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Valentina Perrone,1 Chiara Veronesi,1 Elisa Giacomini,1 Rita Citraro,2 Stefania Dell’Orco,3 Fabio Lena,4 Arrigo Paciello,5 Anna Maria Resta,6 Mihaela Nica,7 Daniela Ritrovato,7 Luca Degli Esposti1 1Clicon S.r.l. Società Benefit, Health Economics & Outcomes Research, Bologna, Italy; 2Dipartimento di Scienze della Salute, Università Magna Grecia di Catanzaro, Unita’ Operativa di Farmaco-logia Clinica e Farmacovigilanza, Azienda Ospedaliero-Universitaria “Mater Domini”, Catanzaro, Italy; 3ASL Roma 6, Rome, Italy; 4USL Toscana Sud Est, Grosseto, Italy; 5ATS Bergamo, Bergamo, Italy; 6Struttura Complessa di Farmacia Territoriale Area Vasta 1, Fano, Italy; 7Novartis Farma S.p.A, Origgio, Varese, ItalyCorrespondence: Valentina Perrone, CliCon S.r.l. Società Benefit, Health, Economics & Outcomes Research, Via Murri, 9, Bologna, 40137, Italy, Tel +39 3450316494, Email valentina.perrone@clicon.itPurpose: A retrospective analysis of real-world data was performed to assess the epidemiology and economic burden of multiple sclerosis (MS), relapsing-remitting MS (RRMS), and secondary-progressive MS (SPMS) in Italy.Patients and Methods: An observational study on administrative databases from a sample of Italian entities was carried-out. Between 01/2010– 12/2017, patients with ≥ 1 MS diagnosis code (ICD-9-CM:340 and/or exemption code:046) and/or ≥ 1 disease-modifying therapies (DMTs) prescription, were included. Among MS-cohort, SPMS patients were identified by ≥ 2 hospitalizations or by ≥ 2 drug prescriptions related to MS progression. MS patients not fulfilling SPMS criteria were included as RRMS. Mean annual healthcare costs were reported during follow-up and stratified by DMT treatment/untreatment.Results: Overall, 9543 MS patients were included; 8397 with RRMS and 1146 with SPMS. Estimated prevalence of MS was 141.6/100,000 inhabitants (RRMS 124.4/100,000 and SPMS 17.2/100,000). Mean annual cost for untreated and treated patient was respectively: € 3638 and € 11796 (MS-cohort), € 3183 and € 11486 (RRMS-cohort), € 6317 and € 15511 (SPMS-cohort). The first-line DMT treatment duration averaged 27.4 ± 22.8 months; the mean cost was 19004€ for the whole period. The second-line DMT treatment lasted on average 31.1 ± 24.5 months; the mean cost was 47293€ for the whole period.Conclusion: This study provided insights into the MS epidemiology in Italy and its economic burden. Healthcare costs associated with MS management were mainly driven by DMTs expenditure. A trend of higher healthcare-resource consumption was observed among SPMS-cohort.Keywords: real-world evidence, clinical practice, multiple sclerosis, epidemiology, healthcare resource consumption

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

Luca Degli Esposti,1 Chiara Veronesi,1 Domenica Daniela Ancona,2 Margherita Andretta,3 Fausto Bartolini,4 Alberto Drei,5 Alessandro Lupi,6 Stefano Palcic,7 Davide Re,8 Francesca Vittoria Rizzi,2 Elisa Giacomini,1 Valentina Perrone1 1CliCon S.r.l. Health, Economics & Outcomes Research, Bologna, Italy; 2Dipartimento Farmaceutico, ASL BAT, Trani, Italy; 3UOC Assistenza Farmaceutica Territoriale, Azienda ULSS 8 Berica, Vicenza, Italy; 4Dipartimento Farmaceutico, Umbria 2, Terni, 05100, Italy; 5Deloitte, Milano, Italy; 6Cardiology Unit, ASL VCO, Omegna, Italy; 7Farmaceutica Territoriale, Azienda Sanitaria Universitaria Integrata Giuliano-Isontina, Trieste, Italy; 8UOC Assistenza Farmaceutica Territoriale, ASL Teramo, Teramo, ItalyCorrespondence: Valentina Perrone, Clicon Srl, Health, Economics and Outcomes Research, Via Murri 9, Bologna, 40137, Italy, Tel +39 544 38393, Fax +39 544 212699, Email valentina.perrone@Clicon.itPurpose: This real-world study investigates the direct healthcare costs from the perspective of the Italian Healthcare National Service of experienced statin users according to their level of adherence to therapy and to their cardiovascular (CV) profile in Italian settings of outpatients clinical practice.Patients and Methods: A retrospective observational analysis was performed based on administrative databases covering approximately 6 million health-assisted individuals. Adult patients with statins prescription between January 2014 and December 2016 were screened, and first prescription within this period was the index date. Follow-up lasted 1 year after index date. Only patients receiving statins prior index date (experienced statin users) were included and distributed in clusters based on their CV profile. Adherence was calculated during follow-up as proportion of days covered (PDC) and classified in low adherence (PDC< 40%), partial adherence (PDC=40– 79%) and adherence (PDC≥ 80%). Mean direct healthcare costs of drugs, hospitalizations, and outpatient services were evaluated during follow-up.Results: A total of 436,623 experienced statin users were included and distributed as follows: 5.5% in the previous CV events, 22.6% in diabetes, 55.7% in CV treatments and 16.2% in the no comorbidity cluster. Total mean annual cost/patient decreased from low adherent to adherent patients from € 4826 to € 3497 in previous CV events, from € 2815 to € 2360 in diabetes cluster, from € 2077 to € 1863 for patients with CV treatments. Same trend was reported for the cost item related to hospitalizations, which was the major determinant of the total costs. In previous CV event cluster, adherence was associated to a saving of € 879 on total costs.Conclusion: The study highlighted a decrease in overall mean costs as adherence levels increase, particularly for patients with previous CV events, showing how improving adherence could be associated to cost savings and suggesting suited strategy based on CV profile should be undertaken for adherence optimization.Keywords: direct costs, lipid-lowering drugs, medication adherence, real-life

Elisa Giacomini, Valentina Perrone, Davide Alessandrini, Daniela Paoli, Carmela Nappi, Luca Degli Esposti CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, ItalyCorrespondence: Valentina PerroneClicon S.r.l, Health, Economics and Outcomes Research, Via Salara, 36, Ravenna, 48100, ItalyTel +39 544 38393Fax +39 544 212699Email valentina.perrone@clicon.itAbstract: The 20th century witnessed the dawn of the antibiotic revolution and is now facing the rising phenomenon of antibiotic resistance. In this narrative review, we aim to describe antibiotic resistance in clinical practice settings through population-based studies from different countries reporting the role of misuse of antibiotics in the development of resistance and the clinical and economic burden associated. The misuse of antibiotics was documented in the wide population as well as in hospitals and care facilities. It was mainly reported as over-use and inappropriate prescribing. Improper dosage regimens and longer treatment duration were regarded as pivotal factors related to antibiotic resistance; the emerging strategy of “antibiotic-de-escalation” could be the key to overcome these issues. The investigation of the self-medication attitude revealed widespread antibiotic use without following medical instructions or medical consultation. Moreover, several studies established the association of antibiotic resistance with increased risk of longer hospitalizations and mortality, highlighting the heavy clinical and economic burden of this phenomenon. In this narrative review, the widespread inappropriate use of antibiotics emerged as one of the main causes of antibiotic resistance, which negative outcomes call for the development of antibiotic stewardship programs and global surveillance networks.Keywords: antibiotic utilization, antimicrobial resistance, real-world

Valentina Perrone,1 Elisa Giacomini,1 Diego Sangiorgi,1 Margherita Andretta,2 Anna Michela Menti,2 Mariantonietta Naclerio,3 Daniela Ritrovato,3 Luca Degli Esposti1 1CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, Italy; 2Health Technology Assessment Unit, Azienda Zero, Padova, Italy; 3Novartis Farma Italy, Origgio, VA, ItalyCorrespondence: Valentina PerroneClicon Srl, Health, Economics and Outcomes Research, Via Salara, 36, 48100, Ravenna, ItalyTel +39 544 38393Fax +39 544 212699Email valentina.perrone@clicon.itPurpose: To analyze the treatment patterns of psoriatic arthritis (PSA) or ankylosing spondylitis (AS) patients under biological therapies and to evaluate in this population the health-care resource consumption and related costs.Patients and Methods: A retrospective analysis was performed on administrative databases of the Veneto region. Patients ≥ 18 years with at least one prescription of biological drugs and a diagnosis at any level for PSA or AS from January 1, 2011 to December 31, 2016 (inclusion period) were included. Index date (ID) was defined as date of first biological drug prescription during inclusion period. Patients were characterized the year before ID and followed-up for one year after ID. The drug utilization profile in terms of adherence, persistence and therapeutic regimen changes, and the health-care resource consumption was analyzed during follow-up.Results: A total of 2602 patients were included: 1857 with PSA and 745 with AS. In the PSA cohort, 40.3% of patients were prescribed adalimumab, 35.6% etanercept, 8.0% golimumab, 7.5% infliximab, 5.6% ustekinumab and 3.0% certolizumab. Percentage of PSA patients adherent to treatment was higher among ustekinumab patients (91.3%) and lower among etanercept users (54.3%). Persistence ranged from 53.2% (infliximab) to 70.3% (etanercept). Regarding AS cohort, 45.5% of patients were prescribed adalimumab, 26% etanercept, 17.3% infliximab, 9.7% golimumab and 1.5% certolizumab. Adherence ranged from 46.9% (etanercept) to 90.9% (certolizumab) and persistence from 62.8% (adalimumab) to 81.8% (certolizumab). Mean annual health-care costs (including costs for drug treatment, diagnostic services, specialist visits and hospital admissions) ranged from € 9727 (certolizumab) to € 14,994 (ustekinumab) among PSA patients and from € 9875 (infliximab) to € 12,991 (golimumab) among AS patients.Conclusion: This study in Veneto region gave a picture of biological treatment patterns among PSA and AS patients in a real-world setting. Our findings showed the high degree of variability concerning utilization of each biological drug and provided insight on the economic burden of both diseases.Keywords: psoriatic arthritis, ankylosing spondylitis, biologic drugs, drug utilization, real-world

Valentina Perrone,1,* Luca Degli Esposti,1,* Elisa Giacomini,1 Chiara Veronesi,1 Valerio Blini,1 Marco Oderda2 1CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, Italy; 2Department of Surgical Sciences - Urology, Città Della Salute e Della Scienza Di Torino, Molinette Hospital, University of Turin, Turin, Italy*These authors contributed equally to this workCorrespondence: Valentina PerroneClicon S.r.l, Health, Economics and Outcomes Research, Ravenna, ItalyTel +39 544 38393Fax +39 544 212699Email valentina.perrone@clicon.itPurpose: To evaluate and compare the incidence of cardiovascular (CV) events in a large contemporary cohort of patients diagnosed with prostate cancer (PCa) and in treatment with GnRH agonists or GnRH antagonists.Patients and Methods: An Italian observational retrospective cohort study based on administrative databases of three local health units and two Regions was performed. PCa patients treated with GnRH agonists or antagonist were included between January 01, 2013 and December 31, 2016. Index date (ID) was the date of first GnRH agonist/antagonist prescription during inclusion period. Follow-up was from ID to December 31, 2017. Patients were excluded if they were under abiraterone treatment or combination therapy with antiandrogens during follow-up. The incidence rate of CV events (acute myocardial infarction, ischemic heart diseases, cerebrovascular diseases, cardiac dysrhythmias, heart failure, atherosclerosis, aneurism, other CV-related conditions) was calculated among patients not switching to androgen deprivation therapy (ADT) in the overall cohort and in a sub-cohort of patients without previous CV events.Results: In total, 9785 (mean age 76.8 ± 8.5) patients were included: 9158 (93.6%) were treated with a GnRH agonist and 627 (6.4%) with a GnRH antagonist. Of them, 9627 did not switch to ADT and were considered in the analyses. The incidence of CV events was significantly higher in patients treated with GnRH agonists rather than antagonists (8.8 vs 6.2, p=0.002). Mean time to CV event was beyond 1 year of treatment in both groups. In the multivariable regression analysis, the risk of experiencing CV events was significantly lower in patients treated with GnRH antagonist rather than those treated with GnRH agonists [HR (95% CI): 0.76 (0.60– 0.95), p=0.018]. These findings were confirmed in the sub-cohort of patients without previous CV events.Conclusion: This Italian observational study shows that most patients received a GnRH agonist rather than a GnRH antagonist prescription. GnRH antagonist seems to have a better CV risk profile than GnRH agonist, both in patients with and without a history of CV events.Keywords: cardiovascular events, GnRH agonists, GnRH antagonist, prostate cancer, real-world setting

Objectives: The Iseult MRI is an actively shielded whole-body magnet providing a homogeneous and stable magnetic field of 11.7 T. After nearly 20 years of research and development, the magnet successfully reached its target field strength for the first time in 2019. This article reviews its commissioning status, the gradient–magnet interaction test results and first imaging experience. Materials and methods: Vibration, acoustics, power deposition in the He bath, and field monitoring measurements were carried out. Magnet safety system was tested against outer magnetic perturbations, and calibrated to define a safe operation of the gradient coil. First measurements using parallel transmission were also performed on an ex-vivo brain to mitigate the RF field inhomogeneity effect. Results: Acoustics measurements show promising results with sound pressure levels slightly above the enforced limits only at certain frequency intervals. Vibrations of the gradient coil revealed a linear trend with the B0 field only in the worst case. Field monitoring revealed some resonances at some frequencies that are still under investigation. Discussion: Gradient-magnet interaction tests at up to 11.7 T are concluded. The scanner is now kept permanently at field and the final calibrations are on-going to pave the road towards the first acquisitions on volunteers. [ABSTRACT FROM AUTHOR]

Study Question: Are uterine fluid-derived extracellular vesicles (UF-EVs) a 'liquid biopsy' reservoir of biomarkers for real-time monitoring of endometrial status?Summary Answer: The transcriptomic cargo of UF-EVs reflects the RNA profile of the endometrial tissue as well as changes between the non-receptive and the receptive phase, possibly supporting its use for a novel endometrial receptivity test.What Is Known Already: EVs have been previously isolated from uterine fluid, where they likely contribute to the embryo-endometrium crosstalk during implantation. Based on a meta-analysis of studies on endometrial tissue implantation-associated genes and the human exosomes database, 28 of the 57 transcripts considered as receptivity markers refer to proteins present in human exosomes. However, the specific transcriptomic content of receptive phase UF-EVs has yet to be defined.Study Design, Size, Duration: Two experimental series were set up. First, we simultaneously sequenced RNA species derived from paired UF-EVs and endometrial tissue samples collected from physiologically cycling women. Second, we analyzed RNA species of UF-EVs collected during the non-receptive (LH + 2) and receptive (LH + 7) phase of proven fertile women and from the receptive (LH + 7) phase of a population of women undergoing ART and transfer of euploid blastocysts.Participants/materials, Setting, Methods: For paired UF-endometrial tissue sampling, endometrial tissue biopsies were obtained with the use of a Pipelle immediately after UF collection performed by lavage of the endometrial cavity. Overall, n = 87 UF samples were collected and fresh-processed for EV isolation and total RNA extraction, while western blotting was used to confirm the expression of EV protein markers of the isolated vesicles. Physical characterization of UF-EVs was performed by Nanoparticle Tracking Analysis. To define the transcriptomic cargo of UF-EV samples, RNA-seq libraries were successfully prepared from n = 83 UF-EVs samples and analyzed by RNA-seq analysis. Differential gene expression (DGE) analysis was used to compare RNA-seq results between different groups of samples. Functional enrichment analysis was performed by gene set enrichment analysis with g:Profiler. Pre-ranked gene set enrichment analysis (GSEA) with WebGestalt was used to compare RNA-seq results with the gene-set evaluated in a commercially available endometrial receptivity array.Main Results and the Role Of Chance: A highly significant correlation was found between transcriptional profiles of endometrial biopsies and pairwise UF-EV samples (Pearson's r = 0.70 P < 0.0001; Spearman's ρ = 0.65 P < 0.0001). In UF-EVs from fertile controls, 942 gene transcripts were more abundant and 1305 transcripts less abundant in the LH + 7 receptive versus the LH + 2 non-receptive phase. GSEA performed to evaluate concordance in transcriptional profile between the n = 238 genes included in the commercially available endometrial receptivity array and the LH + 7 versus LH + 2 UF-EV comparison demonstrated an extremely significant and consistent enrichment, with a normalized enrichment score (NES)=9.38 (P < 0.001) for transcripts up-regulated in LH + 7 in the commercial array and enriched in LH + 7 UF-EVs, and a NES = -5.40 (P < 0.001) for transcripts down-regulated in LH + 7 in the commercial array and depleted in LH + 7 UF-EVs. When analyzing LH + 7 UF-EVs of patients with successful versus failed implantation after transfer of one euploid blastocyst in the following cycle, we found 97 genes whose transcript levels were increased and 64 genes whose transcript levels were decreased in the group of women who achieved a pregnancy. GSEA performed to evaluate concordance in transcriptional profile between the commercially available endometrial receptivity array genes and the comparison of LH + 7 UF-EVs of women with successful versus failed implantation, demonstrated a significant enrichment with a NES = 2.14 (P = 0.001) for transcripts up-regulated in the commercial array in the receptive phase and enriched in UF-EVs of women who conceived, and a not significant NES = -1.18 (P = 0.3) for transcripts down-regulated in the commercial array and depleted in UF-EVs. In terms of physical features, UF-EVs showed a homogeneity among the different groups analyzed except for a slight but significant difference in EV size, being smaller in women with a successful implantation compared to patients who failed to conceive after euploid blastocyst transfer (mean diameter ± SD 205.5± 22.97 nm vs 221.5 ± 20.57 nm, respectively, P = 0.014).Large Scale Data: Transcriptomic data were deposited in NCBI Gene Expression Omnibus (GEO) and can be retrieved using GEO series accession number: GSE158958.Limitations, Reasons For Caution: Separation of RNA species associated with EV membranes might have been incomplete, and membrane-bound RNA species-rather than the internal RNA content of EVs-might have contributed to our RNA-seq results. Also, we cannot definitely distinguish the relative contribution of exosomes, microvesicles and apoptotic bodies to our findings. When considering patients undergoing ART, we did not collect UFs in the same cycle of the euploid embryo transfer but in the one immediately preceding. We considered this approach as the most appropriate in relation to the novel, explorative nature of our study. Based on our results, a validation of UF-EV RNA-seq analyses in the same cycle in which embryo transfer is performed could be hypothesized.Wider Implications Of the Findings: On the largest sample size of human EVs ever analyzed with RNA-seq, this study establishes a gene signature to use for less-invasive endometrial receptivity tests. This report is indeed the first to show that the transcriptome of UF-EVs correlates with the endometrial tissue transcriptome, that RNA signatures in UF-EVs change with endometrial status, and that UF-EVs could serve as a reservoir for potential less-invasive collection of receptivity markers. This article thus represents a step forward in the design of less-invasive approaches for real-time monitoring of endometrial status, necessary for advancing the field of reproductive medicine.Study Funding/competing Interest(s): The study was funded by a competitive grant from European Society of Human Reproduction and Embryology (ESHRE Research Grant 2016-1). The authors have no financial or non-financial competing interests to disclose.Trial Registration Number: NA. [ABSTRACT FROM AUTHOR]

Summary: Extracellular vesicle (EV) exchange is emerging as a novel method of communication at the maternal–fetal interface. The presence of the EVs has been demonstrated in the preimplantation embryo culture medium from different species, such as bovines, porcines and humans. Preimplantation embryo‐derived EVs have been shown to carry molecules potentially able to modulate the local endometrial immune system. The non‐classical major histocompatibility complex (MHC) class I molecule human leucocyte antigen (HLA)‐G, the immunomodulatory molecule progesterone‐induced blocking factor and some regulatory miRNAs species are contained in embryo‐derived EV cargo. The implanted syncytiotrophoblasts are also well known to secrete EVs, with microvesicles exerting a mainly proinflammatory effect while exosomes in general mediate local immunotolerance. This review focuses on the current knowledge on the potential role of EVs released by the embryo in the first weeks of pregnancy on the maternal immune cells. Collectively, the data warrant further exploration of the dialogue between the mother and the embryo via EVs. [ABSTRACT FROM AUTHOR]