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Abstract Emergency general surgeons often provide care to severely ill patients requiring surgical interventions and intensive support. One of the primary drivers of morbidity and mortality is perioperative bleeding. In general, when addressing life threatening haemorrhage, blood transfusion can become an essential part of overall resuscitation. However, under all circumstances, indications for blood transfusion must be accurately evaluated. When patients decline blood transfusions, regardless of the reason, surgeons should aim to provide optimal care and respect and accommodate each patient’s values and target the best outcome possible given the patient’s desires and his/her clinical condition. The aim of this position paper was to perform a review of the existing literature and to provide comprehensive recommendations on organizational, surgical, anaesthetic, and haemostatic strategies that can be used to provide optimal peri-operative blood management, reduce, or avoid blood transfusions and ultimately improve patient outcomes.

Abstract Intra-abdominal infections (IAIs) are common surgical emergencies and are an important cause of morbidity and mortality in hospital settings, particularly if poorly managed. The cornerstones of effective IAIs management include early diagnosis, adequate source control, appropriate antimicrobial therapy, and early physiologic stabilization using intravenous fluids and vasopressor agents in critically ill patients. Adequate empiric antimicrobial therapy in patients with IAIs is of paramount importance because inappropriate antimicrobial therapy is associated with poor outcomes. Optimizing antimicrobial prescriptions improves treatment effectiveness, increases patients’ safety, and minimizes the risk of opportunistic infections (such as Clostridioides difficile) and antimicrobial resistance selection. The growing emergence of multi-drug resistant organisms has caused an impending crisis with alarming implications, especially regarding Gram-negative bacteria. The Multidisciplinary and Intersociety Italian Council for the Optimization of Antimicrobial Use promoted a consensus conference on the antimicrobial management of IAIs, including emergency medicine specialists, radiologists, surgeons, intensivists, infectious disease specialists, clinical pharmacologists, hospital pharmacists, microbiologists and public health specialists. Relevant clinical questions were constructed by the Organizational Committee in order to investigate the topic. The expert panel produced recommendation statements based on the best scientific evidence from PubMed and EMBASE Library and experts’ opinions. The statements were planned and graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence. On November 10, 2023, the experts met in Mestre (Italy) to debate the statements. After the approval of the statements, the expert panel met via email and virtual meetings to prepare and revise the definitive document. This document represents the executive summary of the consensus conference and comprises three sections. The first section focuses on the general principles of diagnosis and treatment of IAIs. The second section provides twenty-three evidence-based recommendations for the antimicrobial therapy of IAIs. The third section presents eight clinical diagnostic-therapeutic pathways for the most common IAIs. The document has been endorsed by the Italian Society of Surgery.

Abstract Background The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD). Aim To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD. Methods A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient. Results In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD. Conclusion In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD.

The management of spinal trauma in the pre-hospital setting is based on techniques of immobilization for prevention of secondary neurological damage in high-risk patients during transportation.1 Since the ’70s, the traditional form of Preventive Spinal Immobilization (PSI) has been carried out using a long spinal board, head blocks, and immobilization straps often associated with the placement of a cervical collar.2 The first documentation of this practice comes from the early 19th century, when pre-hospital trauma care was introduced on the battlefields of the Napoleonic Wars.3 This strategy is still adopted by many pre-hospital medical services worldwide and taught as the gold standard on many trauma courses. The traditional form of PSI is indeed based more on pragmatism than on high-quality studies supporting its efficacy.3 [...]

Abstract Background Nomograms are easy-to-handle clinical tools which can help in estimating the risk of adverse outcome in certain population. This multi-center study aims to create and validate a simple and usable clinical prediction nomogram for individual risk of post-traumatic Intracranial Hemorrhage (ICH) after Mild Traumatic Brain Injury (MTBI) in patients treated with Direct Oral Anticoagulants (DOACs). Methods From January 1, 2016 to December 31, 2019, all patients on DOACs evaluated for an MTBI in five Italian Emergency Departments were enrolled. A training set to develop the nomogram and a test set for validation were identified. The predictive ability of the nomogram was assessed using AUROC, calibration plot, and decision curve analysis. Results Of the 1425 patients in DOACs in the study cohort, 934 (65.5%) were included in the training set and 491 (34.5%) in the test set. Overall, the rate of post-traumatic ICH was 6.9% (7.0% training and 6.9% test set). In a multivariate analysis, major trauma dynamic (OR: 2.73, p = 0.016), post-traumatic loss of consciousness (OR: 3.78, p = 0.001), post-traumatic amnesia (OR: 4.15, p

Lung ultrasound (LUS) is an essential tool for respiratory disease differential diagnosis at Emergency Department (ED), due to easy applicability and safety. During Sars-Cov 2 pandemic, LUS was widely used in every setting. This study aims to demonstrate the prognostic role of LUS independently of other factors and the identification of an LUS score cut-off to be applied in the ED. A multi-center prospective study was conducted on 285 patients, 123 from Pisa University Hospital, 162 from S. Maria Misericordia Hospital of Perugia. All patients received LUS examination by expert sonographers within 48 hours of admission with the same methodology. Univariate logistic analysis demonstrated that LUS is a mortality predictor, OR 2.8 (CL1.5-5.1). Using LUS score cut-off 1.3, the OR was 6.7 (CL2.7-1.6). In multivariate logistic analysis, LUS score significantly predicted death, independently of other factors. ROC curves comparison demonstrated that the introduction of LUS score

Human health is one of the earliest biosensors of climate change, which increases the frequency and severity of many diseases, as reported by Bellone.1 In Europe, air pollution is becoming a severe health problem that needs to be addressed by physicians of all specialties as well as governments and the general public. Unfortunately, it is acknowledged that the Po Valley in Italy is among the most polluted areas in Europe. As physicians practicing in this area, we feel we must remind our colleagues of the increasing impact of the environment on the health of ourselves and our patients. Along with having a substantial negative influence on both human and environmental health, air pollution also has a financial cost since it raises medical expenses and reduces productivity due to missed workdays. We can define this situation as a silent epidemic that affects all people, regardless of age. [...]

Gender-based violence (GBV) is a global issue deeply rooted that grows from gender inequality and represents one of the most severe human rights violations. GBV is violence directed against a person because of their gender. It may include both intimidation and manipulation in addition to sexual, physical, mental, and financial harm done in secret or in a public context. The consequences of GBV can be devastating, with life-long consequences for survivors, or even result in death. Although GBV affects both men and women, the burden belongs mainly to women and girls. According to the 2015 Italian National Institute of Statistics report, almost 1 out of 3 women in Italy have disclosed physical and/or sexual violence. Thirty-one percent of women aged 16—70 have experienced some form of violence (20% physical and 21% sexual violence).1 Up to December 3, 2023, 109 women had died in Italy, 90 of whom in domestic settings, and 58 had been killed by partners or former partners. Analysing the data from the first nine months of 2023 of calls to the national ‘Anti-violence and anti-stalking’ helpline (1522), approximately half of the victims (47.6%) were victims of physical violence. Psychological violence was the second most frequent reason for calling (36.9%). Most of them (79.4%) are victims of domestic violence. Only 15.8% reported the type of violence they suffered (1,311 victims),2 even if the Italian law ensures greater protection for victims and legal aid. [...]

In the recent letter by Pucciarelli et al.,1 the authors comment on an observation reported by Fabbri et al.2 that the pain is treated correctly only in a very small percentage of patients (3%), even those who experienced severe pain, suggesting as a possible solution of this important unsolved issue the introduction (implementation) of sublingual sufentanil use for pain treatment of trauma patients in the pre-hospital setting. [...]

Background: Arterial lactate is a recognized biomarker associated with death in critically ill patients. The prognostic role of arterial lactate in acute respiratory failure due to the novel coronavirus disease 2019 (COVID-19) is unclear. Objectives: We aimed to investigate the prognostic role of arterial lactate levels at admission in patients with COVID-19-related acute respiratory failure. Design and Methods: Cohorts of consecutive patients admitted to nonintensive care units (ICU) at study centers for COVID-19-related respiratory failure were merged into a collaborative database. The prognostic role of lactate levels at admission was assessed for continuous values and values ⩾2.0 mmol/l, and lactate clearance at 24 h through delta-lactate (ΔLac). The study outcome was 30-day in-hospital death. Cox proportional regression model was used to assess independent predictors of the study outcome. Results: At admission, 14.6% of patients had lactate levels ⩾2 mmol/l. In-hospital death at 30 days occurred in 57 out of 206 patients; 22.3% and 56.7% with normal or ⩾ 2 mmol/l lactate at admission, respectively. The median lactate level was 1.0 [interquartile range (IQR) 0.8–1.3] mmol/l and 1.3 (IQR 1.0–2.1) mmol/l in survivors and nonsurvivors, respectively ( p -value

Abstract Background The presence of oral anticoagulant therapy (OAT) alone, regardless of patient condition, is an indication for CT imaging in patients with mild traumatic brain injury (MTBI). Currently, no specific clinical decision rules are available for OAT patients. The aim of the study was to identify which clinical risk factors easily identifiable at first ED evaluation may be associated with an increased risk of post-traumatic intracranial haemorrhage (ICH) in OAT patients who suffered an MTBI. Methods Three thousand fifty-four patients in OAT with MTBI from four Italian centers were retrospectively considered. A decision tree analysis using the classification and regression tree (CART) method was conducted to evaluate both the pre- and post-traumatic clinical risk factors most associated with the presence of post-traumatic ICH after MTBI and their possible role in determining the patient’s risk. The decision tree analysis used all clinical risk factors identified at the first ED evaluation as input predictor variables. Results ICH following MTBI was present in 9.5% of patients (290/3054). The CART model created a decision tree using 5 risk factors, post-traumatic amnesia, post-traumatic transitory loss of consciousness, greater trauma dynamic, GCS less than 15, evidence of trauma above the clavicles, capable of stratifying patients into different increasing levels of ICH risk (from 2.5 to 61.4%). The absence of concussion and neurological alteration at admission appears to significantly reduce the possible presence of ICH. Conclusions The machine-learning-based CART model identified distinct prognostic groups of patients with distinct outcomes according to on clinical risk factors. Decision trees can be useful as guidance in patient selection and risk stratification of patients in OAT with MTBI.

Background: Prone positioning (PP) is an established and commonly used lung recruitment method for intubated patients with severe acute respiratory distress syndrome, with potential benefits in clinical outcome. The role of PP outside the intensive care unit (ICU) setting is debated. Objectives: We aimed at assessing the role of PP in death and ICU admission in non-intubated patients with acute respiratory failure related to COronaVIrus Disease-19 (COVID-19) pneumonia. Design: This is a retrospective analysis of a collaborative multicenter database obtained by merging local non-interventional cohorts. Methods: Consecutive adult patients with COVID-19-related respiratory failure were included in a collaborative cohort and classified based on the severity of respiratory failure according to the partial arterial oxygen pressure to fraction of inspired oxygen ratio (PaO 2 /FiO 2 ) and on clinical severity by the quick Sequential Organ Failure Assessment (qSOFA) score. The primary study outcome was the composite of in-hospital death or ICU admission within 30 days from hospitalization. Results: PP was used in 114 of 536 study patients (21.8%), more commonly in patients with lower PaO 2 /FiO 2 or receiving non-invasive ventilation and less commonly in patients with known comorbidities. A primary study outcome event occurred in 163 patients (30.4%) and in-hospital death in 129 (24.1%). PP was not associated with death or ICU admission (HR 1.17, 95% CI 0.78–1.74) and not with death (HR 1.01, 95% CI 0.61–1.67) at multivariable analysis; PP was an independent predictor of ICU admission (HR 2.64, 95% CI 1.53–4.40). The lack of association between PP and death or ICU admission was confirmed at propensity score-matching analysis. Conclusion: PP is used in a non-negligible proportion of non-intubated patients with COVID-19-related severe respiratory failure and is not associated with death but with ICU admission. The role of PP in this setting merits further evaluation in randomized studies.

The Academy of Emergency Medicine and Care is one of the more than 20 scientific societies promoting the 3rd National Congress of Emergency/Urgency (CEU2023), planned in Florence from March 30th to April 1st.1 This will be a fundamental appointment for update on all clinical and organizing aspects of the Italian emergency system. More that 2500 people will participated to the CEU2023 meeting and courses with the possibility to attend more than 50 sessions with approximately 500 national and international speakers. This organization will ensure elevate quality of updating for specific themes by covering the point of view of hospital and pre-hospital medical doctors and nurses, emergency medicine trainees, but other professionals (drivers, rescuers, technicians, and volunteers). [...]

Abstract Accurate risk stratification in COVID-19 patients consists a major clinical need to guide therapeutic strategies. We sought to evaluate the prognostic role of estimated pulse wave velocity (ePWV), a marker of arterial stiffness which reflects overall arterial integrity and aging, in risk stratification of hospitalized patients with COVID-19. This retrospective, longitudinal cohort study, analyzed a total population of 1671 subjects consisting of 737 hospitalized COVID-19 patients consecutively recruited from two tertiary centers (Newcastle cohort: n = 471 and Pisa cohort: n = 266) and a non-COVID control cohort (n = 934). Arterial stiffness was calculated using validated formulae for ePWV. ePWV progressively increased across the control group, COVID-19 survivors and deceased patients (adjusted mean increase per group 1.89 m/s, P

Abstract With the outbreak of COVID-19 exerting a strong pressure on hospitals and health facilities, clinical decision support systems based on predictive models can help to effectively improve the management of the pandemic. We present a method for predicting mortality for COVID-19 patients. Starting from a large number of clinical variables, we select six of them with largest predictive power, using a feature selection method based on genetic algorithms and starting from a set of COVID-19 patients from the first wave. The algorithm is designed to reduce the impact of missing values in the set of variables measured, and consider only variables that show good accuracy on validation data. The final predictive model provides accuracy larger than 85% on test data, including a new patient cohort from the second COVID-19 wave, and on patients with imputed missing values. The selected clinical variables are confirmed to be relevant by recent literature on COVID-19.

Abstract On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making.

In this issue of Emergency Care Journal we publish a letter from some young colleagues from CoSMEU (the Italian association of Emergency Medicine, EM).1 They express great concern on the several aspects the EM situation in Italy.2 The first issue is the collapse of the Emergency Departments (ED)2,3 caused by crowding/boarding combined with low available resources, particularly regarding EM physicians. The logical consequence is that EM is no longer attractive neither for “older” (indeed, not so much) physicians who are leaving their careers in great number, or “younger” doctors who are not attracted by the EM specialization,4 despite growing available access (up to 1000 training positions) in the recent years. [...]

Abstract High sensitivity troponin T (hsTnT) is a strong predictor of adverse outcome during SARS-CoV-2 infection. However, its determinants remain partially unknown. We aimed to assess the relationship between severity of inflammatory response/coagulation abnormalities and hsTnT in Coronavirus Disease 2019 (COVID-19). We then explored the relevance of these pathways in defining mortality and complications risk and the potential effects of the treatments to attenuate such risk. In this single-center, prospective, observational study we enrolled 266 consecutive patients hospitalized for SARS-CoV-2 pneumonia. Primary endpoint was in-hospital COVID-19 mortality. hsTnT, even after adjustment for confounders, was associated with mortality. D-dimer and CRP presented stronger associations with hsTnT than PaO2. Changes of hsTnT, D-dimer and CRP were related; but only D-dimer was associated with mortality. Moreover, low molecular weight heparin showed attenuation of the mortality in the whole population, particularly in subjects with higher hsTnT. D-dimer possessed a strong relationship with hsTnT and mortality. Anticoagulation treatment showed greater benefits with regard to mortality. These findings suggest a major role of SARS-CoV-2 coagulopathy in hsTnT elevation and its related mortality in COVID-19. A better understanding of the mechanisms related to COVID-19 might pave the way to therapy tailoring in these high-risk individuals.

We present a workflow for clinical data analysis that relies on Bayesian Structure Learning (BSL), an unsupervised learning approach, robust to noise and biases, that allows to incorporate prior medical knowledge into the learning process and that provides explainable results in the form of a graph showing the causal connections among the analyzed features. The workflow consists in a multi-step approach that goes from identifying the main causes of patient's outcome through BSL, to the realization of a tool suitable for clinical practice, based on a Binary Decision Tree (BDT), to recognize patients at high-risk with information available already at hospital admission time. We evaluate our approach on a feature-rich dataset of Coronavirus disease (COVID-19), showing that the proposed framework provides a schematic overview of the multi-factorial processes that jointly contribute to the outcome. We compare our findings with current literature on COVID-19, showing that this approach allows to re-discover established cause-effect relationships about the disease. Further, our approach yields to a highly interpretable tool correctly predicting the outcome of 85% of subjects based exclusively on 3 features: age, a previous history of chronic obstructive pulmonary disease and the PaO2/FiO2 ratio at the time of arrival to the hospital. The inclusion of additional information from 4 routine blood tests (Creatinine, Glucose, pO2 and Sodium) increases predictive accuracy to 94.5%.

SARS-CoV-2 management in Emergency Department: risk stratification and care setting identification proposal based on first pandemic wave in Pisa University Hospital Background: COVID-19 patients require early treatment and admission to an appropriate care setting, considering possible rapid and unpredictable to Severe Acute Respiratory Syndrome. Objective: A flow-chart was developed by a multidisciplinary team of Emergency Department (ED) clinicians, intensivists and radiologists aiming to provide tools for disease severity stratification, appropriate ventilation strategy and hospitalization setting identification. Methods: We conducted a retrospective application of our model on 313 hospitalized patients at Pisa University Hospital including 222 patients admitted to ED for respiratory failure between March and April 2020. Risk stratification score was based on respiratory and chest imaging parameters, while management strategy on comorbidities and age. Results: Age, comorbidities, clinical respiratory and arterial blood gas parameters, semi-quantitative chest computed tomography score were significant predictors of mortality (p

Since a few years ago health systems in the western countries have a new problem to face: being a Medical Doctor (MD), especially a hospital or a general practice physician, is less and less appealing for the young generations. [...]

In Northern Italy the coronavirus infection has spread since February 2020: the increase in admissions of COVID-19 patients corresponded to a drastic decrease in admissions of regular patients to the Emergency Room (ER). This retrospective study was conducted by Academy of Emergency Medicine and Care (AcEMC). During the lockdown period the accesses were reduced by more than 50%, and in the following months of May and June 2020, there was a recovery clearly below (70%) previous year’s numbers. We have observed a drastic reduction in white and green codes, a fair reduction in yellow codes, while red codes remained stable. The decrease in access to the ER mainly concerned patients with low priority color codes, but also the reduction in the number of accesses of yellow and red codes, insignificant at a superficial glance, is notable. If we consider that yellow and red codes during the months of the lockdown included many patients with COVIDrelated respiratory insufficiency, it is evident that there was a clear reduction in the number of serious illnesses not COVID-related. This is certainly another serious consequence of the COVID-19 pandemic.

I have accepted the role of Editor of Emergency Care Journal with great enthusiasm. I wish to thank Ivo Casagranda, who will continue into the future in the role of Senior Editor (and my guide) and all previous Editors for the contribution made to this journal up to now. (...)

Rationale and Aim: This study is aimed at identifying possible patterns of vascular wall disarray and remodeling in radial arteries of patients with fibromuscular dysplasia (FMD), by means of ultrahigh frequency ultrasound (UHFUS). Methods: UHFUS scans of the radial arteries and of 30 FMD patients and 30 healthy controls were obtained by VevoMD (70 MHz probe, FUJIFILM, VisualSonics, Toronto, Canada). 10 end-diastolic frames for each subject were analyzed. 74 radiomic features and 4 engineered parameters were extracted: intima-media thickness (IMT) and adventitia thickness (AT), an adjunctive acoustic interface for each layer (IMT and AT triple signal). The extracted parameters were used to train classification models, using Support Vector Machine Linear (SVM), K-Nearest Neighbors (KNN), Logistic Regression, Linear Discriminant Analysis (LDA). The models were then tested on an independent validation population (38 FMD patients and 28 healthy subjects). Results: IMT (185 ± 46 vs 168 ± 37, p =) and AT (104 ± 34 vs 96 ± 35, p = 0.004) were significantly higher in FMD than in controls. IMT and AT triple signal were also more frequent in FMD than in control images (p < for both). The most accurate classification models were LDA (sensitivity = 0.67, specificity = 0.76, accuracy = 0.71, AUC = 0.71) and Logistic Regression (sensitivity = 0.71, specificity = 0.72, accuracy = 0.71, AUC = 0.71). The models showed and accuracy of about 70% when tested on the validation population. Conclusions: Wall ultrastructure of radial arteries of FMD patients is extensively altered: IMT and AT are thickened and the first and/or second layer of the arterial wall is splitted, showing a triple signal feature. Radiomic descriptors combined with engineered parameters allow to distinguish between radial images from FMD patients and controls with a 70% accuracy.

Starting from 1st case in Italy, on February 20th, 2020, CO-rona VI-rus D-isease 2019 (COVID-19) pandemic spread to whole Italian territory, with different regional distribution. Tuscany has been classified as medium diffusion area (40-100 cases/100000 inhabitants). In this context, all healthcare structures reviewed their organization to meet new needs. Our study’s objectives were description of organizational model outlined to safely manage Emergency Department (ED) and analysis of patients’ flows within Hospital of Pisa during pandemic. The ED has been reorganized with dedicated areas for examination and waiting for tests results. A similar reduction (-62%) of ED accesses comparing to the same period of 2019 and the previous months of 2020 was observed. Hospital Task Force arranged for progressive activation of Units by modules, according to territorial needs. From the beginning of March to the end of April 2020, 315 COVID-19 patients were hospitalized. Overall, a 45% reduction in hospital admissions compared to the same period of 2019 was observed, with increased mortality (4% versus 2%). The University Hospital of Pisa efficiently managed COVID-19 emergency with a logistical reorganization of ED.

Background: Assessment of endothelial function using brachial artery flow-mediated dilation (FMD) predicts future cardiovascular disease (CVD) risk. However, poor adherence to protocol guidelines and lack of reference values hinders widespread FMD use. This study established age- and sex-specific reference intervals for brachial artery FMD in healthy individuals and examined the relation with CVD risk factors. Methods: Collected according to expert-consensus guidelines, we combined brachial artery FMD and subject characteristics/medical history from 5,362 individuals (4–84 years; 2,076 females). We first examined healthy individuals (n = 1,403 [582 females]) to generate age-/sex-specific percentile curves. Subsequently, we included subjects with CVD risk factors but without disease (un-medicated n = 3,167 [1,247 females], and medicated n = 792 [247 females]). Multiple linear regression tested the relation of CVD risk factors with FMD. Results: Healthy men showed a negative, curvilinear relation between FMD and age, whilst females revealed a linear relation that started higher, but declined at a faster rate. Age-/sex-related differences in FMD, at least partly, relate to baseline artery diameter. FMD was affected by CVD risk factors in un-medicated (e.g. systolic-/diastolic blood pressure, diabetes) and medicated subjects (e.g. dyslipidaemia). Importantly, sex mediated these effects (p < 0.05), with (supra) normalisation of FMD in medicated men, but not in women (except for blood pressure). Conclusion: Sex alters the age-related decline in FMD, which is partly explained through differences in artery diameter. Sex also altered the effect of some CVD risk factors and medication on FMD. This work improves interpretation and future use of the FMD technique when strictly adhering to FMD protocol guidelines.

Non-alcoholic fatty liver disease is the most common liver disorder worldwide, and its progressive form non-alcoholic steatohepatitis (NASH) is a growing cause of liver cirrhosis and hepatocellular carcinoma (HCC). Lifestyle changes, which are capable of improving the prognosis, are hard to achieve, whereas a pharmacologic therapy able to combine efficacy and safety is still lacking. Looking at the pathophysiology of various liver diseases, such as NASH, fibrosis, cirrhosis, and HCC, the process of angiogenesis is a key mechanism influencing the disease progression. The relationship between the worsening of chronic liver disease and angiogenesis may suggest a possible use of drugs with antiangiogenic activity as a tool to stop or slow the progression of the disorder. In this review, we highlight the available preclinical data supporting a role of known antiangiogenic drugs (e.g., sorafenib), or phytotherapeutic compounds with multiple mechanism of actions, including also antiangiogenic activities (e.g., berberine), in the treatment of NASH.

Abstract Background Sodium-glucose cotransporter-2 inhibitors reduce blood pressure (BP) and renal and cardiovascular events in patients with type 2 diabetes through not fully elucidated mechanisms. Aim of this study was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms. Methods Neuro-hormonal and vascular variables, together with 24 h diuresis, urinary sodium, glucose, isoprostanes and free-water clearance were assessed before and after a 2-day treatment with dapagliflozin 10 mg QD in sixteen type 2 diabetic patients; data were compared with those obtained in ten patients treated with hydrochlorothiazide 12.5 mg QD. Brachial artery endothelium-dependent and independent vasodilation (by flow-mediated dilation) and pulse wave velocity were assessed. Renal resistive index was obtained at rest and after glyceryl trinitrate administration. Differences were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor; Bonferroni post hoc comparison test was also used. Results Dapagliflozin decreased systolic BP and induced an increase in 24 h diuresis to a similar extent of hydrochlorothiazide; 24 h urinary glucose and serum magnesium were also increased. 24 h urinary sodium and fasting blood glucose were unchanged. Oxidative stress was reduced, as by a decline in urinary isoprostanes. Flow-mediated dilation was significantly increased (2.8 ± 2.2 to 4.0 ± 2.1%, p

Introduction: This study aims to investigate how image settings affect carotid Intima-Media-Thickness (IMT) and diameter estimation performed with Carotid Studio (Quipu-Srl). Methods: Fourteen healthy volunteers (24.4 ± 4.4 years; eight men) were recruited. Longitudinal scans 3-cm-deep of common-carotid-arteries with the same region-of-interest were obtained by expert operator, starting from a “default-setup” (central Time Gain Compensation-TGC; gain: 50 dB; no persistence filter) and adjusting one parameter at a time (oblique TGC; gain: 10 dB increments from 30 to 70 dB; persistence filter). The acquisition was performed twice, and repeatability was expressed for each setup as Coefficient of Variation (CV). Significant changes (p ≤ 0.05) compared with the “default-setup” were analysed by Wilcoxon signed-rank-test. Results: Sixty and 70 dB gain resulted in overestimating IMT (from 0.460 ± 0.001 to 0.506 ± 0.030 mm and 0.538 ± 0.011 mm, p = 0.002 and 0.023 respectively vs. default-50 dB), underestimating the mean diameter (from 6.044 ± 0.040 mm to 5.763 ± 0.004 mm, p = 0.008 and to 5.698 ± 0.225 mm, p = 0.002), and for 70 dB, increasing IMT CV from 2.14 ± 1.92% to 6.85 ± 5.23% (p = 0.01) and diameter CV from 1.79 ± 1.22% to 4.77 ± 4.71% (p = 0.05). Distension CV increased from 5.71 ± 4.31% to 10.84 ± 5.91% (p = 0.041) and to 12.59 ± 7.97% (p = 0.021) for 60 and 70 dB respectively. Persistence and TGC did not affect repeatability, whereas diameter (5.955 ± 0.033 mm, p = 0.005) and distension (from 0.816 ± 0.019 mm to 0.655 ± 0.018 mm, p = 0.002) values were underestimated when persistence filter was active. Discussion: Precision and reproducibility of carotid parameters, automatically assessed by Carotid Studio, are affected by high gain levels, due to image grey-level saturation. Persistence filter activation leads to underestimate diameter and distension, possibly due to mathematical operator behaviour and image temporal filtering. Since ultrasound setup significantly affects carotid parameter assessment, it should be reported and replicated in follow-up scans. HIGHLIGHTS •We investigated how ultrasound imaging setup may affect carotid parameters. •Carotid parameters’ reproducibility was lower with high-gain values. •Persistence filter leads to underestimation of diameter and distension. •The scan projection seems to influence carotid parameter estimation. •Image depth should be kept at the lowest attainable value for best repeatability.

Background and Objectives: Chances of surviving sepsis increase markedly upon prompt diagnosis and treatment. As most sepsis cases initially show-up in the Emergency Department (ED), early recognition of a septic patient has a pivotal role in sepsis management, despite the lack of precise guidelines. The aim of this study was to identify the most accurate predictors of in-hospital mortality outcome in septic patients admitted to the ED. Materials and Methods: We compared 651 patients admitted to ED for sepsis (cases) with 363 controls (non-septic patients). A Bayesian mean multivariate logistic regression model was performed in order to identify the most accurate predictors of in-hospital mortality outcomes in septic patients. Results: Septic shock and positive qSOFA were identified as risk factors for in-hospital mortality among septic patients admitted to the ED. Hyperthermia was a protective factor for in-hospital mortality. Conclusions: Physicians should bear in mind that fever is not a criterium for defining sepsis; according to our results, absence of fever upon presentation might be indicative of greater severity and diagnosis of sepsis should not be delayed.

In a randomized double-blind crossover trial, the effect of 8 week supplementation with grape and wine polyphenols on functional and structural vascular parameters and autonomic activity was evaluated in 40 essential hypertensive patients treated with diuretic monotherapy. Ambulatory blood pressure, brachial artery flow mediated dilation (FMD) and pulse-wave velocity (PWV) were measured at baseline and after each 8-week intervention. Forearm resistance artery endothelial function and muscle sympathetic nerve activity (MSNA) response to mental stress and cold-pressor test were measured in two separate sub-groups. No statistically significant differences were found across time or between groups in either blood pressure, FMD, PWV, or resistance artery endothelial function. The MSNA response to the two stressors was non-significantly attenuated after grape-wine polyphenol supplementation. These results do not support the hypothesis that daily consumption of a high dose of grape and wine polyphenols lowers blood pressure or affects vascular function in patients already on antihypertensive medication.

Brachial artery Flow Mediated Dilation (FMD) is widely used as a non-invasive measure of endothelial function. Adherence to expert consensus guidelines on FMD measurement has been found to be of vital importance to obtain reproducible data. This article lists the literature data which was considered in the development of a tool to aid in the objective judgement of the extent to which published studies adhered to expert guidelines for FMD measurement. Application of this tool in a systematic review of FMD studies (http://dx.doi.org/10.1016/j.atherosclerosis.2016.03.011) (Greyling et al., 2016 [1]) indicated that adherence to expert consensus guidelines is strongly correlated to the reproducibility of FMD data. Keywords: Cardiovascular disease, Atherosclerosis, Endothelial function, Reproducibility, Methodology

Rationale and Aim: Essential hypertension is characterized by extensive alterations of arterial geometry and mechanical properties: increased stiffness, dilation and wall of large arteries, increased thickness in muscular arteries, small artery remodeling. This study is aimed at exploring function and structure of the digital arteries of the hand, muscular arteries with an internal diameter of 500-1000 mm, easily accessible by ultrahigh frequency ultrasound. Methods: 24 hypertensive women (HT) and 37 healthy controls (C) were recruited. 5’-videoclips of left palmar digital arteries were obtained by VevoMD (FUJIFILM, VisualSonics, Toronto, Canada), by means of a 70 MHz probe (axial-lateral resolution 30-65 μm). An automatic system (Cvsuite, Quipu srl; Pisa, Italy) was used to measure intima-media thickness (IMT) and diameter. Distensibility and stiffness were then calculated using left brachial pulse pressure (PP - oscillometric) Results: HT and C had similar age (57 ± 11 vs 53 ± 11 years, p = 0.22), BMI (24.9 ± 4.6 vs 24.5 ± 4.2 vs kg/m2, p = 0.80) and mean blood pressure (BP, 95 ± 12 vs 91 ± 12 mmHg, p = 0.24); HT showed slighlty higher PP (54 ± 14 vs 47 ± 10, p = 0.07). Palmar digital lumen tended to be higher in HT (804 ± 201 vs 696 ± 191 μm, p = 0.10), while IMT was similar (120 ± 23 vs 125 ± 36 μm, p = 0.81). Distensibility was reduced (21.4 ± 18.2 vs 29.0 ± 18.8 kPa −1, p < 0.05), while stiffness was increased (7.95 ± 2.22 vs 6.72 ± 2.11 m/s, p < 0.005). Conclusions: This is the first report of the presence of altered mechanical properties (i.e. increased stiffness) in muscular arteries with lumen

Aim: Mechanisms through which SGLT-2 inhibitors achieve cardiovascular and renal protection are still unknown. We investigated whether dapagliflozin modulates Na and water balance and systemic and renal vascular parameters like endothelial function, arterial stiffness and renal vasodilating capacity. Methods: 40 type2-diabetic hypertensive patients were studied at baseline (V0) and after four weeks (V1) of dapagliflozin 10 mg (Dapa, N = 20) or hydroclorothiazide 12,5 mg (HCT,N = 20), collecting blood and urinary samples for routine analyses, plasma renin activity, aldosterone, cathecolamines and 24 hour-urinary electrolytes. Flow-mediated dilation of the brachial artery (FMD), baseline (RI) and dynamic renal resistive index (DRIN), carotid-femoral pulse-wave velocity (PWV) and Augmentation Index (AIx) were also measured. Results: Both Dapa and HCT marginally lowered systolic and diastolic BP values and did not change blood fasting glucose. Serum magnesium concentration significantly rose in Dapa group (from 1.88 ± 0.27 to 2.01 ± 0.22 mg/dl, p = 0.02 for time*treatment interaction), while magnesiuria was unchanged. 24h diuresis and glycosuria and osmolar clearance increased in Dapa (p < 0.001), with no changes in sodiuria and creatinine clearance. Dapa induced also a rise in aldosterone (p = 0.02). Nor DAPA neither HCT modified FMD, AIx and PWV. Interestingly, in Dapa group DRIN remained unmodified, while tended to increase in HCT group (p = 0.05). Conclusions: 4-week Dapa treatment did not significantly influence BP, glucose and systemic indices of vascular function. However, in comparison to HCT, renal vasodilating capacity was preserved after Dapa, indicating a selective effect on renal vascular function, which may act asnephroprotective mechanism. Furthermore, the increase in serum magnesium might contribute to cardiovascular protection.

Purpose/Background/Objectives: This study aims to investigate how image settings affect carotid Intima-Media-Thickness (IMT) and diameter estimation performed with CarotidStudio (Quipu Srl). Methods: 14 healthy volunteers (24.4 ± 4.4 years; 8 men) were recruited. Longitudinal scans 3cm deep of common-carotid-arteries with the same region-of-interest were obtained by expert operator, starting from a “default” setup (central Time Gain Compensation-TGC; gain:50 dB; no persistence filter) and adjusting one parameter at a time (oblique TGC; gain:10 dB increments from 30 to 70 dB; persistence filter). The acquisition was performed twice and repeatability was expressed for each setup as coefficient of variation (CV). Significant changes (p < 0.05) with respect to the “default” setup were analysed by paired Student-t-test. Results: A 70 dB gain results in overestimating IMT (from 0.46 mm ± 0.01 mm to 0.54 mm ± 0.01 mm), underestimating diameter (from 6.04 mm ± 0.04 mm to 5.70 mm ± 0.23 mm), increasing their CVs (from 2.14% ± 1.92% to 6.85% ± 5.23% for IMT, from 1.79% ± 1.22% to 4.77% ± 4.71% for diameter) and in 4/14 cases the estimation wasn’t possible. Distension CV increases also with 60 dB (from 5.71% ± 4.31% to 10.84% ± 5.91% and to 12.59% ± 7.97%). Persistence and TGC do not affect repeatability, whereas diameter (5.96 mm ± 0.03 mm) and distension (from 0.82 mm ± 0.02 mm to 0.66 mm ± 0.02 mm) values are influenced by persistence. Conclusions: CarotidStudio precision does not show significant alterations except from 70 dB gain, which, due to the image grey-level saturation, results in poor image quality and modified values. Persistence does not affect precision but leads to reduced diameter and distension, possibly for the intrinsic behaviour of mathematical operator and image temporal filtering. Gain and persistence influence ultrasound biomarker estimation; the chosen setup should be documented and replicated in follow-up scans.

Purpose/Background/Objectives: Recently great attention has been placed on innovative cardiovascular biomarkers obtained from wave separation (WS), wave intensity analysis (WIA) and the reservoir-wave (RW) concept. Pressure waveforms needed to implement these techniques can be obtained in different ways. Aim of this study was to evaluate differences in WS, WIA and RW parameters obtained deriving pressure curves in different ways. Methods: Twenty-two individuals (49 ± 17 years, 59% males) were examined. Common carotid blood flow waveforms were obtained from Pulsed-Wave Doppler images. Carotid pressure waveforms were obtained in four different ways: 1) standard method, i.e., with applanation tonometry; 2) linear scaling from ultrasound (US)-derived diameter curve; 3) exponential scaling from US-derived diameter curve; 4) linear scaling from an accelerometric-derived diameter signal. In each case, reflection magnitude (RM) and reflection index (RI) were obtained from WS. The amplitude of the first positive peak (W1), of the second positive peak (W2) and of the negative one (Wb) were calculated from WIA; the maximum of the reservoir (maxPr) and the excess (maxPex) pressure were achieved from RW. Results: According to the intra-class coefficient values, the agreement between the standard method and all the others was excellent in case of RM, RI, maxPrand maxPex(0.82–0.97), while reached only a fair/good level in case of W1, W2and Wb(0.44–0.82). Conclusions: The use of alternative carotid pressure waveforms does not influence the cardiovascular parameters obtained by WS and RW, while those derived by WIA are affected by the carotid pressure curve employed.

Background/Aim: Smooth muscle function is explored by sublingual glyceryl trinitrate (GTN) administration in vascular function protocols, in order to compare with endothelium- dependent vasodilation of the brachial artery by flow-mediated dilation (FMD). The aim of this study is to evaluate the hemodynamic and autonomic effects of the two most often used GTN dosages. Methods: In 80 essential hypertensive patients (HT) and 60 normotensive subjects (NT), we evaluated FMD of the brachial artery and endothelium-independent response to 25 and 400 mg of sublingual GTN by high-resolution ultrasound and automated image analysis. In a subgroup of 10 HT, muscle sympathetic nerve activity (MSNA) was also assessed by microneurography. Results: NT showed significantly (p < 0.01) lower FMD (5.5±3.3%) as compared to healthy controls (6.9±2.2%). The response to GTN 25μg also tended to be lower (HT 7.2±3.3%; NT 7.9±2.9%; p = 0.06), whereas response to GTN 400μg was similar (HT 14.3±4.8%, NT 14.5±54.7%, p = ns). In the whole population, changes in blood pressure (BP) induced by GTN 400μg (systolic BP −3.2±7.7, diastolic BP −4.7±5.0 mmHg) were significantly higher (

Background: We anticipate that in vascular outpatients followed over time, measured changes in arterial stiffness will be the multifactorial result of pressure-dependence, ageing- related degeneration, wall stress homeostasis, and medical treatment. Carotid ultrasound enables assessment of carotid pulse wave velocity (cPWV, via Bramwell- Hill), geometry (relative wall thickness, RWT = 2*IMT/diameter), and intrinsic material stiffness (Young’s-modulus, via Moens-Korteweg). We investigated changes in these carotid properties over time, and their interrelationship. To check whether the change in measured cPWV could be merely due to pressure-dependence, we calculated based on the stiffness index β0 [2] the theoretical pressure-dependent change in cPWV [3]. Methods: Hypertensive outpatients (n = 147) were assessed at baseline and 3.5±1.1 year follow- up, and were stratified according to baseline-to-follow-up change in diastolic blood pressure (ΔDBP) into three groups: decreasedDBP (ΔDBP < −7 mmHg), constantDBP (−7 mmHg ≤ ΔDBP≤7 mmHg) and increasedDBP (ΔDBP > 7 mmHg), with the cut-off being twice the typical DBP measurement error [1]. Results: The theoretical pressure-dependent change in cPWV was 0.4±1.3 m/s lower (p < 0.001, n = 147), corroborating the anticipated multifactorial conditions. Table 1 shows no changes in cPWV, RWT and Young’s-modulus for decreasedDBP. For constantDBP, both cPWV and Young’s-modulus were increased at follow-up. IncreasedDBP showed increases in cPWV and Young’s-modulus and a decreased RWT. The latter implies a 9.2±10.7 kPa increase in circumferential wall stress (p < 0.001), in contrast to a 5.3±6.9 kPa decrease (p < 0.001) in decreasedDBP (p < 0.05 for between groups). n = 147 ΔcPWV [m/s] ΔRWT [−] ΔYoung’s-modulus [MPa] Mean±sd p Mean±sd p Mean±sd p DecreasedDBP (n = 53) −0.1±1.4 0.72 0.00±0.04 0.38 −0.01±0.32 0.87 ConstantDBP (n = 67) +0.6*±1.4

Aim: This case-control study is aimed at identifying radial vascular wall abnormalities in patients with fibromuscular dysplasia (FMD). Methods: High-frequency ultrasound scans of radial arteries were obtained by VevoMD (70 MHz probe, FUJIFILM, VisualSonics). Radial wall showed two echogenic interfaces: the 1st (lumen-media) and the 2nd (media-adventitia). Intima-media (IMT), adventitia (AT), and global thickness (IMAT) and wall cross-sectional area (WCSA) Measured. Vascular wall disarray was assessed calculating the root mean square error (RMSE) between 20 gray-level profiles crossing the two interfaces and the profile obtained averaging them, normalized for the maximum value of the corresponding mean profile (RMSE/mean). Results: 11 treated hypertensive female FMD patients and 8 healthy controls (C) were enrolled (age 52±5 vs 45±13years, p = 0.51; BMI 26±3 vs 23±3kg/mg, p = 0.12; mean BP 97±7 vs 85±10 mmHg, p = 0.01). Radial lumen was similar; IMT (0.166±0.037 vs 0.128±0.022mm, p = 0.03), AT (0.114±0.029 vs 0.083±0.019mm, p = 0.008) and IMAT (0.281±0.042 vs 0.211±0.027mm, p = 0.003) were higher in FMD. Wall/lumen ratio was similar and WCSA increased in FMD. The maximum values of 1st (121±43 vs 157±22, p = 0.09) and 2nd interface 109±44 vs133±18, p = 0.09) tended to be lower, whereas RMSE/mean was higher in FMD (1st 1.31±0.24 vs 0.83±0.32, p = 0.006; 2nd 1.37±0.38 vs 0.94±0.32, p = 0.03). The difference was attenuated for the 1st but not for the 2nd interface when considering age and mean BP as covariates (p = 0.054 and p = 0.016 respectively). Conclusions: The radial artery wall of hypertensive FMD patients shows increased thickness and its ultrastructure is characterized of loss of echogenicity and inhomogeneity of the two echogenic layers.

Background: Dementia has been recently viewed as a predominantly vascular disorder. Indeed, reduced brain NO availability causes increased ß-amyloid deposition by several mechanisms, including hypoperfusion. Purpose: To investigate the relationship between cerebral blood flow in the hippocampal and parahippocampal regions (CBF-hipp and CBF-parahipp), crucial areas for memory and processing of non-verbal/spatial information, and systemic endothelial function in individuals with mild cognitive impairment (MCI), a subclinical condition predisposing to dementia. Methods: CBF-hipp and CBF-parahipp were evaluated by magnetic resonance imaging (arterial spin labeling, GE HDxt 1.5 T Signa Neuro-optimized System) and systemic endothelial function by flow-mediated dilation (FMD) in the brachial artery. Results: Complete data about CBF and FMD at enrollment were available for 66 individuals with MCI and 32 without (non-MCI). The two groups were matched for age (75 ± 5 vs 74 ± 5 years, p = 0.22), sex (men 45 vs 50%, p = 0.18) and mean BP (96 ± 10 vs 97 ± 9 mmHg, p = 0.41). FMD was significantly lower in MCI than in non-MCI (2.93 ± 2.18 vs 3.74 ± 2.03%, p = 0.02); CBF-hipp (64.3 ± 9.43 vs 69.5 ± 7.03 ml/100 gr/min, p = 0.002) and CBF-parahipp (66.3 ± 8.02 vs 70.0 ± 8.12 ml/100 gr/min, p = 0.002) were significantly lower in MCI as well. Among MCI, FMD was significantly correlated with CBF-parahipp (r = 0.26, p = 0.03) and CBF-hipp (r = 0.32, p = 0.009). In multiple regression models, including age, sex, mean BP, BMI, brachial artery diameter as confounders, FMD remained an independent determinant of CBF-parahipp (beta = 0.93, r2 = 0.063, p = 0.04) and CBF-hipp (beta = 1.31, r2 = 0.089, p = 0.01). Nor CBF-parahipp (r = −0.13, p = 0.48) neither CBF-hipp (r = 0.05, p = 0.80) were correlated with FMD in non-MCI group. Conclusions: An independent association between hippocampal and parahippocampal CBF and systemic endothelial function is present in individuals with MCI.

Background: Spontaneous coronary dissection (SCAD) may represent a manifestation of fibromuscular dysplasia (FMD); thus, preclinical lesions might be found in extracoronary vessels with similar size and wall ultrastructure, such as the radial artery. Methods: Two 5′-clips from the left radial artery were obtained by Vevo MD (70 MHz probe, FUJIFILM, VisualSonics). Radial wall showed two echogenic interfaces: the 1st (lumen-media) and the 2nd (media-adventitia). Intima-media (IMT), adventitia (AT), and global thickness (IMAT) and wall cross-sectional area (WCSA) Measured. Vascular wall disarray was assessed calculating the root mean square error (RMSE) between 20 gray-level profiles crossing the two interfaces and the profile obtained averaging them, normalized for the maximum value of the corresponding mean profile (RMSE/mean). Results: 5 female SCAD patients and 9 healthy controls (C) were enrolled (age 45±9 vs 45±13years, p = 0.95; BMI 21±3 vs 23±kg/mq, p = 0.22; mean BP 77±5 vs 85±10 mmHg, p = 0.053). 2nd interface peak was reduced in the SCAD group (97±29 130±19, p = 0.04), whereas RMSE/mean was increased (1.89±0.68 vs 0.97±0.30, p = 0.02). Similar values were found for the 1st interface. IMT (0.165±0.031 vs 0.125±0.022mm, p = 0.03), but not AT (0.095±0.020 vs 0.081±0.020mm, p = 0.20) and IMAT (0.260±0.049 vs 0.206±0.030mm, p = 0.053), was significantly higher in SCAD. Radial internal diameter and wall/lumen ratio were similar: conversely WCSA was increased in SCAD (1.69±0.48 vs 1.07±0.37mm2, p = 0.02). Conclusions: Radial arteries of SCAD patients were characterized by increased wall thickness. Furthermore, the 2nd echogenic layer exhibited loss of echogenicity and inhomogeneity, features similar to FMD patients.