Targeting DGAT1 inhibits prostate cancer cells growth by inducing autophagy flux blockage via oxidative stress.

Impaired macroautophagy/autophagy flux has been implicated in the treatment of prostate cancer (PCa). However, the mechanism underlying autophagy dysregulation in PCa remains unknown. In the current study, we investigated the role of diacylglycerol acyltransferases 1 (DGAT1) and its potential effects on cellular energy homeostasis and autophagy flux in PCa. The results of immunohistochemical staining suggested that DGAT1 expression was positively corrected with tumor stage and node metastasis, indicating DGAT1 is an important factor involved in the development and progression of PCa. Furthermore, targeting DGAT1 remarkably inhibited cell proliferation in vitro and suppressed PCa growth in xenograft models by triggering severe oxidative stress and subsequently autophagy flux blockage. Mechanically, DGAT1 promoted PCa progression by maintaining cellular energy homeostasis, preserving mitochondrial function, protecting against reactive oxygen species, and subsequently promoting autophagy flux via regulating lipid droplet formation. Moreover, we found that fenofibrate exhibits as an upstream regulator of DGAT1. Fenofibrate performed its anti-PCa effect involved the aforementioned mechanisms, and partially dependent on the regulation of DGAT1. Collectively. These findings indicate that DGAT1 regulates PCa lipid droplets formation and is essential for PCa progression. Targeting DGAT1 might be a promising method to control the development and progression of PCa. Schematic representation of DGAT1 affects autophagy flux by regulating lipid homeostasis and maintaining mitochondrial function in prostate cancer (PCa). PCa is characterized up-regulation of DGAT1, leading to the translocation of free fatty acids into lipid droplets, thereby preventing PCa cell from lipotoxicity. Inhibition of DGAT1 suppresses growth of PCa by inducing oxidative stress and subsequently autophagy flux blockage. Further, the current results revealed that fenofibrate exhibits as an upstream regulator of DGAT1, and fenofibrate plays an anti-PCa role partially dependent on the regulation of DGAT1, suggesting a potential therapeutic approach to ameliorate this refractory tumor.

Identification of key genes and pathways in adrenocortical carcinoma: evidence from bioinformatic analysis.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis. The disease originates from the cortex of adrenal gland and lacks effective treatment. Efforts have been made to elucidate the pathogenesis of ACC, but the molecular mechanisms remain elusive. To identify key genes and pathways in ACC, the expression profiles of GSE12368, GSE90713 and GSE143383 were downloaded from the Gene Expression Omnibus (GEO) database. After screening differentially expressed genes (DEGs) in each microarray dataset on the basis of cut-off, we identified 206 DEGs, consisting of 72 up-regulated and 134 down-regulated genes in three datasets. Function enrichment analyses of DEGs were performed by DAVID online database and the results revealed that the DEGs were mainly enriched in cell cycle, cell cycle process, mitotic cell cycle, response to oxygen-containing compound, progesterone-mediated oocyte maturation, p53 signaling pathway. The STRING database was used to construct the protein-protein interaction (PPI) network, and modules analysis was performed using Cytoscape. Finally, we filtered out eight hub genes, including CDK1, CCNA2, CCNB1, TOP2A, MAD2L1, BIRC5, BUB1 and AURKA. Biological process analysis showed that these hub genes were significantly enriched in nuclear division, mitosis, M phase of mitotic cell cycle and cell cycle process. Violin plot, Kaplan-Meier curve and stage plot of these hub genes confirmed the reliability of the results. In conclusion, the results in this study provided reliable key genes and pathways for ACC, which will be useful for ACC mechanisms, diagnosis and candidate targeted treatment.

Obesity and chronic kidney disease.

The prevalence of obesity has increased dramatically during the past decades, which has been a major health problem. Since 1975, the number of people with obesity worldwide has nearly tripled. An increasing number of studies find obesity as a driver of chronic kidney disease (CKD) progression, and the mechanisms are complex and include hemodynamic changes, inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system (RAAS). Obesity-related kidney disease is characterized by glomerulomegaly, which is often accompanied by localized and segmental glomerulosclerosis lesions. In these patients, the early symptoms are atypical, with microproteinuria being the main clinical manifestation and nephrotic syndrome being rare. Weight loss and RAAS blockers have a protective effect on obesity-related CKD, but even so, a significant proportion of patients eventually progress to end-stage renal disease despite treatment. Thus, it is critical to comprehend the mechanisms underlying obesity-related CKD to create new tactics for slowing or stopping disease progression. In this review, we summarize current knowledge on the mechanisms of obesity-related kidney disease, its pathological changes, and future perspectives on its treatment.

Cholecystectomy-induced secondary bile acids accumulation ameliorates colitis through inhibiting monocyte/macrophage recruitment.

Although post-cholecystectomy (PC) patients usually have gastrointestinal complications and a higher risk of colorectal cancer, previous studies undetected a heightened risk of inflammatory bowel disease. Thus, we tried to investigate cholecystectomy's impact and pathophysiological mechanism on murine colitis models and clarify the association among fecal bile acids (BAs), mucosal bacterial microbiota, and immune cells in the PC patients. One month or three months after cholecystectomy, mice have induced colitis and tested BAs and fecal microbiota analysis. Next, mice were treated with various cholecystectomy-accumulated bile acids in drinking water for three months before inducing colitis. All 14 paired PC patients and healthy subjects were enrolled for BAs and mucosal microbiota analysis. Cholecystectomy ameliorated DSS-induced murine colitis, accelerated mucosal repair, and induced a significant shifting of fecal microbiota and BAs profiles under colitis status, which featured a higher relative abundance of species involved in BAs metabolism and increased secondary BAs concentrations. Cholecystectomy-associated secondary BAs (LCA, DCA, and HDCA) also ameliorated DSS-induced colitis and accelerated mucosal repair in mice. Cholecystectomy and specific secondary BAs treatments inhibited monocytes/macrophages recruitment in colitis mice. In vitro, cholecystectomy-associated secondary BAs also downregulated monocytes chemokines in the THP-1 derived macrophages through activation of the LXRα-linked signaling pathway. The alterations of mucosal microbiota and fecal BAs profiles were found in the PC patients, characterized as increased species with potential immuno-modulating effects and secondary BAs, which were negatively associated with peripheral monocytes levels. Cholecystectomy-induced secondary bile acids accumulation ameliorated colitis through inhibiting monocyte/macrophage recruitment, which might be mediated by the LXRα-related signaling pathway. Cholecystectomy, after 3 months follow-up, has an immune-regulatory role in murine colitis, preliminarily explaining that no increased risk of IBD had been reported in the PC patients, which still warrants further studies.

Alterations of Fungal Microbiota in Patients With Cholecystectomy.

Increasing evidence suggests a high risk of gastrointestinal postoperative comorbidities (such as colorectal cancer) in patients with postcholecystectomy (PC). Although previous studies implicated the role of fungi in colon carcinogenesis, few reports focused on the fungal profile in patients with PC. We enrolled 104 subjects, including 52 patients with PC and 52 non-PC controls (CON), for fecal collection to detect the fungal composition by an internal transcribed spacer (ITS) 1 rDNA sequencing. Data showed that Candida (C.) glabrata and Aspergillus (A.) Unassigned were enriched, and Candida albicans was depleted in patients with PC. In addition, postoperative duration was the main factor to affect the fungal composition. Machine learning identified that C. glabrata, A. Unassigned, and C. albicans were three biomarkers to discriminate patients with PC from CON subjects. To investigate the fungal role in colon carcinogenesis, the subjects of the PC group were divided into two subgroups, namely, patients with PC without (non-CA) and with precancerous lesions or colorectal cancer (preCA_CRC), by histopathological studies. C. glabrata was found to be gradually accumulated in different statuses of patients with PC. In conclusion, we found fungal dysbiosis in patients with cholecystectomy, and the postoperative duration was a potent factor to influence the fungal composition. The accumulation of C. glabrata might be connected with carcinogenesis after cholecystectomy.

Immune normalization strategy against suboptimal health status: safe and efficacious therapy using mixed-natural killer cells.

"Immune normalization" has emerged as a new paradigm in immunotherapy, which is proposed in cancer patients instead of conventional "immune-enhancement" therapy. Immune normalization may also be implemented in cancer prevention of "sub-healthy" individuals. We established in vitro cultured mixed-natural killer (NKM) cells to achieve immune normalization. The in vitro cytotoxicity of NKM cells was tenfold higher than that of peripheral blood mononuclear cells (PBMCs). The cytotoxicity of NKM cells was negatively correlated with the proportion of T-helper cells (cluster of differentiation: CD3+CD4+ T), and positively correlated with the proportion of NK cells (especially CD56brightCD16bright NK cells). Then, we defined "sub-healthy individuals" after measuring Programmed cell death protein-1 (PD-1) expression in PBMCs from 95 donors aged > 50 years. Furthermore, we evaluated the potential clinical application of NKM-cell therapy in 11 patients with malignant lymphoma, one patient with pancreatic cancer, and four sub-healthy individuals. NKM-cell therapy elicited good tolerance and side-effects were not found. In sub-healthy individuals, the proportion of CD3+PD-1+ T cells and CD3+CD8+PD-1+ T cells was reduced significantly after NKM-cell treatment. We demonstrated that a new method using NKM cells was safe and efficacious as adjuvant treatment for cancer patients as well as therapy for sub-healthy individuals. Normalization of the peripheral immune system through NKM-cell therapy could expand its scope of application in different disorders.

Bacterial Alterations in Post-Cholecystectomy Patients Are Associated With Colorectal Cancer.

Background: Although increasing evidences showed a correlation between cholecystectomy and the prevalence rate of colorectal cancer (CRC), and shed light on gut microbiota in colorectal pathogenesis, only a few studies focused on microbial alterations after cholecystectomy, and its sequent role in carcinogenesis and progression of CRC has not been reported. Thus, we aimed to investigate the bacterial alterations and tried to clarify their clinical significance. Methods: 104 subjects were enrolled and divided into post-cholecystectomy patients (PC, n = 52) and healthy controls (HC, n = 52). To investigate the bacterial role in carcinogenesis, PC patients were further separated into preCA_CRC (patients with precancerous lesions and/or CRC, n = 9) and non-CA (patients without precancerous lesions and CRC, n = 43) based on the histopathology. Qualified stool samples were collected for 16S rRNA gene sequencing to analyze the bacterial profile. Results: Our data showed noteworthy compositional and abundant alterations of bacterial microbiota in PC patients, characterized as Bacteroides ovatus, Prevotella copri, and Fusobacterium varium remarkably increased; Faecalibacterium prausnitzii, Roseburia faecis, and Bifidobacterium adolescentis significantly decreased. Additionally, the duration after cholecystectomy was the critical factor that affected bacterial composition. Machine learning-based analysis showed a pivotal role of Megamonas funiformis in discriminating PC from HC subjects and involving in the progression of CRC. Conclusions: The bacterial dysbiosis may associate with CRC in PC patients, and the duration after cholecystectomy was highlighted as an important factor. Altered bacterial microbiota was likely to play a pivotal role in related-disease in the long-term follow-up of PC patients.

Changes and roles of intestinal fungal microbiota in coronary heart disease complicated with nonalcoholic fatty liver disease.

BACKGROUND: Patients who suffered coronary heart disease (CHD) complicated with non-alcoholic fatty liver disease (NAFLD) were reported to have worse cardiac function and clinical outcomes than patients with CHD only. The mechanism was unclear. Previous study focused on the metabolism and showed it could be regulated by the microbiota. Few studies related to fungi. We aimed to investigate the characteristics of intestinal fungal microbiota in CHD patients complicated with NAFLD (CHD-NAFLD). METHODS: 72 People were recruited and equally divided into three groups, including CHD patients (without NAFLD), CHD-NAFLD patients, and healthy controls (HCs). Fecal samples were collected. The Illumina sequencing of the internal transcribed spacer 3-4 rRNA was applied. RESULTS: The BMI, uric acid and triglyceride in CHD-NAFLD patients increased compared with CHD patients. The abundance of Exophiala attenuata and Malassezia restricta in all CHD-NAFLD and CHD patients significantly reduced. The intestinal fungal microbiota in CHD-NAFLD patients showed an increase in the abundance of Preussia, Xylodon and Cladorrhinum, and a reduction in the abundance of Candida glabrata and Ganoderma. Among them, the abundance of Ganoderma was significantly lower than that in CHD patients. The ejection fraction was negatively correlated to the abundance of Xylodon. Uric acid was positively correlated with the abundance of Cladorrhinum and Preussia. CONCLUSIONS: These changes of intestinal fungal microbiota in CHD-NAFLD patients may be important factors affecting the degree of metabolic disorder. But there are few reports on these fungi. More studies are needed to confirm the effects of these fungi on human.

Changes of intestinal bacterial microbiota in coronary heart disease complicated with nonalcoholic fatty liver disease.

BACKGROUND: Previous study reported that patients who suffered coronary heart disease (CHD) complicated with non-alcoholic fatty liver disease (NAFLD) had worse cardiac function and clinical outcomes than patients with CHD only. Notably, the mechanism is still unclear. This study aimed to investigate the changes and roles of intestinal bacterial microbiota in CHD-NAFLD patients. METHODS AND RESULTS: People were recruited and divided into three groups, including CHD patients (without NAFLD), CHD-NAFLD patients and healthy controls (HCs). Each group contained 24 people. Fecal samples and clinical information were carefully collected. The Illumina sequencing of 16S rRNA was applied to profile the overall structure of the fecal bacterial microbiota and the characteristics of the bacterial microbiota based on the Operational Taxonomic Units. In clinical information, the CHD-NAFLD patients showed an increase in BMI, uric acid and triglyceride. There was a significant reduction in the abundance of Parabacteroides and Collinsella in overall CHD patients (including CHD-NAFLD and CHD patients). The intestinal bacterial microbiota in CHD-NAFLD patients showed an increase in the abundance of Copococcus and Veillonella, and a reduction in the abundance of Parabacteroides, Bacteroides fragilis, Ruminococcus gnavus, Bacteroides dorei, and Bifidobacterium longum subsp infantis. Among them, the abundance of Ruminococcus gnavus and Bacteroides dorei was significantly lower than that in CHD patients. Additionally, BMI positively correlated with the abundance of Copococcus and negatively correlated with the abundance of Bifidobacterium longum subsp infantis. The abundance of Veillonella positively correlated with AST. The abundance of Bacteroides dorei negatively correlated with ALT and AST. It indicates that the abundance of intestinal microbiota was related to the changes in clinical indexes. CONCLUSIONS: Changes of intestinal bacterial microbiota in CHD-NAFLD patients may be important factors affecting the degree of metabolic disorder, which may be one of the important reasons for the worse clinical outcome and disease progression in CHD-NAFLD patients than in CHD patients.

5-Aminosalicylic Acid Alters the Gut Bacterial Microbiota in Patients With Ulcerative Colitis.

Background: The aim of this study was to clarify the effect of 5-aminosalicylic acid (5-ASA) treatment on gut bacterial microbiota in patients with ulcerative colitis (UC). Methods: A total of 57 UC patients, including 20 untreated and 37 5-ASA-treated, were recruited into an exploration cohort. We endoscopically collected both non-inflamed and inflamed mucosal samples from all patients, and compared the gut bacterial profiles using 16S rDNA sequencing. Ten untreated UC patients were then treated with 5-ASA and subsequently recruited for an independent validation study to confirm the acquired data. Results: In untreated UC patients, compared with those in non-inflamed mucosae, Firmicutes (such as Enterococcus) were decreased and Proteobacteria (e.g., Escherichia-Shigella) were increased in the inflamed mucosae. Compared with the inflamed mucosae of untreated UC patients, there was a higher abundance of Firmicutes (e.g., Enterococcus) and lower Proteobacteria (Escherichia-Shigella) in the inflamed mucosae of 5-ASA treated UC patients. In the validation cohort, after administration of 5-ASA, bacterial alteration was consistent with these data. Furthermore, there was a skewed negative correlation between Escherichia-Shigella and bacterial genera of Firmicutes in the inflamed mucosae. 5-ASA treatment decreased the strength of bacterial correlation and weakened the skewed negative correlation pattern. Conclusion: The microbial dysbiosis (mainly characterized by an increased abundance in the Escherichia-Shigella genus) and the skewed negative correlation between Escherichia-Shigella and bacterial genera of Firmicutes are two characteristics of the inflamed mucosae of UC patients. 5-ASA treatment decreases Escherichia-Shigella and weakens the skewed correlations, which may be related to its treatment efficiency.

Recovery Curves for Pediatric Burn Survivors: Advances in Patient-Oriented Outcomes.

IMPORTANCE: Patient-reported outcomes serving as benchmarks for recovery of pediatric burn survivors are lacking, and new approaches using longitudinal cohorts for monitoring their expected recovery based on statistical models are needed for patient management during the early years following the burn. OBJECTIVE: To describe multidimensional patient-reported outcomes among pediatric burn survivors younger than 5 years to establish benchmarks using recovery curve methods. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of pediatric burn survivors younger than 5 years at 12 burn centers. Age-matched nonburned reference groups were studied to define expected results in normal growth and development. The Burn Outcomes Questionnaire for children aged 0 to 5 years (BOQ0-5) was administered to parents of children who had burns and were younger than 5 years. Mixed models were used to generate 48-month recovery curves for each of the 10 BOQ0-5 domains. The study was conducted between January 1999 and December 2008. MAIN OUTCOMES AND MEASURES: The 10 BOQ0-5 domains including play, language, fine motor skills, gross motor skills, emotional behavior, family functioning, pain/itching, appearance, satisfaction with care, and worry/concern up to 48 months after burn injury. RESULTS: A total of 336 pediatric burn survivors younger than 5 years (mean [SD] age, 2.0 [1.2] years; 58.4% male; 60.2% white, 18.6% black, and 12.0% Hispanic) and 285 age-matched nonburned controls (mean [SD] age, 2.4 [1.3] years; 51.1% male; 67.1% white, 8.9% black, and 15.0% Hispanic) completed the study. Predicted scores improved exponentially over time for 5 of the BOQ0-5 domains (predicted scores at 1 month vs 24 months: play, 48.6 vs 52.1 [P = .03]; language, 49.2 vs 54.4 [P < .001]; gross motor skills, 48.7 vs 53.0 [P = .002]; pain/itching, 15.8 vs 33.5 [P < .001]; and worry/concern, 31.6 vs 44.9 [P < .001]). Pediatric burn survivors had higher scores in language, emotional behavior, and family functioning domains compared with healthy children in later months. CONCLUSIONS AND RELEVANCE: This study demonstrates significant deficits in multiple functional domains across pediatric burn survivors compared with controls. Recovery curves can be used to recognize deviation from the expected course and tailor care to patient needs.

Measurement of treatment adherence with antipsychotic agents in patients with schizophrenia.

The importance of medication adherence in sustaining control of schizophrenic symptoms has generated a great deal of interest in comparing levels of treatment adherence with different antipsychotic agents. However, the bulk of the research has yielded results that are often inconsistent. In this prospective, observational study, we assessed the measurement properties of 3 commonly used, pharmacy-based measures of treatment adherence with antipsychotic agents in schizophrenia using data from the Veterans Health Administration during 2000 to 2005. Patients were selected if they were on antipsychotics and diagnosed with schizophrenia (N = 18,425). A gap of >/=30 days (with no filled index medication) was used to define discontinuation of treatment as well as medication "episodes," or the number of times a patient returned to the same index agent after discontinuation of treatment within a 1-year period. The study found that the 3 existing measures differed in their approaches in measuring treatment adherence, suggesting that studies using these different measures would generate different levels of treatment adherence across antipsychotic agents. Considering the measurement problems associated with each existing approach, we offered a new, medication episode-specific approach, which would provide a fairer comparison of the levels of treatment adherence across different antipsychotic agents.

Patients' self-report of diseases in the Medicare Health Outcomes Survey based on comparisons with linked survey and medical data from the Veterans Health Administration.

We evaluated the patient self-report questions about disease from the Medicare Health Outcomes Survey (HOS), using linked Veterans Health Administration (VA) data for patients who are eligible for both Medicare and Veterans Affairs (VA) care to estimate their utility as measures of illness burden. Patients were classified for 12 diseases on the basis of HOS question responses and these were compared with classifications based on similar questions from a VA survey or diagnostic codes from VA medical records. Agreement between classifications based on the 2 surveys was good with over 75% of patients affirming the disease in the HOS also affirming it in the VA survey for most diseases. HOS disease status also agreed well with VA-based disease status using diagnostic codes for most diseases, with reasonably good specificity (70%-94%) and sensitivity (65%-85%). The relatively poor measures of agreement for some of the conditions could be related to differences in question wording and other factors. These findings varied only slightly by education, age, and race. Furthermore, independent decrements in health status, derived from the SF-36 associated with each disease based on the survey questions, were similar in the 2 surveys. These results suggest that patients can provide reasonably good reports of their morbidity in survey questions and that patient self-report questions about disease can be used reliably in case-mix adjustments and in stratifications of patients by diseases.

Change in health status and mortality as indicators of outcomes: comparison between the Medicare Advantage Program and the Veterans Health Administration.

BACKGROUND: Comparing health outcomes with adequate methodology is central to performance assessments of health care systems. We compared the Medicare Advantage Program (MAP) and the Veterans Health Administration (VHA) with regard to changes in health status and mortality. METHODS: We used the Death-Master-File for vital status and the Short-Form 36 to determine physical (PCS) and mental (MCS) health at baseline and at 2 years. We compared the probability of being alive with the same or better (than would be expected by chance) PCS (or MCS) at 2 years and mortality, while adjusting for case-mix. Given the geographic variations in MAP enrollment, we did a regional sub-analysis. RESULTS: There were no significant differences in the probability of being alive with the same or better PCS except for the South (VHA 65.8% vs. MAP 62.5%, P = .0014). VHA patients had a slightly higher probability than MAP patients of being alive with the same or better MCS (71.8% vs. 70.1%, P = .002) but no significant regional variations. The hazard ratios for mortality in the MAP were higher than in the VHA across all regions. CONCLUSION: With the use of appropriate methodology, we found small differences in 2-year health outcomes that favor the VHA.

An alternative approach to measuring treatment persistence with antipsychotic agents among patients with schizophrenia in the Veterans Health Administration.

Prior studies have demonstrated the importance of treatment persistence with anti-psychotic agents in sustaining control of schizophrenic symptoms. However, the conventional approach in measuring treatment persistence tended to use only the first prescription episode even though some patients received multiple prescriptions (or multiple treatment episodes) of the same medication within one year following the initiation of the index drug. In this study, we used data from the Veterans Health Administration in the United States to assess the extent to which patients received multiple prescriptions. The study found that about a quarter of the patients had two or more treatment episodes and that levels of treatment persistence tended to vary across treatment episodes. Based on these results, we offered an alternative approach in which we calculated treatment persistence with typical and atypical antipsychotic agents separately for patients with one, two, or three treatment episodes. Considering that patients with different number of treatment episodes might differ in disease profiles, this treatment episode-specific approach offered a fair comparison of the levels of treatment persistence across patients with different number of treatment episodes. Future research needs to extend the analyses beyond two antipsychotic classes to individual antipsychotic agents. A more comprehensive assessment using appropriate analytic methods should help physicians make prescription choices that will ultimately improve the care of patients with schizophrenia.

Association of co-morbidities with prescribing patterns and cost savings: olanzapine versus risperidone for schizophrenia.

BACKGROUND: Olanzapine and risperidone are two commonly prescribed atypical antipsychotics for schizophrenia. Prior studies have shown inconsistent results in terms of advantage in cost saving in prescribing these agents. Our preliminary analysis showed that a small percentage of intensive healthcare utilizers had substantial impact on healthcare costs. This study analysed the cost effects of olanzapine and risperidone among those who had intensive utilisation of medical care prior to drug initiation, and the relationship between the choice of the two drugs and patients' co-morbid condition. METHODS: We retrospectively investigated patients first treated with either risperidone or olanzapine between 1 April 1999 and 31 March 2000. According to patients' medication history during the 6 months prior to initial prescription of a study medication we categorised patients into three groups: (i) not receiving olanzapine or risperidone; (ii) not receiving any atypical antipsychotic agent; or (iii) not receiving any antipsychotic agent. We then compared the difference in cost saving by type of care in the 10% most expensive patients through bivariate and multivariate analyses. Based on the records of 18 499 patients with schizophrenia prescribed either olanzapine or risperidone between 1 April 1999 and 31 March 2000 we defined intensive users of healthcare as those who incurred an annual total cost in the top tenth percentile. We measured co-morbidity by number of diseases, and healthcare costs ($US, 1998-2001 values) in the year prior and the year after treatment initiation in six categories of care (inpatient medical/surgical, inpatient psychiatric care, other inpatient, outpatient psychiatric care, other outpatient and outpatient pharmacy). RESULTS: The top 10% most expensive patients accounted for about half of the total cost of the entire cohort and had nearly a 40% cost reduction for the year after treatment initiation versus the prior year, while the entire cohort increased cost between 2% and 12%. Compared with those prescribed olanzapine, patients prescribed risperidone had more medical co-morbidities, higher inpatient medical/surgical costs and lower psychiatric costs. Patients taking olanzapine had greater cost reduction in inpatient psychiatric care, whereas those taking risperidone had greater reduction in inpatient medical/surgical care. CONCLUSIONS: Among the top 10% most expensive patients, olanzapine and risperidone treatments were associated with comparable cost reductions in inpatient care. The choice of agent was associated with patients' co-morbid condition and was correlated with cost reduction in inpatient medical/surgical or psychiatric care.

A Patient-based severity measure of chronic lung disease: evaluating functional health and predicting health services use.

Prior research has consistently shown that among patients with chronic lung disease (CLD), health-related quality of life (HRQOL) is tied more to respiratory symptoms than to physiologic measures. However, traditional methods to quantify the severity of CLD have been restricted to physiologic measures (eg, FEV1, FVC, etc) that are often poor predictors of HRQOL and utilization of health services. Using a patient-based measure of symptom severity for CLD developed in the Veterans Health Study (VHS), this article evaluated the impact of the severity of CLD on patients' self-reported HRQOL and future use of health services. We used data from the VHS, a prospective study of patients receiving ambulatory care services in 4 Veterans Affairs outpatient clinics in the greater Boston area. Three hundred fifty-two (14.5%) patients were identified as having CLD through self-report of having a physician's diagnosis of chronic bronchitis, emphysema, or asthma, and either using inhaled medications or having a productive cough for most days for 3 months. Ordinary least-square regressions were used to ascertain the effects of CLD severity on functional health and health services use. Compared with peak expiratory flow rate, which explained only 10% and 2%, respectively, of the variance in the SF-36 physical component summary (PCS) and in future doctor visits, the symptom severity explained 19% and 19%, respectively, of the variance in PCS and future doctor visits, after adjusting for age, education, and household income. The symptom severity measure is a strong predictor of future functional health (at 12 months of the VHS baseline) and health services use (within 6 months following the baseline). The study findings indicate that our measure of CLD severity is an efficient and easy-to-use approach that can be readily administered in ambulatory setting. It can be used as a case-mix adjustment in evaluating health outcomes and in predicting future utilization of health services.

Dissemination of methods and results from the veterans health study: final comments and implications for future monitoring strategies within and outside the veterans healthcare system.

The Veterans Health Study (VHS) followed a cohort of patients receiving ambulatory care in the Veterans Affairs healthcare system for up to 5 years. One of the principal aims of this study was to develop a library of methodologies including general and disease-specific health outcome questionnaires for use in monitoring the quality of healthcare and for research purposes. The cornerstone for this work is the Veterans RAND 36 and 12 Item Health Surveys (VR-36 and VR-12), a general measure developed in the VHS for measuring the physical and psychologic well-being of the patient. A comprehensive set of disease-specific assessments has also been developed as part of this study for the purposes of monitoring specific chronic conditions more commonly seen in routine ambulatory care settings. Since 1996, more than 2 million questionnaires have been administered in the VA for quality monitoring purposes, using the VR-36 and VR-12. Research studies that have used these batteries span randomized clinical trials in the VA cooperative studies program and clinical effectiveness research. Health assessments using VHS batteries are being disseminated for widespread use outside the VA. Chief among the assessments used is the VR-12, which has recently been included in the 2006 Health Plan Employer Data and Information Set (HEDIS) as part of the Medicare Health Outcomes Survey for monitoring the Medicare Advantage Program. The methods and batteries developed in the VHS are in the public domain and provide a framework for future patient monitoring using standard measures of health.

Risk-adjusted mortality as an indicator of outcomes: comparison of the Medicare Advantage Program with the Veterans' Health Administration.

BACKGROUND: The Medicare Advantage Program (MAP) and the Veterans' Health Administration (VHA) currently provide many services that benefit the elderly, and a comparative study of their risk-adjusted mortality rates has the potential to provide important information regarding these 2 systems of care. OBJECTIVE: The objective of this retrospective study was to compare mortality rates between the MAP and the VHA after controlling for case-mix differences. SUBJECTS: This study consisted of 584,294 MAP patients and 420,514 VHA patients. MEASURES: We used the Death Master File to ascertain the vital status of each study subject over approximately 4 years. We used Cox regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the MAP compared with VHA patients. RESULTS: The average age for male MAP patients was 73.8 years (+/- 5.6) and for male VHA patients was 74.05 years (+/- 6.3). Unadjusted mortality rates of males for VHA and MAP were 25.7% and 22.8%, respectively, over approximately 4 years (P < 0.0001), respectively. The case-mix of VHA patients, however, was sicker than those from MAP. After adjusting for case-mix, the HR for mortality in the MAP was significantly higher than that in the VHA (HR, 1.404; 95% CI = 1.383-1.426). We obtained similar results when we compared the mortality rates of females for VHA and MAP. CONCLUSIONS: After adjusting for their higher prevalence of chronic disease and worse self-reported health, mortality rates were lower for patients cared for in the VHA compared with those in the MAP. Further studies should examine what differences in care structures and processes contribute to lower mortality in the VHA.

Applications of methodologies of the Veterans Health Study in the VA healthcare system: conclusions and summary.

The Veterans Health Study (VHS) had as its overarching goal the development, testing, and application of patient-centered assessments for monitoring patient outcomes in ambulatory care in large integrated care systems such as the Department of Veterans Affairs (VA). Unlike other previous studies, the VHS has capitalized on rich administrative databases restricted to the VA and linked to patient-centered outcomes. The VHS has developed a comprehensive set of general and disease-specific measures for use by systems of care for ambulatory patients. Chief among these assessments is the Veterans SF-36 Health Survey for measuring health-related quality of life in veteran ambulatory populations. The Veterans SF-36 Health Survey provides the cornerstone for this study and historically has been extensively disseminated and used in the VA with close to 2 million administrations nationally as part of its quality management system. National surveys administered by the VA since 1996 using the Veterans SF-36 Health Survey indicate important regional differences with implications for varying resource needs. Based upon the rich foundation provided by the VHS methodology, the VA has implemented some of these approaches as part of its quality monitoring system and can serve as a model for other large integrated systems of care.