Consistent estimation of the fixed effects ordered logit model

The paper considers panel data methods for estimating ordered logit models with individual-specific correlated unobserved heterogeneity. We show that a popular approach is inconsistent, whereas some consistent and efficient estimators are available, including minimum distance and generalized method-of-moment estimators. A Monte Carlo study reveals the good properties of an alternative estimator that has not been considered in econometric applications before, is simple to implement and almost as efficient. An illustrative application based on data from the German Socio-Economic Panel confirms the large negative effect of unemployment on life satisfaction that has been found in the previous literature.

Identification and estimation of thresholds in the fixed effects ordered logit model

This paper proposes a new estimator for the fixed effects ordered logit model. In contrast to existing methods, the new procedure allows estimating the thresholds. The empirical relevance and simplicity of implementation is illustrated in an application on the effect of unemployment on life satisfaction.

Efficacy of experimental treatments compared with standard treatments in non-inferiority trials: a meta-analysis of randomized controlled trials

Background There is concern that non-inferiority trials might be deliberately designed to conceal that a new treatment is less effective than a standard treatment. In order to test this hypothesis we performed a meta-analysis of non-inferiority trials to assess the average effect of experimental treatments compared with standard treatments. Methods One hundred and seventy non-inferiority treatment trials published in 121 core clinical journals were included. The trials were identified through a search of PubMed (1991 to 20 February 2009). Combined relative risk (RR) from meta-analysis comparing experimental with standard treatments was the main outcome measure. Results The 170 trials contributed a total of 175 independent comparisons of experimental with standard treatments. The combined RR for all 175 comparisons was 0.994 [95% confidence interval (CI) 0.978–1.010] using a random-effects model and 1.002 (95% CI 0.996–1.008) using a fixed-effects model. Of the 175 comparisons, experimental treatment was considered to be non-inferior in 130 (74%). The combined RR for these 130 comparisons was 0.995 (95% CI 0.983–1.006) and the point estimate favoured the experimental treatment in 58% (n = 76) and standard treatment in 42% (n = 54). The median non-inferiority margin (RR) pre-specified by trialists was 1.31 [inter-quartile range (IQR) 1.18–1.59]. Conclusion In this meta-analysis of non-inferiority trials the average RR comparing experimental with standard treatments was close to 1. The experimental treatments that gain a verdict of non-inferiority in published trials do not appear to be systematically less effective than the standard treatments. Importantly, publication bias and bias in the design and reporting of the studies cannot be ruled out and may have skewed the study results in favour of the experimental treatments. Further studies are required to examine the importance of such bias.

Does land-based exercise reduce pain and disability associated with hip osteoarthritis? A meta-analysis of randomized controlled trials

Objective To determine if clinical guidelines recommending therapeutic exercise for people with hip osteoarthritis (OA) are supported by rigorous scientific evidence. Methods A meta-analysis of randomized controlled trials (RCTs) recruiting people with hip OA and comparing some form of land-based exercise program (as opposed to exercises conducted in the water) with a non-exercise group in terms of hip pain and/or self-reported physical function. Results Thirty-two RCTs were identified, but only five met the inclusion criteria. Only one of the five included RCTs restricted recruitment to people with hip OA, the other four RCTs also recruiting participants with knee OA. The five included studies provided data on 204 and 187 hip OA participants for pain and physical function, respectively. Combining the results of the five included RCTs using a fixed-effects model demonstrated a small treatment effect for pain (standardized mean difference (SMD) −0.38; 95% confidence interval (CI) −0.67 to −0.09). No significant benefit in terms of improved self-reported physical function was detected (SMD −0.02; 95% CI −0.31 to 0.28). Conclusion Currently there is only silver level evidence (one small RCT) supporting the benefit of land-based therapeutic exercise for people with symptomatic hip OA in terms of reduced pain and improved physical function. The limited number and small sample size of the included RCTs restricts the confidence that can be attributed to these results.

Are mutans streptococci detected in preschool children a reliable predictive factor for dental caries risk? A systematic review

Research suggests that mutans streptococci play an important role in cariogenesis in children but the usefulness of bacterial testing in risk assessment is unknown. Our objective was to summarize the literature assessing the association of mutans streptococci and dental caries in preschool children, (Pre)Medline (1966-2003), Embase (1980-2003), the Cochrane Register of Controlled Trials (2003, issue 3), and reference lists of included studies were searched. All abstracts found by the electronic searches (n = 981) were independently scrutinized by 2 reviewers. Minimal requirements for inclusion were assessment of preschool children without caries at baseline, reporting of mutans streptococci present in saliva or plaque at baseline and assessment of caries presence after a minimum of 6 months of follow-up. Participants' details, test methods, methodological characteristics and findings were extracted by one reviewer and cross-checked by another. Homogeneity was tested using chi2 tests. Results of plaque and saliva testing were pooled separately using a fixed effects model. Methodological quality of reports was low. Out of 9 studies included, data from 3 reports on plaque test assessment alone (n = 300) and from 4 reports on saliva test assessment alone (n = 451) were available for pooled analysis. The pooled risk ratio (95% CI) was 3.85 (2.48-5.96) in studies using plaque tests and 2.11 (1.47-3.02) in those using saliva testing. Presence of mutans streptococci, both in plaque or saliva of young caries-free children, appears to be associated with a considerable increase in caries risk. Lack of adjustment for potential confounders in the original studies, however, limits the extent to which interpretations for practice can be made.

Erythropoietin or Darbepoetin for patients with cancer--meta-analysis based on individual patient data

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality. OBJECTIVES: Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efficacy outcomes in cancer patients. SEARCH STRATEGY: We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials. SELECTION CRITERIA: We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy. DATA COLLECTION AND ANALYSIS: We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment. Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis. Analyses were according to the intention-to-treat principle. Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specified subgroups. The present review reports only the results for the primary endpoint. MAIN RESULTS: A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall. ESAs increased on study mortality (combined hazard ratio [cHR] 1.17; 95% CI 1.06-1.30) and worsened overall survival (cHR 1.06; 95% CI 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 and I(2) 7.1%, p=0.33, respectively). Thirty-eight trials enrolled 10441 patients receiving chemotherapy. The cHR for on study mortality was 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction=0.42). AUTHORS' CONCLUSIONS: ESA treatment in cancer patients increased on study mortality and worsened overall survival. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded.

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

BACKGROUND: Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS: Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS: Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION: Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING: German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

Do individual directors matter?

Paper 1: Pilot study of Swiss firms Abstract Using a fixed effects approach, we investigate whether the presence of specific individuals on Swiss firms’ boards affects firm performance and the policy choices they make. We find evidence for a substantial impact of these directors’ presence on their firms. Moreover, the director effects are correlated across policies and performance measures but uncorrelated to the directors’ background. We find these results interesting but conclude that they should to be substantiated on a dataset that is larger and better understood by researchers. Also, further tests are required to rule out methodological concerns. Paper 2: Evidence from the S&P 1,500 Abstract We ask whether directors on corporate boards contribute to firm performance as individuals. From the universe of the S&P 1,500 firms since 1996 we track 2,062 directors who serve on multiple boards over extended periods of time. Our initial findings suggest that the presence of these directors is associated with substantial performance shifts (director fixed effects). Closer examination shows that these effects are statistical artifacts and we conclude that directors are largely fungible. Moreover, we contribute to the discussion of the fixed effects method. In particular, we highlight that the selection of the randomization method is pivotal when generating placebo benchmarks. Paper 3: Robustness, statistical power, and important directors Abstract This article provides a better understanding of Senn’s (2014) findings: The outcome that individual directors are unrelated to firm performance proves robust against different estimation models and testing strategies. By looking at CEOs, the statistical power of the placebo benchmarking test is evaluated. We find that only the stronger tests are able to detect CEO fixed effects. However, these tests are not suitable to analyze directors. The suitable tests would detect director effects if the inter quartile range of the true effects amounted to 3 percentage points ROA. As Senn (2014) finds no such effects for outside directors in general, we focus on groups of particularly important directors (e.g., COBs, non-busy directors, successful directors). Overall, our evidence suggests that the members of these groups are not individually associated with firm performance either. Thus, we confirm that individual directors are largely fungible. If the individual has an effect on performance, it is of small magnitude.

A new model of interactive effects of alcohol and high-fat diet on hepatic fibrosis

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are the most frequent conditions leading to elevated liver enzymes and liver cirrhosis, respectively, in the Western world. However, despite strong epidemiological evidence for combined effects on the progression of liver injury, the mutual interaction of the pathophysiological mechanisms is incompletely understood. The aim of this study was to establish and analyze an experimental murine model, where we combined chronic alcohol administration with a NASH-inducing high-fat (HF) diet.

Comparison of the effects of bimatoprost and a fixed combination of latanoprost and timolol on circadian intraocular pressure

OBJECTIVE: To compare the effect of bimatoprost and the fixed combination of latanoprost and timolol (LTFC) on 24-hour mean intraocular pressure (IOP) after patients are switched from a nonfixed combination of latanoprost and timolol. DESIGN: Randomized, double-masked, multicenter clinical trial. PARTICIPANTS: Two hundred patients with glaucoma or ocular hypertension. METHODS: Included were patients who were controlled (IOP < 21 mmHg) on the nonfixed combination of latanoprost and timolol for at least 3 months before the baseline visit or patients on monotherapy with either latanoprost or timolol who were eligible for dual therapy not being fully controlled on monotherapy. The latter group of patients underwent a 6-week wash-in phase with the nonfixed combination of latanoprost and timolol before baseline IOP determination and study inclusion. Supine and sitting position IOPs were recorded at 8 pm, midnight, 5 am, 8 am, noon, and 4 pm at baseline, week 6, and week 12 visits. MAIN OUTCOME MEASURE: An analysis of covariance model was used for a noninferiority test of the primary efficacy variable, with mean area under the 24-hour IOP curve after 12 weeks of treatment as response variable and treatment, center, and baseline IOP as factors. A secondary analysis was performed on the within-treatment change from baseline. RESULTS: Mean baseline IOPs were 16.3+/-3.3 mmHg and 15.5+/-2.9.mmHg in the bimatoprost and LTFC groups, respectively. At week 12, mean IOPs were 16.1+/-2.5 mmHg for the bimatoprost group and 16.3+/-3.7 mmHg for the LTFC group, and no significant difference between the 2 treatment groups could be found. As compared with baseline, mean IOP increased by 0.3+/-3.6 mmHg during the day and decreased by 0.8+/-3.8 mmHg during the night in the bimatoprost group, whereas there were increases of 1.43+/-2.6 mmHg and 0.14+/-3.2 mmHg in the LTFC group, respectively. CONCLUSIONS: Bimatoprost is not inferior to the LTFC in maintaining IOP at a controlled level during a 24-hour period in patients switched from the nonfixed combination of latanoprost and timolol.

Interactive effects of mycorrhizae and a root hemiparasite on plant community productivity and diversity

Plant communities can be affected both by arbuscular mycorrhizal fungi (AMF) and hemiparasitic plants. However, little is known about the interactive effects of these two biotic factors on the productivity and diversity of plant communities. To address this question, we set up a greenhouse study in which different AMF inocula and a hemiparasitic plant (Rhinanthus minor) were added to experimental grassland communities in a fully factorial design. In addition, single plants of each species in the grassland community were grown with the same treatments to distinguish direct AMF effects from indirect effects via plant competition. We found that AMF changed plant community structure by influencing the plant species differently. At the community level, AMF decreased the productivity by 15-24%, depending on the particular AMF treatment, mainly because two dominant species, Holcus lanatus and Plantago lanceolata, showed a negative mycorrhizal dependency. Concomitantly, plant diversity increased due to AMF inoculation and was highest in the treatment with a combination of two commercial AM strains. AMF had a positive effect on growth of the hemiparasite, and thereby induced a negative impact of the hemiparasite on host plant biomass which was not found in non-inoculated communities. However, the hemiparasite did not increase plant diversity. Our results highlight the importance of interactions with soil microbes for plant community structure and that these indirect effects can vary among AMF treatments. We conclude that mutualistic interactions with AMF, but not antagonistic interactions with a root hemiparasite, promote plant diversity in this grassland community.

Disabling c-Myc in childhood medulloblastoma and atypical teratoid/rhabdoid tumor cells by the potent G-quadruplex interactive agent S2T1-6OTD

We investigated here the effects of S2T1-6OTD, a novel telomestatin derivative that is synthesized to target G-quadruplex-forming DNA sequences, on a representative panel of human medulloblastoma (MB) and atypical teratoid/rhabdoid (AT/RT) childhood brain cancer cell lines. S2T1-6OTD proved to be a potent c-Myc inhibitor through its high-affinity physical interaction with the G-quadruplex structure in the c-Myc promoter. Treatment with S2T1-6OTD reduced the mRNA and protein expressions of c-Myc and hTERT, which is transcriptionally regulated by c-Myc, and decreased the activities of both genes. In remarkable contrast to control cells, short-term (72-hour) treatment with S2T1-6OTD resulted in a dose- and time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC(50), 0.25-0.39 micromol/L). Under conditions where inhibition of both proliferation and c-Myc activity was observed, S2T1-6OTD treatment decreased the protein expression of the cell cycle activator cyclin-dependent kinase 2 and induced cell cycle arrest. Long-term treatment (5 weeks) with nontoxic concentrations of S2T1-6OTD resulted in a time-dependent (mainly c-Myc-dependent) telomere shortening. This was accompanied by cell growth arrest starting on day 28 followed by cell senescence and induction of apoptosis on day 35 in all of the five cell lines investigated. On in vivo animal testing, S2T1-6OTD may well represent a novel therapeutic strategy for childhood brain tumors.

In vitro effects of arylimidamides against Besnoitia besnoiti infection in Vero cells

The in vitro effects of 4 arylimidamides (DB811, DB786, DB750 and DB766) against the proliferative tachyzoite stage of the apicomplexan parasite Besnoitia besnoiti were investigated. These four compounds had been shown earlier to exhibit in vitro activities in the nanomolar range against the related apicomplexans Neospora caninum and Toxoplasma gondii. Real-time-PCR was used to assess B. besnoiti intracellular proliferation in vitro. Preliminary assessment by light microscopy identified DB811 and DB750 as the most promising compounds, while DB786 and DB766 were much less effective. Three-day-growth assays and quantitative real-time PCR was used for IC50 determination of DB811 (0.079 muM) and DB750 (0.56 muM). Complete growth inhibition was observed at 1.6 muM for DB 811 and 1.7 muM for DB750. However, when infected cultures were treated for 14 days, proliferation of parasites occurred again in cultures treated with DB750 from day 4 onwards, while the proliferation of DB811-treated tachyzoites remained inhibited. Electron microscopy of B. besnoiti-infected fibroblast cultures fixed and processed at different time-points following the initiation of drug treatments revealed that DB811 exerted a much higher degree of ultrastructural alterations compared to DB750. These results show that arylimidamides such as DB811 could potentially become an important addition to the anti-parasitic arsenal for food animal production, especially in cattle.