colorectal cancer with an upregulated Warburg effect.

Circ_0010235 Regulates HOXA10 Expression to Promote Malignant Phenotypes and Radioresistance in Non-small Cell Lung Cancer Cells Via Decoying miR-588

Abstract: Background: Circular RNAs (circRNAs) are key modulators in carcinogenesis and radioresistance in multiple kinds of human cancers. Aims: To explore the role of circ_0010235 in non-small cell lung cancer (NSCLC). Study Design: Cell culture study and animal study. Methods: The detection of circ_0010235, microRNA-588 (miR-588), and homeobox protein A10 (HOXA10) was implemented via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). CCK-8, EdU, flow cytometry, transwell, and wound healing assays. These strategies were applied to evaluate cell functions. The western blot technique was employed for protein examination. The colony formation assay was used to determine cell survival after radiation treatment. In vivo research was performed by tumor xenograft assay. The binding analysis was also carried out through dual-luciferase reporter and RNA immunoprecipitation studies. Results: Circ_0010235 had an enhanced expression in NSCLC. Circ_0010235 deficiency inhibited cell proliferation, invasiveness, and migratory ability but promoted apoptosis and radiosensitivity. Downregulation of circ_0010235 decelerated tumor growth and promoted radiation sensitivity in vivo. Circ_0010235 was controlled biologically in NSCLC cells by combining with miR-588 and targeting miR-588. HOXA10 acted as a target of miR-588. MiR-588 upregulation inhibited NSCLC cell malignant phenotypes and elevated radiosensitivity via downregulating HOXA10. Circ_0010235 could regulate the level of HOXA10 by sponging miR-588. Conclusion: Circ_0010235 contributed to the malignant progression of NSCLC, but suppressed the radiation sensitivity via targeting miR-588 to induce HOXA10 upregulation.

Long-term Follow-up Results of Tinnitus and Dizziness Disorders in Patients after SARS-CoV-2 Infection Based on a Questionnaire

Abstract: The effects and pathological changes of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) on hearing and balance are still under investigation. However, only a few studies have reported neurological findings such as impaired headache, consciousness, and dizziness. 1 This study aimed to investigate the association of dizziness and subjective tinnitus in patients with coronavirus disease 2019 (COVID-19) from an online and face-to-face three-stage questionnaire survey caused by the COVID-19 pandemic about two years follow-up in the ENT clinic. The study included patients with vertigo and dizziness and positive polymerase chain reaction (PCR) nasopharyngeal/oropharyngeal swab for SARS-CoV-2. All data were collected between April 1, 2020, and December 31, 2021, using a researcher-designed online three-staged questionnaire survey. The exclusion criteria were as follows: aged <18 years, intensive care unit hospitalization due to COVID-19, subjective hearing loss, previous ear surgery, audiological pathologies, acoustic trauma, psychiatric and cardiovascular comorbidities, and medical treatment with ototoxic drugs. This study used three questionnaires in three sections:stages: Tinnitus Handicap Inventory scores (THI), in which Dr. Aksoy’s Turkish version of Newman’s questionnaire was used in the study; 2,3 features of tinnitus and dizziness in which author-designed questionnaire in Turkish version was used; and the visual analog scale (VAS). We used this score to measure tinnitus and dizziness severity subjectively. 4

Local Recurrence of Metatarsal Aneurysmal Bone Cyst after Percutaneous Sclerotherapy

Abstract: A 23-year-old male patient applied to the orthopedic outpatient clinic with complaints of right foot swelling and pain without a trauma history. Physical examination revealed swelling and pain with palpation at the third metatarsal dorsal level of the right foot (Figure 1). The patient was examined by foot computed tomography (CT) and contrast magnetic resonance imaging (MRI) for detailed imaging upon detecting an expansive lesion in the third metatarsal bone, revealing the expansive lesion of 37 x 23 x 20 mm in size and with a sclerotic wall with multiple septa (Figure 2). Thereupon, sclerotherapy treatment was percutaneously applied with 10 ml of polidocanol to the lesion. The patient re-applied to the orthopedics outpatient clinic 6 months later because of the metatarsal growth and was examined with MRI. Lesion dimensions were measured as 63 x 45 x 36 mm in MRI and significant dimensional progression was detected in the lesion compared to the previous MRI (Figure 3). Hence, the operation was decided, and a ray amputation was performed on the third metatarsal bone and phalanx. An aneurysmal bone cyst (ABC) was diagnosed based on the histopathological examination (Figure 4).

Cost-of-disease of Heart Failure in Turkey: A Delphi Panel-based Analysis of Direct and Indirect Costs

Abstract: Background: Heart failure (HF) is considered a significant public health issue with a substantial and growing epidemiologic and economic burden in relation to longer life expectancy and aging global population. Aims: To determine cost-of-disease of heart failure (HF) in Turkey from the payer perspective. Study Design: Cross-sectional cost of disease study. Methods: In this cost-of-disease study, annual direct and indirect costs of management of HF were determined based on epidemiological, clinical and lost productivity inputs provided by a Delphi panel consisted of 11 experts in HF with respect to ejection fraction (EF) status (HF patients with reduced EF (HFrEF), mid-range EF (HFmrEF) and preserved EF (HFpEF)) and New York Heart Association (NYHA) classification. Direct medical costs included cost items on outpatient management, inpatient management, medications, and non-pharmaceutical treatments. Indirect cost was calculated based on the lost productivity due to absenteeism and presenteeism. Results: 51.4%, 19.5%, and 29.1% of the patients were estimated to be HFrEF, HFmrEF, and HFpEF patients, respectively. The total annual direct medical cost per patient was $887 and non-pharmaceutical treatments ($373, 42.1%) were the major direct cost driver. Since an estimated nationwide number of HF patients is 1,128,000 in 2021, the total annual national economic burden of HF is estimated to be $1 billion in 2021. The direct medical cost was higher in patients with HFrEF than in those with HFmrEF or HFpEF ($1,147 vs. $555 and $649, respectively). Average indirect cost per patient was calculated to be $3,386 and was similar across HFrEF, HFmrEF and HFpEF groups, but increased with advanced NYHA stage. Conclusion: Our findings confirm the substantial economic burden of HF in terms of both direct and indirect costs and indicate that the non-pharmaceutical cost is the major direct medical cost driver in HF management, regardless of the EF status of HF patients.