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Key points - • National Health Service (NHS) is becoming increasingly aware of the need to support independent research to answer some important questions for patient care in areas of scant commercial interest. • This article reports the main features and strategies of the independent research programme on drugs launched by the Italian Medicines Agency (AIFA) in 2005. • In the three bids launched between 2005 and 2007, a total of 151 studies have been approved for funding for a total of about 78 million Euro. • In this article we describe the Italian legislative framework under which the programme was launched, the types of research funded and discuss how the supported studies could contribute, in an international framework, to the knowledge needed on drug efficacy, effectiveness and safety.

Chronic hepatitis C was a frequent complication in patients treated for malignancy until the introduction of anti-HCV screening tests for blood donors. The association between chronic hepatitis C and progression to cirrhosis and hepatocellular carcinoma has been reported in about 20% and 5% of patients, respectively, within 20-30 years of infection. In adult patients, interferon has proved to be effective in decreasing the abnormal values of transaminases and the level of HCV viremia. Our purpose was to assess efficacy of and tolerance to interferon in a group of young patients who had acquired HCV infection during a period of chemotherapy.Interferon-a (IFN) was administered to 26 adolescents and young adults (13 males, age range 17-36 years; median age 24) with chronic hepatitis C, including 4 with hepatitis B virus co-infection, who had been treated for leukemia or solid tumor 5 to 19 years before joining this trial. Patients were treated with natural IFN alpha at a dose of 4 MU/m(2) thrice weekly for 12 months and followed up for another 6 months thereafter.Nine patients stopped treatment during the first 6 months because of side effects (2 cases) or lack of response. At the end of the trial, 8 (31%) cases had responded, with alanine amino-transferase normalization and clearance of hepatitis C virus (HCV) RNA. A sustained response was only documented in 15% of cases, however, irrespective of any hepatitis B virus co-infection. The 2 patients with HCV genotype 2 were both responders, whereas only 8% of those with genotype 1 responded.These data show that the efficacy of IFN in this series of young patients is similar to that reported for otherwise healthy adults with hepatitis C. Patients with genotype 2 are strong candidates for IFN treatment while other therapeutic strategies should be designed for patients with HCV genotype 1.

Objectives A prospective cohort study was conducted in Italy in order to describe the microbiologic aspects of colonization/infection by carbapenemase-producing Enterobacteriaceae (CPE) in donors and recipients of lung and liver transplants and the possible CPE transmission from donors to recipients. Methods Between 15 January 2014 and 14 January 2015, all recipients of solid organ transplants (SOT) at ten lung and eight liver transplantation centres and the corresponding donors were enrolled. Screening cultures to detect CPE were performed in donors, and screening and clinical cultures in recipients with a 28-day microbiologic follow-up after receipt of SOT. Detection of carbapenemase genes by PCR, genotyping by multilocus sequence typing, and pulsed-field gel electrophoresis and whole-genome sequencing were performed. Results Of 588 screened donors, 3.4% were colonized with CPE. Of the liver first transplant recipients (n = 521), 2.5% were colonized before receipt of SOT and 5% acquired CPE during follow-up. CPE colonization was higher in lung first transplant recipients (n = 111, 2.7% before SOT and 14.4% after SOT). CPE infections occurred in 1.9% and 5.3% of liver or lung recipients, respectively. CPE isolates were mostly Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae belonging to CG258. Three events of donor–recipient CPE transmission, confirmed by whole-genome sequencing and/or pulsed-field gel electrophoresis, occurred in lung recipients: two involving K. pneumoniae sequence type 512 and one Verona integron-encoded metallo-β-lactamase (VIM)-producing Enterobacter aerogenes. Conclusions This study showed a low risk of donor–recipient CPE transmission, indicating that donor CPE colonization does not necessarily represent a contraindication for donation unless colonization regards the organ to be transplanted. Donor and recipient screening remains essential to prevent CPE transmission and cross-infection in transplantation centres.

This study examines the role of corporate social responsibility (CSR) in the investment preferences of tour operators through a discrete choice experiment conducted among tour operator managers worldwide. Stakeholder theory is used as a theoretical platform for explaining the role of CSR within the tour operators’ investment preferences. The findings indicate that, when making investment decisions, tour operators generally tend to balance the interests of the local community, employees and businesses, and to consider the effects of their investments on the local economy and the environment. However, empirical evidence indicates that tour operator’s investment preferences are moderated by three factors, namely: local government pressure, size of the investment, and tour operator profile. In particular, greater attention should be paid to high-scale investments, and to investments made by generalist tour operators if destinations want to preserve their distinctive sociocultural and natural assets and provide well-being to local communities.

PurposeThe purpose of the study is to assess whether a relationship exists between corporate social responsibility (CSR) engagement and tour operators' performances.Design/methodology/approachA web survey was submitted to tour operators worldwide. A large sample of tour operators from different countries and continents participated in the survey. Principal component analysis was performed and a regression model was developed to analyze the relationship among variables.FindingsEmpirical evidence indicates that tour operators with high CSR engagement experienced a significantly higher short-term growth of profits and sales volume. Results also show that applying CSR principles, facilitating CSR values and fostering local economic linkages have a positive and significant influence on tour operators' performances.Practical implicationsTour operators should cultivate a sustainable corporate culture requiring a commitment to sustainability of the company and its suppliers. The findings contradict with the tendency of “enclavisation” of package tourists within self-sufficient tourism complexes and suggest that locals are part of the tourism place-product.Originality/valueThis research reviews the literature on the relationship between CSR and firms' performances in tourism and hospitality. The relevance of this study is its focus on tour operators, a context with a fundamental importance for the sustainability of the tourism industry worldwide. Tour operators are the players that mostly reflect the variety of sectors within the tourism industry, combining travel services such as accommodation, food, transports, entertainment and excursions. This is the first time that a study on the relationship between CSR and firms' performances has been developed on tour operators worldwide. The paper is based on the data collected through a survey on 201 companies from 42 countries from all continents.

Hospitality is a field in which guests’ specific needs and wants should always be given serious consideration by hoteliers. Putting the guest at the centre of all business efforts contributes to generating customer value and enhancing a firm’s competitiveness. Being customer-centric is paramount for hospitality establishments to create and sustain superior customer value. However, there is scant evidence in hospitality marketing literature of a clear understanding of the customer-centricity concept or of the possible effects of its implementation. Using a mixed-methods multiple case study approach, this research studies two different properties that, to some extent, are already engaged in customer-centricity practices through the use of advanced Customer Relationship Manager software. Results clearly show an increase in customer ratings, leading to possible profit implications; a cultural shift within the organizations studied connected with the customer-centricity phenomenon has also been reported.

This study investigates strategic consumer behavior in online hotel booking. Free cancellation policies enable consumers to rebook the hotel room at a later time should the price drop prior to the date of stay. A discrete choice experiment is used to infer consumer preferences for free cancellation and non-refundable rates under different scenarios. The study also examines the moderating role of the risk attitude of consumers. Risk-seeking consumers show preference for a free cancellation rate that increases with the availability of an automatic rebooking service. Although a higher booking window increases the utility of the free cancellation rate, such impact decreases as risk propensity increases. The identification of four distinct consumer segments provides clear implications for industry practitioners.

This paper reviews literature on travel destination choice and organizes these studies systematically. A “cell–system” structure is proposed to describe the psychological process of travel destination choice. When forming decisions on vacations, tourists gather information on potential destinations and evaluate visit intentions among potential destinations (“cell”). The visit intentions are successively compared while information is updated in the process (“system”). The “cell–system” structure provides a clear view of the psychological process of travel destination choice. Empirical studies based on the structure can provide further insights into why and how tourists choose travel destinations.

This study aims to assess tour operators’ sustainability orientation and engagement and to determine whether variations among different tour operators exist, that is, from different continents, with different targets and dimensions. A survey among tour operators worldwide was conducted. A total of 204 answers were obtained with a worldwide coverage. Results affirm relatively high sustainability orientation and engagement and that the more sustainability-oriented the tour operators are, the more sustainability-engaged they are. Moreover, results show that smaller tour operators, specializing in nature and cultural tourism, and owning accommodation facilities are also highly engaged in sustainability. Significant differences are observed among regions, with higher engagement for African and Asian tour operators compared with European ones. This study proposes the development of a new approach to sustainability in this sector: by introducing corporate sustainability strategies, tour operators can maintain their economic capital while preserving natural and social capital.

Infections are a major complication of solid organ transplants (SOTs). This study aimed to describe recipients’ characteristics, and the frequency and etiology of infections and transplant outcome in liver and lung SOTs, and to investigate exposures associated to infection and death in liver transplant recipients. The study population included recipients of SOTs performed in Italy during a 1-year period in ten Italian lung transplant units and eight liver transplant units. Data on comorbidities, infections, retransplantation, and death were prospectively collected using a web-based system, with a 6-month follow-up. The cumulative incidence of infection was 31.7% and 47.8% in liver and lung transplants, respectively, with most infections occurring within the first month after transplantation. Gram-negatives, which were primarily multidrug-resistant, were the most frequent cause of infection. Death rates were 0.42 per 1000 recipient-days in liver transplants and 1.41 per 1000 recipient-days in lung transplants. Infection after SOT in adult liver recipients is associated to an increased risk of death (OR = 13.25; p-value < 0.001). Given the frequency of infection caused by multidrug-resistant microorganisms in SOT recipients in Italy and the heavy impact of infections on the transplant outcome, the reinforcement of surveillance and control activities to prevent the transmission of multidrug-resistant microorganisms in SOT recipients represents a priority. The implementation of the study protocol in liver and lung transplant units and the sharing of results have increased the awareness about the threat due to antimicrobial resistance in the country.

Highlights • A count model for the determinants of hotel advance booking is proposed. • Prices have a decreasing effect that is less than proportional. • Long stays at holiday homes increase the days of advanced booking. • Booking in July and August, as well as large party size, imply longer anticipation. • Reservations through DMO channels are related to longer advanced booking.

Within the discrete choice modelling literature, there has been growing interest in including reference alternatives within stated choice survey tasks. Recent studies have investigated asymmetric utility specifications by estimating discrete choice models that include different parameters according to gains and losses relative to the values of the reference attributes. This paper analyses asymmetric discrete choice models by comparing specifications expressed as deviations from the reference point and specifications expressed in absolute values. The results suggest that the selection of the appropriate asymmetric model specification should be based on the type of the stated choice experiment.

Within a freight transport context, the origin-destination distance and the weight of the shipment play an important role in the decision of the most preferred transport service and in the way logistics managers evaluate the transport service's attributes. In particular, the attributes commonly used in order to describe a freight transport service in a stated choice framework are cost, time, punctuality and risk of damages, respectively. This paper investigates the role of origin-destination distance and weight of freight transport services introducing a conditioning effect, where the standard utility function is conditioned on the freight transport distance. We refer to this model form as a heteroskedastic panel multinomial logit (panel H-MNL) model. This model form outperforms the underlying unconditioned model and suggests that an appropriate conditioning effect leads to an improved understanding of the derived measures, such as measures for marginal rates of substitution.

It is widely recognized that individual decision-making is subject to the evaluation of gains and losses around a reference point. The estimation of discrete choice models increasingly use data from stated choice experiments which are pivoted around a reference alternative. However, to date, the specification of a reference alternative in transport studies has been fixed, whereas it is common to observe individuals adjusting their preferences according to a change in their reference point. This paper focuses on individual reactions, in a freight choice context, to a negative change in the reference alternative values, identifying the behavioural implications in terms of loss aversion and diminishing sensitivity. The results show a significant adjustment in the valuation of gains and losses around a shifted reference alternative. In particular, we find an average increase in loss aversion for cost and time attributes, and a substantial decrease for punctuality. These findings are translated to significant differences in the willingness to pay and willingness to accept measures, providing supporting evidence of respondents' behavioural reaction. © 2010 Springer Science+Business Media, LLC.

Choice behaviour might be determined by asymmetric preferences whether the consumers are faced with gains or losses. This paper investigates loss aversion and diminishing sensitivity, and analyzes their implications on willingness to pay and willingness to accept measures in a reference pivoted choice experiment in a freight transport framework. The results suggest a significant model fit improvement when preferences are treated as asymmetric, proving both loss aversion and diminishing sensitivity. The implications on willingness to pay and willingness to accept indicators are particular relevant showing a remarkable difference between symmetric and asymmetric model specifications. Not accounting for loss aversion and diminishing sensitivity, when present, produces misleading results and might affect significantly the policy decisions. © 2010 Elsevier Ltd.

The objective of this study is to analyse how people process information and make decisions with regard to booking hotel rooms via online booking systems. The authors propose a nested decision process and compare it with the approach of previous literature in analysing the determinants in choosing a hotel. This research attempts to model online hotel bookings in the real market using discrete choice modelling. The methodology is based on the estimates of nested logit models, and the results show that tourists choose a hotel by going through a number of staged decision structures, which is in line with Associative Network Theory and the Cybernetic decision-making model.

In selecting a hotel room, guests evaluate specific room characteristics. After their stay, these characteristics are used as reference levels in deciding which hotel room to stay in the future. According to prospect theory, the gains (i.e., upgrade or improving) and losses (i.e., downgrade or worsening) with respect to the reference level are perceived differently by individuals. In particular, losses are weighted more than gains. This research investigates the asymmetric preference in hotel room choice by performing a stated choice experiment among the guests of a hotel in Hong Kong. A mixed logit model is estimated by deriving different coefficients for improving and worsening conditions, and attribute-specific cluster analyses are performed to identify those segments with similar preferences. The results confirm the validity of reference-dependent specification in hotel room choice and provide insights for revenue managers in relation to their aim to maximize revenue for repeat guests.

Tourist accommodation expenditure is a widely investigated topic as it represents a major contribution to the total tourist expenditure. The identification of the determinant factors is commonly based on supply-driven applications while little research has been made on important travel characteristics. This paper proposes a demand-driven analysis of tourist accommodation price by focusing on data generated from room bookings. The investigation focuses on modeling the relationship between key travel characteristics and the price paid to book the accommodation. To accommodate the distributional characteristics of the expenditure variable, the analysis is based on the estimation of a quantile regression model. The findings support the econometric approach used and enable the elaboration of relevant managerial implications.

Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, they also play unique roles. We recently identified a role for GSK3B in drug resistance by demonstrating that its inhibition enables necroptosis in response to chemotherapy in p53-null drug-resistant colon carcinoma cells. We report here that, similarly to GSK3B, also GSK3A silencing/inhibition does not affect cell proliferation or cell cycle but only abolishes growth after treatment with DNA-damaging chemotherapy. In particular, blocking GSK3A impairs DNA repair upon exposure to DNA-damaging drugs. As a consequence, p53-null cells overcome their inability to undergo apoptosis and mount a necroptotic response, characterized by absence of caspase activation and RIP1-independent, PARP-dependent AIF nuclear re-localization. We therefore conclude that GSK3A is redundant with GSK3B in regulating drug-resistance and chemotherapy-induced necroptosis and suggest that inhibition of only one isoform, or rather partial inhibition of overall cellular GSK3 activity, is enough to re-sensitize drug-resistant cells to chemotherapy.

Purpose – This paper aims to focus on the reason why hoteliers choose to be present in online travel agent (OTA) and social media web sites for sales purposes. It also investigates the technological and human factors related to these two practices. Design/methodology/approach – The research is based on a survey sent to a wide range of hotels in a Swiss touristic region. The empirical analysis involves the specification of two ordered logit models exploring the importance (in terms of online sales) of both social media and the online travel agent, Booking.com. Findings – Findings highlight the constant tension between visibility and online sales in the web arena, as well as a clear distinction in social media and OTA web site adoption between hospitality structures using online management tools and employing personnel with specific skills. Practical implications – The research highlights the need for the hospitality industry to maintain an effective presence on social media and OTAs in order to move towards the creation of a new form of social booking technologies to increase their visibility and sales. Originality/value – This research contributes to understanding the major role played by OTAs and social media in the hospitality industry while underlining the possibility of a major interplay between the two.

This study is the first to compare random regret minimisation (RRM) and random utility maximisation (RUM) in freight transport application. This paper aims to compare RRM and RUM in a freight transport scenario involving negative shock in the reference alternative. Based on data from two stated choice experiments conducted among Swiss logistics managers, this study contributes to related literature by exploring for the first time the use of mixed logit models in the most recent version of the RRM approach. We further investigate two paradigm choices by computing elasticities and forecasting choice probability. We find that regret is important in describing the managers' choices. Regret increases in the shock scenario, supporting the idea that a shift in reference point can cause a shift towards regret minimisation. Differences in elasticities and forecast probability are identified and discussed appropriately. © 2013 Hong Kong Society for Transportation Studies Limited.

The present application describes therapies for the effective treatment of colon and colorectal carcinomas. The present invention relates to a pharmaceutical kit, comprising combinations of a BTK inhibitor and fluorouracil, for the treatment of colon and colorectal carcinomas also in the case in which such carcinomas are drug resistant and therefore allows to overcome cancer drug resistance.

The anti-metastatic ruthenium complex NaCtransRuCI4(DMSO)lm] was given i.p. at 22 and 44 mg/kg/day, on days 8-13 after tumour implantation, to mice carrying S.C. implants of MCa mammary carcinoma. The aim ofthe study was to compare the effects on lung metastasis formation with those on primary tumour cells. This investigation was based on flow cytometry analysis after propidium iodide and acridine orange staining, histology of tumour parenchyma and RT-PCR analysis for the type-IV collagenases MMP-9 and MMP-2 and their respective inhibitors TIMP-I and TIMP-2 mRNAs. NactransRuCl,(DMSO)lm] is not cytotoxic for tumour cells but has the capacity of interacting with nucleic acids, giving a general reduction of nucleic acid content as shown by a marked reduction of acridine orange staining and a tendency to a reduction of DNA polyploidy with marked reduction of 8n and 4n cell populations. Na[trans-RuCI~(DMSO)lm] also influences a proteolytic system which has the potential of degrading the basement membrane and has been related to metastatic aggressiveness: it markedly reduces, in a dose-dependent manner, MMP-2/TIMP-2 balance, but not that of MMP-9/TIMP-I. The different enzyrne/inhibitor mRNA levels between untreated and treated tumours seem to be unaffected by tumourinfiltrating lymphocytes and are paralleled by the maintenance of connective tissue around blood vessels in the tumour mass. Correspondingly, lung metastasis formation is markedly reduced, to less than 10% of that seen in conbols. o 1996 Wiley-Liss, Inc. Basic research on synthetic drugs, effective against tumour metastases, has recently highlighted the effects of a ruthenium complex, namely sodium trans-rutheniumtetrachloridedimethylsulphoxideimidazole (hereafter indicated by Na[transRuCI4(DMSO)Im]) (Sava er al., 1992a, b, 1993, 1994). The effects of this new generation ruthenium(II1) complex on solid metastasizing tumour are particularly evident on the formation of spontaneous metastases. The selectivity of Na[transRuCI4(DMSO)Im] on lung metastases is also marked on advanced metastases and accounts for a significant prolongation of the host's survival time; combined with surgical removal of primary tumour, Na[trans-RuC14(DMSO)Im] prevents the formation of metastases and inhibits the growth of those already formed (Sava et al., 1994). The histological analysis of tumour growth and of healthy host tissues such as lung and kidney epithelia, muscle and liver cells, splenocytes and bone-marrow cells, by light microscopy and by SEM, shows a lack of significant cytotoxicity (Gagliardi et al., 1994). It thus appears that the selective anti-metastatic effects do not result directly from histological modification of the primary tumour structure.

The literature contains evidence that there is a marked heterogeneity in price responses to tourism products, leading to a great variety of tourist sensitivities to price. Thus the role price plays is complex, and a particularly challenging aspect of this complexity is that its effect is not unambiguous, thereby negating the idea that the demand for tourism products and tourist activities can always be regarded as demand for ordinary goods. This article identifies and explains, as a novelty for the tourism industry, price sensitivities to tourism activities individual by individual. The operative formalization uses a mixed logit model to estimate the individual sensitivities to price, and then a regression analysis is applied to detect their determinants. The empirical application finds that motivations, influenced by age, and length of stay with a non-linear effect, are explanatory factors of tourists' price sensitivity to activities.

The importance of willingness to pay (WTP) and its counterpart willingness to accept (WTA), in the evaluation of policy measures has led to a constant stream of research examining survey methods and model specifications seeking to capture and explain the concept of marginal rates of substitution as much as possible. Stated choice experiments pivoted around a reference alternative allow the specification of discrete choice models to accommodate aspects of Prospect Theory, in the particular reference dependence. This permits an investigation of theories related to loss aversion and diminishing sensitivitywidely documented within the literature. This paper seeks to examine a number of theoretical developments. In particular, the paper seeks to empirically examine a number of aspects related to decision making processes that are posited to exist by Prospect Theory, namely reference dependence, loss aversion and diminishing sensitivities. Unlike previous research which has examined these issues in the past, we examine these assumptions on WTP/WTA rather than on the marginal utilities of decision makers. In doing this, the paper simultaneously compares and contrasts different econometric forms, in particular estimating models in preference space with WTP/WTAs calculated post estimation versus models estimated directly in WTP/WTA space where WTP/WTAvalues are directly during estimation. We find evidence for reference dependence and loss aversion in WTP/WTA for different time attributes, however we find less compelling evidence for the existence of diminishing WTP/WTAs., European Journal of Transport and Infrastructure Research, Vol 10 No 4 (2010)

Infrastructure vulnerability is a topic of rising interest in the scientific literature for both the general increase of unexpected events and the strategic importance of certain links. Protective investments are extremely costly and risks are distributed in space and time, which poses important decision problems to the public sector decision makers.In an economic prospective, the evaluation of infrastructure vulnerability is oriented on the estimation of direct and indirect costs of hazards. Although the estimation of direct costs is straightforward, the evaluation of indirect cost involves factors non-directly observable making the approximation a difficult issue. This paper provides an estimate of the indirect costs caused by a two weeks closure of the north-south Gotthard road corridor, one of the most important infrastructure links in Europe, and implements a cost-benefit analysis tool that allows the evaluation of measures ensuring a full protection along the corridor. The identification of the indirect cost relies on the generalized cost estimation, which parameters come from two stated preference experiments, the first based on actual condition whereas the second assumes a road closure. The procedure outlined in this paper proposes a methodology aimed to identify and quantify the economic vulnerability associated with a road transport infrastructure and, to evaluate the economic and social efficiency of a vulnerability reduction by the consideration of protective measures. © 2011 Elsevier Ltd.