UCLouvain Saint-Louis Brussels

BACKGROUND: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. METHODS: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. RESULTS: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. CONCLUSIONS: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.)

BACKGROUND: Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. METHODS: We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. RESULTS: A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. CONCLUSIONS: The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

BACKGROUND: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. METHODS: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). RESULTS: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. CONCLUSIONS: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).

Welch and Goyal (2008) find that numerous economic variables with in-sample predictive ability for the equity premium fail to deliver consistent out-of-sample forecasting gains relative to the historical average. Arguing that model uncertainty and instability seriously impair the forecasting ability of individual predictive regression models, we recommend combining individual forecasts. Combining delivers statistically and economically significant out-of-sample gains relative to the historical average consistently over time. We provide two empirical explanations for the benefits of forecast combination: (i) combining forecasts incorporates information from numerous economic variables while substantially reducing forecast volatility; (ii) combination forecasts are linked to the real economy. The Author 2009. Published by Oxford University Press on behalf of The Society for Financial Studies. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org, Oxford University Press.

BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. METHODS: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. RESULTS: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. CONCLUSIONS: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).

Social scientists frequently study complex constructs. Despite plethora of measures for these constructs, researchers may need to create their own measure for a particular study. When a measure is created, psychometric testing is required, and first step is to study content validity of measure. The purpose of this article is to demonstrate how to conduct a content validity study, including how to elicit most from a panel of experts by collecting specific data. Instructions how to calculate a content validity index, factorial validity index, and an interrater reliability index and guide for interpreting these indices are included. Implications regarding value of conducting a content validity study for practitioners and researchers are discussed. Key words: constructs; content validity; measure; psychometric testing ********** Researchers in social sciences study complex constructs for which valid and reliable measures are needed. The measures should be brief, clear, and easy to administer. Measures that are too long or difficult to read may result in a lowered response rate or inaccurate responses. In addition, measure must be appropriate for use in targeted population. For example, measures designed for use with heterogeneous populations may not be appropriate for a specific population with certain characteristics. A plethora of measures exist with known psychometric properties, but researchers may need to develop a new measure for a particular construct because no measure exists that operationalizes construct as researcher conceptualized it. In these circumstances, a content validity study should be conducted. VALIDITY Traditionally, three types of validity may be demonstrated: content, criterion, and construct validity. Content Validity Content validity refers to extent to which items a measure assess same content or how well content material was sampled in measure. Content validity can be characterized as face validity or logical validity. Face validity indicates that measure appears to be valid, on its face. Logical validity indicates a more rigorous process, such as using a panel of experts to evaluate content validity of a measure. Nunnally and Bernstein (1994) did not distinguish among different types of content validity; but presented alternative ways of assessing content validity. They suggested evaluating content validity by demonstrating internal consistency through correlating scores from measure with another measure of same construct and by showing change in posttest scores over pretest scores. Criterion Validity Criterion validity is demonstrated by finding a statistically significant relationship between a measure and a criterion (Nunnally & Bernstein, 1994). Criterion validity is considered gold standard, and usually a correlation is used to assess statistical relationship. For example, Graduate Record Examination (GRE) has been found to predict graduate school success (as measured by first-year grade-point average) for certain disciplines (Rubio, Rubin, & Brennan, 2003). Three types of criterion validity are postdictive, concurrent, and predictive. If criterion has occurred, validity is postdictive. The validity is concurrent if criterion exists at same time as construct measured. The GRE example demonstrates predictive validity, because graduate school success (criterion) occurs after taking GRE (measure). According to Nunnally and Bernstein, a correlation of .30 indicates adequate criterion validity. Construct Validity Anastasi and Urbina (1997) described construct validity as the extent to which test may be said to measure a theoretical construct or trait (p. 126). Three kinds of construct validity are factorial, known groups; and convergent and discriminant (or divergent) validity. …

ABSTRACT: Sleep is essential for optimal health. The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) developed a consensus recommendation for the amount of sleep needed to promote optimal health in adults, using a modified RAND Appropriateness Method process. The recommendation is summarized here. A manuscript detailing the conference proceedings and evidence supporting the final recommendation statement will be published in SLEEP and the Journal of Clinical Sleep Medicine.

CONTEXT: Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease (AD) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed. OBJECTIVE: To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed the trial. INTERVENTIONS: Participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks. MAIN OUTCOME MEASURES: Change from baseline on the Severe Impairment Battery (SIB), a measure of cognition, and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale). RESULTS: The change in total mean (SE) scores favored memantine vs placebo treatment for SIB (possible score range, 0-100), 0.9 (0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P =.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074) vs 4.66 (0.075), respectively (P =.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively. CONCLUSIONS: In patients with moderate to severe AD receiving stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. These results, together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD.

BACKGROUND: The hemoglobin threshold at which postoperative red-cell transfusion is warranted is controversial. We conducted a randomized trial to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for hip fracture. METHODS: We enrolled 2016 patients who were 50 years of age or older, who had either a history of or risk factors for cardiovascular disease, and whose hemoglobin level was below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a restrictive transfusion strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <8 g per deciliter). The primary outcome was death or an inability to walk across a room without human assistance on 60-day follow-up. RESULTS: A median of 2 units of red cells were transfused in the liberal-strategy group and none in the restrictive-strategy group. The rates of the primary outcome were 35.2% in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for an absolute risk difference of 0.5 percentage points (95% CI, -3.7 to 4.7). The rates of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively (absolute risk difference, -0.9%; 99% CI, -3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, -1.9 to 4.0). The rates of other complications were similar in the two groups. CONCLUSIONS: A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032.).

CONTEXT: Despite evidence of efficacy of antihypertensive agents in treating hypertensive patients, safety and efficacy of antihypertensive agents for coronary artery disease (CAD) have been discerned only from subgroup analyses in large trials. OBJECTIVE: To compare mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy (CAS) or a non-calcium antagonist strategy (NCAS). DESIGN, SETTING, AND PARTICIPANTS: Randomized, open label, blinded end point study of 22 576 hypertensive CAD patients aged 50 years or older, which was conducted September 1997 to February 2003 at 862 sites in 14 countries. INTERVENTIONS: Patients were randomly assigned to either CAS (verapamil sustained release) or NCAS (atenolol). Strategies specified dose and additional drug regimens. Trandolapril and/or hydrochlorothiazide was administered to achieve blood pressure goals according to guidelines from the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) of less than 140 mm Hg (systolic) and less than 90 mm Hg (diastolic); and less than 130 mm Hg (systolic) and less than 85 mm Hg (diastolic) if diabetes or renal impairment was present. Trandolapril was also recommended for patients with heart failure, diabetes, or renal impairment. MAIN OUTCOME MEASURES: Primary: first occurrence of death (all cause), nonfatal myocardial infarction, or nonfatal stroke; other: cardiovascular death, angina, adverse experiences, hospitalizations, and blood pressure control at 24 months. RESULTS: At 24 months, in the CAS group, 6391 patients (81.5%) were taking verapamil sustained release; 4934 (62.9%) were taking trandolapril; and 3430 (43.7%) were taking hydrochlorothiazide. In the NCAS group, 6083 patients (77.5%) were taking atenolol; 4733 (60.3%) were taking hydrochlorothiazide; and 4113 (52.4%) were taking trandolapril. After a follow-up of 61 835 patient-years (mean, 2.7 years per patient), 2269 patients had a primary outcome event with no statistically significant difference between treatment strategies (9.93% in CAS and 10.17% in NCAS; relative risk [RR], 0.98; 95% confidence interval [CI], 0.90-1.06). Two-year blood pressure control was similar between groups. The JNC VI blood pressure goals were achieved by 65.0% (systolic) and 88.5% (diastolic) of CAS and 64.0% (systolic) and 88.1% (diastolic) of NCAS patients. A total of 71.7% of CAS and 70.7% of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg. CONCLUSION: The verapamil-trandolapril-based strategy was as clinically effective as the atenolol-hydrochlorothiazide-based strategy in hypertensive CAD patients.

BACKGROUND: Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. METHODS: At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 microg per kilogram of body weight per week or a low dose of 1.0 microg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 microg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. RESULTS: Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], -2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and -1.1% (95% CI, -5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. CONCLUSIONS: In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials.gov number, NCT00081770.)

BACKGROUND: Inflammatory cytokines such as tumor necrosis factor (TNF) have been implicated in the pathogenesis of psoriasis. We evaluated the safety and efficacy of etanercept, a TNF antagonist, for the treatment of plaque psoriasis. METHODS: In this 24-week, double-blind study, 672 patients underwent randomization and 652 either received placebo or received etanercept subcutaneously at a low dose (25 mg once weekly), a medium dose (25 mg twice weekly), or a high dose (50 mg twice weekly). After 12 weeks, patients in the placebo group began twice-weekly treatment with 25 mg of etanercept. The primary measure of clinical response was the psoriasis area-and-severity index. RESULTS: At week 12, there was an improvement from base line of 75 percent or more in the psoriasis area-and-severity index in 4 percent of the patients in the placebo group, as compared with 14 percent of those in the low-dose--etanercept group, 34 percent in the medium-dose--etanercept group, and 49 percent in the high-dose-etanercept group (P<0.001 for all three comparisons with the placebo group). The clinical responses continued to improve with longer treatment. At week 24, there was at least a 75 percent improvement in the psoriasis area-and-severity index in 25 percent of the patients in the low-dose group, 44 percent of those in the medium-dose group, and 59 percent in the high-dose group. The responses as measured by improvements in the psoriasis area-and-severity index were paralleled by improvements in global assessments by physicians and the patients and in quality-of-life measures. Etanercept was generally well tolerated. CONCLUSIONS: The treatment of psoriasis with etanercept led to a significant reduction in the severity of disease over a period of 24 weeks.

Using two longitudinal panel datasets of Chinese manufacturing firms, we assess whether state ownership benefits or impedes firms’ innovation. We show that state ownership in an emerging economy enables a firm to obtain crucial R&amp;D resources but makes the firm less efficient in using those resources to generate innovation, and we find that a minority state ownership is an optimal structure for innovation development in this context. Moreover, the inefficiency of state ownership in transforming R&amp;D input into innovation output decreases when industrial competition is high, as well as for start-up firms. Our findings integrate the efficiency logic (agency theory), which views state ownership as detrimental to innovation, and institutional logic, which notes that governments in emerging economies have critical influences on regulatory policies and control over scarce resources. We discuss the implications of these findings for research on state ownership and firm innovation in emerging economies.

The 8th Banff Conference on Allograft Pathology was held in Edmonton, Canada, 15-21 July 2005. Major outcomes included the elimination of the non-specific term "chronic allograft nephropathy" (CAN) from the Banff classification for kidney allograft pathology, and the recognition of the entity of chronic antibody-mediated rejection. Participation of B cells in allograft rejection and genomics markers of rejection were also major subjects addressed by the conference.

'Deliberative democracy' is often dismissed as a set of small-scale, academic experiments. This volume seeks to demonstrate how the deliberative ideal can work as a theory of democracy on a larger scale. It provides a new way of thinking about democratic engagement across the spectrum of political action, from towns and villages to nation states, and from local networks to transnational, even global systems. Written by a team of the world's leading deliberative theorists, Deliberative Systems explains the principles of this new approach, which seeks ways of ensuring that a division of deliberative labour in a system nonetheless meets both deliberative and democratic norms. Rather than simply elaborating the theory, the contributors examine the problems of implementation in a real world of competing norms, competing institutions and competing powerful interests. This pioneering book will inspire an exciting new phase of deliberative research, both theoretical and empirical.

BACKGROUND: Type 17 helper T cells have been suggested to play a pathological role in psoriasis. They secrete several proinflammatory cytokines, including interleukin-17A (also known as interleukin-17). We evaluated the safety and efficacy of ixekizumab (LY2439821), a humanized anti-interleukin-17 monoclonal antibody, for psoriasis treatment. METHODS: In our phase 2, double-blind, placebo-controlled trial, we randomly assigned 142 patients with chronic moderate-to-severe plaque psoriasis to receive subcutaneous injections of 10, 25, 75, or 150 mg of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks. The primary end point was the proportion of patients with reduction in the psoriasis area-and-severity index (PASI) score by at least 75% at 12 weeks. Secondary end points included the proportion of patients with reduction in the PASI score by at least 90% or by 100%. RESULTS: At 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 10-mg dose)--150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%)--than with placebo (7.7%, P<0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P<0.001 for each comparison). Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P<0.001 for both comparisons). Significant differences occurred at as early as 1 week and were sustained through 20 weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major cardiovascular events were observed. CONCLUSIONS: Use of a humanized anti-interleukin-17 monoclonal antibody, ixekizumab, improved the clinical symptoms of psoriasis. Further studies are needed to establish its long-term safety and efficacy in patients with psoriasis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT01107457.).

Narrative forms of communication-including entertainment education, journalism, literature, testimonials, and storytelling-are emerging as important tools for cancer prevention and control. To stimulate critical thinking about the role of narrative in cancer communication and promote a more focused and systematic program of research to understand its effects, we propose a typology of narrative application in cancer control. We assert that narrative has four distinctive capabilities: overcoming resistance, facilitating information processing, providing surrogate social connections, and addressing emotional and existential issues. We further assert that different capabilities are applicable to different outcomes across the cancer control continuum (e.g., prevention, detection, diagnosis, treatment, survivorship). This article describes the empirical evidence and theoretical rationale supporting propositions in the typology, identifies variables likely to moderate narrative effects, raises ethical issues to be addressed when using narrative communication in cancer prevention and control efforts, and discusses potential limitations of using narrative in this way. Future research needs based on these propositions are outlined and encouraged.

OBJECTIVES: The purpose of this study was to estimate the prevalence of child maltreatment in the United States and examine its relationship to sociodemographic factors and major adolescent health risks. METHODS: The National Longitudinal Study of Adolescent Health is a prospective cohort study following a national sample of adolescents into adulthood. The wave III interview, completed by 15 197 young adults in 2001-2002 (77.4% response rate), included retrospective measures of child maltreatment. We used these measures to estimate the prevalence of self-reported supervision neglect, physical neglect, physical assault, and contact sexual abuse during childhood. Next, we investigated the relationship between sociodemographic characteristics and maltreatment. Finally, we examined the association between child maltreatment and adolescent self-rated health; overweight status; depression; cigarette, alcohol, marijuana, and inhalant use; and violent behavior. RESULTS: Having been left home alone as a child, indicating possible supervision neglect, was most prevalent (reported by 41.5% of respondents), followed by physical assault (28.4%), physical neglect (11.8%), and contact sexual abuse (4.5%). Each sociodemographic characteristic was associated with > or = 1 type of maltreatment, and race/ethnicity was associated with all 4. Each type of maltreatment was associated with no fewer than 8 of the 10 adolescent health risks examined. CONCLUSIONS: Self-reported childhood maltreatment was common. The likelihood of maltreatment varied across many sociodemographic characteristics. Each type of maltreatment was associated with multiple adolescent health risks.

Demographic data clearly demonstrate that the percentage of the population in the older age group is increasing. Androgen deficiency in the aging male has become a topic of increasing interest and debate throughout the world. Cross-sectional and longitudinal data indicate that the testosterone falls progressively with age and that a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men (1, 2, 3, 4). The principal questions raised by these observations are whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention. The past decade has brought evidence of benefit of androgen treatment of hypogonadal men on multiple target organs and the recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men. This has been comprehensively reviewed and summarized by the Institute of Medicine in ‘Testosterone and Aging: Clinical Research Directions’ (5). Long-term data on the effects of testosterone treatment in the older population are limited mainly to effects on body composition and bone mass (6, 7, 8, 9, 10, 11). Key questions of the effects of testosterone on patient reported outcomes and functional benefits that may retard physical or mental frailty of the elderly or improve the quality of life are not yet available. Specific risk data on the prostate and cardiovascular systems are needed. Recent guidelines for the testosterone treatment of younger hypogonadal men are available from professional societies (12, 13, 14). Recommendations on the diagnosis, treatment, and monitoring of late-onset hypogonadism (LOH) were published by International Society for the Study of Aging Male (ISSAM) in 2002 (15). In 2005, a writing committee formed by the International Society of Andrology (ISA), the ISSAM, and the European Association of Urology (EAU) prepared a set of recommendations specifically on the ‘Investigation, treatment and monitoring of LOH’. In order to reach a large audience, these recommendations were published in the International Journal of Andrology, the Journal of Andrology, the Aging Male, and European Urology (16, 17, 18, 19). In view of the growing interest from practitioners on the treatment of older men with testosterone, the ISA, ISSAM, EAU, European Academy of Andrology, and American Society of Andrology convened meetings of the writing group with expert representatives from each of the societies. The writing group membership from 2005 was expanded to include additional urologists. Members of the writing group met in Berlin 2007, Toronto 2007, and Tampa 2008 to revise these recommendations. There was no corporate funding or support for the development of these recommendations. The revised recommendations are supported by a selection of appropriate references and categorized by the level of evidence and grade of recommendation according to the US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research (1992; Table 1). Level of evidence and grade of recommendation utilized in the recommendations. Level of evidence and grade of recommendation utilized in the recommendations. To ensure broad outreach to multidisciplinary audiences, these recommendations are published in several journals simultaneously. LOH, also referred to as age-associated testosterone-deficiency syndrome (TDS), is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels (below the young healthy adult male reference range) (16, 17, 18, 19, 20). This condition may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems. 2.1. At present, the diagnosis of treatable hypogonadism requires the presence of symptoms and signs suggestive of testosterone deficiency (Level 3, Grade A) (12, 16, 17, 18, 19). The symptom most associated with hypogonadism is low libido (Level 3, Grade A) (21, 22). Other manifestations of hypogonadism include: erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone mineral density and osteoporosis, and decreased vitality and depressed mood. None of these symptoms are specific to the low androgen state but may raise suspicion of testosterone deficiency. One or more of these symptoms must be corroborated with a low serum testosterone level (Level 3, Grade A) (1, 23, 24, 25). 2.2. Questionnaires such as Aging Male Symptom Score (AMS) (26, 27) and Androgen Deficiency in Aging Men (ADAM) (28) are not recommended for the diagnosis of hypogonadism because of low specificity (Level 3, Grade B) (24, 29, 30). 3.1. In patients at risk or suspected of hypogonadism, a thorough physical and biochemical work-up is necessary (Level 4, Grade A). Transient decreases of serum testosterone levels such as those due to acute illnesses should be excluded by careful clinical evaluations and repeated hormone measurement. Hypogonadism (primary or secondary) can occur at all ages including elderly men. Risk factors for hypogonadism in older men may include chronic illnesses (including diabetes mellitus, chronic obstructive lung disease, inflammatory arthritic disease, renal disease, and HIV-related disease), obesity, metabolic syndrome, and hemochromatosis (12). Such chronic diseases should be investigated and treated (Level 4, Grade A). 3.2. A serum sample for total testosterone determination should be obtained between 0700 and 1100 h (Level 2a, A) (31). The most widely accepted parameters to establish the presence of hypogonadism is the measurement of serum total testosterone. There are no generally accepted lower limits of normal. There is, however, general agreement that the total testosterone level above 12 nmol/l (350 ng/dl) does not require substitution. Similarly, based on the data of younger men, there is consensus that patients with serum total testosterone levels below 8 nmol/l (230 ng/dl) will usually benefit from testosterone treatment. If the serum total testosterone level is between 8 and 12 nmol/l, repeating the measurement of total testosterone with sex hormone-binding globulin (SHBG) to calculate free testosterone or free testosterone by equilibrium dialysis may be helpful (see 3.5 and 3.7 below) (Level 2b, Grade A). 3.3. Measurements of serum luteinizing hormone will assist in differentiating between primary and secondary hypogonadism and serum prolactin is indicated when the serum testosterone is lower than 5.2 nmol/l (150 ng/dl) (32, 33, 34, 35) or when secondary hypogonadism is suspected (12, 36, 37) (Level 3, Grade B). 3.4. Since there are known variations between assay methods, it is imperative that the practitioners utilize reliable laboratories and are acquainted with the reference ranges for testosterone from their local laboratory (38, 39, 40, 41) (Level 2b, Grade A). 3.5. Current immunometric methods for the measurement of testosterone can distinguish between hypogonadism and normal adult men. However, the methods based on mass spectrometry are more accurate and precise (39, 40, 41) (Level 2b, Grade A) and are increasingly recognized as the method of choice for serum testosterone measurement. 3.6. The measurement of free or bioavailable testosterone should be considered when the serum total testosterone concentration is not diagnostic of hypogonadism, particularly in obese men. There are no generally accepted lower limits of normal for free testosterone for the diagnosis of hypogonadism. However, a free testosterone level below 225 pmol/l (65 pg/ml) can provide supportive evidence for testosterone treatment (37, 38, 42) (Level 3, Grade C). Threshold values for bioavailable testosterone depend on the method used and are not generally available (38). 3.7. Equilibrium dialysis is the gold standard for free testosterone measurement. Free testosterone assays based on analog displacement immunoassays are widely available but do not give an accurate measurement of free testosterone; thus they should not be used (43, 44). Alternately, measuring serum SHBG levels together with reliable serum total testosterone levels provides the data necessary for calculating free testosterone levels (Level 2b, Grade A). Calculated free testosterone correlates well with free testosterone by equilibrium dialysis (38, 42). Efforts to create standardization of testosterone assays, agreement on standards for testosterone measurement and accurate reference ranges for testosterone by liquid chromatography mass spectrometry (LC–MS)/MS are being developed. International reference standards, characterization of methodology, and population-based reference ranges for free testosterone by equilibrium dialysis are needed. Consensus on the equilibrium constants for testosterone binding to SHBG and albumin will allow improved calculation of free testosterone (38). 3.8. Salivary testosterone has also been shown to be a reliable substitute for free testosterone measurements but cannot be recommended for general use at this time, since the methodology has not been standardized and adult male ranges are not available in most hospital or reference laboratories (45) (Level 3, Grade B). 3.9. Alterations in other endocrine systems occur in association with aging (i.e., estradiol, growth hormone (GH), and DHEA) but the significance of these changes is not well understood. Determinations of estradiol, thyroid hormones, cortisol, DHEA, DHEA-S, melatonin, GH, and insulin-like growth factor-I are not indicated unless other endocrine disorders are suspected based on the clinical signs and symptoms of the patient (12) (Level 2, Grade A). Improvement in signs and symptoms of testosterone deficiency should be sought. Failure to benefit clinical manifestations within a reasonable time interval (3–6 months is adequate for libido and sexual function, muscle function, and improved body fat; improvement in bone mineral density requires a longer interval to show improvement) should result in discontinuation of treatment. Further investigation for other causes of symptoms is then mandatory (Level 1b, Grade A). In men with hypogonadal values of testosterone, testosterone administration improves body composition (decrease of fat mass, increase of lean body mass (5, 7, 9, 10, 46) (Level 1b, Grade A). Secondary benefits of these changes of body composition on strength, muscle function, and metabolic and cardiovascular dysfunction are suggested by available data but require confirmation by large-scale studies. Osteopenia, osteoporosis, and fracture prevalence rates are greater in hypogonadal younger and older men (47). Bone density in hypogonadal men of all ages increases under testosterone substitution (8, 11, 48) (Level 1b, Grade A). Fracture data are not yet available and thus the long-term benefit of testosterone requires further investigation. Assessment of bone density at 2-year intervals is advisable in hypogonadal men and serum testosterone measurements should be obtained in all men with osteopenia (49, 50). 7.1. The initial assessment of all men with erectile dysfunction and/or diminished libido should include determination of serum testosterone. These dysfunctions, with or without a testosterone deficiency, might be related to co-morbidities (i.e., diabetes mellitus, hyperprolactinemia, the metabolic syndrome, bladder outlet obstruction, peripheral vascular disease, or medications (51)) (Level 2a, Grade A). 7.2. Men with erectile dysfunction and/or diminished libido and documented testosterone deficiency are candidates for testosterone therapy (Level 2a, Grade A). An inadequate response to testosterone treatment requires reassessment of the causal mechanisms responsible for the erectile dysfunction (see 7.4 below). 7.3. In the presence of a clinical picture of testosterone deficiency and borderline serum testosterone levels, a short (e.g., 3 months) therapeutic trial may be justified. An absence of response calls for discontinuation of testosterone administration. A satisfactory response might be placebo generated, so that continued assessment is advisable before long-term treatment is recommended (52) (Level 2a, Grade B). 7.4. There is evidence suggesting therapeutic synergism with combined use of testosterone and phosphodiesterase-5 inhibitors in hypogonadal or borderline eugonadal men (53, 54) (Level 1b, Grade B). These observations are still preliminary and require additional study. However, the combination treatment should be considered in hypogonadal patients with erectile dysfunction failing to respond to either treatment alone. It is unclear whether men with hypogonadism and erectile dysfunction should be treated initially with phosphodiesterase-5 inhibitor (PDE-5-I), testosterone, or the combination of the two. 8.1. Many of the components of the metabolic syndrome (obesity, hypertension, dyslipidemia, impaired glucose regulation, and insulin resistance) are also present in hypogonadal men. Numerous epidemiological studies have established a close relationship between obesity and low serum testosterone levels in healthy men (55). Obese men of 20–64% have a low serum total or free testosterone levels (56). The metabolic syndrome and type 2 diabetes mellitus are associated with low plasma testosterone (25, 55, 57, 58, 59, 60, 61, 62). Serum testosterone should be measured in men with type 2 diabetes mellitus with symptoms suggestive of testosterone deficiency (Level 2b, Grade A). 8.2. The effects of testosterone administration on glycemic control of men with diabetes mellitus are much less certain (63, 64, 65). It is premature to recommend testosterone treatment for the metabolic syndrome or diabetes mellitus in the absence of laboratory and other clinical evidence of hypogonadism. In men with hypogonadism and diabetes and/or the metabolic syndrome, the testosterone treatment for traditional hypogonadal symptoms may have other unproven benefits on their metabolic status (Level 2a, Grade B). 9.1. At the present time, there is no conclusive evidence that testosterone therapy increases the risk of prostate cancer or BPH (66, 67). There is also no evidence that testosterone treatment will convert subclinical prostate cancer to clinically detectable prostate cancer (Level 4, Grade C). However, there is unequivocal evidence that testosterone can stimulate growth and aggravate symptoms in men with locally advanced and metastatic prostate cancer (68, 69) (Level 2a, Grade A). Currently, adequately powered and optimally designed long-term prostate disease data are not available to determine whether there is any additional risk from testosterone replacement. Hypogonadal older (>45 years) men should be counseled on the potential risks and benefits of testosterone replacement before treatment and carefully monitored for prostate safety during treatment (Level 3, Grade A). 9.2. Prior to therapy with testosterone, a man's risk of prostate cancer must be assessed using, as a minimum, digital rectal examination (DRE) and determination of serum prostate-specific antigen (PSA). However, the pretreatment assessment can be improved by incorporating other risk predictors such as age, family history, and ethnicity/race. Several tools have been developed to assist the clinician in assessing prostate cancer risk (e.g., on-line prostate cancer risk calculator) (70, 71). These tools have not been validated for patients with LOH TDS. If the patient and physician feel that the risk is sufficiently high, further assessment may be desirable (71, 72) (Level 2a, Grade B). However, pretreatment prostate ultrasound examinations or biopsies are not recommended as routine requirements. 9.3. After initiation of testosterone treatment, patients should be monitored for prostate disease at 3–6 months, 12 months, and at least annually thereafter (Level 3, Grade C). Should the patient's prostate cancer risk be sufficiently high (suspicious finding on DRE; increased PSA or as calculated using a combination of risk factors as noted above) transrectal ultrasound-guided biopsies of the prostate are indicated (73, 74, 75, 76) (Level 2b, Grade A). 9.4. Severe symptoms of lower urinary tract symptoms (LUTS) evident by a high (>21) International Prostate Symptom Score due to benign prostate hyperplasia represents a relative contraindication (although there are no compelling data to suggest that testosterone treatment causes exacerbation of LUTS or promotes acute urinary retention) (Level 3, Grade C). After successful treatment of lower urinary tract obstruction, this contraindication is no longer applicable (Level 4, Grade C). 9.5. Men successfully treated for prostate cancer and suffering from confirmed symptomatic hypogonadism are potential candidates for testosterone substitution after a prudent interval, if there is no clinical or laboratory evidence of residual cancer (77, 78, 79, 80). As long-term outcome data are not available, clinicians must exercise good clinical judgment together with adequate knowledge of advantages and drawbacks of testosterone therapy in this situation (81, 82) (Level 2b, Grade C). The risk and benefits must be clearly discussed with and understood by the patient and the follow-up must be particularly careful. 10.1. Preparations of natural testosterone should be used for substitution therapy. Currently available i.m., subdermal, transdermal, oral, and buccal preparations of testosterone are safe and effective (Level 1b, Grade A). The treating physician should have sufficient knowledge and adequate understanding of the pharmacokinetics as well as of the advantages and drawbacks of each preparation. The selection of the preparation should be a joint decision of an informed patient and physician (83). 10.2. Since the possible development of an adverse event during treatment (especially elevated hematocrit or prostate carcinoma) (84) requires rapid discontinuation of testosterone substitution, short-acting preparations may be preferred over long-acting depot preparations in the initial treatment of patients with LOH (Level 4, Grade C). 10.3. Inadequate data are available to determine the optimal serum testosterone level for efficacy and safety. For the present time, mid to lower young adult male serum testosterone levels seem appropriate as the therapeutic goal (85). Sustained supraphysiological levels should be avoided. No evidence exists for or against the need to maintain the physiological circadian rhythm of serum testosterone levels (Level 3, Grade B). 10.4. Obese men are more likely to develop adverse effects (83, 85) (Level 2b, Grade B). 10.5. 17-α-alkylated androgen preparations such as 17α-methyl testosterone are obsolete because of their potential liver toxicity and should no longer be prescribed (Level 2b, Grade A). 10.6. There is not enough evidence to recommend substitution of DHT in aging men; other non-testosterone androgen precursor preparations such as DHEA, DHEA-S, androstenediol, or androstenedione are not recommended (Level 1b, Grade A). 10.7. Human chorionic gonadotropin (hCG) stimulates testosterone production of Leydig cells, albeit at a lower rate in older than in younger men. Since insufficient information exists about the therapeutic and adverse effects of hCG treatment in older men and its higher cost, this treatment cannot be recommended in LOH except when fertility is an issue (Level 1b, Grade B). 10.8. Anti-estrogens and aromatase inhibitors have been shown to increase endogenous testosterone levels (Level 2b, Grade B). Adequate evidence does not exist to recommend their use. Selective androgen receptor modulators are under development, but not yet clinically available. Many of these compounds are non-aromatizable and the risks of long-term use are unclear. 11.1. Testosterone treatment is contraindicated in men with prostate or breast cancer (Level 3, Grade A). Testosterone treatment is relatively contraindicated in men at the high risk of developing prostate cancer. It is unclear whether localized low-grade (Gleason score <7) prostate cancer represents a relative or absolute contraindication for treatment. (See Section 9 for more details; Level 4, Grade, C) (83, Men with significant Level 3, Grade obstructive (Level 3, Grade (Level 3, Grade B) should not be on treatment with testosterone without of the condition (83, can develop during testosterone treatment, in older men treated by testosterone assessment is before treatment, then and 12 months in the of treatment and annually it is not yet what is and/or may be necessary to hematocrit below (12, (Level 3, Grade A). is not a contraindication to testosterone treatment. assessment of co-morbidities possible causes of and potential risks benefits of testosterone treatment is particularly in elderly men (Level 2a, Grade A). 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