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The Municipality of Venice, through Insula srl (Insula, 2024), started the RAMSES (Rilievo Altimetrico, Modellazione Spaziale E Scansione 3D) project in 2005 with the unprecedented intention of conducting a static laser scanner survey of an entire city. The authors of this paper, who have been involved in the project on behalf of the client, including drafting general contract technical specifications, wished to revisit the survey’s findings nearly two decades later. This contribution illustrates the procedures implemented to guarantee the future accessibility of the surveyed data. It is interesting to highlight how the detailed technical specifications outlined in the general technical contract section have facilitated the retrieval of the historical three-dimensional laser scanner measurements archive. Tests have been conducted to determine how the existing mobile mapping technologies may be utilised to update the three-dimensional historical data obtained in the Ramses project efficiently. Furthermore, the paper describes the surveying approach that has never been adequately described in the literature. The surveying and geo-referencing methodologies continue to have several interesting and relevant aspects, especially regarding how the topographic network has been implemented. The Ramses three-dimensional model represents an extraordinary, valuable digital archive containing portraits of the city’s conditions at the time of the mapping. Ramses 3D model, when enriched with field activities conducted using more updated technologies, can provide interesting and unique evaluations of the evolution of Venice’s landscape.

The increase in the number of patients with CKD starting dialysis treatment has become a major health problem in recent years. Osteoporosis is a typical feature of advanced age, which, in the dialysis population, is almost always accompanied by uremic osteodystrophy (CKD-MBD). These two factors are involved in the pathogenesis of fractures, which represent an important risk factor for the outcome of patients. The real consistency of fractures in CKD patients on kidney replacement therapy (KRT) requiring hospitalization in the Lombardy region (over 9,000,000 inhabitants) was analyzed using data from the regional administrative databases in the years 2011–2012. Among 8109 prevalent patients, 251 (45.8% women), with fractures after 1 January 2011, entered the analysis. A follow-up of two years (2011–2012) was considered to evaluate the incidence of more frequent fractures (femur, pelvis, hip, and spine) using ICD-9-CM codes. The most frequent sites of fractures were the femur (68.5%), hip and pelvis (47.4%), and vertebrae (12%). The patients on hemodialysis (HD) had more events than PD (3.3% vs. 1.4%; p = 0.03), while patients undergoing kidney transplantation (KTx) had a significantly lower percentage of fractures (0.6% vs. 3.3%; p < 0.001). Observed mortality was very high: the estimated gross mortality rate for any cause was 25.9% at 90 days and 34.7% at 180 days. Diabetes, peripheral vasculopathy, and heart failure were associated with a numerical increase in fractures, although this was not significant. Proton pump inhibitor drugs (PPI), vitamin K antagonists, and diphosphonates were more frequently associated with fracture occurrence. The average total cost of fractured patients was 11.4% higher than that of non-fractured patients. On multivariate analysis, age >65 years, female gender, PPI therapy, and cerebrovascular disease were found to be strongly associated with fractures in dialysis patients, whereas undergoing renal transplantation presented a reduced risk.

Silvia Tognella,1 Claudio Micheletto,2 Alessandro Roggeri,3 Guido Polese,4 Denise Artioli,1 Gianenrico Senna,5 Marco Caminati,5,6 Daniela Paola Roggeri3 1Pulmonology Unit, Mater Salutis Hospital, Legnago (Verona), Italy; 2Pulmonology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; 3ProCure Solutions, Nembro, Bergamo, Italy; 4Pulmonology Unit, Magalini Hospital, Villafranca (Verona), Italy; 5Asthma Center and Allergy Unit, Verona University Hospital, Verona, Italy; 6Department of Medicine, Allergy and Clinical Immunology Section, University of Verona and Verona University Hospital, Verona, 37134, ItalyCorrespondence: Alessandro RoggeriProCure Solutions, Via Camozzi 1/C, Nembro, 24027, BG, ItalyTel +39 035 521121Email alessandro.roggeri@procuresolutions.itPurpose: A Regional Technical Commission was set in 2017 by Veneto region (Italy) to provide opinions and recommendations on drug prescriptions and to implement treatment-pathway guidelines for severe asthma. In this observational study, we describe the first structured, integrated, multidisciplinary, patient-centered outpatient clinic for the care of severe-asthma patients in Italy, and characterize patients referring to the center for specialist visits.Patients and Methods: To characterize patients that accessed the outpatient clinic in 2018, data on demographic characteristics, treatments, severity of asthma, phenotypes, and relevant comorbidities by phenotype were collected. Use of biologic agents and indicators of the performance of the outpatient clinic were described.Results: A structured multidisciplinary outpatient pathway for taking charge of patients and for administration and monitoring of biological agents was developed. A total of 146 patients accessed the outpatient clinic in 2018: 62.3% had uncontrolled asthma upon admission and 27.4% were already being treated with biologic agents. Among patients with uncontrolled asthma, 66% had severe uncontrolled asthma, 22% had moderate–severe uncontrolled asthma, and 12% had mild–moderate uncontrolled asthma. Main asthma phenotypes in uncontrolled-asthma patients were allergic (58% of patients), eosinophilic (22%), allergic plus eosinophilic (10%) and non-atopic asthma (10%). Among patients affected by severe asthma, 47% had allergic asthma, 28% had eosinophilic asthma, 13% had allergic plus eosinophilic asthma, and 12% had non-atopic asthma. Nasal polyps were more frequent in eosinophilic and allergic plus eosinophilic asthma, while gastro-esophageal reflux disease was more frequent in non-atopic asthma.Conclusion: This structure of an outpatient clinic for the treatment of severe asthma, with its dedicated pathway and multidisciplinary approach, may allow a stricter control of asthma and optimization of therapies, as well as minimization of drug misuse.Keywords: asthma, severe, multidisciplinary, outpatient

Autoantibodies against NMDA and AMPA receptors have been identified in the central nervous system of patients suffering from brain disorders characterized by neurological and psychiatric symptoms. It has been demonstrated that these autoantibodies can affect the functions and/or the expression of the targeted receptors, altering synaptic communication. The importance to clarify, in preclinical models, the molecular mechanisms involved in the autoantibody-mediated effects has emerged in order to understand their pathogenic role in central disorders, but also to propose new therapeutic approaches for preventing the deleterious central consequences. In this review, we describe some of the available preclinical literature concerning the impact of antibodies recognizing NMDA and AMPA receptors in neurons. This review discusses the cellular events that would support the detrimental roles of the autoantibodies, also illustrating some contrasting findings that in our opinion deserve attention and further investigations before translating the preclinical observations to clinic.

This study provides evidence of the existence of presynaptic inhibitory sphingosine-1-phosphate receptor 1 (S1P1R) and facilitatory S1P3R in cortical nerve endings (synaptosomes) of healthy mice. The conclusion relies on the findings that (i) the S1P1R agonist CS-2100 (0.1–30 nM) inhibits the 12 mM KCl-evoked glutamate exocytosis (quantified as the release of [3H]D-aspartate) while the S1P3R allosteric agonist CYM-5541 potentiates it and (ii) these effects are inhibited by the S1P1R antagonist Ex 26 (30–300 nM) and the S1P3R antagonist TY-52156 (100–1000 nM), respectively. Confocal microscopy and western blot analysis confirmed the presence of S1P1R and S1P3R proteins in cortical glutamatergic synaptosomes, which were scarcely accessible to biotin in a biotinylation study. Then, we demonstrated that S1P1R and S1P3R densities and their release activity are amplified in cortical synaptosomes of mice suffering from experimental autoimmune encephalomyelitis (EAE), despite receptors maintain their preferential internal distribution. Receptor changes recover following chronic oral therapeutic FTY720 (0.03 mg/Kg/day). These results improve our knowledge of the role of presynaptic release-regulating S1P1Rs and S1P3Rs controlling glutamate transmission in the CNS also unravelling functional adaptations during EAE that recover following chronic FTY720. In a whole, these findings provide new information on the central neuroprotectant activities of FTY720.

Background: Patients on dialysis often have secondary hyperparathyroidism (SHPT), a disorder associated with renal osteodystrophy, progressive vascular calcification, cardiovascular disease, and death. The objective of this retrospective observational study was to evaluate, in dialysis patients with SHPT, the impact of different levels of adherence to cinacalcet therapy on hospitalisations and direct healthcare costs charged to the Lombardy Regional Health Service (Italy). Methods: Data recorded in the administrative databases on all citizens undergoing dialysis between 1 January 2011 and 31 December 2011 were selected. For the aim of this study, patients with SHPT already on dialysis in the first 6 months of 2009 who had been treated with cinacalcet for at least 365 days were selected and retrospectively analysed through to end of 2012. Healthcare resource utilisation, cinacalcet adherence, and costs for medication, hospitalisations, and diagnostic/therapeutic procedures were estimated. Results: A total of 994 patients were identified (mean age 63.0 years, females 43.5%). The first patient tertile had an adherence to cinacalcet of

Background and Purpose: To deepen our knowledge of the role of complement in synaptic impairment in experimental autoimmune encephalomyelitis (EAE) mice, we investigated the distribution of C1q and C3 proteins and the role of complement as a promoter of glutamate release in purified nerve endings (synaptosomes) and astrocytic processes (gliosomes) isolated from the cortex of EAE mice at the acute stage of the disease (21 ± 1 day post‐immunization). Experimental Approach: EAE cortical synaptosomes and gliosomes were analysed for glutamate release efficiency (measured as release of preloaded [3H]D‐aspartate ([3H]D‐ASP)), C1q and C3 protein density, and for viability and ongoing apoptosis. Key Results: In healthy mice, complement releases [3H]D‐ASP from gliosomes more efficiently than from synaptosomes. The releasing activity occurs in a dilution‐dependent manner and involves the reversal of the excitatory amino acid transporters (EAATs). In EAE mice, the complement‐induced releasing activity is significantly reduced in cortical synaptosomes but amplified in cortical gliosomes. These adaptations are paralleled by decreased density of the EAAT2 protein in synaptosomes and increased EAAT1 staining in gliosomes. Concomitantly, PSD95, GFAP, and CD11b, but not SNAP25, proteins are overexpressed in the cortex of the EAE mice. Similarly, C1q and C3 protein immunostaining is increased in EAE cortical synaptosomes and gliosomes, although signs of ongoing apoptosis or altered viability are not detectable. Conclusion and Implications: Our results unveil a new noncanonical role of complement in the CNS of EAE mice relevant to disease progression and central synaptopathy that suggests new therapeutic targets for the management of MS. [ABSTRACT FROM AUTHOR]

The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT2A heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [3H]D-aspartate ([3H]D-asp) release (which mimics glutamate exocytosis). The concomitant activation of the two receptors nulls their inhibitory activities, whereas blockade of the 5-HT2A heteroreceptors with MDL11,939 (1 μM) strengthens the inhibitory effect elicited by the mGlu2/3 receptor agonist LY329268 (1 μM). 5-HT2A receptor antagonists (MDL11,939; ketanserin; trazodone) amplify the impact of low (3 nM) LY379268. Clozapine (0.1–10 μM) mimics the 5-HT2A agonist (±) DOI and inhibits the KCl-evoked [3H]D-asp overflow in a MDL11,939-dependent fashion, but does not modify the (±) DOI-induced effect. mGlu2 and 5-HT2A proteins do not co-immunoprecipitate from synaptosomal lysates, nor does the incubation of PFc synaptosomes with MDL11,939 (1 μM) or clozapine (10 µM) modify the insertion of mGlu2 subunits in synaptosomal plasma membranes. In conclusion, 5-HT2A and mGlu2/3 receptors colocalize, but do not physically associate, in PFc glutamatergic terminals, where they functionally interact in an antagonist-like fashion to control glutamate exocytosis. The mGlu2/3-5-HT2A metamodulation could be relevant to therapy for central neuropsychiatric disorders, including schizophrenia, but also unveil cellular events accounting for their development, which also influence the responsiveness to drugs regimens.

Prophylaxis is recognized as the most effective treatment regimen for patients with severe hemophilia A. Prophylaxis with standard half-life (SHL) FVIII products requires frequent intravenous administrations, at least two-three times per week. Frequency of injections is reported as one of the major obstacles to adherence to treatment and caused impairment in quality of life (QoL) and possible clinical implications. The extended half-life (EHL) rFVIII products recently reimbursed by Italian National Health Service (NHS), give the possibility of prophylactic dosage regimens characterized by reduced administration frequency with the potential to increase adherence to therapy and to improve QoL and clinical outcomes. Based on the approved dosing regimens the minimum and maximum number of administrations per year and the annual consumption for the marketed EHL rFVIII products were estimated. Compared to Adynovi® and Elocta®, Jivi® is the drug associated with the lowest number of administrations per year while versus Esperoct® is associated to a slightly higher maximum number of administrations per year. Furthermore, Jivi® has an annual mean consumption per kg lower than Adynovi®, Elocta® and Esperoct® (-24%, -27% and -22%, respectively). The contemporary reduction of number of injections per year and the lower annual mean consumption (IU) represent important benefits for the patient. From the economic point of view, at the prices published in Italian Official Journal, Jivi® weighted average annual expenditure per patient is 26% lower than Adynovi® and 29% lower than Elocta® and a saving is possible even considering a 10% increase in Jivi®’s price per IU versus comparators. Among the EHL rFVIII concentrates Jivi® appears to be more suitable to cover patients’ needs due to the possibility to adopt different dosage regimens (up to every 7 days) and is associated with the lowest average annual consumption per patient allowing a more predictable budget forecast and overall reducing the NHS expenditure.

Daniela Paola Roggeri, Alessandro Roggeri ProCure Solutions, Nembro, Bergamo, Italy Purpose: Hepatic encephalopathy (HE) is associated with a reduced survival, an increased risk of hospitalization for recurrences, and a reduced health-related quality of life. The purpose of the present economic analysis was to evaluate the impact on the Italian National Health Service (INHS) expenditure of the treatment with rifaximin 550 mg twice daily (Tixteller®/Tixtar®) for the reduction of the recurrences of overt HE, with respect to the current treatment approach. Patients and methods: Costs associated with patients treated with rifaximin 550 mg twice daily were estimated considering the reduction in hospitalizations for HE recurrences revealed by registrative clinical trial (−50%) applied to the hospitalization rate (42.5%) emerging from an Italian observational real-world study; costs associated with patients not treated with rifaximin were estimated based on the hospitalization rate, resulting from the same Italian observational study. Sensitivity analyses considering possible different discount levels to INHS structures for rifaximin were performed. The INHS perspective for a period of 3 years was considered. Results: The treatment with rifaximin 550 mg twice daily, although increasing drug costs, is associated with a reduction in hospitalizations for HE recurrences that leads to an overall reduction of total costs charged to INHS, which could be estimated, based on the forecasted uptake of the treatment, at about €130,000 in the first year, reaching ~€260,000 in the third year. Considering a possible discount for rifaximin 550 mg to INHS structure of 20%, the total saving at the third year accounts for ~€3,000,000. Moreover, a relevant reduction in the number of hospitalizations and bed days is associated with rifaximin treatment. Conclusion: The treatment with rifaximin 550 mg twice daily, even if associated with an increase in drug expenditure, results in a reduction in total health care costs charged to INHS due to a reduction in hospitalizations for HE recurrences. Keywords: overt hepatic encephalopathy recurrences, health care expenditure, costs, hospitalizations, budget impact

We investigated whether chronic sciatic ligation modifies the glutamate release in spinal cord nerve endings (synaptosomes) as well as the expression and the function of presynaptic release-regulating mGlu2/3 autoreceptors and 5-HT2A heteroreceptors in these particles. Synaptosomes were from the spinal cord of animals suffering from the sciatic ligation that developed on day 6 post-surgery a significant decrease of the force inducing paw-withdrawal in the lesioned paw. The exocytosis of glutamate (quantified as release of preloaded [3H]D-aspartate, [3H]D-Asp) elicited by a mild depolarizing stimulus (15 mM KCl) was significantly increased in synaptosomes from injured rats when compared to controls (uninjured rats). The mGlu2/3 agonist LY379268 (1000 pM) significantly inhibited the 15 mM KCl-evoked [3H]D-Asp overflow from control synaptosomes, but not in terminals isolated from injured animals. Differently, a low concentration (10 nM) of (±) DOI, unable to modify the 15 mM KCl-evoked [3H]D-Asp overflow in control spinal cord synaptosomes, significantly reduced the glutamate exocytosis in nerve endings isolated from the injured rats. Acute oral trazodone (TZD, 0.3 mg/kg on day 7 post-surgery) efficiently recovered glutamate exocytosis as well as the efficiency of LY379268 in inhibiting this event in spinal cord synaptosomes from injured animals. The sciatic ligation significantly reduced the expression of mGlu2/3, but not of 5-HT2A, receptor proteins in spinal cord synaptosomal lysates. Acute TZD recovered this parameter. Our results support the use of 5-HT2A antagonists for restoring altered spinal cord glutamate plasticity in rats suffering from sciatic ligation.

A new formulation of a pomegranate-peel extract (PEm) obtained by PUAE (Pulsed Ultrasound-Assisted Extraction) and titrated in both ellagic acid (EA) and punicalagin is proposed, characterized and then analyzed for potential health properties in mice suffering from the experimental autoimmune encephalomyelitis (EAE). PEm effects were compared to those elicited by a formulation containing EA (EAm). Control and EAE mice were chronically administered EAm and Pem dissolved in the drinking water, starting from the day 10 post-immunization (d.p.i.), with a “therapeutic” protocol to deliver daily 50 mg/kg of EA. Treated EAE mice did not limit their daily access to the beverage, nor did they show changes in body weight, but they displayed a significant amelioration of “in vivo” clinical symptoms. “Ex vivo” histochemical analysis showed that spinal-cord demyelination and inflammation in PEm and EAm-treated EAE mice at 23 ± 1 d.p.i. were comparable to those in the untreated EAE animals, while microglia activation (measured as Ionized Calcium Binding Adaptor 1, Iba1 staining) and astrocytosis (quantified as glial fibrillar acid protein, GFAP immunopositivity) significantly recovered, particularly in the gray matter. EAm and PEm displayed comparable efficiencies in controlling the spinal pathological cellular hallmarks in EAE mice, and this would support their delivery as dietary supplementation in patients suffering from multiple sclerosis (MS).

Polyphenol ellagic acid (EA) possesses antioxidant, anti-inflammatory, anti-carcinogenic, anti-diabetic and cardio protection activities, making it an interesting multi-targeting profile. EA also controls the central nervous system (CNS), since it was proven to reduce the immobility time of mice in both the forced swimming and the tail-suspension tests, with an efficiency comparable to that of classic antidepressants. Interestingly, the anti-depressant-like effect was almost nulled by the concomitant administration of selective antagonists of the noradrenergic receptors, suggesting the involvement of these cellular targets in the central effects elicited by EA and its derivatives. By in silico and in vitro studies, we discuss how EA engages with human α2A-ARs and α2C-AR catalytic pockets, comparing EA behaviour with that of known agonists and antagonists. Structurally, the hydrophobic residues surrounding the α2A-AR pocket confer specificity on the intermolecular interactions and hence lead to favourable binding of EA in the α2A-AR, with respect to α2C-AR. Moreover, EA seems to better accommodate within α2A-ARs into the TM5 area, close to S200 and S204, which play a crucial role for activation of aminergic GPCRs such as the α2-AR, highlighting its promising role as a partial agonist. Consistently, EA mimics clonidine in inhibiting noradrenaline exocytosis from hippocampal nerve endings in a yohimbine-sensitive fashion that confirms the engagement of naïve α2-ARs in the EA-mediated effect.

Daniela Paola Roggeri,1 Alessandro Roggeri,1 Elisa Rossi,2 Salvatore Cataudella,2 Nello Martini,3 1ProCure Solutions, Nembro, Bergamo, 2CINECA Interuniversity Consortium, Bologna, 3Accademia Nazionale di Medicina, Rome, Italy Purpose: Bronchiolitis is an acute inflammatory injury of the bronchioles, and is the most frequent cause of hospitalization for lower respiratory tract infections in preterm infants. This was a retrospective, observational, case-control study conducted in Italy, based on administrative database analysis. The aim of this study was to evaluate differences in health care costs of preterm infants with and without early hospitalization for bronchiolitis. Patients and methods: Preterm infants born in the period between January 1, 2009 and December 31, 2010 and hospitalized for bronchiolitis in the first year of life were selected from the ARNO Observatory database and observed for the first 4 years of life. These preterm infants were compared (paired 1–3) with preterm infants who were not hospitalized for bronchiolitis in the first year of life and with similar characteristics. Only direct health care costs reimbursed by the Italian National Health Service were considered for this study (drugs, hospitalizations, and diagnostic/therapeutic procedures). Results: Of 40,823 newborns in the accrual period, 863 were preterm with no evidence of prophylaxis, and 22 preterm infants were hospitalized for bronchiolitis (cases) and paired with 62 controls. Overall, cases had 74% higher average cost per infant in the first 4 years of life than controls (18,624€ versus 10,189€, respectively). The major cost drivers were hospitalizations, accounting for >90% in both the populations. The increase in total yearly health care cost between cases and controls remained substantial even in the fourth year of life for all cost items. A relevant increase in hospitalizations and drug consumption linked to respiratory tract diseases was noted in infants hospitalized for bronchiolitis during the entire follow-up period. Conclusion: Preterm infants hospitalized for bronchiolitis in the first year of life were associated with increased resource consumption and costs throughout the entire period of observation; even in the fourth year, the difference versus paired controls was relevant. Keywords: bronchiolitis, cost, preterm, hospitalizations

[Article in Italian]

Alessandro Roggeri,1 Claudio Micheletto,2 Daniela Paola Roggeri1 1ProCure Solutions, Nembro, Bergamo, Italy, 2Respiratory Unit, Mater Salutis Hospital, Legnago, Verona, Italy Background: Different inhalation devices are characterized by different techniques of use. The untrained switching of device in chronic obstructive pulmonary disease (COPD) and asthma patients may be associated with inadequate inhalation technique and, consequently, could lead to a reduction in adherence to treatment and limit control of the disease. The aim of this analysis was to estimate the potential economic impact related to errors in inhalation in patients switching device without adequate training. Methods: An Italian real-practice study conducted in patients affected by COPD and asthma has shown an increase in health care resource consumption associated with misuse of inhalers. Particularly, significantly higher rates of hospitalizations, emergency room visits (ER), and pharmacological treatments (steroids and antimicrobials) were observed. In this analysis, those differences in resource consumption were monetized considering the Italian National Health Service (INHS) perspective. Results: Comparing a hypothetical cohort of 100 COPD patients with at least a critical error in inhalation vs 100 COPD patients without errors in inhalation, a yearly excess of 11.5 hospitalizations, 13 ER visits, 19.5 antimicrobial courses, and 47 corticosteroid courses for the first population were revealed. In the same way, considering 100 asthma patients with at least a critical error in inhalation vs 100 asthma patients without errors in inhalation, the first population is associated with a yearly excess of 19 hospitalizations, 26.5 ER visits, 4.5 antimicrobial courses, and 21.5 corticosteroid courses. These differences in resource consumption could be associated with an increase in health care expenditure for INHS, due to inhalation errors, of €23,444/yr in COPD and €44,104/yr in asthma for the considered cohorts of 100 patients. Conclusion: This evaluation highlights that misuse of inhaler devices, due to inadequate training or nonconsented switch of inhaled medications, is associated with a decrease in disease control and an increase in health care resource consumption and costs. Keywords: inhalers, devices, switch, training, errors, costs, asthma, COPD

Daniela Paola Roggeri,1 Alessandro Roggeri,1 Elisa Rossi,2 Elisa Cinconze,2 Antonio Gasbarrini,3 PierAlessandro Monici Preti,4 Marisa De Rosa,2 1ProCure Solutions, Nembro, Bergamo, 2CINECA, Interuniversity Consortium, Bologna, 3Catholic University of Sacred Heart, Policlinic A Gemelli, Rome, 4Alfa Wassermann, Bologna, Italy Purpose: Hepatic encephalopathy (HE) is a recurrent severe complication of progressive hepatic cirrhosis. The aim of this study is to evaluate the average annual direct healthcare costs for the treatment of patients with overt HE in Italy. Patients and methods: This retrospective, observational study analyzed information from the database of ARNO Observatory. Patients with at least one hospitalization due to overt HE in the period from January 1, 2011 to December 31, 2011, were selected and observed during the year following the hospitalization. Costs for drugs, diagnostic and therapeutic procedures, and hospitalizations were estimated from the Italian National Health Service perspective. Results: Out of a population of 2,678,462 subjects, 381 patients were identified, of whom, 21.5% died during the first hospitalization and 5.8% during the follow-up; the survival rate was 72.7% at the end of the observation period. The direct healthcare costs per patient amounted to €13,393/year (15,295 USD) (88% for hospitalizations, 8% for drugs, and 4% for diagnostic procedures). During the follow-up, 42.5% of patients had at least one rehospitalization due to HE. Patients readmitted for HE had an average annual cost of €21,272 (24,293 USD), almost doubled if compared to patients without readmissions (€12,098 [13,816 USD]). Conclusion: This analysis showed that patients with HE had relevant direct healthcare costs, in which hospitalizations were the most important cost drivers. Keywords: hepatic encephalopathy, costs, hospitalizations, relapses

Somatostatin is widely diffused in the central nervous system, where it participates to control the efficiency of synaptic transmission. This peptide mainly colocalizes with GABA, in inhibitory, GABA-containing interneurons from which it is actively released in a Ca2+ dependent manner upon application of depolarizing stimuli. Once released in the synaptic cleft, somatostatin acts locally, or it diffuses in the extracellular space through “volume diffusion”, a mechanism(s) of distribution which mainly operates in the cerebrospinal fluid and that assures the progression of neuronal signalling from signal-secreting sender structures towards receptor-expressing targeted neurons located extrasynaptically, in a non-synaptic, inter-neuronal form of communication. Somatostatin controls the efficiency of central glutamate transmission by either modulating presynaptically the glutamate exocytosis or by metamodulating the activity of glutamate receptors colocalized and functionally coupled with somatostatin receptors in selected subpopulations of nerve terminals. Deciphering the role of somatostatin in the mechanisms of “volume diffusion” and in the “receptor-receptor interaction” unveils new perspectives in the central role of this fine tuner of synaptic strength, paving the road to new therapeutic approaches for the cure of central disorders.

BACKGROUND: Venous thromboembolism (VTE) is frequently leading to severe complications, particularly deep vein thrombosis (DVT) and pulmonary embolism (PE), and requires high cost healthcare intevention. Rivaroxaban, a novel oral factor Xa inhibitor approved for treatment of DVT, PE and reduction of the risk of recurrence, may represent a cost‑effective anticoagulant choice. OBJECTIVE: This study aims to evaluate the economic impact of the use of rivaroxaban for preventing DVT and PE in Italy. METHODS: We conducted a budget impact analysis to estimate clinical outcomes and economic consequences associated to rivaroxaban vs. standard therapy (low molecular weight heparin + vitamin K antagonists) in the prevention of DVT and PE, over a three‑year time horizon. In the analysis we performed two hypothesis: complete replacement of LMWH/VKA with rivaroxaban (hypothesis 1) and partial and progressive replacement of LMWH/VKA in the first three years of reimbursement (hypothesis 2). Only direct healthcare costs have been considered. RESULTS: Total replacement of LMWH/VKA with rivaroxaban in DVT and PE is associated to a reduction of recurrent symptomatic thromboembolism, major bleeding, vascular events and mortality, with an expenditure saving of about € 11.3 mln (DVT) and € 6.6 mln (PE), corresponding to an average savings per patient treated with rivaroxaban amounted to € 112.9 and € 123,3, respectively. In hypothesis 2 it is estimated that 22%, 25%, and 27% of DVT patients and 12%, 16%, and 20% of PE patients, would be treated with rivaroxaban over the first three years. This would translate into a total saving on healthcare expenditure of € 8.4 mln for DVT and € 3.2 mln for PE and reduction of length of stay with a slight increase in pharmaceutical expenditure. CONCLUSIONS: Rivaroxaban provides significant advantages in terms of events avoided and related costs that would result in a reduction in the total expenditure on the Italian NHS.

Daniela Paola Roggeri,1 Mario Cozzolino,2 Sandro Mazzaferro,3 Diego Brancaccio,4 Ernesto Paoletti,5 Alessandro Roggeri,1 Anna Maria Costanzo,6 Umberto di Luzio Paparatti,6 Vincenzo Festa,6 Piergiorgio Messa7 1ProCure Solutions, Nembro, Bergamo, 2Department of Health Sciences, University of Milan, Milan, 3Department of Cardiovascular, Respiratory, Nephrologic and Geriatric Sciences, Sapienza University of Rome, Rome, 4Dialysis Unit NephroCare Simone Martini, Milan, 5Department of Nephrology, San Martino Hospital, Genoa, 6AbbVie Italy, Campoverde, Latina, 7Nephrology, Dialysis and Renal Transplant, Fondazione Ca Granda IRCCS Policlinico, Milan, Italy On behalf of the FARO Study Group Background: The aim of this analysis was to estimate biochemical parameters and the costs of treatment of secondary hyperparathyroidism (SHPT) in a subpopulation of the FARO-2 study. Methods: The FARO-2 observational study aimed at evaluating the patterns of treatment for SHPT in naïve hemodialysis patients. Data related to pharmacological treatments and biochemical parameters (parathyroid hormone [PTH], calcium, phosphate) were recorded at entry to hemodialysis (baseline) and 6 months later (second survey). The analysis was performed from the Italian National Health Service perspective. Results: Two prominent treatment groups were identified, ie, one on oral calcitriol (n=105) and the other on intravenous paricalcitol (n=33); the intravenous calcitriol and intravenous paricalcitol + cinacalcet combination groups were not analyzed due to low patient numbers. At baseline, serum PTH levels were significantly higher in the intravenous paricalcitol group (P

Alessandro Roggeri,1 Claudio Micheletto,2 Daniela Paola Roggeri11ProCure Solutions, Bergamo, Italy; 2Respiratory Unit, Mater Salutis Hospital, Legnago, Verona, ItalyPurpose: Fixed-dose combinations of inhaled corticosteroids and long-acting ß2-agonists have proven to prevent and reduce chronic obstructive pulmonary disease (COPD) exacerbations. The aim of this analysis was to explore the clinical consequences and direct health care costs of applying the findings of the PATHOS (An Investigation of the Past 10 Years Health Care for Primary Care Patients with Chronic Obstructive Pulmonary Disease) study to the Italian context.Patients and methods: Effectiveness data from the PATHOS study, a population-based, retrospective, observational registry study conducted in Sweden, in terms of reduction in COPD and pneumonia-related hospitalizations, were considered, in order to estimate the differences in resource consumption between patients treated with budesonide/formoterol and fluticasone/salmeterol. The base case considers the average dosages of the two drugs reported in the PATHOS study and the actual public price in charges to the Italian National Health Service, while the difference in hospitalization rates reported in the PATHOS study was costed based on Italian real-world data.Results: The PATHOS study demonstrated a significant reduction in COPD hospitalizations and pneumonia-related hospitalizations in patients treated with budesonide/formoterol versus fluticasone/salmeterol (-29.1% and -42%, respectively). In the base case, the treatment of a patient for 1 year with budesonide/formoterol led to a saving of €499.90 (€195.10 for drugs, €193.10 for COPD hospitalizations, and €111.70 for pneumonia hospitalizations) corresponding to a -27.6% difference compared with fluticasone/salmeterol treatment.Conclusion: Treatment of COPD with budesonide/formoterol compared with fluticasone/salmeterol could lead to a reduction in direct health care costs, with relevant improvement in clinical outcomes.Keywords: disease management, pharmacoeconomics, direct health care costs, hospitalizations

Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to reduce the severity of the pathology during the early inflammatory stages, but they are not effective in the chronic stage of the disease. In this phase, failure in endogenous remyelination is associated with the impairment of oligodendrocytes progenitor cells (OPCs) to migrate and differentiate into mature myelinating oligodendrocytes. Therefore, stimulating differentiation of OPCs into myelinating oligodendrocytes has become one of the main goals of new therapeutic approaches for MS. Different disease-modifying therapies targeting sphingosine-1-phosphate receptors (S1PRs) have been approved or are being developed to treat MS. Besides their immunomodulatory effects, growing evidence suggests that targeting S1PRs modulates mechanisms beyond immunomodulation, such as remyelination. In this context, this review focuses on the current understanding of S1PR modulators and their direct effect on OPCs and oligodendrocytes.

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in “ex-vivo, in vitro” parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.