The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule HIF-pathway inhibitor NSC-134754. METHODS: Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought. RESULTS: In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c-Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC-134754-treated tumours revealed lower expression of HIF-1α and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment. CONCLUSION: NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent.

[Are American physicians more satisfied?--results from an International Study of Physicians in University Hospitals]. / Sind amerikanische Arzte zufriedener?--Ergebnisse einer internationalen Studie unter Arzten an Universitätskliniken.

Understanding the factors that affect physicians' job satisfaction is important not only to physicians themselves, but also to patients, health system managers, and policy makers. Physicians represent the crucial resource in health-care delivery. In order to enhance efficiency and quality in health care, it is indispensable to analyse and consider the motivators of physicians. Physician job satisfaction has significant effects on productivity, the quality of care, and the supply of physicians. The purpose of our study was to assess the associations between work-related monetary and non-monetary factors and physicians' work satisfaction as perceived by similar groups of physicians practicing at academic medical centres in Germany and the U.S.A., two countries that, in spite of differing health-care systems, simultaneously experience problems in maintaining their physician workforce. We used descriptive statistics, factor and correlation analyses to evaluate physicians' responses to a self-administered questionnaire. Our study revealed that overall German physicians were less satisfied than U.S. physicians. With respect to particular work-related predictors of job satisfaction we found that similar factors contributed to job satisfaction in both countries. To improve physicians' satisfaction with working conditions, our results call for the implementation of policies that reduce the time burden on physicians to allow more time for interaction with patients and colleagues, increase monetary incentives, and enhance physicians' participation in the development of care management processes and in managerial decisions that affect patient care.

Male infertility is associated with altered treatment course of men with cancer.

This study aims to evaluate whether cancer treatments differ in infertile men compared to men who have undergone vasectomy and age-matched controls. We analyzed subjects from the Truven Health MarketScan Claims database from 2001 to 2009. Infertile men were identified through diagnosis and treatment codes. Comparison groups included vasectomized men and an age-matched cohort who were not infertile and had not undergone vasectomy. We considered cancer types previously associated with infertility that were diagnosed after the diagnosis of infertility. The treatment regimens were determined based on the presence of claims with CPT codes for chemotherapy (CTX), radiation (RTX) or surgical treatment (ST) for each entity in all study groups. Cases with multimodal treatments were also identified. As a result, CTX was similarly distributed among the infertile, vasectomized, and control groups. In contrast, RTX treatment length was shorter in infertile men. The frequency of multimodal treatment (i.e., radiation and chemotherapy) was twofold lower in men with infertility compared to other men. By focusing on treatment patterns for each cancer type among these groups, the duration of RTX and CTX was shorter in infertile men diagnosed with NHL compared to controls. We conclude that Infertile men diagnosed with cancer and specific cancer types experience different treatment courses, with shorter RTX and less combined RTX/CTX compared to fertile and vasectomized men. These differences could reflect differences in stage at presentation, biological behavior, or treatment responses in infertile men.

Increased risk of autoimmune disorders in infertile men: analysis of US claims data.

Aberrations in reproductive fitness may be a harbinger of medical diseases in men. Existing data suggest that female infertility is associated with autoimmune disorders; however, this has not been examined in men. As immune surveillance and hormonal factors can impact male fertility and autoimmunity, we sought to determine the association between male infertility and incident autoimmune disorders. We analyzed subjects from the Truven Health MarketScan claims database from 2001 to 2008. Infertile men were identified through diagnosis and treatment codes. We examined the most common immune disorders, which were identified by ICD9 diagnosis codes. Men diagnosed with an immune disorder at baseline or within 1 year of follow-up were excluded. Infertile men were compared to vasectomized men (i.e., men who are likely fertile) and to age-matched control (10 : 1) group using Cox regression analysis. A total of 33,077 infertile men (mean age of 33 years), 77,693 vasectomized men (mean age 35), and 330,770 age-matched control men (mean age 33) were assembled with a total follow-up of 1.49 M person-years. Overall, immune disorders were rare in the group with the individual conditions occurring in <0.1% of men. However, infertile men displayed the highest risk of many conditions. Infertile men had a higher risk of developing rheumatoid arthritis compared to both vasectomized men (HR 1.56, 95% CI 1.19-2.05) and age-matched controls (HR 1.29, 95% CI 1.02-1.62). Additionally, this higher risk was seen in general immune disorders (under which systemic lupus erythematosus is categorized) compared to vasectomized men (HR 3.11, 95% CI 2.00-4.86) and age-matched men (HR 2.12, 95% CI 1.52-2.96). This same risk trend was seen in psoriasis, when compared to vasectomized men (HR 1.28, 95% CI 1.09-1.50) and age-matched controls (HR 1.20, 95% CI 1.04-1.37). A similar trend was seen in the analysis comparing infertile men and vasectomized men in developing multiple sclerosis (HR 1.91, 95% CI 1.10-3.31) and Grave's disease (HR 1.46, 95% CI 1.10-1.92), as well as the higher risk of infertile men compared to the age-matched group at developing thyroiditis (HR 1.60, 95% CI 1.02-2.52). The current analysis shows that infertile men have a higher risk of developing certain autoimmune disorders in the years following an infertility evaluation. Specifically, infertile men had higher rates of developing rheumatoid arthritis, multiple sclerosis, psoriasis, thyroiditis, and Grave's disease. Given these findings, further research should focus on confirmation of these associations and elucidation of the pathways between fertility and immunity.

Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia.

The heterogeneous distribution of ion channels in ventricular muscle gives rise to spatial variations in action potential (AP) duration (APD) and contributes to the repolarization sequence in healthy hearts. It has been proposed that enhanced dispersion of repolarization may underlie arrhythmias in diseases with markedly different causes. We engineered dominant negative transgenic mice that have prolonged QT intervals and arrhythmias due to the loss of a slowly inactivating K(+) current. Optical techniques are now applied to map APs and investigate the mechanisms underlying these arrhythmias. Hearts from transgenic and control mice were isolated, perfused, stained with di-4-ANEPPS, and paced at multiple sites to optically map APs, activation, and repolarization sequences at baseline and during arrhythmias. Transgenic hearts exhibited a 2-fold prolongation of APD, less shortening (8% versus 40%) of APDs with decreasing cycle length, altered restitution kinetics, and greater gradients of refractoriness from apex to base compared with control hearts. A premature impulse applied at the apex of transgenic hearts produced sustained reentrant ventricular tachycardia (n=14 of 15 hearts) that did not occur with stimulation at the base (n=8) or at any location in control hearts (n=12). In transgenic hearts, premature impulses initiated reentry by encountering functional lines of conduction block caused by enhanced dispersion of refractoriness. Reentrant VT had stable (>30 minutes) alternating long/short APDs associated with long/short cycle lengths and T wave alternans. Thus, optical mapping of genetically engineered mice may help elucidate some electrophysiological mechanisms that underlie arrhythmias and sudden death in human cardiac disorders.

The impact of practice setting on physician perceptions of the quality of practice and patient care in the managed care era.

BACKGROUND: Managed care is practiced in both traditional institutional health maintenance organization (HMO) settings and in a variety of complex and decentralized office-based arrangements. This study examines how practice setting affects physician perceptions of the quality of professional practice and patient care in a managed care environment. PARTICIPANTS AND METHODS: A survey was conducted in 1998 of 1081 physicians in San Mateo County, California, who practice in either a traditional staff group model HMO (SGM-HMO) (n = 113) or office-based independent practice (OBIP) (n = 250). Respondents were surveyed about current and past practice characteristics, income changes, current satisfaction with professional and patient care matters, utility of treatment guidelines and formularies, and general perceptions of managed care. Responses were compared between practice settings using bivariate comparisons and logistic regression analyses. RESULTS: Physicians in the SGM-HMO and those in OBIP reported similar hours worked per week, time spent with patients during office visits, and total patient encounters per week. Declining income was more frequent in OBIP (61% vs 47%) and relatively more substantial (27% with income declines >25% vs 4% in SGM-HMO). Adjusting for income changes, practice setting, years in practice, and sex, SGM-HMO physicians were significantly more satisfied with a variety of professional and quality of care issues (P<.001), viewed more favorably the utility of treatment guidelines and drug formularies (P<.001), and held more positive general perceptions of managed care (P<.001) than OBIP physicians. CONCLUSIONS: In a managed care environment, SGM-HMO physicians are significantly more satisfied with the quality of practice and patient care than physicians in OBIP. This study suggests that the myriad managed care contracts, formularies, and guidelines received by physicians in OBIPs may lead to more negative perceptions of the quality of professional practice and patient care.

Managed care and technology diffusion: the case of MRI.

A growing body of evidence suggests that managed care can reduce overall health care costs but provides little insight into how this could happen. One possibility is that managed care influences the adoption of new medical technologies. In examining the relationship between health maintenance organization (HMO) activity and market-level availability and use of magnetic resonance imaging (MRI), we find that high HMO market share is associated with low levels of MRI availability and use. This suggests that managed care may be able to reduce health care costs by influencing the adoption and use of new medical equipment and technologies.

Physician satisfaction under managed care.

Data from a survey of young physicians have been analyzed to study the relationship between practicing medicine under managed care and the levels of perceived professional autonomy, practice satisfaction, and career satisfaction. Although practicing under managed care is associated with lower levels of perceived autonomy in patient selection and time allocation, it is associated with higher levels of perceived autonomy in use of hospital care, tests, and procedures. Specialists associated with managed care perceive more autonomy than generalists. Analyses of physicians' satisfaction with their practices and careers show that practicing under managed care is not uniformly associated with lower levels of satisfaction. Overall, managed care does not seem to have had the deleterious impact on medical practice that was forecast for it.

Twenty-four-hour coverage and workers' compensation insurance.

Workers' compensation insurance provides cash benefits and health care for workers who are injured on the job. This DataWatch considers the costs and benefits of combining the health insurance component of workers' compensation with universal health insurance, creating a twenty-four-hour coverage plan. The paper documents a large potential savings from twenty-four-hour coverage: Workers' compensation medical charges are about twice as high as those for comparable off-work injuries. This disparity seems to result from price discrimination and lack of cost controls in workers' compensation. Twenty-four-hour coverage, however, may be difficult to implement.

Physicians' perceptions of autonomy and satisfaction in California.

This study compares levels of satisfaction and autonomy among California physicians using data from a 1991 survey of physicians and a 1996 survey of California physicians. The surveys measured physicians' perceived freedom to undertake eight common activities that may be threatened by marketplace changes, satisfaction with current practice, and inclination to attend medical school again. Young physicians in 1996 were significantly less likely to report that they were able to spend enough time on the eight identified patient-care activities. They also were significantly less satisfied with their current practice and less likely to say that they would go to medical school again. Satisfaction also declined for older physicians between 1991 and 1996.

Excess cost of emergency department visits for nonurgent care.

After examining data for patients with selected conditions and statistically adjusting for patient, diagnosis, and treatment characteristics, this Data Watch finds that charges for emergency department visits were two to three times more than charges for visits in other settings. Large differences persist when conditions are examined individually and when total episode charges are examined. Based on our findings, a rough estimate of nationwide excess charges is $5-$7 billion for 1993.

HMO market penetration and costs of employer-sponsored health plans.

Using two employer surveys, we evaluate the role of increased health maintenance organization (HMO) market share in containing costs of employer-sponsored coverage. Total costs for employer health plans are about 10 percent lower in markets in which HMOs' market share is above 45 percent than they are in markets with HMO enrollments of below 25 percent. This is the result of lower premiums for HMOs than for non-HMO plans, as well as the competitive effect of HMOs that leads to lower non-HMO premiums for employers that continue to offer these benefits. Slower growth in premiums in areas with high HMO enrollments suggests that expanded HMO market share may also lower the long-run growth in costs.

Managed care and technology adoption in health care: evidence from magnetic resonance imaging.

This paper empirically examines the relationship between HMO market share and the diffusion of magnetic resonance imaging (MRI) equipment. Across markets, increases in HMO market share are associated with slower diffusion of MRI into hospitals between 1983 and 1993, and with substantially lower overall MRI availability in the mid- and later 1990s. High managed care areas also had markedly lower rates of MRI procedure use. These results suggest that technology adoption in health care can respond to changes in financial and other incentives associated with managed care, which may have implications for health care costs and patient welfare.

The effect of HMOs on fee-for-service health care expenditures: evidence from Medicare.

This paper examines the relationship between HMO market share and fee-for-service health care expenditures using 1986-1990 county- and metropolitan statistical area-level data on Medicare expenditures and HMO market share. Fixed-effects estimates imply that fee-for-service expenditures are concave and decreasing in market share. Increases in market share from 20% to 30% are associated with 3-7% expenditure reductions. Instrumental variable estimates that exploit cross-sectional variation in HMO activity also indicate a concave relationship, with expenditures declining in market share for market shares above 15-18%, but imply larger expenditure responses to market share changes.

Medical costs in workers' compensation insurance.

We examine whether patients covered by workers' compensation insurance, which covers the cost of medical care for injured workers without cost sharing and with relatively little oversight, are charged more for treatment or receive more services than patients covered by traditional insurance. Our findings indicate that workers compensation recipients are charged more for treatment. This difference persists in individual services--workers' compensation recipients are charged more per X-ray and per examination than our patients. We consider different explanations and argue that price discrimination probably plays a role.

Measuring competition in health care markets.

OBJECTIVE: Measuring competition is increasingly important for analysis of health care markets and policies. Measurement of competition in health care is made complex by the breadth of potential issues under study, by the lack of necessary data, and by rapid changes in health care financing and delivery. This study reviews key issues in the measurement of competition and is designed to familiarize researchers and policymakers interested in competition measurement, but not steeped in its practice, with key concepts, data sources, and ways of adapting measures to fit ongoing changes in health care markets. PRINCIPAL FINDINGS: Attention to several key issues will strengthen measurement. Important components of successful measurement are: careful identification of the products and market areas for study; selection of Herfindahl-Hirschman or other indices to fit the issues being considered; consideration of econometric problems, like endogeneity, with common measures; and attention to the ways that current marketplace changes, like growth in managed care, affect the performance of classic measures. Data needed for constructing measures are also frequently scarce, insufficient, or both. Measurement could be improved with access to better data.

Factors associated with women's adherence to mammography screening guidelines.

OBJECTIVE: To examine individual and environmental factors associated with adherence to mammography screening guidelines. DATA SOURCES: A unique data set that combines a national probability sample (1992 National Health Interview Survey); a national probability sample of mammography facility characteristics (1992 National Survey of Mammography Facilities); county-level data on 1990 HMO market share; and county-level data on the supply of primary care providers (1991 Area Resource File). STUDY DESIGN: The design was cross-sectional. DATA EXTRACTION/ANALYSIS: Data sets were linked to create an individual-level sample of women ages 50-74 (weighted n = 2,026). We used multipart, sequential logistic regression models to examine the predictors of having ever had mammography, having had recent mammography, and adherence to guidelines. We categorized women as adherent if they reported a lifetime number of exams appropriate for their age (based on screening every two years) and they reported having had an exam in the past two years. PRINCIPAL FINDINGS: Only 27 percent of women had the age-appropriate number of screening exams (range 16 percent-37 percent), while 59 percent of women had been screened within two years. Women were significantly more likely to adhere to screening guidelines if they reported participating with their doctor in the decision to be screened; were younger; had smaller families, higher education and income, and a recent Pap smear; reported breast problems; and lived in an area with a higher percentage of mammography facilities with reminder systems, no shortage of primary care providers, higher HMO market share, and higher screening charges. CONCLUSIONS: A small percentage of women adhere to screening guidelines, suggesting that adherence needs to become a focus of clinical, programmatic, and policy efforts.

Factors associated with the perception that debt influences physicians' specialty choices.

PURPOSE: To investigate the responses of individual physicians to educational debt. METHOD: Data on 5,175 physicians were taken from the 1991 Robert Wood Johnson Foundation Survey of Young Physicians, a nationally representative survey of physicians under age 45 who had had two to ten years of practice experience as of 1991. The physicians' overall perceptions about the extents to which debt had been an important determinant of specialty choice were explored using multivariate logistic regression analyses. RESULTS: Only 3.2% of the physicians indicated that debt had had a major influence on their specialty choices. About half (56%) of those who felt that debt had been a major influence indicated that they had foregone some training because of their debt levels. Controlling for debt level, the physicians who had had children during medical school and those whose parents had less education and lower incomes were more likely to say that debt had been an influence (p < .05). An examination of the specialties that the physicians reported having foregone because of debt indicated that these physicians had reacted to debt in different ways--some had chosen more specialized fields while others had chosen more generalized fields. CONCLUSION: While the overall effect of debt was small, some individuals were influenced by debt in a variety of ways. Paying attention to the effects of debt on this small population may improve training for some physicians and help better target programs that attempt to influence physicians by alleviating debt.

Market-level health maintenance organization activity and physician autonomy and satisfaction.

Managed care is widely expected to affect physicians throughout the healthcare system. In this study, we examined the relationship between health maintenance organization (HMO) activity and the level of competition, autonomy, and satisfaction perceived by physicians who do not work for HMOs. We obtained data on physicians from the 1991 Survey of Young Physicians, which contains a nationally representative sample of physicians younger than age 45 who had 2 to 9 years of practice experience in 1991. We examined the relationships between HMO market share and perceived competition, autonomy, and satisfaction using multivariate logistic regression. The main outcome measures were perceived level of competition; several measures of physicians' freedom to undertake common tasks that might be threatened by managed care (e.g., hospitalizing patients, ordering tests and procedures); satisfaction with current practice situation; perceived ability to practice quality medicine; whether the physician would attend medical school again; and satisfaction with medicine as a career. We found that an increase of 10 percentage points in HMO market share was associated with a 28% increase in the probability that physicians will regard their practice situation as very competitive as opposed to somewhat or not competitive (P < 0.01). Examinations of the relationship between HMO market share and autonomy and satisfaction revealed few significant results. We found no evidence that increases in HMO activity adversely affect physician autonomy. Only a limited amount of evidence indicates that increases in HMO activity reduce the satisfaction of specialist physicians, and no evidence associates HMO activity with the satisfaction of generalists. Although physicians perceive HMOs as competitors, HMO activity has not had a strong negative effect on the autonomy and satisfaction of physicians.

The effects of maternal smoking on infant birth weight.

A prospective cohort study was designed to examine the independent effects of maternal smoking on infant birth weight adjusted for length of gestation. Obstetrical patients were enrolled from four university based family practice clinics; 772 mother-infant pairs were included in the final analyses. A multiple regression analysis found 53% of the variance in infant birth weight to be explained by length of gestation, race, pre-pregnancy weight, weight gain, gender of the infant, highest systolic blood pressure, and smoking. After adjusting for the effects of other independent variables, women who were self-reported smokers delivered infants who weighed 141.8 g less, on the average, than infants of nonsmoking mothers. Women who smoked fewer than 10, 10-19, or 20+ cigarettes per day delivered infants weighing 96 g, 183 g, and 200 g less, respectively, than infants born to nonsmokers, a clear dose-response effect among relatively low-risk obstetrical patients in a primary care setting. Multiple regression analysis within each smoking group found the effect of length of gestation upon infant birth weight to be markedly reduced among the heavy smokers; this indicates a strong association between heavy (one pack a day) smoking and infant birth weight adjusted for length of gestation.