Restoration of the activated Rig-I pathway in hepatitis C virus (HCV) replicon cells by HCV protease, polymerase, and NS5A inhibitors in vitro at clinically relevant concentrations.

Development of persistent hepatitis C virus (HCV) infection may be mediated by HCV NS3 · 4A protease-dependent inhibition of host innate immunity. When double-stranded RNA (dsRNA) is detected in virus-infected cells, host innate immunity mounts an antiviral response by upregulating production of type I interferons (α/ß interferon [IFN-α/ß]); HCV counters by cleaving the IFN-ß stimulator 1 (IPS-1) adaptor protein, decreasing synthesis of IFN-α/ß. We evaluated HCV protease (telaprevir, boceprevir, and TMC435350), polymerase (HCV-796 and VX-222), and NS5A (BMS-790052) inhibitors for the ability to restore IPS-1-mediated Rig-I signaling by measuring Sendai virus-induced IFN-ß promoter activation in HCV replicon cells after various exposure durations. All direct-acting HCV antivirals tested restored mitochondrial localization of IPS-1 and rescued Sendai virus-induced IRF3 signaling after 7 days by inhibiting HCV replication, thereby reducing the abundance of HCV NS3 · 4A protease. With 4-day treatment, HCV protease inhibitors, but not polymerase inhibitors, restored mitochondrial localization of IPS-1 and rescued IFN-ß promoter activation in the presence of equivalent levels of NS3 protein in protease or polymerase inhibitor-treated cells. The concentrations of HCV protease and polymerase inhibitors needed to rescue IRF3-mediated signaling in vitro were in the range of those observed in vivo in the plasma of treated HCV patients. These findings suggest that (i) HCV protease, polymerase, and NS5A inhibitors can restore virus-induced IRF3 signaling by inhibiting viral replication, thereby reducing NS3 protease levels, and (ii) HCV protease inhibitors can restore innate immunity by directly inhibiting NS3 protease-mediated cleavage of IPS-1 at clinically achievable concentrations.

Pathway to dry skin prevention and treatment.

BACKGROUND: This article presents an evidence-supported clinical pathway for dry skin prevention and treatment. OBJECTIVE: The development of the pathway involved the following: a literature review was conducted and demonstrated that literature on dry skin is scarce. To compensate for the gap in the available literature, a modified Delphi method was used to collect information on prevention and treatment practice through a panel, which included 10 selected dermatologists who currently provide medical care for dermatology patients in Ontario. An advisor experienced in this therapeutic area guided the process, including a central meeting. Panel members completed a questionnaire regarding their individual practice in caring for these patients and responded to questions on assessment of dry skin etiology, frequency of skin care visits for consultation and follow-up, assessment, and referral to other specialties. The panel members reviewed a summary of all responses and reached a consensus. The result was presented as a clinical pathway. CONCLUSION: The panel concluded that our current awareness of dry skin and therefore prevention and effective treatment is limited; that identifying dry skin and its clinical issues requires tools such as clinical pathways, which may improve patient outcomes; and that additional research on dry skin etiology, prevention, and treatment is necessary.

Guideline-based antibiotics and mortality in healthcare-associated pneumonia.

BACKGROUND: Guidelines recommend administration of antibiotics with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa for treatment of healthcare-associated pneumonia (HCAP). It is unclear if this therapy improves outcomes for patients with HCAP. OBJECTIVE: To determine if administration of guideline-similar therapy (GST) was associated with a reduction in 30-day mortality for HCAP. DESIGN: Multi-center retrospective study. PARTICIPANTS: Thirteen hundred and eleven admissions for HCAP in six Veterans Affairs Medical Centers. INTERVENTIONS: Each admission was classified as receiving GST, anti-MRSA or anti-pseudomonal components of GST, or other non-HCAP therapy initiated within 48 hours of hospitalization. Association between 30-day mortality and GST was estimated with a logistic regression model that included GST, propensity to receive GST, probability of recovering an organism from culture resistant to antibiotics traditionally used to treat community-acquired pneumonia (CAP-resistance), and a GST by CAP-resistance probability interaction. MAIN MEASURES: Odds ratios and 95% confidence intervals [OR (95% CI)] of 30-day mortality for patients treated with GST and predicted probability of recovering a CAP-resistant organism, and ratio of odds ratios [ROR (95% CI)] for treatment by CAP-resistance probability interaction. KEY RESULTS: Receipt of GST was associated with increased odds of 30-day mortality [OR = 2.11 (1.11, 4.04), P = 0.02)] as was the predicted probability of recovering a CAP-resistant organism [OR = 1.67 (1.26, 2.20), P < 0.001 for a 25% increase in probability]. An interaction between predicted probability of recovering a CAP-resistant organism and receipt of GST demonstrated lower mortality with GST at high probability of CAP resistance [ROR = 0.71(≤1.00) for a 25% increase in probability, P = 0.05]. CONCLUSIONS: For HCAP patients with high probability of CAP-resistant organisms, GST was associated with lower mortality. Consideration of the magnitude of patient-specific risk for CAP-resistant organisms should be considered when selecting HCAP therapy.

Predicting antibiotic resistance to community-acquired pneumonia antibiotics in culture-positive patients with healthcare-associated pneumonia.

OBJECTIVE: To develop and validate a model to predict resistance to community-acquired pneumonia antibiotics (CAP-resistance) among patients with healthcare-associated pneumonia (HCAP), and to compare the model's predictive performance to a model including only guideline-defined criteria for HCAP. DESIGN: Retrospective cohort study. SETTING: Six Veterans Affairs Medical Centers in the northwestern United States. PATIENTS: Culture-positive inpatients with HCAP. MEASUREMENTS: Patients were identified based upon guideline-defined criteria for HCAP. Relevant cultures obtained within 48 hours of admission were assessed to determine bacteriology and antibiotic susceptibility. Medical records for the year preceding admission were assessed to develop predictive models of CAP-resistance with logistic regression. The predictive performance of cohort-developed and guideline-defined models was compared. RESULTS: CAP-resistant organisms were identified in 118 of 375 culture-positive patients. Of guideline-defined criteria, CAP-resistance was associated (odds ratio (OR) [95% confidence interval (CI)]) with: admission from nursing home (2.6 [1.6-4.4]); recent antibiotic exposure (1.7 [1.0-2.8]); and prior hospitalization (1.6 [1.0-2.6]). In the cohort-developed model, CAP-resistance was associated with: admission from nursing home or recent nursing home discharge (2.3 [1.4-3.8]); positive methicillin-resistant Staphylococcus aureus (MRSA) history within 90 days of admission (6.4 [2.6-17.8]) or 91-365 days (2.3 [0.9-5.9]); cephalosporin exposure (1.8 [1.1-2.9]); recent infusion therapy (1.9 [1.0-3.5]); diabetes (1.7 [1.0-2.8]); and intensive care unit (ICU) admission (1.6 [1.0-2.6]). Area under the receiver operating characteristic curve (aROC [95% CI]) for the cohort-developed model (0.71 [0.65-0.77]) was significantly higher than for the guideline-defined model (0.63 [0.57-0.69]) (P = 0.01). CONCLUSIONS: Select guideline-defined criteria predicted CAP-resistance. A cohort-developed model based primarily on prior MRSA history, nursing home residence, and specific antibiotic exposures provided improved prediction of CAP-resistant organisms in HCAP.

Gender differences in veterans health administration mental health service use: effects of age and psychiatric diagnosis.

PURPOSE: The objective of this study was to compare gender differences in mental health disease burden and outpatient mental health utilization among veterans utilizing Veterans Health Administration (VHA) mental health services in fiscal year 1999 (FY99), after the first Gulf War and significant restructuring of VHA services. METHODS: We used logistic regression to examine the relationships among gender, age, diagnostic groups, and utilization of mental health and specialty mental health services in a national sample of veterans. The sample included 782,789 veterans with at least 1 outpatient visit in the VHA in FY99 associated with a mental health or substance abuse (SA) diagnosis. Subgroup analyses were performed for 4 diagnostic categories: 1) posttraumatic stress disorder (PTSD), 2) SA disorders, 3) bipolar and psychotic disorders, and 4) mood and anxiety disorders. MAIN FINDINGS: Younger women veterans (<35 years old) were significantly less likely and older women (> or =35) more likely to use any mental health services in comparison with their male counterparts. Similar findings were observed for younger women diagnosed with SA or mood and anxiety disorders, but not among veterans with PTSD or bipolar and psychotic disorders, among whom no there were no gender or age differences. In the case of specialized services for SA or PTSD, women younger than 55 with SA or PTSD were significantly less likely to use services than men. CONCLUSION: Women veterans underutilized specialty mental health services in relation to men but receipt of mental health care overall in FY99 varied by age and diagnosis. Examining gender differences alone, without taking other factors into account, may not provide an adequate picture of women veterans' current mental health service needs.

Efficacy of oral beta-lactam versus non-beta-lactam treatment of uncomplicated cellulitis.

BACKGROUND: Preferred therapy for purulent skin and soft tissue infections is incision and drainage, but many infections cannot be drained. Empiric therapies for these infections are ill-defined in the era of community-acquired methicillin-resistant Staphylococcus aureus. METHODS: A multicenter retrospective cohort study of outpatients treated for cellulitis was conducted to compare clinical failure rates of oral beta-lactam and non-beta-lactam treatments. Exclusion criteria included purulent infection requiring incision and drainage, complicated skin and soft tissue infection, chronic ulceration, and intravenous antibiotics. Failure rates were compared using logistic regression to adjust for both covariates associated with failure and a propensity score for beta-lactam treatment. RESULTS: Of 2977 patients, 861 met inclusion criteria and were classified by treatment: beta-lactam (n = 631) or non-beta-lactam therapy (n = 230). Failure rates were 14.7% versus 17.0% (odds ratio [OR] 0.85, 95% confidence interval [CI], 0.56-1.31) for beta-lactam and non-beta-lactam therapy, respectively. Failure was associated with: age (P = .02), acute symptom severity (P = .03), animal bites (P = .03), Charlson score > 3 (P = .02), and histamine-2 receptor antagonist use (P = .09). Relative efficacy of beta-lactam therapy was greater after adjustment for factors associated with failure but remained statistically insignificant (adjusted OR 0.81, 95% CI, 0.53-1.24); adjusted including propensity score covariate (OR 0.71, 95% CI, 0.45-1.13). Discontinuation due to adverse effects differed between beta-lactam (0.5%) and non-beta-lactam (2.2%) therapies (P = .04). CONCLUSION: There was no significant difference in clinical failure between beta-lactam and non-beta-lactam antibiotics for the treatment of uncomplicated cellulitis. Increased discontinuation due to adverse events with non-beta-lactam therapy was observed.

Racial differences in the evaluation and treatment of hepatitis C among veterans: a retrospective cohort study.

OBJECTIVES: We examined the association between race and hepatitis C virus (HCV) evaluation and treatment of veterans in the Northwest Network of the Department of Veterans Affairs (VA). METHODS: In our retrospective cohort study, we used medical records to determine antiviral treatment of 4263 HCV-infected patients from 8 VA medical centers. Secondary outcomes included specialty referrals, laboratory evaluation, viral genotype testing, and liver biopsy. Multiple logistic regression was used to adjust for clinical (measured through laboratory results and International Classification of Diseases, Ninth Revision, codes) and sociodemographic factors. RESULTS: Blacks were less than half as likely as Whites to receive antiviral treatment (odds ratio [OR]=0.38; 95% confidence interval [CI]=0.23, 0.63). Both had similar odds of referral and liver biopsy. However, Blacks were significantly less likely to have complete laboratory evaluation (OR=0.67; 95% CI=0.52, 0.88) and viral genotype testing (OR=0.68; 95% CI=0.51, 0.90). CONCLUSIONS: Race is associated with receipt of medical care for various medical conditions. Further investigation is warranted to help understand whether patient preference or provider bias may explain why HCV-infected Blacks were less likely to receive medical care than Whites.

Outpatient treatment engagement and abstinence rates following inpatient opioid detoxification.

Many patients with chronic opioid dependence are referred to drug-free outpatient treatment following inpatient detoxification even though successful outpatient treatment engagement and abstinence from opioids occur only in a minority of cases. This retrospective cohort analysis of medical records documents the post-discharge outcome in a treatment setting that maximizes the support during transition to abstinence-oriented outpatient care, with comprehensive social, medical and mental health services, including the availability of naltrexone. Participants were male veterans (N = 112) admitted at an urban VA medical center. Most patients (78%) successfully completed acute detoxification, 49% initiated naltrexone, and 76% accepted a VA aftercare plan. At 90-day follow-up, only 22% remained in aftercare, and < 3% had toxicology-verified abstinence from opioids. At one-year follow-up, 1 out of 5 had been readmitted for detoxification and 4.5% had died. Most patients successfully detoxified from opioids, but very few remained engaged and stabilized in abstinence-oriented outpatient treatment.

Low serum testosterone and mortality in male veterans.

BACKGROUND: Low serum testosterone is a common condition in aging associated with decreased muscle mass and insulin resistance. This study evaluated whether low testosterone levels are a risk factor for mortality in male veterans. METHODS: We used a clinical database to identify men older than 40 years with repeated testosterone levels obtained from October 1, 1994, to December 31, 1999, and without diagnosed prostate cancer. A low testosterone level was a total testosterone level of less than 250 ng/dL (<8.7 nmol/L) or a free testosterone level of less than 0.75 ng/dL (<0.03 nmol/L). Men were classified as having a low testosterone level (166 [19.3%]), an equivocal testosterone level (equal number of low and normal levels) (240 [28.0%]), or a normal testosterone level (452 [52.7%]). The risk for all-cause mortality was estimated using Cox proportional hazards regression models, adjusting for demographic and clinical covariates over a follow-up of up to 8 years. RESULTS: Mortality in men with normal testosterone levels was 20.1% (95% confidence interval [CI], 16.2%-24.1%) vs 24.6% (95% CI, 19.2%-30.0%) in men with equivocal testosterone levels and 34.9% (95% CI, 28.5%-41.4%) in men with low testosterone levels. After adjusting for age, medical morbidity, and other clinical covariates, low testosterone levels continued to be associated with increased mortality (hazard ratio, 1.88; 95% CI, 1.34-2.63; P<.001) while equivocal testosterone levels were not significantly different from normal testosterone levels (hazard ratio, 1.38; 95% CI, 0.99%-1.92%; P=.06). In a sensitivity analysis, men who died within the first year (50 [5.8%]) were excluded to minimize the effect of acute illness, and low testosterone levels continued to be associated with elevated mortality. CONCLUSIONS: Low testosterone levels were associated with increased mortality in male veterans. Further prospective studies are needed to examine the association between low testosterone levels and mortality.

Development and validation of a psychiatric case-mix system.

BACKGROUND: Although difficulties in applying risk-adjustment measures to mental health populations are increasingly evident, a model designed specifically for patients with psychiatric disorders has never been developed. OBJECTIVE: Our objective was to develop and validate a case-mix classification system, the "PsyCMS," for predicting concurrent and future mental health (MH) and substance abuse (SA) healthcare costs and utilization. SUBJECTS: Subjects included 914,225 veterans who used Veterans Administration (VA) healthcare services during fiscal year 1999 (FY99) with any MH/SA diagnosis (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] codes 290.00-312.99, 316.00-316.99). METHODS: We derived diagnostic categories from ICD-CM codes using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition definitions, clinical input, and empiric analyses. Weighted least-squares regression models were developed for concurrent (FY99) and prospective (FY00) MH/SA costs and utilization. We compared the predictive ability of the PsyCMS with several case-mix systems, including adjusted clinical groups, diagnostic cost groups, and the chronic illness and disability payment system. Model performance was evaluated using R-squares and mean absolute prediction errors (MAPEs). RESULTS: Patients with MH/SA diagnoses comprised 29.6% of individuals seen in the VA during FY99. The PsyCMS accounted for a distinct proportion of the variance in concurrent and prospective MH/SA costs (R=0.11 and 0.06, respectively), outpatient MH/SA utilization (R=0.25 and 0.07), and inpatient MH/SA utilization (R=0.13 and 0.05). The PsyCMS performed better than other case-mix systems examined with slightly higher R-squares and lower MAPEs. CONCLUSIONS: The PsyCMS has clinically meaningful categories, demonstrates good predictive ability for modeling concurrent and prospective MH/SA costs and utilization, and thus represents a useful method for predicting mental health costs and utilization.

Randomized trial of onsite versus referral primary medical care for veterans in addictions treatment.

BACKGROUND: Patients presenting for treatment of substance use disorders (SUDs) often exhibit medical comorbidities that affect functional health status and healthcare costs. Providing primary care within addictions clinics (onsite care) may improve medical and SUD treatment outcomes in this population. OBJECTIVE: The objective of this study was to compare outcomes among Veterans' Administration (VA) patients who receive medical care within the SUD clinic and those referred to a general medicine clinic at the same facility. METHODS: Veterans entering SUD treatment with a chronic medical condition and no current primary care were randomized to receive primary medical care: 1) onsite in the VA SUD clinic (n = 358), or 2) in the VA general internal medicine clinic (n = 362). Subjects were assessed at baseline and at 3, 6, and 12 months postrandomization. Intention-to-treat analyses used random-effects regression. MEASURES: Measures included SF-36 Physical and Mental Component Summaries (PCS, MCS), VA service utilization, SUD treatment retention, Addiction Severity Index (ASI) scores, 30-day abstinence, and total VA healthcare costs. RESULTS: Over the study year, patients assigned to onsite care were more likely to attend primary care (adjusted odds ratio [OR] = 2.20; 95% confidence interval [CI] = 1.53-3.15) and to remain engaged in SUD treatment at 3 months (adjusted OR = 1.36; 1.00-1.84). Overall, outcomes on the MCS (but not the PCS) and the ASI improved significantly over time but did not differ by treatment condition. Total VA healthcare costs did not differ reliably across conditions. CONCLUSIONS: Compared with referral care, providing primary care within a VA addiction clinic increased primary care access and initial SUD treatment retention but showed no effect on overall health status or costs.

CD155/PVR enhances glioma cell dispersal by regulating adhesion signaling and focal adhesion dynamics.

We recently identified the immunoglobulin-CAM CD155/PVR (the poliovirus receptor) as a regulator of cancer invasiveness and glioma migration, but the mechanism through which CD155/PVR controls these processes is unknown. Here, we show that expression of CD155/PVR in rat glioma cells that normally lack this protein enhances their dispersal both in vitro and on primary brain tissue. CD155/PVR expression also reduced substrate adhesion, cell spreading, focal adhesion density, and the number of actin stress fibers in a substrate-dependent manner. Furthermore, we found that expression of CD155/PVR increased Src/focal adhesion kinase signaling in a substrate-dependent manner, enhancing the adhesion-induced activation of paxillin and p130Cas in cells adhering to vitronectin. Conversely, depletion of endogenous CD155/PVR from human glioma cells inhibited their migration, increased cell spreading, and down-regulated the same signaling pathway. These findings implicate CD155/PVR as a regulator of adhesion signaling and suggest a pathway through which glioma and other cancer cells may acquire a dispersive phenotype.

Substantial weight gain during adulthood: the road to bariatric surgery.

We sought to examine the relationship of body mass index (BMI) at age 18 years with the degree and rate of rise in body weight during adulthood among the morbidly obese. We evaluated 196 patients with a standard medical history form and a structured interview with questions regarding weight at age 18 years. The study included 40 (20.4%) men and 156 (79.6%) women. The mean BMI was 50.2+/-8.0 kg/m2, range 37.0-80.0 kg/m2. Based on self-reported weight, 133 (67.9%) were overweight/obese (BMI >25 kg/m2) and 68 (34.7%) were obese (BMI > or =30 kg/m2) at age 18 years. The distribution of cumulative weight gain was normal with a mean of 60.8+/-23.7 kg. There was a positive relationship (r=0.36, p<0.0001) between BMI at age 18 years and BMI in adulthood at a mean of 44+/-10.6 years. Independent predictors for cumulative adult weight gain were BMI at age 18 years (p<0.0001); women (p<0.0001); African Americans (p=0.05). These data suggest that modestly overweight young adults can have excessive weight gains during adult life, resulting in morbid obesity and high rates of obesity-related comorbidities.

Functional proteomic screen identifies a modulating role for CD44 in death receptor-mediated apoptosis.

Apoptotic evasion is a hallmark of cancer and its resistance to chemotherapeutic drugs. Identification of cellular proteins that mediate apoptotic programs is a critical step toward the development of therapeutics aimed at overcoming apoptosis resistance. We developed an innovative high-throughput screen to identify proteins that modulate Fas ligand-mediated apoptosis using fluorophore-assisted light inactivation (HTS-FALIpop). The FALI protein knockdown strategy was coupled to a caspase activity assay with the ability to detect both proapoptotic and antiapoptotic surface molecules expressed by HT-1080 human fibrosarcoma cells. FALI of the Fas receptor (Fas/CD95) using a fluorescein-conjugated anti-Fas antibody abrogated Fas ligand-mediated caspase activation. Ninety-six single-chain variable fragment antibodies (scFv), selected for binding to the surface of HT-1080 cells, were screened by HTS-FALIpop. Three of the scFvs caused decreases in caspase induction after FALI of their protein targets. One of the targets of these positive scFvs was identified as CD44 and was validated by performing FALI using a CD44-specific monoclonal antibody, which resulted in similar protection from Fas apoptosis. CD44-targeted FALI was antiapoptotic in multiple human cancer cell lines, including both Fas signaling type I and II cells, and was also protective against other ligands of the tumor necrosis factor death receptor family. FALI of CD44 inhibited formation and activation of the death-inducing signaling complex, suggesting that CD44 regulates Fas at the cell surface. This mechanism of death receptor regulation represents a novel means of apoptosis modulation that could be exploited by pharmacologic agents.

Cost effectiveness of testing strategies for chronic hepatitis C.

OBJECTIVE: This paper compares nine strategies for determining hepatitis C antibody and viral status. They combine two tests for antibodies (enzyme immunoassays (EIA), recombinant immunoblot assays (RIBA)) and one for viremia (reverse transcription polymerase chain reaction (PCR)). Using optical density to divide EIA results into three categories (high positive, low positive, negative) was also considered. METHODS: Decision analysis compared strategies on cost as well as sensitivity and specificity with regard to antibody and viral status. Parameters in the decision tree included antibody prevalence, proportion viremic, sensitivity, specificity, and cost of individual tests. RESULTS: The two best strategies are EIA followed by PCR (EIA-->PCR); and EIA with three levels of optical density (EIA-OD), followed by RIBA for EIA-OD low positives, and then PCR for all positives (EIA-OD-->RIBA-->PCR). EIA-->PCR has equal viral sensitivity, slightly lower cost, slightly higher antibody sensitivity, but lower antibody specificity compared to EIA-OD-->RIBA-->PCR. The cost per false antibody positive avoided using EIA-OD-->RIBA-->PCR rather than EIA-->PCR is $36 when prevalence is 5%, and $193 when prevalence is 50%. Using EIA-OD-->RIBA-->PCR rather than EIA-->PCR results in 112 false antibody positives avoided for every true antibody positive missed when prevalence is 5%; this ratio is 18:1 when prevalence is 25%; and 6:1 when prevalence is 50%. CONCLUSIONS: EIA-OD-->RIBA-->PCR is the best choice when prevalence in the tested group is below 20%. As prevalence increases, the choice of EIA-OD-->RIBA-->PCR versus EIA-->PCR will depend on the relative importance of avoiding false antibody positives versus missing true antibody positives. Our analysis makes explicit the magnitude of this trade-off.

Low testosterone levels predict incident depressive illness in older men: effects of age and medical morbidity.

OBJECTIVE: Prior studies found that chronic low testosterone levels are associated with an increased risk of depression. We investigated whether low testosterone levels in older men predict depressive illness over 2 years, while controlling for age and medical morbidity. METHOD: Participants were 748 men, aged 50 years or older, without prior ICD-9-diagnosed depressive illness, with a testosterone level obtained between 1995 and 1997. Measures were age, mean total testosterone levels (low: < or = 2.5 ng/mL), medical morbidity, and incidence and time to depressive illness. RESULTS: Men with low testosterone levels had a greater 2-year incidence of depressive illness (18.5% vs. 10.4%, df = 1, p = .006) and a shorter time to onset of depressive illness (log-rank chi(2) = 8.1, df = 1, p = .004). The unadjusted hazard ratio (HR) for depressive illness in men with low testosterone levels was 1.9 (95% confidence interval [CI] = 1.2 to 3.0, p = .005). After adjustment for age and medical morbidity, men with low testosterone levels continued to have a shorter time to depressive illness (adjusted HR = 2.1; 95% CI = 1.3 to 3.2, p = .002). Due to a significant interaction between age and medical morbidity, we conducted stratified Cox regression analyses and found that low testosterone levels and high medical morbidity or an age of 50 to 65 years were associated with increased depressive illness (p = .002). CONCLUSION: Low testosterone levels are associated with an earlier onset and greater incidence of depressive illness. Men with low testosterone levels who had high medical morbidity or were aged 50 to 65 years had an increased risk for depressive illness. Further prospective studies are needed to examine the role of testosterone in depressive illness in older men.

CD155/PVR plays a key role in cell motility during tumor cell invasion and migration.

BACKGROUND: Invasion is an important early step of cancer metastasis that is not well understood. Developing therapeutics to limit metastasis requires the identification and validation of candidate proteins necessary for invasion and migration. METHODS: We developed a functional proteomic screen to identify mediators of tumor cell invasion. This screen couples Fluorophore Assisted Light Inactivation (FALI) to a scFv antibody library to systematically inactivate surface proteins expressed by human fibrosarcoma cells followed by a high-throughput assessment of transwell invasion. RESULTS: Using this screen, we have identified CD155 (the poliovirus receptor) as a mediator of tumor cell invasion through its role in migration. Knockdown of CD155 by FALI or by RNAi resulted in a significant decrease in transwell migration of HT1080 fibrosarcoma cells towards a serum chemoattractant. CD155 was found to be highly expressed in multiple cancer cell lines and primary tumors including glioblastoma (GBM). Knockdown of CD155 also decreased migration of U87MG GBM cells. CD155 is recruited to the leading edge of migrating cells where it colocalizes with actin and alphav-integrin, known mediators of motility and adhesion. Knockdown of CD155 also altered cellular morphology, resulting in cells that were larger and more elongated than controls when plated on a Matrigel substrate. CONCLUSION: These results implicate a role for CD155 in mediating tumor cell invasion and migration and suggest that CD155 may contribute to tumorigenesis.

The Addiction Severity Index medical and psychiatric composite scores measure similar domains as the SF-36 in substance-dependent veterans: concurrent and discriminant validity.

BACKGROUND: Recently attention has focused on the assessment of functional health status in substance-dependent individuals. The addiction severity index (ASI) is a widely used assessment instrument that includes scales to reflect current medical and psychiatric status. This study examines the concurrent validity of these ASI composite scores in relation to the short form 36-item health survey (SF-36), a well-established measure of health-related quality of life/functional health status. METHODS: Veterans (n=674) were assessed at admission to substance dependence treatment. Correlations were performed between ASI composite scores and SF-36 scales and the physical and mental summary components (PSC and MSC, respectively). Areas under receiver operating characteristic (ROC) curves determined the descriminative ability of the ASI composites to ascertain impairment. RESULTS: The ASI medical composite score demonstrated robust correlations with the four SF-36 scales that relate to physical health and with the PCS. The ASI psychiatric composite score had robust correlations with the four SF-36 scales related to mental health and with the mental component summary (MCS). ROC curves indicated that the ASI medical (AUC=0.83) and psychiatric composites (AUC=0.90) accurately detected subjects with impairment. CONCLUSIONS: ASI medical and psychiatric composite scores provide effective initial screening for patients with impaired functional status as measured by the corresponding SF-36 component summary scores.

Use of electronic medical record data for quality improvement in schizophrenia treatment.

An understanding of the strengths and limitations of automated data is valuable when using administrative or clinical databases to monitor and improve the quality of health care. This study discusses the feasibility and validity of using data electronically extracted from the Veterans Health Administration (VHA) computer database (VistA) to monitor guideline performance for inpatient and outpatient treatment of schizophrenia. The authors also discuss preliminary results and their experience in applying these methods to monitor antipsychotic prescribing using the South Central VA Healthcare Network (SCVAHCN) Data Warehouse as a tool for quality improvement.

Hepatitis C tested prevalence and comorbidities among veterans in the US Northwest.

GOALS: (1) Investigate the epidemiology of hepatitis C virus infection among patients seen in the Veterans Administration Northwest Network; (2) examine time trends in testing practices and results; and (3) estimate the prevalence of hepatitis C virus infection among active patients. BACKGROUND: Hepatitis C virus infection causes chronic hepatitis and cirrhosis and is a leading cause of end-stage liver disease. Hepatitis C virus antibodies are estimated to be present in 1.8% of the US population, but reports of its prevalence among US veterans range from 1.7 to 35%. STUDY: Retrospective review of computerized medical records of veterans tested for hepatitis C from October 1994 through December 2000 (n = 37,938) at 8 Northwest Veterans Administration Medical Centers. RESULTS: Among tested veterans, 8230 (21.7%) had evidence of hepatitis C virus infection. The number of patients tested increased annually from 2335 to 18,191, while the proportion with first-time positive hepatitis C test results decreased from 35 to 10%. This drop in tested prevalence was associated with a shift away from testing individuals at highest risk--those with positive hepatitis B serostatus, repeatedly elevated alanine transaminase levels, and drug use disorder diagnoses. We estimate that 11.4% of the Northwest Network veteran users are hepatitis C virus seropositive, with a lower bound of 4.0% and upper bound of 19.5%. CONCLUSIONS: Although estimates of hepatitis C virus infection rates among veteran users of the Veterans Administration system remain higher than those for the general population, changes in testing practice make generalizations from earlier studies hazardous.