Involvement of DMT1 in uptake of Cd in MDCK cells: role of protein kinase C.

The involvement of iron (Fe) transporters in the uptake of cadmium (Cd) was examined in Madin-Darby kidney cells (MDCK). The uptake of Cd displayed properties that are associated with the Fe transporter divalent metal transporter 1 (DMT1). For example, the uptake of Cd and Fe was reduced by altering the cell membrane potential. The uptake of Cd was blocked by Fe, and the uptake of Fe was blocked by Cd. Also, the uptake of Cd and Fe was higher in MDCK cells bathed in a buffer at low pH. Increased uptake of Fe and Cd was observed in the HEK-293 cell line overexpressing DMT1. Overnight treatment of MDCK cells with the protein kinase C activator phorbol 12,13-dibutyrate (PDBu) resulted in increased uptake of Cd and Fe and an increase in DMT1 mRNA. An increase in newly transcribed DMT1 mRNA was not observed, suggesting that PDBu does not increase DMT1 mRNA by activating transcription. Rather, the increase was most likely due to greater stability of DMT1 mRNA, because the rate of degradation of DMT1 mRNA was slower in MDCK cells treated with PDBu. Our results suggest that Fe and Cd are transported in MDCK cells by a transporter with biochemical properties similar to those of DMT1.

Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer.

A phase II trial evaluated the effectiveness and toxicity of combination paclitaxel (Taxol), gemcitabine (Gemzar), and trastuzumab (Herceptin) as first-line therapy for patients with newly diagnosed HER2-overexpressing metastatic breast cancer. To date, 27 patients have received paclitaxel at 175 mg/m2 over 3 hours on day 1, plus gemcitabine at 1,200 mg/m2 on days 1 and 8, plus trastuzumab at a 4-mg/kg loading dose on day 1, followed by 2 mg/kg weekly. Treatment cycles were repeated every 21 days. Responding or stable patients who had received six cycles of combination therapy continued single-agent trastuzumab weekly until disease progression. Treatment was generally well tolerated with grade 4 toxicity limited to myelosuppression. In all, 12 patients have achieved a partial remission and 1 patient had progressive disease; 14 patients continue treatment and have not yet been evaluated for response. Combination treatment with paclitaxel, gemcitabine, and trastuzumab is well tolerated and appears to be highly active. Accrual will continue to a total enrollment of 46 patients.

Preventive service use and Medicaid managed care in New York City.

OBJECTIVE: To examine the effect of managed care enrollment on the use of preventive services among New York City's Medicaid population. STUDY DESIGN: An analysis of survey results from a sample of Medicaid beneficiaries in managed care plans and in traditional Medicaid. METHODS: This study is based on a 1994 survey of 1038 Medicaid beneficiaries enrolled in any of 5 managed care plans and a comparison group of 410 beneficiaries in traditional Medicaid in New York City. The survey data are used to examine the effect of managed care on the self-reported use of Pap smears, mammograms, and infant immunizations. We performed bivariate analysis to compare the use of preventive services between managed care enrollees and beneficiaries in traditional Medicaid. We also used multivariate logistic analysis to explore this comparison, controlling for factors that may confound the relationship. RESULTS: Medicaid beneficiaries in managed care were no more or less likely to receive infant immunizations, Pap smears, or mammograms than those in the traditional Medicaid program. CONCLUSIONS: Our analysis suggests that Medicaid managed care and the traditional program performed the same in getting appropriate preventive services to beneficiaries.

Modeling age differences in cost-effectiveness analysis. A review of the literature.

OBJECTIVES: Cost-effectiveness analysts often present cost-effectiveness results by age to help inform decisions about the use of an intervention. Yet it is not known how well studies model the risks and costs associated with age. We reviewed published studies to examine their modeling of age differences. METHODS: MEDLINE searches identified all cost-effectiveness analyses published between 1985 and 1997 that included adults 50 years of age and older, were based on data for developed countries, and compared cost-effectiveness ratios for adults of different ages or for initiation of an intervention at different ages; 36 articles met these criteria. They were reviewed to determine the extent to which they incorporated age-specific data. Studies that justified using the same data for all ages were counted as having varied the data element by age. RESULTS: All studies varied life expectancy by age. Most also varied the incidence/prevalence of the target condition and the case fatality rate. Only 36% varied the effectiveness rate of the intervention by age. Costs were usually assumed constant: 42% of studies varied the cost of treating adverse effects and 17% varied the cost of treating the target condition. Whether a data element was varied did not appear to be related to the pattern of cost-effectiveness ratios by age. CONCLUSIONS: Many studies have not modeled age differences in sufficient detail to ensure that differences in cost-effectiveness ratios by age are accurate and a sound basis for decisions. As cost-effectiveness analysis becomes more widespread, analysts should strive to incorporate more complete age-specific data.

Combination versus sequential doxorubicin and docetaxel as primary chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group.

PURPOSE: To evaluate the efficacy and toxicity of combination and sequential dose-dense chemotherapy with doxorubicin and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) as primary chemotherapy of breast cancer. PATIENTS AND METHODS: Patients with newly diagnosed stage II or noninflammatory stage III breast cancer were randomly assigned to receive the same total doses of doxorubicin and docetaxel over a 12-week period before definitive surgery. Patients in arm A received sequential therapy with doxorubicin 75 mg/m(2) every 2 weeks for three cycles followed by docetaxel 100 mg/m(2) every 2 weeks for three cycles. Patients in arm B received combination therapy with doxorubicin 56 mg/m(2) plus docetaxel 75 mg/m(2) every 3 weeks for four cycles. Granulocyte colony-stimulating factor was administered on days 2 to 12 of each cycle in both groups. RESULTS: Forty patients were entered onto the trial. Pretreatment tumor size averaged 5.7 cm with clinically positive axillary lymph nodes in 23 patients (57%). As expected, myelosuppression was severe in both groups; however, >/= 80% of planned dose-intensity was delivered. Hand-foot syndrome was more common after sequential therapy. Clinical responses were similar in both groups, with an overall response rate of 87%, including 20% clinical complete remissions. Pathologic complete remission or residual in situ disease only was confirmed in five patients (12.8%). Patients who received sequential therapy had fewer positive lymph nodes (mean, 2.17 v 4.81; P <.037) at definitive surgery. CONCLUSION: Primary chemotherapy with doxorubicin and docetaxel is well tolerated and highly active. A sequential treatment schedule increases toxicity but may result in more substantial lymph node clearance than combination therapy.

Probabilistic sensitivity analysis in cost-effectiveness. An application from a study of vaccination against pneumococcal bacteremia in the elderly.

OBJECTIVES: We explore the policy implications of probabilistic sensitivity analysis in cost-effectiveness analysis by applying simulation methods to a decision model. METHODS: We present the multiway sensitivity analysis results of a study of the cost-effectiveness of vaccination against pneumococcal bacteremia in the elderly. We then execute a probabilistic sensitivity analysis of the cost-effectiveness ratio by specifying posterior distributions for the uncertain parameters in our decision analysis model. In order to estimate probability intervals, we rank the numerical values of the simulated incremental cost-effectiveness ratios (ICERs) to take into account preferences along the cost-effectiveness plane. RESULTS: The 95% probability intervals for the ICER were generally much narrower than the difference between the best case and worst case results from a multiway sensitivity analysis. Although the multiway sensitivity analysis had indicated that, in the worst case, vaccination in the 85 and older age group was not acceptable from a policy standpoint, probabilistic methods indicated that the cost-effectiveness of vaccination was below $50,000 per quality-adjusted life-year in greater than 92% of the simulations and below $100,000 in greater than 95% of the simulations. CONCLUSIONS: Probabilistic methods can supplement multiway sensitivity analyses to provide a more comprehensive picture of the uncertainty associated with cost-effectiveness ratios and thereby inform policy decisions.

How are health care organizations using clinical guidelines?

Although policymakers are increasingly interested in how integrated delivery systems and managed care plans implement clinical guidelines and improve performance and quality of care, few data have been compiled about how these organizations are undertaking change. Interviews with officials in organizations that are engaged in improving practice across the country documented that there is a profound transformation under way with substantial similarity in the approaches being used by otherwise very different plans. Better evaluation of the effectiveness and cost-effectiveness of these approaches could provide a more solid foundation for policies to improve quality of care.

Women in New York City's Medicaid program: a report on satisfaction, access, and use.

This article analyzes the experiences of women in New York City's Medicaid program regarding their satisfaction with, access to, and use of medical care during an early phase of a managed care enrollment initiative. Data for this study are from a 1994 survey of New York City Medicaid beneficiaries (1,221 women) as well as from focus group discussions. Differences in reported satisfaction levels, access, and use between managed care enrollees and conventional Medicaid beneficiaries are examined, as are differences between women in fair and poor health and those in excellent, very good, and good health. Multivariate analyses found that women enrolled in Medicaid managed care overall were significantly more likely to report greater satisfaction with access, interpersonal quality, technical skills, and arrangements for choosing a personal doctor; equivalent use; and better access compared to those in conventional Medicaid. Female managed care beneficiaries who reported worse health, however, were significantly more likely than those in better health to also report less satisfaction in 13 dimensions of medical care. Continued evaluation of Medicaid managed care is warranted, particularly as more vulnerable groups are enrolled.

A proposed framework for economic evaluation of telemedicine.

Economic evaluation of telemedicine compares the costs and other consequences of delivering specific services through telemedicine vs. alternative means. Cost-effectiveness analysis, the most common method used for health issues, helps to assess whether the expected health benefits are worth the investment. Telemedicine raises particular challenges for evaluators: a telemedicine system may have multiple uses and joint costs that are difficult to apportion to one service, the existence of a system may lead to expanded indications for use, and technological change may rapidly make an evaluation outdated. Public and private regulation and payment may affect the diffusion of telemedicine. Uncertainty surrounds the policy of the U.S. Food and Drug Administration, which is still formulating its position. Changes are underway in policies on licensure and credentialing of clinicians, which have traditionally been done by state and by site, to reflect the fact that telemedicine services may cross these regional boundaries. Lack of insurance coverage for telemedicine services has been considered an impediment to adoption with fee-for-service payment. Under capitation payment and fixed budgets, however, providers have financial incentives to use the most efficient method to deliver services, and these arrangements would favor telemedicine if it is the less costly alternative. If telemedicine were most costly and the health benefits worth the cost, monitoring might be needed to ensure the quality of care.

Increased competition and the quality of health care.

Available information does not indicate either that quality has deteriorated as price competition has increased or that quality has improved. To reward plans for providing what consumers want, public and private policies have crucial roles in the following areas: mandating minimal requirements for plans; funding research to improve knowledge and methods related to quality-of-care assessment; publication of quality-of-care information; selective contracting and regionalizing of services; and payment for physician services. Learning what degree of trade-off between cost versus quality and other benefits is acceptable to consumers will be an iterative process that informs future policies to safeguard the quality of care.

Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people.

CONTEXT: Clinical, epidemiologic, and policy considerations support updating the cost-effectiveness of pneumococcal vaccination for elderly people and targeting the evaluation only to prevention of pneumococcal bacteremia. OBJECTIVE: To assess the implications for medical costs and health effects of vaccination against pneumococcal bacteremia in elderly people. DESIGN: Cost-effectiveness analysis of pneumococcal vaccination compared with no vaccination, from a societal perspective. SETTING AND PARTICIPANTS: The elderly population aged 65 years and older in the United States in 3 geographic areas: metropolitan Atlanta, Ga; Franklin County, Ohio; and Monroe County, New York. MAIN OUTCOME MEASURES: Incremental medical costs and health effects, expressed in quality-adjusted life-years per person vaccinated. RESULTS: Vaccination was cost saving, ie, it both reduced medical expenses and improved health, for all age groups and geographic areas analyzed in the base case. For people aged 65 years and older, vaccination saved $8.27 and gained 1.21 quality-adjusted days of life per person vaccinated. Vaccination of the 23 million elderly people unvaccinated in 1993 would have gained about 78000 years of healthy life and saved $194 million. In univariate sensitivity analysis, the results remained cost saving except for doubling vaccination costs, including future medical costs of survivors, and lowering vaccination effectiveness. With assumptions most unfavorable to vaccination, cost per quality-adjusted life-year ranged from $35 822 for ages 65 to 74 years to $598 487 for ages 85 years and older. In probabilistic sensitivity analysis, probability intervals were more narrow, with less than 5% probability that the ratio for ages 85 years and older would exceed $100000. CONCLUSIONS: Pneumococcal vaccination saves costs in the prevention of bacteremia alone and is greatly underused among the elderly population, on both health and economic grounds. These results support recent recommendations of the Advisory Committee on Immunization Practices and public and private efforts under way to improve vaccination rates.

Evaluation of Medicaid managed care. Satisfaction, access, and use.

OBJECTIVE: To evaluate the effects of managed care on Medicaid beneficiaries' satisfaction with, access to, and use of medical care during early implementation of an enrollment initiative. DESIGN: Cross-sectional survey of a random sample of Medicaid beneficiaries in 5 managed care plans and in the conventional Medicaid program. SETTING: New York, NY. PARTICIPANTS: Adults aged 18 to 64 years who received Medicaid insurance benefits through Aid to Families With Dependent Children or State Home Relief and had been enrolled in a managed care plan or receiving benefits under conventional Medicaid for at least 6 months. Of the 2500 enrollees in managed care plans and the 600 other beneficiaries in conventional Medicaid whom we surveyed, 1038 enrollees and 410 nonenrollees responded. OUTCOME MEASURES: Beneficiaries' ratings of overall satisfaction and 13 dimensions of satisfaction related to access, interpersonal and technical quality, and cost; reports of access, including regular source (location) of care, waiting time for appointment, waiting time in office, and ability to obtain care; and reports of use, including inpatient, emergency department, and ambulatory visits. RESULTS: Compared with beneficiaries in conventional Medicaid, managed care enrollees in general gave higher ratings of satisfaction. The results were not consistent, however, between the proportion who were extremely satisfied and the proportion who were extremely dissatisfied. Managed care enrollees had significantly greater odds of being extremely satisfied (excellent and very good ratings), but fewer differences were statistically significant for levels of extreme dissatisfaction (fair and poor ratings). With regard to access, managed care enrollees had significantly greater odds of having a usual source of care (odds ratio [OR], 2.33) and seeing the same clinician there (OR, 2.72) and had significantly shorter appointment and office waiting times. Managed care and conventional Medicaid beneficiaries reported no significant differences in obtaining or delays in getting needed care and in inpatient or emergency department use. CONCLUSIONS: Medicaid managed care enrollees in New York City reported better access to care and higher levels of satisfaction compared with conventional Medicaid beneficiaries. Differences between these findings and those for privately insured populations highlight the pitfalls of generalizing from other groups to Medicaid for policy purposes. Given growing reliance on consumer satisfaction surveys for clinical and public policy, future research should focus on factors that explain extreme satisfaction vs extreme dissatisfaction. New York State's initiative, which has been associated with careful state and local monitoring, merits continuing evaluation as managed care enrollment grows and may become mandatory.

Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies.

The clinical distinction between patients with a disorder of peroxisome assembly (e.g., Zellweger syndrome) and those with a defect in a peroxisomal fatty acid beta-oxidation enzyme can be difficult. We studied 29 patients suspected of belonging to the latter group. Using complementation analysis, 24 were found to be deficient in enoylcoenzyme A hydratase/3-hydroxyacylcoenzyme A dehydrogenase bifunctional enzyme and 5 were deficient in acyl-CoA oxidase. Elevated plasma very long-chain fatty acids (VLCFA), impaired fibroblast VLCFA beta-oxidation, decreased fibroblast phytanic acid oxidation, normal plasmalogen synthesis, normal plasma L-pipecolic acid level, and normal subcellular catalase distribution were characteristic findings in both disorders. The elevation in plasma VLCFA levels and impairment in fibroblast VLCFA beta-oxidation were more severe in bifunctional-deficient than in oxidase-deficient patients. The clinical course in bifunctional deficiency (profound hypotonia, neonatal seizures, dysmorphic features, age at death approximately 9 months) was more severe than in oxidase deficiency (moderate hypotonia without dysmorphic features, development of a leukodystrophy, age at death approximately 4 yr). Based on these findings, accurate early diagnosis of these deficiencies of peroxisomal beta-oxidation enzymes is possible.

Innovation under federal health care reform.

Health care reform, which seeks to expand coverage and control spending, contains mixed messages for innovators. Policies that advance reform goals are likely to shift resources away from hospitals, specialists, and expensive procedures and toward areas such as prevention and primary care where innovation may yield greater health improvements per dollar spent. The size of these effects depends critically on the extent of cost containment achieved. Constraining spending will be politically difficult because it requires that consumers forego some possible health benefits in return for lower costs. In a climate of cost containment, systematic evaluation of new technology is vital to identify and expand coverage to worthwhile innovations and to assure a fair hearing for innovators.

Supporting future surgical innovation. Lung transplantation as a case study.

OBJECTIVE: Using lung transplantation as a case study, this article addressed the problem of supporting innovative clinical surgery in an era of increasing pressures for cost containment. SUMMARY BACKGROUND DATA: After sporadic attempts at lung transplantation during the 1960s and 1970s, its clinical development began in earnest during the early 1980s. As a result of a wide range of incremental advances, the results have improved significantly. The Health Care Financing Administration, however, has not yet issued a national policy covering lung transplants and has left the coverage decision to the discretion of its regional contractors. METHODS: The authors surveyed the major commercial insurers, the Blue Cross Blue Shield Association, and a sample of Medicare intermediaries to evaluate the coverage of lung transplantation. They also interviewed the National Heart, Lung, and Blood Institute and industrial firms about their support for clinical research. RESULTS: Government and industry funding were limited, and the development and assessment of lung transplants have been financed predominantly by academic institutions through cross-subsidization from patient care and teaching funds. The major private payers and Blue Cross Blue Shield decided to cover this procedure in the early 1990s. Coverage decisions by Medicare intermediaries, however, revealed considerable variability. Moreover, the absence of a specific diagnosis-related group for lung transplants had considerable consequences for institutions in all-payer states, in which payments appeared to be considerably lower than the mean costs of a transplant procedure (about $110,000). CONCLUSIONS: This analysis indicated that there was a growing disparity between the increasing demand for outcomes data about new procedures and the limited resources available for supporting the development and assessment of new operations. It this disparity is not addressed, the rate of surgical innovation may be jeopardized, and timely outcomes data may not be acquired. It was concluded that provisional coverage within a predetermined research protocol may be a promising mechanism to remedy this situation, providing timely assessment of new procedures before widespread application.