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Over the past decade, remote monitoring (RM) has become an increasingly popular way to improve healthcare and health outcomes. Modern cardiac implantable electronic devices (CIEDs) are capable of recording an increasing amount of data related to CIED function, arrhythmias, physiological status and hemodynamic parameters, providing in-depth and updated information on patient cardiovascular function. The extensive use of RM for patients with CIED allows for early diagnosis and rapid assessment of relevant issues, both clinical and technical, as well as replacing outpatient follow-up improving overall management without compromise safety. This approach is recommended by current guidelines for all eligible patients affected by different chronic cardiac conditions including either brady- and tachy-arrhythmias and heart failure. Beyond to clinical advantages, RM has demonstrated cost-effectiveness and is associated with elevated levels of patient satisfaction. Future perspectives include improving security, interoperability and diagnostic power as well as to engage patients with digital health technology. This review aims to update existing data concerning clinical outcomes in patients managed with RM in the wide spectrum of cardiac arrhythmias and Hear Failure (HF), disclosing also about safety, effectiveness, patient satisfaction and cost-saving.

Aim: We examined whether metabolic dysfunction-associated steatotic liver disease (MASLD) with or without significant fibrosis (assessed by validated non-invasive biomarkers) was associated with an increased risk of prevalent chronic kidney disease (CKD) or diabetic retinopathy in people with type 1 diabetes mellitus (T1DM). Methods: We performed a retrospective multicenter cross-sectional study involving 1,409 adult outpatients with T1DM, in whom hepatic steatosis index (HSI) and fibrosis (FIB)-4 index were calculated for non-invasively detecting hepatic steatosis (defined by HSI > 36), with or without coexisting significant fibrosis (FIB-4 index ≥ 1.3 or < 1.3). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or urine albumin/creatinine ratio ≥ 3.0 mg/mmol. The presence of diabetic retinopathy was also recorded in all participants. Results: Patients with MASLD and significant fibrosis (n = 93) had a remarkably higher prevalence of CKD and diabetic retinopathy than their counterparts with MASLD without fibrosis (n = 578) and those without steatosis (n = 738). After adjustment for sex, diabetes duration, hemoglobin A1c, hypertension, and use of antihypertensive or lipid-lowering medications, patients with SLD and significant fibrosis had a higher risk of prevalent CKD (adjusted-odds ratio 1.76, 95 % confidence interval 1.05–2.96) than those without steatosis. Patients with MASLD without fibrosis had a higher risk of prevalent retinopathy (adjusted-odds ratio 1.49, 95 % CI 1.13–1.46) than those without steatosis. Conclusion: This is the largest cross-sectional study showing that MASLD with and without coexisting significant fibrosis was associated, independently of potential confounders, with an increased risk of prevalent CKD and retinopathy in adults with T1DM.

Aims A previous randomized study demonstrated that the subcutaneous implantable cardioverter defibrillator (S-ICD) was noninferior to transvenous ICD with respect to device-related complications and inappropriate shocks. However, that was performed prior to the widespread adoption of pulse generator implantation in the intermuscular (IM) space instead of the traditional subcutaneous (SC) pocket. The aim of this analysis was to compare survival from device-related complications and inappropriate shocks between patients who underwent S-ICD implantation with the generator positioned in an IM position in comparison with an SC pocket. Methods and results We analysed 1577 consecutive patients who had undergone S-ICD implantation from 2013 to 2021 and were followed up until December 2021. Subcutaneous patients (n = 290) were propensity matched with patients of the IM group (n = 290), and their outcomes were compared. : During a median follow-up of 28 months, device-related complications were reported in 28 (4.8%) patients and inappropriate shocks were reported in 37 (6.4%) patients. The risk of complication was lower in the matched IM group than in the SC group [hazard ratio 0.41, 95% confidence interval (CI) 0.17-0.99, P = 0.041], as well as the composite of complications and inappropriate shocks (hazard ratio 0.50, 95% CI 0.30-0.86, P = 0.013). The risk of appropriate shocks was similar between groups (hazard ratio 0.90, 95% CI 0.50-1.61, P = 0.721). There was no significant interaction between generator positioning and variables such as gender, age, body mass index, and ejection fraction. Conclusion Our data showed the superiority of the IM S-ICD generator positioning in reducing device-related complications and inappropriate shocks.

Background and aims: Interest in the role of atrial substrate in maintaining Atrial Fibrillation (AF) is growing. Fibrosis is the culprit in the electrical derangement of the myocytes. Many cardiovascular risk factors are known to be linked to atrial scarring; among them Uric Acid (UA) is emerging. The purpose of our study is to find whether UA is associated with Left Atrium (LA) with pathological substrate. Methods and results: 81 patients who underwent radiofrequency transcatheter ablation for nonvalvular AF at the cardiological department of the Niguarda Hospital were enrolled in an observational, cross-sectional, single-center study. UA levels were analysed before the procedure. High density electroanatomic mapping of the LA was performed and patients were divided according to the presence or not of areas of pathological substrate (bipolar voltage <0.5 mV in sinus rhythm). 19 patients showed a LA with pathological substrate. These subjects showed a significant higher prevalence of persistent phenotype of AF (84.2 vs. 25.8%, p < 0.001). UA levels were significantly higher in the group of patients with LA with pathological substrate (6.8 ± 1.9 vs 5.3 ± 1.4 mg/dL, p < 0.001) as well as the prevalence of hyperuricemia (26.5 vs. 6.5%, p = 0.021). The association between uric acid LA with pathological substrate remains significant even after correction for confounding factors (age, left ventricular dysfunction, valvular disease, arrythmia phenotype and furosemide use) and also when the ratio UA/creatinine was evaluated. Conclusions: In a population of patients who underwent AF ablation, higher UA levels were significantly associated with pathological LA substrate at electro-anatomical mapping.

According to Mann and Wainwright, climate change will lead to a reorganisation of the political. There is therefore an urgent need to understand how this will impact the currently dominant power relations: for the two authors, the need to find a balance between human beings and climate will lead to an unprecedented form of planetary sovereignty, which will develop from nation-states along two main dichotomous lines (sovereignty and capitalism). Why, however, is the climatic Leviathan slow to make its appearance and establish its hegemony? Perhaps, it is possible to assume that the climate issue – assuming the role of amplifier of 21st century constitutional tendencies – will prove to be fertile ground for the growth of uncontrolled private power.

The Sun is magnetically active and often produces eruptive events on different energetic and temporal scales. Until recently, the upper limit of such events was unknown and believed to be roughly represented by direct instrumental observations. However, two types of extreme events were discovered recently: extreme solar energetic particle events on the multi-millennial time scale and super-flares on sun-like stars. Both discoveries imply that the Sun might rarely produce events, called extreme solar events (ESE), whose energy could be orders of magnitude greater than anything we have observed during recent decades. During the years following these discoveries, great progress has been achieved in collecting observational evidence, uncovering new events, making statistical analyses, and developing theoretical modelling. The ESE paradigm lives and is being developed. On the other hand, many outstanding questions still remain open and new ones emerge. Here we present an overview of the current state of the art and the forming paradigm of ESE from different points of view: solar physics, stellar–solar projections, cosmogenic-isotope data, modelling, historical data, as well as terrestrial, technological and societal effects of ESEs. Special focus is paid to open questions and further developments. This review is based on the joint work of the International Space Science Institute (ISSI) team #510 (2020–2022).

Aim: We examined whether different insulin administration modalities, i.e., multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII by insulin pumps), are differently associated with the risk of having metabolic dysfunction-associated fatty liver disease (MAFLD), with or without coexisting significant liver fibrosis (assessed by validated non-invasive biomarkers), in adults with type 1 diabetes mellitus (T1DM). Methods: We conducted a retrospective, multicenter, cross-sectional study involving 1,417 adult individuals with established T1DM treated with MDI or CSII. We calculated hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting MAFLD (defined by HSI >36), with or without coexisting significant fibrosis (defined by FIB-4 index ≥ 1.3 or <1.3, respectively). Results: Compared to the MDI group (n = 1,161), insulin-pump users (n = 256; 18.1%) were more likely to be younger (mean age: 40 vs. 48 years, P < 0.001), had better glycemic control (mean hemoglobin A1c: 7.7% vs. 7.9%, P = 0.025) and a markedly lower prevalence of MAFLD with coexisting significant fibrosis (2.7% vs. 8.1%, P = 0.010), but a comparable prevalence of MAFLD without fibrosis. In multinomial logistic regression analysis, CSII therapy was associated with a ∼70%-lower risk of MAFLD with significant fibrosis (unadjusted odds ratio 0.32, 95% confidence interval 0.14–0.70; P = 0.004), but this association was no longer significant after adjustment for age, hemoglobin A1c and other potential confounders. Conclusion: The lower prevalence of MAFLD with coexisting significant fibrosis we observed in adults with T1DM using CSII therapy, compared to those using MDI therapy, is primarily mediated by inter-group differences in age.

Background: We assessed whether hepatic steatosis with or without significant fibrosis (determined by validated non-invasive biomarkers) is associated with an increased 10-year estimated risk for cardiovascular disease (CVD) in people with type 1 diabetes mellitus (T1DM). Methods: We conducted a retrospective, multicenter, cross-sectional study involving 1,254 adults with established T1DM without pre-existing CVD. We used the hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting hepatic steatosis (defined as HSI > 36), with or without coexisting significant fibrosis (defined as FIB-4 index ≥ 1.3 or < 1.3). We calculated the Steno type 1 risk engine and the atherosclerotic CVD (ASCVD) risk score to estimate the 10-year risk of developing a first fatal or nonfatal CVD event. Results: Using the Steno type 1 risk engine, a significantly greater proportion of patients with hepatic steatosis and significant fibrosis (n = 91) had a high 10-year estimated CVD risk compared to those with hepatic steatosis alone (n = 509) or without steatosis (n = 654) (75.8% vs. 23.2% vs. 24.9%, p < 0.001). After adjustment for sex, BMI, diabetes duration, hemoglobin A1c, chronic kidney disease, and lipid-lowering medication use, patients with hepatic steatosis and significant fibrosis had an increased 10-year estimated risk of developing a first fatal or nonfatal CVD event (adjusted-odds ratio 11.4, 95% confidence interval 3.54–36.9) than those without steatosis. We observed almost identical results using the ASCVD risk calculator. Conclusions: The 10-year estimated CVD risk is remarkably greater in T1DM adults with hepatic steatosis and significant fibrosis than in their counterparts with hepatic steatosis alone or without steatosis.

Aims: Patients with type 1 diabetes (T1D) have higher cardiovascular disease (CVD) risk compared to the general population. This observational study aims to evaluate sex-related differences in CVD prevalence and CVD risk estimates in a large cohort of T1D adults. Materials and methods: We conducted a multicenter, cross-sectional study involving 2,041 T1D patients (mean age 46 years; 44.9% women). In patients without pre-existing CVD (primary prevention), we calculated the Steno type 1 risk engine to estimate the 10-year risk of developing CVD events. Results: CVD prevalence (n=116) was higher in men than in women aged ≥55 years (19.2 vs 12.8%, p=0.036), but comparable between the two sexes in those aged <55 years (p=0.91). In patients without pre-existing CVD (n=1,925), mean 10-year estimated CVD risk was 15.4±0.4% without any significant sex difference. However, stratifying this patient group by age, the 10-year estimated CVD risk was significantly higher in men than in women until age 55 years (p<0.001), but this risk equalized after this age. Carotid-artery plaque burden was significantly associated with age ≥55 years and with a medium and high 10-year estimated CVD risk, without any significant sex difference. Diabetic retinopathy and sensory-motor neuropathy were also associated with higher 10-year CVD risk and female sex. Conclusions: Both men and women with T1D are at high CVD risk. The 10-year estimated CVD risk was higher in men aged <55 years than in women of similar age, but these sex differences disappeared at age ≥55 years, suggesting that female sex was no longer protective.

Recursive processing in sentence comprehension is considered a hallmark of human linguistic abilities. However, its underlying neural mechanisms remain largely unknown. We studied whether a modern artificial neural network trained with “deep learning” methods mimics a central aspect of human sentence processing, namely the storing of grammatical number and gender information in working memory and its use in long-distance agreement (e.g., capturing the correct number agreement between subject and verb when they are separated by other phrases). Although the network, a recurrent architecture with Long Short-Term Memory units, was solely trained to predict the next word in a large corpus, analysis showed the emergence of a very sparse set of specialized units that successfully handled local and long-distance syntactic agreement for grammatical number. However, the simulations also showed that this mechanism does not support full recursion and fails with some long-range embedded dependencies. We tested the model's predictions in a behavioral experiment where humans detected violations in number agreement in sentences with systematic variations in the singular/plural status of multiple nouns, with or without embedding. Human and model error patterns were remarkably similar, showing that the model echoes various effects observed in human data. However, a key difference was that, with embedded long-range dependencies, humans remained above chance level, while the model's systematic errors brought it below chance. Overall, our study shows that exploring the ways in which modern artificial neural networks process sentences leads to precise and testable hypotheses about human linguistic performance.

Background: Atherogenic dyslipidaemia has been implicated in the residual risk for cardiovascular morbidity and mortality, which remains despite attainment of LDL cholesterol goals especially in individuals with type 2 diabetes. However, its relationship with all-cause death has not been sufficiently explored. This analysis evaluated the independent association of increased triglycerides and triglyceride:HDL cholesterol ratio (TG:HDL) and decreased HDL cholesterol with total mortality and the possible modifying effect of gender in a large cohort of patients with type 2 diabetes. Methods: This observational, prospective study enrolled 15,773 patients in 19 Diabetes Clinics throughout Italy in the years 2006–2008. Triglycerides and total and HDL cholesterol were measured by colorimetric enzymatic methods. Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%). Participants were stratified by quartiles of triglycerides, HDL cholesterol, and TG:HDL. Results: There were 3,602 deaths over a follow-up 7.42 ± 2.05 years (31.0 × 1000 person-years). In the unadjusted analyses, the highest TG:HDL (but not triglyceride) and the lowest HDL cholesterol quartile were associated with increased death rate and mortality risk. When sequentially adjusting for confounders, including total, LDL, or non-HDL cholesterol and lipid-lowering treatment, mortality risk was significantly higher in the highest triglyceride (hazard ratio 1.167 [95% confidence interval 1.055–1.291], p = 0.003) and TG:HDL (1.192 [1.082–1.314], p < 0.0001) and the lowest HDL cholesterol (1.232 [1.117–1.360], p < 0.0001) quartile, though the association of triglycerides and HDL cholesterol disappeared after further adjustment for each other. Interaction with gender was significant only for HDL cholesterol (p = 0.0009). The relationship with death was stronger for triglycerides in males and HDL cholesterol in females, with these associations remaining significant even after adjustment for

Background: Several studies suggested cross talk among components of hemostasis, inflammation, and immunity pathways in the pathogenesis, neurodegeneration, and occurrence of cerebral microbleeds (CMBs) in multiple sclerosis (MS). Objectives: This study aimed to evaluate the combined contribution of the hemostasis inhibitor protein C (PC) and chemokine C-C motif ligand 18 (CCL18) levels to brain atrophy in MS and to identify disease-relevant correlations among circulating levels of hemostasis inhibitors, chemokines, and adhesion molecules, particularly in CMB occurrence in MS. Methods: Plasma levels of hemostasis inhibitors (ADAMTS13, PC, and PAI1), CCL18, and soluble adhesionmolecules (sNCAM, sICAM1, sVCAM1, and sVAP1) were evaluated by multiplex in 138MS patients [85 relapsing-remitting (RR-MS) and 53 progressive (P-MS)] and 42 healthy individuals (HI) who underwent 3-T MRI exams. Association of protein levels with MRI outcomes was performed by regression analysis. Correlations among protein levels were assessed by partial correlation and Pearson’s correlation. Results: In all patients, regression analysis showed that higher PC levels were associated with lower brain volumes, including the brain parenchyma (p = 0.002), gray matter (p < 0.001), cortex (p = 0.001), deep gray matter (p = 0.001), and thalamus (p = 0.001). These associations were detectable in RR-MS but not in P-MS patients. Higher CCL18 levels were associated with higher T2-lesion volumes in all MS patients (p = 0.03) and in the P-MS (p = 0.003). In the P-MS, higher CCL18 levels were also associated with lower volumes of the gray matter (p = 0.024), cortex (p = 0.043), deep gray matter (p = 0.029), and thalamus (p = 0.022). PC-CCL18 and CCL18-PAI1 levels were positively correlated in both MS and HI, PC–sVAP1 and PAI1–sVCAM1 only in MS, and PC–sICAM1 and PC–sNCAM only in HI. In MS patients with CMBs (n = 12), CCL18–PAI1 and PAI1–sVCAM1 levels were better correlated than those in MS patients without

Background: Several studies suggested cross talk among components of hemostasis, inflammation, and immunity pathways in the pathogenesis, neurodegeneration, and occurrence of cerebral microbleeds (CMBs) in multiple sclerosis (MS). Objectives: This study aimed to evaluate the combined contribution of the hemostasis inhibitor protein C (PC) and chemokine C-C motif ligand 18 (CCL18) levels to brain atrophy in MS and to identify disease-relevant correlations among circulating levels of hemostasis inhibitors, chemokines, and adhesion molecules, particularly in CMB occurrence in MS. Methods: Plasma levels of hemostasis inhibitors (ADAMTS13, PC, and PAI1), CCL18, and soluble adhesionmolecules (sNCAM, sICAM1, sVCAM1, and sVAP1) were evaluated by multiplex in 138MS patients [85 relapsing-remitting (RR-MS) and 53 progressive (P-MS)] and 42 healthy individuals (HI) who underwent 3-T MRI exams. Association of protein levels with MRI outcomes was performed by regression analysis. Correlations among protein levels were assessed by partial correlation and Pearson’s correlation. Results: In all patients, regression analysis showed that higher PC levels were associated with lower brain volumes, including the brain parenchyma (p = 0.002), gray matter (p < 0.001), cortex (p = 0.001), deep gray matter (p = 0.001), and thalamus (p = 0.001). These associations were detectable in RR-MS but not in P-MS patients. Higher CCL18 levels were associated with higher T2-lesion volumes in all MS patients (p = 0.03) and in the P-MS (p = 0.003). In the P-MS, higher CCL18 levels were also associated with lower volumes of the gray matter (p = 0.024), cortex (p = 0.043), deep gray matter (p = 0.029), and thalamus (p = 0.022). PC-CCL18 and CCL18-PAI1 levels were positively correlated in both MS and HI, PC–sVAP1 and PAI1–sVCAM1 only in MS, and PC–sICAM1 and PC–sNCAM only in HI. In MS patients with CMBs (n = 12), CCL18–PAI1 and PAI1–sVCAM1 levels were better correlated than those in MS patients without

Background: Increasing evidence for contribution of hemostasis components in multiple sclerosis (MS) has been reported. Hemostasis protein inhibitors display key regulatory roles, extending to regulation of innate immune response and inflammation, and promotion of blood–brain barrier integrity. Whereas the effects on hemostasis of exercise and rehabilitation strategies have been extensively investigated, relationships between MS rehabilitation strategies and hemostasis have not been previously reported. Objectives: To investigate in MS patients the association between outcomes of rehabilitative exercise and plasma levels of selected hemostasis inhibitors. Methods: Sixty-one severely disabled progressive-MS (P-MS) patients were randomized in the RAGTIME trial to receive 12 walking session of robot-assisted gait training (RAGT) or conventional overground therapy (CT). Outcome parameters were: timed 25-foot walk test (T25FWT) speed, 6-minute walking test (6MWT), Berg Balance Scale (BBS), and MS impact scale-29 (MSIS-29). Plasma levels of coagulation inhibitors protein S (PS), soluble thrombomodulin (sTM), and tissue factor pathway inhibitor (TFPI) were assayed by multiplex assay and ELISA at 4-time points: baseline (T0), intermediate (T1), end of rehabilitation (T2), 3-month follow-up (T3). Descriptive analysis, trend analysis, Spearman's rank and Pearson's correlations, and multiple regression models were used. Results: Rehabilitative exercises moderately modified plasma protein concentrations. A significant trend to increase was observed for PS (p=0.015) and TFPI (p=0.047) in the whole population, and for PS (p=0.011) in the CT group. Correlation between TFPI and sTM levels was detectable at all time points in the whole P-MS patients and in RAGT group. The correlation between TFPI and PS, present at T0, was lost during the rehabilitation, and recovered at T3 in the whole population and CT group. During rehabilitation, positive variations of TFPI were inversely relate

In this paper, we provide a comprehensive overview of the state-of-knowledge of dust flux and variability in time and space in different sectors of East Antarctica during the Holocene. By integrating the literature data with new evidences, we discuss the dust flux and grain-size variability during the current interglacial and its provenance in the innermost part of the East Antarctic plateau as well as in peripheral regions located close to the Transantarctic Mountains. The local importance of aeolian mineral dust aerosol deflated from low-elevation areas of peripheral East Antarctica is also discussed in the light of new data from several coastal, low-elevation sites.

The essay starts from the consideration that the new frontiers of the AI are forcing the jurist to rethink the fundamental categories of personal identity and identification. Today, these categories are characterised by greater fluidity and interchangeability: identification relies on data, while the analysis of big data makes it possible to trace the (digital) identity of each individual. In this complex scenario, the EU appears to be driven by the will to build an anthropocentric protection system. That is made possible through what is identified in the contribution as an equilateral triangle whose sides are cybersecurity, data protection, and AI regulation. After a brief examination of the current regulatory framework, the essay analyzes two case studies that illustrate the opportunities/criticalities inherent in the relationship between AI and personal identity. In conclusion, the question arises as to what the frontiers of the next AI regulatory framework might be.

The essay starts from the consideration that the new frontiers of the AI are forcing the jurist to rethink the fundamental categories of personal identity and identification. Today, these categories are characterised by greater fluidity and interchangeability: identification relies on data, while the analysis of big data makes it possible to trace the (digital) identity of each individual. In this complex scenario, the EU appears to be driven by the will to build an anthropocentric protection system. That is made possible through what is identified in the contribution as an equilateral triangle whose sides are cybersecurity, data protection, and AI regulation. After a brief examination of the current regulatory framework, the essay analyzes two case studies that illustrate the opportunities/criticalities inherent in the relationship between AI and personal identity. In conclusion, the question arises as to what the frontiers of the next AI regulatory framework might be.

The essay starts from the consideration that the new frontiers of the AI are forcing the jurist to rethink the fundamental categories of personal identity and identification. Today, these categories are characterised by greater fluidity and interchangeability: identification relies on data, while the analysis of big data makes it possible to trace the (digital) identity of each individual. In this complex scenario, the EU appears to be driven by the will to build an anthropocentric protection system. That is made possible through what is identified in the contribution as an equilateral triangle whose sides are cybersecurity, data protection, and AI regulation. After a brief examination of the current regulatory framework, the essay analyzes two case studies that illustrate the opportunities/criticalities inherent in the relationship between AI and personal identity. In conclusion, the question arises as to what the frontiers of the next AI regulatory framework might be.

BACKGROUND: Venous Access Devices (VADs) are the most used devices in COVID-19 patients.OBJECTIVE: Identify VADs implanted, catheter related thrombosis (CRT), catheter-related bloodstream infection (CRBSI), and accidental remove of VADs in both COVID-19 positive and COVID-19 free patients. Successive analysis was conducted comparing COVID-19 positive patients with COVID-19 free with inverse probability propensity score weights using simple regression to account for these two confounders (peripheral tip as central/peripheral and hospitalization as no/yes).METHODS: This multicenter, retrospective cohort study collected data from seven hospitals in Lombardy during the pandemic period from February 21st to May 31st 2020.RESULTS: A total of 2206 VADs were evaluated, 1107 (50.2%) of which were inserted in COVID-19 patients. In COVID-19 cohort the first choice was Long Peripheral Cannula in 388 patients (35.1%) followed by Midline Catheter in 385 (34.8%). The number of "central tip" VADs inserted in COVID-free inpatients and COVID-19 positive were similar (307 vs 334). We recorded 42 (1.9%) CRT; 32 (79.2%) were observed in COVID-19 patients. A total of 19 CRBSI were diagnosed; 15 (78.95%) were observed in COVID-19. Accidental removals were the more represented complication with 123 cases, 85 (69.1%) of them were in COVID-19. COVID-19 significantly predicted occurrence of CRT (OR=2.00(1.85-5.03); p<0.001), CRSB (OR=3.82(1.82-8.97); p<0.001), and Accidental Removal (OR=2.39(1.80-3.20); p<0.001) in our propensity score weighted models.CONCLUSIONS: CRT, CRBSI, and accidental removal are significantly more frequent in COVID-19 patients. Accidental removals are the principal complication, for this reason, the use of subcutaneously anchored securement is recommended for a shorter period than usual.

Background: Resistant hypertension is independently associated with an increased risk of death in the general hypertensive population. We assessed whether resistant hypertension is an independent predictor of all-cause mortality in individuals with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study. Methods: On 31 October 2015, vital status information was retrieved for 15,656 of the 15,773 participants enrolled in 2006-2008. Based on baseline blood pressure (BP) values and treatment, participants were categorized as normotensive, untreated hypertensive, controlled hypertensive (i.e., on-target with < 3 drugs), uncontrolled hypertensive (i.e., not on-target with 1-2 drugs), or resistant hypertensive (i.e., uncontrolled with > 3 drugs or controlled with > 4 drugs). Kaplan-Meier and Cox proportional hazards regression analyses were used to assess the association with all-cause mortality. Results: Using the 130/80 mmHg targets for categorization, crude mortality rates and Kaplan-Meier estimates were highest among resistant hypertension participants, especially those with controlled resistant hypertension. As compared with resistant hypertension, risk for all-cause mortality was significantly lower for all the other groups, including individuals with controlled hypertension (hazard ratio 0.81 [95% confidence interval 0.74-0.89], P < 0.0001), but became progressively similar between resistant and controlled hypertension after adjustment for cardiovascular risk factors and complications/comorbidities. Also when compared with controlled resistant hypertension, mortality risk was significantly lower for all the other groups, including controlled hypertension, even after adjusting for cardiovascular risk factors (0.77 [0.63-0.95], P = 0.012), but not for complications/comorbidities (0.88 [0.72-1.08], P = 0.216). BP was well below target in the controlled hypertensive groups (resistant and non-resistant) and values < 120/7

Background: Resistant hypertension is independently associated with an increased risk of death in the general hypertensive population. We assessed whether resistant hypertension is an independent predictor of all-cause mortality in individuals with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study. Methods: On 31 October 2015, vital status information was retrieved for 15,656 of the 15,773 participants enrolled in 2006-2008. Based on baseline blood pressure (BP) values and treatment, participants were categorized as normotensive, untreated hypertensive, controlled hypertensive (i.e., on-target with < 3 drugs), uncontrolled hypertensive (i.e., not on-target with 1-2 drugs), or resistant hypertensive (i.e., uncontrolled with > 3 drugs or controlled with > 4 drugs). Kaplan-Meier and Cox proportional hazards regression analyses were used to assess the association with all-cause mortality. Results: Using the 130/80 mmHg targets for categorization, crude mortality rates and Kaplan-Meier estimates were highest among resistant hypertension participants, especially those with controlled resistant hypertension. As compared with resistant hypertension, risk for all-cause mortality was significantly lower for all the other groups, including individuals with controlled hypertension (hazard ratio 0.81 [95% confidence interval 0.74-0.89], P < 0.0001), but became progressively similar between resistant and controlled hypertension after adjustment for cardiovascular risk factors and complications/comorbidities. Also when compared with controlled resistant hypertension, mortality risk was significantly lower for all the other groups, including controlled hypertension, even after adjusting for cardiovascular risk factors (0.77 [0.63-0.95], P = 0.012), but not for complications/comorbidities (0.88 [0.72-1.08], P = 0.216). BP was well below target in the controlled hypertensive groups (resistant and non-resistant) and values < 120/7

Background: Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Several observations support interactions between vascular and neurodegenerative mechanisms in multiple sclerosis (MS). To investigate the contribution of the extracranial venous compartment, we analysed expression profiles of internal jugular vein (IJV), which drains blood from CNS, and related plasma protein levels. Methods: We studied a group of MS patients (n = 19), screened by echo-color Doppler and magnetic resonance venography, who underwent surgical reconstruction of IJV for chronic cerebrospinal venous insufficiency (CCSVI). Microarray-based transcriptome analysis was conducted on specimens of IJV wall from MS patients and from subjects undergoing carotid endarterectomy, as controls. Protein levels were determined by multiplex assay in: i) jugular and peripheral plasma from 17 MS/CCSVI patients; ii) peripheral plasma from 60 progressive MS patients, after repeated sampling and iii) healthy individuals. Results: Of the differentially expressed genes (≥ 2 fold-change, multiple testing correction, P < 0.05), the immune-related CD86 (8.5 fold-change, P = 0.002) emerged among the up regulated genes (N = 409). Several genes encoding HOX transcription factors and histones potentially regulated by blood flow, were overexpressed. Smooth muscle contraction and cell adhesion processes emerged among down regulated genes (N = 515), including the neuronal cell adhesion L1CAM as top scorer (5 fold-change, P = 5 × 10 − 4 ). Repeated measurements in jugular/peripheral plasma and overtime in peripheral plasma showed conserved individual plasma patterns for immune-inflammatory (CCL13, CCL18) and adhesion (NCAM1, VAP1, SELL) proteins, despite significant variations overtime (SELL P < 0.0001). Both age and MS disease phenotypes were determinants of VAP1 plasma levels. Data supported cerebral related-mechanisms regulating ANGPT1 levels, which were

Background: Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Several observations support interactions between vascular and neurodegenerative mechanisms in multiple sclerosis (MS). To investigate the contribution of the extracranial venous compartment, we analysed expression profiles of internal jugular vein (IJV), which drains blood from CNS, and related plasma protein levels. Methods: We studied a group of MS patients (n = 19), screened by echo-color Doppler and magnetic resonance venography, who underwent surgical reconstruction of IJV for chronic cerebrospinal venous insufficiency (CCSVI). Microarray-based transcriptome analysis was conducted on specimens of IJV wall from MS patients and from subjects undergoing carotid endarterectomy, as controls. Protein levels were determined by multiplex assay in: i) jugular and peripheral plasma from 17 MS/CCSVI patients; ii) peripheral plasma from 60 progressive MS patients, after repeated sampling and iii) healthy individuals. Results: Of the differentially expressed genes (≥ 2 fold-change, multiple testing correction, P < 0.05), the immune-related CD86 (8.5 fold-change, P = 0.002) emerged among the up regulated genes (N = 409). Several genes encoding HOX transcription factors and histones potentially regulated by blood flow, were overexpressed. Smooth muscle contraction and cell adhesion processes emerged among down regulated genes (N = 515), including the neuronal cell adhesion L1CAM as top scorer (5 fold-change, P = 5 × 10 − 4 ). Repeated measurements in jugular/peripheral plasma and overtime in peripheral plasma showed conserved individual plasma patterns for immune-inflammatory (CCL13, CCL18) and adhesion (NCAM1, VAP1, SELL) proteins, despite significant variations overtime (SELL P < 0.0001). Both age and MS disease phenotypes were determinants of VAP1 plasma levels. Data supported cerebral related-mechanisms regulating ANGPT1 levels, which were

Background and purpose: The aim was to investigate the plasma levels of hemostasis components in multiple sclerosis (MS) and their association with clinical and magnetic resonance imaging (MRI) outcomes. Methods: In all, 138 MS patients [85 with relapsing–remitting MS (RR-MS) and 53 with progressive MS (P-MS) with a mean age of 54 years; 72.5% female; median Expanded Disability Status Scale 3.5; mean disease duration 21 years] and 42 age- and sex-matched healthy individuals (HI) were studied. All subjects were examined with 3 T MRI and clinical examinations. Plasma levels of hemostasis factors [procoagulant, factor XII (FXII)] and inhibitors [tissue factor pathway inhibitor (TFPI), thrombomodulin, heparin cofactor II, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) and plasminogen activator inhibitor 1 (PAI-1)] were evaluated by magnetic Luminex assays and enzyme-linked immunosorbent assay. Associations between hemostasis plasma levels and clinical and MRI outcomes were assessed. Results: Lower ADAMTS13 levels were found in MS patients compared to HI (P = 0.008) and in MS patients presenting with cerebral microbleeds compared to those without (P = 0.034). Higher PAI-1 levels were found in MS patients compared to HI (P = 0.02). TFPI levels were higher in the P-MS subgroup compared to RR-MS patients (P = 0.011) and compared to HI (P = 0.002). No significant associations between hemostasis plasma levels and clinical or MRI outcomes were found. Conclusions: Decreased ADAMTS13, particularly in MS patients with cerebral microbleeds, which deserves further investigation, and increased PAI-1 and TFPI levels were observed in MS patients, which deserves further investigation. No relationship between hemostasis plasma levels and measures of disease severity was detected.

Aims To obtain the normal ranges for echocardiographic measurements of left atrial (LA) function from a large group of healthy volunteers accounting for age and gender. Methods and results A total of 371 (median age 45 years) healthy subjects were enrolled at 22 collaborating institutions collaborating in the Normal Reference Ranges for Echocardiography (NORRE) study of the European Association of Cardiovascular Imaging (EACVI). Left atrial data sets were analysed with a vendor-independent software (VIS) package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire data sets. The lowest expected values of LA function were 26.1%, 48.7%, and 41.4% for left atrial strain (LAS), 2D left atrial emptying fraction (LAEF), and 3D LAEF (reservoir function); 7.7%, 24.2%, and â '0.53/s for LAS-Active, LAEF-Active, and LA strain rate during LA contraction (SRa) (pump function) and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function). Left atrial reservoir and conduit function were decreased with age while pump function was increased. All indices of reservoir function and all LA strains had no difference in both gender and vendor. However, inter-vendor differences were observed in LA SRa despite the use of VIS. Conclusion The NORRE study provides contemporary, applicable echocardiographic reference ranges for LA function. Our data highlight the importance of age-specific reference values for LA functions.

The SIMBIO-SYS (Spectrometer and Imaging for MPO BepiColombo Integrated Observatory SYStem) is a complex instrument suite part of the scientific payload of the Mercury Planetary Orbiter for the BepiColombo mission, the last of the cornerstone missions of the European Space Agency (ESA) Horizon + science program. The SIMBIO-SYS instrument will provide all the science imaging capability of the BepiColombo MPO spacecraft. It consists of three channels: the STereo imaging Channel (STC), with a broad spectral band in the 400-950 nm range and medium spatial resolution (at best 58 m/px), that will provide Digital Terrain Model of the entire surface of the planet with an accuracy better than 80 m; the High Resolution Imaging Channel (HRIC), with broad spectral bands in the 400-900 nm range and high spatial resolution (at best 6 m/px), that will provide high-resolution images of about 20% of the surface, and the Visible and near-Infrared Hyperspectral Imaging channel (VIHI), with high spectral resolution (6 nm at finest) in the 400-2000 nm range and spatial resolution reaching 120 m/px, it will provide global coverage at 480 m/px with the spectral information, assuming the first orbit around Mercury with periherm at 480 km from the surface. SIMBIO-SYS will provide high-resolution images, the Digital Terrain Model of the entire surface, and the surface composition using a wide spectral range, as for instance detecting sulphides or material derived by sulphur and carbon oxidation, at resolutions and coverage higher than the MESSENGER mission with a full co-alignment of the three channels. All the data that will be acquired will allow to cover a wide range of scientific objectives, from the surface processes and cartography up to the internal structure, contributing to the libration experiment, and the surface-exosphere interaction. The global 3D and spectral mapping will allow to study the morphology and the composition of any surface feature. In this work, we describe the on

Introduction: Web‐based cognitive tests have potential for standardized screening in neurodegenerative disorders. We examined accuracy and consistency of cCOG, a computerized cognitive tool, in detecting mild cognitive impairment (MCI) and dementia. Methods: Clinical data of 306 cognitively normal, 120 mild cognitive impairment (MCI), and 69 dementia subjects from three European cohorts were analyzed. Global cognitive score was defined from standard neuropsychological tests and compared to the corresponding estimated score from the cCOG tool containing seven subtasks. The consistency of cCOG was assessed comparing measurements administered in clinical settings and in the home environment. Results: cCOG produced accuracies (receiver operating characteristic‐area under the curve [ROC‐AUC]) between 0.71 and 0.84 in detecting MCI and 0.86 and 0.94 in detecting dementia when administered at the clinic and at home. The accuracy was comparable to the results of standard neuropsychological tests (AUC 0.69–0.77 MCI/0.91–0.92 dementia). Conclusions: cCOG provides a promising tool for detecting MCI and dementia with potential for a cost‐effective approach including home‐based cognitive assessments.

The SIMBIO-SYS (Spectrometer and Imaging for MPO BepiColombo Integrated Observatory SYStem) is a complex instrument suite part of the scientific payload of the Mercury Planetary Orbiter for the BepiColombo mission, the last of the cornerstone missions of the European Space Agency (ESA) Horizon + science program. The SIMBIO-SYS instrument will provide all the science imaging capability of the BepiColombo MPO spacecraft. It consists of three channels: the STereo imaging Channel (STC), with a broad spectral band in the 400-950 nm range and medium spatial resolution (at best 58 m/px), that will provide Digital Terrain Model of the entire surface of the planet with an accuracy better than 80 m; the High Resolution Imaging Channel (HRIC), with broad spectral bands in the 400-900 nm range and high spatial resolution (at best 6 m/px), that will provide high-resolution images of about 20% of the surface, and the Visible and near-Infrared Hyperspectral Imaging channel (VIHI), with high spectral resolution (6 nm at finest) in the 400-2000 nm range and spatial resolution reaching 120 m/px, it will provide global coverage at 480 m/px with the spectral information, assuming the first orbit around Mercury with periherm at 480 km from the surface. SIMBIO-SYS will provide high-resolution images, the Digital Terrain Model of the entire surface, and the surface composition using a wide spectral range, as for instance detecting sulphides or material derived by sulphur and carbon oxidation, at resolutions and coverage higher than the MESSENGER mission with a full co-alignment of the three channels. All the data that will be acquired will allow to cover a wide range of scientific objectives, from the surface processes and cartography up to the internal structure, contributing to the libration experiment, and the surface-exosphere interaction. The global 3D and spectral mapping will allow to study the morphology and the composition of any surface feature. In this work, we describe the on

Caloric Restriction Mimetics (CRMs) are promising molecules to prevent age-related diseases as they activate pathways driven by a true caloric restriction. Hydroxycitric acid (HCA) is considered a bona fide CRM since it depletes Acetyl-CoA pools by acting as a competitive inhibitor of ATP citrate lyase (ACLY), ultimately repressing protein acetylation and promoting autophagy. Importantly, it can reduce inflammation and tumour development. In order to identify phenotypically relevant new HCA targets we have investigated HCA effects in S. cerevisiae, where ACLY is lacking. Strikingly, the drug revealed a powerful anti-aging effect, another property proposed to mark bona fide CRMs. Chronological life span (CLS) extension but also resistance to acetic acid of HCA treated cells were associated to repression of cell apoptosis and necrosis. HCA also largely prevented cell deaths caused by a severe oxidative stress. The molecule could act widely by negatively modulating cell metabolism similarly to citrate. Indeed, it inhibited both growth reactivation and the oxygen consumption rate of yeast cells in stationary phase. Genetic analyses on yeast CLS mutants indicated that part of the HCA effects can be sensed by Sch9 and Ras2, two conserved key regulators of nutritional and stress signal pathways of primary importance. Our data together with published biochemical analyses indicate that HCA may act with multiple mechanisms together with ACLY repression and allowed us to propose an integrated mechanistic model as a basis for future investigations.

Aims : To obtain the normal range for 2D echocardiographic (2DE) measurements of left ventricular (LV) layer-specific strain from a large group of healthy volunteers of both genders over a wide range of ages. Methods and results : A total of 287 (109 men, mean age: 46 ± 14 years) healthy subjects were enrolled at 22 collaborating institutions of the EACVI Normal Reference Ranges for Echocardiography (NORRE) study. Layer-specific strain was analysed from the apical two-, three-, and four-chamber views using 2DE software. The lowest values of layer-specific strain calculated as ±1.96 standard deviations from the mean were -15.0% in men and -15.6% in women for epicardial strain, -16.8% and -17.7% for mid-myocardial strain, and -18.7% and -19.9% for endocardial strain, respectively. Basal-epicardial and mid-myocardial strain decreased with age in women (epicardial; P = 0.008, mid-myocardial; P = 0.003) and correlated with age (epicardial; r = -0.20, P = 0.007, mid-myocardial; r = -0.21, P = 0.006, endocardial; r = -0.23, P = 0.002), whereas apical-epicardial, mid-myocardial strain increased with the age in women (epicardial; P = 0.006, mid-myocardial; P = 0.03) and correlated with age (epicardial; r = 0.16, P = 0.04). End/Epi ratio at the apex was higher than at the middle and basal levels of LV in men (apex; 1.6 ± 0.2, middle; 1.2 ± 0.1, base 1.1 ± 0.1) and women (apex; 1.6 ± 0.1, middle; 1.1 ± 0.1, base 1.2 ± 0.1). Conclusion : The NORRE study provides useful 2DE reference ranges for novel indices of layer-specific strain.

Introduction: Venous bed specificity could contribute to differential vulnerability to thrombus formation, and is potentially reflected in mRNA profiles. Materials and methods: Microarray-based transcriptome analysis in wall and valve specimens from internal jugular (IJV) and saphenous (SV) veins collected during IJV surgical reconstruction in patients with impaired brain outflow. Multiplex antigenic assay in paired jugular and peripheral plasma samples. Results: Most of the top differentially expressed transcripts have been previously associated with both vascular and neurological disorders. Large expression differences of HOX genes, organ patterning regulators, pinpointed the vein positional identity. The “complement and coagulation cascade” emerged among enriched pathways. In IJV, upregulation of genes for coagulation inhibitors (TFPI, PROS1), activated protein C pathway receptors (THBD, PROCR), fibrinolysis activators (PLAT, PLAUR), and downregulation of the fibrinolysis inhibitor (SERPINE1) and of contact/amplification pathway genes (F11, F12), would be compatible with a thromboprotective profile in respect to SV. Further, in SV valve the prothrombinase complex genes (F5, F2) were up-regulated and the VWF showed the highest expression. Differential expression of several VWF regulators (ABO, ST3GAL4, SCARA5, CLEC4M) was also observed. Among other differentially expressed hemostasis-related genes, heparanase (HPSE)/heparanase inhibitor (HPSE2) were up-/down-regulated in IJV, which might support procoagulant features and disease conditions. The jugular plasma levels of several proteins, encoded by differentially expressed genes, were lower and highly correlated with peripheral levels. Conclusions: The IJV and SV rely on differential expression of many hemostasis and hemostasis-related genes to balance local hemostasis, potentially related to differences in vulnerability to thrombosis.

Background and purpose The involvement of protein C (PC) pathway components in multiple sclerosis (MS) has scarcely been explored. The aim was to investigate their levels in relation to clinical and neurodegenerative magnetic resonance imaging (MRI) outcomes in patients. Methods In all, 138 MS patients and 42 healthy individuals were studied. PC, protein S (PS) and soluble endothelial protein C receptor (sEPCR) were evaluated by multiplex assays and enzyme-linked immunosorbent assay. Regression analyses between 3 T MRI outcomes and PC pathway components were performed. ancova was used to compare MRI volumes based on protein level quartiles. Partial correlation was assessed amongst levels of PC pathway components and hemostasis protein levels, including soluble thrombomodulin (sTM), heparin cofactor II (HCII), plasminogen activator inhibitor 1 (PAI-1) and factor XII (FXII). The variation of PC concentration across four time points was evaluated in 32 additional MS patients. Results There was an association between PC concentration, mainly reflecting the zymogen PC, and MRI measures for volumes of total gray matter (GM) (P = 0.003), thalamus (P = 0.007), cortex (P = 0.008), deep GM (P = 0.009) and whole brain (P = 0.026). Patients in the highest PC level quartile were characterized by the lowest GM volumes. Correlations of PC-HCII, PC-FXII and sEPCR-sTM values were detectable in MS patients, whilst PC-PS and PS-PAI-1 correlations were present in healthy individuals only. Conclusions Protein C plasma concentrations might be associated with neurodegenerative MRI outcomes in MS. Several differences in correlation amongst protein plasma levels suggest dysregulation of PC pathway components in MS patients. The stability of PC concentration over time supports a PC investigation in relation to GM atrophy in MS.

AIMS: The present study sought to evaluate the correlation between indices of non-invasive myocardial work (MW) and left ventricle (LV) size, traditional and advanced parameters of LV systolic and diastolic function by 2D echocardiography (2DE). METHODS AND RESULTS: A total of 226 (85 men, mean age: 45 ± 13 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. Global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE) were estimated from LV pressure-strain loops using custom software. Peak LV pressure was estimated non-invasively from brachial artery cuff pressure. LV size, parameters of systolic and diastolic function and ventricular-arterial coupling were measured by echocardiography. As advanced indices of myocardial performance, global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were obtained. On multivariable analysis, GWI was significantly correlated with GLS (standardized beta-coefficient = -0.23, P < 0.001), ejection fraction (EF) (standardized beta-coefficient = 0.15, P = 0.02), systolic blood pressure (SBP) (standardized beta-coefficient = 0.56, P < 0.001) and GRS (standardized beta-coefficient = 0.19, P = 0.004), while GCW was correlated with GLS (standardized beta-coefficient = -0.55, P < 0.001), SBP (standardized beta-coefficient = 0.71, P < 0.001), GRS (standardized beta-coefficient = 0.11, P = 0.02), and GCS (standardized beta-coefficient = -0.10, P = 0.01). GWE was directly correlated with EF and inversely correlated with Tei index (standardized beta-coefficient = 0.18, P = 0.009 and standardized beta-coefficient = -0.20, P = 0.004, respectively), the opposite occurred for GWW (standardized beta-coefficient =--0.14, P = 0.03 and standardized beta-coefficient = 0.17, P = 0.01, respectively). CONCLUSION: The non-invasive MW indices show a good correlati

Background: The ample heterogeneity of veins, related to their specific role and position should modulate the transcriptional profile of anticoagulants and procoagulant genes which contribute to the “in situ” hemostasis balance, and could modulate the ability of the individual vascular bed to counteract prothrombotic stimuli. The internal jugular vein (IJV) has a major role in cerebral venous return towards the heart, and differs from saphenous vein (SV) for morphological and hemodynamic characteristics. The differential vulnerability to thrombus formation between IJV and SV is potentially reflected in mRNA profiles. Methods: Microarray-based transcriptome analysis in wall and valve specimens from IJV and SV collected during surgical reconstruction of IJV by patch angioplasty in multiple sclerosis patients with impaired brain outflow. Multiplex antigenic assay in paired jugular and peripheral plasma samples. Results: 3375 differentially expressed transcripts in walls defined distinct venous expression profiles. The “complement and coagulation cascade” emerged among the enriched pathways (P<1.0E-4). In IJV, upregulation of genes for coagulation inhibitors (TFPI, PROS1), activated protein C pathway receptors (THBD, PROCR), fibrinolysis activators (PLAT, PLAUR), and downregulation of the fibrinolysis inhibitor (SERPINE1, PAI-1) and of contact/amplification pathway genes (F11, F12), would be compatible with a thromboprotective profile in respect to SV. In the SV valve the VWF showed the highest expression, and differential expression of several VWF regulators (ST3GAL4 , SCARA5, CLEC4M) was observed. For several proteins (soluble Thrombomodulin, Protein S, PAI-1), encoded by differentially expressed genes, the jugular plasma levels were lower (p=0.006, p=0.011, p=0.039, respectively) and highly correlated with peripheral levels (p<0.001). Conclusions: The IJV and SV rely on differential expression of many hemostasis and hemostasis-related genes to balance local hem

Background: The progressive failure of blood–brain barrier (BBB) integrity, which may have the pathological feature of cerebral microbleeds (CMBs), leads to focal extravascular leakage of blood components and subsequently induces several inflammatory responses. CMBs have been associated with worsening of physical and cognitive disability in multiple sclerosis (MS). Adhesion molecules, which participate in BBB disruption and in inflammatory responses, could be involved in the formation of CMBs. The anti-inflammatory properties of hemostasis inhibitors offer a rational link for their study in the presence of CMBs. Aims: To explore plasma levels, and correlations of hemostasis inhibitors and adhesion molecules in relation to CMBs in MS. Methods: Plasma levels of coagulation inhibitors (PC, TM, EPCR, PS, TFPI, HCII, ADAMTS13, PAI1) and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, sVAP1), were evaluated by Multiplex and ELISA in 125 MS patients and 42 healthy individuals (HI) who underwent 3T MRI exams. CMBs were assessed on susceptibility-weighted minimum intensity projection images and susceptibility maps. Spearman’s correlation and Mann–Whitney test were used, as appropriate. Results: Patients with CMBs (n=12) showed, in addition to significantly lower ADAMTS13 levels (p=0.025), significantly higher sNCAM levels (p=0.017) and a trend for higher levels of VAP1 compared to MS patients without CMBs (n=113). Only in MS with CMBs, ADAMSTS13-VAP1 levels were correlated (r=0.67, p=0.020). In MS with CMBs and in HI, levels of PAI1-sVCAM1 were correlated (r=0.73, p=0.009 and r=0.33, p=0.031). Conclusions: With the limitation of the low number of patients with CMBs, our findings suggest an intriguing molecular relationship between adhesion molecules and hemostasis inhibitors in development of CMBs in MS. The reactive oxygen species produced by VAP-1, an inflammatory adhesion molecule endowed with enzymatic properties, could interfere with ADAMTS13/von Willebrand factor fu

Aims To report normal reference ranges for echocardiographic dimensions of the proximal aorta obtained in a large group of healthy volunteers recruited using state-of-the-art cardiac ultrasound equipment, considering different measurement conventions, and taking into account gender, age, and body size of individuals. Methods A total of 704 (mean age: 46.0+13.5 years) healthy volunteers (310 men and 394 women) were prospectively recruited from the collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. A comprehensive echocardiographic examination was obtained in all subjects following pre-defined protocols. Aortic dimensions were obtained in systole and diastole, following both the leading-edge to leading-edge and the inner-edge to inner-edge conventions. Diameters were measured at four levels: ventricular-arterial junction, sinuses of Valsalva, sinotubular junction, and proximal tubular ascending aorta. Measures of aortic root in the short-axis view following the orientation of each of the three sinuses were also performed. Men had significantly larger body sizes when compared with women, and showed larger aortic dimensions independently of the measurement method used. Dimensions indexed by height and body surface area are provided, and stratification by age ranges is also displayed. In multivariable analysis, the independent predictors of aortic dimensions were age, gender, and height or body surface area. Conclusion The NORRE study provides normal values of proximal aorta dimensions as assessed by echocardiography. Reference ranges for different anatomical levels using different (i) measurement conventions and (ii) at different times of the cardiac cycle (i.e. mid-systole and end-diastole) are provided. Age, gender, and body size were significant determinants of aortic dimensions.

Aims To obtain the normal ranges for 2D echocardiographic (2DE) measurements of left ventricular (LV) strain from a large group of healthy volunteers accounting for age and gender Methods and results A total of 549 (mean age: 45.6 ± 13.3 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. 2DE data sets have been analysed with a vendorindependent software package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire the data sets. The lowest expected values of LV strains and twist calculated as ± 1.96 standard deviations from the mean were-16.7% in men and-17.8% in women for longitudinal strain,-22.3% and-23.6% for circumferential strain, 20.6% and 21.5% for radial strain, and 2.2 degrees and 1.9 degrees for twist, respectively. In multivariable analysis, longitudinal strain decreased with age whereas the opposite occurred with circumferential and radial strain. Male gender was associated with lower strain for longitudinal, circumferential, and radial strain. Inter-vendor differences were observed for circumferential and radial strain despite the use of vendor-independent software. Importantly, no intervendor differences were noted in longitudinal strain. Conclusion The NORRE study provides contemporary, applicable 2D echocardiographic reference ranges for LV longitudinal, radial, and circumferential strain. Our data highlight the importance of age-and gender-specific reference values for LV strain.

Aim To obtain the normal ranges for 3D echocardiography (3DE) measurement of left ventricular (LV) volumes, function, and strain from a large group of healthy volunteers. Methods and results A total of 440 (mean age: 45613 years) out of the 734 healthy subjects enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study had good-quality 3DE data sets that have been analysed with a vendor-independent software package allowing homogeneous measurements regardless of the echocardiographic machine used to acquire the data sets. Upper limits of LV end-diastolic and end-systolic volumes were larger in men (97 and 42 mL/m2) than in women (82 and 35 mL/m2; P<0.0001). Conversely, lower limits of LV ejection fraction were higher in women than in men (51% vs. 50%; P<0.01). Similarly, all strain components were higher in women than in men. Lower range was -18.6% in men and -19.5% in women for 3D longitudinal strain, -27.0% and -27.6% for 3D circumferential strain, -33.2% and -34.4% for 3D tangential strain and 38.8% and 40.7% for 3D radial strain, respectively. LV volumes decreased with age in both genders (P<0.0001), whereas LV ejection fraction increased with age only in men. Among 3DE LV strain components, the only one, which did not change with age was longitudinal strain. Conclusion The NORRE study provides applicable 3D echocardiographic reference ranges for LV function assessment. Our data highlight the importance of age- and gender-specific reference values for both LV volumes and strain. All rights reserved.

Sophisticated senator and legislative onion. Whether or not you have ever heard of these things, we all have some intuition that one of them makes much less sense than the other. In this paper, we introduce a large dataset of human judgments about novel adjective-noun phrases. We use these data to test an approach to semantic deviance based on phrase representations derived with compositional distributional semantic methods, that is, methods that derive word meanings from contextual information, and approximate phrase meanings by combining word meanings. We present several simple measures extracted from distributional representations of words and phrases, and we show that they have a significant impact on predicting the acceptability of novel adjective-noun phrases even when a number of alternative measures classically employed in studies of compound processing and bigram plausibility are taken into account. Our results show that the extent to which an attributive adjective alters the distributional representation of the noun is the most significant factor in modeling the distinction between acceptable and deviant phrases. Our study extends current applications of compositional distributional semantic methods to linguistically and cognitively interesting problems, and it offers a new, quantitatively precise approach to the challenge of predicting when humans will find novel linguistic expressions acceptable and when they will not

By the time they reach early adulthood, English speakers are familiar with the meaning of thousands of words. In the last decades, computational simulations known as distributional semantic models (DSMs) have demonstrated that it is possible to induce word meaning representations solely from word co-occurrence statistics extracted from a large amount of text. However, while these models learn in batch mode from large corpora, human word learning proceeds incrementally after minimal exposure to new words. In this study, we run a set of experiments investigating whether minimal distributional evidence from very short passages suffices to trigger successful word learning in subjects, testing their linguistic and visual intuitions about the concepts associated with new words. After confirming that subjects are indeed very efficient distributional learners even from small amounts of evidence, we test a DSM on the same multimodal task, finding that it behaves in a remarkable human-like way. We conclude that DSMs provide a convincing computational account of word learning even at the early stages in which a word is first encountered, and the way they build meaning representations can offer new insights into human language acquisition.