Plasma P-selectin is an early marker of thromboembolism in COVID-19

Objectives: The aim of this study was to explore the association of the plasma levels of coagulation proteins with venous thromboembolic events (VTE) in COVID-19 and identify candidate early markers of VTE. Background(s): Coagulopathy and thromboembolism are known complications of SARS-CoV-2 infection. The mechanisms of COVID-19-associated hematologic complications involve endothelial cell and platelet dysfunction and immunothrombosis and have been intensively studied. Yet, a full understanding of the pathogenesis and factors that lead to COVID-19 associated coagulopathy is lacking. Previous studies investigated only small numbers of coagulation proteins together, and they were limited in their ability to adjust for confounders. Method(s): This study was a post-hoc analysis of a previously published dataset (Filbin et al., 2021). We included in our analysis 305 subjects with confirmed SARS-CoV-2 infection who presented to an urban Emergency Department with acute respiratory distress during the first COVID-19 surge in 2020;13 (4.2%) were subsequently diagnosed with venous thromboembolism during hospitalization. Serial samples were obtained on days 0, 3, and 7 and assays were performed on two highly-multiplexed proteomic platforms, that in combination cover 1472 + 4776 proteins. We included 31 coagulation proteins in our analysis. Result(s): Nine coagulation proteins were differentially expressed in patients with thromboembolic events. In multivariable models, day 0 levels of P-selectin, a cell adhesion molecule on the surface of activated endothelial cells, displayed the strongest association with the diagnosis of VTE, independent of disease severity and other confounders (p=0.0025). P-selectin together with D-dimer upon hospital presentation provided better discriminative ability for VTE diagnosis than D-dimer alone (AUROC = 0.834 vs. 0.783). Conclusion(s): Our results suggest that plasma P-selectin is a potential early biomarker for the risk stratification of VTE in COVID-19 disease. Our findings support the importance of endothelial activation in the mechanistic pathway of venous thromboembolism in COVID-19.Copyright © 2023

A Mini-Review on Cardiovascular and Hematological Complications of COVID-19

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is named as the coronavirus disease of 2019 (COVID-19). Patients with SARS-CoV-2 infection experience a wide range of symptoms and they are at the risk of various systemic complications. Besides the pulmonary complications, COVID-19 cases may develop cardiovascular and hematological complications. This study aimed to review the most important hematological and cardiovascular complications caused by SARS-CoV-2 infection. Method(s): The English databases, including Pubmed, ScienceDirect, Cochrane Library, Scopus, and Google Scholar, were searched. The published papers were selected and reviewed based on the subject of this study. Result(s): The review of the literature showed that several cardiovascular complications related to COVID-19, including acute myocardial infarction, cardiomyopathy, acute heart failure, and venous thromboembolic events due to coagulation abnormalities, have been reported. COVID-19 associated hematological complications include elevated levels of hematological factors including C-reactive pro-tein, lactate dehydrogenase, procalcitonin, and ferritin. Furthermore, the levels of blood cells, including lymphocytes and thrombocytes, can be reduced. Conclusion(s): This study reviewed COVID-19-associated cardiovascular and hematopoietic complica-tions. In conclusion, the patients may experience a wide range of cardiovascular and hematological is-sues during the illness. These complications are often associated with the need for ICU support and care which imposes further costs to the healthcare system. So the healthcare team must consider the possible complications when treating COVID-19 patients to reduce the treatment costs and mortality of patients.Copyright © 2021 Bentham Science Publishers.

Venous and arterial thromboses in hospitalized patients with acute COVID-19 at University Hospital Dubrava

Since COVID-19 pandemic has started, there have been reports that SARS-CoV-2 infection induces pro-thrombotic state. Even though the disease presents foremost with respiratory symptoms, high frequencies of both venous and arterial thromboses have been observed while suggesting different molecular mechanisms. University Hospital Dubrava has been Croatia capital's COVID-19 centre for almost a year and a half treating almost 10.000 patients until today. We retrospectively analysed venous and arterial thrombotic events among 4014 patients hospitalized due to COVID-19. Venous thromboembolic events (VTE) occurred in 5.3% and arterial thrombotic events (ATE) in 5.8% of patients. Majority of ATE occurred prior or on the day of admission while VTE were mainly detected during hospitalization (screening). Majority of both occurred prior to intensive care unit (ICU) admission, but both were associated with higher need for ICU care and prolonged immobilization. In multivariate logistic regression analysis independent factors associated with VTE were metastatic malignancy, known thrombophilia, higher D-dimers, longer duration of disease on admission, bilateral pneumonia, longer duration of hospitalization and immobilization for at least one day. On the other hand, factors that showed to be associated with ATE were less severe COVID-19, higher Charlson comorbidity index, history of arterial diseases, aspirin use, lower C reactive protein, better functional status on admission and immobilization for at least one day. In conclusion, venous and arterial thromboses differ in all above mentioned factors thus leaving room for appropriate prevention, intervention and treatment.

Contribution of Cardiovascular Disease to Adverse Hospital Outcomes in Covid-19 Hospitalizations: Results from National Inpatient Sample

Background It is a well-established fact that cardiovascular disease (CVD) adversely affects COVID-19 outcomes. However, the extend of the burden posed by CVD on hospitalized COVID-19 patients in the United States is unknown. In this study, using a national database, we estimated the effects CVD on COVID-19 hospitalizations in the United States. Methods This study is a retrospective analysis of National Inpatient Sample data, collected during 2020. Patients >=18 years of age, admitted with primary diagnosis of COVID-19 were included in the analysis. CVD was defined as presence of coronary artery disease, myocardial infarction, heart failure, sudden cardiac arrest, conduction disorders, cardiac dysrhythmias, cardiomyopathy, pulmonary heart disease, venous thromboembolic disorders, pericardial diseases, heart valve disorders, or peripheral arterial disease. The primary outcomes of the study were in-hospital mortality rate, prolonged hospital length of stay, mechanical ventilation, and disposition other than home. Multivariable logistic regression analysis was done to examine the association between presence of CVD and primary outcomes. Results During 2020 there were 1,050,040 COVID-19 hospitalizations in the United Sates. Of these 454650 (43.3%) had CVD. COVID-19 patients with CAD were older, males, and had higher comorbidity burden. The odds of in-hospital mortality (OR, 3.40;95% CI: 3.26-3.55), prolonged hospital length (OR, 1.71;95% CI: 1.67-1.76) and mechanical ventilation use (OR, 3.40;95% CI: 3.26-3.55), and disposition other than home (OR, 2.11;95% CI: 2.06-2.16) were significantly higher for COVID-19 hospitalizations with CAD. Mean hospitalization costs were also significantly higher among COVID-19 patients with CAD ($24,023 versus $15,320, P<0.001). The total cost of all COVID-19 hospitalizations during 2020 was $19.9 billion - $10.9 billion for those with CAD and $9.0 billion for those without CVD. Conclusion Cardiovascular disease was present in a substantial proportion of COVID-19 patients hospitalized in the United States and contributed to considerable adverse hospital outcomes and significantly higher hospitalization cost.Copyright © 2023 American College of Cardiology Foundation

A RARE PRESENTATION OF COVID-19-ASSOCIATED CENTRAL VENOUS THROMBOSIS

SESSION TITLE: COVID-19 Case Report Posters 3 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Due to a wide range of clinical presentations, central venous thrombosis (CVT) is a rare neurologic condition that can be difficult to diagnose. Since the COVID-19 pandemic, more cases of venous thromboembolic events have emerged and been found associated with COVID-19. We detail a potential case of COVID-19 associated CVT. CASE PRESENTATION: A 28-year-old female with past medical history of obesity, polycystic ovary syndrome, recurrent sinusitis, and presumed history of COVID-19 infection with anosmia, ageusia, and sinusitis symptoms three- months prior presented to the hospital with 1-month history of worsening, right-sided pain behind her ear, eye, head, posterior neck and shoulder, nausea, and photophobia, which had worsened in the last 5 days. She initially tried over-the-counter medications with no improvement. Vital signs were unremarkable. Examination was notable for frontal sinus and right postauricular tenderness to palpation. C- reactive protein was elevated at 26.2 mg/L. Non- contrasted brain computed tomography (CT) was concerning for right transverse sinus and superior sagittal sinus thrombosis. Brain magnetic resonance imaging (MRI) showed early signs of cortical edema and venous infarction and findings concerning for right mastoiditis. Intracranial venous MRI showed complete thrombosis of the right transverse and sigmoid sinus, superior sagittal sinus, and most of the superior draining cortical veins. Heparin drip was started. Initial empiric antibiotics for mastoiditis were stopped. Hyper-coagulopathy work-up with beta- 2 glycoprotein 1 antibodies and phospholipid antibodies were negative. As there were no other inciting factors for CVT found and no history of positive COVID-19 test, a COVID-19 antibody immunoassay was obtained and returned positive. The patient did not have a history of COVID vaccination. She was discharged on warfarin and enoxaparin. Anticoagulation was stopped after 6 months with repeat imaging showing resolution of clot burden. DISCUSSION: Usual risk factors associated with CVT are morbid obesity, hormone replacement therapy, oral contraceptive use, hereditary thrombophilia, and pregnancy. Literature on CVT related to COVID-19 is limited. In 41 documented cases, the average age of incidence is 50 years old and median onset of neurological symptoms from initial COVID-19 diagnosis is 7 days [0 to 21 days]. Our patient's neurological symptoms began about 3 months after her initial diagnosis, potentially making it the first known case of COVID-19 associated CVT with symptom onset past 21 days. Anticoagulation is the mainstay treatment for CVT, and duration depends on the presence of provoking factor. CONCLUSIONS: In patients with new neurologic symptoms and recent diagnosis of COVID-19, CVT should be considered in the differential diagnosis as it can initially present in a subtle manner. Early recognition could improve patient morbidity and mortality. Reference #1: Abdalkader, M., Shaikh, S. P., Siegler, J. E., Cervantes-Arslanian, A. M., Tiu, C., Radu, R. A., Tiu, V. E., Jillella, D. v., Mansour, O. Y., Vera, V., Chamorro, Á., Blasco, J., López, A., Farooqui, M., Thau, L., Smith, A., Gutierrez, S. O., Nguyen, T. N., Jovin, T. G. (2021). Cerebral Venous Sinus Thrombosis in COVID-19 Patients: A Multicenter Study and Review of Literature. Journal of Stroke and Cerebrovascular Diseases. https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.105733 Reference #2: Idiculla, P. S., Gurala, D., Palanisamy, M., Vijayakumar, R., Dhandapani, S., Nagarajan, E. (2020). Cerebral Venous Thrombosis: A Comprehensive Review. European Neurology (Vol. 83, Issue 4). https://doi.org/10.1159/000509802 Reference #3: Ostovan VR, Foroughi R, Rostami M, et al. Cerebral venous sinus thrombosis associated with COVID-19: a case series and literature review. Journal of Neurology. 2021 Oct;268(10):3549-3560. DOI: 10.1007/s00415-021-10450-8. PMID: 33616740;PMCID: PMC7897893. DI CLOSURES: No relevant relationships by Shu Xian Lee No relevant relationships by Arif Sarwari No relevant relationships by Benita Wu

CLOTTING AND COVID-19: IT IS NOT ALWAYS VTE

SESSION TITLE: COVID-19 Case Report Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Coronavirus disease 2019 (COVID-19) is an enveloped positive stranded RNA virus that affects multiple organ systems in the body. COVID-19 venous and thromboembolic events are well documented;however, few reports of arterial thrombosis exist. Arterial embolism is reported to occur in one to five percent of patients. We present a case of a patient who experienced arterial thromboembolism. CASE PRESENTATION: A 38-year-old woman with a history of diabetes, hypertension, and recent COVID-19 pneumonia three weeks prior presented to the hospital for lower extremity weakness, paresthesias, and pain in her bilateral lower extremities. Upon examination, she was found to have bilateral cold feet, lack of sensation to toes or plantar aspect of feet, nondopplerable pedal or dorsalis pedis pulses bilaterally, dopplerable femoral pulses bilaterally. A CT angiogram of the abdomen with bilateral runoff revealed distal abdominal aortic and bilateral iliac artery thrombus, thrombus in bilateral runoff arteries. She was evaluated by vascular and started on a heparin drip. She underwent bilateral iliofemoral thromboembolectomy and bilateral iliac stents. Surgery recommended allowing demarcation in the outpatient setting, however, due to intractable pain vascular surgery determined that bilateral below the knee amputations were necessary. She underwent testing for possible hypercoagulable state and was found to have an elevated cardiolipin antibody and lupus anticoagulant (LA) screen positive which are reported in 50% of critically ill COVID-19 patients, though the clinical or pathological value of these results are unclear at this time. DISCUSSION: Several mechanisms for hypercoagulability in COVID-19 infection have been postulated. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to host angiotensin converting enzyme 2 (ACE2) proteins. ACE2 receptors can be found throughout multiple organs and specifically on endothelial cells. ACE2 maintains the endothelial integrity of vessels. Coagulation testing in COVID-19 patients reveal increased prothrombin, activated partial thromboplastin time (aPTT), platelet counts, fibrinogen levels. Increased inflammation and cytokine release lead to a hypercoagulable state. Studies have shown that cardiolipin antibodies and LA positivity are higher in patients with COVID-19 which predispose patients to venous and arterial thrombosis. CONCLUSIONS: Venous thrombosis is often considered in patients with COVID-19 and clotting complications, however, due to the growing number of case reports regarding arterial thrombosis – arterial complications must be considered in the differential. Further research regarding the mechanism of arterial thrombosis are required to better understand the pathogenesis and develop targeted therapies to prevent occurrence of arterial thrombosis. Reference #1: Cheruiyot I, Kipkorir V, Ngure B, Misiani M, Munguti J, Ogeng'o J. Arterial Thrombosis in Coronavirus Disease 2019 Patients: A Rapid Systematic Review. Ann Vasc Surg. 2021;70:273-281. doi:10.1016/j.avsg.2020.08.087 Reference #2: Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium ;Nature Reviews Cardiology Reference #3: Taha, M., & Samavati, L. (2021). Antiphospholipid antibodies in COVID-19: a meta-analysis and systematic review. RMD open, 7(2), e001580. https://doi.org/10.1136/rmdopen-2021-001580 DISCLOSURES: No relevant relationships by Gretchen Grosch No relevant relationships by Stephanie Link No relevant relationships by Soophia Naydenov No relevant relationships by Tanner Wallen

AORTIC THROMBUS DESPITE THERAPEUTIC DOSE OF ANTICOAGULATION IN A PATIENT POSITIVE FOR COVID-19

SESSION TITLE: Extraordinary Cardiovascular Reports SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: Hypercoagulability is a well-known complication of COVID-19, with the most common vascular events being pulmonary embolism and deep vein thrombosis (1). Arterial thrombotic events, specifically aortic thrombosis, are rarely observed in COVID-19 infections. Literature review reveals less than 10 cases of aortic thrombosis have been reported in patients with COVID-19 infection. Here, we report a unique case of acute aortic thrombosis despite administration of therapeutic anticoagulation. CASE PRESENTATION: A 77 y.o. female with no known medical history presented to the hospital after a diagnosis of COVID-19 five days prior. Upon arrival, she was hypoxic requiring supplemental oxygen via non-rebreather (NRB) mask. CT chest with contrast revealed bilateral ground-glass opacities without evidence of pulmonary embolism or aortic thrombus. She was treated with remdesivir, dexamethasone, baricitinib and enoxaparin 40mg BID (essentially therapeutic dosing based on patient's body weight of 45kg). Adequate oxygenation was maintained with nasal cannula and NRB. However, on day eight of admission she was noted to desaturate to 80% requiring BiPAP. D-dimer and CRP drastically increased from 0.36ug/ml to 1.75ug/ml and 13.0 to 102.2, respectively. Repeat CT chest with contrast revealed multiple intraluminal thrombi in the distal thoracic aorta. Treatment with clopidogrel was initiated, however patient remained BiPAP dependent. Due to DNR/DNI status, intubation was not pursued. Ultimately, patient was transitioned to comfort care and expired. DISCUSSION: Thrombotic events are poorly understood but remain a well-documented sequela of COVID-19 infection. The pathophysiology of thrombosis in COVID-19 patients has not been fully elucidated, however, it likely involves amplification of the hypercoagulable state due to viral infection. Some of the proposed theories regarding this effect include endothelial dysfunction secondary to direct virus invasion and immuno-thrombosis due to viral mediated endothelial inflammation with resultant platelet activation (2,3). Regarding COVID-19 associated arterial thrombi, myocardial infarction and stroke are the most commonly encountered events. The few reported cases of aortic thrombi occurred almost exclusively in males with significant cardiovascular risk factors and not on anticoagulation (1,3). CONCLUSIONS: Due to the increased risk of venous thromboembolic events, prophylaxis is routinely used in patients with COVID-19. However, in our case, the patient developed multiple aortic thrombi without any typical risk factors for endothelial lesions despite being fully anticoagulated. This case highlights the need for continued research and trials related to appropriate anticoagulation therapies in hospitalized patients with COVID-19. Additionally, physicians should be aware of potential arterial thrombi in patients infected with COVID-19. Reference #1: de Carranza M, Salazar DE, Troya J, et al. Aortic thrombus in patients with severe COVID-19: review of three cases. J Thromb Thrombolysis. 2021;51(1):237-242. doi:10.1007/s11239-020-02219-z Reference #2: Loo J, Spittle DA, Newnham MCOVID-19, immunothrombosis and venous thromboembolism: biological mechanismsThorax 2021;76:412-420. doi:10.1136/ thoraxjnl-2020-216243 Reference #3: Woehl B, Lawson B, Jambert L, Tousch J, Ghassani A, Hamade A. 4 Cases of Aortic Thrombosis in Patients With COVID-19. JACC Case Rep. 2020;2(9):1397-1401. doi:10.1016/j.jaccas.2020.06.003 DISCLOSURES: No relevant relationships by Chelsey Bertrand- Hemmings No relevant relationships by Alyssa Foster No relevant relationships by Kyle Foster No relevant relationships by Yelena Galumyan No relevant relationships by Veronica Jacome No relevant relationships by Viet Nguyen

MTHFR C677T GENOTYPE IN CORRELATION WITH THROMBOSIS AND ASSOCIATION WITH FVIII COAGULANT ACTIVITY IN GREEK PAEDIATRIC POPULATION

Background: The polymorphism C>T substitution in position 677 (C677T) of the encoding gene of methylenetetrahydrofolate reductase (MTHFR), creates a thermolabile enzyme with reduced activity that may predispose to hyperhomocysteinemia , an established risk factor for arterial thrombosis and premature atherosclerosis and a probable risk factor for venous thromboembolic disease and its recurrence in the general population. There are conflicting results as to the role of the MTHFR C677T polymorphism as a risk factor for thrombosis. Although the homozygous substitution is often associated with hyperhomocysteinemia, mainly in folate deficiency, a clear association between this genetic marker and thrombosis has not yet been established. Aims: Primary aim was to evaluate the prevalence of mutant C677T MTHFR and its association with thrombosis in the Greek paediatric population. Secondary aim was to evaluate whether different MTHFR genotype is associated with evidence of activation of coagulation cascade through increased factor VIII activity. Methods: Data were retrospectively collected from children referred to our Haemostasis and Thrombosis Centre for laboratory screening of thrombophilia between 2018 and 2020. Some of them were checked due to history of thrombosis. Children were categorized according to MTHFR C677T genotype. FVIII Coagulant activity (%) was measured by One Stage Assay, away from acute thrombosis. The identification of mutations was based on polymerase chain reaction (PCR) and reverse- hybridization. Statistical analysis was performed with t-test and ANOVA. Results: A total of 688 children (boys: 49 %) of mean age 8.9± 8 years (0-18) were investigated. Twelve percent (81/688) of them had history of thrombosis, mainly venous thromboembolic disease. Children were categorized as follows: homozygous MTHFR C677T (15%), heterozygous (47%) and normal (38%). There was thrombosis history in 12% of homozygous MTHFR C677T, 11% heterozygous and 12 % of normal, fact showing that there is no association between MTHFR C677T genotype with thrombosis. Children with homozygosity MTHFR C677T, compared to children with heterozygosity and normal MTHFR C677T showed increased factor VIII values (132.8 vs 126.4 and 131.6, %, respectively), but without statistically significant difference. However, independently of MTHFR C677T genotype, mean factor VIII values were significantly increased in all children, with thrombosis history when they were compared to children without thrombosis history (161.3 vs 125.1, %, p<0.001). Interestingly, in children with thrombosis, mean factor VIII level was statistically increased in heterozygous and normal MTHFR C677T in contrast to children with MTHFR C677T homozygosity, in whom no statistically significant increase was found (166.9 vs 121.4, %-p<0.05, 160.2 vs 127.6, %-p<0.05 and 148.3 vs 130.6, %-p>0.05, respectively). Finally, it should be noticed that during the year 2020 mean factor VIII values were much increased in all children in comparison to the years 2018, 2019 and 2021 (137 vs 129, 123 and 127, %, respectively), probably reflecting the effects of unknown pandemic COVID-19 which initiated in 2020, and showing that factor VIII could be an evidence of stress condition. Summary/Conclusion: There is no probably association between MTHFR C677T genotype and thrombosis in our paediatric population. Moreover, it was not proved that different MTHFR genotypes affect factor VIII activity.

Catatonia Associated With Cerebral Venous Thrombosis in a COVIDPositive Adolescent

BACKGROUND: Catatonia is a psychomotor syndrome characterized by abnormal movements and decreased responsiveness. Diagnosis is made by observing or eliciting at least 3 of the following 12 criteria: stupor, catalepsy, waxy flexibility, mutism, negativism, posturing, mannerism, stereotypy, agitation, grimacing, echolalia, and echopraxia. It is commonly associated with psychiatric disorders but can also be secondary to a medical condition, more commonly neurologic or metabolic conditions. CASE DESCRIPTION: Patient was a 17-year-old female brought in by her guardian for evaluation at a psychiatric assessment center following a month of regressive behavior and concerns of possible hallucinations. While at the assessment center, the patient began hyperventilating and had 3 seizures. She was transferred to a nearby hospital and continued to seize, becoming hypoxic and requiring intubation. Computed tomography was unremarkable;urine drug testing was positive for THC and benzodiazepines. The patient was transferred to the intensive care unit of a children's hospital. She continued to have poverty of speech, decreased responsiveness, and disorganized behavior after extubation. Child psychiatric services was consulted for these concerns, and differential included psychotic disorder and catatonia, either secondary to psychiatric or medical cause. Patient underwent extensive medical evaluation, which was overall unremarkable, to rule out medical causes (including electroencephalography, cerebrospinal fluid studies, complete blood counts, C-reactive protein, and anti-NMDA antibodies). She did test positive for COVID, which resulted in delay of brain magnetic resonance imaging (MRI) being obtained. She had partial response to lorazepam challenge, and scheduled doses of lorazepam were started after. Bush Francis Catatonia Scale scores did lower partially with scheduled lorazepam, but full resolution of symptoms was not observed. MRI done on day 10 showed findings suspicious for superior sagittal thrombosis. Brain magnetic resonance venography showed superior sagittal and bilateral transverse venous thrombosis. The patient was started on anticoagulation therapy and discharged from hospital with the recommendation of psychiatry and neurology outpatient follow-up. She did not follow up with neurology but did have slow resolution of symptoms per outpatient psychiatry records. DISCUSSION: Catatonia typically results in resolution of symptoms with treatment of underlying cause along with benzodiazepines or electroconvulsive therapy. It is commonly associated with psychiatric disorders, but it is important to evaluate for medical causes as well, especially when there are concerning signs/symptoms. In this patient, there was only a partial response to benzodiazepines, but further improvement with anticoagulation therapy. This along with no previous psychiatric history supports an underlying medical cause. This patient had no history of health conditions associated with hyper-coagulopathies. However, COVID has been associated with risk for arterial and venous thromboembolic complications.

EFFICACY and SAFETY of UPADACITINIB in PATIENTS with ACTIVE ANKYLOSING SPONDYLITIS REFRACTORY to BIOLOGIC THERAPY: A DOUBLEBLIND, RANDOMIZED, PLACEBO-CONTROLLED PHASE 3 TRIAL

Background: Upadacitinib (UPA) was shown to be safe and effective through 2 years in patients (pts) with active ankylosing spondylitis (AS) naïve to biologic disease-modifying antirheumatic drugs (bDMARDs) in the pivotal phase 2/3 SELECT-AXIS 1 trial.1,2 Objectives: To assess the efficacy and safety of UPA in pts with active AS with an inadequate response (IR) to bDMARDs. Methods: SELECT-AXIS 2 (NCT04169373) was conducted under a master protocol and includes two separate studies (one for AS bDMARD-IR and one for non-radiographic axial spondyloarthritis [nr-axSpA]). The AS bDMARD-IR study is a randomized, double-blind, placebo (PBO)-controlled, phase 3 trial that enrolled adults ≥18 years with AS who met modifed New York criteria, had BAS-DAI and pt's assessment of total back pain scores ≥4 (numeric rating scale 0-10) at study entry, and had an IR to one or two bDMARDs (TNF inhibitor or IL-17 inhibitor). Pts were randomized 1:1 to receive oral UPA 15 mg once daily (QD) or PBO during the 14-week (wk) double-blind treatment period. The primary endpoint was ASAS40 response at wk 14. Multiplicity-controlled secondary endpoints evaluated at wk 14 were improvements from baseline in disease activity (ASDAS [CRP], ASDAS ID [<1.3], ASDAS LDA [<2.1], BASDAI50, ASAS20, and ASAS PR), pain (total and nocturnal back pain), function (BASFI), objective measure of infammation (SPARCC MRI score of the spine), spinal mobility (BASMI), enthesitis (MASES), and quality of life (ASQoL and ASAS HI). Non-responder imputation incorporating multiple imputation (NRI-MI) was used to handle intercurrent events and missing data for binary endpoints. Cochran-Mantel-Haenszel (CMH) test and mixed-effect model for repeated measures (MMRM) were used for analyzing binary and continuous endpoints, respectively. Treatment-emergent adverse events (TEAEs) assessed through wk 14 are reported for pts who had ≥1 dose of study drug. Results: All 420 randomized pts with active AS received assigned treatment (UPA 15 mg, n=211;PBO, n=209);409 (97%) received study drug through wk 14. Baseline demographic and disease characteristics were generally similar between treatment groups and refective of an active AS bDMARD-IR population (74% male;mean age 42.4 years;mean disease duration 7. 7 years;83% HLA-B27 positive;mean BASDAI 6.8). Signifcantly more pts achieved the primary endpoint of ASAS40 response at wk 14 with UPA vs PBO (45% vs 18%;P<0.0001;Figure 1);UPA showed onset of effect in ASAS40 as early as wk 4 (nominal P≤0.05). All multiplicity-controlled secondary endpoints met statistical signifcance for UPA vs PBO at wk 14 across multiple clinical domains of AS (P<0.0001;Figure 1). The rate of TEAEs was similar between treatment groups through wk 14 (UPA, 41%;PBO, 37%). TEAEs led to discontinuation in 3 (1.4%) pts treated with PBO and none with UPA. Serious infections occurred with UPA (2.4%) but not with PBO and included 4 events of COVID-19 and 1 event of uveitis. Additional events of uveitis were reported in 3 (1.4%) pts treated with PBO. Infammatory bowel disease (IBD) occurred in 1 (0.5%) pt on UPA and none on PBO. No malignancy, major adverse cardiovascular events, venous thromboembolic events, or death were reported with UPA;1 event of malignancy was observed with PBO. Conclusion: UPA 15 mg QD was signifcantly more effective than PBO over 14 wks of treatment in pts with active AS and IR to bDMARDs. No new safety risks were identifed with UPA compared with its known safety profile.3,4 These fndings are consistent with and complementary to those of SELECT-AXIS 1 (bDMARD-naïve AS population),1,2 and support the use of UPA in pts with active AS, including those who had a previous IR to bDMARD therapy.

RISK FACTORS OF HIGH RISK UPPER GASTROINTESTINAL BLEEDING IN PATIENTS WITH CORONAVIRUS 2019 INFECTION

Background: Gastrointestinal (GI) bleeding is one of the impactful complications in patients hospitalized from Covid-19 infection. The previous study showed the risk factors of overall (upper and lower) GI bleeding in patients with Covid-19 infection but no study focused on patients with upper GI bleeding (UGIB). This study aimed to identify the risk factors and outcomes of patients who were hospitalized from Covid-19 infection and developed UGIB. Methods: This is a retrospective in university-hospital which enrolled patients who were admitted due to Covid-19 infection and developed UGIB between April and October 2021. The primary outcome was the associated factors of high risk UGIB defined by having hematemesis or fresh blood from NG tube or hematochezia plus hemodynamic instability. The secondary outcomes were etiologies of high risk UGIB and mortality in those patients. Results: Of 7,214 patients hospitalized though the period, 49 patients (0.7%) had evidence of UGIB. The majority were male (63.3%) with mean ages of 70+12 years. Twenty-seven from 49 patients (55.1%) had mechanical ventilator, 40 patients (81.6%) received systemic corticosteroids, and 13 patients (26.5%) received anticoagulants for venous thromboembolic prophylaxis. Seven from 49 patients (14%) had high risk UGIB;5 hematemesis (71.4%), 1 fresh blood from NG tube (14.3%), and 1 hematochezia (14.3%). There was no significant difference in term of number of patient taking antiplatelets, anticoagulants, or steroids and severity of COVID-19 infection (e.g. Mechanical ventilator needed) between two groups. The emergency endoscopy was performed in 6/7 (85.7%) patients and showed 5 peptic ulcer with non-bleeding visible vessel and 1 gastric lymphoma with blood oozing (Table 1). All 6 patients underwent endoscopic hemostasis including adrenaline injection, bipolar coaptation, clipping, Hemospray®, and over-the-scope clip. There was a robust result when conducting uni- (p=0.005) and multi-variate analysis (OR 6.38;95%CI 1.04-38.92;p= 0.045) that an absence of proton-pump inhibitor (PPI) use was the significant risk factor of high risk UGIB in targeted patients (Table 2). The overall mortality rate in patients with UGIB was 20/49 (40.8%) and 1 from 20 patients (5.0%) expired from UGIB due to moribund condition and unsuitable for endoscopy. None of patients with high risk UGIB and underwent therapeutic endoscopy expired during admission. Conclusion: Our study demonstrated that the absence of PPI use was a sole significant risk factor for high risk UGIB which required therapeutic endoscopy in patients with COVID-19 infection. We suggest that PPI prophylaxis should be prescribed in those patients once they need hospitalization regardless of the severity of COVID-19 infection and anticoagulant usage to minimize the severity of UGIB.(Table Presented)

Modern a COVID-19 Vaccine-Induced Immune Thrombosis of Central Retinal Artery-Report of a Case

Objective: To report a rarely isolated central retinal artery occlusion (CRAO) following Coronavirus disease 2019 (COVID-19) Vaccine Moderna (mRNA-1273). Background: COVID-19 caused by severe acute respiratory syndrome coronavirus was firstly reported in Dec 2019 and became pandemic as of Mar 2020. Fortunately, novel rapidly developed COVID-19 vaccines are capable of lessening the pandemic effectively. As billions of people vaccinated, however, COVID-19 vaccine-induced thrombosis (VIT) are gradually emerging. Design/Methods: A previously healthy 70-year-old man presented with acute painless visual loss of the right eye five days after the first dose of Moderna vaccine. On examination of the right eye, visual acuity (VA) was counting finger at 15 cm. Fundoscopy revealed a diffuse whitened retina with cherry-red spot. Optical coherence tomography (OCT) showed hyperreflectivity. Screening tests for platelet and D-Dimer levels were unremarkable. CRAO was treated with clopidogrel and hyperbaric oxygen therapy. The serum level of anti-platelet factor-4 (PF4) antibody was 73.34 ng/ml (ref, 0-49.99 ng/ml).Two months later, VA was counting finger at 10 cm3 and OCT revealed hyperreflectivity and mild inner retina atrophy Results: COVID-19 vaccine-induced thrombosis and thrombocytopenia (VITT) based on the victims receiving AstraZeneca and Johnson & Johnson vaccines is through autoimmune antibody against PF4. VITT is typically manifested within 6-24 days post-vaccination;thrombotic sites are in the cerebral sinus, portal vein, splanchnic vein, and pulmonary emboli;as well as thrombocytopenia and increased level of D-Dimer. Our patient had isolated CRAO five days post-Moderna vaccination but normal platelet count and D-Dimer level. Moreover, VIT with isolated CRAO was not published on PubMed. Conclusions: VIT could occur in the unusual site such as CRAO in our case. Normal platelet and D-Dimer levels might not be sensitive tools to exclude VIT. Suspected patient with thrombotic event after COVID-19 vaccines should have anti-PF4 antibody test to assure an effective treatment.

D-dimer elevation and anticoagulation therapy in COVID-19 patients

Background: In approximately 30% of COVID-19 cases, the hospitalized patients are developing venous thrombo-embolic complications, due to imune-mediated hypercoagulable responce and inadequate thromboprophylaxis. D-dimer elevattion can be seen in severe critically ill COVID-19 patients. and those with other medical conditions associated with increased thrombotic risk. Aims: The aim of the study was to analyse the fibrinolytic activity, and to monitor the anticoagulation therapy in the hospitalized COVID-19 patients at the Clinic for Infectious Diseases and Febrile States in Skopje. Methods: In a retrospective study, 1728 patients with COVID -19 infection hospitalized at the Clinic for Infectious Diseases and Febrile States with COVID-19 from March-September 2020 were analized. The D-dimers level was measured with the coagulometer Dade Behring BCS XP-Siemens with commercial reagents from Siemens. The anti-factor Xa level was measured with chromogenic anti-Xa assay. Results: Analized data from 1728 hospitalized patients showed increased level of D-dimers. The average level was 1974 ng/ml (0- 500 ng/ml). Peak D-dimer levels were seen in some patients during the hospitalization period (>35,000 ng/ml). Patients received anticoagulation therapy with low-molecular heparin. The anti-factor Xa assay was analized in nine patients, three of them were in the prophylactic range (0.2-0.5 IE), and 6 were in the therapeutic range (0.5-1.2 IE). Summary/Conclusions: Increased D-dimers in hospitalized patients with severe COVID-19 are common laboratory findings, and the are prognostic marker for in-hospital mortality. Prolonged immobility and other risk factors for VTE in those patients may lead to thrombotic complications. The dosage regimen of low molecular weight heparin must be evaluated in every patient, especially in patients with severe renal impairment, low platelet count and weight disproportions, in order for appropritate anticoagulation and avoiding the associated bleeding risk.

Cardiovascular disease after COVID-19 infection in elderly patients. Results of annual follow-up of a cohort of survivors

Introduction: Although the effects of SARS-CoV-2 infection on the cardiovascular system are well known in the acute phase, the cardiovascular impact in the elderly population surviving respiratory COVID-19 infection after 1-year follow-up has not been sufficiently studied. Methods: Observational registry of 240 elderly patients (75 years or older) consecutively admitted for and surviving COVID-19 respiratory infection between March 1 and April 30, 2020. The incidence of major cardiovascular events [MACE] (cardiovascular death [CD], acute coronary syndrome [ACS], cerebrovascular disease [CVD], venous thromboembolic disease [VTE], and heart failure [HF]) was prospectively analyzed. Results: The mean age was 83.8 ± 5.6 years (range 75-103 years). A total of 54.2% were women. Most patients had a personal history of cardiovascular risk factors: hypertension (83.3%), diabetes mellitus (27.9%), dyslipidemia (43.8%). Among the main cardiological comorbidities, a history of atrial fibrillation was the most frequent (18.8%). Of note was the high percentage of institutionalized patients (37.1%) and those with moderate-severe dementia (16.7%). After a mean follow-up of 352.2±70.4 days, 13.8% of patients died and 9.6% had MACE, the most frequent being heart failure (7.5%), with no differences in the severity or overall evolution of the acute disease. Of the 33 patients who developed HF, only 3 died of cardiovascular causes. Only 2 patients suffered a stroke, in both cases without a history of AF or anticoagulants. Only 2 patients had a thromboembolic event (0.8%). The low incidence of thrombotic events may be due in part to the high rate of anticoagulation and chronic antiplatelet therapy and the high percentage of prophylactic heparin prescription at discharge, as well as the fact that only cases with clinical repercussions. COPD, CKD, institutionalization and moderate-severe dementia are associated with an increased risk of MACE, although only COPD and prescription of loop diuretics were identified as independent risk markers in the multivariate analysis. Conclusions: In elderly COVID-19 survivors, the incidence of MACE after one year of follow-up is high, the main manifestation being heart failure. COPD and the prescription of loop diuretics were identified as independent risk markers for the development of MACE in the multivariate analysis. Baseline clinical characteristics Cox survival analysis.Predictors of MACE.

Venous thrombotic risk related to SARS-CoV-2: prevalence, recommendations and perspectives

Since the SARS-CoV-2 pandemic outbreak, growing evidence suggests that patients suffering from COVID-19 are at increased risk of thrombotic events. The sepsis-related activation of the coagulation combined with a high prevalence of common thrombotic risk factors could contribute to this prothrombotic state. Coagulation biomarkers could help in the identification of patients at risk of complications and mortality. The incidence of venous thromboembolic events appears to be increased, especially in severe COVID-19 patients. Based on that knowledge, several societies have provided recommendation on the prevention of venous thromboembolism. In this narrative review, we summarize available epidemiologic data on venous thromboembolism and recommendations on thromboprophylaxis in COVID-19.

Pegylated Interferon is an effective and well-tolerated cytroreductive agent in patients with myeloproliferative neoplasms aged over 60 years

Pegylated Interferon (PegIFN) is the recommended first-line cytoreductive therapy in patients aged <40 years with essential thrombocythaemia (ET) or polycythaemia vera (PV). However, its use in patients >60 years is often limited due to concerns about tolerability. In this study, we evaluate the efficacy and tolerability of PegIFN in patients >60 years at University College London Hospitals (UCLH). Using electronic medical records, we identified patients with ET, PV or myelofibrosis at UCLH who commenced treatment with PegIFN between 2010 and 2020 and were aged >60 years on starting therapy. Data were collected until April 2021 to allow a minimum of 1-year follow-up. Complete Haematological responses were defined as per standard European Leukaemia Net criteria. Adverse events (AE) were graded 1-5 according to Common Terminology Criteria for Adverse Events (CTCAE). Thrombosis risk was graded according to IPSET criteria for ET patients. Patients with PV were classed as high risk if they were aged >65 or had a previous history of thrombosis. Eighteen patients were included in the study. The median age was 75.1 years (range 63-91), 61% were female. Ten out of 18 (56%) had a diagnosis of ET, seven out of 18 (39%) of PV and 1/18 (6%) of post-ET myelofibrosis. Fifteen out of 18 (83%) were positive for JAK2 V617F, and two out of 18 (17%) were positive for CALR mutation. Ten out of 18 (56%) had significant cardiovascular co-morbidities at diagnosis. Five out of 18 (28%) had arterial or venous thromboembolic disease at diagnosis. Sixteen out of 18 (89%) were high-risk for thromboembolic events at diagnosis. Seventeen (94%) patients had PegIFN as a second-or thirdline agent. Of these, 15 out of 17 had received hydroxycarbamide (HU) as first-line therapy;two out of 17 had interferon alpha. PegIFN was started at a median age of 70 years (range 50-86) and continued for 5.7 years (range 2-13). Twelve out of 18 (67%) patients achieved complete remission (CR) on PegIFN monotherapy;1 out of 18 (6%) achieved CR on PegIFN and HU combination therapy, and the remaining 5 out of 18 (28%) achieved a partial remission (PR). The median time to CR was 5 months (range 1-40 months). Ten out of 18 (56%) had grade 1-2 AEs including skin rashes, cytopenia and fatigue. Three out of 18 (17%) developed a major thromboembolic event while on treatment (brachial artery embolism, transient ischaemic attack and a non-ST elevation myocardial infarction). Of these, two out of three failed to achieve a CR on PegIFN and required ongoing venesection. The third had suboptimal response due to dose escalation limited by grade 3 neutropenia. Thirteen patients (72%) remained on pegIFN at the end of the study period. Of those who discontinued, three out of five stopped due to cytopenias, one out of five died during the study period of Covid-19 infection and one out of five transformed to myelodysplastic syndrome. In this study, we present a group of patients who were at high risk for thrombosis due to their age and cardiovascular risk factors. The majority of AEs documented were grade 1-2, with only three out of 18 (17%) patients discontinuing due to AEs. The rate of CR 72% similar to that quoted in imminent studies including MPN-RC (Knudsen et al, 2018) and DALIAH trials (Mascarenhas et al, 2018), which recruited larger numbers of youngers ET and PV patients on PegIFN. Over 20% of MPN patients develop resistance or intolerance to HU (Sever et al, 2014);therefore, there is a need for alternative cytoreductive agents. Our study demonstrates PegIFN to be effective and well-tolerated for use in patients >60 years and is an excellent cytoreductive option in this cohort.

Recommendations on the treatment of venous thromboembolic disease on patients with COVID-19

Since the beginning of the COVID-19 pandemic there has been many reports regarding venous and arterial thrombotic complications in patients infected with the SARS-CoV-2 virus, however the exact mechanisms for patients with COVID-19 to develop hypercoagulability states are still unknown. Prophylactic anticoagulation is considered a fundamental strategy to avoid the aforementioned complications. The objective of the present review is to guide the treatment of thromboembolic venous disease in hospitalized patients infected with SARS-CoV-2.The present article aims to review on specific recommendations of thromboembolic prophylaxis for the treatment of venous thrombotic disease in COVID-19 hospitalized patients. Hence, we differentiate between critically and non-critically ill patients as well as the duration of treatment and the recommended strategies when discharging these patients.There is still uncertainty regarding treatment options for the aforementioned complications, until an effective strategy is found, international recommendations are our best option to follow.

SARS-CoV-2 infection, hypercoagulability and hereditary thrombophilia factors

Coronavirus disease (COVID-19) is a potentially fatal infectious disease caused by the SARS-CoV-2 virus, a virus of zoonotic origin (1). It has been observed that clinical manifestations of SARS-CoV-2 infection range from asymptomatic disease to severe viral pneumonia accompanied by severe respiratory failure and may result in death (2). The most common initial symptoms of COVID-19 disease are fever, cough, and fatigue. Transmission primarily occurs through direct contact or droplets spread from an infected person (1). The binding of a receptor expressed by host cells is the first step of viral infection. Lung epithelial cells are thought to be the primary target of the virus. Most of the used drugs are drugs used in the treatment of other diseases, and their effectiveness in the treatment of COVID-19 is still at the research level. Specific anti-infection drugs are under development for potential treatment in humans (1). Veklury (Remdesivir) is the first treatment for COVID-19 to receive FDA approval. It is used in adults and pediatric patients [12 years and older and at least 40 kilograms] for the treatment of COVID-19 requiring hospitalization (3). The treatment of COVID-19 in our country is carried out by the recommendations of the Ministry of Health's Guide 'COVID-19 (SARS-CoV-2 infection)' prepared by the recommendations of the Coronavirus Science Council and updated by the developments (4). All of the drugs recommended in the manual are used under the approval of the Ministry of Health within the framework of non-indication drug use. In this pandemic, where new waves are constantly coming, scientists have succeeded in developing a large number of COVID-19 vaccine types in a short time as a result of intensive studies. The mRNA-based Pfizer-BioNTech COVID-19 vaccine is the first FDA-approved vaccine [23.08.2021] (5). The information about the COVID-19 disease, which is spreading rapidly around the world, is increasing with new researches day by day. Thrombophilia is a hypercoagulable condition that predisposes patients to thrombosis. It is a multifactorial condition that can result from genetic factors, acquired factors, or a combination of both. The prothrombin gene (F2), factor V Leiden (F5), and PAI-1 are important biomarkers of thrombophilia. Patients with multiple gene defects have a high risk of thrombosis (6). It is known that thromboembolic events can develop in patients with COVID-19 and the incidence of death increases accordingly. Studies have shown that VTE can be induced in patients with COVID-19 and severe pneumonia, and the incidence of VTE in COVID-19 patients hospitalized in the intensive care unit due to severe pneumonia has been reported to be high (7). The risk of thrombosis and arterial and venous thromboembolic complications seen in 30% of hospitalized subjects due to Novel Coronavirus pneumonia has been reported in many studies, which can be explained by the prolonged inflammatory response, decreased physical activity during infection, and reduced oxygen levels in the circulation (6). Thrombotic and microangiopathic effects of the SARS-CoV-2 virus have been reported in COVID-19 patients (8). Circulatory disorders in the toes of COVID-19 patients are also reported as 'Covid toe (acro ischemia)' (9). Although it is reported that the disease progresses more severely in the elderly, patients with sub-diseases, and smoking history, it is also observed that the clinical course is severe and patient losses are experienced in young patients who do not have any underlying disease. The mechanisms of the development of thromboembolic events are the binding of the virus to the ACE-2 receptor and/or direct endothelial damage, activation of inflammatory and microthrombotic pathways as a result of endothelial damage by complement activation as in sepsis, and stasis due to hospitalization and immobility (10). DIC clinic may develop in patients with severe clinical course. The pathophysiology of DIC is reported to be complex and multifactorial, involving the interaction between the hemostatic system and components of the innate immune response to the infecting pathogen (11). However, there is no comprehensive research on inherited thrombophilia factors that may affect the hemostatic system. Severe clinical course in young patients, a similar clinical course in individuals from the same family even though they are in different cities, elderly patients recovering from the clinic safely and being discharged, VTE in different locations in COVID-19 patients, microangiopathic thrombus, etc. monitoring of the findings, the use of anticoagulants due to their positive contributions in treatment are included in the observations in this process. In the light of all this information, it is aimed to examine and reveal the possible relationship between the genetic variations evaluated in the thrombophilia panel and COVID-19 and presented with the literature data findings and recent studies. Gralinski et al. suggested that PAI-1 plays a protective role against infection in the viral pathogenesis studies of SARS-coronavirus disease (12). In another study, no statistically significant difference in thrombophilia polymorphic biomarkers between the severely ill COVID-19 group and the healthy population was found (6). Various studies that will provide new information on the subject are also actively continuing. In conclusion, thrombosis is frequently seen in severe COVID-19 patients. Essentially, the determination of the thrombophilia profile can assist in determining bleeding risk, mortality, ARDS incidence, and admission to the ICU. Latent genetic risk factors for thrombotic events may affect the outcome of COVID-19. Therefore, the identification of these factors may be useful for understanding the various COVID-19 outcomes and assessing COVID-19 patients' risk of thrombosis, severe disease, and vaccination policies.

Venous thromboembolic disease in children associated with COVID-19

Background: Coronavirus disease 2019 (COVID-19) is associated with venous thromboembolism (VTE) in adults and there are guidelines for prevention and management in adults but in children, no evidence based standard guidelines exist for prevention or management of VTE associated with COVID-19 as little is known about VTE in children in association with COVID-19. Antiphospholipid antibodies (lupus anticoagulant antibody, cardiolipin antibodies and beta-2 glycoprotein 1 antibodies) in conjunction with COVID-19 in adult patients with VTE have been noted. Objectives: N/A Methods: We identified 5 cases of VTE in children from April 10th 2020 till May 29th 2020. Each of those patient was tested for SARS-CoV- 2 RNA and/or SARS-CoV- 2 IgG and IgM. Diagnosis of VTE was made either using venous doppler or magnetic resonance (MR) imaging. Thrombophilia work up was sent on each patient, including testing for antiphospholipid antibodies. Results: Five cases of VTE had various types of clots including pulmonary embolism (PE) and upper or lower extremity DVT (Table 1) and all had one or more antiphospholipid antibody positivity. One case was positive for SARS-CoV- 2 RNA, two had SARS-CoV- 2 IgM positivity and two had neither RNA nor antibody positivity. Two females had DVT with PE, and two adolescent females were diagnosed with new onset of systemic lupus erythematosus (SLE) during the time of VTE diagnosis. All patients were treated with systemic anticoagulation with heparin. Conclusions: Venous thromboembolic disease in children associated with anti-phospholipid antibody is rare but we noted five cases of VTE in association with antiphospholipid antibodies in short period during pandemic, of which one case was associated with SARS-CoV- 2 RNA and two cases suggestive of recent infection with SARS-CoV- 2 RNA as IgM was positive. We conclude that our case series suggest VTE in children, in association with SARS-CoV- 2, is mediated through generation of antiphospholipid antibodies. Further prospective studies can provide clarity on this supposition. (Table Presented).

26 Congresso Nazionale della Societa Scientifica FADOI

The proceedings contain 316 papers. The topics discussed include: usefulness of NEWS and NEWS-c in predicting dismal outcomes in acute medical unit: a lesson from CoViD-19 pandemic;Efficacy and safety of anti SARS-CoV-2 monoclonal antibodies treatment in the real world;incidental pheochromocytoma: is it really silent a case series;the mesentery as an uncommon site of involvement of IgG-related disease, a rare autoimmune disorder;Risk of venous and arterial thromboembolic events in women with advanced breast cancer treated with CDK 4/6 inhibitors: a systematic review and meta-analysis;nine-year efficacy and safety of azathioprine treatment in the maintenance of steroid-free remission in inflammatory bowel disease patients;helmet CPAP in severe CoViD-19: an experience in an internal medicine ward;disease knowledge and self-care in patients with chronic venous leg ulcers: preliminary short-term results of a randomized controlled study;and Casirivimab-imdevimab combination therapy for inpatients with early diagnosis of hospital-acquired CoViD-19: a single center experience.