Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials.

PURPOSE: Several studies observed a female advantage in the prognosis of cutaneous melanoma, for which behavioral factors or an underlying biologic mechanism might be responsible. Using complete and reliable follow-up data from four phase III trials of the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, we explored the female advantage across multiple end points and in relation to other important prognostic indicators. PATIENTS AND METHODS: Patients diagnosed with localized melanoma were included in EORTC adjuvant treatment trials 18832, 18871, 18952, and 18961 and randomly assigned during the period of 1984 to 2005. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for women compared with men, adjusted for age, Breslow thickness, body site, ulceration, performed lymph node dissection, and treatment. RESULTS: A total of 2,672 patients with stage I/II melanoma were included. Women had a highly consistent and independent advantage in overall survival (adjusted HR, 0.70; 95% CI, 0.59 to 0.83), disease-specific survival (adjusted HR, 0.74; 95% CI, 0.62 to 0.88), time to lymph node metastasis (adjusted HR, 0.70; 95% CI, 0.51 to 0.96), and time to distant metastasis (adjusted HR, 0.69; 95% CI, 0.59 to 0.81). Subgroup analysis showed that the female advantage was consistent across all prognostic subgroups (with the possible exception of head and neck melanomas) and in pre- and postmenopausal age groups. CONCLUSION: Women have a consistent and independent relative advantage in all aspects of the progression of localized melanoma of approximately 30%, most likely caused by an underlying biologic sex difference.

Serum Leptin Concentration, Body Mass Index and Incident Heart Failure: The Health, Aging, and Body Composition Study

Background: Leptin is produced primarily by adipocytes. Although originally associated with the central regulation of satiety and energy metabolism, increasing evidence indicates that leptin may be an important factor for congestive heart faire (CHF). In the study, we aimed to test the hypothesis that leptin may influence CHF pathophysiology via a pathway of increasing body mass index (BMI). Methods: We studied 2,389 elderly participants aged 70 and older (M; 1161, F: 1228) without CHF and with serum leptin measures at the Health Aging, and Body Composition study. We analyzed the association between serum leptin level and risk of incident CHF using Cox hazard proportional regression models. Elevated leptin level was defined as more than the highest quartile (Q4) of leptin distribution in the total sample for each gender. Adjusted-covariates included demographic, behavior, lipid and inflammation variables (partially-adjusted models), and further included BMI (fully-adjusted models). Results: In a mean 9-year follow-up, 316 participants (13.2%) developed CHF. The partially-adjusted models indicated that men and women with elevated serum leptin levels (>=9.89 ng/ml in men and >=25 ng/ml in women) had significantly higher risks of developing CHF than those with leptin level of less than Q4. The adjusted hazard ratios (95%CI) for incident CHF was 1.49 (1.04 -2.13) in men and 1.71 (1.12 -2.58) in women. However, these associations became non-significant after adjustment for including BMI for each gender. The fully-adjusted hazard ratios (95%CI) were 1.43 (0.94 -2.18) in men and 1.24 (0.77-1.99) in women. Conclusion: Subjects with elevated leptin levels have a higher risk of CHF. The study supports the hypothesis that the influence of leptin level on risk of CHF may be through a pathway related to increasing BMI.

Impact of low-level viremia on clinical and virological outcomes in treated HIV-1-infected patients.

BACKGROUND: The goal of antiretroviral therapy (ART) is to reduce HIV-related morbidity and mortality by suppressing HIV replication. The prognostic value of persistent low-level viremia (LLV), particularly for clinical outcomes, is unknown. OBJECTIVE: Assess the association of different levels of LLV with virological failure, AIDS event, and death among HIV-infected patients receiving combination ART. METHODS: We analyzed data from 18 cohorts in Europe and North America, contributing to the ART Cohort Collaboration. Eligible patients achieved viral load below 50 copies/ml within 3-9 months after ART initiation. LLV50-199 was defined as two consecutive viral loads between 50 and 199 copies/ml and LLV200-499 as two consecutive viral loads between 50 and 499 copies/ml, with at least one between 200 and 499 copies/ml. We used Cox models to estimate the association of LLV with virological failure (two consecutive viral loads at least 500 copies/ml or one viral load at least 500 copies/ml, followed by a modification of ART) and AIDS event/death. RESULTS: Among 17 902 patients, 624 (3.5%) experienced LLV50-199 and 482 (2.7%) LLV200-499. Median follow-up was 2.3 and 3.1 years for virological and clinical outcomes, respectively. There were 1903 virological failure, 532 AIDS events and 480 deaths. LLV200-499 was strongly associated with virological failure [adjusted hazard ratio (aHR) 3.97, 95% confidence interval (CI) 3.05-5.17]. LLV50-199 was weakly associated with virological failure (aHR 1.38, 95% CI 0.96-2.00). LLV50-199 and LLV200-499 were not associated with AIDS event/death (aHR 1.19, 95% CI 0.78-1.82; and aHR 1.11, 95% CI 0.72-1.71, respectively). CONCLUSION: LLV200-499 was strongly associated with virological failure, but not with AIDS event/death. Our results support the US guidelines, which define virological failure as a confirmed viral load above 200 copies/ml.

On the Relationship between Market Power and Bank Risk Taking

We analyse risk-taking behaviour of banks in the context of spatial competition. Banks mobilise unsecured deposits by offering deposit rates, which they invest either in a prudent or a gambling asset. Limited liability along with high return of a successful gamble induce moral hazard at the bank level. We show that when the market power is low, banks invest in the gambling asset. On the other hand, for sufficiently high levels of market power, all banks choose the prudent asset to invest in. We further show that a merger of two neighboring banks increases the likelihood of prudent behaviour. Finally, introduction of a deposit insurance scheme exacerbates banks’ moral hazard problem.

Export-market dynamics and the probability of firm closure: Evidence for the UK

This study presents the first empirical analysis of the determinants of firm closure in the UK with an emphasis on the role of export-market dynamics, using panel data for a nationally representative group of firms operating in all-market based sectors during 1997-2003. Our findings show that the probability of closure is (cet. par.) significantly lower for exporters, particularly those experiencing export-market entry and exit. Having controlled for other attributes associated with productivity (such as size and export status), the following factors are found to increase the firm’s survival prospects: higher capital intensity and TFP, foreign ownership, young age, displacement effects (through relatively high rates of entry of firms in each industry), and belonging to certain industries. Interestingly, increased import penetration (a proxy for lower trade costs) leads to a lower hazard rate for exporting entrants and continuous exporters, whilst inducing a higher hazard rate for domestic producers or those that quit exporting.

Why is it so Hard to Value Intangibles? Evidence from Investments in High-Technology Start-Ups

The paper uses a range of primary-source empirical evidence to address the question: ‘why is it to hard to value intangible assets?’ The setting is venture capital investment in high technology companies. While the investors are risk specialists and financial experts, the entrepreneurs are more knowledgeable about product innovation. Thus the context lends itself to analysis within a principal-agent framework, in which information asymmetry may give rise to adverse selection, pre-contract, and moral hazard, post-contract. We examine how the investor might attenuate such problems and attach a value to such high-tech investments in what are often merely intangible assets, through expert due diligence, monitoring and control. Qualitative evidence is used to qualify the more clear cut picture provided by a principal-agent approach to a more mixed picture in which the ‘art and science’ of investment appraisal are utilised by both parties alike

Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.

BACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts. METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications. RESULTS: Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR,1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95%CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03). CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

Testing for Proportional Hazards with Unrestricted Univariate Unobserved Heterogeneity

We develop tests of the proportional hazards assumption, with respect to a continuous covariate, in the presence of unobserved heterogeneity with unknown distribution at the individual observation level. The proposed tests are specially powerful against ordered alternatives useful for modeling non-proportional hazards situations. By contrast to the case when the heterogeneity distribution is known up to …nite dimensional parameters, the null hypothesis for the current problem is similar to a test for absence of covariate dependence. However, the two testing problems di¤er in the nature of relevant alternative hypotheses. We develop tests for both the problems against ordered alternatives. Small sample performance and an application to real data highlight the usefulness of the framework and methodology.

Financial Distress in Chinese Industry: Microeconomic, Macroeconomic and Institutional Infuences

We study the impact of both microeconomic factors and the macroeconomy on the financial distress of Chinese listed companies over a period of massive economic transition, 1995 to 2006. Based on an economic model of financial distress under the institutional setting of state protection against exit, and using our own firm-level measure of distress, we find important impacts of firm characteristics, macroeconomic instability and institutional factors on the hazard rate of financial distress. The results are robust to unobserved heterogeneity at the firm level, as well as those shared by firms in similar macroeconomic founding conditions. Comparison with related studies for other economies highlights important policy implications.

Oxidative potential for fine/ultrafine particles in occupational situations

Introduction : The redox properties of fine/ultrafine particles as well as nanoparticles (NP) are suggested to be important to explain their biological activity and could constitute a novel and promising metric for hazard evaluation. The acellular in vitro dithiothreitol (DTT) assay allows measuring this property. Objectives : (1) to evaluate sampling requirements for fine/ultrafine particle allowing measurement of their oxidative potential (2) to apply the methodology to occupational situations where particle from combustion sources are generated. Material and method : Sampling parameters (type of filters and loaded amount) and storage duration affecting the DTT measurements were evaluated. Based on these results, a methodological approach was defined and applied in two occupational situations where diesel and other combustion particles are present (toll station in a tunnel and mechanical yard for bus reparation). Results : Teflon filters loaded with diesel particles were found more suitable for the DTT assay, due to their better chemical inertness compared to quartz filters: after storage durations larger than 150 hours, an increased reactivity toward DTT was observed only with quartz filters. Reactivity was linearly correlated to the loaded mass until about 1000 μg/filter. Different redox reactivities were determined in both working places, with the mechanical yard presenting a higher DTT consumption rate. Discussion and conclusions : These results demonstrate the feasibility of this method to determine the oxidative potential of fine/ultrafine particles in occupational situations. We propose to include this approach for hazard assessment of work places with exposure to manufactured and other NP.

Using Effluent Charges in Promoting Investment in Water Pollution Control Technology: A Model of Coordination Failure among Firms

Untreated wastewater being directly discharged into rivers is a very harmful environmental hazard that needs to be tackled urgently in many countries. In order to safeguard the river ecosystem and reduce water pollution, it is important to have an effluent charge policy that promotes the investment of wastewater treatment technology by domestic firms. This paper considers the strategic interaction between the government and the domestic firms regarding the investment in the wastewater treatment technology and the design of optimal e­ffluent charge policy that should be implemented. In this model, the higher is the proportion of non-investing firms, the higher would be the probability of having to incur an e­ffluent charge and the higher would be that charge. On one hand the government needs to impose a sufficiently strict policy to ensure that firms have strong incentive to invest. On the other hand, it cannot be too strict that it drives out firms which cannot afford to invest in such expensive technology. The paper analyses the factors that affect the probability of investment in this technology. It also explains the difficulty of imposing a strict environment policy in countries that have too many small firms which cannot afford to invest unless subsidised.

Establiment de bases científiques per al desenvolupament d'una estratègia integrada per avaluar toxicitat en reproducció

Report for the scientific sojourn at the National Institute for Public Health and the Environment (RIVM), Netherlands, from 2006 to 2008. This project aimed at creating scientific elements that could help deriving an integrated testing strategy for reproductive toxicity. Part of the project focused on the use of alternative tests for regulatory purposes. An in vitro-in vivo extrapolation method for embryotoxicity was proposed and evaluated. In vitro and in vivo dose descriptors were correlated; however, the scatter in the correlation was too large to allow an accurate estimation of an in vivo dose from an in vitro dose. The in vitro-in vivo extrapolation method together with toxicokinetic data was also applied to a category of substances (phthalates). Although based on a limited number of substances, the results suggested that in vitro-in vivo extrapolation for embryotoxicity is possible within a category of compounds if adequate toxicokinetic data is available. Because of the limitations that still remain in the use of alternative tests for reproductive toxicicity, other approaches to reduce animal testing were explored. Thus, a database of reproductive toxicity studies was created to retrospectively evaluate the comparative value of some studies or elements in a particular study. When compared to the subchronic toxicity study, the rat two-generation reproductive toxicity study had a considerable impact on the identification of hazard for reproductive toxicity, but not on the overall NOAEL. Among the two-generation studies included in our database, the second generation affected neither the overall NOAEL nor the critical effect. The rat and the rabbit developmental toxicity studies were, on average, similarly sensitive. However, for certain substances the developmental study in either one of the two species appeared to be more sensitive than in the other species.

Universal banking, competition and risk in a macro model

A stylized macroeconomic model is developed with an indebted, heterogeneous Investment Banking Sector funded by borrowing from a retail banking sector. The government guarantees retail deposits. Investment banks choose how risky their activities should be. We compared the benefits of separated vs. universal banking modelled as a vertical integration of the retail and investment banks. The incidence of banking default is considered under different constellations of shocks and degrees of competitiveness. The benefits of universal banking rise in the volatility of idiosyncratic shocks to trading strategies and are positive even for very bad common shocks, even though government bailouts, which are costly, are larger compared to the case of separated banking entities. The welfare assessment of the structure of banks may depend crucially on the kinds of shock hitting the economy as well as on the efficiency of government intervention.

Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.

BACKGROUND: A single infusion of intravenous zoledronic acid decreases bone turnover and improves bone density at 12 months in postmenopausal women with osteoporosis. We assessed the effects of annual infusions of zoledronic acid on fracture risk during a 3-year period. METHODS: In this double-blind, placebo-controlled trial, 3889 patients (mean age, 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included bone mineral density, bone turnover markers, and safety outcomes. RESULTS: Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk, 0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). Zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs. 20 patients, P<0.001). CONCLUSIONS: A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. (ClinicalTrials.gov number, NCT00049829.)

Market Competition and Lower Tier Incentives

The relationship between competition and performance-related pay has been analyzed in single-principal-single-agent models. While this approach yields good predictions for managerial pay schemes, the predictions fail to apply for employees at lower tiers of a firm's hierarchy. In this paper, a principal-multi-agent model of incentive pay is developed which makes it possible to analyze the effect of changes in the competitiveness of markets on lower tier incentive payment schemes. The results explain why the payment schemes of agents located at low and mid tiers are less sensitive to changes in competition when aggregated firm data is used. Journal of Economic Literature classiffication numbers: D82, J21, L13, L22. Keywords: Cournot Competition, Contract Delegation, Moral Hazard, Entry, Market Size, Wage Cost.