Efficacy of bacillus Calmette-Guérin Strains for Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Network Meta-Analysis.

PURPOSE: We sought to determine the efficacy of genetically distinct bacillus Calmette-Guérin strains in preventing disease recurrence in patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We conducted a systematic review and network meta-analysis of trials evaluating bacillus Calmette-Guérin strains against all possible comparators (different bacillus Calmette-Guérin strains, chemotherapy and nonbacillus Calmette-Guérin biological therapies) with intravesical chemotherapy as the common comparator. MEDLINE® (http://www.ncbi.nlm.nih.gov/pubmed) served as the primary data source, with the search from inception to October 2016 for clinical trials involving patients with nonmuscle invasive bladder cancer receiving bacillus Calmette-Guérin. Primary outcome measure was bladder cancer recurrence, defined as recurrent bladder tumor of any grade or stage. Random effect network meta-analysis provided estimates for outcomes and is presented as odds ratios. RESULTS: Across all possible comparators (65 trials, 12,246 patients, 9 strains) there were 2,177 recurrences in 5,642 treated patients (38.6%) and 2,316 recurrences in 5,441 comparators (42.6%). With chemotherapy as the common comparator (28 trials, 5,757 patients, 5 strains) Tokyo-172 (OR 0.39, 95% CI 0.16-0.93), Pasteur (OR 0.49, 95% CI 0.28-0.86) and TICE® (OR 0.61, 95% CI 0.40-0.93) strains were significantly better than chemotherapy at preventing recurrence. No bacillus Calmette-Guérin strain demonstrated significant superiority when compared to any other strain at preventing recurrence in the network meta-analysis. CONCLUSIONS: Bacillus Calmette-Guérin strains exhibited significant differences in efficacy compared to chemotherapy. However, no definitive conclusions could be reached regarding strain superiority, and head-to-head trials are greatly needed to further understand the importance of strain selection in determining bacillus Calmette-Guérin efficacy.

Spleen contributes significantly to increased circulating levels of fibroblast growth factor 23 in response to lipopolysaccharide-induced inflammation.

Background: Circulating levels of fibroblast growth factor 23 (FGF23) increase progressively and correlate with systemic inflammation in chronic kidney disease (CKD). The aim of this study was to identify and characterize the causal relationship between FGF23 and inflammation in CKD. Methods: Circulating FGF23 and inflammatory cytokines were correlated in healthy subjects and patients with varying levels of CKD. In addition, FGF23 expression in blood and solid organs was measured in normal mice that were exposed acutely (one time) or chronically (2-week) to low-dose lipopolysaccharide (LPS); chronic exposure being either sustained (subcutaneous pellets), intermittent (daily injections) or combined sustained plus acute (subcutaneous pellets plus acute injection on the day of sacrifice). Blood was analyzed for both terminal (cFGF23) and intact (iFGF23) FGF23 levels. Solid tissues were investigated with immunohistochemistry, enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction. Results: FGF23 levels correlated significantly with neutrophil gelatinase-associated lipocalin ( r = 0.72, P < 0.001), C-reactive protein ( r = 0.38, P < 0.001), tumor necrosis factor-α ( r = 0.32, P = 0.001) and interleukin-6 ( r = 0.48, P < 0.001). Acute LPS administration increased tissue FGF23 mRNA and plasma levels of cFGF23 but not iFGF23. Neither chronic sustained nor chronic pulsatile LPS increased the tissue or circulating levels of FGF23. However, acute on chronic LPS raised tissue FGF23 mRNA and both circulating cFG23 and iFGF23. Interestingly, the spleen was the major source of FGF23. Conclusion: Acute on chronic exposure to LPS stimulates FGF23 production in a normal mouse model of inflammation. We provide the first evidence that the spleen, under these conditions, contributes substantially to elevated circulating FGF23 levels.

Older Stroke Patients with High Stroke Scores Have Delayed Door-To-Needle Times.

INTRODUCTION: The timely administration of intravenous (IV) tissue plasminogen activator (t-PA) to acute ischemic stroke patients from the period of symptom presentation to treatment, door-to-needle (DTN) time, is an important focus for quality improvement and best clinical practice. METHODS: A retrospective review of our Get With The Guidelines database was performed for a 5-hospital telestroke network for the period between January 2010 and January 2015. All acute ischemic stroke patients who were triaged in the emergency departments connected to the telestroke network and received IV t-PA were included. Optimal DTN time was defined as less than 60 minutes. Logistic regression was performed with clinical variables associated with DTN time. Age and National Institutes of Health Stroke Scale (NIHSS) score were categorized based on clinically significant cutoffs. RESULTS: Six-hundred and fifty-two patients (51% women, 46% White, 45% Hispanic, and 8% Black) were included in this study. The mean age was 70 years (range 29-98). Of the variables analyzed, only arrival mode, initial NIHSS score, and the interaction between age and initial NIHSS score were significant. DTN time more than or equal to 60 minutes was most common in patients aged more than 80 years with NIHSS score higher than 10. CONCLUSIONS: The cause of DTN time delay for older patients with higher NIHSS score is unclear but was not related to presenting blood pressure or arrival mode. Further study of this subgroup is important to reduce overall DTN times.

Random-effects meta-analysis of inconsistent effects: a time for change.

A primary goal of meta-analysis is to improve the estimation of treatment effects by pooling results of similar studies. This article explains how the most widely used method for pooling heterogeneous studies--the Der Simonian-Laird (DL) estimator--can produce biased estimates with falsely high precision. A classic example is presented to show that use of the DL estimator can lead to erroneous conclusions. Particular problems with the DL estimator are discussed, and several alternative methods for summarizing heterogeneous evidence are presented. The authors support replacing universal use of the DL estimator with analyses based on a critical synthesis that recognizes the uncertainty in the evidence,focuses on describing and explaining the probable sources of variation in the evidence, and uses random-effects estimates that provide more accurate confidence limits than the DL estimator.

NOX5 in human spermatozoa: expression, function, and regulation.

Physiological and pathological processes in spermatozoa involve the production of reactive oxygen species (ROS), but the identity of the ROS-producing enzyme system(s) remains a matter of speculation. We provide the first evidence that NOX5 NADPH oxidase is expressed and functions in human spermatozoa. Immunofluorescence microscopy detected NOX5 protein in both the flagella/neck region and the acrosome. Functionally, spermatozoa exposed to calcium ionophore, phorbol ester, or H(2)O(2) exhibited superoxide anion production, which was blocked by addition of superoxide dismutase, a Ca(2+) chelator, or inhibitors of either flavoprotein oxidases (diphenylene iododonium) or NOX enzymes (GKT136901). Consistent with our previous overexpression studies, we found that H(2)O(2)-induced superoxide production by primary sperm cells was mediated by the non-receptor tyrosine kinase c-Abl. Moreover, the H(V)1 proton channel, which was recently implicated in spermatozoa motility, was required for optimal superoxide production by spermatozoa. Immunoprecipitation experiments suggested an interaction among NOX5, c-Abl, and H(V)1. H(2)O(2) treatment increased the proportion of motile sperm in a NOX5-dependent manner. Statistical analyses showed a pH-dependent correlation between superoxide production and enhanced sperm motility. Collectively, our findings show that NOX5 is a major source of ROS in human spermatozoa and indicate a role for NOX5-dependent ROS generation in human spermatozoa motility.

Construct Validation of the Self-Efficacy Teaching and Knowledge Instrument for Science Teachers-Revised (SETAKIST-R): Lessons Learned.

Described herein is the academic lineage and independent validation of the Self-Efficacy Teaching and Knowledge Instrument for Science Teachers-Revised (SETAKIST-R). Data from 334 K-12 science teachers were analyzed using Partial Credit Rasch models. Principal components analysis on the person-item residuals suggest two latent dimensions: Knowledge and Teaching Self-Efficacies. Item-fit statistics were used to select items for each subscale. Person and item separation (reliability) indices were quite low, and we noted disordered response patterns on the person-item maps that revealed problems with item content and/or scaling for both subscales. These issues include the presence of: verbal negatives, ambiguous modifiers, counter-intuitive scaling, and an "undecided/uncertain" option. The SETAKIST-R, in its current form, cannot be recommended as a measure of science teacher self-efficacy.

Metabolic responses to early and high protein supplementation in a randomized trial evaluating the prevention of hyperkalemia in extremely low birth weight infants.

OBJECTIVE: To determine whether early and higher intravenous amino acid (EHAA) supplementation decreases hyperkalemia in extremely low birth weight (ELBW) infants (<1000 g). STUDY DESIGN: Infants were enrolled at birth in a randomized, double-masked, prospective fashion and treated for 7 days. The standard group (SAA) infants received intravenous amino acid (AA) starting at 0.5 g x kg(-1) x d(-1) and increased by 0.5 g x kg(-1) every day to a maximum of 3 g x kg(-1) x d(-1). EHAA group infants received 2 g x kg(-1) x d(-1) of AA soon after birth and advanced by 1 g x kg(-1) every day to 4 g x kg(-1) x d(-1). Data analysis was by SPSS 11.5, with statistical significance at alpha = 0.05 and 90% power to determine a difference in mean K(+) level of 2. RESULTS: Sixty-two patients, mean gestational age of 26.0 +/- 2.0 weeks and birth weight of 775 +/- 136 g, were enrolled. Hyperkalemia (K(+) > or =6.5 mEq/L) occurred in 13% of the studied population; no difference in incidence of hyperkalemia was found between the SAA and EHAA groups (16% vs 10%, respectively, P = .70). Serum blood urea nitrogen was higher in the EHAA group. AA infusion was stopped early in 6 patients for high blood urea nitrogen or elevated ammonia level. CONCLUSIONS: During the study period, hyperkalemia decreased significantly and was not affected by EHAA supplementation in the first week of life.

Systematic review of the chronic care model in chronic obstructive pulmonary disease prevention and management.

BACKGROUND: Implementation of the chronic care model (CCM) has been shown to be an effective preventative strategy to improve outcomes in diabetes mellitus, depression, and congestive heart failure, but data are lacking regarding the effectiveness of this model in preventing complications in patients with chronic obstructive pulmonary disease. METHODS: We searched the MEDLINE, CINAHL, and Cochrane databases from inception to August 2005 and included English-language articles that enrolled adults with chronic obstructive pulmonary disease and (1) contained intervention(s) with CCM component(s), (2) included a comparison group or measures at 2 points (before/after), and (3) had relevant outcomes. Two reviewers independently extracted data. RESULTS: Symptoms, quality of life, lung function, and functional status were not significantly different between the intervention and control groups. However, pooled relative risks (95% confidence intervals) for emergency/unscheduled visits and hospitalizations for the group that received at least 2 CCM components were 0.58 (0.42-0.79) and 0.78 (0.66-0.94), respectively. The weighted mean difference (95% confidence interval) for hospital stay was -2.51 (-3.40 to -1.61) days shorter for the group that received 2 or more components. There were no significant differences for those receiving only 1 CCM component. CONCLUSIONS: Limited published data exist evaluating the efficacy of CCM components in chronic obstructive pulmonary disease management. However, pooled data demonstrated that patients with chronic obstructive pulmonary disease who received interventions with 2 or more CCM components had lower rates of hospitalizations and emergency/unscheduled visits and a shorter length of stay compared with control groups. The results of this review highlight the need for well-designed trials in this population.

Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor.

Transforming growth factor-beta (TGF-beta) signaling has been shown to promote invasion and metastasis in various models of human cancers. In this study, we investigated the efficacy of a TGF-beta type I receptor kinase inhibitor (TbetaRI-I) to limit early systemic metastases in an orthotopic xenograft model of lung metastasis and in an intracardiac injection model of experimental bone and lung metastasis using human breast carcinoma MDA-MB-435-F-L cells, a highly metastatic variant of human breast cancer MDA-MB-435 cells, expressing the enhanced green fluorescent protein (EGFP). Treatment of the cells with the TbetaRI-I had no effect on their growth but blocked TGF-beta-stimulated expression of integrin alpha(v)beta(3) and cell migration in vitro. Systemic administration of the TbetaRI-I via i.p. injection effectively reduced the number and size of the lung metastasis in both orthotopic xenograft and experimental metastasis models with no effects on primary tumor growth rate compared with controls. TbetaRI-I treatment also reduced the incidence of widespread early skeletal metastases in the femur, tibia, mandible, and spine detected by whole-body EGFP fluorescence imaging. Tumor burden in femora and tibiae was also reduced after TbetaRI-I treatment as detected by histomorphometry analysis compared with the placebo controls. Our results indicate for the first time that abrogation of TGF-beta signaling by systemic administration of the TbetaRI-I can inhibit both early lung and bone metastasis in animal model systems and suggest antimetastatic therapeutic potential of the TbetaRI-I.