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Introduction/Objective: The efficacy of biologic therapy in the treatment of rheumatoid arthritis (RA) has been well-established but, in practice, a quarter of patients will either not respond to the first biologic agent or will suffer an adverse event requiring a switch to a different drug. While clinical guidelines exist to help guide therapy and previous studies have examined sequential use of anti-TNF agents, there is little data to inform a multiple switch strategy. Our aim was to measure the efficacy of multiple switches of biologic in severe refractory RA. Methods: We enrolled 111 patients whose therapy with one anti-TNF agent had failed in this open-label observational study. These patients were all treated with a second biologic agent and 27 ultimately required treatment with a third. The response to the therapy and disease activity were assessed at 6 and 12 months after each switch. Results: The remission rates at 6 months were lower than previously reported and the initiation of a second biologic agent resulted in significant improvement at 12 months, including DAS remission in 36% of patients. The response in those receiving a third biologic was less pronounced, as might be expected in this relatively treatment-refractory population. In this group, only patients treated with tocilizumab had maintained remission at one year. Conclusion: Patients who do not respond to an anti-TNF agent often benefit from being switched to a second, or even third, biologic. Importantly, it may take longer than expected to fully assess the effectiveness of a second or third agent in patients with refractory disease.

Background: Endocan is a soluble dermatan sulfate PG (50kDa), expressed and secreted by endothelial cells of the dermal microvasculature, the coronary, the pulmonary arteries and the capillaries from adipose tissue. It plays an important role in the pathogenesis of vascular disorders, inflammation, endothelium dysfunction and neoangiogenesis. The biosynthesis of endocan is upregulated by inflammatory cytokines like TNF-α, IL-1, TGF-β1 and by proangiogenic and growth factors like VEGF, EGF and FGF-2; conversely, it is downregulated by INF-γ and insulin level, but this event in obese patients is attenuated by insulin resistance. Methods: The study included 19 patients with obesity (10 males and 9 females), aged between 2-18 years, screened at the pediatric Endocrinology Clinic of our Department in Messina (Italy). Results: The results, compared with the healthy controlled group, have shown upraised endocan serum levels in children with BMI higher than normal (30,044 ±0,984), demonstrating a positive correlation trend between endocan and BMI (rho 0.356, p = 0.13). Furthermore endocan serum levels were significantly correlated to the insulin levels (rho 0.474, p = 0.047) and HOMA-IR (rho 0.434, p = 0.072). These findings confirm the correlation between endothelial damage and insulin resistance in obese children. Instead we did not found any association between Endocan and lipid serum levels, nor with the fasting blood glucose value (rho 0.024, p = 0.926). An elevated correlation was also revealed with steatosis, and with the ultrasound grade of liver steatosis (rho 0.514, p = 0.087 and rho 0.512, p = 0.088, respectively), despite not raising statistically significant results, given the small sample size, indeed only 12 children of the study underwent ultrasound. Conclusions: We can assume that endocan could be used also in children with obesity as a biomarker and that could be a valid predictor in order to stratify the future cardiovascular risk in adulthood. Retrospectively registered

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease characterized by the thickening of the heart muscle, which can lead to symptoms such as chest pain, shortness of breath, and an increased risk of sudden cardiac death. However, not all patients with HCM have the same underlying genetic mutations, and some have conditions that resemble HCM but have different genetic or pathophysiological mechanisms, referred to as phenocopies. Cardiac magnetic resonance (CMR) imaging has emerged as a powerful tool for the non-invasive assessment of HCM and its phenocopies. CMR can accurately quantify the extent and distribution of hypertrophy, assess the presence and severity of myocardial fibrosis, and detect associated abnormalities. In the context of phenocopies, CMR can aid in the differentiation between HCM and other diseases that present with HCM-like features, such as cardiac amyloidosis (CA), Anderson–Fabry disease (AFD), and mitochondrial cardiomyopathies. CMR can provide important diagnostic and prognostic information that can guide clinical decision-making and management strategies. This review aims to describe the available evidence of the role of CMR in the assessment of hypertrophic phenotype and its diagnostic and prognostic implications.

To realize a machine learning (ML) model to estimate the dose of low molecular weight heparin to be administered, preventing thromboembolism events in COVID-19 patients with active cancer. Methods: We used a dataset comprising 131 patients with active cancer and COVID-19. We considered five ML models: logistic regression, decision tree, random forest, support vector machine and Gaussian naive Bayes. We decided to implement the logistic regression model for our study. A model with 19 variables was analyzed. Data were randomly split into training (70%) and testing (30%) sets. Model performance was assessed by confusion matrix metrics on the testing data for each model as positive predictive value, sensitivity and F1-score. Results: We showed that the five selected models outperformed classical statistical methods of predictive validity and logistic regression was the most effective, being able to classify with an accuracy of 81%. The most relevant result was finding a patient-proof where python function was able to obtain the exact dose of low weight molecular heparin to be administered and thereby to prevent the occurrence of VTE. Conclusions: The world of machine learning and artificial intelligence is constantly developing. The identification of a specific LMWH dose for preventing VTE in very high-risk populations, such as the COVID-19 and active cancer population, might improve with the use of new training ML-based algorithms. Larger studies are needed to confirm our exploratory results.

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) represents a public health problem worldwide. COVID-19 triggers a maladaptive cytokine release commonly referred to as cytokine storm syndrome with increased production of proinflammatory cytokines, which also appears to contribute to chronic neuroinflammation and neurodegenerative disorders’ appearance, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. In this context, SARS-CoV-2 might enter the central nervous system through binding with the angiotensin converting enzyme 2 receptors which are highly expressed in glial cells and neurons. For this reason, an association between COVID-19, its dependent cytokine storm, and the development and/or progression of neurodegenerative disorders might be evaluated. Therefore, the aim of this review was to assess the impact of COVID-19 on neurodegenerative disorders, focusing on the possible increased mortality risk and/or deterioration of the clinical course of pre-existing chronic neurological diseases in patients with dementia.

Introduction. The actual prevalence of pulmonary hypertension (PH) in Italy is unknown. Echocardiography is useful in the screening of patients with suspected PH by estimation of the pulmonary artery systolic pressure (PASP) from the regurgitant tricuspid flow velocity evaluation, according to the simplified Bernoulli equation. Objectives. We aimed to evaluate the frequency of suspected PH among unselected patients. Methods. We conducted a retrospective cross-sectional database search of 7005 patients, who underwent echocardiography, to estimate the prevalence of PH, between January 2013 and December 2014. Medical and echocardiographic data were collected from a stratified etiological group of PH, using criteria of the European Society of Cardiology classifications. Results. The mean age of the study population was 57.1 ± 20.5 years, of which 55.3% were male. The prevalence of intermediate probability of PH was 8.6%, with nearly equal distribution between men and women (51.3 vs. 48.7%, p = 0.873). The prevalence of high probability of PH was 4.3%, with slightly but not significant higher prevalence in female patients (43.2 vs. 56.8%, p = 0.671). PH is predominant in patients with chronic obstructive pulmonary disease (COPD) or left ventricle (LV) systolic dysfunction and related with age. PASP was significantly linked with left atrial increase and left ventricular ejection fraction. In addition, an increased PASP was related to an enlargement of the right heart chamber. Conclusions. PH has a frequency of 4.3% in our unselected population, but the prevalence may be more relevant in specific subgroups. A larger epidemiological registry could be an adequate strategy to increase quality control and identify weak points in the evaluation and treatment of these patients.

The COVID-19 outbreak has had a dramatic impact on the healthcare system due to the rapid, worldwide spread of the virus, highlighting several considerations on the best management of infected patients and also potential risks and prognostic factors in patients with pre-existing chronic diseases exposed to the virus. Neurodegenerative disorders are known to be chronic, disabling diseases that imply a higher vulnerability to infections, and for this reason, it has been suggested that SARS-CoV-2 infection may have a worse course in these patients. In the present study, we report our experience with 12 patients affected by Parkinson's disease (PD) who became infected with SARS-Cov-2 due to a COVID-19 outbreak in a care residency, and thus hospitalised in our COVID hospital. Most of the PD patients had a long disease duration and multiple comorbidities even though SARS-CoV-2 manifestations were mild, and none required intensive care. Despite lung conditions, most of our PD patients had mild symptoms: 7 patients were clinically asymptomatic (58.3%); 3 patients had fever, cough, and myalgia (25%) and 2 patients had dyspnoea (16%) that needed high-flow oxygen therapy. Few complications related to PD were seen. All patients were discharged after a mean hospitalisation period of 30 days. Mortality rate during hospitalisation was zero. Our findings suggest that SARS-CoV-2 infection does not have a poor prognosis in patients with PD. More extensive data and evaluations, however, are needed to confirm our data, and caution is warranted.

Percutaneous coronary intervention (PCI) is one of the most common procedures performed in medicine. However, its net benefit among patients with chronic kidney disease (CKD) is less well established than in the general population. The prevalence of patients suffering from both CAD and CKD is high, and is likely to increase in the coming years. Planning the adequate management of this group of patients is crucial to improve their outcome after PCI. This starts with proper preparation before the procedure, the use of all available means to reduce contrast during the procedure, and the implementation of modern strategies such as radial access and drug-eluting stents. At the end of the procedure, personalized antithrombotic therapy for the patient’s specific characteristics is advisable to account for the elevated ischemic and bleeding risk of these patients.

The novel Coronavirus 19 infection spread rapidly from Wuhan, Hubei Province – China, to the worldwide, becoming a pandemic. The infection does not cause only flu-like syndrome (fever, dry cough and shortness of breath) and respiratory distress of varying severity but also affects the kidneys, the heart, the nervous system and the circulatory apparatus, causing thromboembolic events. Usually these problems occur in patients with severe respiratory failure admitted to Intensive Care Unit and with pre-existing comorbidities.We report the case of a patient without Covid symptoms who had thrombotic stroke as the presenting features of Coronavirus infection.

Although myocarditis can be a severe cardiac complication of COVID-19 patients, few data are available in the literature about the incidence and clinical significance in patients affected by SARS-CoV-2. This study aims to describe the prevalence and the clinical features of suspected myocarditis in 3 cohorts of patients hospitalized for COVID-19. We retrospectively evaluated all the consecutive patients admitted for COVID-19 without exclusion criteria. Suspect myocarditis was defined according to current guidelines. Age, sex, in-hospital death, length of stay, comorbidities, serum cardiac markers, interleukin-6, electrocardiogram, echocardiogram, and therapy were recorded. Between March 4 to May 20, 2020, 1169 patients with COVID-19 were admitted in 3 Italian Medicine wards. 12 patients (1%) had suspected acute myocarditis; 5 (41.7%) were men, mean age was 76 (SD 11.34; median 78.5 years); length of stay was 38 days on average (SD 8, median value 37.5); 3 (25%) patients died. 8 (66.7%) had a history of cardiac disease; 7 (58.33%) patients had other comorbidities like diabetes, chronic obstructive pulmonary disease, or renal insufficiency. Myocarditis patients had no difference in sex prevalence, rate of death, comorbidities, elevations in serum cardiac markers as compared with patients without myocardial involvement. Otherwise, there was a significantly higher need for oxygen-support and a higher prevalence of cardiac disease in the myocarditis group. Patients with suspected myocarditis were older, had a higher frequency of previous cardiac disease, and significantly more prolonged hospitalization and a lower value of interleukin-6 than other COVID-19 patients. Further studies, specifically designed on this issue, are warranted.

Rheumatic diseases are associated with accelerated atherosclerosis and with increased risk of cardiovascular morbidity and mortality. The mechanisms underlying the higher prevalence of cardiovascular disease are not completely clarified, but it is likely that a pivotal role is played by vascular inflammation and consequently to altered vascular endothelium homeostasis. Also, high prevalence of traditional risk factors, proatherogenic activation and endothelial dysfunction further contribute to vascular damage. Circulating endothelial progenitor cells (EPCs) can restore dysfunctional endothelium and protect against atherosclerotic vascular disease. However, abnormalities in number and function of these cells in patients with rheumatic condition have been extensively reported. During the last years, growing interest in the mechanisms of endothelial renewal and its potential as a therapy for CVD has been shown; in addition, pioneering studies show that EPC dysfunction might be improved with pharmacological strategies. However, how to restore EPC function, and whether achieving this aim may be effective in preventing cardiovascular complications in rheumatic disease, remain to be established. In this review we report an overview on the current stand of knowledge on the effect of pharmaceutical and lifestyle intervention in improving EPCs number and function in rheumatic disease.

Patient: Female, 56 Final Diagnosis: Hereditary thombophilia Symptoms: Dyspnea Medication: — Clinical Procedure: — Specialty: Hematology Objective: Congenital defects/diseases Background: Thrombophilia is a predisposition to thrombosis. Genetic causes include antithrombin III, protein C, protein S, factor V Leiden, prothrombin 20210A allele, and MTHFR mutations. Other genetic factors causing thrombosis and pulmonary embolism have been identified in recent studies, including 4G/4G polymorphism of the PAI-1 gene. Case Report: A patient with a personal and family history of recurrent thrombosis and pulmonary embolism was admitted to our Internal Medicine Department. After the most common acquired risk factors for thromboembolism were ruled out, the patient and her family members underwent genetic diagnostic testing. These tests showed homozygous 4G/4G polymorphism of the PAI-1 gene in 14 subjects, homozygous 4G/4G polymorphism of the PAI-1 gene and C677T/A1298C polymorphism of the MTHFR gene in 4 subjects, and heterozygous 4G/4G polymorphism of the PAI-1 gene and C677T/A1298C polymorphism of the MTHFR gene in 3 subjects. Afterwards, we initiated the administration of Rivaroxaban, with beneficial results. Conclusions: No thrombotic recurrence has been observed in the patient since 2014. This case report shows the efficacy and superiority of Rivaroxaban over traditional anticoagulants in the treatment of hereditary thrombophilia. Further studies are clearly needed before Rivaroxaban can be recommended as a standard treatment in patients with inherited thrombophilia.

Strongyloides stercoralis (S. stercoralis) is a parasite, endemic in tropical, subtropical, and also not rarely in temperate regions, that infects up to 100 million people worldwide [1]. Patients m...

Background and aims Suboptimal vitamin D status was recently acknowledged as an independent predictor of cardiovascular diseases and all-cause mortality in several clinical settings, and its serum levels are commonly reduced in Rheumatoid Arthritis (RA). Patients affected by RA present accelerated atherosclerosis and increased cardiovascular morbidity and mortality with respect to the general population. In RA, it has been reported an impairment of the number and the activity of circulating proangiogenic haematopoietic cells (PHCs), including CD34+, that may play a role in endothelial homeostasis. The purpose of the study is to investigate the association between vitamin D levels and PHCs, inflammatory markers, and arterial stiffening in patients with RA. Methods and results CD34+ cells were isolated from 27 RA patients and 41 controls. Vitamin D levels, C-reactive protein (CRP), fibrinogen, pulse wave velocity (PWV), and carotid intima-media thickness (cIMT) were also evaluated. CD34+ count and vitamin D levels were lower in RA patients as compared to controls, while fibrinogen, CRP, PWV and cIMT were higher in RA patients. CD34+ cell number appeared to be associated with vitamin D levels, and negatively correlated to fibrinogen and early atherosclerosis markers (PWV and cIMT); vitamin D levels appear also to be inversely associated to fibrinogen. Conclusions RA patients with moderate disease activity presented with low vitamin D levels, low CD34+ cell count, increased PWV and cIMT; we found that vitamin D deficiency is associated to CD34+ cell reduction in peripheral blood, and with fibrinogen levels. This suggests that vitamin D might contribute to endothelial homeostasis in patients with RA.

Objective : Cigarette smokers present early signs of vascular damage and systemic inflammation. Biglycan (BGN), an ubiquitous component of extracellular matrix orchestrating several physiological functions, has recently been indicated as a major source of low-density lipoprotein retention in the normal arterial intima-media layer. We evaluated whether BGN-mRNA expression was enhanced in peripheral monocytes of smokers with no additional cardiovascular risk factors (CVRFs), and if it was associated with altered carotid arterial stiffness (AS) or intima media thickness (cIMT). We also evaluated plasma markers of systemic and vascular inflammation, and correlation with BGN-mRNA. Methods : Two-hundred-fifty-one young smokers were enrolled, with no additional CVRFs, and 60 controls. Plasma lipids, fibrinogen, C-reactive protein (CRP), interleukin-6 (IL-6), AS and cIMT were assessed. A smoke exposure index (SEIx) was calculated. Results : Fibrinogen, CRP, AS indices, cIMT, and BGN-mRNA were higher in smokers compared to controls; HDL-C levels were lower, no difference was detected in IL-6 levels. After stratification of smokers in quartiles based on SEIx values, smokers in the highest quartiles presented highest fibrinogen, CRP, AS, cIMT, BGN, and also IL-6 values, and lowest HDL-C. Conclusion : BGN-mRNA was enhanced in young smokers, compared to controls, and appears associated to a proatherogenic profile, characterized by increased fibrinogen, CRP, and IL-6, lower HDL-C, altered AS and cIMT values, particularly in those with higher SEIx: the more cigarettes smoked over years, the more marked the alterations. Although we cannot state whether BGN have a direct causal role in inducing, maintaining and developing vascular damage, including intima-media wall thickening and arterial stiffening, our data could suggest that it may represent a link between proatherogenic status induced by cigarette smoking, and the development and progression of vascular damage.

Cardiovascular (CV) diseases and related complications are the main causes of morbidity and mortality in the elderly. CV progenitor cells, including CD34+ cells, play a role in delaying the progression of atherosclerosis. In the present study we observed 100 octogenarians for seven years, in order to address the question of whether CD34+ cell number is a predictor of longevity in selected survivors. We also checked for associations of cell expression of manganese superoxide dismutase (Mn-SOD), catalase (CAT), and glutathione peroxidase type-1 (GPx-1) antioxidative enzymes, with number of CD34+ progenitor cells and mortality. We found that in very old subjects the number of CD34+ cells at baseline were higher in subjects who reached older age at death or were still living at the end of observation period, with respect to subjects who died from all causes, including CV deaths. On the other hand, HDL-C plasma levels and, with the exception of diabetes, the classic CV risk factors (hypertension, smoking, hypercholesterolemia) showed a loss of their predictive power. A significant association between the redox system of CD34+ cells and mortality was also observed. These data suggest that, even in the elderly, CD34+ cells maintain their role in predicting mortality. CD34+ cells could thus be considered as a biomarker of longevity.

Background Circulating progenitor cells (CPCs), including CD34+ cells and endothelial progenitor cells (EPCs), play a role in delaying atherosclerosis and cardiovascular disease. Toll-like receptor 3 (TLR3), a member of the pathogen recognition receptors that mediates immune response and activates inflammatory genes, is involved in the development of atherosclerosis. TLR3 has been recently detected in EPCs and its “in vitro” activation appears to induce cytokine expression and apoptosis. We measured the expression of TLR3 and Interleukine1β- mRNA in CPCs isolated from patients with rheumatoid arthritis. Objectives The aim was to evaluate whether systemic inflammation is associated with CPC number and CPC expression of TLR3 and IL-1β. Methods CD34+ cells were isolated from peripheral blood from 21 patients with rheumatoid arthritis (RA patients) and from 21 matched controls. TLR3 and IL-1β -RNA expression were measured in enriched sample of CD34+ cells. Plasma C-reactive protein (CRP) and fibrinogen levels were also measured. Results With respect to controls, CD34+ cell number was lower in RA patients. CRP and fibrinogen levels were higher in RA patients than in controls. TLR3-mRNA anf IL-1βexpression were significantly higher in RA patients with respect to controls. CRP and fibrinogen levels were associated with IL-1β e TLR3 expression; moreover, the increased expression of TLR3 and IL-1β were associated with lowering CPC number. Conclusions RA is associated to an increased expression of TLR3 and of IL-1β in CPCs, which appear to affect the decrease of CPC number. It is likely that this novel association may at least in part contribute to explain the increase of cardiovascular morbidity and mortality in patients suffering from RA. Further studies could clarify whether the modulation of TLR3 expression in CPCs may modify the CV risk in patients affected by RA. References Herbrig K et al. Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells. Ann Rheum Dis 2006;65(2):157-63. Yang M et al. The functional expression of TLR3 in EPCs impairs cell proliferation by induction of cell apoptosis and cell cycle progress inhibition. Int Immunopharmacol 2011, 11(12):2118-2124. Raicevic G et al. Inflammation modifies the pattern and the function of Toll-like receptors expressed by human mesenchymal stromal cells. Hum Immunol 2010, 71(3):235-244. Ito C et al. Cilostazol enhances IL-1beta-induced NO production and apoptosis in rat vascular smooth muscle via PKA-dependent pathway. Cell Signal 2002, 14(7):625-632. Zimmer S et al. Activation of endothelial toll-like receptor 3 impairs endothelial function. Circ Res 2011, 108(11):1358-1366. Disclosure of Interest None Declared

This study investigated the behavior of soluble intercellular adhesion molecule-1 (sICAM-1) and serum nitric oxide (NO) products, nitrite/nitrate (NO 2-NO,-), in subjects with primary hypercholesterolemia (HCh) without other risk factors and atherosclerosis. The effect of a short-term cholesterol-lowering treatment with atorvastatin, an HMG-CoA reductase inhibitor, on the levels of sICAM-1 and NO2-/NO3 were also investigated. After 4 weeks of placebo administration, 40 HCh (15 males and 25 females) were randomized in 2 groups: 20 subjects (atorvastatin group) received 10 mg/day of atorvastatin and the remaining 20 (placebo group) continued to take placebo. At baseline and after 4 and 12 weeks of atorvastatin or placebo administration, serum sICAM-1 and NO2-/NO3-levels were evaluated. The basal levels of these parameters were compared with those of 20 healthy subjects (C), matched for sex and age. Hypercholesterolemic subjects showed sICAM-1 and NO2-/NO3-basal values that were higher (331.7 ± 60.3 ng/mL vs. 202.3 ± 32.3 ng/mL, p