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The market for new drugs is changing: personalised drugs will increase the heterogeneity in patients' responses and, possibly, costs. In this context, price regulation will play an increasingly important role. In this article, we argue that personalised medicine opens new scenarios in the relationship between value-based prices, regulation and industry listing strategies. Our focus is on the role of asymmetry of information and competition. We show that, if the firm has more information than the payer on the heterogeneity in patients' responses and it adopts a profit-maximising listing strategy, the outcome may be independent of the choice of the type of value-based price. In this case, the information advantage that the manufacturer has prevents the payer from using marginal value-based prices to extract part of the surplus. However, in a dynamic setting where competition by a new entrant is possible, the choice of the type of value-based price may matter. We suggest that more research should be devoted to the dynamic analysis of price regulation for personalised medicines.

Background/Aims: There is growing interest in the use of adaptive designs to improve the efficiency of clinical trials. We apply a Bayesian decision-theoretic model of a sequential experiment using cost and outcome data from the ProFHER pragmatic trial. We assess the model’s potential for delivering value-based research. Methods: Using parameter values estimated from the ProFHER pragmatic trial, including the costs of carrying out the trial, we establish when the trial could have stopped, had the model’s value-based stopping rule been used. We use a bootstrap analysis and simulation study to assess a range of operating characteristics, which we compare with a fixed sample size design which does not allow for early stopping. Results: We estimate that application of the model could have stopped the ProFHER trial early, reducing the sample size by about 14%, saving about 5% of the research budget and resulting in a technology recommendation which was the same as that of the trial. The bootstrap analysis suggests that the expected sample size would have been 38% lower, saving around 13% of the research budget, with a probability of 0.92 of making the same technology recommendation decision. It also shows a large degree of variability in the trial’s sample size. Conclusions: Benefits to trial cost stewardship may be achieved by monitoring trial data as they accumulate and using a stopping rule which balances the benefit of obtaining more information through continued recruitment with the cost of obtaining that information. We present recommendations for further research investigating the application of value-based sequential designs.

Managed entry agreements (MEAs) have been used for several years, with the aim of curbing the growth of pharmaceutical expenditure and enhancing patient access to innovation. Yet, much remains to be understood about their economic implications. This paper studies the impact of MEAs on list prices, that is, prices before the deduction of any discount. Using a theoretical model, we show that, under most price setting regimes, the introduction of an MEA leads to a higher list price. This is confirmed by our empirical analysis of a sample of 156 medicines in six countries, providing a conservative estimate of the increase in price due to the MEA of 5.9%. A relevant policy implication is that payers may overestimate the financial gains that can be achieved through this tool.

We utilize a large administrative dataset of sickness leave in Italy (a) to investigate whether private firms are more effective than the public insurer in choosing who to monitor and (b) to study the correlation between potentially opportunistic behavior and the observable characteristics of the employee. We find that private employers are more likely to select into monitoring employees who are fit for work despite being on sick leave, if the public insurer is not supported by any data-driven tool. However, the use of a scoring mechanism, based on past records, allows the public insurer to be as effective as the employer. This result suggests that the application of machine learning to appropriate databases may improve the targeting of public monitoring to detect opportunistic behavior. Concerning the association between observable characteristics and potentially opportunistic behavior, we find that males, employees younger than 50, those on short leaves, or without a history of illness are more likely to be found fit for work.

Since the early 80s, incentives have been introduced to stimulate R&D for rare diseases. We develop a theoretical model to study the impact of push and pull incentives on the intensive and extensive margin of optimal R&D investments. The model describes the mechanisms by which the type of incentives provided may favor R&D for orphan diseases with comparatively high prevalence. In our empirical analysis, we merge data on orphan drug designations by the Food and Drug Administration with Orphanet data on disease characteristics. In line with the theoretical results, we find evidence supporting the idea that the incentives adopted may have contributed substantially to widening the gap between more and less rare diseases classified as orphan. Our theoretical and empirical findings together suggest that, if providing some therapeutic option to patients with very rare diseases is a priority, a revision of the current system of incentives should be considered.

We present a model of the strategic interaction among authorities regulating pharmaceutical prices in different countries and the R&D investment decisions of pharmaceutical firms. Regulators’ decisions affect consumer surplus directly, via prices, and indirectly via firms’ profits and R&D investment policies, which in turn affect patient health. The positive externality of a price increase in one country provides an incentive for other countries to free-ride, and we show how country-level characteristics affect optimal pricing decisions and equilibria. Our theoretical predictions are tested using price data for a set of 70 cancer drugs in 25 OECD countries. We find evidence of behaviour that is consistent with the free-riding hypothesis and which, in line with the theoretical predictions, differs according to country-level characteristics. Countries with comparatively large market shares tend to react to increases in other countries’ prices by lowering their own prices; in countries with comparatively small market shares, regulators’ decisions are consistent with the objective of introducing the product at as low a price as possible. We discuss the policy implications of our results for incentivising global pharmaceutical R&D and the recent proposal to move towards a joint pharmaceutical procurement process at the European level.

We study the determinants of redistribution at the municipal level in the context of public childcare in Italy. Within a substantially homogeneous legislative framework, different municipalities autonomously define how participation fees vary with a compound indicator of income and wealth (ISEE), thus redistributing resources across households using the service. The nearly one hundred municipalities we take into account exhibit wide heterogeneity in redistributive attitudes. We find statistically significant correlations of these with a number of individual characteristics of policy-makers and municipalities, but not with those of the ex-ante distribution of income, which should be central according to both normative and positive theory. Since the price of public childcare is subsidized, resources are also redistributed from tax-payers to users. The evidence that we find is consistent with the hypothesis that this type of redistribution is a public good.

The paper uses a real option approach to investigate the properties of two widely used schemes of regulating the reimbursement of new pharmaceutical products: standard cost-effectiveness thresholds and performance-based risk-sharing agreements. The use of the latter has been quickly spreading and often criticized in recent times. The results show that the exact definition of the risk-sharing agreement is key in determining its economic effects. In particular, despite the concerns expressed by some authors, the incentive for a firm to invest in R&D may be the same or even greater than under cost-effectiveness thresholds. The greater flexibility on the timing of commercialization allowed by risk-sharing schemes plays a key role, by increasing the value of the option to invest in R&D under uncertainty. Under this scheme, a higher value for the firm is associated with earlier access to innovations for patients. The price for this is less value for money for the insurer at the time of adoption of the innovation.

We use a simple model to study the static and dynamic efficiency of alternative regulation regimes for the reimbursement of medical innovations when responses to a new treatment (effectiveness) are heterogeneous across the eligible population. When the rational behavior of profit-maximizing firms is taken into account, only average value-based prices can ensure both static and dynamic efficiency, but they imply higher expenditure and lower consumer surplus. Ignoring dynamic efficiency, if patients' responses are sufficiently homogeneous, marginal value-based prices may dominate from the payer's perspective. We also present a refinement of average value-based prices that could reverse this result. Overall, the cost of ensuring static and dynamic efficiency is increasing in the degree of heterogeneity. A real-world example is used to illustrate these results.

The paper uses a real option approach to investigate the potential impact of performance-based risk-sharing agreements for the reimbursement of new drugs in comparison with standard cost-effectiveness thresholds. The results show that the exact definition of the risk-sharing agreement is key in determining its economic effects. In particular, despite the concerns expressed by some authors, the incentive for a firm to invest in R&D may be the same or even greater than under cost-effectiveness thresholds, if the agreement is sufficiently mild in defining the conditions under which the product is not (fully) reimbursed to the firm. In this case, patients would benefit from earlier access to innovations. The price for this is less value for money for the insurer at the time of adoption of the innovation.

The paper presents a large scale overlapping generation model with heterogeneous agents, where the household is the decision unit. We calibrate the model for three European countries – France, Italy and Sweden – which show marked differences in the design of some public programmes. We examine the properties in terms of annual and life cycle redistribution of a number of tax-benefit programmes, by studying the impact of removing from our model economies some or all of them. We find that whether one considers a life cycle or an annual horizon, and whether behavioural responses are accounted for or not, has a large impact on the results. The model may provide useful insights for policy makers on which kind of reforms are more likely to achieve specific equity objectives.

This paper explores the inequality related to the lifetime redistributive impact of public sector intervention across living generations. While fiscal policies are typically assessed with respect to the inter-personal dimension of inequality, they may well have heterogeneous impacts across different cohorts, thus raising the issue of intergenerational fairness. We take the case of Italy over the period 1990-2008 to show how such possibly unfair effects can be measured by adapting the methods developed in the context of the generational accounting literature. Importantly, we aim to work on a comprehensive approach, so that reforms involving several taxation and spending programmes, possibly implemented over several years, can be assessed. We find that a significant improvement in public finance sustainability came at the price of an unequal distribution of sacrifices across living generations, with younger cohorts contributing far more over their residual life-cycle.

Summary We present a Bayes sequential economic evaluation model for health technologies in which an investigator has flexibility over the timing of a decision to stop carrying out research and to conclude that one technology is preferred to another on cost-effectiveness grounds. We implement the model by using an evaluation of the treatment of bacterial sinusitis and derive approximations of the optimal stopping rule as a function of accumulated sample size. We compare the performance of the model with existing frequentist and Bayes sequential designs and investigate the sensitivity of the stopping rule to changes in the parameters of the model. Our results suggest that accounting for the dynamic nature of experimentation, together with its economic parameters, should lead to greater efficiency in resource allocation within healthcare systems.

© 2016 Elsevier B.V.We present a model combining the two regulatory stages relevant to the approval of a new health technology: the authorisation of its commercialisation and the insurer's decision about whether to reimburse its cost. We show that the degree of uncertainty concerning the true value of the insurer's maximum willingness to pay for a unit increase in effectiveness has a non-monotonic impact on the optimal price of the innovation, the firm's expected profit and the optimal sample size of the clinical trial. A key result is that there exists a range of values of the uncertainty parameter over which a reduction in uncertainty benefits the firm, the insurer and patients. We consider how different policy parameters may be used as incentive mechanisms, and the incentives to invest in R&D for marginal projects such as those targeting rare diseases. The model is calibrated using data on a new treatment for cystic fibrosis.

In this paper we use a simple theoretical model to compare alternative regulation regimes for the reimbursement of medical innovations when responses to a new treatment (effectiveness) are heterogeneous within the eligible population. We study two dimensions: i) efficiency in selecting sub-groups of patients for which the new technology is reimbursed, ii) distribution of rent between firm and payer. We show that when rational behaviour of profit maximizing firms is taken into account stratified cost-effectiveness analysis and marginal value based prices lead to the same equilibrium, which is efficient only if the population is sufficiently homogeneous. Inefficiency arises because some patients that should be treated are not. On the other hand, prices based on the average value may allow for an efficient solution even when heterogeneity is large. With limited heterogeneity efficiency may be achieved even if part of the rent is retained by the payer. We show that stratified cost-effectiveness analysis is an optimal policy for the payer under the constraint that the price is set by the firm, who knows that the payer will define the number of patients to reimburse in order to maximize total net benefit. However, this policy is only efficient from the societal perspective when the eligible population is sufficiently homogeneous. When heterogeneity is substantial, the number of patients treated is inefficiently low. On the other hand, average value based prices always allow for an efficient solution, provided that some conditions are satisfied. These conditions imply that the fraction of rent that needs to be left to the firm to achieve efficiency is non-decreasing in the degree of heterogeneity in effectiveness.

We present a two-period framework, which combines real option and decision-theoretic approaches to health technology assessment under uncertainty. By viewing adoption, treatment and research decisions as a single economic project, we illustrate how their key dimensions affect optimal rules. We consider the results in relation to the existing literature and argue that developments in this direction could contribute substantially to efficiency gains in resource allocation.

The paper studies the incentive for providers to invest in new health care technologies under alternative payment systems, when the patients' benefits are uncertain. If the reimbursement by the purchaser includes both a variable (per patient) and a lump-sum component, efficiency can be ensured both in the timing of adoption (dynamic) and the intensity of use of the technology (static). If the second instrument is unavailable, a trade-off may emerge between static and dynamic efficiency. In this context, we also discuss how the regulator could use control of the level of uncertainty faced by the provider as an instrument to mitigate the trade-off between static and dynamic efficiency. Finally, we calibrate the model to study a specific technology and estimate the cost of a regulatory failure.

Background Glial cell line–derived neurotrophic factor (GDNF) and a related family member, neurturin (NTN), and their cognate receptors (GFRα-1 and GFRα-2, for GDNF and NTN, respectively) are distal members of the transforming growth factor-β superfamily. They are involved in the control of murine hair follicle (HF) cycling. This study tests the hypothesis that GDNF and NTN, and their cognate receptors, are expressed in the human HF and their expression varies in the different stages of the HF cycle. Methods The expression pattern of these proteins was examined in human HF by immunofluorescence, immunoalkalinephosphatase staining methods, and reverse transcription-polymerase chain reaction (GDNF). The functional effects (GDNF and NTN) were examined in organ culture of the microdissected HFs. Results GDNF, NTN, GFRα-1, GFRα-2, and c-Ret proteins were weakly expressed in catagen and telogen HFs. In contrast, they were strongly expressed in the epithelial and mesenchymal compartments of the anagen HF. GDNF gene was transcribed, both in the human scalp skin and in the isolated anagen HFs (reverse transcription-polymerase chain reaction). In HF organ culture, GDNF (but not NTN) increased the number of the proliferating HF keratinocytes (Ki 67 + cells). GDNF partially protected HFs from transforming growth factor-β2–induced premature catagen transition. Limitations None. Conclusions GDNF, NTN, GFRα-1, GFRα-2, and c-Ret proteins are differentially expressed in the different stages of HF cycle. GFRα-mediated signaling involves c-Ret and may play a role in human HF biology.

The trimethylated amino acid l-carnitine plays a key role in the intramitochondrial transport of fatty acids for beta-oxidation and thus serves important functions in energy metabolism. Here, we have tested the hypothesis that l-carnitine, a frequently employed dietary supplement, may also stimulate hair growth by increasing energy supply to the massively proliferating and energy-consuming anagen hair matrix. Hair follicles (HFs) in the anagen VI stage of the hair cycle were cultured in the presence of 0.5-50 microm of l-carnitine-l-tartrate (CT) for 9 days. At day 9, HFs treated with 5 microm or 0.5 microm of CT showed a moderate, but significant stimulation of hair shaft elongation compared with vehicle-treated controls (P < 0.05). Also, CT prolonged the duration of anagen VI, down regulated apoptosis (as measured by TUNEL assay) and up regulated proliferation (as measured by Ki67 immunohistology) of hair matrix keratinocytes (P < 0.5). By immunohistology, intrafollicular immunoreactivity for TGFbeta2, a key catagen-promoting growth factor, in the dermal papilla and TGF-beta II receptor protein in the outer root sheath and dermal papilla was down regulated. As shown by caspase activity assay, caspase 3 and 7, which are known to initiate apoptosis, are down regulated at day 2 and day 4 after treatment of HFs with CT compared with vehicle-treated control indicating that CT has an immediate protective effect on HFs to undergo programmed cell death. Our findings suggest that l-carnitine stimulates human scalp hair growth by up regulation of proliferation and down regulation of apoptosis in follicular keratinocytes in vitro. They further encourage one to explore topical and nutraceutical administration of l-carnitine as a well-tolerated, relatively safe adjuvant treatment in the management of androgenetic alopecia and other forms of hair loss.

We use a large and unique administrative dataset from Italy, covering the period 2009-2014, to investigate opportunistic behavior (moral hazard) and the effectiveness of monitoring policies related to insurance against illness-related income losses. The analysis is based on the outcome of mandatory medical visits aimed at verifying the health status of employees during sickness spells. We find that employers are more effective than the public insurer in selecting sickness episodes to monitor. However, a reduction in the number and a better targeting of visits with the support of appropriate statistical tools may close the gap. We discuss the impact of using direct measures of health, such as the outcome of a medical visit, on the study of the determinants of opportunistic behavior and argue that simply looking at days of work lost, without appropriately controlling for health status, may lead to misleading conclusions if the goal is studying moral hazard.

In the recent past, pharmaceutical expenditure has been steadily increasing, but the productivity of the sector—measured as the number of New Molecular Entities (NMEs)—has been decreasing. In this chapter we review and analyse the price regulation policies that are currently used by regulators worldwide and we will describe the salient features of these policies from a public health point of view. We will also discuss this in terms of their impact on innovation.

Peripheral intracrine sex steroid synthesis from adrenal precursors dehydroepiandrosterone (DHEA) and DHEA-sulfate has evolved in humans. We sought to establish if there are differences in intracrine, paracrine, and endocrine regulation of sex steroids by primary cultures of human skin epidermal keratinocytes and dermal fibroblasts. Microarray analysis identified multifunctional genes modulated by steroids, quantitative RT-PCR (qRT-PCR) mRNA expression, enzymatic assay aromatase activity, scratch assay cell migration, immunocytochemistry α-smooth muscle actin (α-SMA), and collagen gel fibroblast contraction. All steroidogenic components were present, although only keratinocytes expressed the organic anion organic anion transporter protein (OATP) 2B1 transporter. Both expressed the G-protein-coupled estrogen receptor (GPER1). Steroids modulated multifunctional genes, up-regulating genes important in repair and aging [angiopoietin-like 4 (ANGPTL4), chemokine (C-X-C motif) ligand 1 (CXCL1), lamin B1 (LMNB1), and thioredoxin interacting protein (TXNIP)]. DHEA-sulfate (DHEA-S), DHEA, and 17β-estradiol stimulated keratinocyte and fibroblast migration at early (4 h) and late (24-48 h) time points, suggesting involvement of genomic and nongenomic signaling. Migration was blocked by aromatase and steroid sulfatase (STS) inhibitors confirming intracrine synthesis to estrogen. Testosterone had little effect, implying it is not an intermediate. Steroids stimulated fibroblast contraction but not α-SMA expression. Mechanical wounding reduced fibroblast aromatase activity but increased keratinocyte activity, amplifying the bioavailability of intracellular estrogen. Cultured fibroblasts and keratinocytes provide a biologically relevant model system to investigate the complex pathways of sex steroid intracrinology in human skin.

The paper presents a large scale overlapping generation model with heterogeneous agents, where the family is the decision unit. We calibrate the model for three European countries – France, Italy and Sweden – which show marked differences in the design of some public programs. We examine the properties in terms of annual and lifetime redistribution of a number of tax-benefit programs, by studying the impact of removing from our model economies some or all of them. We find that whether one considers a life-cycle or an annual horizon, and whether behavioral responses are accounted for or not, has a large impact on the results. The model may provide useful insights for policy makers on which kind of reforms are more likely to achieve specific equity objectives.

Glycerophosphoinositol 4-phosphate (GroPIns-4P) is a biologically active, water-soluble phospholipase A metabolite derived from phosphatidylinositol 4-phosphate, whose cellular concentrations have been reported to increase in Ras-transformed cells. It is therefore important to understand its biological activities. Herein, we have examined whether GroPIns-4P can regulate the organization of the actin cytoskeleton, because this could be a Ras-related function involved in cell motility and metastatic invasion. We find that in serum-starved Swiss 3T3 cells, exogenously added GroPIns-4P rapidly and potently induces the formation of membrane ruffles, and, later, the formation of stress fibers. These actin structures can be regulated by the small GTPases Cdc42, Rac, and Rho. To analyze the mechanism of action of GroPIns-4P, we selectively inactivated each of these GTPases. GroPIns-4P requires active Rac and Rho, but not Cdc42, for ruffle and stress fiber formation, respectively. Moreover, GroPIns-4P induces a rapid translocation of the green fluorescent protein-tagged Rac into ruffles, and increases the fraction of GTP-bound Rac, in intact cells. The activation of Rac by GroPIns-4P was near maximal and long-lasting. Interestingly, this feature seems to be critical in the induction of actin ruffles by GroPIns-4P.

The data relating to the distribution of income and wealth (ISEE- Equivalent Economic Situation Indicator) in Italy are not available to the scientific community. This makes difficult the possibility of performing simulations of hypothetical reforms. In this paper, we show how to reconstruct the ISEE using the information provided in EU-SILC 2008 for Italy.

The small GTPase ADP-ribosylation factor (ARF) regulates the structure and function of the Golgi complex through mechanisms that are understood only in part, and which include an ability to control the assembly of coat complexes and phospholipase D (PLD). Here we describe a new property of ARF, the ability to recruit phosphatidylinositol-4-OH kinase-beta and a still unidentified phosphatidylinositol-4-phosphate-5-OH kinase to the Golgi complex, resulting in a potent stimulation of synthesis of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate; this ability is independent of its activities on coat proteins and PLD. Phosphatidylinositol-4-OH kinase-beta is required for the structural integrity of the Golgi complex: transfection of a dominant-negative mutant of the kinase markedly alters the organization of the organelle.

The vascular access guidelines recommend that arteriovenous fistulas (AVFs) with access dysfunction and an access blood flow (Qa)300-500 mL/min be referred for stenosis imaging and treatment. Significant (50%) stenosis, however, may be detected in a well-functioning AVF with a Qa500 mL/min, too, but whether it is worth correcting or not remains to be seen.In October 2006, we began an open randomized controlled trial enrolling patients with an AVF with subclinical stenosis and Qa500 mL/min, to see how elective stenosis repair [treatment group (TX)] influenced access failure (thrombosis or impending thrombosis requiring access revision), or loss and the related cost compared with stenosis correction according to the guidelines, i.e. after the onset of access dysfunction or a Qa400 mL/min [control group (C)]. An interim analysis was performed in July 2012, by which time the trial had enrolled 58 patients (30 C and 28 TX).TX led to a relative risk of 0.47 [95% confidence interval (CI): 0.17-1.15] for access failure (P = 0.090), 0.37 [95% CI: 0.12-0.97] for thrombosis (P = 0.033) and 0.36 [95% CI: 0.09-0.99] for access loss (P = 0.041). In the setting of our study (in which all surgery was performed as in patient procedure) no significant differences in costs emerged between the two strategies. The mean incremental cost-effectiveness ratio for TX was €282 or €321 to avoid one episode of thrombosis or access loss, respectively.Our interim analysis showed that elective repair of subclinical stenosis in AVFs with Qa500 mL/min cost-effectively reduces the risk of thrombosis and access loss in comparison with the approach of the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, raising the question of whether the currently recommended criteria for assessing and treating stenosis should be reconsidered.

Recent years have witnessed much progress in the incorporation of economic considerations into the evaluation of public health interventions. In England, the Centre for Public Health Excellence within the National Institute for Health and Care Excellence works to develop guidance for preventing illness and assessing which public health interventions are most effective and provide best value for money...

The paper uses a real option approach to investigate the impact of performance-based risk-sharing agreements for the reimbursement of new drugs in comparison with standard cost-effectiveness thresholds. The results show that the exact definition of the risk-sharing agreement is key in determining its economic effects. In particular, despite the concerns expressed by some authors, the incentive for a firm to invest in R&D may be the same or even greater than under cost-effectiveness thresholds. When this is the case, patients would benefit from earlier access to innovations. The price for this is less value for money for the insurer at the time of adoption of the innovation.

CD4 serves as a cell-cell adhesion molecule, with specific affinity for class II MHC molecules, and as a receptor for the human immunodeficiency virus type 1 (HIV-1) viral coat protein. Phosphoinositide (PI)-3-kinase and 1-phosphatidylinositol (PtdIns)-4-kinase activities were previously found to associate with the CD4:p56lck complex, but the protein responsible for PtdIns 4-kinase activity was not identified. Here we demonstrate that the 53 kDa type 2 PtdIns 4-kinase associates with CD4 using a monoclonal antibody specific for this enzyme. We also show that an increase in PtdIns 4-kinase activity is due to recruitment of the type 2 PtdIns 4-kinase protein to the CD4:p56lck complex after cross-linking with anti-CD4.

The paper studies the impact of alternative reimbursement systems on two provider decisions: whether to adopt a technology whose provision requires a sunk investment cost and how many patients to treat with it. Using a simple economic model we show that the optimal pricing policy involves a two-part payment: a price equal to the marginal cost of the patient whose benefit of treatment equals the cost of provision, and a separate payment for the partial reimbursement of capital costs. Departures from this scheme, which are frequent in DRG tariff systems designed around the world, lead to a trade-off between the objective of making effective technologies available to patients and the need to ensure appropriateness in use.

In this paper we investigate the relationship between the DRG system for hospital reimbursement and investment in technologies. We use a simple economic model where the reimbursement policy for treatments whose provision requires a sunk investment cost has an impact on both the decision whether to adopt the technology and many patients to treat with it. The optimal pricing policy involves a two-part tariff: a price equal to the marginal cost of the patient whose benefit of treatment equals the cost of provision, and a separate payment for the partial reimbursement of capital costs. Departures from this scheme, which are frequent in DRG tariff systems designed around the world, lead to a trade-off between the objective of making effective technologies available to patients and the need to ensure appropriateness in use.

The following paper reports the main objective and the expected outcomes of an ambitious project that aims to develop a model for the analysis of both inter-household and intra-household distribution in a life-cycle perspective. In reporting such research objectives, this anal- ysis focuses in particular on the di erent methods and events that will be taken into consideration as starting point for the general project.

The paper is a contribution to the study of the redistributive impact of public sector intervention across living generations. We aim to work on a comprehensive approach, so that reforms involving several taxation and spending programmes, possibly implemented over several years, may be assessed. By adapting methods from the generational accounting literature, we investigate the impact on fairness between living generations of fiscal policies undertaken in Italy between 1990 and 2008. Large intergenerational differences exist in net tax rates calculated over the residual lifetime horizon, which tend to be substantially higher for young generations. Pension reforms introduced in the '90s play a major role in explaining these differences. We conclude that a significant contribution to the sustainability of these reforms might have come at the price of an unequal distribution of sacrifices across living generations. Awareness of these differences could help in designing additional consolidation efforts in the perspective of achieving intergenerational fairness in Italy.

The activation of phospholipase D (PLD) is a receptor-mediated event that has been implicated in signal transduction and membrane traffic in eukaryotic cells. Little is known about the biochemical and molecular properties of signal-activated PLDs, and none has been isolated. Here we report that phosphatidylinositol 4,5-bisphosphate (PIP2) potently stimulates brain membrane PLD activity in vitro in a highly specific manner. PIP2 increases 10-fold the maximal activity of a partially purified PLD with an EC50 of0.5 mol %. Other acidic phospholipids, including phosphatidylinositol 4-phosphate, phosphatidylinositol, phosphatidylserine, and phosphatidic acid, are completely or nearly ineffective. Neomycin, a high affinity ligand of PIP2, inhibits membrane-bound PLD but has no effect on the activity of a detergent-solubilized or partially purified enzyme. The addition of PIP2 restores the sensitivity of partially purified PLD to neomycin inhibition, indicating that neomycin blocks membrane PLD activity by binding to endogenous PIP2. These results define a novel function of PIP2 as a cofactor for brain membrane PLD and suggest that PIP2 synthesis and hydrolysis could be important determinants in regulating PLD action in signal transduction and membrane transport.

We observed that peripheral T cells activated in vivo or in vitro by superantigens are susceptible to cell death when their antigen receptor is cross-linked with the appropriate anti-alpha beta TCR mAb. TCR ligation by mAbs specifically drove the T cell clonal deletion in both CD4+ and CD8+ cell subsets. An IL-2/IL-2R interaction seems to be a critical step in predisposing superantigen activated cells to death; in fact, in vivo IL-2R blockade reversed T cell deletion in superantigen plus anti-alpha beta TCR mAb treated mice. TCR ligation by mAbs also produced cell death of the relevant targets in in vitro IL-2 activated T cells. Surprisingly, no T cell deletion was demonstrable in IL-2 activated cells following staphylococcal enterotoxin B--TCR interaction, ruling out the possibility that superantigen in itself can induce cell death. Thus, while superantigen activation opens the cell death program, a subsequent TCR--antigen (self) interaction appears necessary to produce clonal deletion in mature T lymphocytes.

We present a two-period framework, which combines real option and decision-theoretic approaches to health technology assessment under uncertainty. By viewing adoption, treatment and research decisions as a single economic project, we illustrate how their key dimensions affect optimal rules. We consider the results in relation to the existing literature and argue that developments in this direction could contribute substantially to efficiency gains in resource allocation.

A simple, two period framework is used to interpret existing contributions to the literature on decision rules for HTA under uncertainty and to contrast them with a dynamic, economic model solved using backward induction.

Referring to the literature on optimal stopping under sequential sampling developed by Chernoff and collaborators, we solve a dynamic model of the economic evaluation of a new health technology, deriving optimal rules for technology adoption, research abandonment and continuation as functions of sample size. The model extends the existing literature to the case where an adoption decision can be deferred and involves a degree of irreversibility. We explore the model's applicability in a case study of the economic evaluation of Drug Eluting Stents (DES), deriving dynamic adoption and abandonment thresholds which are a function of the model's economic parameters. A key result is that referring to a single cost-effectiveness threshold may be sub-optimal.

This paper presents the economic evaluation from a hospital’s perspective of the investment in positron emission tomography, adopting a real options approach. The installation of this equipment requires a major capital outlay, while uncertainty on several key variables is substantial. The value of several timing strategies, including sequential investment, is determined taking into account that future decisions will be based on the information available at that time. The results show that adopting this approach may have an impact on the timing of investment, because postponing the investment may be optimal even when the Expected Net Present Value of the project is positive.

This paper aims to incorporate option values into the economic evaluation of positron emission tomography (PET). The installation of this equipment requires a substantial capital outlay, while uncertainty, especially regarding the possibility of new applications, is relevant, because the evidence available is still insufficient. Treating the number of examinations to provide as a stochastic variable, the cost-effectiveness analysis is extended to include the value of flexibility both with respect to the timing of investment and to the size of the project. The threshold values of the stochastic variable that ensure the cost-effectiveness of a PET scan according to this approach are obtained as a function of the value of the incremental effectiveness.

This paper studies the optimal timing of investment in innovative technology by health care providers competing for patients, in a real option framework. The innovative technology provides a better health outcome, thus attracting a larger number of patients. On the other hand, at the early stages of innovation it is assumed to involve a larger degree of uncertainty and higher operational costs. Since further development of the technology is expected to improve eciency over time, each provider faces a trade-o between gaining a competitive advantage by investing first, and fully exploiting the option to delay investment under uncertainty. The model is set up so that the role of the payment system on investment decisions may be investigated. This turns out not to be always intuitive. In particular, it is showed that a more generous scheme does not always induce to anticipate investment. By comparing the competitive solution with the social optimal timing, some policy implications are finally discussed.

With economic integration rapidly growing at all level, understanding the incentives that this provides in the design of fiscal policies at the national level is fundamental. The most obvious implication of international competition on the taxation of mobile factors is a race to the bottom in the determination of tax rates. However, empirical evidence on the relationship between the strength of competitive pressures and corporate tax rates is mixed. The present paper aims to provide an in depth analysis of the implications of the diverse assumptions that have been made in the theoretical literature. Moreover, the main approaches to the empirical analysis of the relationship between competition and the level of taxation are presented. The paper shows that a large number of factors play a role and accounting for the interactions among all of them in a single model is extremely complicated. This may be seen as a main determinant of the variety in the results obtained so far, both in theoretical and empirical research.

Homologues of two major components of the well-characterized erythrocyte plasma-membrane-skeleton, spectrin (a not-yet-cloned isoform, βIΣ* spectrin) and ankyrin (Ank G119 and an ≈195-kDa ankyrin), associate with the Golgi complex. ADP ribosylation factor (ARF) is a small G protein that controls the architecture and dynamics of the Golgi by mechanisms that remain incompletely understood. We find that activated ARF stimulates the in vitro association of βIΣ* spectrin with a Golgi fraction, that the Golgi-associated βIΣ* spectrin contains epitopes characteristic of the βIΣ2 spectrin pleckstrin homology (PH) domain known to bind phosphatidylinositol 4,5-bisphosphate (PtdInsP 2 ), and that ARF recruits βIΣ* spectrin by inducing increased PtdInsP 2 levels in the Golgi. The stimulation of spectrin binding by ARF is independent of its ability to stimulate phospholipase D or to recruit coat proteins (COP)-I and can be blocked by agents that sequester PtdInsP 2 . We postulate that a PH domain within βIΣ* Golgi spectrin binds PtdInsP 2 and acts as a regulated docking site for spectrin on the Golgi. Agents that block the binding of spectrin to the Golgi, either by blocking the PH domain interaction or a constitutive Golgi binding site within spectrin’s membrane association domain I, inhibit the transport of vesicular stomatitis virus G protein from endoplasmic reticulum to the medial compartment of the Golgi complex. Collectively, these results suggest that the Golgi-spectrin skeleton plays a central role in regulating the structure and function of this organelle.