The role of health technology assessment bodies in shaping drug development.

This is the final version of the article. Available from the publisher via the DOI in this record.The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company's perspective, as market prospects are strongly influenced by third-party payers' coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed

No free lunch, buddy: housing transfers and informal care later in life

Previous empirical literature on intergenerational transfers of assets and services has mostly focused on the contemporary exchange or on the bequest motive. Differently, using Italian data, we provide evidence that parents who help their adult children with housing at the time of marriage are rewarded by higher chances of receiving informal care later in life. We show that this relation is robust to controlling for a wide set of individual and family characteristics and we discuss three possible explanations: (i) increased geographical distance; (ii) parents' reinforcement through support for the production of grandchildren; (iii) correlation with future nancial transfers

The influence of phosphatidylserine localisation and lipid phase on membrane remodelling by the ESCRT-II/ESCRT-III complex

The endosomal sorting complex required for transport (ESCRT) organises in supramolecular structures on the surface of lipid bilayers to drive membrane invagination and scission of intraluminal vesicles (ILVs), a process also controlled by membrane mechanics. However, ESCRT association with the membrane is also mediated by electrostatic interactions with anionic phospholipids. Phospholipid distribution within natural biomembranes is inhomogeneous due to, for example, the formation of lipid rafts and curvature-driven lipid sorting. Here, we have used phase-separated giant unilamellar vesicles (GUVs) to investigate the link between phosphatidylserine (PS)-rich lipid domains and ESCRT activity. We employ GUVs composed of phase separating lipid mixtures, where unsaturated DOPS and saturated DPPS lipids are incorporated individually or simultaneously to enhance PS localisation in liquid disordered (Ld) and/or liquid ordered (Lo) domains, respectively. PS partitioning between the coexisting phases is confirmed by a fluorescent Annexin V probe. Ultimately, we find that ILV generation promoted by ESCRTs is significantly enhanced when PS lipids localise within Ld domains. However, the ILVs that form are rich in Lo lipids. We interpret this surprising observation as preferential recruitment of the Lo phase beneath the ESCRT complex due to its increased rigidity, where the Ld phase is favoured in the neck of the resultant buds to facilitate the high membrane curvature in these regions of the membrane during the ILV formation process. Ld domains offer lower resistance to membrane bending, demonstrating a mechanism by which the composition and mechanics of membranes can be coupled to regulate the location and efficiency of ESCRT activity

Profiling acquired pedophilic behavior: Retrospective analysis of 66 Italian forensic cases of pedophilia

Neurological disorders can be mis-diagnosed as psychiatric ones. This might happen to pedophilia emerging as a symptom of brain insult (i.e. acquired pedophilic behavior). This paper aims to delineate a behavioral profile that might help to identify defendants whose pedophilic behavior is likely to be the consequence of a neurological disorder. Through a systematic review of the literature, seventeen clinical and behavioral variables of the modus operandi and victimology that can distinguish between acquired and developmental pedophilic behavior have been collected. Seven of these were found to be consistent behavioral indicators (i.e. red flags) for acquired pedophilia. Cluster hierarchical analysis on the seventeen variables collected through the systematic review of the literature on cases of acquired pedophilic behavior was applied to a new dataset including 66 Italian closed cases of pedophilia. Stepwise regression and correlation analyses were carried out to further examine the differences between the clusters identified in the cluster analysis. Results revealed that the new sample was partitioned into two clusters. Individuals with ascertained acquired pedophilia were grouped together. The clusters widely differed for the prevalence of red flags (mean number of red flags in each cluster: 2.14 ± 0.79 vs 4.96 ± 0.93, p < 0.001), while no between cluster difference emerged for the other clinical and behavioral variables. Regression analysis provided a robust model that included the three most significant red flags that explain over 64.5% of the variance (absence of masking, spontaneous confession and offenders older age). An organic origin of pedophilic behavior should be suspected if red flags are present in a defendant charged with pedophilia. In those cases, an in depth trans-disciplinary neuroscientific investigation is advocated. The behavioral profile identified might help to provide a proper assessment of defendants

Proliferation of cerebellar precursor cells is negatively regulated by nitric oxide in newborn rat.

The diffusible messenger, nitric oxide plays multiple roles in neuroprotection, neurodegeneration and brain plasticity. Its involvement in neurogenesis has been disputed, on the basis of results on models in vivo and in culture. We report here that pharmacological blockade of nitric oxide production in rat pups resulted, during a restricted time window of the first three postnatal days, in increased cerebellar proliferation rate, as assessed through tritiated thymidine or BrdU incorporation into DNA. This was accompanied by increased expression of Myc, a transcription factor essential for cerebellar development, and of the cell cycle regulating gene, cyclin D1. These effects were mediated downstream by the nitric oxide-dependent second messenger, cGMP. Schedules of pharmacological NO deprivation targeted to later developmental stages (from postnatal day 3 to 7), no longer increased proliferation, probably because of partial escape of the cGMP level from nitric oxide control. Though limited to a brief temporal window, the proliferative effect of neonatal nitric oxide deprivation could be traced into adulthood. Indeed, the number of BrdU-labeled surviving cells, most of which were of neuronal phenotype, was larger in the cerebellum of 60-day-old rats that had been subjected to NO deprivation during the first three postnatal days than in control rats. Experiments on cell cultures from neonatal cerebellum confirmed that nitric oxide deprivation stimulated proliferation of cerebellar precursor cells and that this effect was not additive with the proliferative action of sonic hedgehog peptide. The finding that nitric oxide deprivation during early cerebellar neurogenesis, stimulates a brief increase in cell proliferation may contribute to a better understanding of the controversial role of nitric oxide in brain development

A divergent canonical WNT-signaling pathway regulates microtubule dynamics: Dishevelled signals locally to stabilize microtubules

Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3β (GSK-3β). In the canonical WNT pathway, the negative regulator Axin forms a complex with β-catenin and GSK-3β, resulting in β-catenin degradation. Inhibition of GSK-3β by DVL increases β-catenin stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3β through a transcription- and β-catenin–independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3β–mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3β, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability

Reliability analysis of wireless sensor network for smart farming applications

Wireless Sensor Networks are subjected to some design constraints (e.g., processing capability, storage memory, energy consumption, fixed deployment, etc.) and to outdoor harsh conditions that deeply affect the network reliability. The aim of this work is to provide a deeper understanding about the way redundancy and node deployment affect the network reliability. In more detail, the paper analyzes the design and implementation of a wireless sensor network for low-power and low-cost applications and calculates its reliability considering the real environmental conditions and the real arrangement of the nodes deployed in the field. The reliability of the system has been evaluated by looking for both hardware failures and communication errors. A reliability prediction based on different handbooks has been carried out to estimate the failure rate of the nodes self-designed and self-developed to be used under harsh environments. Then, using the Fault Tree Analysis the real deployment of the nodes is taken into account considering the Wi-Fi coverage area and the possible communication link between nearby nodes. The findings show how different node arrangements provide significantly different reliability. The positioning is therefore essential in order to obtain maximum performance from a Wireless sensor network

The Dusty Starburst Nucleus of M33

We have thoroughly characterized the ultraviolet to near-infrared (0.15 - 2.2 micron) spectral energy distribution (SED) of the central parsec of the M33 nucleus through new infrared photometry and optical/near-infrared spectroscopy, combined with ultraviolet/optical observations from the literature and the HST archive. The SED shows evidence for a significant level of attenuation, which we model through a Monte Carlo radiative transfer code as a shell of clumpy Milky Way-type dust (tau_V ~ 2 +/- 1). The discovery of Milky Way-type dust (with a strong 2175 A bump) internal to the M33 nucleus is different from previous work which has found SMC-like dust (no bump) near starburst regions. The amount by which dust can be processed may be related to the mass and age of the starburst as well as the extent to which the dust can shield itself. Our starburst models include the effects of this dust and can fit the SED if the nucleus was the site of a moderate (~10^8 L_sun at 10 Myrs) episode of coeval star formation about 70 Myrs ago. This result is quite different from previous studies which resorted to multiple stellar populations (between 2 and 7) attenuated by either no or very little internal dust. The M33 nuclear starburst is remarkably similar to an older version (70 Myr versus 10 Myr) of the ultra-compact starburst in the center of the Milky Way.Comment: 29 pages, 9 embedded figures, ApJ, in pres

Trans-arterial radioembolization in intermediate-advanced hepatocellular carcinoma: systematic review and meta-analyses.

Published onlineJournal ArticleThis is the final version of the article. Available from Impact Journals via the DOI in this record.Trans-arterial radioembolization (TARE) is a recognized, although not explicitly recommended, experimental therapy for unresectable hepatocellular carcinoma (HCC).A systematic literature review was performed to identify published studies on the use of TARE in intermediate and advanced stages HCC exploring the efficacy and safety of this innovative treatment.Twenty-one studies reporting data on overall survival (OS) and time to progression (TTP), were included in a meta-analysis. The pooled post-TARE OS was 63% (95% CI: 56-70%) and 27% (95% CI: 21-33%) at 1- and 3-years respectively in intermediate stage HCC, whereas OS was 37% (95% CI: 26-50%) and 13% (95% CI: 9-18%) at the same time intervals in patients with sufficient liver function (Child-Pugh A-B7) but with an advanced HCC because of the presence of portal vein thrombosis. When an intermediate and advanced case-mix was considered, OS was 58% (95% CI: 48-67%) and 17% (95% CI: 12-23%) at 1- and 3-years respectively. As for TTP, only four studies reported data: the observed progression probability was 56% (95% CI: 41-70%) and 73% (95% CI: 56-87%) at 1 and 2 years respectively. The safety analysis, focused on the risk of liver decompensation after TARE, revealed a great variability, from 0-1% to more than 36% events, influenced by the number of procedures, patient Child-Pugh stage and treatment duration.Evidence supporting the use of radioembolization in HCC is mainly based on retrospective and prospective cohort studies. Based on this evidence, until the results of the ongoing randomized trials become available, radioembolization appears to be a viable treatment option for intermediate-advanced stage HCC.The present study was funded by ASBM Srl through an unrestricted grant to CERGAS, Bocconi University, Via Roentgen 1, 20136 Milan, Italy