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Item Promising Drug Fondaparinux for the Treatment of COVID-19: an In Silico Analysis of Low Molecular Weight Heparin, Direct Oral Anticoagulant, and Antiplatelet Drug Interactions with Host Protease Furin(2022) Ertan-Bolelli, Tugba; Bolelli, Kayhan; Elci, Sitki Doga; Belen-Apak, F. Burcu; 0000-0002-2179-997X; 0000-0002-9278-6703; 36401727; G-5289-2013Purpose As of July 2022, the COVID-19 pandemic has affected over 555 million worldwide confirmed cases and caused more than 6.3 million deaths. The studies showed that the D-dimer levels were increased in non-survivors compared to survivors and heparin treatment has begun to be administered to the patients in severe clinics. As we knew that the entrance of SARS-CoV-2 to the host cell needs to be facilitated by host proteases; we published our hypothesis that heparin as a serine protease inhibitor may block the interaction between spike protein receptor-binding domain and host proteases. In our study, we aimed to investigate the interactions between not only heparins but also other antiplatelet and anticoagulant drugs including fondaparinux. Methods In this study, docking studies were carried out to evaluate the interactions between low molecular weight heparins (LMWHs) (enoxaparin, dalteparin, tinzaparin), direct oral anticoagulant, and antiplatelet drugs with host proteases. Molecular docking studies were performed by using Schrodinger molecular modeling software. 3D structures of the ligands were obtained from the 2D structures by assigning the OPLS-2005 force field using the Maestro 12.7. The 3D crystal structure of the furin complexed with an inhibitor, 2,5-dideoksistreptamin derivative, was extracted from the Protein Data Bank (PDB ID: 5MIM). Docking studies were carried out using the Grid-based Ligand Docking with Energetics module of the Schrodinger Software. Results The docking studies revealed that fondaparinux was the most relevant molecule to interact with furin with a docking score of - 12.74. It showed better interaction than the natural ligand of furin with an increased score compared to the docking score of - 8.155 of the natural ligand. AnaGA*IsA structure representing LMWH structure has shown a docking score of - 11.562 which was also better than the score of the natural ligand of furin. Conclusion Our findings have shown that LMWHs and fondaparinux can be used for their possible antiviral effects in COVID-19 patients. Our results have shown that in accordance with heparin and LMWH, fondaparinux can also be a candidate for "drug repurposing" in COVID-19 therapy, not only because of their anticoagulant but also possible antiviral effects.Item Comparison Of Confirmed And Probable COVID-19 Patients In The Intensive Care Unit During The Normalization Period(2022) Yesiler, Fatma Irem; Capras, Mesher; Kandemir, Emre; Sahinturk, Helin; Gedik, Ender; Zeyneloglu, Pinar; https://orcid.org/0000-0002-0612-8481; https://orcid.org/0000-0003-0159-4771; 34812130; AAJ-4212-2021; AAJ-1419-2021The decrease in social distance together with the normalization period as of June 1, 2020, in our country caused an increase in the number of coronavirus disease 2019 (COVID-19) patients. Our aim was to compare the demographic features, clinical courses, and outcomes of confirmed and probable COVID-19 patients admitted to our intensive care unit (ICU) during the normalization period. Critically ill 128 COVID-19 patients between June 1, 2020, and December 2, 2020, were analyzed retrospectively. The mean age was 69.7 +/- 15.5 y (61.7% male). Sixty-one patients (47.7%) were confirmed. Dyspnea (75.0%) was the most common symptom and hypertension (71.1%) was the most common comorbidity. The mean Acute Physiology and Chronic Health Evaluation System (APACHE II) score; Glasgow Coma Score; Sequential Organ Failure Assessment scores on ICU admission were 17.4 +/- 8.2,12.3 +/- 3.9, and 5.9 +/- 3.4, respectively. One hundred and one patients (78.1%) received low-flow oxygen, 48 had high-flow oxygen therapy (37.5%), and 59 (46.1%) had invasive mechanical ventilation. Fifty-three patients (41.496) had vasopressor therapy and 30 (23.4%) patients had renal replacement therapy due to acute kidney injury (AKI). Confirmed patients were more tachypneic (p= 0.005) and more hypoxemic than probable patients (p < 0.001). Acute respiratory distress syndrome and AKI were more common in confirmed patients than probable (both p < 0.001). Confirmed patients had higher values of hemoglobin, C- reactive protein, fibrinogen, and D-dimer than probables (respectively, p = 0.028. 0.006, 0.000. and 0.019). The overall mortality was higher in confirmed patients (p = 0.209, 52.6% vs. 47.4%). Complications are more common among confirmed COVID-19 patients admitted to ICU. The mortality rate of confirmed COVID-19 patients admitted to the ICU was found to be higher than probable patients. Mortality of confirmed cases was higher than prediction of APACHE-II scoring system.Item SARS-CoV-2 Mutations and their Viral Variants(2022) Cosar, Begum; Karagulleoglu, Zeynep Yagmur; Unal, Sinan; Ince, Ahmet Turan; Uncuoglu, Dilruba Beyza; Tuncer, Gizem; Kilinc, Bugrahan Regaip; Ozkan, Yunus Emre; Ozkoc, Hikmet Ceyda; Demir, Ibrahim Naki; Eker, Ali; Karagoz, Feyzanur; Simsek, Said Yasin; Yasar, Bunyamin; Pala, Mehmetcan; Demir, Aysegul; Atak, Irem Naz; Mendi, Aysegul Hanife; Bengi, Vehdi Umut; Sevel, Guldane Cengiz; Altuntas, Evrim Gunes; Kilic, Pelin; Demir-Dora, Devrim; https://orcid.org/0000-0003-0359-6308; 34580015Mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occur spontaneously during replication. Thousands of mutations have accumulated and continue to since the emergence of the virus. As novel mutations continue appearing at the scene, naturally, new variants are increasingly observed.Since the first occurrence of the SARS-CoV-2 infection, a wide variety of drug compounds affecting the binding sites of the virus have begun to be studied. As the drug and vaccine trials are continuing, it is of utmost importance to take into consideration the SARS-CoV-2 mutations and their respective frequencies since these data could lead the way to multi-drug combinations. The lack of effective therapeutic and preventive strategies against human coronaviruses (hCoVs) necessitates research that is of interest to the clinical applications.The reason why the mutations in glycoprotein S lead to vaccine escape is related to the location of the mutation and the affinity of the protein. At the same time, it can be said that variations should occur in areas such as the receptor-binding domain (RBD), and vaccines and antiviral drugs should be formulated by targeting more than one viral protein.Item The Changing Dynamics Of Neutralizing Antibody Response Within 10 Months Of SARS-Cov-2 Infections(2022) Bastug, Aliye; Bodur, Hurrem; Aydos, Omer; Filazi, Nazlican; Oksuz, Ergun; https://orcid.org/0000-0002-5723-5965; 34967013; K-8238-2012There are limited data on how long neutralizing antibody (NAb) response elicited via primary SARS-CoV-2 infection will last. Eighty-four serum samples were obtained from a prospective cohort of 42 laboratory-confirmed COVID-19 inpatients at the time of discharge from the hospital and in the late convalescent phase. A virus neutralization assay was performed to determine the presence and titers of NAbs with authentic SARS-CoV-2. Long-term dynamics of NAbs and factors that may have an impact on humoral immunity were investigated. Mild and moderate/severe patients were compared. The mean sampling time was 11.12 +/- 5.02 days (4-28) for the discharge test and 268.12 +/- 11.65 days (247-296) for the follow-up test. NAb response was present in 83.3% of the patients about 10 months after infection. The detectable long-term NAb rate was significantly higher in mild patients when compared to moderate/severe patients (95.7% vs. 68.4%, p = 0.025). In the follow-up, NAb-positive and -negative patients were compared to determine the predictors of the presence of long-term humoral immunity. The only significant factor was disease severity. Patients with mild infections have more chance to have NAbs for a longer time. Age, gender, and comorbidity did not affect long-term NAb response. NAb titers decreased significantly over time, with an average rank of 24.0 versus 19.1 (p = 0.002). Multivariate generalized estimating equation analysis revealed that no parameter has an impact on the change of NAb titers over time. The majority of the late convalescent patients still had detectable low levels of neutralizing antibodies. The protective effect of these titers of NAbs from re-infections needs further studies.Item Cross-Sectional Analysis Of Tobacco Addiction In Hospitalized COVID-19 Patients(2022) Darilmaz Yuce, Gulbahar; Torun, Serife; Hekimoglu, Koray; Tuna, Derin; Sozbilici, Betul Rana; Cetin, Hikmet Oguz; Narlioglu, Mehmet Emin; Balli, Murat; Ozyesil, Ahmet Suheyl; Yavuz Colak, Meric; Ulubay, Gaye; Akcay, Muserref Sule; https://orcid.org/0000-0002-0805-0841; 36164949; AAD-9097-2021Introduction: The COVID-19 pandemic has become an important health issue with consequences for special populations since 2019. Tobacco use is an important public health issue and tobacco users are a risk group for lung infections.Materials and Methods: The aim of this study is to obtain information about disease prevalence and severity, laboratory parameters, and changes in radio-logical findings between smokers and non-smokers who were hospitalized, followed up, and treated for COVID-19, and to find answers to critical questi-ons regarding the response to antiviral and supportive therapy. Two hundred eighty-six patients who were hospitalized and treated between March 2020-February 2021 in the COVID-19 Isolation Ward of Baskent University Hospital were included in the study. The patients were grouped as current smokers, non-smokers, and ex-smokers. The groups were compared in terms of symptoms, laboratory findings, radiological findings, and treatment respon-se.Results: The median age of the patients included in the study was 59 (IQR= 32). Of the patients, 40.6% were female and 59.4% were male. In our study, we discovered that there were fewer female smokers (p< 0.001). When the current smokers (n= 56), non-smokers (n= 159), and ex-smokers (n= 71) were compared based on their findings, it was found that dyspnea was more common in current smokers (p= 0.009). Lung involvement was found to be more common (p= 0.002) and multifocal in the current smokers group (p= 0.038). The levels of oxygen saturation at the times of admission and discharge were lower in current smokers (p= 0.002 and p= 0.038). The need for nasal oxygen and noninvasive mechanical ventilation was also found to be higher in current smokers (p= 0.008 and p= 0.039). Systemic steroid requirement was higher in current smokers (p= 0.013). There was no statistically significant differen-ce in terms of mortality between current smokers, ex-smokers, and non-smokers (p= 0.662).Conclusion: The analysis of the findings of the patients hospitalized in the COVID-19 isolation ward indicated that COVID-19 leads to a more serious course in patients with a history of smoking.Item Predominant Mutations of SARS-CoV-2: Their Geographical Distribution and Potential Consequences(2021) Unlu, Sezin; Uskudar Guclu, Aylin; Basustaoglu, Ahmet; 0000-0001-7490-7981; 0000-0002-1872-028X; AAQ-4702-2021; AAU-6196-2020Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) emerged in late December 2019 in Wuhan, China. More than 83 million people have been infected, and more than 1.8 million people have died, as reported to the World Health Organization on the 3rd of January, 2021. Analysis of genetic variations is critical for understanding the spreading pattern of SARS-CoV-2 across several countries. This review aimed to gather information about the prominent mutations of SARS-CoV-2 by analyzing the origin, viral pathogenesis, and mutation rate. Moreover, we concluded their potential impacts on SARS-CoV-2 therapeutics. Mutations in the spike protein (D614G, N501Y, E484K, A222V, S477N, and G485R), ORF1ab (P323L, N628N, Y455Y, A97V, and F106F), nucleocapsid protein (R203K and G204R), ORF8 (L84S), and ORF3a (Q57H and G251V) were examined in this review by analyzing relevant articles from the beginning of the current pandemic to the most recent date. A detailed analysis of articles demonstrates that D614G is the major variation distributed globally, and its frequency increased rapidly from early in March, followed by several other variations in either spike or different proteins. In addition, it was seen that the currently circulating N501Y and E484K variants revealed a public concern regarding vaccines' efficacy. Investigation of variations of SARS-CoV-2 would lead to understanding their potential mechanism of action against SARS-CoV-2, thereby suggesting suitable therapeutics. Several mechanisms were suggested to have a role in SARS-CoV-2 mutation rate and evolution. Possible therapeutics and vaccines against SARS-CoV-2 were proposed.Item Comparison of the clinical course of COVID-19 infection in sickle cell disease patients with healthcare professionals(2021) Boga, Can; Asma, Suheyl; Leblebisatan, Goksel; Sen, Nazan; Tombak, Anil; Demiroglu, Yusuf Ziya; Yeral, Mahmut; Akin, Sule; Yesilagac, Hasan; Habesoglu, Mehmet Ali; Aribogan, Anis; Kasar, Mutlu; Korur, Asli; Ozdogu, Hakan; 0000-0002-9866-2197; 34032899; AAZ-9711-2021; AAY-2668-2021It is highly expected that COVID-19 infection will have devastating consequences in sickle cell disease (SCD) patients due to endothelial activation and decreased tissue and organ reserve as a result of microvascular ischemia and continuous inflammation. In this study, we aimed to compare the clinical course of COVID-19 in adult SCD patients under the organ injury mitigation and clinical care improvement program (BASCARE) with healthcare professionals without significant comorbid conditions. The study was planned as a retrospective, multicenter and cross-sectional study. Thirty-nine SCD patients, ages 18 to 64 years, and 121 healthcare professionals, ages 21 to 53, were included in the study. The data were collected from the Electronic Health Recording System of PRANA, where SCD patients under the BASCARE program had been registered. The data of other patients were collected from the Electronic Hospital Data Recording System and patient files. In the SCD group, the crude incidence of COVID-19 was 9%, while in healthcare professionals at the same period was 23%. Among the symptoms, besides fever, loss of smell and taste were more prominent in the SCD group than in healthcare professionals. There was a significant difference between the two groups in terms of development of pneumonia, hospitalization, and need for intubation (43 vs 5%, P < 0.00001; 26 vs 7%, P = 0.002; and 10 vs 1%, P = 0.002, respectively). Prophylactic low molecular weight heparin and salicylate were used more in the SCD group than in healthcare professionals group (41 vs 9% and 28 vs 1%; P < 0.0001 for both). The 3-month mortality rate was demonstrated as 5% in the SCD group, while 0 in the healthcare professionals group. One patient in the SCD group became continously dependent on respiratory support. The cause of death was acute chest syndrome in the first case, hepatic necrosis and multi-organ failure in the second case. In conclusion, these observations supported the expectation that the course of COVID-19 in SCD patients will get worse. The BASCARE program applied in SCD patients could not change the poor outcome.Item Antibody Screening and Risk Assessment of Healthcare Professionals in the COVID-19 Pandemic(2021) Gumus, Hatice Hale; Demiroglu, Yusuf Ziya; Aliskan, Hikmet Eda; Odemis, İlker; Ceylan, Ozgur; Pocan, Ahmet Gurhan; Karagum, Ozlem; 0000-0001-9060-3195; 0000-0003-2638-0163; 0000-0002-9866-2197; 0000-0003-2638-0163; 0000-0001-6910-7250; 0000-0003-0681-8375; 0000-0003-3128-1602; 0000-0001-9071-9606; 34416802; AAE-2282-2021; AFK-3690-2022; AAX-9250-2021; AAZ-9711-2021; AAG-2486-2022; AAK-8276-2021; U-4084-2017; AAE-6310-2021; AAJ-2108-2021Globally 364102 healthcare professionals have been infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and 1253 of them died until 15 January 2021. Healthcare professionals serving at the forefront of combating the pandemic are in the high risk group. In our country, the data about coronavirus-2019 (COVID-19) among healthcare professionals are limited. The aim of this study was to investigate the anti-SARS-CoV-2 IgG seroprevalence in healthcare professionals, to evaluate the risks they encountered during work, and to examine their relationships with antibody positivity. A total of 572 healthcare professionals serving in various units of our hospital participated in our study and the presence of anti-nucleocapsid IgG was investigated by chemiluminescent microparticle immunoassay (SARS-CoV-2 IgG test, Abbott Laboratories Diagnostics, USA) method in serum samples collected between May 18, 2020 and June 30, 2020. The demographic characteristics, medical history, work conditions, medical procedures performed and possible risk factors were questioned with a questionnaire form. The average age of the participants was 33.5 +/- 9.2 (19-61) years, and 62.9% (360/572) of them were women. In our study, the anti-SARS-CoV-2 IgG seroprevalence was 3.7% (21/572). The association of the antibody positivity with age, gender and occupational status was not statistically significant (p> 0.05). Comorbid diseases which were significantly higher in seropositive healthcare professionals were hypertension (19%) and diabetes mellitus (14.3%) (p< 0.05). It was observed that antibody positivity was significantly higher in healthcare professionals working in high (52.4%) and medium risk (33.3%) areas, those who treat and/or examine patients with suspicious or positive COVID-19 (66.7%) and those who spend more than 30 minutes in COVID-19 patient rooms (76%) (p< 0.05). The symptoms associated with seropositivity in healthcare workers with a history of symptoms (46%) were loss of smell (23.5%), loss of taste (20.0%) and respiratory distress (16.7%) (p< 0.05). It was observed that the probability of being infected with SARS-CoV-2 increased 12 times if there was a colleague with COVID-19 in the hospital, four times if there was a patient in the house/lodging and six times if there was an infected person in the social environment (p< 0.05). The rate of those who had the flu vaccine among the participants was 10.8% (62/572) and 9.7% of them were found to be anti-SARS-CoV-2 IgG positive (p< 0.05, 95% CI= 1.31-9.48). The seropositivity was significantly higher in non-smokers (4.8 %) compared to smokers (0.0%) (p< 0.05). In our study, it was determined that the rate of seropositivity was 12 times higher in healthcare professionals who stated that they received hydroxychloroquine prophylaxis due to risky contact compared to those who did not receive prophylaxis (p< 0.05, 95% CI= 4.11-40.64). The ratio of the personnel who answered "always" to the frequency of wearing gloves, masks, goggles/face shields and overalls was 85.7%, 96.9%, 62.1% and 65.4%, respectively. In conclusion, regular and large-scale sero-epidemiological screening of healthcare professionals in the COVID-19 pandemic can contribute to the control of the pandemic by providing a better understanding of transmission dynamics and risk factors.Item Host variations in SARS-CoV-2 infection(2021) Altiok, Doruk; Savci, Elif Zeynep; Ozkara, Busra; Alkan, Kamil; Namdar, Dilara Sultan; Tuncer, Gizem; Kilinc, Bugrahan Regaip; Suicmez, Evren; Cetin, Guneysu; Unal, Sinan; Donmus, Beyza; Karagulleoglu, Zeynep Yagmur; Uncuoglu, Dilruba Beyza; Tekeli, Cansu; Mendi, Hanife Aysegul; Bengi, Vahdi Umut; Seval, Guldane Cengiz; Kilic, Pelin; Altuntas, Evrim Gunes; Demir-Dora, Devrim; 0000-0001-7996-5427; 34803443The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the zoonotic pathogen that causes the "Coronavirus Disease of 2019 (COVID-19)", and COVID-19 itself is yet to be thoroughly understood. Both the disease as well as the mechanisms by which the host interacts with the SARS-CoV-2 have not been fully enlightened. The epidemiological factors -e.g. age, sex, race-, the polymorphisms of the host proteins, the blood types and individual differences have all been in discussions about affecting the progression and the course of COVID-19 both individually and collectively, as their effects are mostly interwoven. We focused mainly on the effect of polymorphic variants of the host proteins that have been shown to take part in and/or affect the pathogenesis of COVID-19. Additionally, how the procedures of diagnosing and treating COVID-19 are affected by these variants and what possible changes can be implemented are the other questions, which are sought to be answered.Item A new DoE-MTOPSIS based prediction model suggestion to capture potential SARS-CoV-2 reactivated patients(2021) Tansel, Yusuf I. C.; 0000-0001-9274-7467; AGE-3003-2022Difficulties to use convenient data during the Severe Acute Respiratory Syndrome Coronavirus2 (SARS-CoV-2) pandemic outbreak and complexities of the problem attitude crucial challenges in infectious disease modelling studies. Motivated by the on-going reach to predict a potential reactivated SARS-CoV-2 (COVID-19), we suggest a prediction model that beyond the clinical characteristics based evaluation approaches. In particular, we developed a possibly available and more efficient prediction model to predict a potential reactivated SARS-CoV-2 (COVID-19) patient. Our paper aims to explore the applicability of a modified Technique for Order Preference by Similarity to Ideal Solutions (MTOPSIS) integrated Design of Experiment (DoE) method to predict a potential reactivated COVID-19 patient in real-time clinical or laboratory applications. The presented novel model may be of interest to the readers studying similar research areas. We illustrate MTOPSIS integrated DoE method by applying it to the COVID-19 pandemic real clinical cases from Wuhan/China-based data. Despite the small sample size, our study provides an encouraging preliminary model framework. Finally, a step by step algorithm is suggested in the study for future research perspectives.