Cost-effectiveness analysis of additional docetaxel for metastatic hormone-sensitive prostate cancer treated with androgen-deprivation therapy from a Chinese perspective.

The E3805 (CHAARTED) study found that docetaxel combined with androgen-deprivation therapy (ADT) significantly improved overall survival of patients with metastatic hormone-sensitive prostate cancer. This study aims to determine whether docetaxel combined with ADT is a cost-effective strategy for advanced prostate cancer in China. According to the E3805 study, two groups (docetaxel + ADT and ADT alone) and three health states [progression-free survival (PFS), progressive disease (PD) and death] were analysed in a Markov model. All medical costs were calculated from the Chinese societal perspective. Quality-adjusted life year (QALY) and incremental cost-effectiveness ratios (ICERs) were applied as the primary outcome. Overall, the addition of docetaxel was estimated to increase the cost by $12 816.93, with a gain of 0.48 QALY. Additionally, for patients with high-volume disease, the increased cost and effectiveness were $14 627.75 and 0.69 QALYs in docetaxel + ADT group versus the ADT alone group, and the ICER was $21 199.63 per QALY. These ICERs are far more than the commonly accepted willingness-to-pay (WTP) threshold of $20 301 per QALY in China. In spite of longer survival time, docetaxel combined with ADT is not a recommended cost-effective treatment for metastatic hormone-sensitive prostate cancer in the Chinese setting.

Molecular and cellular effects of chemicals disrupting steroidogenesis during early ovarian development of brown trout (Salmo trutta fario).

A range of chemicals found in the aquatic environment have the potential to influence endocrine function and affect sexual development by mimicking or antagonizing the effects of hormones, or by altering the synthesis and metabolism of hormones. The aim of this study was to evaluate whether the effects of chemicals interfering with sex hormone synthesis may affect the regulation of early ovarian development via the modulation of sex steroid and insulin-like growth factor (IGF) systems. To this end, ex vivo ovary cultures of juvenile brown trout (Salmo trutta fario) were exposed for 2 days to either 1,4,6-androstatriene-3,17-dione (ATD, a specific aromatase inhibitor), prochloraz (an imidazole fungicide), or tributyltin (TBT, a persistent organic pollutant). Further, juvenile female brown trout were exposed in vivo for 2 days to prochloraz or TBT. The ex vivo and in vivo ovarian gene expression of the aromatase (CYP19), responsible for estrogen production, and of IGF1 and 2 were compared. Moreover, 17ß-estradiol (E2) and testosterone (T) production from ex vivo ovary cultures was assessed. Ex vivo exposure to ATD inhibited ovarian E2 synthesis, while T levels accumulated. However, ATD did not affect ex vivo expression of cyp19, igf1, or igf2. Ex vivo exposure to prochloraz inhibited ovarian E2 production, but did not affect T levels. Further prochloraz up-regulated igf1 expression in both ex vivo and in vivo exposures. TBT exposure did not modify ex vivo synthesis of either E2 or T. However, in vivo exposure to TBT down-regulated igf2 expression. The results indicate that ovarian inhibition of E2 production in juvenile brown trout might not directly affect cyp19 and igf gene expression. Thus, we suggest that the test chemicals may interfere with both sex steroid and IGF systems in an independent manner, and based on published literature, potentially lead to endocrine dysfunction and altered sexual development.

Ecotoxicology of synthetic pyrethroids.

In this chapter we review the ecotoxicology of the synthetic pyrethroids (SPs). SPs are potent, broad-spectrum insecticides. Their effects on a wide range of nontarget species have been broadly studied, and there is an extensive database available to evaluate their effects. SPs are highly toxic to fish and aquatic invertebrates in the laboratory, but effects in the field are mitigated by rapid dissipation and degradation. Due to their highly lipophilic nature, SPs partition extensively into sediments. Recent studies have shown that toxicity in sediment can be predicted on the basis of equilibrium partitioning, and whilst other factors can influence this, organic carbon content is a key determining variable. At present for SPs, there is no clear evidence for adverse population-relevant effects with an underlying endocrine mode of action. SPs have been studied intensively in aquatic field studies, and their effects under field conditions are mitigated from those measured in the laboratory by their rapid dissipation and degradation. Studies with a range of test systems have shown consistent aquatic field endpoints across a variety of geographies and trophic states. SPs are also highly toxic to bees and other nontarget arthropods in the laboratory. These effects are mitigated in the field through repellency and dissipation of residues, and recovery from any adverse effects tends to be rapid.

Development of an ex vivo brown trout (Salmo trutta fario) gonad culture for assessing chemical effects on steroidogenesis.

A variety of natural and synthetic environmental substances have been shown to disrupt vertebrate reproduction through mimicking or modifying the regulation of the endocrine system. Tests to screen for any such chemicals that directly interact with the steroid hormone receptors are widely available; however, few tests have been developed to identify chemicals that affect endocrine function through non-receptor mediated mechanisms. The aim of this study was, therefore, to develop an assay for the identification of substances that disrupt the activity of enzymes involved in the sex steroid biosynthesis cascade, in particular the aromatase enzyme, CYP19, that catalyses the final conversion of androgens to estrogens. A gonad ex vivo assay was developed using gonad explants harvested from juvenile brown trout and cultured in a modified Leibovitz medium. Effects on sex steroid biosynthesis were quantified through measurement of 17ß-estradiol (E2) and testosterone (T) concentrations in the medium after 2 days incubation. Exposure of ovary explants to 100 ng/mL 1,4,6-androstatriene-3,17-dione (ATD), a potent pharmaceutical aromatase inhibitor, reduced E2 concentrations and elevated T concentrations confirming that CYP19 activity could be inhibited in the assay. Exposure of ovary explants to 250 ng/mL prochloraz, an imidazole fungicide, also reduced E2 concentrations but did not affect T levels, consistent with reports that in addition to inhibiting CYP19 activity, prochloraz also inhibits enzymes in the steroidogenic pathway upstream of the CYP19 enzyme. Exposure to a third chemical, tributyltin (TBT), did not affect T or E2 concentrations, further supporting previous evidence that the CYP19 modulating effects of this chemical are not mediated through direct inhibition of CYP19 activity. These results demonstrate that the gonad ex vivo assay developed here can be successfully used to identify substances that disrupt sex steroid biosynthesis and further that it has the potential to inform on their specific mode of action.

Effects of a weak oestrogenic active chemical (4-tert-pentylphenol) on pair-breeding and F1 development in the fathead minnow (Pimephales promelas).

A fish full life-cycle (FFLC) is the most comprehensive test to determine reproductive toxicity of chemicals to fish and this is likely to apply equally to endocrine active chemicals (EACs). However, FFLC tests use large numbers of animals, are expensive and time consuming. Alternative chronic tests, to the FFLC, potentially include sensitive life-stage windows of effect, such as sexual differentiation, early gonadal development and reproduction. In this paper, a fish pair-breeding study was applied to assess the biological effects of a weak environmental oestrogen, 4-tert-pentylphenol (4TPP), on reproduction and subsequent development of the F1 generation. The results of this study were then compared with the results for a published FFLC study, with this chemical. Fathead minnows (Pimephales promelas) were held in pairs and their reproductive performance assessed over two concurrent 21-day periods, the first without exposure to the test chemical, followed by the second with exposure to the test chemical, in a flow-through system at 25+/-1 degrees C. Embryos from two pairs, per treatment, were subsequently grown up in clean water until 90 days post-hatch to assess developmental effects of the parental exposure on the F1 generation. Nominal (measured geometric mean, time weighted) test concentrations of 4TPP were 56 (48), 180 (173) and 560 (570) microg l(-1). A significant decrease in fecundity was observed in all 4TPP exposed fish (mean number of eggs spawned per pair and number of spawns per pair) when compared to the solvent control. Vitellogenin (VTG) was significantly elevated in F0 males exposed to 560 microg 4TPPl(-1). Somatic endpoints, secondary sexual characteristics (SSC) and gonadosomatic index (GSI) were not affected by the 4TPP exposure. In the F1 generation, there were no treatment-related effects on hatching success, survival, growth, SSC or GSI. Histological examination of the gonads of the F1 fish revealed no treatment-related effects on sex ratio, sexual differentiation or sexual development. However, plasma VTG concentrations were significantly elevated in F1 male fish, derived from parents that had previously been exposed to 4TPP at concentrations of > or = 180 microg l(-1). These data show that the reproductive performance test is suitable for detecting weak environmental oestrogenic chemicals and that exposure of adult fish to oestrogens can result in altered biomarker expression (VTG) of the F1 generation. Our findings indicate that the reproductive performance test was as sensitive for detecting effects on reproduction when compared with a published FFLC test for 4TPP.

Species sensitivity distributions: data and model choice.

Species sensitivity distributions (SSDs) are increasingly incorporated into ecological risk assessment procedures. Although these new techniques offer a more transparent approach to risk assessment they demand more and superior quality data. Issues of data quantity and quality are especially important for marine datasets that tend to be smaller (and have fewer standard test methods) when compared with freshwater data. An additional source of uncertainty when using SSDs is appropriate selection from the range of methods used in their construction. We show through examples the influence of data quantity, data quality, and choice of model. We then show how regulatory decisions may be affected by these factors.

The comparison of rapid bioassays for the assessment of urban groundwater quality.

Groundwater is a complex mixture of chemicals that is naturally variable. Current legislation in the UK requires that groundwater quality and the degree of contamination are assessed using chemical methods. Such methods do not consider the synergistic or antagonistic interactions that may affect the bioavailability and toxicity of pollutants in the environment. Bioassays are a method for assessing the toxic impact of whole groundwater samples on the environment. Three rapid bioassays, Eclox, Microtox and ToxAlert, and a Daphnia magna 48-h immobilisation test were used to assess groundwater quality from sites with a wide range of historical uses. Eclox responses indicated that the test was very sensitive to changes in groundwater chemistry; 77% of the results had a percentage inhibition greater than 90%. ToxAlert, although suitable for monitoring changes in water quality under laboratory conditions, produced highly variable results due to fluctuations in temperature and the chemical composition of the samples. Microtox produced replicable results that correlated with those from D. magna tests.

Extent and sources of geographic variation in Medicare end-stage renal disease expenditures.

Geographic variations in practices and expenditures have been widely documented, leading to concerns that care in some regions is clinically suboptimal and/or economically inefficient. Our objectives are to determine the extent and sources of geographic variation in Medicare expenditures per patient with end-stage renal disease (ESRD) per year. The study population included all patients with ESRD with Medicare as primary payer during 1997 (n = 284,670). Medicare expenditures were summarized at the hospital referral region (HRR) level. Using regression analysis, we estimated the relationship between expenditures and demographics, case mix, dialysis provider characteristics, distribution of patients across renal replacement therapy modalities, standardized hospitalization ratios, and healthcare wages. Spending per patient-year varied threefold across HRRs, ranging from $17,791 to $59,025 (mean, $38,966 +/- $6,774 [SD]). The regression equation explained 80% of this variation. Although several demographic and case-mix indicators that have been related to spending at the individual level were statistically significant predictors of spending at the HRR level, they did not show enough geographic variation to explain a large fraction of spending variation. Rather, patient distributions across renal replacement modalities, hospitalization patterns, and healthcare wages were the most powerful predictors of spending. Compared with Medicare generally, both the mean and SD of ESRD expenditures were approximately seven times larger. The substantial geographic variability in expenditures for patients with ESRD indicates the potential for improving efficiency and quality of care. Interventions designed to increase transplantation rates, ensure access to peritoneal dialysis, and reduce hospitalization appear most promising.

The use of volume standards in health services.

The ways in which volume standards are implemented by health services organizations are not clear. Therefore, the authors sought to evaluate the extent of use of volume standards, the purposes for which such standards were developed, and the sources of the standards in a sample of health services organizations. The authors found that volume standards were used widely by accrediting organizations, professional societies, and hospitals in their sample, but almost never by health maintenance organizations. Volume standards were used for ensuring adequate experience among residents, providing guidelines to residency programs, and privileging and credentialing physicians. Expert consensus appeared to be the usual source of volume standards.

Analysis of the physician variable in pain management.

BACKGROUND: The role of physician variability in pain management is unknown. OBJECTIVE: To assess the role of physician variability in the management of pain and provide quantitative data regarding the status of pain management in Michigan. DESIGN: A multi-item mail survey was used to determine the physician's perceived knowledge of pain management modalities, goals, satisfaction, and confidence with pain treatment. Participants. The focus of this report was a group of 368 licensed Michigan physicians who provide clinical care. RESULTS: Overall, 30% of the study group reported no formal education in pain management, although younger physicians reported more education (correlation coefficient = -0.252, P <.001). The physicians reported greater confidence in their knowledge of meperidine than other Schedule II opioids (P <.001 ). In regards to the opinion that prescribing strong opioids would attract a medical review, the physician responses ranged from 1 (strongly disagree) to 5 (strongly agree). The median score for this scale was 4, accounting for 46% of the responses. The study group expressed less satisfaction with their treatment of chronic pain as well as lower goals for relief (mean: 3.8; 95% confidence interval: 3.7-3.9). CONCLUSIONS: Lower expectations for relief and less satisfaction in its management may contribute to the undertreatment of chronic pain. Perceptions of regulatory scrutiny may contribute to suboptimal pain management. These preliminary data highlight physician variability in pain decision making while providing insights into educational needs.

Can saltwater toxicity be predicted from freshwater data?

The regulation of substances discharged to estuarine and coastal environments relies upon data derived from ecotoxicity tests. Most such data are generated for freshwater rather than saltwater species. If freshwater toxicity data are related to saltwater toxic effects in a systematic and predictable way, the former can be used to predict the latter. This would have economic advantages due to a reduction in toxicity testing of saltwater species. If toxicity data are plotted as species sensitivity distributions, four theoretical relationships between freshwater and saltwater can be envisaged. Examples show that each one of these relationships is supported by empirical data. These examples show that although there is considerable potential for freshwater to saltwater prediction, species parity and representativeness need to be examined for each chemical substance to avoid bias.

The finance-strategy relationship.

The connection between the finance function and strategy in health systems is explored through discussions with chief financial officers (CFOs). The integration of finance into strategy is explored through the use of balanced scorecards, strategic investments and the analysis of core competencies and core enterprises. Divestiture of investments in health plans, physician practices and long-term care facilities is common, while outsourcing activity is increasing.

Health care capital market and product market constraints and the role of the chief financial officer.

To understand better the financial management practices and strategies of modern health care organizations, we conducted interviews with chief financial officers (CFOs) of several leading health care systems. The constraints imposed on health care systems by both capital and product markets has made the role of the CFO a challenge.

Private and public ownership in outpatient substance abuse treatment: do we have a two-tiered system?

As investor-owned organizations increase their presence in the mental health care sector, questions emerge regarding the effects of ownership type on service delivery. One important question is whether ownership is related to patient access to care for persons requiring treatment for substance abuse problems. Using data from a 1995 national survey of outpatient substance abuse treatment units, the authors investigate whether there are differences in measures of patient access to care among investor-owned, not-for-profit, and public provider organizations. Results indicate investor-owned units cater to and serve a clientele that differs from that of not-for-profit and public units, suggesting the presence of a two-tiered system of substance abuse treatment.

Financial management in leading health care systems.

To understand better the financial management practices and strategies of modern health care organizations, we conducted interviews with chief financial officers (CFOs) of several leading health care systems. In this introduction, we present an overview of the project and summary responses on corporate financial structures and strategic challenges facing CFOs.

Capital investment strategies in health care systems.

Capital investment decisions are among the most important decisions made by firms. They determine the firm's capacity for providing services and commit the firm's cash for an extended period of time. Interviews with chief financial officers of leading health care systems reveal capital investment strategies that generally follow the recommendations of modern finance theory. Still, there is substantial variation in capital budgeting techniques, methods of risk adjustment, and the importance of qualitative considerations in investment decision making. There is also variation in delegation of investment decision making to operating units and methods of performance evaluation. Health care systems face the same challenges as other organizations in developing and implementing capital investment strategies that use consistent methods for evaluation of projects that have inconsistent aims and outcomes.

Capital structure strategy in health care systems.

The capital structures (the relative use of debt and equity to support assets) of leading health care systems are viewed as a strategic component of their financial plans. While not-for-profit hospitals as a group have maintained nearly constant levels of debt over the past decade, investor-owned hospitals and a group of leading health care systems have reduced their relative use of debt. Chief financial officers indicated that in addition to reducing debt because of less favorable reimbursement incentives, there was a focus on maintaining high bond ratings. Debt levels have not been reduced as sharply in these health care systems as they have in investor-owned hospitals, in part due to the use of debt to support investments in financial markets. Because these health care systems do not have easy access to equity, high bond ratings and solid investment earnings are central to their capital structure policies of preserving access to debt markets.

Sources of project financing in health care systems.

Through discussions with chief financial officers of leading health care systems, insights are offered on preferences for project financing and development efforts. Data from these same systems provide at least anecdotal evidence in support of pecking-order theory.

Cash management in health care systems.

Cash is one of the most precious assets held by health systems. This article presents results of discussions on cash management and investment policies at a dozen major not-for-profit health systems. Health system data indicate that cash holdings have increased dramatically since 1993, mostly due to investment earnings. Discussions with chief financial officers of these health systems reveal that cash holdings are significant, that decisions about cash balances are strategic, and that most systems aim to increase cash balances to levels that permit access to capital markets on more favorable terms.