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Italy is one of the European Countries with the highest level of antimicrobial consumption, both in the community and in hospital settings, and with the highest prevalence of antimicrobial resistant microorganisms. In 2015, the Project "Good practices for the surveillance and control of antimicrobial resistance" was funded by the Italian National Centre for Disease Prevention and Control (CCM): the aim was to promote integrated actions at national level to control antimicrobial resistance, favouring the transfer of existing good practices. The principal objectives of the project were: to describe the Italian scenario of good practices based on literature review; to improve the capacity of surveillance, through achieving consensus on a core set of indicators, including paediatrics, and through the strengthening of the national surveillance system of antimicrobial resistance coordinated by the Italian National Institute of Health; to define tools useful for priority setting; to evaluate the efficacy of intervention programme aimed at promoting the appropriate use of antibiotics among children for upper respiratory tract infections in the community; to set up training programmes on the prudent use of antibiotics in veterinary medicine. Seven regions were enrolled in the project (Emilia-Romagna with the role of programme coordinator, Campania, Calabria, Lazio, Lombardy, Piedmont, Tuscany) and the Italian National Health Institute. The project allowed to document: the scarce spread of control practices at national level (out of 277 studies reviewed, only 6.1% of the cases were targeted to evaluating the effectiveness of intervention programmes); a significant variability among regions both in relation to antimicrobial consumption and antimicrobial resistance prevalence, with a worrying spread in some regions of several antimicrobial resistant organisms responsible for "critical" infections with great potential health impact; the effectiveness of an intervention aimed at promoting appropriate use of antibiotics in frequent infections for children in the community, such as pharingotonsillitis and acute otitis media (35% reduction of antimicrobial consumption between 2010 and 2017 in Emilia-Romagna; an inversion of the ratio amoxicillin/amoxicillin-clavulanate); the need for new indicators to monitor antimicrobial consumption in hospital paediatric wards and of a new national system for timely identification of new antimicrobial resistance profiles; a positive evaluation of the training programme for veterinary physicians. In conclusion, the project has contributed to identify the most critical areas for antimicrobial resistance control and to select appropriate solutions, potentially transferable to the national level.

Background and Purpose - The best time for administering anticoagulation therapy in acute cardioembolic stroke remains unclear. This prospective cohort study of patients with acute stroke and atrial fibrillation, evaluated (1) the risk of recurrent ischemic event and severe bleeding; (2) the risk factors for recurrence and bleeding; and (3) the risks of recurrence and bleeding associated with anticoagulant therapy and its starting time after the acute stroke. Methods - The primary outcome of this multicenter study was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding within 90 days from acute stroke. Results - Of the 1029 patients enrolled, 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or transient ischemic attack or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding, and 14 (1.4%) major extracranial bleeding. At 90 days, 50% of the patients were either deceased or disabled (modified Rankin score ≥3), and 10.9% were deceased. High CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesion and type of anticoagulant were predictive factors for primary study outcome. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared with initiating treatment before 4 or after 14 days: hazard ratio 0.53 (95% confidence interval 0.30-0.93). About 7% of the patients treated with oral anticoagulants alone had an outcome event compared with 16.8% and 12.3% of the patients treated with low molecular weight heparins alone or followed by oral anticoagulants, respectively (P=0.003). Conclusions - Acute stroke in atrial fibrillation patients is associated with high rates of ischemic recurrence and major bleeding at 90 days. This study has observed that high CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesions, and type of anticoagulant administered each independently led to a greater risk of recurrence and bleedings. Also, data showed that the best time for initiating anticoagulation treatment for secondary stroke prevention is 4 to 14 days from stroke onset. Moreover, patients treated with oral anticoagulants alone had better outcomes compared with patients treated with low molecular weight heparins alone or before oral anticoagulants. © 2015 American Heart Association, Inc.

Activated polymorphonuclear leukocytes (PMNs) may affect the integrity of blood vessels by endothelial cell injury. We investigated the effects of cathepsin G purified from human neutrophils on the fibrinolytic potential of cultured human umbilical vein endothelial cells (HUVECs). Cathepsin G (5 and 10 micrograms/ml) induced marked intercellular gap formation after 1 hour of treatment, whereas 1 microgram/ml did not, even after 6 hours incubation. In contrast, plasminogen activator inhibitor-1 (PAI-1) antigen levels, measured by a double antibody enzyme-linked immunosorbent assay, were significantly increased in culture media (CM) on cathepsin G (1 microgram/ml) treatment after 15 minutes (5.1 +/- 1.2 ng/ml vs 2.6 +/- 0.6 ng/ml for controls, p0.01) and 6 hours of incubation (69.6 +/- 17.5 ng/ml vs 40.0 +/- 9.0 ng/ml for controls, p0.01). Likewise, PAI activity, measured by reverse fibrin autography, increased on cell treatment with cathepsin G. Preincubation of cathepsin G with eglin C (10 micrograms/ml) almost completely abolished the increase in both PAI antigen and activity levels induced by cathepsin G. Cycloheximide, a protein synthesis inhibitor, did not block cathepsin G-induced PAI-1 release. PAI-1 mRNA levels were not affected by HUVEC treatment with cathepsin G (1 microgram/ml for 15 minutes), even after 24 hours. In the extracellular matrix (ECM) PAI-1 antigen levels decreased to 77% and 40% of controls, respectively, after 15 minutes and 6 hours of cathepsin G (1 micrograms/ml) treatment. Reverse fibrin autography also demonstrated a dose-dependent reduction of PAI activity in the ECM on 6 hours of cell treatment with 1 or 5 micrograms/ml cathepsin G. Moreover, ECM prepared from confluent HUVECs released PAI-1 in supernatants on 1 micrograms/ml cathepsin G incubation in a cell-free system. Tissue-type plasminogen activator (t-PA) activity was strongly depressed on cathepsin G treatment, both in CM from HUVECs or in a cell-free system. Finally, PAI-1 was also released from cathepsin G-stimulated platelets in a dose-dependent manner. In summary, our results support a potentially thrombogenic role of cathepsin G, which could impair the fibrinolytic potential of the endothelium. These data give a new insight into the mechanisms by which activated PMNs may promote thrombus formation. On the other hand, the decrease of PAI-1 in ECM could favor penetration and migration of inflammatory or tumor cells through the subendothelial layers.

We studied a series of hemostasis factors in a group of patients selected from a cohort of 916 patients affected by MI from the GISSI-2 study population. Following a case-control design, 73 patients with a family history of thrombosis (the presence of at least two first degree relatives affected by MI and/or stroke before 65 years) were matched with MI patients with no family history of thrombosis. Blood collection could be performed 6 +/- 1 months after the acute phase following MI in 53 pairs of such patients. The presence of mixed disulphides (MDS) was significantly higher in patients with family history than in controls; MDS were detected in 7 cases and only in 1 control. No difference was found in contrast in the distribution of fibrinogen, factor VII, factor VIII, vWF, protein C, protein S, AT III, HC II, PAI-1, lipoprotein (a). Nevertheless, independently from the family history, in the whole population of MI patients studied, 21 cases of suspected deficiency of protein C were found. Sixteen out of 53 patients with family history of MI and/or stroke had a family history of MI only. In patients with family history of MI the t-PA antigen levels were significantly lower than in the control group (7.5 +/- 4.4 vs 11.1 +/- 3.5 ng/ml, t = -2.6, p0.02). In the whole population of MI patients and in patients with a family history of thrombosis t-PA antigen was positively correlated with PAI-1 antigen and vWF. The correlation with PAI-1 was lost in patients with family history of MI.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the relationships among different polymorphisms of FVII gene in determining FVII levels, in a sample of 335 male and female Italian volunteers. The hypervariable region 4 (HVR4), the promoter decanucleotide insertion (-323 0/10 bp) and the R353Q polymorphisms of FVII gene were evaluated. The association of HVR4 or -323 0/10 bp polymorphism with plasma FVII levels differed between gender (Interaction term: p = 0.02 and p = 0.03, respectively), showing stronger effect in males than in females. In males, the R353Q and the HVR4 polymorphisms showed an incremental influence on FVII variance (F = 8.9, p0.001 and F = 4.4, p = 0.01, respectively). Moreover, the effects of Q and 10 bp alleles on the reduction of FVII activity levels were significantly potentiated by the presence of H7 allele of HVR4 (Interaction term p = 0.03 for R353Q*HVR4 and p = 0.03 for -323 0/10 bp*HVR4). In conclusion, the effect of FVII polymorphisms on FVII levels was gender dependent and derived from a complex interaction among them. The HVR4 polymorphism seems to add an independent, albeit small, contribution to the regulation of FVII plasma levels.

Background Urine flow rate (UFR)-guided and left-ventricular end-diastolic pressure (LVEDP)-guided hydration regimens have been proposed to prevent contrast-induced acute kidney injury (CIAKI). The REnal Insufficiency Following Contrast MEDIA Administration triaL III (REMEDIAL III) is a randomized, multicenter, investigator-sponsored trial aiming to compare these two hydration strategies. Methods Patients at high risk for CIAKI (that is, those with estimated glomerular filtration rate ≤ 45 mL/min/1.73 m2 and/or with Mehran's score ≥11 and/or Gurm's score >7) will be enrolled. Patients will be randomly assigned to (a) LVEDP-guided hydration with normal saline (LVEDP-guided group) and (b) UFR-guided hydration carried out by the RenalGuard system (RenalGuard group). Seven-hundred patients (350 in each arm) will be enrolled. In the LVEDP-guided group the fluid infusion rate will be adjusted according to the LVEDP as follows: 5 mL kg-1 hr-1 for LVEDP ≤12 mmHg, 3 mL kg-1 hr-1 for LVEDP 13-18 mmHg, and 1.5 mL kg-1 hr-1 for LVEDP >18 mmHg. In the RenalGuard group hydration with normal saline plus low-dose of furosemide is controlled by the RenalGuard system, in order to reach and maintain a high (>300 mL/hr) UFR. In all cases, iobitridol (a low-osmolar, nonionic contrast agent) will be administered. Results The primary endpoint is the composite of CIAKI (i.e., serum creatinine increase ≥25% and/or ≥0.5 mg/dL from the baseline to 48 hr after contrast media exposure) and/or acute pulmonary edema. Conclusion The REMEDIAL III will test the hypothesis that the UFR-guided hydration is superior to the LVEDP-guided hydration to prevent the composite of CIAKI and/or acute pulmonary edema.

Background Erythropoiesis-stimulating agents (ESAs) are biological molecules approved for the treatment of anemia associated with chronic renal failure. Biosimilars were licensed for use in Europe in 2007. Aim This study aimed to compare the safety profile of biosimilars with respect to the reference product in a nephrology setting. Methods A prospective study was conducted in four Italian regions between 1 October 2013 and 30 June 2015. The study population included patients aged ≥ 18 years undergoing hemodialysis and treated with epoetins as per the clinical practice of the participating centers. The two comparison cohorts included patients treated with either an originator or a biosimilar epoetin alfa. Each patient was followed up until occurrence of any safety outcome of interest (grouped into three major categories), switch to a different ESA product, transplant or peritoneal dialysis, death, or end of the study period, whichever came first. Results Overall, 867 subjects were included in the study (originator: N = 423; biosimilar: N = 444). Biosimilar users were older than originator users (median age of 76 vs 64 years, respectively), more frequently affected by arrhythmia (29.3 vs 22.5%), and less frequently candidates for transplantation (3.8 vs 18.2%). Cox-regression analysis showed no increase in risk of safety outcomes in biosimilar users, even after adjusting for confounding factors: 1.0 (95% confidence interval [CI] 0.7–1.3) for any outcomes; 1.1 (95% CI 0.7–1.8) for problems related to dialysis device; 0.9 (95% CI 0.6–1.5) for cardio- and cerebro-vascular conditions; 0.9 (95% CI 0.6–1.5) for infections. Conclusion This study confirms the comparable safety profiles of originator and biosimilar epoetin alfa drugs when used in patients receiving dialysis. Electronic supplementary material The online version of this article (10.1007/s40259-018-0293-2) contains supplementary material, which is available to authorized users.

We assessed the impact of type 2 diabetes, in the presence of other major cardiovascular risk factors, on coronary microvascular function and myocardial perfusion in patients without obstructive coronary artery disease (CAD).In this prospective study, 23 patients with type 2 diabetes and 26 nondiabetic patients matched for age, sex and other cardiovascular risk factors underwent a cold pressure test (CPT) and dipyridamole transthoracic echocardiography to determine their coronary flow (CF) ratio. Within 2 weeks, all diabetic patients also underwent dipyridamole-rest myocardial perfusion single-photon emission (MPS) CT. None of the patients with or without diabetes had significant CAD on invasive coronary angiography.

Hepatic transport and metabolism of glutamate and glutamine are regulated by intervention of several proteins. Glutamine is taken up by periportal hepatocytes and is the major source of ammonia for urea synthesis and glutamate for N-acetylglutamate (NAG) synthesis, which is catalyzed by the N-acetylglutamate synthase (NAGS). Glutamate is taken up by perivenous hepatocytes and is the main source for the synthesis of glutamine, catalyzed by glutamine synthase (GS). Accumulation of glutamate and ammonia is a common feature of chronic liver failure, but mechanism that leads to failure of the urea cycle in this setting is unknown. The Farnesoid X Receptor (FXR) is a bile acid sensor in hepatocytes. Here, we have investigated its role in the regulation of the metabolism of both glutamine and glutamate. In vitro studies in primary cultures of hepatocytes from wild type and FXR −/− mice and HepG2 cells, and in vivo studies, in FXR −/− mice as well as in a rodent model of hepatic liver failure induced by carbon tetrachloride (CCl 4 ), demonstrate a role for FXR in regulating this metabolism. Further on, promoter analysis studies demonstrate that both human and mouse NAGS promoters contain a putative FXRE, an ER8 sequence. EMSA, ChIP and luciferase experiments carried out to investigate the functionality of this sequence demonstrate that FXR is essential to induce the expression of NAGS. In conclusion, FXR activation regulates glutamine and glutamate metabolism and FXR ligands might have utility in the treatment of hyperammonemia states.

To asses the accuracy of stress myocardial perfusion scintigraphy (MPS) and stress echocardiography for the diagnosis of coronary artery disease (CAD) in patients with arterial hypertension. We searched for studies in which stress MPS or stress echocardiography were performed to detect CAD in hypertensive patients, with coronary angiography used as the reference test, published from January 1980 to December 2010. Studies performed in patients with known CAD, acute coronary syndrome and previous revascularization procedures were excluded. Of 1,263 studies, 13 met the inclusion criteria. Pooled summary estimates showed that stress MPS had a sensitivity of 0.90 [95% confidence interval (CI) 0.82-0.95] and a specificity of 0.63 (95% CI 0.53-0.72). For stress MPS, the area under the curve (AUC) at the summary receiver-operating characteristic (SROC) graph was 0.83 (95% CI 0.80-0.86). At meta-regression analysis, the presence of positive stress electrocardiography as inclusion criterion was the only significant effect modifier (p < 0.01). Pooled summary estimates showed that stress echocardiography had a sensitivity of 0.77 (95% CI 0.69-0.83) and a specificity of 0.89 (95% CI 0.83-0.93). For stress echocardiography, the AUC at SROC was 0.91 (95% CI 0.88-0.93). At the meta-regression analysis no significant effect modifier was detected. In conclusion, MPS has high sensitivity for detecting CAD in hypertensive patients, with specificity comparable to that reported in the general population, whereas stress echocardiography shows higher specificity but substantially reduced sensitivity compared to MPS.

Hepatitis B virus (HBV) reactivation during immunosuppression can lead to severe acute hepatitis, fulminant liver failure, and death. Here, we investigated hepatitis B surface antigen (HBsAg) genetic features underlying this phenomenon by analyzing 93 patients: 29 developing HBV reactivation and 64 consecutive patients with chronic HBV infection (as control). HBsAg genetic diversity was analyzed by population-based and ultradeep sequencing (UDS). Before HBV reactivation, 51.7% of patients were isolated hepatitis B core antibody (anti-HBc) positive, 31.0% inactive carriers, 6.9% anti-HBc/anti-HBs (hepatitis B surface antibody) positive, 6.9% isolated anti-HBs positive, and 3.4% had an overt HBV infection. Of HBV-reactivated patients, 51.7% were treated with rituximab, 34.5% with different chemotherapeutics, and 13.8% with corticosteroids only for inflammatory diseases. In total, 75.9% of HBV-reactivated patients (vs. 3.1% of control patients; P

The purpose of this study was to clarify whether changes in cardiopulmonary haemodynamics induced by pharmacological therapy correlate with exercise capacity and clinical events in patients with pulmonary arterial hypertension. 16 randomised trials including 2353 patients, followed up for 16.4±10.6 weeks, measuring cardiopulmonary haemodynamics by right heart catheterisation and reporting clinical events were included. Meta-analysis and meta-regression analysis were performed to assess the effects of treatments on clinical events and the relationship between haemodynamic changes (pulmonary artery pressure, pulmonary vascular resistance, cardiac index and right atrial pressure) and clinical events. Treatments significantly reduced all-cause death (OR 0.5, 95% CI 0.3-0.7; p

Background and Purposes: In a case-control study in patients with acute ischemic stroke and extracranial internal carotid artery (eICA) occlusion, thrombolytic treatment was associated with increased mortality. The aim of this cohort study was to assess the efficacy and safety of thrombolysis in patients with eICA occlusion compared to those without eICA occlusion. Methods: Consecutive patients treated with intravenous tissue-type plasminogen activator within 4.5 h from symptom onset included in the Safe Implementation of Thrombolysis in Stroke – International Stroke Thrombolysis Registry (SITS-ISTR) in 20 Italian centres were analyzed. Acute carotid occlusion was diagnosed using ultrasound examination, angio-CT scan or angio-MRI. Since the SITS-ISTR database did not plan to report the site of vessel occlusion, each participating center provided the code of the patient with eICA occlusion. Patients were divided into 2 groups, those with and those without eICA occlusion. Main outcome measures were: death, disability (modified Rankin Scale, mRS, 3–6) and any intracranial bleeding at 3 months. Multiple logistic regression analysis was performed to reveal predictors for main outcomes. The following variables of interest were included in the analysis: presence of eICA occlusion, age, gender, diabetes mellitus, hyperlipidemia, atrial fibrillation, congestive heart failure, previous stroke, current smoking, antiplatelet treatment at stroke onset, baseline NIHSS score, baseline blood glucose, cholesterol and blood pressure, history of hypertension and stroke onset to treatment time. Results: A total of 1,761 patients without eICA occlusion and 137 with eICA occlusion were included in the study. At 3 months, 42 patients were lost to follow-up (3 with eICA occlusion). Death occurred in 30 (22.4%) patients with eICA occlusion and in 175 (10.2%) patients without (p < 0.0001). Death or disability at 3 months occurred in 91 of 134 patients with eICA occlusion (67.9%) compared with 654 of 1,722 patients without eICA occlusion (37.9%, p < 0.0001). No or minimal disability at 3 months (mRS 0–1) was reported in 25 (18.7%) patients with eICA occlusion and in 829 (48.2%) patients without (p < 0.0001). Any intracranial bleeding detected by CT or MRI at posttreatment imaging was seen in 16 (11.7%) patients with eICA occlusion and in 314 (17.8%) of those without (p = 0.09). The proportion of symptomatic intracerebral hemorrhage was 5.8% for patients with eICA occlusion and 8.0% for patients without (p = 0.16). At logistic regression analysis, eICA occlusion was associated with mortality (odds ratio, OR 5.7; 95% confidence interval, CI 2.9–11.1) and mortality or disability (OR 5.0; 95% CI 2.9–8.7) at 90 days. Conclusions: This cohort study in patients with acute ischemic stroke treated with thrombolysis showed an association between eICA occlusion and adverse outcome.

Silica gel column chromatography, followed by HPLC purification on the apolar fraction of the methanol extract of marine sponge Theonella swinhoei, resulted in the isolation of a library of 10 polyhydroxylated steroids which we named theonellasterols B-H (1-7) and conicasterols B-D (8-10). The structures were determined on the basis of extensive spectroscopic data (MS, (1)H and (13)C NMR, COSY, HSQC, HMBC, and ROESY) analysis, and the putative binding mode to nuclear receptors (NRs) has been obtained through docking calculations. Pharmacological and structure-activity relationship analysis demonstrate that these natural polyhydroxylated steroids are potent ligands of human nuclear pregnane receptor (PXR) and modulator of farnesoid-X-receptor (FXR). In addition, the molecular characterization of theonellasterol G allowed the identification of the first FXR modulator and PXR ligand so far identified. Exposure of liver cells to this agent resulted in potent induction of PXR-regulated genes and modulation of FXR-regulated genes, highlighting its pharmacological potential in the treatment of liver disorders.

Sleep apnea, defined as a pathologic pause in breathing during sleep10 s, promotes the progression of chronic heart failure and may be a predictor of poor prognosis. It causes, in fact, several mechanical, hemodynamic, chemical and inflammatory changes that negatively compromise cardiovascular homeostasis of heart failure patients. Sleep apnea is recognized as sleep apnea syndrome when specific symptoms, such as sleepiness and headache during the daytime and snoring, are present and is diagnosed with an overnight test called polysomnography. There are two different forms of sleep apnea, central and obstructive. Breathing is interrupted by the loss of respiratory drive and the lack of respiratory effort in the central form, which affects about 40-60% of heart failure patients. In obstructive sleep apnea, breathing stops when throat muscles relax, despite respiratory effort. This form affects about 3% of the general population, while it is present in at least 30% of heart failure patients. The diagnosis of sleep disorders in heart failure becomes very important to help patients adopting lifestyle changes and starting specific therapies to improve quality of life and retard the progression of chronic heart failure.

The increase in average life expectancy will move the burden of coronary artery disease (CAD) to older patients. Myocardial perfusion imaging by single photon emission computed tomography (SPECT) has been extensively validated for diagnosis and prognostic evaluation in large population series. Yet, its use is usually limited in elderly patients in whom, despite increased absolute cardiovascular risk, diagnostic and therapeutic work-up is often underperformed. American College of Cardiology/American Heart Association guidelines recommend exercise ECG testing as the initial noninvasive method for assessment of CAD in patients with a normal or near-normal resting ECG, regardless of age. However, a considerable proportion of elderly patients is unable to reach an adequate workload during the exercise test and the majority of those undergoing for standard exercise treadmill score are classified as intermediate risk. In elderly patients, SPECT imaging may provide valuable diagnostic and prognostic information for clinical management. In particular, normal or near normal SPECT identifies elderly patients at low risk of major adverse cardiac events at the short-term follow-up.

Purpose: Endothelial dysfunction (ED) is a common feature of Chronic Kidney Disease (CKD) and Diabetes Mellitus (DM), and is thought to underlie the increased cardiovascular risk of both conditions. However, while the association between coronary artery ED and DM has been evidenced in previous studies, no data are available about the relationship between CKD and coronary ED. Methods: 63 consecutive patients (mean age 60±10; 40 males), 25 of whom affected by Type II DM (mean age 62±10; 13 males) and 38 non diabetic subjects (mean age 59±11; 27 males), underwent, on the same day, transthoracic echocardiographic coronary flow reserve (CFR) evaluation during cold pressure test (CPT), to assess endothelium dependent vasodilation, and dipyridamole (Dip) infusion (0.84 mg/kg i.v. in 6 min), to evaluate endothelium independent vasodilation. Glomerular Filtration Rate (GFR), as an index of renal function, was estimated by serum creatinine values using Cockroft-Gault formula. All patients had no significant stenosis at coronary angiography performed within one month from enrolment. Results: Mean GFR was 90.27±26.98 ml/min in the whole population, 86.2±27.9 ml/min in DM patients and 92.94±26.39 ml/min in non DM patients (p=ns). Mean Dip-CFR (2.42±0.72 vs 2.84±0.73; p=0.028), as well as CPT-CFR (1.47±0.28 vs 1.65±0.29; p=0.02) were significantly lower in DM compared to non DM patients. In diabetic group, GFR correlated with both Dip-CFR (r=0.41; p=0.042) and CPT-CFR (r=0.579; p=0.002); moreover, DM patients in stage II/III of CKD (GFR