Anna Citarella

Polypharmacy is a major health concern among older adults. While deprescribing may reduce inappropriate medicine use, its effect on clinical end points remains uncertain.To assess the clinical implications of discontinuing the use of statins while maintaining other drugs in a cohort of older patients receiving polypharmacy.This retrospective, population-based cohort study included the 29 047 residents in the Italian Lombardy region aged 65 years or older who were receiving uninterrupted treatment with statins, blood pressure-lowering, antidiabetic, and antiplatelet agents from October 1, 2013, until January 31, 2015, with follow-up through June 30, 2018. Data were collected using the health care utilization database of Lombardy region in Italy. Data analysis was conducted from March to November 2020.Cohort members were followed up to identify those who discontinued statins. Among this group, those who maintained other therapies during the first 6 months after statin discontinuation were 1:1 propensity score matched with patients who discontinued neither statins nor other drugs.The pairs of patients discontinuing and maintaining statins were followed up from the initial discontinuation until June 30, 2018, to estimate the hazard ratios (HRs) and 95% CIs for fatal and nonfatal outcomes associated with statin discontinuation.The full cohort inclued 29 047 patients exposed to polypharmacy (mean [SD] age, 76.5 [6.5] years; 18 257 [62.9%] men). Of them, 5819 (20.0%) discontinued statins while maintaining other medications, and 4010 (68.9%) of them were matched with a comparator. In the discontinuing group, the mean (SD) age was 76.5 (6.4) years, 2405 (60.0%) were men, and 506 (12.6%) had Multisource Comorbidity Scores of 4 or 5. In the maintaining group, the mean (SD) age was 76.1 (6.3) years, 2474 (61.7%) were men, and 482 (12.0%) had multisource comorbidity scores of 4 or 5. Compared with the maintaining group, patients in the discontinuing group had increased risk of hospital admissions for heart failure (HR, 1.24; 95% CI, 1.07-1.43) and any cardiovascular outcome (HR, 1.14; 95% CI, 1.03-1.26), deaths from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.05-1.19).In this study of patients receiving polypharmacy, discontinuing statins while maintaining other drug therapies was associated with an increase in the long-term risk of fatal and nonfatal cardiovascular outcomes.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC.

To estimate the impact of diabetes and its complications, overall and in different age classes, on the likelihood of hospital admission for specific causes.We carried out a record-linkage analysis of administrative registers including data on 8,940,420 citizens in 21 Local Health Authorities in Italy. Individuals with pharmacologically treated diabetes (≥2 prescriptions of antidiabetic agents during the year 2008) were paired in a 1:1 proportion with those who did not receive such drugs (controls) based on propensity-score matching. Odds Ratios (ORs) of hospitalization for macro and microvascular conditions in individuals with diabetes as compared to controls were estimated. The system identified 498,825 individuals with diabetes pharmacologically treated (prevalence of 5.6%). Prevalence of diabetes in people aged <14 years, 14-39 years, 40-65 years, and ≥65 years was 0.1%, 0.6%, 6.4%, and 18.2%, respectively. Overall, 23.9% of subjects with diabetes and 11.5% of controls had had at least a hospital admission during 12 months for the causes considered. Diabetes increased the likelihood of hospitalization by two to six times for the different causes examined. In absolute terms, diabetes was responsible for an excess of over 12,000 hospital admissions per 100,000 individuals/year.Despite the availability of effective treatments to prevent or delay major complications, diabetes still places an enormous burden on both patients and the health care system. Given the continuous rise in diabetes prevalence both in middle-aged and elderly individuals, we can expect an additional, hardly sustainable increase in the demand for health care in the near future.

Histone H3K4 methylation is a feature of meiotic recombination hotspots shared by many organisms including plants and mammals. Meiotic recombination is initiated by programmed double-strand break (DSB) formation that in budding yeast takes place in gene promoters and is promoted by histone H3K4 di/trimethylation. This histone modification is recognized by Spp1, a PHD finger containing protein that belongs to the conserved histone H3K4 methyltransferase Set1 complex. During meiosis, Spp1 binds H3K4me3 and interacts with a DSB protein, Mer2, to promote DSB formation close to gene promoters. How Set1 complex- and Mer2- related functions of Spp1 are connected is not clear. Here, combining genome-wide localization analyses, biochemical approaches and the use of separation of function mutants, we show that Spp1 is present within two distinct complexes in meiotic cells, the Set1 and the Mer2 complexes. Disrupting the Spp1-Set1 interaction mildly decreases H3K4me3 levels and does not affect meiotic recombination initiation. Conversely, the Spp1-Mer2 interaction is required for normal meiotic recombination initiation, but dispensable for Set1 complex-mediated histone H3K4 methylation. Finally, we provide evidence that Spp1 preserves normal H3K4me3 levels independently of the Set1 complex. We propose a model where Spp1 works in three ways to promote recombination initiation: first by depositing histone H3K4 methylation (Set1 complex), next by "reading" and protecting histone H3K4 methylation, and finally by making the link with the chromosome axis (Mer2-Spp1 complex). This work deciphers the precise roles of Spp1 in meiotic recombination and opens perspectives to study its functions in other organisms where H3K4me3 is also present at recombination hotspots.

Abstract Colorectal cancer (CRC) is a leading cause of cancer death. Chemoresistance is a pivotal feature of cancer cells leading to treatment failure and ATP-binding cassette (ABC) transporters are responsible for the efflux of several molecules, including anticancer drugs. The Hedgehog-GLI (HH-GLI) pathway is a major signalling in CRC, however its role in chemoresistance has not been fully elucidated. Here we show that the HH-GLI pathway favours resistance to 5-fluorouracil and Oxaliplatin in CRC cells. We identified potential GLI1 binding sites in the promoter region of six ABC transporters, namely ABCA2, ABCB1, ABCB4, ABCB7, ABCC2 and ABCG1. Next, we investigated the binding of GLI1 using chromatin immunoprecipitation experiments and we demonstrate that GLI1 transcriptionally regulates the identified ABC transporters. We show that chemoresistant cells express high levels of GLI1 and of the ABC transporters and that GLI1 inhibition disrupts the transporters up-regulation. Moreover, we report that human CRC tumours express high levels of the ABCG1 transporter and that its expression correlates with worse patients’ prognosis. This study identifies a new mechanism where HH-GLI signalling regulates CRC chemoresistance features. Our results indicate that the inhibition of Gli1 regulates the ABC transporters expression and therefore should be considered as a therapeutic option in chemoresistant patients.

This study evaluates the feasibility of a local action program for HCV micro-elimination in highly endemic areas. Retrospective analysis: administrative and laboratory data (Local Health Unit, southern Italy) were integrated to quantize the anti-HCV-positive subjects not RNA tested and untreated HCV-infected subjects (2018-2022). Prospective analysis: all subjects admitted to a division of the LHU largest hospital (2021-2022) were tested for HCV, with linkage of active-infected patients to care. Overall, 49287 subjects were HCV-Ab tested: 1071 (2.2%) resulted positive without information for an HCV RNA test and 230 (0.5%) had an active infection not yet cured. Among 856 admitted subjects, 54 (6.3%) were HCV-Ab+ and 27 (3.0%) HCV RNA+. Of HCV-infected patients, 22.2% had advanced liver disease, highlighting the need for earlier diagnosis; 27.7% were unaware of HCV infection; and 20.4% were previously aware but never referred to a clinical center. Of these, 26% died and 74% received treatment. Our study emphasizes the value of an active HCV hospital case-finding program to enhance diagnosis in patients with several comorbidities and to easily link them to care. Our data strongly suggest extending this program to all hospital wards/access as a standard of care, particularly in highly endemic areas, to help HCV disease control and take steps in achieving the elimination goals.

Background and aimThe aim of this study was to compare the use of insulin glargine and intermediate/long-acting human insulin (HI) in relation to the incidence of complications in diabetic patients.Methods and resultsA population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients without macrovascular diseases and treated with either intermediate/long-acting HI or glargine were followed for 3-years; the incidence of diabetic (macrovascular, microvascular and metabolic) complications was ascertained by hospital discharge claims and estimated using Cox proportional hazard models. Propensity score (PS) matching was also used to adjust for significant differences in the baseline characteristics between the two groups.ResultsOverall, 1921 diabetic patients were included: 744 intermediate/long-acting HI and 1177 glargine users. During the 3-year follow-up, 209 (28.1%) incident events of any diabetic complication occurred in the intermediate/long-acting HI and 159 (13.5%) in the glargine group. After adjustment for covariates, glargine users had an HR (95% CI) of 0.57 (0.44–0.74) for any diabetic complication and HRs of 0.61 (0.44–0.84), 0.58 (0.33–1.04) and 0.35 (0.18–0.70) for macrovascular, microvascular and metabolic complications, respectively, compared to intermediate/long-acting HI users. PS analyses supported these findings.ConclusionsThe use of glargine is associated with a lower risk of macrovascular complications compared with traditional basal insulins. However, limitations inherent to the study design including the short length of observation and the lack of data on metabolic control or diabetes duration, do not allow us to consider this association as a proof of causality.

This study aims to assess use of hormone therapy (HT) after cervical cancer treatment in women of premenopause age.We identified 837 women aged 45 years or younger at diagnosis of cervical cancer in the Swedish Cancer Register from January 1, 2005 to September 30, 2009 with a minimal follow-up of 1.5 years. Information on cancer treatment (surgical operation, radiotherapy, and/or chemotherapy) was obtained through the National Patient Register. Use of HT was estimated through HT dispensing during follow-up as recorded in the Prescribed Drug Register. Percentage of recommended dose was assessed by frequency of HT dispensing at half-year intervals up to April 1, 2011 or a maximal age of 50 years.A total of 257 women (31%) received acute estrogen deprivation due to bilateral salpingo-oophorectomy and/or radiotherapy. Among these women, 171 (67%) of 257 had at least one dispensing of HT during the period 0.5 to 1 year after diagnosis, and 118 (46%) of 257 were dispensed 75% or more of the recommended dose. Proportion users decreased to 39% at 4.5 to 5 years after diagnosis (21% with ≥ 75% of the recommended dose). Women younger than 40 years had a higher prevalence of HT use at 0.5 to 1 year (79%), decreasing to 45% after 4.5 to 5 years. The results did not vary by cancer histology.Fewer than half of cervical cancer survivors with therapy-induced early menopause used HT at or close to the recommended dose, and the use decreased during follow-up. Increased awareness of the health benefits of HT for this patient group is needed among professionals and women.

Abstract Purpose/methods The determination of tumour biomarkers is paramount to advancing personalized medicine, more so in rare tumours like medullary thyroid carcinoma (MTC), whose diagnosis is still challenging. The aim of this study was to identify non-invasive circulating biomarkers in MTC. To achieve this goal, paired MTC tissue and plasma extracellular vesicle samples were collected from multiple centres and microRNA (miRNA) expression levels were evaluated. Results The samples from a discovery cohort of 23 MTC patients were analysed using miRNA arrays. Lasso logistic regression analysis resulted in the identification of a set of circulating miRNAs as diagnostic biomarkers. Among them, miR-26b-5p and miR-451a, were highly expressed and their expression decreased during follow-up in disease-free patients in the discovery cohort. Circulating miR-26b-5p and miR-451a were validated using droplet digital PCR in a second independent cohort of 12 MTC patients. Conclusion This study allowed the identification and validation of a signature of two circulating miRNAs, miR-26b-5p and miR-451a, in two independent cohorts reporting a significant diagnostic performance for MTC. The results of this study offer advancements in molecular diagnosis of MTC proposing a novel non-invasive tool to use in precision medicine.

This work aims to study the effects of hormone therapy (HT) on the risk of cardiovascular outcomes and all-cause mortality in women treated with statins.We included women aged 40 to 74 years and living in Sweden who filled a first statin prescription between 2006 and 2007. Women were categorized as HT users or as nonusers. Information on dispensed drugs, comorbidity, cardiovascular outcomes, and all-cause mortality was obtained from national health registers.A total of 40,958 statin users--2,862 (7%) HT users and 38,096 nonusers--were followed for a mean of 4.0 years. In total, 70% of the women used statins as primary prevention. Among HT users, there were five cardiovascular deaths per 10,000 person-years. The corresponding rate among nonusers was 18, which yielded a hazard ratio of 0.38 (95% CI, 0.12-1.19). The all-cause mortality rates were 33 and 87, respectively, and the hazard ratio was 0.53 (95% CI, 0.34-0.81). There were no associations with cardiovascular events. A similar pattern was found for both primary and secondary prevention.HT is associated with a reduced risk of all-cause mortality in women treated with statins. Although confounding factors, such as lifestyle and disease severity, might have influenced the results, HT does not seem to be detrimental to statin-treated women.

The antidiabetic sodium-glucose cotransporter type 2 inhibitor (SGLT2i) empagliflozin efficiently reduces heart failure (HF) hospitalization and cardiovascular death in type 2 diabetes (T2D). Empagliflozin-cardioprotection likely includes anti-inflammatory effects, regardless glucose lowering, but the underlying mechanisms remain unclear. Inflammation is a primary event in diabetic cardiomyopathy (DCM) and HF development. The interferon (IFN)γ-induced 10-kDa protein (IP-10/CXCL10), a T helper 1 (Th1)-type chemokine, promotes cardiac inflammation, fibrosis, and diseases, including DCM, ideally representing a therapeutic target. This preliminary study aims to explore whether empagliflozin directly affects Th1-challenged human cardiomyocytes, in terms of CXCL10 targeting. To this purpose, empagliflozin dose-response curves were performed in cultured human cardiomyocytes maintained within a Th1-dominant inflammatory microenvironment (IFNγ/TNFα), and CXCL10 release with the intracellular IFNγ-dependent signaling pathway (Stat-1) was investigated. To verify possible drug-cell-target specificity, the same assays were run in human skeletal muscle cells. Empagliflozin dose dependently inhibited CXCL10 secretion (IC50 = 76,14 × 10-9 M) in association with Stat-1 pathway impairment only in Th1-induced human cardiomyocytes, suggesting drug-selective cell-type-targeting. As CXCL10 plays multifaceted functions in cardiac remodeling toward HF and currently there is no effective method to prevent it, these preliminary data might be hypothesis generating to open new scenarios in the translational approach to SGLT2i-dependent cardioprotection.

Purpose To describe the characteristics of new users of cilostazol in Europe with the aim to support the evaluation of its benefit/risk as used in regular clinical practice before the implementation of labeling changes recommended by the European Medicines Agency. Methods New users of cilostazol were identified in populations enrolled in five European health automated databases in the UK (The Health Improvement Network [THIN]), Spain (EpiChron cohort and Information System for the Improvement of Research in Primary Care [SIDIAP]), Sweden (National Registers), and Germany (German Pharmacoepidemiological Research Database [GePaRD]) between 2002 and 2012. New users were characterized according to the prevalence of cardiovascular disease and other comorbidities, concurrent use of interacting medications, new contraindications, duration of use, and potential off-label prescribing. Results We identified 22 593 new users of cilostazol. The median age was between 68.0 (THIN) and 73.7 (Sweden) years. More than 78% of users had concomitant cardiovascular disease, and between 78.8% (GePaRD) and 91.6% (THIN) were treated with interacting medications. Prevalence of new cardiovascular contraindications ranged from 1.5% (THIN) to 11.6% (GePaRD), and concurrent use of two or more antiplatelet drugs ranged from 6.3% (SIDIAP) to 13.5% (EpiChron cohort). Between 39.4% (Sweden) and 52.9% (THIN) of users discontinued cilostazol in the first 3 months. Between 41.0% (SIDIAP) and 93.4% (THIN) were considered to have received cilostazol according to the European Medicines Agency labeling. Conclusions In this collaborative European study, most cilostazol users were elderly patients with a high prevalence of cardiovascular diseases and other comorbidity and concurrent use of interacting drugs, indicating that this is a vulnerable population at high risk of complications, especially cardiovascular events. © 2017 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Scarce data are available on the epidemiological trend of diverticulitis and its financial burden in Italy. The aim of this work was to explore a potential variation in the rate and costs of hospital admissions for uncomplicated and complicated diverticulitis over the last decade.We selected all hospitalizations for diverticulitis of residents in the Abruzzo Region, Italy between 2005 and 2015. Age-standardized hospitalization rates (HRs) per 100,000 inhabitants for overall, uncomplicated and complicated diverticulitis were calculated. A linear model on the log of the age-standardized rates was used to calculate annual percentage changes (APC). Costs were derived from the official DRG tariff.From 2005 to 2015, the HR for acute diverticulitis increased from 38.9 to 45.2 per 100,000 inhabitants (APC + 1.9%). The HR for complicated diverticulitis increased from 5.9 to 13.3 (APC + 7.6%), whereas it remained stable for uncomplicated diverticulitis. The mean hospital cost was 1.8-times higher for complicated diverticulitis compared with that for uncomplicated disease and 3.5-times higher for patients with a surgery stay compared with that for patients with a medical stay.During the last decade, in the Abruzzo Region, the HRs for diverticulitis and their costs increased significantly, mainly due to disease complications. Further studies are needed to explore strategies to prevent complications and to realise cost-saving policies.

Eur J Clin Invest 2012; 42 (10): 1068–1078 Abstract Background In many countries, the introduction of generic proton pump inhibitors (PPIs) onto the pharmaceutical market increased the phenomenon of therapeutic substitution in acid‐related disorders (ARDs). Aim To investigate the treatment of ARDs in an Italian primary care setting from 2005 to 2008 by verifying: (i) dynamics of PPI prescribing; (ii) predictors of PPI switching; and (iii) healthcare resource consumption costs. Methods This was a retrospective cohort study of 102 general practitioners (GPs) who managed an average of 150 000 inhabitants in Naples. Multilevel logistic regression was used to assess the potential predictors of both PPI switching and termination. Primary care costs were expressed as the cost of ARD management per PPI user year. Results The percentage of PPI users with ARD increased from 5·5% (2005) to 7·0% (2008) ( P &lt; 0·0001), especially for dyspepsia (from 9·5% to 13·7%; P &lt; 0·0001) and chronic treatments (from 23·4% to 29·4%; P &lt; 0·0001). PPI switching rose from 13·0% to 16·7% during the period observed ( P &lt; 0·0001). Calendar years, long‐term treatments and gastroesophageal reflux disease were positive predictors of PPI switching. Primary care costs relating to PPI switchers increased by 61·14€ compared with nonswitchers ( P &lt; 0·0001). Conclusions The introduction of generic PPIs onto the Italian market was associated with an increasing amount of PPI prescribing related to chronic treatments, unlicensed indications (e.g. dyspespsia) and therapeutic substitutions. Growing overall costs linked to the phenomenon of PPI switching was also found. Our data support the need to assess the effects of the introduction of generic drugs on both clinical outcomes and the cost management of ARDs.

Objective This work aims to determine whether discontinuation of hormone therapy (HT) in perimenopausal and postmenopausal women is associated with an increased risk of initiating antidepressant therapy. Methods A population-based cohort study was conducted using data from the Swedish Prescribed Drug Register and the Total Population Register for the period July 2005 to June 2009. We included women aged 45 to 70 years who had used HT continuously for more than 6 months before July 2008. Women with previous use of antidepressants since July 2005 were excluded. We compared the incidence rates of initiating antidepressant therapy during HT and after withdrawal of HT. The women were followed from July 2008 until the first dispensing of antidepressants, restart of HT, migration, death, or end of the study period, whichever occurred first. Poisson regression analysis was used to estimate the incidence rate ratios adjusting for potential confounders (age, calendar time, duration of HT use, and number of HT prescriptions). Results Of the 101,911 women enrolled in the cohort, 39.8% discontinued HT during follow-up. Discontinuation of HT was associated with an increased risk of antidepressant use (incidence rate ratio, 1.24; 95% CI, 1.11-1.38). Women 65 years or older and women who had used HT for 3 years or more had the highest risk estimates, but effect modification by age and duration was not significant. Conclusions We found a slightly increased risk in the use of antidepressant therapy after discontinuation of HT.

Background: Due to the success of antiretroviral therapy, human immunodeficiency virus (HIV) infection has been transformed into a lifelong condition. In Italy, little is known about the impact of comorbidities (CMs) on the risk of hospitalization and related costs for people who live with HIV (PWLHIV). The objective of the study was to quantify the risk of hospitalization and costs associated with CMs in an Italian cohort of PWLHIV. Methods: The study population included subjects aged ≥18 years with HIV infection, identified in the Abruzzo’s hospital discharge database among files stored from 2004 until 2013 and then followed up until December 2015. Patients’ CMs (Charlson Comorbidity Index [CCI)] were extracted from International Classification of Diseases, Ninth Revision, Clinical Modification codes in the hospital discharge abstracts. Poisson regression was used to compare the incidence rate of hospital admissions in patients with and without each CM class. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were adjusted for age, sex and the other CMs. A generalized linear model under gamma distribution was used to estimate adjusted mean hospital costs. Costs were derived from official Italian Diagnosis-related group (DRG) based reimbursements. Results: Among 1,026 HIV patients identified (mean age 47 years), 30% had at least one CM and 14.5% underwent hospital admission during the follow-up period. The risk of acute hospitalization significantly increased among patients with hepatitis C virus (HCV) coinfection (adjusted IRR 1.98; 95% CI: 1.59–2.47), renal (adjusted IRR 2.27; 95% CI: 1.45–3.56), liver (adjusted IRR 2.21; 1.57–3.13) and chronic pulmonary CMs (adjusted IRR 2.31; 1.63–3.32). Adjusted mean hospital costs were €2,494 in patients without CMs and €4,422 and €9,734 in those with CCI=1 or CCI ≥2, respectively. Conclusion: The presence of renal, liver and chronic pulmonary CMs, as well as HCV coinfection doubled the risk of hospitalization in the PWLHIV cohort. A CCI ≥2 is associated with a fourfold increase in hospitalization costs. Our study provides new evidence that CMs in PWLHIV increase the risk of hospitalization and local health service facilities. Keywords: HIV, comorbidity, hospitalization, real-world data, inpatient cost, administrative data Corrigendum for this paper has been published

Abstract Background Rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are autoimmune disorders associated with an increased risk for depression, anxiety and sleeping problems. The objective of this study was to analyze use of antidepressants and benzodiazepine-related hypnotics (BRH) in Sweden before and after first time treatment with anti-TNF and non-biological systemic (NBS) treatments among patients with the above diagnoses, and to correlate such use with that of randomly selected population controls. Methods Patients and dispensed drugs were identified in nationwide Swedish healthcare registers. Proportions of subjects filling prescriptions of antidepressants and BRH from 2 years before start of treatment (index-date), and 2 years after index date were assessed. Using the period -6 months to index-date as reference, prevalence rate ratios were computed for 6 months’ intervals before and after index. For up to ten randomly selected population controls per patient, the same measures were calculated. Results A total of 6256 patients started anti-TNF treatment, and 13,241 NBS treatment. The mean age at index was 52.0 for the anti-TNF group and 56.1 for NBS. Use of antidepressants and BRH was similar in both treatment groups (10.4–12.8%), significantly more common than in the controls (6.6 to 7.6%). For all patients, proportions filling prescriptions for antidepressants and BRH decreased directly or soon after the index; no such changes were seen in the controls, who all showed a slow but steady increase in use over time. Starters of anti-TNF treatment did not show clearer decreases in use of psychotropics than those initiating NBS. Conclusions Decreased rates of dispensed psychotropic drugs after the time of anti-TNF and NBS treatment initiation were seen among patients with autoimmune disorders but not population controls. This may correspond to treatment effects of anti-TNF and NBS also on psychiatric symptoms among these patients.

Medullary thyroid carcinoma (MTC) is a malignant tumor with challenging management. Multi-targeted kinase inhibitors (MKI) and tyrosine-kinase inhibitors (TKI) with high specificity for RET protein are approved for advanced MTC treatment. However, their efficacy is hindered by evasion mechanisms of tumor cells. Thus, the aim of this study was the identification of an escape mechanism in MTC cells exposed to a highly selective RET TKI. TT cells were treated with TKI, MKI, and/or the HH-Gli inhibitors, GANT61 and Arsenic Trioxide (ATO), in the presence or absence of hypoxia. RET modifications, oncogenic signaling activation, proliferation and apoptosis were assessed. Additionally, cell modifications and HH-Gli activation were also evaluated in pralsetinib-resistant TT cells. Pralsetinib inhibited RET autophosphorylation and RET downstream pathways activation in normoxic and hypoxic conditions. Additionally, pralsetinib impaired proliferation, induced the activation of apoptosis and, in hypoxic cells, downregulated HIF-1α. Focusing on escape molecular mechanisms associated with therapy, we observed increased Gli1 levels in a subset of cells. Indeed, pralsetinib stimulated the re-localization of Gli1 into the cell nuclei. Treatment of TT cells with both pralsetinib and ATO resulted in Gli1 down-regulation and impaired cell viability. Moreover, pralsetinib-resistant cells confirmed Gli1 activation and up-regulation of its transcriptionally regulated target genes. Altogether, we showed that pralsetinib impairs MTC cell growth and induces cell death, also in hypoxic conditions. The HH-Gli pathway is a new molecular mechanism of escape to pralsetinib therapy that can be overcome through combined therapy.

Real-world data on the therapeutic management of hepatic encephalopathy (HE) patients are limited. The aim of this study was to evaluate the HE medications prescribed in an Italian cohort of HE patients post-discharge and to assess the real-world rifaximin adherence and persistence over 1 year. An observation retrospective study was conducted using data retrieved from outpatient pharmaceutical databases and hospital discharge records of the Campania region. For all subjects hospitalized for HE during 2019 (cohort 1), the HE medications prescribed within 60 days after discharge were evaluated. Adherence (proportion of days covered, PDC) and persistence were estimated for rifaximin 550 mg incident users over 1 year (cohort 2). Patients with PDC ≥80% were considered adherents. Persistence was defined as the period of time from the first rifaximin prescription to the date of discontinuation. Discontinuation was assessed using the permissible gap method. In cohort 1, 544 patients were identified; 58.5% received rifaximin while 15.6% only received non-absorbable disaccharides and 25.9% did not receive any HE medications. In cohort 2, 650 users were selected; only 54.5% were adherents and 35% were persistent users at 1 year. This real-world study highlights that quality improvement in therapeutic management is needed to potentially improve the outcomes of HE patients.

Few studies are available evaluating the impact of rapid-acting insulin analogues on long-term diabetes outcomes. Our aim was to compare the use of rapid-acting insulin analogues versus human regular insulin in relation to the occurrence of diabetic complications in a cohort of diabetic patients through the analysis of administrative databases.A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients free of macrovascular disease at baseline and treated either with human regular insulin or rapid-acting insulin analogues were followed for a maximum of 3 years. The incidence of diabetic complications was ascertained by hospital discharge claims. Hazard ratios (HRs) and 95% CIs of any diabetic complication and macrovascular, microvascular and metabolic complications were estimated separately using Cox proportional hazard models adjusted for patients' characteristics and anti-diabetic drug use. Propensity score matching was also used to adjust for significant difference in the baseline characteristics between the two treatment groups.A total of 2,286 patients were included: 914 receiving human regular insulin and 1,372 rapid-acting insulin analogues. During the follow-up, 286 (31.3%) incident events occurred in the human regular insulin group and 235 (17.1%) in the rapid-acting insulin analogue group. After propensity score-based matched-pair analyses, rapid-acting insulin analogues users had a HR of 0.73 (0.58-0.92) for any diabetes-related complication and HRs of 0.73 (0.55-0.93) and 0.55 (0.32-0.96) for macrovascular and metabolic complications respectively, as compared with human regular insulin users. No difference between the two groups was found for microvascular complications.Our findings suggest that the use of rapid-acting insulin analogues is associated with a lower risk of cardiovascular and metabolic complications compared with human regular insulin use.

Background & aims Hepatitis C (HCV) is associated with several extrahepatic manifestations, and estimates of the hospitalization burden related to these comorbidities are still limited. The aim of this study is to quantify the hospitalization risk associated with comorbidities in an Italian cohort of HCV-infected patients and to assess which of these comorbidities are associated with high hospitalization resource utilization. Methods Individuals aged 18 years and older with HCV-infection were identified in the Abruzzo’s and Campania’s hospital discharge abstracts during 2011–2014 with 1-year follow-up. Cardio-and cerebrovascular disease, diabetes and renal disease were grouped as HCV-related comorbidities. Negative binomial models were used to compare the hospitalization risk in patients with and without each comorbidity. Logistic regression model was used to identify the characteristics of being in the top 20% of patients with the highest hospitalization costs (high-cost patients). Results 15,985 patients were included; 19.9% had a liver complication and 48.6% had one or more HCV-related comorbidities. During follow-up, 36.0% of patients underwent at least one hospitalization. Liver complications and the presence of two or more HCV-related comorbidities were the major predictors of hospitalization and highest inpatient costs. Among those, patients with cardiovascular disease had the highest risk of hospitalization (Incidence Rate Ratios = 1.42;95%CI:1.33–1.51) and the highest likelihood of becoming high-cost patients (Odd Ratio = 1.37;95%CI:1.20–1.57). Conclusion Beyond advanced liver disease, HCV-related comorbidities (especially cardiovascular disease) are the strongest predictors of high hospitalization rates and costs. Our findings highlight the potential benefit that early identification and treatment of HCV might have on the reduction of hospitalization costs driven by extrahepatic conditions.

Hepatitis C virus (HCV) infection remains a pressing public health issue. Our aim is to assess the linkage to care of patients with HCV diagnosis and to support the proactive case-finding of new HCV-infected patients in an Italian primary care setting. This was a retrospective cohort study of 44 general practitioners (GPs) who managed 63,955 inhabitants in the Campania region. Adults with already known HCV diagnosis or those with HCV high-risk profile at June 2019 were identified and reviewed by GPs to identify newly diagnosed of HCV and to assess the linkage to care and treatment for the HCV patients. Overall, 698 HCV patients were identified, 596 with already known HCV diagnosis and 102 identified by testing the high-risk group (2614 subjects). The 38.8% were already treated with direct-acting antivirals, 18.9% were referred to the specialist center and 42.3% were not sent to specialist care for treatment. Similar proportions were found for patients with an already known HCV diagnosis and those newly diagnosed. Given that the HCV infection is often silent, case-finding needs to be proactive and based on risk information. Our findings suggested that there needs to be greater outreach, awareness and education among GPs in order to enhance HCV testing, linkage to care and treatment.

In the era of personalized medicine, fetal sex-specific research is of utmost importance for comprehending the mechanisms governing pregnancy and pregnancy-related complications. In recent times, noncoding RNAs (ncRNAs) have gained increasing attention as critical players in gene regulation and disease pathogenesis, and as candidate biomarkers in human diseases as well. Different types of ncRNAs, including microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), participate in every step of pregnancy progression, although studies taking into consideration fetal sex as a central variable are still limited. To date, most of the available data have been obtained investigating sex-specific placental miRNA expression. Several studies revealed that miRNAs regulate the (patho)-physiological processes in a sexually dimorphic manner, ensuring normal fetal development, successful pregnancy, and susceptibility to diseases. Moreover, the observation that ncRNA profiles differ according to cells, tissues, and developmental stages of pregnancy, along with the complex interactions among different types of ncRNAs in regulating gene expression, strongly indicates that more studies are needed to understand the role of sex-specific ncRNA in pregnancy and associated disorders.

Diabetic nephropathy is the most frequent cause of end stage renal disease (ESRD). As ESRD incidence increases continuously, more resources are needed for treatment. The objective was to evaluate the economic impact of losartan added to the standard care administered to diabetic subjects with ESRD. The analysis has involved more than 500 million inhabitants. Standard methods have been used in order to conduct an economic evaluation comparing the economic outcomes deriving from the administration of losartan added to standard care versus standard care alone in patients with type 2 diabetes mellitus (DM) and nephropathy over 3.4 years. The study was hence conducted from the perspective of the third-party payer. The clinical outcome data were based on the results from the Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial. Direct medical costs are referred to the purchase costs of losartan and to the costs of hospitalization. The costs were discounted back at an annual rate of 3%. Also sensitivity analysis was performed. The RENAAL study showed that losartan confers strong renal protection in patients with DM and nephropathy. Losartan results into cost saving in all countries considered: 3 602.98€/Italy, 4 531.35€/France, 3 019.66€/Germany, 3 949.50€/Switzer-land, and 3 855.50€/US per patient. Results are not sensitive to both clinical and economic variables. In addition to the medical benefits, this analysis demonstrates the economic relevance of the treatment with losartan in DM patients affected by nephropathy.

Pericardial malignant mesothelioma (MM) is a rare tumour which accounts for about 1% of all mesotheliomas, 4% of the primary heart and pericardial tumours. It carries an extremely poor prognosis, with a reported overall survival of less than 6 months. Clinical symptoms and signs are frequently nonspecific, and the diagnosis is usually made after surgery or at autopsy. We report a case of a 72 years old woman with primary pericardial malignant mesothelioma involving the right atrium. Nine months following surgery, the patient is alive with good performance status.

Pediatric low-grade gliomas (pLGGs), particularly incompletely resected supratentorial tumours, can undergo progression after surgery. However to date, there are no predictive biomarkers for progression. Here, we aimed to identify pLGG-specific microRNA signatures and evaluate their value as a prognostic tool.We identified and validated supratentorial incompletey resected pLGG-specific microRNAs in independent cohorts from four European Pediatric Neuro-Oncology Centres.These microRNAs demonstrated high accuracy in differentiating patients with or without progression. Specifically, incompletely resected supratentorial pLGGs with disease progression showed significantly higher miR-1248 combined with lower miR-376a-3p and miR-888-5p levels than tumours without progression. A significant (p < 0.001) prognostic performance for miR-1248 was reported with an area under the curve (AUC) of 1.00. We also highlighted a critical oncogenic role for miR-1248 in gliomas tumours. Indeed, high miR-1248 levels maintain low its validated target genes (CDKN1A (p21)/FRK/SPOP/VHL/MTAP) and consequently sustain the activation of oncogenic pathways.Altogether, we provide a novel molecular biomarker able to successfully identify pLGG patients associated with disease progression that could support the clinicians in the decision-making strategy, advancing personalized medicine.

Since its approval in Italy in 1987, rifaximin has been licensed in over 30 countries for the treatment of a wide range gastrointestinal diseases. The aim of the study was to analyze the real world use of rifaximin 200 mg in the Campania region.An observation retrospective study was conducted analysing the prescriptions of rifaximin received by the subjects ≥18 years old resident in the Campania Region. For each user the first rifaximin prescription in 2019 was defined as index date. All the prescriptions during the 12 months following the index date were analyzed. The subjects were categorized according to the number of packages/year received (1-4, 5-12, 13-24, >24).231,207 subjects received at least one package/year of rifaximin 200 mg with a prevalence of use of 4.9% and a total annual expenditure of 9.2 million euros. The 73.9% of users received 1-4 packages/year, 16.4% between 5-12 packages/year and 7.7% between 13-24 packages/year. The 2.0% of the users received more than 24 packages/year with an incidence on total expenditure equal to 14.8% (5% is due to those who received more than 40 packages/year).About two thirds of rifaximin users received no more than three packages, presumably for the treatment of the infectious gastroenteritis or diarrheal syndromes, while 24% received 5-24 packages/year probably for the relapsing chronic intestinal pathologies. The 15% of the expenditure and consumption is related to subjects receiving more than 24 packages/year, probably due to the treatment of chronic liver diseases.The use of rifaximin 200 mg should be further investigated in different recurrent chronic diseases, especially to verify which schemes and dosages are used in real life compared to those tested in clinical trials.

Abstract Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine tumour whose diagnosis includes evaluating calcitonin serum levels, which can present fluctuations unrelated to MTC. Here, we investigated circulating DNA fragmentation and methylation changes as potential biomarkers using ddPCR on cell-free DNA (cfDNA) isolated from the plasma of MTC patients. For cfDNA fragmentation analysis, we investigated the fragment size distribution of a gene family and calculated short fragment fraction (SFF). Methylation analyses evaluated the methylation levels of CG_16698623, a CG dinucleotide in the MGMT gene that we found hypermethylated in MTC tissues by analyzing public databases. The SFF ratio and methylation of CG_16698623 were significantly increased in plasma from MTC patients at diagnosis, and patients with clinical remission or stable disease at follow-up showed no significant SFF difference compared with healthy subjects. Our data support the diagnostic value of cfDNA traits that could enable better management of MTC patients.

A study on the coverage of influenza vaccination among elderly people was carried out. Fity-six per cent of those interviewed had been vaccinated (weighted coverage 50%), compared with the target of 75%, but higher rates were reported in those older than 74 years and those with chronic diseases.

Low back pain is one of the most frequent causes of consultation of the General Practitioner (GP). The purpose of the present study is to analyze the therapeutic management of low back pain, in relation to pain intensity, in the primary care setting and to assess its impact on the patient's quality of life.From the computerized medical records of 65 GPs, all working in the Salerno province (South of Italy), data concerning non-cancer subjects affected by low back or sciatica pain, over 18 years, who consulted the GP in the period between February 1, 2015 and January 31, 2016, were extracted. Pain intensity and quality of life were reported using the 0-10 numeric rating scale (NRS) and the EQ-5D instruments, respectively.A total of 2555 subjects were identified: 28.7% reported mild pain (NRS 0-3), 55.6% moderate pain (NRS 4-6) and 15.7% severe pain (NRS 7-10). Only 35% of patients received a prescription for pain therapy (24.5% in mild pain; 34.1% in moderate pain and 57.1% in severe pain); non-steroidal anti-inflammatory drugs in monotherapy were the most prescribed therapeutic category regardless of pain intensity (61.1% in mild pain, 65.1% in moderate pain and 57.6% in severe pain, p=0.099), followed by strong opioids (17.2%, 15.3% and 24.5%, p=0.011). Overall, mean value for EQ-5D utility was 0.44 (0.61 in mild pain, 0.47 in moderate pain, 0.22 in severe pain).The results of this study highlight that low back pain is a highly debilitating condition, probably still under-treated or inadequately treated by the GP.

To quantify the annual healthcare resource utilization, costs and mortality rate for a large cohort of Italian patients with compensated (CC) and decompensated cirrhosis (DC).A population-based cohort study was conducted through the data-linkage of mortality for all-cause, hospitalizations and outpatient drugs and service databases of the Campania Region. All adults hospitalized with cirrhosis diagnosis (2007-2015) were grouped in CC and DC (prevalent patients) on January 1, 2016 and followed for 1-year. Incident patients with DC (2015) were also retrieved and followed from discharge date up to 1-year. Negative binomial regression was used to estimate Incidence Rate Ratios (IRRs) for predictors of all-cause hospitalizations. Costs were evaluated from the Italian National Health Service perspective and expressed in euro patient/year.A total of 21,433 prevalent cirrhotic patients (57.1% CC and 42.9% DC) and 1,371 incident patients with DC were identified. During a 1-year, 21.5% of prevalent patients with CC were admitted for acute events, 26.8% of those with DC and 55.4% of incident patients with DC. Ascites (IRR=1.71;95% CI: 1.37-2.14) and hepatic encephalopathy (IRR=1.35; 95% CI: 1.04-1.77) at index admission were strong predictors of hospitalizations in incident DC patients. The 1-year mortality rate was respectively 5.8% and 10.1% for prevalent patients with CC and DC and 35.6% for incident patients with DC. Direct costs amounted to 3,194€ patient/year for the prevalent CC group and 4,001€ patient/year for the DC group and 13,806 € patient/year for incident individuals with DC.The burden of cirrhosis dramatically differs between CC and DC patients, especially after the first decompensation episode. Ascites and hepatic encephalopathy at index admission were strong predictors of hospitalizations in incident DC patients.

Changes in HIV treatment guidelines over the last two decades reflect the evolving challenges in this field. Our study examined treatment change patterns throughout a 7-year period in a large Italian cohort of HIV patients as well as the reasons and direction of changes. Treatment-naïve and -experienced HIV patients managed by Cotugno Hospital of Naples between 2014 and 2020 were analyzed. During the period, the proportion of single-tablet regimen treatment sharply increased for the naïve and experienced patients. Regimens containing integrase strand transfer inhibitors rapidly replaced those containing protease inhibitor and non-nucleoside reverse transcriptase inhibitors. The use of the tenofovir alafenamide fumarate/emtricitabine backbone increased rapidly after its introduction in the Italian pharmaceutical market, making up 63.7 and 54.9% of all treatments in naïve and experienced patients, respectively, in 2020. The main reason for treatment changes was optimization and/or simplification (90.6% in 2018; 85.3% in 2019; 95.5 in 2020) followed by adverse effects and virological failure. Our real-world analysis revealed that the majority of treatment-naïve and treatment-experienced patients received antiretroviral drugs listed as preferred/recommended in current recommendations. Regimen optimization and/or simplification is a leading cause of treatment modification, while virologic failure or adverse effects are less likely reasons for modification in the current treatment landscape.

Non-valvular atrial fibrillation (NVAF) is the most common cardiac arrhythmia and it is associated with a 5-fold increase in risk of ischemic stroke. Although clinical guidelines recommend antithrombotic therapy for stroke prevention in patients at moderate or high risk for stroke, little is known on the extent to which the increase of the risks influence the choice of the therapy.The aim of the study was to assess the level of adherence to the guidelines for the prevention of thromboembolic risk in patients with NVAF.A population-based cohort study was conducted using administrative data from a local health authority in the Campania Region (~1,000,000 inhabitants). NVAF was defined as one or more claims for atrial fibrillation between July, 2013 and June, 2014 where none of the claims were associated with cardioversion or cardiac ablation during the identification period and there was no evidence of valve-related diagnoses or procedures. The cohort was classified according to the first drug dispensing during 6 months from the discharge date for atrial fibrillation. Patients were categorized in low ischemic stroke risk (LR, score = 0), moderate-risk (MR, score = 1), high-risk (HR, score≥2) according to the CHA2DS2-VASc score. Multivariable logistic regression was used to evaluate the associations between ischemic stroke risk with the choice of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) therapy.A total of 1963 patients were identified: 4.9% LR, 7.6% MR and 87.5% HR patients. Overall, 36.4% of patients were not treated (LR: 56.7%, MR: 55.0%, HR: 33.7%patients). The Vitamin K antagonists were prescribed to 17% of the patients (LR: 10.3%, MR: 12,1%, HR: 17,8%), NOAC to 12,7% (LR: 10,3%, MR: 8,1%, HR: 13,2%), low-dose aspirin to 17.5% (LR: 13,4%, MR: 15,4%, HR: 17,9%), other antiplatelet to 12,3% (LR: 7,2%, MR: 6,0%, HR: 13,2%). The ischemic stroke was not significantly associated with the choice of anticoagulant drug.High proportion of NVAF patients with CHA2DS2-VASc score of 2 or greater not received oral anticoagulant as recommended. In contrast with recent guidelines, aspirin was commonly prescribed even in HR patients. The stroke risk stratification did not influence the choice of anticoagulant drug.

Introduction: cardiovascular diseases are the most common reason of mortality and morbidity in the world, despite therapeutic interventions have improved patients’ prognosis in the last decades. Aggressive lipid lowering treatment with atorvastatin has demonstrated to be effective in preventing the occurrence of new cardiovascular events requiring hospitalizations, in patients previously affected by coronary syndromes. However, the increasing costs of managing cardiovascular diseases impose a careful analysis of the economic benefits of these therapies. Objective: to assess the economic sustainability of using atorvastatin for the secondary prevention of cardiovascular events. Material and Methods: we derived clinical information from five randomized, multicenter trials (AVERT, IDEAL, MIRACL, PROVE-IT, TNT) evaluating efficacy and tolerability of high dosage treatment with atorvastatin over control groups in different patient populations and for different follow up periods. A costeffectiveness analysis in the perspective of the NHS has been performed, under the hypothesis of the imminent price reduction of atorvastatin, due to the loss of exclusivity. Results: in trials AVERT, MIRACL, PROVE IT, the treatment with atorvastatin has demonstrated to reduce both cardiovascular events and overall healthcare direct costs, compared to the respective control groups. In trials IDEAL and TNT, the therapy with atorvastatin has resulted to be cost effective, with incremental cost-effectiveness ratio respectively of € 6,310 for avoided event (vs simvastatin 10 mg) and € 9,058 for CV disease free patient (vs atorvastatin 10 mg). Discussion: the present study represents an update of previous cost-effectiveness analyses, which have previously evaluated the economic consequences of using atorvastatin for the secondary prevention of cardiovascular events. The present analysis has proved the economic benefits deriving from the usage of atorvastatin, which is a dominant alternative in the AVERT, MIRACL and PROVE-IT clinical settings, and a cost effective option in the IDEAL and TNT study populations.

Current international guidelines strongly recommend the use of high-intensity lipid-lowering therapy (LLT) after hospitalization for atherosclerotic cardiovascular disease (ASCVD) events. With this study, our aim was to evaluate LLT prescribing in a large Italian cohort of patients after discharge for an ASCVD event, exploring factors associated with a lower likelihood of receiving any LLT and high-intensity LLT. Individuals aged 18 years and older discharged for an ASCVD event in 2019-2020 were identified using hospital discharge abstracts from two local health units of the Campania region. LLT treatment patterns were analyzed in the 6 months after the index event. Logistic regression models were developed for estimating patient predictors of any LLT prescription and to compare high-intensity and low-to-moderate-intensity LLT. Results: A total of 8705 subjects were identified. In the 6 months post-discharge, 56.7% of patients were prescribed LLT and, of those, 48.7% were high-intensity LLT. Female sex, older age, and stroke/TIA or PAD conditions were associated with a higher likelihood of not receiving high-intensity LLT. Similar predictors were found for LLT prescriptions. LLT utilization and the specific use of high-intensity LLT remain low in patients with ASCVD, suggesting a substantial unmet need among these patients in the contemporary real-world setting.

In this study we compare the cost-effectiveness of saxagliptin (Onglyza®) in combination with metformin to that of either sulphonylurea (SU) plus metformin or a thiazolidinedione (TZD) plus metformin, in type 2 diabetes mellitus patients who are not well-controlled on metformin alone. By using decision-analytic modeling, long-term costs and health outcomes associated with the investigated treatment strategies are estimated. This is achieved by modeling the risk of experiencing diabetes-related events (e.g. myocardial infarction) or side-effects such as hypoglycemia and weight gain. The risk of these events depends on baseline characteristics as well as risk factors (which can be altered by the treatment strategies). Ultimately, costs (NHS perspective) and quality-adjusted life years (QALYs) for each treatment strategy are based on the occurrence of these events. Based on these estimates incremental cost-effectiveness ratios (cost per QALYs) are calculated. In the analysis comparing saxagliptin + metformin with SU + metformin in 1,000 patients in a 40 years time horizon, the total QALY gain with saxagliptin + metformin is 111. The incremental cost with saxagliptin + metformin is € 1,300,000, resulting in a total cost per QALY gained with saxagliptin + metformin of € 11,800 in the base case scenario. Similarly, the comparison with TZD + metformin resulted in a total QALY gain with saxagliptin + metformin of 127, with an incremental cost of € 144,000, resulting in a total cost per QALY gained with saxagliptin + metformin of € 1,100 in the base case scenario. The results are mainly driven by differences in hypoglycemias (associated with a utility decrement and a monetary cost) and weight gain (which is associated with a utility decrement and also increases the risk for diabetes-related events). Saxagliptin + metformin is associated with small difference in macrovascular events such as myocardial infarction, congestive heart failure compared to SU or TZD plus metformin strategies, probably due to the difference of action on net weight. Since the treatment cost is higher with saxagliptin + metformin, total costs are also higher for the Onglyza®-based strategy although the higher drug cost is partially offset by the lower rate of macrovascular costs and reduced cost of severe hypoglycemias. The present analysis suggests that saxagliptin, when added to metformin, is a cost-effective treatment alternative for type 2 diabetes mellitus patients in Italy who are not well-controlled on metformin alone. Both compared to SU + metformin and TZD + metformin, the cost-effectiveness results of saxagliptin + metformin are robust to various assumptions concerning input variables. Hence, the favorable safety profile for saxagliptin, with a risk of hypoglycemia and impact on weight similar to placebo, makes it possible to increase the utility for patients since it is not reducing risk of diabetes-related events per se.

Introduction: recent clinical trials found that high-dose statin therapy, compared with conventional-dose statin therapy, reduces the risk of cardiovascular events in patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD). With the introduction of simvastatin and pravastatin generics and the next patent expiration of atorvastatin, projected for 2011 in Italy, it is natural to ask: what is the most cost-effective treatment for a rational use of resources?Aim: the aim of this study was to estimate the cost-effectiveness of high-dose atorvastatin versus conventional standard-dose statins based on the scenario of atovastatin price evolution.Methods: a cost-effectiveness analysis was conducted in the perspective of the Italian National Health Service over the 4.9 years time horizon. Clinical data were obtained from a pooled analyses of the 3 clinical trials that directly compared high-dose atorvastatin with conventional standard-dose statins in patients with either ACS or CAD. Hospitalizations were quantified based on the Italian National Health Service tariffs and drug costs according to the Italian National Therapeutic Formulary (2009). Assuming the cost of atorvastatin reduces in line with that observed for simvastatin when the patent expires, 3 scenarios were constructed: atorvastatin current price (scenario 1); 55% price discount (scenario 2); 65% price discount (scenario 3). Effects were measured in terms of primary composite endpoint (coronary death or any adverse cardiovascular event). All costs were discounted at 3% per annum. Sensitivity analyses were performed to assess the robustness of findings. Results: intensive therapy with atorvastatin provided a hospitalization cost saving of 245,519.36 € per 1,000 patients. Under the assumptions established for scenario 1 and scenario 2, the incremental cost-effectiveness of treatment with atorvastatin 80 mg was estimated to be 20,289.72 € and 917.05 € for patient free from event, respectively; it was cost-saving for the scenario 3. Conclusions: high-dose atorvastatin represented a cost-effective use of healthcare resources in Italy. If the cost of atorvastatin reduces by 65% when the patent expires, for every million patient with SCA or CAD stable, treated for 5 years, the high-dose atorvastatin strategy potentially yields a cost-saving of ~2,4 billion € for the NHS.

Abstract Purpose To estimate the risk of kidney disease in high‐potency statin users compared to those treated with low‐potency statins without history of kidney disease at statin initiation, linking the Swedish national healthcare registers and laboratory data. Methods Incident users of statins, ≥40 years of age, with estimated Glomerular Filtration Rate (eGFR) &gt;60 ml/min/1.73 m 2 and no diagnosis of kidney disease at treatment initiation were identified between 2006 and 2007 and then followed for 2‐years. The outcome was the incidence of kidney disease identified by the presence of the diagnostic code in the healthcare registers or eGFR &lt;60 ml/min/1.73 m 2 . We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with adjusted and propensity score (PS)‐matched Cox proportional hazards models. Results A total of 27 385 patients were identified, 25.2% of which treated with a high‐potency statin. During the follow‐up, 68 (0.25%) patients were identified with a diagnosis of kidney disease from the registers. The number increased to 2498 (9.1%) when the criteria of eGFR &lt;60 ml/min/1.73 m 2 was added. The adjusted HR of kidney disease in high‐potency statin users was 1.14 (95%CI 1.03–1.25) compared to low‐potency users; the result was unchanged after the PS approach. Conclusions Adding information from laboratory data to those from the national health registers, a slightly increased risk for kidney disease was found in high‐potency statin users without pre‐existing kidney disease at treatment initiation compared to those treated with low‐potency statins.

To determine the direct healthcare costs associated with non-valvular atrial fibrillation (NVAF). A population-based cohort study was conducted using administrative data from a local health authority in the Campania Region (~1,000,000 inhabitants). NVAF was defined as one or more claims for atrial fibrillation (ICD-9-CM code 427.31) between January 1, 2005 and June 30, 2014, where none of the claims was associated with cardioversion or cardiac ablation and there was no evidence of valve-related diagnoses or procedures. All patients were followed from June 30, 2014 until death or end of study follow-up (December 31, 2014). The direct costs were reported as average annualized cost (per patient per month multiplied by 12). Costs were divided into hospitalizations, outpatient services and pharmacy claims. Generalised linear mixed models under gamma distribution were used to identify predictors of cumulative healthcare costs. Rate Ratios (RRs) and 95% confidence intervals (CIs) were adjusted for age, gender, incident patients, switcher, CHA2DS2-VASc and HAS-BLED clinical risk score. Totally, 10,099 patients fulfilled our study criterions. The total annualized direct cost of NVAF patient was 1,627.9 euro ±1,076.6. The main cost component was the hospitalization (68.0%), followed by drug use (24.6%) and outpatient services (7.4%). The predictors of the total cost were male (RR: 1.37, CI: 1.29-1.45 versus female), incident (RR: 4.60, CI: 4.30-4.92 versus prevalent patient), switcher (RR: 1.88, CI: 1.72-2.06 versus no switcher), CHA2DS2-VASc score (RR: 6.34, CI:5.08-7.92 for score 7 versus score 0) and HAS-BLED (RR: 1.36, CI:1.25-1.48 for score >3 versus score ≤3). NVAF places an enormous burden on health care system. Hospitalization as major cost driver highlights the potential cost-effectiveness of disease management targeted at reducing risks of serious cerebrovascular events among NVAF patients.

To assess the level of adherence to the guidelines for the prevention of thromboembolic risk in patients with Non-Valvular Atrial Fibrillation (NVAF). A population-based cohort study was conducted using administrative data from a local health authority in the Campania Region (~1,000,000 inhabitants). NVAF was defined as one or more claims for atrial fibrillation (ICD-9-CM code 427.31) between July, 2013 and June, 2014 where none of the claims were associated with cardioversion or cardiac ablation during the identification period and there was no evidence of valve-related diagnoses or procedures. The cohort was classified according to the first drug dispensing during 6 months from the discharge date. Patients were categorized in low ischemic stroke (CHA2DS2-VASc) (LR, score=0), moderate-risk (MR, score=1), high-risk (HR, score≥2).Multivariable logistic regression was used to evaluate the associations between ischemic stroke and bleeding (HAS-BLED) risk with the choice of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) therapy. A total of 1,963 patients were identified: 4.9% LR, 7.6% MR and 87.5% HR patients. Overall, 36.4% of patients were not treated (LR: 56.7%, MR: 55.0%, HR: 33.7%patients). Among patients treated, VKA in monotherapy was prescribed to 26.7% of the patients (LR: 23.8%, MR: 26.9%, HR: 26.8%), aspirin in monotherapy to 27.5% (LR: 31.0%, MR: 34.3%, HR: 27.0%), NOAC in monotherapy to 19.3% (LR: 23.8%, MR: 17.9%, HR: 19.2%), other antiplatelet in monotherapy to 19.4% (LR: 16.7%, MR: 13,4%, HR: 19.8%), and associations to 7.1% (LR: 4.8%, MR: 7.5%, HR: 7.2%). The ischemic stroke and bleeding risks were not significantly associated with the choice of anticoagulant drug. High proportion of NVAF patients with moderate or high stroke risk did not receive antithrombotic therapy as recommended by guidelines. Moreover, aspirin was commonly prescribed even in HR patients. The risk stratification did not influence the choice of anticoagulant drug.

To assess the effectiveness of an educational patient-centered program on the reduction of Blood Pressure (BP) by a better adherence to pharmacological and non pharmacological treatment. A randomized controlled study including hypertensive patients (SBP>135 mmHg and DBP>85 mmHg) 18 years of age or older. Patients were enrolled by the Center for the Diagnosis and Treatment of Hypertension Cardarelli Hospital and were randomly assigned to Control group (C) and Intervention group (I ). Group I, in addition to the routine care, received a Patient Information Leaflet giving information on hypertension and participated to three educational group sessions (designed according to the focus group and role playing methods), respectively at 2,4 and 9 months after the recruitment. Group C received the routine care. Both groups received a control visit with BP measure at 2, 4 and 9 months after the recruitment. The primary outcome was the change in BP values. BP measurements were assessed according to the international guidelines. Information on patients' demographics, co-morbidity and drugs were collected at baseline and at 12-month-follow-up. A total of 627 patients were randomly assigned to the study (418 in the Group C and 209 in the Group I). There were no significant differences (P>0.05) in both groups concerning age and gender. A greater reduction of SBP was observed in the Group I (-6.0 mmHg +14.0 vs -3.4 mmHg +11.3, P<0.05 ) Educational patient-centered program may be an effective strategy to improve blood pressure control, due a better adherence to therapy and a more careful health behavior.

No studies are available evaluating the impact of rapid-acting insulin analogues on long-term outcomes. Our aim was to compare the use of rapid-acting insulin analogues versus human regular insulin in relation to the occurrence of diabetic complications in a cohort of diabetic patients. Diabetic patients free of macrovascular disease at baseline were followed up for 3 years. All patients were residents in Abruzzo Region of central Italy. The incidence of diabetic complications was ascertained by hospital discharge claims. Patients receiving human regular insulin were compared with those treated with rapid-acting insulin analogues. HRs and 95% CIs of any diabetic complication and macrovascular, microvascular and metabolic complications were estimated separately using Cox proportional hazard models adjusted for patients' characteristics. Propensity score matching was also used to adjust for significant difference in the baseline characteristics between the two treatment groups. Overall, 2,286 patients were included into the analyses: 914 in the human regular insulin group and 1,372 in the rapid-acting insulin analogue group. During the 3-year follow-up, there were 286 incident events (31.3%) in the human regular insulin group and 235 (17.1%) in the rapid-acting insulin analogue group, with a difference between the two treatment groups in the cumulative HR for any diabetic complications that increased over time (p<0.0001). After adjustment for covariates, rapid-acting insulin analogues had a HR (95% CI) of 0.63 (0.51-0.77) for any diabetes-related complication and HRs of 0.62 (0.48-0.79) and 0.44 (0.27-0.73) for macrovascular and metabolic complications respectively, as compared with human regular insulin users. No difference between the two groups was found for microvascular complications. All endpoint results were supported by propensity score-based matched-pair analyses. Our findings suggest that the use of rapid-acting insulin analogues is associated with a lower risk of cardiovascular and metabolic complications compared with human regular insulin use.

To compare health care expenditures following rapid-acting insulin analogues or human regular insulin utilization in a cohort of diabetic patients through the analysis of administrative databases. A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients free of macrovascular disease at baseline and treated either with human regular insulin or rapid-acting insulin analogues were followed for a maximum of 3 years. Propensity score matching was used to adjust for significant differences in the baseline characteristics between the two treatment groups. The direct cost was calculated as the sum of drug use, financial compensation by hospital DRG and outpatient activities (laboratory tests, services use and specialistic consultations), all regulated by government contracts. Generalised linear mixed models under gamma distribution were used to evaluate the costs. In case of cost variables with a large proportion of zeros, a two part model (logistic regression and glm with gamma distribution) was employed. After PS approach, 566 patients treated with human regular insulin were matched with an equal number of patients receiving rapid-acting insulin analogues. During the 3-year follow-up, the average number of hospitalizations was higher (0.54 vs. 0.47; P=0.028), and the average length of stay was 4,7 days longer (P < 0.004), among patients receiving human regular insulin in comparison with those receiving rapid-acting insulin analogues. The annualized total health care costs were significantly lower in the rapid-acting insulin analogues group than human regular insulin group with an estimated difference between the two groups of 1336.7 € per patient per year (P=0.001) . This analysis from real-world clinical practice suggests that rapid-acting insulin analogue is associated with lower rates of hospitalizations and lower overall health care costs in diabetic patients.

Abstract Histone H3K4 methylation is a feature of meiotic recombination hotspots shared by many organisms including plants and mammals. Meiotic recombination is initiated by programmed double-strand break (DSB) formation that in budding yeast takes place in gene promoters and is promoted by histone H3K4 di/trimethylation. This histone modification is recognized by Spp1, a PHD-finger containing protein that belongs to the conserved histone H3K4 methyltransferase Set1 complex. During meiosis, Spp1 binds H3K4me3 and interacts with a DSB protein, Mer2, to promote DSB formation close to gene promoters. How Set1 complex- and Mer2- related functions of Spp1 are connected is not clear. Here, combining genome-wide localization analyses, biochemical approaches and the use of separation of function mutants, we show that Spp1 is present within two distinct complexes in meiotic cells, the Set1 and the Mer2 complexes. Disrupting the Spp1-Set1 interaction mildly decreases H3K4me3 levels and does not affect meiotic recombination initiation. Conversely, the Spp1-Mer2 interaction is required for normal meiotic recombination initiation, but dispensable for Set1 complex-mediated histone H3K4 methylation. Finally, we evidence that Spp1 preserves normal H3K4me3 levels independently of the Set1 complex. We propose a model where the three populations of Spp1 work sequentially to promote recombination initiation: first by depositing histone H3K4 methylation (Set1 complex), next by “reading” and protecting histone H3K4 methylation, and finally by making the link with the chromosome axis (Mer2-Spp1 complex). This work deciphers the precise roles of Spp1 in meiotic recombination and opens perspectives to study its functions in other organisms where H3K4me3 is also present at recombination hotspots. Author summary Meiotic recombination is a conserved pathway of sexual reproduction that is required to faithfully segregate homologous chromosomes and produce viable gametes. Recombination events between homologous chromosomes are triggered by the programmed formation of DNA breaks, which occur preferentially at places called hotspots. In many organisms, these hotspots are located close to a particular chromatin modification, the methylation of lysine 4 of histone H3 (H3K4me3). It was previously shown in the budding yeast model that one protein, Spp1, plays an important function in this process. We further explored the functional link between Spp1 and its interacting partners, and show that Spp1 shows genetically separable functions, by depositing the H3K4me3 mark on the chromatin, “reading” and protecting it, and linking it to the recombination proteins. We provide evidence that Spp1 is in three independent complexes to perform these functions. This work opens perspectives for understanding the process in other eukaryotes such as mammals, where most of the proteins involved are conserved.

The rise of welfare culture, which culminates in most European States in the mid-twentieth century, has its roots in the 18th century, already with the French Enlightenment. At first, the Church and the clergy played a major role in welfare, then - thanks to a secularization process - this role was taken on by the State, at least until the triumph of neo-liberal ideas. In particular, this paper proposes a descriptive analysis of the conditions of «projetti» and «projette», abandoned children, entrusted with public and private assistance in the Kingdom of the Two Sicilies, and of the nurses («balie»), an intermediate figure in the welfare process, which were in very bad economic situation: exploited by municipal administrations, they were often offended and not considered real workers despite their important action. The analysis, also based on the documents of the Naples State Archive, highlights how, during the period from the early 19th century to the Unity of Italy, the difficulties of State finances in the Kingdom of the Two Sicilies led to choices in terms of assistance, in which gender discrimination was strong, as mirror of a society with its privileges for males and its prejudices against women. Only in 1840, an ordinary State budget was started, some orphanages were created also for females and there were also some relief initiatives to take them free of charge in factories: the fate of the «projette» was increasingly placed at the forefront of Kingdom. However, the results were limited and slow and the discrimination remained strong: boys, even in the context of lack of assistance, were more safeguarded, girls were mostly ignored, whereas nurses were outraged and little paid.

Due to the success of highly active antiretroviral therapy, HIV-infection has been transformed into a lifelong condition. Therefore, HIV-infected patients are more likely to experience age-associated comorbidities. Little is known about the impact of the comorbidities on the risk of hospitalization and related costs in HIV patients.Our aim was to quantify the risk of hospitalization and costs associated with comorbidities in HIV-infected patients. The study population included subjects aged ≥18 years with HIV infection, identified from the Abruzzo’s hospital discharge database during the years 2004-2013. Patients were then followed in the years 2014-2015 and all admissions were recorded. Patients’ comorbidities (Charlson Comorbidity Index, CCI) were extracted from ICD-9-CM codes in the hospital discharge abstracts. Poisson regression was used to compare the Incidence Rate Ratios (IRRs) of acute hospital admissions in patients with and without each comorbidity class. A generalized linear model under gamma distribution was used to estimate adjusted mean hospital costs. IRRs with 95% confidence interval (CI) were adjusted for age, gender and the other comorbidities. Costs were derived from official Italian DRG-based reimbursements. Among 1026 HIV patients identified (mean age 47 years), 30% experienced at least one comorbidity and 14.5% needed acute hospital admission during the follow-up period. The risk of acute hospitalization significantly increased among patients with renal (Adjusted IRR 2.27; 95%CI: 1.45-3.56), liver (IRR 2.21; 1.57-3.13), and chronic pulmonary comorbidities (IRR 2.31; 1.63-3.32). Adjusted mean hospital costs were €2,130 in patients without comorbidities, and €4,111 and €8,488 in those with CCI=1 or CCI≥2, respectively. The presence of renal, liver and chronic pulmonary comorbidities doubled the risk of hospitalization. A CCI≥2 was associated with a four-fold increase in hospitalization costs. Our experience underlines that antiretroviral treatment should be tailored in accordance with HIV-associated comorbidities, to minimize the risk of acute events during the chronic management of HIV-infection.

Introduction: the IDEAL (“High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction”) study was carried out to compare intensive lowering of low-density lipoprotein (LDL)-cholesterol using the highest recommended dose of atorvastatin 80 mg with simvastatin 20 mg. Aim: our aim was to investigate the economic consequence of high dose of atorvastatin vs usual-dose of simvastatin in reducing major coronary events in patients with a history of acute myocardial infarction (AMI). Methods: the analysis is based on clinical outcome data from the IDEAL study. We conducted a cost-effectiveness analysis, comparing high dose of atorvastatin (80 mg/die) versus usual-dose of simvastatin (20 mg/die) in the perspective of the Italian National Health Service. We identified and quantified medical costs: drug costs according to the Italian National Therapeutic Formulary and hospitalizations were quantified based on the Italian National Health Service tariffs (2008). Effects were measured in terms of morbidity reduction (frequency of hospitalizations). We considered an observation period of 4.8 years. The costs borne after the first 12 months were discounted using an annual rate of 3%. We conducted one and multi-way sensitivity analyses on unit cost and effectiveness. Results: the cost of atorvastatin therapy over the 4.8 years period amounted to approximately 2.4 millions euro per 1,000 patients. The total cost of atorvastatin high dose was about 3.9 millions euro, the incremental cost per patient free from event is 31.176,03 euro. Discussion: this evaluation found that atorvastatin therapy is cost-effective. Results were sensitive to either clinical or economic variables.

Use of antisecretory drugs has greatly increased in recent years in Italy. After the launching of generic lansoprazole (early 2006), several Italian Regional Health Authorities have introduced measures to favour the prescription of less expensive PPI. The aim of this study is to evaluate general practitioners’ prescription (GPs) of different Proton Pump Inhibitors (PPIs) in the period between 2005 to 2008. Analysis has been performed on a database of 99 medical practitioners that have managed an average of 150,000 inhabitants. We evaluate the PPIs prescriptions from Jan 2005 to Dec 2008. Evaluations performed are the following: 1) PPI prescription (total and separately for lansoprazole, esomeprazole, pantoprazole, rabeprazole, and omeprazole); 2) prevalence of the reimbursement purpose (Gastroprotection – G; Acid-Related Disease – ARD); 3) PPI prescriptions separately for ARD diagnostic codes. Data were expressed as Compound Annual Growth Rate (CAGR). PPI consumption were quantified using Defined Daily Dose system (DDD). The total volume of PPI’s prescribing increased progressively over the 4 years (CAGR +15%). The proportion of defined daily doses accounted for by lansoprazole increased from 12.0% in 2005 to 30.9% in 2008. The prescription of omeprazole decreased from 42.2% to 26.7%, while that of esomeprazole remained costant. The reimbursement purpose was higher for G (CAGR +43%) than for ARD (CAGR +7%). We found an increase of lansoprazole prescriptions especially for heartburn (CAGR +52.4%), gastroesophageal reflux (CAGR 34,5%) and upper abdominal pain (CAGR 37,2%). Generic PPIs has unexpectedly increased the prescription of whole drug class during the period 2005-2008. Our data suggest that the appropriateness of PPI prescription after generic PPI introduction should be carefully monitored to distinguish between cost-effective from cost-ineffective PPI treatment.

Aim: to assess the economic and epidemiologic impact of diabetes in Campania, a region of approximately 5.7 million inhabitants in the south of Italy. Method: we collected, from an electronic database, all prescriptions for antidiabetic drugs reimbursed in the first half year of 2005 in 8 local health authorities (60% of the overall population) of Campania. The diabetic cohort was defined as the population of subjects receiving at least 2 prescriptions of an antidiabetic agent in 6-month, classified according to their therapeutic role using Anatomic Therapeutic Chemical (ATC) classification. Characterization is given of the patients and their antidiabetic medication. Subsequently, the prescription of concomitant treatment, in comparison with a control group, is presented. Drugs cost and drugs consumption were quantified using NHS prospective (expressed in Euro 2005) and Defined Daily Dose system (DDD) respectively. Results: the diabetic cohort included 183,614 subjects (5.3% of the observed population), mean age was 65.0 years and female represented 54.8% of the sample. Total cost for diabetic patients represents 16.8% of the total drug expenditure. The average drug/cost/patient was € 355.7; only 19.0% was spent for antidiabetic drugs. The reported use of medication was higher for subjects with diabetes compared with the control population regarding overall use (2,363.5 versus 1259.8 DDD/1,000 inhabitants/die), the use of cardiovascular drugs (1,499.3 versus 663.5 DDD/1,000 inhabitants/day), use of haematologic drugs (277.1 versus 120.3 DDD/1,000 inhabitants/day), and use of ophthalmological drugs (48.3 versus 21.0 DDD/1,000 inhabitants/day). Discussion: chronic-degenerative pathologies, such as diabetes, implies a relevant social and economic impact. Expenses that are associated to the treatment and the prevention of complications, in particular cardiovascular problems, are registered among the main items listed in the healthcare budget.

Introduction: the antibiotic usage in Italy is above the European average. From several years the Campania was the first Italian region in terms of antimicrobial consumption. Aim: to evaluate antibiotic utilisation in primary health care in Campania, a region of approximately 5.7 million inhabitants in the south of Italy. Method: we collected, from an electronic database, all prescription drugs reimbursed in 2005. The cohort was defined as the population of subjects receiving at least one prescription of any antimicrobial agent for systemic use, classified according to their therapeutic role using Anatomic Therapeutic Chemical (ATC) classification. Drugs cost and consumption were quantified using National Health Service (NHS) prospective and Defined Daily Dose system (DDD) respectively. All costs were expressed in Euro 2005. Results: antiinfectives agents (ATC J) was the second class of drugs in terms of cost, representing 16.1% of the regional drug expenditure. Their consumption were 33 DDD/1000 inhabitants/day. Stratifying by age antibiotic use was highest in children and elderly subjects. Penicillins, macrolides and cephalosporins were the most prescribed antibiotic classes in all age groups. Discussion: despite guidelines introduced to limit the prescription of parenteral antibiotics to the patients who are most likely to benefit from it, they were mostly prescribed. This represented a serious problem for the development of drug-resistant bacteria.

Introduction: the PROVE-IT (“Intensive versus moderate lipid lowering with statins after acute coronary syndromes”) was a comparison of pravastatin 40 mg/die versus atorvastatin 80 mg/die in patients with an acute coronary syndrome (ACS). Aim: our aim was to investigate the economic consequence of high dose of atorvastatin vs usual-dose of pravastatin in Italian patients with a history of acute coronary syndrome. Methods: the analysis is conducted on the basis of clinical outcomes of the PROVE-IT study. We conducted a cost-effectiveness analysis, comparing high dose of atorvastatin (80 mg/die) versus usual-dose of pravastatin (40 mg/die) in the perspective of the Italian National Health Service. We identified and quantified medical costs: drug costs according to the Italian National Therapeutic Formulary and hospitalizations were quantified based on the Italian National Health Service tariffs (2008). Effects were measured in terms of morbidity reduction (number of deaths and frequency of hospitalizations). We considered an observation period of 24 months. The costs borne after the first 12 months were discounted using an annual rate of 3%. We conducted one and multi-way sensitivity analyses on unit cost and effectiveness. Results: the cost of pravastatin or atorvastatin therapy over the 2 years period amounted to approximately 664.684 millions euro and 909.006 euro per 1,000 patients respectively. Atorvastatin was more efficacious compared to pravastatin and the overall cost of care per 1,000 patients over 24 months of follow-up was estimated at 2.58 millions euro in the pravastatin and 2.57 millions euro in the atorvastatin group, resulting into a cost saving of about 11.000 euro. Discussion: this study demonstrates that high dose atorvastatin treatment leads to a reduction of direct costs for the National Health System. Atorvastatin therapy is dominant since it is both less costly and more effective than pravastatin. Results were sensitive to either clinical or economic variables.

Additional file 2: Table S1. Methylation profiling of 18 Cohort I samples. Table S2. MicroRNAs displaying significantly upregulated and downregulated expression in supratentorial PA and non-PA tumours with and without progression (Cohort I). Table S3. MicroRNAs displaying significantly upregulated and downregulated expression in supratentorial PAs with and without progression (Cohort II). Table S4. Univariate analyses of miR-1248 in pLGG in pLGG samples of ddPCR.

Introduction: the Treating to New Targets (TNT) study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/die provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/die in patients with stable coronary heart disease (CHD). Objective: our aim was to investigate the economic consequence of high dose of atorvastatin in Italian patients with stable coronary heart disease (CHD). Methods: data were derived from the Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease (TNT) study. We conducted a cost-effectiveness analysis, comparing high dose of atorvastatin (80 mg/die) versus usual-dose of atorvastatin (10 mg/die) in the perspective of the Italian National Health Service. We identified and quantified medical costs: drug costs according to the Italian National Therapeutic Formulary and hospitalizations were quantified based on the Italian National Health Service tariffs (2006). Effects were measured in terms of patients free from any event. We considered an observation period of 4.9 years. The costs borne after the first 12 months were discounted using an annual rate of 3%. We conducted one and multi-way sensitivity analyses on unit cost and effectiveness. Results: the cost of atorvastatin 10 mg or 80 mg therapy over the 4.9 years period amounted to approximately € 1.6 millions and € 2.5 millions per 1,000 patients respectively. The total cost of atorvastatin high dose was about € 3.7 millions, the incremental cost per patient free from event is about € 12,600. Discussion: this evaluation found that atorvastatin therapy is cost-effective. Sensitivity analysis shows that cost consequences parameters are substantially sensitive to fluctuation.

Introduction: the PROVE-IT (“Intensive versus moderate lipid lowering with statins after acute coronary syndromes”) was a comparison of pravastatin 40 mg/die versus atorvastatin 80 mg/die in patients with an acute coronary syndrome (ACS). Aim: our aim was to investigate the economic consequence of high dose of atorvastatin vs usual-dose of pravastatin in Italian patients with a history of acute coronary syndrome. Methods: the analysis is conducted on the basis of clinical outcomes of the PROVE-IT study. We conducted a cost-effectiveness analysis, comparing high dose of atorvastatin (80 mg/die) versus usual-dose of pravastatin (40 mg/die) in the perspective of the Italian National Health Service. We identified and quantified medical costs: drug costs according to the Italian National Therapeutic Formulary and hospitalizations were quantified based on the Italian National Health Service tariffs (2006). Effects were measured in terms of mortality and morbidity reduction (number of deaths, life years gained and frequency of hospitalizations). We considered an observation period of 24 months. The costs borne after the first 12 months were discounted using an annual rate of 3%. We conducted one and multi-way sensitivity analyses on unit cost and effectiveness. We also conducted a threshold analysis. Results: the cost of pravastatin or atorvastatin therapy over the 2 years period amounted to approximately 1.3 millions euro and 870,000 euro per 1,000 patients respectively. Atorvastatin was more efficacious compared to pravastatin and the overall cost of care per 1,000 patients over 24 months of follow-up was estimated at 3.2 millions euro in the pravastatin and 2.5 millions euro in the atorvastatin group, resulting into a cost saving of about 700,000 euro that is 27% of total costs occurred in the pravastatin group. Discussion: this study demonstrates that high does atorvastatin treatment leads to a reduction of direct costs for the National Health System. Atorvastatin therapy is dominant since it is both less costly and more effective than pravastatin. Results of sensitivity analysis showed that atorvastatin therapy remains dominant even in the most unfavourable hypotheses.

Introduction: the IDEAL (“High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction”) study was carried out to compare intensive lowering of low-density lipoprotein (LDL)-cholesterol using the highest recommended dose of atorvastatin 80 mg with simvastatin 40 mg. Aim: our aim was to investigate the economic consequence of high dose of atorvastatin vs usual-dose of simvastatin in reducing major coronary events in patients with a history of acute myocardial infarction (AMI). Methods: the analysis is based on clinical outcome data from the IDEAL study. We conducted a cost-effectiveness analysis, comparing high dose of atorvastatin (80 mg/die) versus usual-dose of simvastatin (20 mg/die) in the perspective of the Italian National Health Service. We identified and quantified medical costs: drug costs according to the Italian National Therapeutic Formulary and hospitalizations were quantified based on the Italian National Health Service tariffs (2006). Effects were measured in terms of mortality and morbidity reduction (number of deaths, life years gained and frequency of hospitalizations). We considered an observation period of 4.8 years. The costs borne after the first 12 months were discounted using an annual rate of 3%. We conducted one and multi-way sensitivity analyses on unit cost and effectiveness. We also conducted a threshold analysis. Results: the cost of simvastatin or atorvastatin therapy over the 4.8 years period amounted to approximately 2.3 millions euro and 2.6 millions euro per 1,000 patients respectively. Atorvastatin was more efficacious compared to simvastatin and the overall cost of care per 1,000 patients over 4.8 years of follow-up was estimated at 4.3 millions euro in the simvastatin and 4,18 millions euro in the atorvastatin group, resulting into a cost saving of 121,518 euro that is 2.8% of total costs occurred in the simvastatin group. Discussion: this study is the first economic evaluation of IDEAL study based on the Italian context. Atorvastatin therapy is dominant since it is both less costly and more effective than simvastatin. Results of sensitivity analysis showed that atorvastatin therapy remains dominant even in the most unfavourable hypotheses.

This study explores which patient characteristics could affect the likelihood of starting low back pain (LBP) treatment with opioid analgesics vs. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in an Italian primary care setting. Through the computerized medical records of 65 General Practitioners, non-malignant LBP subjects who received the first pain intensity measurement and an NSAID or opioid prescription, during 2015–2016, were identified. Patients with an opioid prescription 1-year before the first pain intensity measurement were excluded. A multivariable logistic regression model was used to determine predictive factors of opioid prescribing. Results were reported as Odds Ratios (ORs) with a 95% confidence interval (CI), with p &lt; 0.05 indicating statistical significance. A total of 505 individuals with LBP were included: of those, 72.7% received an NSAID prescription and 27.3% an opioid one (64% of subjects started with strong opioid). Compared to patients receiving an NSAID, those with opioid prescriptions were younger, reported the highest pain intensity (moderate pain OR = 2.42; 95% CI 1.48–3.96 and severe pain OR = 2.01; 95% CI 1.04–3.88) and were more likely to have asthma (OR 3.95; 95% CI 1.99–7.84). Despite clinical guidelines, a large proportion of LBP patients started with strong opioid therapy. Asthma, younger age and pain intensity were predictors of opioid prescribing when compared to NSAIDs for LBP treatment.

Une etude sur la couverture vaccinale contre la grippe chez les personnes âgees a ete menee. Cinquante-six pour cent des personnes interrogees ont ete vaccinees (taux de vaccination pondere de 50%), alors que l’objectif vise etait de 75%. Cependant les taux de vaccination etaient superieurs chez les plus de 74 ans et ceux atteints de maladies chroniques.

Foi efectuado um estudo sobre a cobertura da vacina contra a gripe entre os individuos idosos. Cinquenta e seis porcento dos entrevistados haviam sido vacinados (cobertura ponderada de 50%), em comparacao com o objectivo de 75%, mas foram referidas taxas mais elevadas nos individuos com idades superiores a 74 anos e naqueles com doencas cronicas.

Da uno studio sulla copertura vaccinale contro l'influenza tra gli anziani, e risultato che il 56% degli intervistati era stato vaccinato (copertura pesata 50%), rispetto all'obiettivo del 75%. Tassi piu elevati sono stati riscontrati negli anziani con piu di 74 anni e in quelli affetti da malattie croniche