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Background Sodium-glucose co-transporter 2 inhibitors (SGLT2-I) currently receive intense clinical interest in patients with and without diabetes mellitus (DM) with pleiotropic beneficial effects. Nowadays, the inflammation response in the setting of acute myocardial infarction (AMI) has been proposed as a potential pharmacological intervention target. In this setting, we tested the hypothesis that the SGLT2-I displays anti-inflammatory effect along with glucose-lowering properties. We investigated the relationship between stress hyperglycemia, inflammation burden and infarct size in a cohort of type 2 diabetic AMI patients treated with SGLT2-I versus other oral anti-diabetic (OAD) agents alone. Methods In this multicenter international registry, all diabetic patients with AMI treated with percutaneous coronary intervention (PCI) between 2018 and 2021 were enrolled. Based on the admission anti-diabetic therapy, patients were divided into those receiving SGLT2-I versus other OAD agents alone. Patients on insulin therapy alone or combined with OAD agents were excluded from the study. The following inflammatory markers were evaluated at different time points: total white blood cell, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and neutrophil-to-platelet ratio (NPR), C-reactive protein. Infarct size was assessed by peak troponin levels and echocardiographic parameters. Results The final study population consisted of 583 patients hospitalized for AMI (both STEMI and NSTEMI) classified as SGLT2-I users (n=98) versus other OAD agents alone (n=485). Admission hyperglycemia was more prevalent among the other OAD agents group. Reduced infarct size was detected in patients treated with SGLT2-I compared to those treated with other OAD agents alone. Both at admission, and after 24 hours, inflammatory indices were significantly higher in patients treated with other OAD agents alone, with a significant increase in neutrophils levels at 24 hours, compared to the SGLT2-I group. In multivariate analysis, SGLT2-I emerged as a significant predictor of reduced inflammatory response (OR 0.45, 95% CI 0.27–0.75, p=0.002), together with peak troponin values, independently of age, admission creatinine values and admission glycemia. Conclusions Type 2 Diabetic patients hospitalized for AMI and receiving SGLT2-I exhibited modest inflammatory response and myocardial damage/infarct size compared to other OAD agents alone, independently of glucose-metabolic control. Our findings pave the way for new pathophysiological and therapeutic insights regarding the cardioprotective effect of SGLT2-I in the setting of coronary artery disease. Funding Acknowledgement Type of funding sources: None.

Background Killip classification is a simple clinical tool for risk stratification in patients with acute myocardial infarction (AMI). However, predictors of high Killip class at admission and its prognostic role in myocardial infarction with non-obstructive coronary artery (MINOCA) are still poorly explored. Purpose To identify clinical predictors of high Killip class and its potential prognostic role in patients with MINOCA compared to patients with myocardial infarction with obstructive coronary artery (MIOCA). Methods We included patients with AMI undergoing coronary angiogram from January 2016 to June 2021. MINOCA were defined according to the current European guidelines criteria. We compared the Killip classes of MINOCA with those of MIOCA and defined a high Killip class if greater than 1. Kaplan-Meier (KM) curves were developed for the comparison of all-cause mortality among MIOCA and MINOCA with high Killip class (>1) compared to the others. Multivariate logistic regression analysis was used to determine the predictors of high Killip class. Results Among 3261 AMI, 261 were MINOCA. The median follow-up time was 36.1±15.2 months. Killip class >1 occurred in 24 (8.8%) MINOCA patients compared to 518 (17.3%) MIOCA cases (p=0.001). During long-term follow-up, a high Killip class was associated with a 3-fold increased mortality both in MIOCA and MINOCA populations (p Conclusions High Killip class at admission is a high-risk marker of adverse cardiovascular events even in patients with MINOCA. Simple baseline characteristics (such as older age, diabetes, ST-segment-elevation) predict a high Killip class in MINOCA subjects and can help to identify a high-risk population who might benefit from a stricter management. Furthermore, LVEF and elevated cardiac troponin were identified as predictors of a high Killip class in MIOCA but they did not show a similar impact in the setting of MINOCA. This may reflect the different pathogenesis and myocardial damage extent in MINOCA compared to MIOCA. Funding Acknowledgement Type of funding sources: None.

Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) represents a significant proportion of acute myocardial infarction (AMI) population. MINOCA is a working diagnosis and an accurate investigation of the underlying causes should always be performed. In this setting, cardiac magnetic resonance (CMR) imaging plays a pivotal diagnostic role. However, a prognostic stratification based on the CMR findings in ischemic MINOCA is still unavailable. Purpose To evaluate the potential prognostic impact of specific CMR findings - especially ischemic late gadolinium enhancement (LGE) patterns - in order to look for measurable parameters that may guide the management of this still troubled clinical entity. Methods We assessed 461 MINOCA from January 2016 to June 2021. We excluded acute myocarditis, Tako-tsubo syndromes, cardiomyopathies, or non-pathological CMR. According to CMR findings, MINOCA were classified in two phenotypes: LGE-positive (an ischemic subendocardial or transmural LGE pattern) or LGE-negative (cases without LGE but exhibiting regional myocardial injury defined by myocardial edema in a coronary territory with a typically ischemic “wave-front” and/or regional wall motion abnormality consistent with coronary distribution). All-cause mortality, re-infarction, stroke, heart failure (HF) and the composite endpoint (MACE) were evaluated. Extended LGE was considered as the presence of >2 segments with transmural LGE. The mean follow-up was 36.1±15.2 months and CMR was performed at a mean of 6±2.9 days from the acute presentation. Results The final cohort included 175 MINOCA with a likely-ischemic etiology: 121 (69.1%) constituted the LGE-positive group. The mean age of the study population was 62.3±12.9 years and more than 61% were females. During follow-up, HF (15.7% vs 1.9%, p=0.008) and MACE (20.7% vs 7.4%, p=0.029) occurred more frequently in MINOCA “LGE-positive” compared to the “LGE-negative” ones. Extended LGE was significantly more prevalent in patients with versus without subsequent HF. On multivariable Cox regression, extended LGE was an independent predictor of HF occurrence (HR 18.49, 95% CI 4.65–73.61, p Conclusions Our data suggest that in MINOCA patients the detection of LGE is correlated with the incidence of major cardiovascular events and heart failure during long-term follow-up. In fact, LGE extension was identified as the strongest predictor of cardiac adverse events. The early execution of CMR is useful in the prognostic stratification of MINOCA and this could guide the subsequent clinical and therapeutic management. Funding Acknowledgement Type of funding sources: None.

Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous clinical entity and in its complex diagnostic approach cardiovascular magnetic resonance (CMR) plays a pivotal role. Purpose To characterize the differences of MINOCA patients with and without late gadolinium enhancement (LGE) at CMR and to identify the predictors for ischemic LGE development and extension. Methods We assessed 461 MINOCA cases from January 2016 to June 2021. MINOCA were defined according to the current European guidelines criteria. We excluded acute myocarditis, Tako-tsubo syndromes, cardiomyopathies, or non-pathological CMR. According to CMR imaging findings, our cohort was divided into two CMR phenotypes based on regional myocardial necrosis detected throughout LGE (“LGE-positive MINOCA”) or regional ischemic injury without LGE (“LGE-negative MINOCA”). Extended LGE was considered as the presence of >2 segments with transmural LGE. Multivariate logistic regression analysis was used to determine the predictors of LGE and extended LGE. Results The final cohort included 175 MINOCA: 121 (69.1%) constituted the LGE-positive group. The mean time delay between acute clinical presentation and CMR was 6±2.9 days. At admission MINOCA LGE-patients more frequently presented angina and ST segment elevation (24% vs 7.4%, p=0.01), compared to LGE negative ones. Furthermore, the LGE positive group had a significantly greater infarct size, measured by peak hs-Troponin I values and left ventricular function (LVEF). The only predictor of LGE was the peak troponin value (OR 1.64, 95% CI 1.18–2.28, p=0.003), while predictors of extended LGE were ST-segment elevation at admission (OR 7.44, 95% CI 1.57–35.22, p=0.01), peak troponin values (OR 1.07, 95% CI 1.02–1.13, p=0.01) and the presence of non-obstructive coronary artery disease at coronary angiography (OR 5.49, 95% CI 1.20–25.09, p=0.028). Conclusion The presence and extension of LGE at early CMR evaluation is an important feature in the setting of MINOCA. In addition, simple baseline characteristics (such as ST elevation, peak troponin value and LVEF) may aid the identification of a greater ischemic necrosis burden at CMR and therefore these high-risk MINOCA subjects could be benefit from a stricter management effort. Funding Acknowledgement Type of funding sources: None.

Background The Fourth Universal Definition of Myocardial Infarction (UDMI) defines acute myocardial infarction (AMI) as an acute myocardial injury associated with clinical evidence of acute myocardial ischemia. However, the prognostic role of each single diagnostic criteria has never been explored. Purpose To evaluate the prognostic role of the different diagnostic criteria of AMI according to the Fourth UDMI in patients with non-ST-segment elevation myocardial infarction. Methods We enrolled all consecutive patients with NSTEMI undergoing coronary angiography at our Centre. The admission diagnosis was performed according to the current guidelines criteria, namely the detection of an increase and/or decrease of high-sensitivity cardiac troponin I, with at least one value above the 99th percentile of the upper reference limit and at least one of the following: symptoms of ischemia, ECG changes (new ST depression or negative T-waves), echocardiographic evidence of new regional wall motion abnormality. Patients with very high-risk NSTEMI were excluded. Patients were then divided into different subgroups according to the combination of diagnostic criteria presented at admission. A composite endpoint of all-cause mortality, re-hospitalization for myocardial reinfarction or heart failure was collected. The predictive value of AMI diagnostic criteria alone and their combination were evaluated using Kaplan-Meier survival curves and subsequent Cox-regression analysis to find independent predictors of major adverse events. Results Our study population consisted of 2791 patients. The mean age was 68.3±13.4 and 31.5% were female. The mean follow-up time was 23.3±14.5 months. Depending on the AMI diagnostic criteria and their combination, patients were divided into three subgroups: 196 patients fulfilling only clinical criteria (group A), 187 with clinical and ECG-graphic criteria (group B) and 829 patients with clinical, ECG-graphic and echo-graphic criteria (group C). Baseline characteristics of the three groups were similar. At two-year follow-up, patients with clinical criteria alone exhibited the best outcome, whereas those with all three criteria fulfilled showed the worse prognosis (14.8% for group A vs 23.6% for group B vs 28.0% for group C; p-value Conclusions In non-very high-risk NSTEMI, not all diagnostic criteria have the same prognostic value. In fact, prognosis is significantly more favorable in patients exhibiting only the clinical criteria at admission. We hypothesize that the absence of ECG-graphic and echocardiographic alterations may indirectly indicate smaller infarct sizes that contribute to patients' outcomes. These findings could enhance the current risk stratification in patients admitted with NSTEMI. Funding Acknowledgement Type of funding sources: None.

Background Myocardial infarction with non-obstructed coronary arteries (MINOCA) is common in current clinical practice and cardiac magnetic resonance (CMR) plays an important role in the present management of this group of patients. However, there are still a lot of controversies concerning the etiology behind the syndrome of MINOCA. Furthermore, the prognostic value of CMR in patients with MINOCA is still undetermined. Purpose We aimed to determine the diagnostic and prognostic value of CMR in the management of patients with MINOCA. Methods A systematic review was performed to identify studies reporting the results of CMR findings in MINOCA patients (non-obstructive CAD or normal coronary arteries). Random effects models were used to determine the prevalence of different disease entities – myocarditis, myocardial infarction, Takotsubo cardiomyopathy or normal CMR findings. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the prognostic value of CMR diagnosis in the subgroup of studies that reported clinical outcomes. Major adverse clinical events (MACE) were defined based on the specific study definitions and included cardiovascular death, non-fatal myocardial infarction, and cardiovascular hospitalization. Results 31 studies comprising 4119 patients were included. Mean age was 54.1±3.3, 59% were males. The pooled prevalence of myocarditis was 32% (95% CI 0.25 to 0.39), myocardial infarction (MI) - 21% (95% CI 0.17 to 0.24), Takotsubo cardiomyopathy −12% (95% CI 0.09 to 0.16). Normal findings were found in 23% (95% CI 0.14 to 0.35), figure 1. In a subgroup analysis of seven studies (900 patients) that reported clinical outcomes the prognostic value of the CMR was assessed. CMR diagnosis of myocarditis was not significantly associated with increased risk of MACE (pooled OR, 1.50; 95% CI, 0.46 to 4.87; p=0.459). However, both diagnosis of MI and Takotsubo were significantly associated with increased risk of combined clinical outcomes (pooled OR, 1.75; 95% CI, 1.12 to 3.59; p Conclusion In patients with MINOCA CMR brings important diagnostic and prognostic role. The pooled prevalence of myocarditis was 32%, of MI – 21% and of Takotsubo – 12%. The CMR diagnosis of MI and Takotsubo was associated with increased risk of MACE. Funding Acknowledgement Type of funding sources: None.

Background Myocardial Infarction (MI) with Non–Obstructive Coronary Arteries (MINOCA) accounts above 6 % of patients presenting with acute MI (AMI) and it’s known to be more prevalent in females. Differences in terms of clinical features and prognosis in MINOCA patients according to gender have been poorly understood. Purpose: To evaluate clinical and prognostic differences between male and female patients with MINOCA. Methods We included all consecutive patients with AMI undergoing coronary angiography between 2016 and 2020 in our multicentric Registry. We considered as MINOCA all patients fulfilling the European Society of Cardiology diagnostic criteria. We analyzed the baseline clinical characteristics of MINOCA patients by dividing the population according to gender. We performed a multivariate logistic regression analysis including all AMI patients to determine independent predictors of MINOCA at admission. We considered the composite endpoint (MACE) of death, re AMI, stroke and heart failure at follow–up (FU, mean of 36 ± 14.8 months). Outcomes were evaluated also using Kaplan–Meier survival curves. Results Among 289 patients affected by MINOCA, 191 were female (66%). Males were more frequently smokers (56.1% vs 33.9 %, p=0.001) while females were older (68.9± 13.1 vs 58.4±14.5 years, p=0.0001), more affected by hypertension (69.3% vs 55.1%, p=0.017) and dyslipidemia (65.6% vs 49%, p=0.005), more frequently on beta–blockers (39% vs 20%, p=0.002) and statins (33% vs 19%, p=0.015) and had a lower degree of coronary stenosis (9.1% vs 15.5%, p=0.019) than males. During follow–up, females had more MACE (33% vs 19.3%, p=0.015), also shown at Kaplan Meier curves (χ2 = 5.997, p=0.014). Finally, multivariate analysis revealed that age is an independent predictor of MINOCA (HR 1.04, CI 1.01–2.07, p=0.006), rather than sex, diabetes, and hypertension. Conclusions In our MINOCA population, females had a higher incidence of MACE than males: this could reflect the different pathogenesis of myocardial damage in our subgroups. Statins and estrogens have a well–known protective role towards the progression of atherosclerosis, but they have less impact on other causes of MINOCA more frequent in females.

A 66–year–old woman with a history of anxious–depressive syndrome and osteoporosis, without significant cardiological history, reported onset of cardiopalmus and dyspnoea for a few days due to moderate efforts, in conjunction with a period of strong emotional stress. Due to the persistence of these symptoms and the onset of epigastric pain, she underwent a cardiological examination which found low blood pressure values associated with the presence of a systolic murmur. The ECG showed diffuse changes in repolarization compatible with ischemia. Access to the emergency room (ER) was recommended. In ER, the first high–sensitivity troponin value was significantly high (1542 ng/L). Therefore, in the suspect of ACS, the patient was transferred to the cardiological intensive care unit. Echocardiogram showed akinesia of the mid–apical segments, hypercontractility of the bases (EF 35%) and a SAM (systolic anterior motion) with a dynamic outflow tract pressure gradient of 80 mmHg which resulted in severe mitral regurgitation. During the first days of hospitalization, persistent hypotension was observed requiring intravenous infusion of fluids to maintain systolic blood pressure values between 90–100 mmHg. Coronary angiography showed only severe ostial stenosis of a branch of the first diagonal branch. At the same time, ventriculography was performed which showed basal hypercontractility with muscle salience at the base and systolic obliteration of the outflow tract with a small apical aneurysm. 5 days after admission, another echocardiogram showed the almost complete normalization of the global systolic function (EF 68%) with apical hypokinesia and hypercontractility of the basal segments. However, the SAM persisted with a dynamic outflow tract pressure gradient of 140 mmHg with the presence of multiple and dislocated papillaries, accessory tendon cords and insertion of muscle tendon at the level of the septum. To complete the diagnosis, cardiac MRI was performed which documented a diffuse increase in T2 relaxation times more evident in the apical area, absence of LGE areas and normalization of contractility of the left ventricle with disappearance of the SAM. These findings, together with the absence of significant hypertrophy and the complete regression of the ECGgraphic changes, allowed us to exclude the presence of an unrecognized hypertrophic cardiomyopathy and to diagnose Takotsubo syndrome.

Background Although an early invasive strategy (coronary angiography performed Purpose This study tested the hypothesis that, compared to early ( Methods From 2016 to 2020, all consecutive MINOCA patients diagnosed according to the current ESC diagnostic criteria (angiographic conventional cut–off of Results 198 NSTE–MINOCA patients were enrolled, of which 79 underwent coronary angiography Conclusions We demonstrated for the first time that in the MINOCA population the prognosis is not influenced by an early versus deferred coronary angiography, as opposed to AMI patients with obstructive coronary arteries. These results add another piece to the puzzle and pave the way for the initial use of a non–invasive imaging strategy (eg. Coronary–CT), mostly in patients with NSTEMI and high clinical suspicion of non–obstructive coronary arteries.

An 85–year–old woman experienced cardiac arrest while she was at the supermarket. Cardiopulmonary resuscitation was promptly performed with ROSC after DC shock on ventricular fibrillation and immediate hemodynamic and neurological recovery. The first ECG performed by the rescuers did not show acute ischemic changes and the patient was admitted to the Cardiological Intensive Care Unit. Past medical history revealed only a previous episode of acute pulmonary embolism for which she was on oral anticoagulant therapy for a limited period of time. She had not family history of sudden cardiac death or cardiomyopathies. Before admission she was completely asymptomatic and she never complained of angina pectoris, palpitation or dyspnoea. The echocardiogram at admission showed moderate left atrial enlargement and hypokinesia of left ventricle apex and mid–apical lateral wall with global EF of 50%. Pulmonary and aortic CT angiography showed no pathological findings. In order to rule out an ACS, the patient underwent a coronary angiography which documented the absence of critical coronary stenosis. Finally, a cardiac MRI with gadolinium was performed, revealing the presence of two small areas of transmural LGE affecting inferior basal and lateral mid–apical segments with no edema, consistent with ischaemic myocardial scars. In light of this findings and to rule out paradoxical coronary artery embolism we decided to perform a transcranial echocolordoppler that showed the absence of a patent foramen ovale. Furthermore, continuous ECG monitoring during the hospital stay did not document arrhythmic recurrences. In consideration of the high probability of ischemic heart disease, therapy with antiplatelet agent, beta–blocker, ace–inhibitor and statin was introduced and the patient was discharged after ICD implantation. Three months later, during her first follow–up visit, we documented short episodes of atrial fibrillation at ICD interrogation. This was in line with the hypothesis of a ventricular fibrillation and cardiac arrest in the contest of an ischemic heart disease with myocardial scars probably due to undatale coronary artery embolism. Oral anticoagulant therapy was started in addition to previous therapy.

Background Although the majority of patients with NSTEMI share similar risk factors and similar pathophysiology, their outcomes differ considerably. The Fourth Universal Definition of Myocardial Infarction (UDMI) defined acute myocardial infarction (AMI) by an acute myocardial injury together with clinical evidence of acute myocardial ischaemia. However, the prognostic role of each single diagnostic criteria has never been explored. Purpose To evaluate the prognostic role of the different diagnostic criteria of AMI according to the Fourth UDMI in NSTEMI patients. Methods We enrolled all consecutive patients with AMI undergoing coronary angiogram at our Centre. We used a combination of criteria, according to the current ESC guidelines, to meet the diagnosis, namely the detection of an increase and/or decrease of high–sensitivity cardiac troponin I, with at least one value above the 99th percentile of the upper reference limit and at least one of the following: symptoms of ischaemia; ECG changes (new ST–T changes or new LBBB); development of pathological Q waves in the ECG; echocardiographic evidence of new loss of viable myocardium or new regional wall motion abnormality. Patients with STEMI and very high risk NSTEMI were excluded. A composite endpoint of all–cause mortality, re–hospitalization for heart failure, and myocardial reinfarction was collected. The predictive value of diagnostic criteria alone and their association were evaluated using Kaplan–Meier survival curves and subsequent Cox–regression analysis to find independent predictors of adverse events. Results 2791 patients with NSTEMI were evaluate. At admission 196 had clinical criteria alone, 187 had clinic + ECG and 829 had clinic + ECG + echo. The total number of events was 689. The median follow–up was 23.3±14.5 months. We found that patients with clinical criteria alone had a better prognosis at 2 years follow–up (p Conclusions Our data suggest that in NSTEMI the prognosis is considerably better if clinical criteria alone is present at admission. We hypothesize that the absence of electrocardiographic and echocardiographic alterations in NSTEMI could indirectly indicate smaller infarct sizes or other causes of acute myocardial injury.

We hereby present the case of a 36–year–old woman with neither a history of cardiovascular disease nor any cardiovascular risk factors. Her only past medical history included a pregnancy from in vitro fertilization and endometriosis treated with progestin. She was admitted to A&E for sudden onset severe stabbing thoracic pain, which occurred at rest and was exacerbated by respiratory efforts, and with spontaneous resolution shortly after admission. While the ECG did not show any signs of ischemic, blood tests revealed a minor rise in inflammatory markers and a significant rise in troponin values, the latter consistent with acute myocardial injury. Given the clinical suspicion of myopericarditis vs acute coronary syndrome, the patient was admitted to cardiac intensive care unit. Bedside echocardiogram performed shortly after admission demonstrated minor pericardial effusion and regional wall motion abnormalities. Thus, the patient underwent urgent coronary angiography, which revealed pronounced vasospasm at the proximal segment of the circumflex artery, which subsided after administration of nitrate, as well as spontaneous dissection of the mid left anterior descending artery extending to its apical branch. Since no high–risk features were identified (single vessel, mid–distal coronary lesion, no symptoms of persistent ischemia), revascularisation was not attempted and conservative therapy was undertaken. During the following days, genetic evaluation and further diagnostic tests were performed to exclude vascular abnormalities in other anatomical sites, which all resulted negative. Outpatient follow–up with CT coronary angiogram demonstrated full patency of left anterior descending artery with spontaneous resolution of the former dissection. This clinical scenario represents an example of an uncommon and thus often overlooked cause of acute coronary syndrome with yet limited evidence on optimal therapeutic and follow–up strategies.

Funding Acknowledgements Type of funding sources: None. Background Myocardial strain assessed with speckle tracking echocardiography is a sensitive marker of cardiac dysfunction, with long-term prognostic value in many cardiac conditions. Both left ventricular global longitudinal strain (LV-GLS) and right ventricular longitudinal strain (RV-LS) were affected by severe SARS-CoV 2 infection but little is known about cardiac involvement in patients with asymptomatic/mild disease that did not require hospitalization. Aim To assess if subclinical myocardial dysfunction could be identified using LV-GLS and RV-LS in patients with previous asymptomatic/mild SARS-CoV 2 infection. Methods 40 young adults patients (70% males, mean age 24.4 ± 8.4 years), who had a confirmed diagnosis of SARS-CoV-2 infection and were asymptomatic or only mildly symptomatic, without previous known comorbidities/cardiovascular risk factors, were retrospectively included. Patients underwent standard transthoracic echocardiogram and speckle tracking echocardiographic study at least 3 months after diagnosis. A total of 44 age, sex, and body surface area comparable healthy subjects were used as control group. Results LV-GLS was within normal limits but significantly lower in the cases group compared to controls (-22.7 ± 1.6% vs. -25.7 ± 2.3%; p Moreover, in the infection group, there were 25 subjects (30.1% vs 9.6% in the control group, p Conclusion SARS-CoV-2 infection may affect left ventricular deformation in 30% of young adults patients despite an asymptomatic or only mildly symptomatic acute illness. Speckle tracking echocardiography could help in early identification of patients with subclinical cardiac involvement. Since long-term complications of COVID-19 are not yet known, myocardial deformation imaging could be important for risk stratification, treatment and planning of long-term follow-up.

The time-dependent neutron diffusion equation approximates the neutronic power evolution inside a nuclear reactor core. Applying a Galerkin finite element method for the spatial discretization of these equations leads to a stiff semi-discrete system of ordinary differential equations. For time discretization, an implicit scheme is used, which implies solving a large and sparse linear system of equations for each time step. The GMRES method is used to solve these systems because of its fast convergence when a suitable preconditioner is provided. This work explores several matrix-free strategies based on different updated preconditioners, which are constructed by low-rank updates of a given initial preconditioner. They are two tuned preconditioners based on the bad and good Broyden’s methods, initially developed for nonlinear equations and optimization problems, and spectral preconditioners. The efficiency of the resulting preconditioners under study is closely related to the selection of the subspace used to construct the update. Our numerical results show the effectiveness of these methodologies in terms of CPU time and storage for different nuclear benchmark transients, even if the initial preconditioner is not good enough.

Background The CHA2DS2-VASc score is the most used in predicting thromboembolic risk in patients with atrial fibrillation (AF). However, a higher CHA2DS2-VASc score predicts cardiovascular events even in patients without AF. Up to date, there is limited evidence about the association between CHA2DS2-VASc score and the embolic risk in patient with cardiac tumours (CT). Purpose To evaluate the role of the CHA2DS2-VASc score in predicting embolism and to identify other markers of embolization in patients with CT. Methods We included all patients with a CT who had a complete echocardiographic evaluation and a histologic diagnosis. We excluded patients with cardiac thrombi because of their higher embolic risk. Results Our sample consisted of 221 patients (mean age 60.9±15.6, 7% female). 132 (59.7%) patients had benign CT, usually left-sided (84.8%). In the malignant tumours, 28 (31.5%) were primary and 61 (68.5%) were metastasis. Compared to benign tumours, malignant ones were predominantly right-sided (47.2%) or with pericardial (20.2%) or great-vessels involvement (16.9%). A total of 59 patients (26.6%) experienced an embolic event, of which 33 patients had peripheral embolism, while 28 had pulmonary embolism (PE), 2 patients had both. Patients with embolism were older (p=0.013), had a higher prevalence of diabetes or previous stroke (p=0.019 and p3 had an AUC=0.835 in predicting a peripheral embolic event in the overall population (p Also in patients with right-sided CT, CHA2DS2-VASc score (p=0.017), together with some tumours characteristics (mobility, pericardial effusion and absence of myocardial infiltration (p Embolization did not impact survival when considering the overall population. Otherwise, when focusing on patients with malignant CT, those who had an embolic event had a worse prognosis (p=0.02), as well as those with PE (p=0.037). Conclusions CHA2DS2-VASc and left-side localization are the best markers of embolism. In particular, CHA2DS2-VASc seems to predict embolization in CT, regardless of histology or localization. Many patients with CT and embolism may not be offered surgical treatment given their assumed high-risk profile. By contrast, our analysis showed that survival is not related to the embolic event per se, but by histology. In patients with CT and high CHA2DS2-VASc score, further studies are needed to evaluate the best therapeutic strategy to minimize the embolic risk. Funding Acknowledgement Type of funding sources: None.

Background The term acute myocardial infarction (AMI) reflects cell death of cardiac myocytes caused by ischaemia. The Fourth Universal Definition of Myocardial Infarction (UDMI) defined AMI by a typical rise and fall in the level of biochemical markers of myocardial necrosis together with criteria of myocardial ischaemia. However, the prognostic role of each single diagnostic criteria has never been explored. Purpose To evaluate the prognostic role of the different diagnostic criteria of AMI according to the Fourth UDMI. Methods We enrolled all consecutive patients with AMI admitted from 2016 to 2019. We used a combination of criteria, according to the current ESC guidelines, to meet the diagnosis, namely the detection of an increase and/or decrease of high-sensitivity cardiac troponin I, with at least one value above the 99th percentile of the upper reference limit and at least one of the following: symptoms of ischaemia; ECG changes (new ST-T changes or new LBBB); development of pathological Q waves in the ECG; imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, in our study evaluated by transthoracic echocardiogram. All-cause mortality and a composite endpoint of all-cause mortality, re-hospitalization for heart failure and myocardial re-infarction were collected. The predictive value of diagnostic criteria alone and its association were evaluated using Kaplan-Meier survival curves and subsequent Cox-regression analysis to find independent predictors of adverse events. Results 2386 patients were evaluated. The median follow-up time was 23.3±14.5 months. The total number of events was 703 (29.3%). Kaplan-Meier curves showed that major adverse cardiac events (MACE) were statistically different depending on the diagnostic criteria of AMI at admission. Particularly, clinical criteria alone showed a better predictive value (p Conclusions Our data suggest that the prognosis is considerably better among patients with a diagnosis of AMI if clinical criteria alone are present at admission. We also demonstrated that clinical criteria are a strong prognostic predictor of good outcomes in patients with AMI. We hypothesize that the absence of electrocardiographic and echocardiographic alterations could indirectly indicate a smaller infarct sizes that contribute to patients' outcome. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): None

Extracellular Vesicles analysis in cerebrospinal fluid of transgenic pigs: a model for biomarker discovery in Amyotrophic Lateral Sclerosis

Renal cell carcinoma (RCC) has traditionally been considered radioresistant with a limited role for conventional fractionation as a local approach. Nevertheless, since the appearance of stereotactic body radiation therapy (SBRT), radiotherapy (RT) has been increasingly employed in the management of metastatic RCC (mRCC). The aim of this study was to evaluate the role of SBRT for synchronous and metachronous oligo metastatic RCC patients in terms of local control, delay of systemic treatment, overall survival and toxicity.A Monocentric single institution retrospective data collection was performed. Inclusion criteria were: (1) oligo-recurrent or oligo-progressive disease (less than 5 metastases) in mRCC patients after radical/partial nephrectomy or during systemic therapy, (2) metastasectomy or other metastasis-directed, rather than SBRT not feasible, (3) any contraindication to receive systemic therapy (such as comorbidities), (4) all the histologies were included, (5) available signed informed consent form for treatment. Tumor response and toxicity were evaluated using the response evaluation criteria in solid tumors and the Common Terminology Criteria for Adverse Events version 4.03, respectively. Progression-free survival in-field and out-field (in-field and out-field PFS) and overall survival (OS) were calculated via the Kaplan-Meier method. The drug treatment-free interval was calculated from the start of SBRT to the beginning of any systemic therapy.From 2010 to December 2018, 61 patients with extracranial and intracranial metastatic RCC underwent SBRT on 83 lesions. Intracranial and extracranial lesions were included. Forty-five (74%) patients were treated for a solitary metastatic lesion. Median RT dose was 25 Gy (range 10-52) in 5-10 fractions. With a median follow-up of 2.3 years (range 0-7.15), 1-year in-field PFS was 70%, 2-year in-field PFS was 55%. One year out-field PFS was 39% and 1-year OS was 78%. Concomitant systemic therapy was employed for only 11 (18%) patients, for the others 50 (82%) the drug treatment-free rate was 70% and 50% at 1 and 2 years, respectively. No G1 acute and late toxicities were reported.The pattern of failure was pre-dominantly out-of-field, even if the population was negatively selected and the used RT dose could be considered palliative. Therefore, SBRT appears to be a well-tolerated, feasible and safe approach in oligo metastatic RCC patients with an excellent in-field PFS. SBRT might play a role in the management of selected RCC patients allowing for a delay systemic therapy begin (one out of two patients were free from new systemic therapy at 2 years after SBRT). Further research on SBRT dose escalation is warranted.

Liver plays a major role in metabolism and acts as a source of energy for the body by storing glycogen. With the growing interest and investigation in the biological effects in recent years, it is important and necessary to develop accurate and comparable analytical methods for elements in bio-samples. It has, however, been 10 years since the tissue sample (bovine liver) of CCQM-K49 key comparison. The purpose of CCQM-K145 is to ensure the comparable and traceable measurement results for essential and toxic elements such as P, S, Zn, Mn, Ni, Mo, Sr, Cr, Co, Pb, As and Hg in bovine liver among NMIs and other designated measurement bodies worldwide. The comparison was agreed by IAWG as 6th IAWG Benchmarking Exercise with Zn and Ni as exemplary elements at the meeting in Korea in the early October 2016. The results of CCQM-K145 are expected to cover the measurement capability and support CMCs claiming for inorganic elements in the similar biological tissue materials and food samples. 30 NMIs and DIs registered in CCQM-K145. With respect to the methodology, a variety of techniques such as IDMS, ICP-OES, ICP-MS(non-ID), AAS and NAA were adopted by the participants. For Zn, Ni, Sr, Pb and Hg measurements, most participants chose ID-ICP-MS method, which showed the better performance in terms of consistency and reliability of the measurement results. In aspect of the traceability for the measurement results in CCQM-K145, most participants used their own (in house) CRMs or other NMI's CRMs to guarantee trace to SI unit. Most participants used similar matrix CRMs for quality control or method validation. Base on different statistic way to calculate the reference mass fraction values and associated uncertainties for each measurand, removal of the suspected extreme values, and discussion at the IAWG meetings, the median values are proposed as the KCRV for Zn, Ni, Mn, Mo, Cr, Pb and Hg; the arithmetic mean values are proposed as the KCRV for P, S, Sr, Co and As. In general, the performances of the majority of CCQM-K145 participants are very good, illustrating their measurement capabilities for Zn, Ni, P, S, Mn, Mo, Sr, Cr, As, Co, Pb and Hg in a complex biological tissue matrix. Bovine liver contains many kinds of nutrients and microelements, it can be regarded as a typical representative material of biological tissue and food. In CCQM-K145, the analytes involved alkali metals and transition elements, metalloids / semi-metals and non metals with a range of mass fraction from mg/g to μg/kg. CCQM-K145 also tested the ability of NMIs/DIs to determine elements that were easy to be lost and polluted, and interfered significantly. The chemical pretreatment methods of samples used in the comparison is suitable for general food and biological matrix samples. A variety of measurement methods used in the comparison represent the main instrumental technology for elemental analysis. Therefore, for supporting CMC claim, CCQM-K145 is readily applicable to measurement of more elements in a wide range of biological materials (including liquids and solids) and meat products. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

APMP.QM-S10 was coordinated by Government Laboratory, Hong Kong SAR (GLHK) under the auspices of the Inorganic Analysis Working Group (IAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM). Fourteen national metrology institutes (NMIs) or designated institutes (DIs) registered for the examination of zinc, manganese, calcium and magnesium. All institutes submitted the results for zinc and manganese, and twelve institutes submitted the results for calcium and magnesium. The supplementary comparison was designed to enable participating institutes to demonstrate their measurement capabilities in measuring the mass fractions of the analytes at mg/kg levels in a test sample of food supplement by various analytical techniques. For examination of zinc, manganese, calcium and magnesium, most of the participants used microwave-assisted acid digestion methods for sample dissolution. A variety of instrumental techniques including inductively coupled plasmas mass spectrometry (ICP-MS), isotope dilution inductively coupled plasmas mass spectrometry (ID-ICP-MS), inductively coupled plasmas optical emission spectrometry (ICP-OES), flame atomic absorption spectrometry (FAAS), and instrumental neutron action analysis (INAA) were employed by the participants for determination. For this supplementary comparison, inorganic core capabilities have been demonstrated by the concerned participants with respect to methods including ICP-MS (without isotope dilution), ID-ICP-MS, ICP-OES, FAAS and INAA on the determination of elements (zinc, manganese, calcium and magnesium) in a food matrix of food supplement. Generally, the participants' results of APMP.QM-S10 were found to be consistent for all measurands according to their equivalence statements. Except with some extreme values, most of the participants obtained the values of d i/U(d i) within ± 1 for the measurands. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

The results of analytical measurements performed with solid-sampling techniques are affected by the distribution of the analytes within the matrix. The effect becomes significant in case of determination of trace elements in small subsamples. In this framework we propose a measurement model based on Instrumental Neutron Activation Analysis to determine the relative variability of the amount of an analyte among subsamples of a material. The measurement uncertainty is evaluated and includes the counting statistics, the full-energy gamma peak efficiency and the spatial gradient of the neutron flux at the irradiation position. The data we obtained in a neutron activation experiment and showing the relative variability of As, Au, Ir, Sb and W among subsamples of a highly pure Rh foil are also presented., Comment: 11 pages, 5 figures, 1 table

This paper examines signal detection in the presence of noise, with particular emphasis on nuclear activation analysis. The specific problem is to decide whether the signal-plus-background or the no-signal hypothesis fits the data better. Our solution is based on the use of Bayesian inferences to test the two hypotheses.

The National Institute of Metrological Research (INRiM), in Italy, has among its duties the development, the maintenance and the dissemination of primary standards for establishing a correct traceability chain at national level. For this reason, INRiM has been developing research activities on reference materials, mainly in the chemical field, dealing both with the characterization and the certification of reference materials. The present paper focuses on the certified reference solutions for electrolytic conductivity, on the primary reference gas mixtures, and on INRiM contribution in the certification of various reference materials by determining trace element mass fraction by means of Instrumental Neutron Activation Analysis. The description of the main features of the produced reference materials, of the used procedures, and of the uncertainty evaluation are given.

The CCQM-P106 pilot study was organized by the inorganic working group of the Comite Consultatif pour la Quantite de Matiere (CCQM) as a feasibility comparison to study the applicability of different analysis methods to the polypropylene sample and test the abilities of the participants for measuring the Cd, Cr, Hg and Pb in polypropylene. National Institute of Metrology P.R. China (NIM) acted as the coordinating laboratory of this pilot study. There were 21 laboratories that submitted the final results. The median values of the mass fraction of Cd, Cr, Hg and Pb were 36.12 mg kg−1 (the median absolute deviation about the median (MADe) = 0.46 mg kg−1), 252.5 mg kg−1 (MADe = 3.4 mg kg−1), 387.0 mg kg−1 (MADe = 10.1 mg kg−1) and 466.2 mg kg−1 (MADe = 8.9 mg kg−1), respectively. Isotope dilution mass spectrometry (IDMS), inductively coupled plasma-mass spectrometry (ICP-MS), inductively coupled plasma-optical emission spectrometry (ICP-OES), atomic absorption spectrometry (AAS), instrumental neutron activation analysis (INAA) and X-ray fluorescence (XRF) measurement methods were used, and microwave digestion was used by the most of the participants. In general, very good agreement of the results was observed. Moreover, compared to the results of other methods, the results of IDMS still showed less spread amongst laboratories and had a smaller uncertainty. In addition, the results of some analytes used by XRF and INAA also got satisfactory agreement with the median value.

Radioactive solutions of 177g,mLuIIICl3 are used for labeling organic compounds for metabolic radiotherapy and radioimmunotherapy. The labeling process involves Lu in III oxidation state, so the presence of other stable impurities in the same oxidation state could result in an isomorphous dilution of radioactive 177gLu. Samples of 177gLuCl3 were analyzed to quantify the chemical impurities with a special regard for trivalent elements with instrumental neutron activation analysis (INAA), carried out in the research nuclear reactor TRIGA MARK II (GA, USA) of the Universita degli Studi di Pavia, and electrothermal atomic absorption spectroscopy (ET-AAS) (Varian, USA) at LASA.

The capacity to accumulate trace elements from the atmosphere of the lichens Hypogymnia physodes, Parmelia sulcata, Pseudevernia furfuracea and Usnea gr. hirta transplanted to an urban site of N Italy was compared. Twenty-nine elements (Al, As, Br, Ca, Cd, Ce, Cl, Co, Cr, Cs, Cu, Fe, Hg, I, K, La, Mg, Mn, Ni, Pb, Rb, Sb, Sc, Se, Sm, Th, Ti, V, Zn) were analyzed by Instrumental Neutron Activation Analysis (INAA) and Electro-Thermal Atomic Absorption Spectroscopy (ET-AAS). The ratio between the concentrations of each element in exposed samples to that of control samples (exposed-to-control ratio and EC ratio) was used to investigate the accumulation rates of lichen thalli. The results showed that in general elements did not exhibit well defined trends, but rather showed fluctuations, and indicated that H. physodes, P. furfuracea and U. gr. hirta have a similar accumulation capacity, while that of P. sulcata is lower.

Lichens as biomonitors and neutron activation analysis as analytical technique have been employed to evaluate the trace element atmospheric pollution in the metropolitan area of the city of Pavia (Northern Italy). Transplanted lichens (Parmelia sulcata and Usnea gr. hirta) and air particulate matter have been monthly collected and analyzed during the winter 2001-2002. INAA and ET-AAS have been used for the determination of 28 elements in air particulate matter and 25 elements in lichens. Trace metals concentrations as well as the corresponding enrichment factors were evaluated and compared.

Trace element (TE) characterization and analysis in epiphytic lichens collected in different areas of the Himalayas (Nepal) and of the Alps (Italy) is presented. The results give information for the assessment of TE distribution present in the two different areas. The evaluation of the enrichment factors may provide information for many elements about their association to long-distance atmospheric transport phenomena. To this purpose, samples of superficial soils, collected in the same areas of those of the lichens, have also been analyzed. Most of the trace elements were determined by instrumental neutron activation analysis (INAA), while lead and cadmium measurements were carried out with electrothermal atomic absorption spectroscopy (ET-AAS).

The possibility of using neutron activation analysis to link up a secondary to a primary mono-elemental solution was investigated. A procedure was developed for the determination of the ratio between the mass fractions of two solutions. The use of a monitor element was essential to limit the effect of the non-uniformity of the neutron flux during irradiation. The proposed procedure was tested in the case of two molybdenum solutions having the same mass fraction. Although the experiment did not reach the goal, possible ways are suggested to reach the target expanded uncertainty of 0.1 %.

We investigated the use of neutron activation to estimate the 30Si mole fraction of the ultra-pure silicon material highly enriched in 28Si for the measurement of the Avogadro constant. Specifically, we developed a relative method based on instrumental neutron activation analysis and using a natural-Si sample as a standard. To evaluate the achievable uncertainty, we irradiated a 6 g sample of a natural-Si material and modelled experimentally the signal that would be produced by a sample of the 28Si-enriched material of similar mass and subjected to the same measurement conditions. The extrapolation of the expected uncertainty from the experimental data indicates that a measurement of the 30Si mole fraction of the 28Si-enriched material might reach a 4% relative combined standard uncertainty.

Analytical measurements of the 28Si crystal used for the determination of the Avogadro constant are essential to prevent biased results or under-estimated uncertainties. A review of the existing data confirms the high-purity of silicon with respect to a large number of elements. In order to obtain a direct evidence of purity, we developed a relative analytical method based on neutron activation. As a preliminary test, this method was applied to a sample of the Avogadro crystal WASO 04. The investigation concerned twenty-nine elements. The mass fraction of Au was quantified to be 1.03(18) x 10-12. For the remaining twenty-eight elements, the mass fractions are below the detection limits, which range between 1 x 10-12 and 1 x 10-5., 11 pages, 1 figure, 4 tables

The CCQM-K108 key comparison was organised by the Inorganic Analysis Working Group (IAWG) of CCQM to test the abilities of national metrology institutes (NMIs) or designated institutes (DIs) to measure the mass fractions of arsenic species, total arsenic and cadmium in brown rice flour. The National Metrology Institute of Japan (NMIJ) acted as the coordinating laboratory. The participants used different measurement methods, though most of them used inductively coupled plasma mass spectrometry (ICP-MS) or isotope-dilution inductively coupled plasma mass spectrometry (ID-ICP-MS) for Cd and ICP-MS for total arsenic. Regarding arsenic speciation, all participants used ICP-MS coupled with liquid chromatography (LC). Accounting for relative expanded uncertainty, comparability of measurement results for each of total arsenic and cadmium was successfully demonstrated by the participating NMIs or DIs for the measurement of the measurand at the level of less than 0.5 mg/kg. Regarding arsenic species (inorganic arsenic and dimethylarsinic acid (DMAA)), there was, however, a measurement problem still to be solved and that part of CCQM-K108 will be repeated. It is expected that arsenic, cadmium and other metals at mass fractions greater than approximately 0.1 mg/kg in rice flour can be determined by each participant using the same technique(s) employed for this key comparison to achieve similar uncertainties mentioned in the present report. Furthermore, the results of this key comparison can be utilised along with the IAWG core capability approach. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

In 1990, following an agreement with the Royal Nepal Academy of Science, the Italian National Research Council (CNR) installed a scientific laboratory (Pyramid) at 5,050 m (s.l.) in the Himalayan region. Among the environmental related researches, the task project RATEAP (Remote Areas Trace Elements Atmospheric Pollution), started in 2001, aims at obtaining information about the chemical composition of the high altitude airborne particulate matter. During the period of March-April 2002 series of samplings have been carried out by pump aspiration. Samples of total suspended particles (TSP) as well as of the particles size fraction PM10 and PM 2.5 have been collected and submitted to INAA for the determination of more than 30 elements present, at nanogram levels, in few micrograms of air dust. Data quality assurance has been performed by the analysis of different NIST SRMs and, in particular, the SRM 2783 Air particulate on Filter Media.

The results of a survey aimed at providing baseline element composition of lichens from unpolluted or very low polluted areas are reported. Lichen samples collected at high elevation areas in Himalayas (Nepal), Mt. Kenya (Kenya) and the Alps (Italy) were analyzed for their trace element content, mostly by INAA, allowing for a multi-element analysis. The elemental composition of lichen samples was essentially influenced by natural occurrence, mainly airborne soil dust. However, also anthropogenic input determined by long-distance atmospheric transport of pollutants was involved for some highly volatile elements such as Br, Cd and Sb. To avoid the influence of soil contamination and air pollution, and obtain baseline concentrations to be used as reference (the “natural” elemental composition of lichens), the average of the lowest concentrations is suggested.

Within the framework of the Ev-K2-CNR research program of the Italian National Research Council a specific task project has been initiated for the identification of trace elements in lichens in remote high altitude areas. This is to evaluate the possibility of using lichens as biomonitors of trace elements of atmospheric pollution. In this preliminary study, more than 20 elements havebeen determined in some species of lichens collected at different altitudes (from 1300 to 5000 in) in the region of the Sagarmatha National Park (Nepal). Samples of superficial soils were also collected and analyzed to calculate the trace element enrichment factors (EF) using scandium as a normalizing element. Most of the trace elements were determined by instrumental neutron activation analysis (INAA), while lead and cadmium measurements were carried out with electrothermal atomic absorption spectroscopy (ET-AAS). The EF values as well as the elemental concentrations are reported and discussed.