Statistics of extremes through m-component distribution

Cet article presente un modèle probabiliste à composantes multiples en s'appuyant sur l'analyse des chroniques de crues mesurées sur 19 rivières du sud de l'Italie. Un tel modèle peut être modifié si des points aberrants figurent dans l'échantillon considéré. L'identification de tels points aberrants est menée au moyen d'une estimation empirique de deux seuils appropriés, valables pour les rivières du sud de l'Italie. La combinaison de ces seuils permet de déterminer quatre classe de distribution caractérisées par le nombre de composantes (m=1, 2 et 3) du modèle probabiliste. (Résumé d'auteur

Combined Bulk and Surface Radiation Damage Effects at Very High Fluences in Silicon Detectors: Measurements and TCAD Simulations

In this work we propose a new combined TCAD radiation damage modelling scheme, featuring both bulk and surface radiation damage effects, for the analysis of silicon detectors aimed at the High Luminosity LHC. In particular, a surface damage model has been developed by introducing the relevant parameters (NOX, NIT) extracted from experimental measurements carried out on p-type substrate test structures after gamma irradiations at doses in the range 10-500 Mrad(Si). An extended bulk model, by considering impact ionization and deep-level cross-sections variation, was included as well. The model has been validated through the comparison of the simulation findings with experimental measurements carried out at very high fluences (2 10^16 1 MeV equivalent n/cm^2) thus fostering the application of this TCAD approach for the design and optimization of the new generation of silicon detectors to be used in future HEP experiments.Comment: 8 pages, 14 figures. arXiv admin note: text overlap with arXiv:1611.1013

Investigations on Arthropods Associated with Decay Stages of Buried Animals in Italy

Burial could be used by criminals to conceal the bodies of victims, interfering with the succession of sarcosaprophagous fauna and with the evaluation of post-mortem interval. In Italy, no experimental investigation on arthropods associated with buried remains has been conducted to date. A first experimental study on arthropods associated with buried carcasses was carried out in a rural area of Arcavacata di Rende (Cosenza), Southern Italy, from November 2017 to May 2018. Six pig carcasses (Sus scrofa Linnaeus) were used, five of which were buried in 60-cm deep pits, leaving about 25-cm of soil above each carcass, and one was left above ground. One of the buried carcasses was periodically exhumed to evaluate the effects of disturbance on decay processes and on arthropod fauna. The other four carcasses were exhumed only once, respectively after 43, 82, 133, and 171 days. As expected, the decay rate was different among carcasses. Differences in taxa and colonization of arthropod fauna were also detected in the above ground and periodically exhumed carcasses. In carcasses exhumed only once, no arthropod colonization was detected. The results showed that a burial at about 25 cm depth could be sufficient to prevent colonization by sarcosaprophagous taxa and these data could be relevant in forensic cases involving buried corpses

Necrodes littoralis (Coleoptera: Silphidae) visiting and breeding on a carcass in Italy

The community that progressively colonizes a decaying corpse can be considered a small ecosystem mostly composed of sarcosaprophagous arthropods belonging to the orders Diptera and Coleoptera. Studies on these species are often performed through animal models to obtain data on their succession, behaviour and life cycle, together with information on habitat, corpse conditions, season and association with other species. These data may be relevant for forensic investigations, especially concerning the estimation of Post Mortem Interval (PMI). An investigation on the sarcosaprophagous insect community in a rural area was set in Calabria (Southern Italy), using a pig, Sus scrofa Linnaeus, 1758 (Artiodactyla: Suidae) as experimental model. Analyses of the community of Diptera and Coleoptera revealed the massive presence of Necrodes littoralis (Linnaeus, 1758) (Coleoptera: Silphidae). Adults of this species reached the carcass during the bloated stage and a large amount of larvae was detected from the decay stage onwards, simultaneous to the sharp decrease in dipteran larvae and pupae. The occurrence and the activity of N. littoralis should be considered to avoid misinterpretation and errors in estimating PMI in forensic investigation

Development of a new generation of 3D pixel sensors for HL-LHC

This paper covers the main technological and design aspects relevant to the development of a new generation of thin 3D pixel sensors with small pixel size aimed at the High-Luminosity LHC upgrades. (C) 2015 Elsevier B.V. All rights reserved

Management of Myelofibrosis during Treatment with Ruxolitinib: A Real-World Perspective in Case of Resistance and/or Intolerance

The development and approval of ruxolitinib, the first JAK1/2 inhibitor indicated to treat myelofibrosis, has improved patient outcomes, with higher spleen and symptoms responses, improved quality of life, and overall survival. Despite this, several unmet needs remain, including the absence of resistance criteria, suboptimal response, the timing of allogeneic transplant, and the management of patients in case of intolerance. Here, we report the results of the second survey led by the “MPN Lab” collaboration, which aimed to report physicians’ perspectives on these topics. As in our first survey, physicians were selected throughout Italy, and we included those with extensive experience in treating myeloproliferative neoplasms and those with less experience representing clinical practice in the real world. The results presented here, summarized using descriptive analyses, highlight the need for a clear definition of response to ruxolitinib as well as recommendations to guide the management of ruxolitinib under specific conditions including anemia, thrombocytopenia, infections, and non-melanoma skin cancers

The INFN-FBK "Phase-2" R&D program

We report on the 3-year INFN ATLAS-CMS joint research activity in collaboration with FBK, started in 2014, and aimed at the development of new thin pixel detectors for the High Luminosity LHC Phase-2 upgrades. The program is concerned with both 3D and planar active-edge pixel sensors to be made on 6" p-type wafers. The technology and the design will be optimized and qualified for extreme radiation hardness (2×1016 neq cm-2). Pixel layouts compatible with present (for testing) and future (RD53 65nm) front-end chips of ATLAS and CMS are considered. The paper covers the main aspects of the research program, from the sensor design and fabrication technology, to the results of initial tests performed on the first prototypes. © 2015 Elsevier B.V

Treatment of Lenalidomide Exposed or Refractory Multiple Myeloma: Network Meta-Analysis of Lenalidomide-Sparing Regimens

Over the past 10 years, the treatment of multiple myeloma (MM) dramatically changed due to the introduction of a number of new agents and combination regimens both in the frontline and in the relapsed/refractory setting. Currently, at least 11 classes of therapeutic agents, including steroids, alkylators (melphalan and cyclophosphamide), proteasome inhibitors (PI: bortezomib, carfilzomib, ixazomib), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), monoclonal antibodies (mAbs: elotuzumab, daratumumab), HDAC-inhibitors (panobinostat), BCL2 inhibitors (venetoclax), selective inhibitors of nuclear export (selinexor), drug-conjugated mAbs (belantamab mafodotin), bispecific agents and CAR-T, are approved (or are going to be approved) alone or in different combinations for the treatment of this disease, while few or no data are available to guide the therapeutic strategy to adopt at diagnosis or relapse (1). The choice of the treatment at relapse (2), in particular, poses particular challenges, and is currently dependent on patients (age, comorbidities, fitness, renal impairment, frailty) and disease characteristics (aggressive vs biochemical relapse, cytogenetics, presence of extra-medullary disease), previous treatments (classes of agents, duration of response, progression while on therapy), regional drug access (approval of combinations, reimbursement, costs) and, finally, patient’s choice. Unfortunately, there is a lack of trials specifically designed to help in this choice, and often, pre-planned subgroup analyses, do not include a sufficient number of patients to reach statistical evidence. Recently, since lenalidomide is progressively becoming the preferred one-line option to treat MM patients (and often, it is administered until progression), the choice of the treatment to be offered at relapse should be carefully evaluated. Interestingly, it has been reported that the longest prior lenalidomide treatment duration (>12 months) and IMiD-free interval (>18 months) could positively impact patients’ outcome (3), making the choice of a lenalidomide-sparing regimen of particular interest in this setting. On the bases of these premises, we performed a systematic review and a frequentist network meta-analysis in R [by using the netmeta package (4)] comparing direct and indirect evidence on the efficacy of seven different lenalidomide-sparing regimens (bortezomib-dexamethasone, VD; daratumumab-VD, DVD; carfilzomib-D, KD; daratumumab-KD, KdD; pomalidomide-VD, PVD; isatuximab-KD, IKD; selinexor-VD, SVD) in lenalidomide-exposed and lenalidomide-refractory patients, to provide statistical evidence to support clinical decision makin

Long-Term Remission Achieved by Ponatinib and Donor Lymphocytes Infusion in a Ph+ Acute Lymphoblastic Leukemia Patient in Molecular Relapse After Allogenic Stem Cell Transplant and Dasatinib: A Case Report

Currently, the prognosis of Ph+ acute lymphoblastic leukemia (Ph+ ALL) patients relapsing after an allogenic hematopoietic stem cell transplantation (allo-SCT) remains poor, with few therapeutic options available. Here we present the case of a 32 years old patient with dasatinib-resistant post-transplant molecular relapse of ALL, who received, as second-line therapy, the combination of ponatinib and donor lymphocyte infusion (DLI). The therapy was safe and the patient achieved a sustained minimal residual disease negative disease, still ongoing after 22 months, which was accompanied by several changes in the immune populations distribution within the bone marrow (i.e., the increase in the CD8/CD4 lymphocytes ratio). Our report provides evidence of the efficacy of the third generation TKI inhibitor ponatinib in combination with DLI as second line therapy for Ph+ ALL relapsing after an allo-SCT

The strategic relevance of manufacturing technology : an overall quality concept to promote innovation preventing drug shortage

Manufacturing is the bridge between research and patient: without product, there is no clinical outcome. Shortage has a variety of causes, in this paper we analyse only causes related to manufacturing technology and we use shortage as a paradigm highliting the relevance of Pharmaceutical Technology. Product and process complexity and capacity issues are the main challenge for the Pharmaceutical Industry Supply chain. Manufacturing Technology should be acknowledged as a R&D step and as a very important matter during University degree in Pharmacy and related disciplines, promoting collaboration between Academia and Industry, measured during HTA step and rewarded in terms of price and reimbursement. The above elements are not yet properly recognised, and manufacturing technology is taken in to consideration only when a shortage is in place. In a previous work, Panzitta et al. proposed to perform a full technology assessment at the Health Technological Assessment stage, evaluating three main technical aspects of a medicine: manufacturing process, physicochemical properties, and formulation characteristics. In this paper, we develop the concept of manufacturing appraisal, providing a technical overview of upcoming challenges, a risk based approach and an economic picture of shortage costs. We develop also an overall quality concept, not limited to GMP factors but broaden to all elements leading to a robust supply and promoting technical innovation