A large and feasible national survey representative of population exposure to outdoor gamma radiation in urban areas.

Background: Although data on outdoor gamma radiation are available for many countries, they have generally been obtained with measurements performed in undisturbed environments instead of in urban areas where most of the population lives. Only one large national survey, with on-site measurements in urban areas, has been identified worldwide, probably due to high costs (e.g., personnel and instrumentation) and difficulties in selecting measuring points. Methods: A campaign of outdoor gamma radiation measurements has been carried out in the entire Italian territory. All measurement points were selected at the infrastructures of an Italian telecommunications company as representatives of all the possible situations of outdoor exposure to gamma radiation for population in urban areas. Ten replicates of portable gamma (X) detectors carried out all the measurements. Results: Approximately 4,000 measurements have been performed. They are distributed across 2,901 Italian municipalities, accounting for 75% of the Italian population. The national population-weighted mean of the gamma ambient dose equivalent rate (ADER) is 117 nSv h-1, and it ranges from 62 to 208 nSv h-1 and from 40 to 227 nSv h-1 for 21 regions and 107 provinces, respectively. The average variability at the municipal level, in terms of the coefficient of variation (CV) is 21%, ranging from 3 to 84%. The impact of land coverage and the distance from a building on the outdoor gamma radiation level was assessed with complementary measurements, leading to differences ranging from -40 to 50% and to 50%, respectively. Conclusion: A representative campaign of outdoor gamma dose rate measurements has been performed in Italy, only in urban areas, to assess the exposure effect due to outdoor gamma radiation on the population. It is the largest national campaign in urban areas worldwide, with a total of 3,876 on-site measurements. The land coverage and the distance from surrounding buildings were recognized to strongly affect outdoor gamma radiation levels, leading to high variability within small areas. The collaboration with a company that owns a network of facilities on a national territory as dense as the residing population made this survey feasible and affordable. Other countries might adopt this methodology to conduct national surveys in urban environments.

Thoron Interference on Performance of Continuous Radon Monitors: An Experimental Study on Four Devices and a Proposal of an Indirect Method to Estimate Thoron Concentration.

The performance of continuous radon monitors (CRMs) is usually evaluated under controlled conditions in a radon chamber during calibrations or intercomparison exercises. The impact of thoron on CRMs response is rarely evaluated; in case the evaluation is performed, it is carried out in a controlled atmosphere with relatively constant, homogeneous, and generally high thoron concentrations and very low radon levels. In a real indoor environment, both radon and thoron concentrations are extremely variable, so the thoron interference evaluations reported in the literature are generally not applicable to CRMs used to measure radon concentration indoors. For this reason, an experimental study was carried out with four different CRMs in an indoor environment (an office room) where medium-to-high concentrations of both radon and thoron were expected. Thoron concentration has been separately evaluated throughout two different active monitors. Three CRMs resulted in overestimations of radon concentration by about 10% due to thoron interference, whereas such interference results were negligible for the fourth CRM. However, the thoron interference can also be used to assess thoron concentration by using CRM not specifically designed to do so. Based on the results of this study, an indirect method to assess thoron concentration is indeed proposed, relying on the combination of two identical monitors (one placed right close to the wall and the other one far enough from there).

Cost-effectiveness analysis to assess the protection of workers from exposure to radon at work: A first application to Italian retail shops.

For the implementation of the requirements in the Council Directive 2013/59/Euratom (2013 EUBSS), the cost-effectiveness analysis (CEA) is generally considered a useful tool to compare different radon policies aimed at reducing radon exposure both at home and at work. In the framework of the EU funded RADPAR project, a methodology to perform CEA analysis of radon control in dwellings was developed - and used also for WHO's radon recommendations of 2009 - and it is based on the evaluation of the health effectiveness in terms of life years and/or QALYs (Quality Adjusted Life Years) gained. In this work, starting from the RADPAR model used for dwellings, a so-called RADPAR4workplaces model was developed to carry out CEA focused on reduction of radon exposure at workplaces. In particular, different radon policies in existing workplaces were considered and their cost-effectiveness were estimated, as a case study, for the Italian retail shops located at ground floor. Main results show that a policy that requires remedial actions where radon concentration is above a certain reference level (RL) and that recommends them also below this RL has a good cost-effectiveness ratio and it is more effective than a policy with no provisions for radon levels below RL. In particular, the further implementation of remediation below RL improves the health effectiveness increasing QALYs gained of 20% while cost per QALY increases of only 14%. Finally, promoting the remediation of workplaces below RL, QALYs gained and cost per QALY increase of about 80% and 20%, respectively, if remediation rate rises from 10% to 50% below RL.

A 10-year follow-up study of yearly indoor radon measurements in homes, review of other studies and implications on lung cancer risk estimates.

Uncertainty on long-term average radon concentration has a large impact on lung cancer risk assessment in epidemiological studies. The uncertainty can be estimated by year-to-year radon concentration variability, however few data are available. In Italy a study has been planned and conducted to evaluate year-to-year radon variability over several years in normally inhabited dwellings, mainly located in Rome. This is the longest study of this kind in Europe; repeat radon measurements are carried out for 10 years using LR-115 radon detectors in the same home in consecutive years. The study includes 84 dwellings with long-term average radon concentration ranging from 28 to 636 Bq/m3. The result shows that year-to-year variability of repeated measurements made in the same home in different years is low, with an overall coefficient of variation of 17%. This is smaller than most of those observed in studies from other European countries and USA, ranging from 15% to 62%. Influencing factors that may explain the differences between this study and other studies have been discussed. Due to the low yearly variability estimated in the present 10-year study, a negligible impact on lung cancer risk estimate for the Italian epidemiological study is expected.

[Establishing the value of new drugs in Italy.] / Quanto vale la negoziazione del prezzo di un nuovo farmaco in Italia?

Italy was used as a case study to investigate the determinants of the difference between the price proposal for medicines submitted by the industry and the final negotiated price (∆P). Data was gathered through the information system used by Italian Medicines Agency (AIFA) and the time-frame for this analysis is 2013-2017. Factors influencing the delta price were analyzed through a regression analysis. Forty four orphan drugs and 89 new other molecular entities obtained reimbursement in the period considered. Following the negotiation process, prices proposed by Marketing Authorization Holders (MAH) were lowered during the negotiation process by 25.1% and 28.6% on average for orphan drugs and other molecules respectively. The price reduction was higher for innovative drugs (-32.2%). Statistically significant determinants associated to higher price reduction were: i) the implementation of a product specific monitoring registry, ii) the negotiation of a financial-based (FB) Managed Entry Agreement, iii) a target population larger than 20,000 patients, iv) an expected National Health Service expenditure larger than € 200 million. The impact of some variables on the delta price was predictable (e.g. for drugs with an expected higher budget impact and a larger target population), others were more surprising (e.g. a significant price reduction for "innovative" drugs). The implementation of FB agreements, which often rely on confidential arrangements, was one of the determinants with higher impact on price reduction.

Determinants of price negotiations for new drugs. The experience of the Italian Medicines Agency.

OBJECTIVES: The aim of this paper is to investigate the determinants of the difference between the price proposal submitted by the industry and the final negotiated price. We used Italy as a case-study. METHODS: Data were gathered through the information system used by Italian Medicines Agency. The time-frame for this analysis is 2013-2017. Factors influencing the delta price were analyzed through a regression analysis. RESULTS: 44 orphan drugs and 89 new other molecular entities obtained reimbursement in the last five years. Following the negotiation process, prices were lowered by 25.1% and 28.6% on average for orphan drugs and other molecules respectively. The price reduction was higher for innovative drugs (-32.2%). Statistically significant determinants associated to higher price reduction were: i) the implementation of a product specific monitoring registry, ii) the negotiation of a financial-based Managed Entry Agreement, iii) a target population larger than 20,000 patients, iv) an expected National Health Service expenditure larger than €200 million. DISCUSSION: The impact of some variables on the delta price was predictable (e.g. for drugs with an expected higher budget impact and a larger population target), others were more surprising (e.g. a significant price reduction for "innovative" drugs). The implementation of financial-based agreements, which often rely on confidential arrangements, was one of the determinants with higher impact on price reduction.

Changes in the expression of hypothalamic lipid sensing genes in rat model of intrauterine growth retardation (IUGR).

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. The mechanisms underlying this phenomenon are unknown. Recent data suggest that some of the molecular defects underlying type 2 diabetes reside in the CNS. The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where LCFA undergo beta-oxidation. Hypothalamic inhibition of CPT1 decreases food intake and suppresses endogenous glucose production. Our aim was to investigate the effects of uterine artery ligation, a procedure that mimics uteroplacental insufficiency, on the CNS expression of CPT1 and other key enzymes of LCFA metabolism. Bilateral uterine artery ligation was performed on d 19 of gestation in the pregnant rat; sham-operated pregnant rats served as controls. Hypothalamus, cerebellum, hippocampus, and cortex were dissected and analyzed at birth by real-time PCR. Nonesterified fatty acid (NEFA) serum levels were significantly higher in IUGR pups (p<0.0001). In IUGR rats, the hypothalamic expression of CPT1 isoform C (p=0.005) and acetyl-CoA carboxylase (ACC) isoforms alpha (p<0.05) and beta (p=0.005) were significantly decreased. The data presented here support the hypothesis that an abnormal intrauterine milieu can induce changes in hypothalamic lipid sensing.