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Iria Neri,1 Elena Galli,2 Ilaria Baiardini,3,4 Mario Picozza,5,6 Ana B Rossi,7 Paolo Matruglio,8 Devis Moretti,8 Filippo Cipriani8 1Dermatology Unit, IRCCS Azienda Ospedaliero Universitaria Bologna, University of Bologna, Bologna, Italy; 2UOS Immuno-Allergologia dell’Età evolutive, Ospedale S.Pietro-Fatebenefratelli, Rome, Italy; 3Respiratory Unit for Continuity of Care, IRCCS, Ospedale Policlinico San Martino, Genova, Italy; 4Personalized Medicine Asthma, & Allergy Clinic, IRCCS Humanitas Research Hospital, Milan, Italy; 5National Association of Atopic Dermatitis (ANDeA), Prato, Italy; 6Neuroimmunology Unit, Santa Lucia Foundation IRCCS, Rome, Italy; 7Sanofi, Cambridge, MA, USA; 8Sanofi, Milan, ItalyCorrespondence: Filippo Cipriani, Sanofi, Viale Bodio 37b, Milan, Italy, Email filippo.cipriani@sanofi.comPurpose: Atopic dermatitis (AD) is a chronic, relapsing and remitting inflammatory skin disease characterized by intense itch. The disease burden includes physical limitations, psychosocial discomfort, and a reduced quality of life (HRQoL). This study presents the results of a parent-reported survey on the psychosocial impact of AD on Italian pre-adolescent children (6– 11 years old), with a specific focus on bullying, self-isolation, absenteeism, and presenteeism.Methods: An online questionnaire was sent to 3067 random recipients and 160 matched the inclusion criteria for age, self-reported AD diagnosis, localizations (according to ISAAC), and disease severity (POEM ≥ 8). 100 children, with comparable ages, not matching the inclusion criteria for AD, were recruited as a control group.Results: Children with AD and their caregivers had a significantly lower quality of sleep (QoS) compared to the control group. The presence of AD was directly responsible for many restless nights, both in children and caregivers (58.9 and 55.4 respectively). Children with AD and their parents also experienced significantly more daytime drowsiness (43.6 and 54.6 days, respectively). Children with AD were more frequently victims of bullying at school (20.0% vs 9.0%; p≤ 0.05) or in other social environments (16.9% vs 3.0%; p≤ 0.05). AD caused 17.7 days of absenteeism and 20.1 days of presenteeism per student over the previous 12 months, accounting for 37.8 days of study impairment overall. Severe/very severe AD had a significantly greater impact on presenteeism than moderate AD (25.1 vs 17.5 days; p≤ 0.05). Presenteeism, which was more pronounced among bullied students, was positively correlated with absenteeism only in the AD cohort.Conclusion: AD has a detrimental impact on the HRQoL of pediatric patients, causing stigmatization and social isolation. Functional distress was also reported by caregivers. Our study might inform the public and policymakers about the disease burden of AD at a young age.Keywords: atopic dermatitis, absenteeism, presenteeism, sleep impairment, daily drowsiness

Luca Stingeni,1 Anna Belloni Fortina,2 Ilaria Baiardini,3,4 Katharina Hansel,1 Devis Moretti,5 Filippo Cipriani5 1Dermatology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy; 2Unit of Dermatology, Department of Medicine - DIMED, University of Padua, Padua, Italy; 3Respiratory Unit for Continuity of Care, IRCCS, Ospedale Policlinico San Martino, Genova, Italy; 4Personalized Medicine Asthma, & Allergy Clinic, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; 5Sanofi Genzyme, Sanofi S.r.l., Milan, ItalyCorrespondence: Anna Belloni FortinaUnit of Dermatology, Department of Medicine – DIMED, University of Padua, Via Gallucci, 4, Padova, 35128, ItalyEmail anna.bellonifortina@unipd.itBackground: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent eczematous lesions and intense pruritus. AD patients are known to face a considerable disease burden, including physical and emotional limitations. There is still limited knowledge about daily implications in education and occupation. We describe disease social stigmatization by measuring bullying and self-isolation in students and professional discrimination in workers. Overall loss of productivity, either at school and at the workplace, was quantified as the sum of absenteeism (number of days AD sick leave) and presenteeism (number of days with decreased focus and functionality).Methods: An on-line web survey was sent to 3235 random recipients and 401 met the inclusion criteria (self-reporting AD and ≥ 12 yo). The survey domains included daily limitations, QoL, feelings and relationships, together with specific questions about bullying, discrimination and loss of productivity.Results: AD negatively affected QoL in 51.6% of respondents, whereas 68.8% considered AD as a real limit to daily routine. More in detail, 39.3% of students were victims of bullying and 33.9% of workers felt discriminated because of AD. On average, absenteeism in students was for 17.1 days/year (presenteeism: 19.5 days/year), whereas in workers, the estimate was 10.9 days/year (presenteeism: 13.1 days/year). Absenteeism and presenteeism were more pronounced in bullied/discriminated subjects.Conclusion: AD multidimensional implications deeply affect and undermine personal and professional fulfillments. Our results contribute to a better understanding of what living with AD means.Keywords: atopic dermatitis, discrimination, absenteeism, presenteeism

Adeno-associated virus (AAV) is a small, non-enveloped virus used as vector in gene therapy, mainly produced in human cells and in baculovirus systems. Intense studies on these platforms led to the production of vectors with titers between 103 and 105 viral genomes (vg) per cells. In spite of this, vector yields need to be improved to satisfy the high product demands of clinical trials and future commercialization. Our studies and those of other groups have explored the possibility to exploit the yeast Saccharomyces cerevisiae to produce rAAV. We previously demonstrated that yeast supports AAV genome replication and capsid assembly. The purpose of this study was to evaluate the quality of the encapsidated AAV DNA. Here, we report the construction of a yeast strain expressing Rep68/40 from an integrated copy of the Rep gene under the control of the yeast constitutive ADH promoter and Capsid proteins from the Cap gene under the control of an inducible GAL promoter. Our results indicate that a portion of AAV particles generated by this system contains encapsidated AAV DNA. However, the majority of encapsidated DNA consists of fragmented regions of the transgene cassette, with ITRs being the most represented sequences. Altogether, these data indicate that, in yeast, encapsidation occurs with low efficiency and that rAAVs resemble pseudo-vectors that are present in clinical-grade rAAV preparations.

A cellular coating based on hydrophobic interactions of an elastin-like recombinamer (ELR) with the cell membrane is presented. It is well-documented that biophysical properties such as net charge, hydrophobicity, and protein-driven cell-ligand (integrin binding) interactions influence the interaction of polymers, proteins or peptides with model membranes and biological cells. Most studies to enhance membrane-substrate interactions have focused on the introduction of positively charged groups to foster electrostatic interactions with the negatively charged membrane. Herein, we present an antagonistic approach based on ELRs with varying amounts of hydrophobic cholesteryl groups (ELRCTAs). The ability of the membranes to stabilize cholesteryl groups is hypothesized to assist the coordination of hydrophobic ELRs with the membrane. The main objective was to generate a defined cellular coating of a recombinant protein that allows for total sequence control and less host, or batch-to-batch, variation as a substitute for the existing coatings like alginate, polyelectrolytes, collagens, and fibronectin. We used an in vitro cell-binding assay to quantify cell-substrate interactions, showing enhanced cellular recognition and matrix distribution with an increasing number of cholesteryl groups incorporated. These novel materials and the versatile nature of their protein sequence have great potential as cellular markers, drug carriers, or hydrophobic cell-binding domains.

BACKGROUND In multiple phase 3 trials, dupilumab improved signs, symptoms (including pruritus), and quality-of-life (QoL) in adults with moderate-to-severe atopic dermatitis (AD). In Italy, dupilumab received innovation status but is currently only reimbursed by the National Health Service for adults with Eczema Area Severity Index (EASI) scores ≥24. This analysis assesses disease burden and dupilumab efficacy in adults with EASI scores above and below this threshold. METHODS This post-hoc analysis included 299 adults pooled from two, randomized, placebocontrolled, phase 3 trials, LIBERTY AD CAFE (NCT02755649) and LIBERTY AD CHRONOS (NCT02260986), who received the approved dupilumab regimen (300mg every 2 weeks) or placebo, with concomitant topical corticosteroids. EASI, Peak Pruritus Numerical Rating Scale (PP-NRS), and Dermatology Life Quality Index (DLQI) were assessed in patients with EASI scores ≥20 to

The paper explores the topic of design, materialization and release of open source wearables that can increase awareness about the mental, behavioral and physical conditions of people with health impairments. The first part, which is based on literature review, investigates the design of healthcare wearables connected to the emerging phenomena of open and user innovation. The second part describes the whole process of design and materialization of DermAware, an open source “experiential” wearable developed within the project Distributed Design Market Platform (Creative Europe Programme) and specifically conceived to increase the social awareness on a pathology such as Atopic Dermatitis. The final part defines an operational framework to design open source wearables, evidencing the process - from design to materialization – and the main critical aspects and opportunities related to the development of “experiential” devices. The conclusions of the paper identify a possible field for designing healthcare wearables called “Wear-to-Care”.

Adeno-associated virus (AAV) is a small, non-enveloped virus used as vector in gene therapy, mainly produced in human cells and in baculovirus systems. Intense studies on these platforms led to the production of vectors with titers between 10

Background and research question: Label extension for treatments and the relevant disease cross-coverage may produce an economic benefit. This paper assesses this benefit for dupilumab in the perspective of the Italian National Health Service. Dupilumab was approved for reimbursement for severe atopic dermatitis (AD), severe and refractory asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The analysis focused on the crowding-out effect of dupilumab on alternative treatments. Methods: The research relied on a simplified budget impact model. The model was populated by data from published evidence and relied on three alternative scenarios for market penetration (15%-30%-100%). Results: Avoidable direct health annual costs due to cross-coverage for (i) asthma in patients treated for AD ranged from 0.46 to 3.43 million euros, (ii) asthma in patients treated for CRSwNP ranged from 0.08 to 0.88 million euros, (iii) CRSwNP in patients treated for asthma ranged from 0.41 to 4.05 million euros respectively. The total economic benefit ranges from 0.95 to 8.36 million euros. Discussion: The research estimated the crowding-out effect of dupilumab on alternative treatments. It did not incorporate avoided/incremental events due to a possible better/worse risk-benefit profile of dupilumab vs alternative treatments and the economic benefit of cross-coverage on lower diseases severity (for example mild asthma). Nonetheless, the analysis relies on the best available evidence for Italy to shed light on a topic which has not been sufficiently investigated, and provides data that will be potentially very important for policy-makers, payers and those who manage new treatments.

Producción Científica, Tissue engineering for cartilage repair requires biomaterials that show rapid gelation and adequate mechanical properties. Although the use of hydrogel is the most promising biomaterial, it often lacks in rigidity and anchorage of cells when they are surrounded by synovial fluid while they are subjected to heavy loads. We developed and produced the Silk Elastin-Like co-Recombinamer (SELR), which contains both the physical interaction from elastin motifs and from silk motifs. In the first part of this work, we set up and optimized a preannealing treatment based on the evolution of silk motifs into β-sheet structures in order to fulfill the required mechanical properties of hydrogels for cartilage repair. The new preannealed SELRs (pA(EIS)2-(I5R)6) were characterized with the combination of several experimental techniques (CD, TEM, SEM, and rheology) to provide a deep insight into the material features. Finally, the regeneration properties of the pA(EIS)2-(I5R)6 hydrogel embedded with chondrocytes were evaluated. After 4 weeks of culturing in a standardized and representative ex vivo model, the biochemical and histological analysis revealed the production of glycosaminglycans and collagen. Moreover, the immunohistochemistry showed the absence of fibro-cartilage and the presence of hyaline cartilage. Hence, we conclude that the pA(EIS)2-(I5R)6 hydrogel presents improved mechanical properties while conserving the injectability, which leads to successful regeneration of hyaline cartilage in an ex vivo model., 2019-10-20, Ministerio de Economía, Industria y Competitividad (Proyects PCIN-2015-010, MAT2015-68901-R, MAT2016-78903-R,MAT2016-79435-R, Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. Project VA015U16), European Union’sHorizon 2020 research and innovation programme under theMarie Sklodowska-Curie grant agreement No. 64268

Biomaterial design in tissue engineering aims to identify appropriate cellular microenvironments in which cells can grow and guide new tissue formation. Despite the large diversity of synthetic polymers available for regenerative medicine, most of them fail to fully match the functional properties of their native counterparts. In contrast, the few biological alternatives employed as biomaterials lack the versatility that chemical synthesis can offer. Herein, we studied the HUVEC adhesion and proliferation properties of elastin-like recombinamers (ELRs) that were covalently functionalized with each three high-affinity and selectivity α

The aim of this study was to evaluate injectable, in situ cross-linkable elastin-like recombinamers (ELRs) for osteochondral repair. Both the ELR-based hydrogel alone and the ELR-based hydrogel embedded with rabbit mesenchymal stromal cells (rMSCs) were tested for the regeneration of critical subchondral defects in 10 New Zealand rabbits. Thus, cylindrical osteochondral defects were filled with an aqueous solution of ELRs and the animals sacrificed at 4 months for histological and gross evaluation of features of biomaterial performance, including integration, cellular infiltration, surrounding matrix quality and the new matrix in the defects. Although both approaches helped cartilage regeneration, the results suggest that the specific composition of the rMSC-containing hydrogel permitted adequate bone regeneration, whereas the ELR-based hydrogel alone led to an excellent regeneration of hyaline cartilage. In conclusion, the ELR cross-linker solution can be easily delivered and forms a stable well-integrated hydrogel that supports infiltration and de novo matrix synthesis This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 642687. The authors are grateful for the funding from the European Commission (NMP-2014-646075), the Spanish Government (PCIN-2015-010, MAT2015-68901-R, MAT2016-78903-R, MAT2016-79435-R), Junta de Castilla y León (VA015U16) and Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León. The authors also wish to thank Maria Victoria Saez Velasco for her important contribution to cell culture experiments SI

Regenerative Medicine is a well-established field of science that aims to replace, engineer and regenerate human cells, damaged tissues or organs to restore their normal function. This branch of translational research finds a deep interest in the Science of Biomaterials; indeed, the knowledge acquired in that field goes proportionally with the development of novel biomaterials. There is a great need in developing advanced biomaterials capable to fulfil the requirements of stability and bioactivity for their application in biomedicine. Moreover, considering the complexity of the human body, this system needs a certain rate of versatility in order to be tailored to a specific area of application. For all these reasons, recombinant proteins are an interesting approach, in which, elastin-like recombinamers (ELRs) represent one of the most promising biomaterials.ELRs are obtained through DNA recombinant technology, which allows the precise control at the genetic level, affording exquisite control over final protein functionality. ELRs are protein-based polypeptides that comprise repetitive units of the Val−Pro−Gly−X−Gly (VPGXG)n pentapeptide, in which X (guest residue) could be any amino acid except L-proline. In terms of biomaterial design, ELRs show several outstanding properties. ELRs are inspired by elastin, which is a component of natural extracellular matrix (ECM), showing excellent biocompatibility. One of the most important features of ELRs is that they exhibit thermo-responsiveness; this is due to the change of protein conformation above the so-called transition temperature (Tt), which depends on the amino acid composition of the polymer. Moreover, according to the ELRs design, they can be processed as several supramolecular structures, such as micelles, nanoparticles, films, and hydrogels. The large variety of ELRs, both in terms of structures and bioactivity, permits the application of these protein-based biomaterials to diverse biomedical applications. This Thesis represents a sort of journey towards the exploration of the evolution of ELRs as a powerful tool with great potential in the biomedical field., Departamento de Bioquímica y Biología Molecular y Fisiología, Doctorado en Investigación Biomédica

Producción Científica, Biomaterial design in tissue engineering aims to identify appropriate cellular microenvironments in which cells can grow and guide new tissue formation. Despite the large diversity of synthetic polymers available for regenerative medicine, most of them fail to fully match the functional properties of their native counterparts. In contrast, the few biological alternatives employed as biomaterials lack the versatility that chemical synthesis can offer. Herein, we studied the HUVEC adhesion and proliferation properties of elastin-like recombinamers (ELRs) that were covalently functionalized with each three high-affinity and selectivity αvβ3- and α5β1-binding bicyclic RGD peptides. Next to the bicycles, ELRs were also functionalized with various integrin-binding benchmark peptides, i.e. knottin-RGD, cyclo-[KRGDf] and GRGDS, allowing for better classification of the obtained results. Covalent functionalization with the RGD peptides, as validated by MALDI-TOF analysis, guarantees flexibility and minimal steric hindrance for interactions with cellular integrins. In addition to the covalently modified RGD-ELRs, we also synthesized another benchmark ELR comprising RGD as part of the backbone. HUVEC adhesion and proliferation analysis using the PicoGreen® assay revealed a higher short-term adhesion and proliferative capacity of cells on ELR surfaces functionalized with high affinity, integrin-binding bicyclic RGD-peptides compared with the ELRs containing RGD in the backbone., 2020-01-20, European Commission (NMP-2014-646075, MSCA-ITN-2014-ETN-642687), Ministerio de Economía, Industria y Competitividad (Projects PCIN-2015-010, 26 MAT2015-68901-R, MAT2016-78903-R), Junta de Castilla y León (programa de apoyo a proyectos de investigación - Ref. VA015U16)

Sex assessment is a crucial part of the biological profile in forensic and archaeological context, but it can be hardly performed in cases of commingled and charred human remains where DNA tests often are not applicable. With time literature have analyzed the sexual dimorphism of teeth (and especially canines), but very few articles take into consideration the teeth volume, although with time several technologies have been introduced in order to assess 3D volume (CT-scan, laser scanner, etc.). This study aims at assessing the sexual dimorphism of dental and pulp chamber volumes of a sample of canines. Cone beam computed tomography analyses were performed by 87 patients (41 males and 46 females, aged between 15 and 83 years) for clinical purposes, and were acquired in order to measure canine volumes. Results show that the dental volume amounted to 0.745 cm(3) (SD 0.126 cm(3)) in males, 0.551 cm(3) (SD 0.130 cm(3)) with a statistically significant difference (p0.01). A diagnostic threshold of 0.619 cm(3) was stated, which provides a percentage of correct answer of 80.5% in the chosen sample. The novel method was then applied with success to 7 archaeological: where in all the cases the results were concordant with those provided by the assessment of the cranium and pelvis. The study adds a contribution to the wide analysis of dental sexual dimorphism confirming the statistically significant differences of volume between males and females and providing a method for the diagnosis of sex applicable to forensic cases.

Elastin-like recombinamers (ELRs) are novel biomaterials inspired by natural elastin, a fibrous and insoluble protein that constitutes one of the most important structural and functional components of the extracellular matrix. ELR-based hydrogels are biocompatible, have specific mechanical properties and can also interact with the organism to improve the “nativeness” of regenerated tissue. Furthermore, bioactive groups can be incorporated into ELR peptides to obtain stronger and faster cell responses on tissues or coated biomaterial interfaces, thus promoting better regeneration or implant integration. Studies into the use of ELRs in tissue regeneration have increased steadily over the last 10 years, and the range of applications for tissue engineering has also increased. Indeed, recent studies have shown how different types of ELRs can be applied in some of the most challenging fields in tissue regeneration, such as cardiovascular, ocular prostheses, and osteochondral applications. One of the greatest advantages of ELRs is that their biological and mechanical properties can be readily tailored at the genetic level to satisfy end-user applications, thus offering numerous choices for the development of cell-culture matrices for tissue engineering.

BACKGROUND: Radioiodine ablation is an adjuvant procedure used to treat patients with differentiated thyroid cancer. For ablation to be successful, patients must have elevated levels of thyroid stimulating hormone (TSH). This can be achieved by withholding thyroid hormone therapy (endogenous stimulation), or by administration of recombinant human thyroid stimulating hormone (rhTSH; Thyrogen®; exogenous stimulation) to patients in the euthyroid state.AIM: To compare the estimated health benefits, cost and cost-effectiveness of TSH stimulation with and without Thyrogen® in the Italian setting.METHODS: A cost-utility analysis was undertaken to assess the impact of exogenous vs. endogenous TSH stimulation before radioiodine remnant ablation of patients with newly diagnosed, well-differentiated papillary or follicular thyroid cancer who have undergone total or near-total thyroidectomy. A Markov model was developed to simulate treatment costs and health outcomes associated with exogenous and endogenous stimulation in four distinct health states: pre-ablation, ablation, post-ablation, and well/recovery. Treatment was stratified by patients who receive high- and low-activity (30-100 mCi, respectively) in the ablation state. The Italian National Health System perspective was adopted in the base case scenario while the impact of indirect costs was explored in a sensitivity analysis. Costs and quality-adjusted life years (QALY) specific to each health state were estimated, summarized and converted into a corresponding incremental cost-effectiveness ratio (ICER).RESULTS: We calculated a cost-effectiveness ratio of 18,357.18 €/QALY gained whereas the inclusion of indirect cost and accident cost produced reductions of the ICER to € 14,609.51 and € 15,515.26 per QALY, respectively. Finally, all results in the sensitivity analysis are below the lower bound of national and international cost- effective threshold.CONCLUSION: Thyrogen® represents a cost-effective option for patients with differentiated thyroid cancer who underwent total or near-total thyroidectomy in Italy. Our findings are consistent with other cost-utility analyses.

Ba ckground : Lysosomal storage diseases (LSDs) are a heterogeneous group of rare chronic genetic conditions. The standard-of-care treatment for LSDs is hospital-based infusion of enzyme replacement therapy (ERT), however, over time this can be stressful and inconvenient. The Italian TuTor program, established in 2011 by Sanofi Genzyme, is a professional nursing service providing home-based ERT to patients with LSDs. Objectives: The current questionnaire-based study was conducted to investigate the level of patient satisfaction with the TuTor program and to shed light on disease perception. Methods: Patients were enrolled in the TuTor program from 2011 onwards. The first 100 patients enrolled were interviewed at baseline with follow-up interviews conducted at 6, 12 and 18 months. R esults: Overall, 52 patients were female; 46 had Gaucher’s disease, 46 had Fabry disease and 8 had mucopolysaccharidosis type 1. Patients took on average >2 hours to receive hospital-based ERT, plus time associated with the infusion; 2 out of 3 patients needed a caregiver to travel to the hospital. After receiving home-based ERT for 6 months, 37% of patients considered their quality of life ‘greatly improved’ (60% at 18 months). Overall, 99% to 100% of patients rated the home-based nursing service as ‘positive’ or ‘very positive’ and reported that they would recommend the service to other patients with their condition. Conclusions: For patients with LSDs eligible for ERT, a disease-specific home-based nursing service increased their perception of quality of life over a hospital-based service and was advantageous in terms of their time and expenditure.

The AP-1 transcription factor c-Jun is essential for cellular proliferation in many cell types, but the molecular link between growth factors and c-Jun activation has been enigmatic. In this study we identify a previously uncharacterized RING-domain-containing protein, RACO-1 (RING domain AP-1 co-activator-1), as a c-Jun co-activator that is regulated by growth factor signalling. RACO-1 interacted with c-Jun independently of amino-terminal phosphorylation, and was both necessary and sufficient for c-Jun/AP-1 activation. Growth factor-mediated stimulation of AP-1 was attributable to MEK/ERK-dependent stabilization of RACO-1 protein. Stimulation of the MEK/ERK pathway strongly promoted Lys 63-linked ubiquitylation of RACO-1, which antagonized Lys 48-linked degradative auto-ubiquitylation of the same Lys residues. RACO-1 depletion reduced cellular proliferation and decreased expression of several growth-associated AP-1 target genes, such as cdc2, cyclinD1 and hb-egf. Moreover, transgenic overexpression of RACO-1 augmented intestinal tumour formation triggered by aberrant Wnt signalling and cooperated with oncogenic Ras in colonic hyperproliferation. Thus RACO-1 is a co-activator that links c-Jun to growth factor signalling and is essential for AP-1 function in proliferation.

Techniques for estimation of biological age are constantly evolving and are finding daily application in the forensic radiology field in cases concerning the estimation of the chronological age of a corpse in order to reconstruct the biological profile, or of a living subject, for example in cases of immigration of people without identity papers from a civil registry. The deposition of teeth secondary dentine and consequent decrease of pulp chamber in size are well known as aging phenomena, and they have been applied to the forensic context by the development of age estimation procedures, such as Kvaal–Solheim and Cameriere methods. The present study takes into consideration canines pulp chamber volume related to the entire teeth volume, with the aim of proposing new regression formulae for age estimation using 91 cone beam computerized scans and a freeware open-source software, in order to permit affordable reproducibility of volumes calculation.

Objectives: To conduct a cost-effectiveness analysis of sevelamer versus calcium carbonate in patients with non-dialysis-dependent CKD (NDD-CKD) from the Italian NHS perspective using patient-level data from the INDEPENDENT-CKD study. Methods: Patient-level data on all-cause mortality, dialysis inception and phosphate binder dose were obtained for all 107 sevelamer and 105 calcium carbonate patients from the INDEPENDENT-CKD study. Hospitalization and frequency of dialysis data were collected post hoc for all patients via a retrospective chart review. Phosphate binder, hospitalization, and dialysis costs were expressed in 2012 euros using hospital pharmacy, Italian diagnosis-related group and ambulatory tariffs, respectively. Total life years (LYs) and costs per treatment group were calculated for the 3-year period of the study. Bootstrapping was used to estimate confidence intervals around outcomes, costs, and cost-effectiveness and to calculate the cost-effectiveness acceptability curve. A subgroup analysis of patients who did not initiate dialysis during the INDEPENDENT-CKD study was also conducted. Results: Sevelamer was associated with 0.06 additional LYs (95% CI -0.04 to 0.16) and cost savings of EUR -5,615 (95% CI -10,066 to -1,164) per patient compared with calcium carbonate. On the basis of the bootstrap analysis, sevelamer was dominant compared to calcium carbonate in 87.1% of 10,000 bootstrap replicates. Similar results were observed in the subgroup analysis. Results were driven by a significant reduction in all-cause mortality and significantly fewer hospitalizations in the sevelamer group, which offset the higher acquisition cost for sevelamer. Conclusions: Sevelamer provides more LYs and is less costly than calcium carbonate in patients with NDD-CKD in Italy.

In Aosta Valley region 77,9% of women (aged 25-64) are screened regularly, meaning every 3 years. Considering regional tariffs and vaccine acquisition cost, the vaccination of 12-year-old girls with a 90% coverage could prevent 2 cases of cervicocarcinoma and 1 related death and thus results to be cost-effective (33.211 €/QALY). When the vaccination programme is extended to 16-year-old girls a further 1 cancer case could be prevented, with a very similar cost-effectiveness ratio. In Aosta Valley region, the net cost for woman vaccinated is 209 € for the single cohort and 211 € for the multiple cohort.

The recent multicenter, randomized, open-label INDEPENDENT study demonstrated that sevelamer improves survival in new to hemodialysis (HD) patients compared with calcium carbonate. The objective of this study was to determine the cost-effectiveness of sevelamer versus calcium carbonate for patients new to HD, using patient-level data from the INDEPENDENT study. Cost-effectiveness analysis. Adult patients new to HD in Italy. A patient-level cost-effectiveness analysis was conducted from the perspective of the Servizio Sanitario Nazionale, Italy’s national health service. The analysis was conducted for a 3-year time horizon. The cost of dialysis was excluded from the base case analysis. Sevelamer was compared to calcium carbonate. Total life years (LYs), total costs, and the incremental cost per LY gained were calculated. Bootstrapping was used to estimate confidence intervals around LYs, costs, and cost-effectiveness and to calculate the cost-effectiveness acceptability curve. Sevelamer was associated with a gain of 0.26 in LYs compared to calcium carbonate, over the 3-year time horizon. Total drug costs were €3,282 higher for sevelamer versus calcium carbonate, while total hospitalization costs were €2,020 lower for sevelamer versus calcium carbonate. The total incremental cost of sevelamer versus calcium carbonate was €1,262, resulting in a cost per LY gained of €4,897. The bootstrap analysis demonstrated that sevelamer was cost effective compared with calcium carbonate in 99.4 % of 10,000 bootstrap replicates, assuming a willingness-to-pay threshold of €20,000 per LY gained. Data on hospitalizations was taken from a post hoc retrospective chart review of the patients included in the INDEPENDENT study. Patient quality of life or health utility was not included in the analysis. Sevelamer is a cost-effective alternative to calcium carbonate for the first-line treatment of hyperphosphatemia in new to HD patients in Italy.

Background The aim of the present study was to assess the cost-effectiveness of cement-less versus hybrid prostheses in total hip replacement (THR) in patients diagnosed with primary osteoarthritis. Methods Effectiveness data were obtained from the Emilia-Romagna Regional Registry on Orthopaedic Prosthesis (RIPO), which collects information on all orthopaedic intervention performed in Emilia-Romagna (41,199 total hip replacements performed from 2000 to 2007), and from which we obtained survival curves and transition probabilities for the cement-less and hybrid prostheses, respectively. Conversely, costs were derived from regional databases through a specific procedure, which allowed us to register individual component's costs for both primary and subsequent revision interventions. A specific Markov transition model was constructed in order to consider the 3 types of revisions that an implant could possibly undergo through its life-span: total, cup or stem, head insert or neck. The cost-effectiveness was expressed in terms of cost per “revision-free” life year. Results and conclusions Considering a 70-y old patient undergoing THR, the cementless strategy resulted more effective but more costly than the hybrid solution, with an incremental cost effectiveness ratio of 2401.63 € per revision-free life year. Following a deterministic sensitivity analysis, hybrid and cementless fixation showed, respectively, a dominance profile for patients older than 83 y and younger than 43 y, whereas for all ages in between, we report a progressive increase in the ICER of cementless prostheses. Our results proved to be robust, as underlined by the probabilistic sensitivity analysis performed using cost distributions.

Introduction: the impact of cervical cancer prevention, in particular through HPV female vaccination, has been published for many countries at the national level. However, to our knowledge no attempt has been made to address the impact at a regional level. Since the Italian health reforms of the early 1990s, introducing “managerialism”, decentralization and quasi-market mechanisms, regional authorities have consequently been experimenting with different organizational and funding models to achieve an acceptable combination of equity, efficiency, freedom of choice and cost-containment. Methods: a Markov model, previously described and successfully adapted to the national scenario [La Torre, 2007], has been used to explore the impact of preventive cervical cancer vaccination with Cervarix™ at a regional level in Italy. Resource use was based on a standard therapeutic path applied to all regions. However we quantified the impact of the so-called “decentralization progress” by collecting regional data on: pap-test coverage, tariffs for treatments and cost of the vaccination course. We performed for each Italian region a cost-effectiveness analysis combined with a regional budget impact analysis. The regional analyses compared HPV vaccination, both of a single female cohort (12 years old) and a multiple female cohort (12+16 years old), plus screening to screening only. Results: 21 regional reports were produced presenting regional results on screening coverage, treatments costs, ICER and ICUR, net cost per subject vaccinated etc. Conclusions: national and regional analyses have two different aims: the former wants to address national regulatory agencies and needs to be representative of the national population whereas the latter deals with the real budget-holders, accountable in the eyes of patients. Furthermore in the Italian scenario, characterized by decentralization and local autonomy, a further level of detail is essential in order to describe the specific local settings and implications of a new health intervention.