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Valentina Perrone,1 Elisa Giacomini,1 Diego Sangiorgi,1 Margherita Andretta,2 Fausto Bartolini,3 Alessandro Lupi,4 Fulvio Ferrante,5 Stefano Palcic,6 Davide Re,7 Luca Degli Esposti1 1CliCon S.r.l. Società Benefit – Health, Economics & Outcome Research, Bologna, Italy; 2UOC Assistenza Farmaceutica Territoriale, Azienda ULSS 8 Berica, Vicenza, Italy; 3Dipartimento Farmaceutico-USL Umbria 2, Terni, Italy; 4ASL VCO, Omegna (VB), Italy; 5ASL Frosinone, Frosinone, Italy; 6Azienda Sanitaria Universitaria Integrata Giuliano-Isontina (ASUGI), Trieste, Italy; 7U.O.C. Servizio Assistenza Farmaceutica Territoriale, ASL Teramo, Teramo, ItalyCorrespondence: Valentina Perrone, CliCon S.r.l. Società Benefit – Health, Economics & Outcome Research, Via Murri 9, Bologna, 40137, Italy, Tel +39 3450316494, Email valentina.perrone@clicon.itPurpose: The study aimed to analyze, in hypercholesterolemic patients under statin medication, patient characteristics and their lipid profile at baseline, the therapeutic pathway, and the pharmaco-utilization, using real-world data in Italy.Patients and Methods: A retrospective study was conducted using administrative databases of a sample of entities covering 6.5 million health-assisted individuals. Between January 2010 and June 2019, patients with non-familial hypercholesterolemia (nFH) were identified by 1) ≥ 1 low-density lipoprotein cholesterol (LDL-C) measurement (LDL-C assessment date was the index-date) and 2) statin prescription during 6 months before the index-date (pharmaco-utilization period). FH patients were defined by LDL-C evaluation, statin treatment during the pharmaco-utilization period, and a score ≥ 6 according to the Dutch Lipid Clinic Network criteria. nFH patients were divided into four exclusive cohorts based on CV-risk class: 1) with previous CV disease (CVD); 2) with diabetes mellitus; 3) with mixed-dyslipidemia diagnosis; 4) in primary-prevention. Based on LDL-C index values, patient was defined with LDL-C “controlled” if its levels were ≤ 70mg/dl (CVD), ≤ 100mg/dl (diabetes, FH), ≤ 130mg/dl (mixed-dyslipidemia, primary-prevention).Results: Overall 164,161 nFH patients were included (mean age 72 years, 51% male); of these, 46,782 (28.5%) were CVD (mean age 74 years, 66% male), 34,803 (21.2%) were diabetic (mean age 72 years, 51% male), 1617 (1%) were with mixed-dyslipidemia (mean age 71 years, 48% male) and 80,959 (49.3%) were in primary-prevention (mean age 71 years, 42% male). The proportion of nFH patients with controlled LDL-C was 41.2% for CVD, 73.6% for diabetic, 80.7% for mixed-dyslipidemia, and 79.5% for primary-prevention patients; 49% of nFH patients were adherent to therapy. Overall, 1287 FH patients (mean age 64 years, 42% male) were included; in 39.2% of the patients, LDL-C was controlled, and 44% of the patients were adherent to therapy.Conclusion: The results of this study highlighted non-optimal therapeutic management of hypercholesterolemic patients in Italian clinical practice, with a notable quote of patients non-adherent to therapy.Keywords: lipid-lowering agents, pharmacoutilization, real-world evidence, clinical practice

Valentina Perrone,1 Chiara Veronesi,1 Melania Dovizio,1 Domenica Daniela Ancona,2 Margherita Andretta,3 Fausto Bartolini,4 Arturo Cavaliere,5 Alessandro Chinellato,6 Andrea Ciaccia,7 Mariarosaria Cillo,8 Adele De Francesco,9 Nicola Enieri,6 Fulvio Ferrante,10 Simona Gentile,11 Cataldo Procacci,2 Loredana Ubertazzo,12 Adriano Vercellone,13 Domenico Lucatelli,14 Michela Procaccini,14 Luca Degli Esposti1 1CliCon S.r.l., Società Benefit-Health, Economics & Outcomes Research, Bologna, Italy; 2Dipartimento Farmaceutico, ASL BAT, Andria, Italy; 3UOC Assistenza Farmaceutica Territoriale, Azienda ULSS 8 Berica, Vicenza, Italy; 4Dipartimento Farmaceutico, USL Umbria 2, Terni, Italy; 5Farmaceutica Aziendale, ASL Viterbo, Viterbo, Italy; 6Unità Operativa Farmacia Ospedaliera, ULSS 3 Serenissima, Mestre, Italy; 7ASL Foggia, Foggia, Italy; 8Dipartimento Farmaceutico, ASL Salerno, Salerno, Italy; 9Azienda Ospedaliero-Universitaria “Mater Domini”, Catanzaro, Italy; 10ASL Frosinone, Frosinone, Italy; 11Direzione Generale per la Salute, Campobasso, Italy; 12ASL Roma 4, Civitavecchia, Roma, Italy; 13ASL Napoli 3 sud, Napoli, Italy; 14Angelini Pharma, Roma, ItalyCorrespondence: Valentina Perrone, CliCon S.r.l., Società Benefit-Health, Economics & Outcomes Research, Via Murri 9, Bologna, 40137, Italy, Tel +39 3450316494, Email valentina.perrone@clicon.itPurpose: A retrospective analysis was conducted to estimate the number of patients with focal epilepsy and drug-resistant epilepsy (DRE) and their characteristics, the therapeutic patterns, the consumption of health resources in a real-world Italian setting.Patients and Methods: A retrospective study was carried out on the administrative databases of a sample of Italian Health Departments, covering approximately 8.7 million health-assisted individuals. All adult patients with at least one hospitalization for focal epilepsy and an electroencephalogram (between 01/2010 and 12/2019), and at least one prescription of antiseizure medication (ASM) (between 01/2011 and 12/2018) were included in the study. Patients with at least two treatment failures and treated with a subsequent ASM were considered DRE.Results: Overall, 1897 patients with focal epilepsy (mean age 56 years, 47% male) were identified, of which 485 (25.6%) with DRE (mean age 53 years, 43% male). Among patients with focal epilepsy and DRE, respectively, 48% and 54% had essential hypertension, 23.4% and 26.6% had cardiovascular disease, and 46.3% and 62.1% had peptic ulcer/prescription of gastric secretion inhibitors. During follow-up, patients with focal epilepsy maintained first-line treatment for 53.9 months; among these, 52% passed to the second-line, and 485 (25.6% of the total) began third-line treatment. In patients with focal epilepsy, the mean cost was € 4448 (of which € 1410 were epilepsy-related), and in DRE patients total expenditures averages € 5825 (of which € 2165 were epilepsy-related). In both patients with focal epilepsy and DRE, hospitalizations represented the most impacting item of expenditure.Conclusion: The present analysis conducted in a setting of Italian clinical practice has shown that 25% of patients with focal epilepsy were resistant to antiepileptic treatments. Furthermore, these results showed that health-care costs for the management of epileptic patients were mainly accountable for the costs related to the disease-management and to hospitalizations.Keywords: epilepsy, real-world evidence, clinical practice, pharmacoutilization, healthcare resource consumption

Bruno Monaldi,1 Giovanni Bologna,2 Geeta Giulia Costa,3 Carlo D'Agostino,4 Fulvio Ferrante,5 Maurizio Filice,6 Anna Maria Grion,7 Alessandra Mingarelli,8 Leonardo Paloscia,9 Roberto Tettamanti,10 Chiara Veronesi,11 Luca Degli Esposti11 1Servizio Farmaceutico, Ospedale G Mazzoni, ASUR Marche, Ascoli Piceno, 2Dipartimento Farmaceutico, Ospedale di Piacenza, AUSL di Piacenza, SSR Emilia-Romagna, Piacenza, 3Dipartimento Scienze Cardiologiche, Toraciche e Vascolari, Università degli Studi di Padova, Padua, 4Unità Operativa Cardiologia, Ospedale Di Venere, ASL di Bari, Bari, 5SC Monitoraggio Attività Farmaceutica, Azienda USL Frosinone, Frosinone, 6Dipartimento Medico, Ospedale Piero Palagi, Azienda Sanitaria di Firenze (ASF), Florence, 7Servizio Farmaceutico, ULSS 16 Padova, Padua, 8Dipartimento Funzionale del Farmaco, ASL di Latina, Latina, 9Unità Operativa UTIC e Cardiologia Interventistica, Ospedale Santo Spirito, ASL di Pescara, Pescara, 10Unità Operativa Complessa Osservatorio Epidemiologico e Sistemi Informativi, ASL della Provincia di Como, Como, 11CliCon Health, Economics and Outcomes Research, Ravenna, Italy Background: Statins are standard therapies after myocardial infarction (MI) in the general population. In the current study, we assessed adherence to statin treatment by patients after an MI in Italy, and estimated the effect of in-hospital statin therapy on persistence in treatment during a 2-year follow-up.Patients and methods: This was a retrospective cohort observation study of patients who experienced their MI between January 1, 2004 and December 31, 2005. Patients to enroll were identified by a diagnosis of MI at discharge from hospital. Previous drug therapies and hospital admissions for cardiovascular reasons in the 12 months before hospitalization for MI, statin treatment and lipid levels during hospitalization, indication for statin treatment at hospital discharge, and adherence to statin treatment in the following 24 months using an integrated analysis of administrative databases and hospital case records were evaluated. Also, factors associated either positively or negatively with consistent acute and long-term use of this efficacy-proven therapy were evaluated.Results: We identified 3,369 patients: 28.5% of patients had not been consistently treated with statins during their hospital stay for MI, and 36.2% of patients did not receive a statin prescription at hospital discharge. Of the 2,629 patients persistent with treatment during the follow-up, only 1,431 had an adherence to statins >80%. Either during the hospitalization or during the follow-up, the use of statins was negatively associated with older age and the presence of diabetes and chronic kidney disease. Lipid levels were significantly higher in treated than in untreated patients, but did not contribute to adherence to treatment. An important factor in long-term adherence to statin treatment was a statin prescription at the time of hospital discharge.Conclusion: Since the statin undertreatment rate in routine care is still high, physicians need to increase the awareness of patients regarding the implications of discontinuation and/or underuse of their medications and encourage higher adherence. Keywords: myocardial infarction, statins, adherence to treatment, discontinuation

The microscopic structure of supercritical water-CO2 mixture is investigated by neutron diffraction experiments exploiting the isotopic H/D substitution. The investigated water reach mixtures are in the liquidlike region of the phase diagram, according to the behavior of the radial distribution functions, yet a reduction of the average number of hydrogen bonds, compared to equivalent states of pure water, is found. As a consequence, the average dimension of water clusters is reduced and the system stays below the percolation threshold. These results, along with the shift of the main peaks of the site-site radial distribution functions, suggest that the excess volume in these supercritical mixtures is likely associated with the CO2 solvation shell. [ABSTRACT FROM AUTHOR]

In this work, the problem of stabilization of general systems of linear transport equations with in-domain and boundary couplings is investigated. It is proved that the unstable part of the spectrum is of finite cardinal. Then, using the pole placement theorem, a linear full state feedback controller is synthesized to stabilize the unstable finite-dimensional part of the system. Finally, by a careful study of semigroups, we prove the exponential stability of the closed-loop system. As a by product, the linear control constructed before is saturated and a fine estimate of the basin of attraction is given.

Background and Objectives. Multiple processes have been identified as potential contributors to chronic pain, with increasing evidence illustrating an association with aberrant levels of neuroimmune mediators. The primary objectives of the present study were to examine central nervous system cytokines, chemokines, and growth factors present in a chronic pain population and to explore patterns of the same mediator molecules over time. Secondary objectives explored the relationship of central and peripheral neuroimmune mediators while examining the levels of anxiety, depression, sleep quality, and perception of pain associated with the chronic pain patient experience. Methods. Cerebrospinal fluid (CSF) from a population of majority postlaminectomy syndrome patients (N=8) was compared with control CSF samples (N=30) to assess for significant differences in 10 cytokines, chemokines, and growth factors. The patient population was then followed over time, analyzing CSF, plasma, and psychobehavioral measures. Results. The present observational study is the first to demonstrate increased mean CSF levels of interleukin-8 (IL-8; P< 0.001) in a small population of majority postlaminectomy syndrome patients, as compared with a control population. Over time in pain patients, CSF levels of IL-8 increased significantly (P< 0.001). Conclusions. These data indicate that IL-8 should be further investigated and psychobehavioral components considered in the overall chronic pain paradigm. Future studies examining the interactions between these factors and IL-8 may identify novel targets for treatment of persistent pain states. [ABSTRACT FROM AUTHOR]

Background: Many studies have assessed the efficacy of radiofrequency ablation to denervate the facet joint as an interventional means of treating axial low-back pain. In these studies, varying procedural techniques were utilized to ablate the nerves that innervate the facet joints. To date, no comparison studies have been performed to suggest superiority of one technique or even compare the prevalence of side effects and complications. Materials and methods: A retrospective chart review was performed on patients who underwent a lumbar facet denervation procedure. Each patient's chart was analyzed for treatment technique (early versus advanced Australian), preprocedural visual numeric scale (VNS) score, postprocedural VNS score, duration of pain relief, and complications. Results: Pre- and postprocedural VNS scores and change in VNS score between the two groups showed no significant differences. Patient-reported benefit and duration of relief was greater in the advanced Australian technique group (P=0.012 and 0.022, respectively). The advanced Australian technique group demonstrated a significantly greater median duration of relief (4 months versus 1.5 months, P=0.022). Male sex and no pain-medication use at baseline were associated with decreased postablation VNS scores, while increasing age and higher preablation VNS scores were associated with increased postablation VNS scores. Despite increasing age being associated with increased postablation VNS scores, age and the advanced Australian technique were found to confer greater patient self-reported treatment benefit. Conclusion: The advanced Australian technique provides a significant benefit over the early Australian technique for the treatment of lumbar facet pain, both in magnitude and duration of pain relief. [ABSTRACT FROM AUTHOR]

Objectives This observational prospective study analyzed the effect of an incremental cardiopulmonary exercise test (CPET) on the secretion of salivary biomarkers of the adrenergic nervous system and hypothalamus-pituitary-adrenal (HPA) axis activity by measuring salivary α-amylase and cortisol diurnal trajectories in the setting of long-term hormone replacement therapy (HRT). Methods Fifteen healthy sedentary postmenopausal women who were current HRT users and 15 women who had never used HRT were consecutively recruited. α-Amylase and cortisol were measured in salivary samples collected on the CPET day and on a rest day. Cardiovascular and respiratory fitness parameters were recorded during the CPET challenge. Results The participants had very homogeneous somatic characteristics, and they were all in generally good health. The postmenopausal never-HRT users presented an abnormal diurnal pattern of α-amylase at baseline and a flattened response to CPET. In contrast, women on HRT had a physiological α-amylase diurnal pattern and increased salivary α-amylase production during the CPET-induced challenge. The CPET challenge physiologically activated the HPA axis activity, as shown by the increase in the concentration of salivary cortisol during the effort test. HPA axis activity was not affected by long-term HRT. Postmenopausal women using HRT exhibited a cardiorespiratory functional capacity that was significantly ( p < 0.05) higher than that of non-users. Conclusions Our findings show that healthy postmenopausal women present an asymmetry between adrenergic nervous system and HPA axis activities under both basal and stress conditions. HRT was able to modify the abnormal adrenergic nervous system activity, most likely by reducing the sympathetic hyperactivity that characterizes menopause. [ABSTRACT FROM AUTHOR]

A new symmetric naphthalenediimidequaterthiophene (s-NDI2ODT4) was synthesized and exhibited the capability to electropolymerize alone or with EDOT affording polymers with controlled donor/acceptor monomer ratios. s-NDI2ODT4-EDOT-based copolymers showed low band gaps, wide optical absorption ranges extending to the near IR region, tuned electrical properties, thin-film surface morphology and hydrophilicity as well as high coloration efficiency in electrochromic devices. [ABSTRACT FROM AUTHOR]

BackgroundEmotion dysregulation is a key feature of schizophrenia, a brain disorder strongly associated with genetic risk and aberrant dopamine signalling. Dopamine is inactivated by catechol-O-methyltransferase (COMT), whose gene contains a functional polymorphism (COMT Val158Met) associated with differential activity of the enzyme and with brain physiology of emotion processing. The aim of the present study was to investigate whether genetic risk for schizophrenia and COMT Val158Met genotype interact on brain activity during implicit and explicit emotion processing.MethodA total of 25 patients with schizophrenia, 23 healthy siblings of patients and 24 comparison subjects genotyped for COMT Val158Met underwent functional magnetic resonance imaging during implicit and explicit processing of facial stimuli with negative emotional valence.ResultsWe found a main effect of diagnosis in the right amygdala, with decreased activity in patients and siblings compared with control subjects. Furthermore, a genotype × diagnosis interaction was found in the left middle frontal gyrus, such that the effect of genetic risk for schizophrenia was evident in the context of the Val/Val genotype only, i.e. the phenotype of reduced activity was present especially in Val/Val patients and siblings. Finally, a complete inversion of the COMT effect between patients and healthy subjects was found in the left striatum during explicit processing.ConclusionsOverall, these results suggest complex interactions between genetically determined dopamine signalling and risk for schizophrenia on brain activity in the prefrontal cortex during emotion processing. On the other hand, the effects in the striatum may represent state-related epiphenomena of the disorder itself. [ABSTRACT FROM PUBLISHER]

The use of ReFacto Laboratory Standard(RLS) in the one-stage clotting assay was proposed to reduce the underestimation of factor VIII (FVIII) plasma concentration after the infusion of ‘ReFacto®’ (B-domain deleted recombinant FVIII) in haemophilia A patients. Both ReFacto® and RLS were recently recalibrated, with the resulting materials containing approximately 20% more protein than the previous products. The aim of this study was to evaluate the performance of recalibrated RLS in the measurement of FVIII plasma concentration after the infusion of recalibrated ReFacto®. In 13 severe haemophilia A patients, 25 IU kg−1 of ReFacto® were injected intravenously. Venous blood samples were collected at 0.25, 0.5, 1, 3, 6, 9, 24, 28 and 32 h after the end of the infusion. Pharmacokinetic parameters were measured for the chromogenic and one-stage assays using International Plasma Standard (IPS) and RLS for both assays and assuming a non-compartmental drug disposition. Comparisons among assays and standards were performed usinganova. Pharmacokinetic estimates obtained with the chromogenic method were in agreement with those published in the literature. The one-stage method was confirmed to be more sensitive to lower plasma concentrations of FVIII. The measured maximum plasma concentration ( Cmax) was slightly higher than theoretical values and independent of the assay used. Cmax, area under the curve(AUC) and volume of distribution at steady state ( Vss) presented non-significant differences among the methods and standards used. The clinical utility of RLS in the evaluation of FVIII concentration after the infusion of ReFacto® seems to be reduced since recalibration of the product. [ABSTRACT FROM AUTHOR]

Background and Objectives: Subdural injection is a well-known but often poorly recognized complication of neuraxial anesthesia/analgesia. This report aims to further describe the clinical presentation of subdural injection by analyzing radiographically proven cases. A new diagnostic algorithm is then proposed. Methods: A literature search identified 70 radiographically confirmed cases of subdural injection. The prevalence of numerous presenting characteristics and their relationship to the volume of injected local anesthetics were examined. The ability of 2 previously published diagnostic paradigms to detect proven subdural injection was compared with that of a newly proposed algorithm. Results: The dermatomal distribution of sensory blockade was excessive in 74% of cases, restricted in 17%, and neither in 9%. Motor blockade and respiratory depression were associated with larger local anesthetic injection volumes (median volume = 14 vs. 8 mL [P <.009] and 15 vs. 10 mL [P <.035], respectively), but segmental spread and cardiovascular depression were not. Only 33% of cases were positive for 2 or more of Collier''s criteria; Lubenow et al.''s diagnostic paradigm detected 71% of cases. We propose a diagnostic algorithm structured as a “roadmap,” whereby the clinician inputs the assumed neuraxial block (epidural vs. subarachnoid), and distribution of sensory blockade (excessive, restricted, neither). Specific minor criteria are then applied to diagnose subdural injections. This algorithm detected 93% of subdurals with excessive sensory block distribution, and all of those with restricted and normal distribution. Conclusions: Radiographically proven subdural injections were used to further define the clinical presentation of subdural analgesia/analgesia and a new diagnostic algorithm is proposed. [Copyright &y& Elsevier]

BACKGROUND: Oral bosentan is an established treatment for pulmonary arterial hypertension (PAH). OBJECTIVE: To evaluate safety, tolerability, and clinical and haemodynamic effects of bosentan in patients with PAH related to congenital heart disease (CHD). PATIENTS: 22 patients with CHD related PAH (8 men, 14 women, mean (SD) age 38 (10) years) were treated with oral bosentan (62.5 mg x 2/day for the first 4 weeks and then 125 mg x 2/day). MAIN OUTCOME MEASURES: Clinical status, liver enzymes, World Health Organisation (WHO) functional class, resting oxygen saturations and 6-min walk test (6MWT) were assessed at baseline and at 1, 3, 6, and 12 months. Haemodynamic evaluation with cardiac catheterisation was performed at baseline and at 12 month follow-up. RESULTS: 12 patients had ventricular septal defect, 5 atrioventricular canal, 4 single ventricle, and 1 atrial septal defect. All patients tolerated bosentan well. No major side effects were seen. After a year of treatment, an improvement was seen in WHO functional class (2.5 (0.7) v 3.1 (0.7); p<0.05), oxygen saturation at rest (87 (6%) v 81 (9); p<0.001), heart rate at rest (81 (10) v 87 (14) bpm; p<0.05), distance travelled in the 6MWT (394 (73) v 320 (108) m; p<0.001), oxygen saturation at the end of the 6MWT (71 (14) v 63 (17%); p<0.05), Borg index (5.3 (1.8) v 6.5 (1.3); p<0.001), pulmonary vascular resistances index (14 (9) v 22 (12) WU m(2); p<0.001), systemic vascular resistances index (23 (11) v 27 (10) WU.m(2); p<0.01), pulmonary vascular resistances index/systemic vascular resistances index (0.6 (0.5) v 0.9 (0.6); p<0.05); pulmonary (4.0 (1.3) v 2.8 (0.9) l/min/m2; p<0.001) and systemic cardiac output (4.2 (1.4) v 3.4 (1.1) l/min/m2; p<0.05). CONCLUSIONS: Bosentan was safe and well tolerated in adults with CHD related PAH during 12 months of treatment. Clinical status, exercise tolerance, and pulmonary haemodynamics improved considerably. [ABSTRACT FROM AUTHOR]