Sample Size Determination and Power Ryan, Thomas P., Jr; Ryan, Thomas P
Wiley series in probability and statistics,
2013, 2013-06-10, 2013-05-28
eBook
Odprti dostop
A comprehensive approach to sample size determination and power with applications for a variety of fields Sample Size Determination and Power features a modern introduction to the applicability of ...sample size determination and provides a variety of discussions on broad topics including epidemiology, microarrays, survival analysis and reliability, design of experiments, regression, and confidence intervals. The book distinctively merges applications from numerous fields such as statistics, biostatistics, the health sciences, and engineering in order to provide a complete introduction to the general statistical use of sample size determination. Advanced topics including multivariate analysis, clinical trials, and quality improvement are addressed, and in addition, the book provides considerable guidance on available software for sample size determination. Written by a well-known author who has extensively class-tested the material, Sample Size Determination and Power: * Highlights the applicability of sample size determination and provides extensive literature coverage * Presents a modern, general approach to relevant software to guide sample size determination including CATD (computer-aided trial design) * Addresses the use of sample size determination in grant proposals and provides up-to-date references for grant investigators An appealing reference book for scientific researchers in a variety of fields, such as statistics, biostatistics, the health sciences, mathematics, ecology, and geology, who use sampling and estimation methods in their work, Sample Size Determination and Power is also an ideal supplementary text for upper- level undergraduate and graduate-level courses in statistical sampling.
Praise for the Second Edition'As a comprehensive statistics reference book for quality improvement, it certainly is one of the best books available.' —TechnometricsThis new edition continues to ...provide the most current, proven statistical methods for quality control and quality improvementThe use of quantitative methods offers numerous benefits in the fields of industry and business, both through identifying existing trouble spots and alerting management and technical personnel to potential problems. Statistical Methods for Quality Improvement, Third Editionguides readers through a broad range of tools and techniques that make it possible to quickly identify and resolve both current and potential trouble spots within almost any manufacturing or nonmanufacturing process. The book provides detailed coverage of the application of control charts, while also exploring critical topics such as regression, design of experiments, and Taguchi methods.In this new edition, the author continues to explain how to combine the many statistical methods explored in the book in order to optimize quality control and improvement. The book has been thoroughly revised and updated to reflect the latest research and practices in statistical methods and quality control, and new features include:Updated coverage of control charts, with newly added toolsThe latest research on the monitoring of linear profiles and other types of profilesSections on generalized likelihood ratio charts and the effects of parameter estimation on the properties of CUSUM and EWMA proceduresNew discussions on design of experiments that include conditional effects and fraction of design space plotsNew material on Lean Six Sigma and Six Sigma programs and trainingIncorporating the latest software applications, the author has added coverage on how to use Minitab software to obtain probability limits for attribute charts. new exercises have been added throughout the book, allowing readers to put the latest statistical methods into practice. Updated references are also provided, shedding light on the current literature and providing resources for further study of the topic.Statistical Methods for Quality Improvement, Third Editionis an excellent book for courses on quality control and design of experiments at the upper-undergraduate and graduate levels. the book also serves as a valuable reference for practicing statisticians, engineers, and physical scientists interested in statistical quality improvement.
To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid ...tumors.
The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin.
There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies.
rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.
Abstract
Background
Empirical models to predict β-lactam pharmacokinetics (PK) using information from routine aminoglycoside therapeutic drug monitoring (TDM) have been proposed for critically ill ...patients; however, no such models exist for patients with cystic fibrosis (CF).
Objectives
To investigate whether PK parameters of tobramycin could be used to predict those of piperacillin.
Methods
A non-interventional, open-label PK study was conducted in hospitalized adults treated with piperacillin/tazobactam and tobramycin for acute pulmonary exacerbations of CF. Six serum samples per patient were collected and analysed. One- and two-compartment population PK models with linear, Michaelis–Menten or mixed elimination were evaluated for both drugs within the PmetricsTM package for R. Models were developed and compared iteratively using the log-likelihood and Akaike information criterion (AIC) objective functions.
Results
Nine primarily female (n = 8) and Caucasian (100%) adult CF patients were enrolled. The median (IQR) age, height, weight and serum creatinine of included patients was 31 (27–32) years, 51.4 (49.9–55.8) kg, 162.6 (160.0–165.1) cm and 0.6 (0.5–0.6) mg/dL, respectively. The final model with the lowest objective function values consisted of one compartment with first-order elimination for tobramycin and two compartments with mixed-order elimination for piperacillin with the elimination rate constant of piperacillin modelled as a linear function of the elimination rate constant of tobramycin.
Conclusions
A relationship was identified between the elimination rate constants of tobramycin and piperacillin. Validation of this relationship in larger studies of adult patients with CF is needed before application to the precision dosing of piperacillin/tazobactam in this patient population.
High-throughput screening for inhibitors of the human metalloprotease, methionine aminopeptidase-2 (MetAP2), identified a potent class of 3-anilino-5-benzylthio-1,2,4-triazole compounds. Efficient ...array and interative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazole moeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of several inhibitors with potencies in the 50−100 picomolar range. The deleterious effects on inhibitor potency by methylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound in the active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobalt atoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR within the triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in the SAR studies led to the identification of potent inhibitors (103 and 104) of endothelial cell proliferation. Triazoles 103 and 104 also exhibited dose-dependent activity in an aortic ring tissue model of angiogenesis highlighting the potential utility of MetAP2 inhibitors as anticancer agents.
Purpose: STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models.
A phase I clinical trial was undertaken to determine the maximum ...tolerated dose, toxicity profile, and pharmacokinetics of
STA-4783 in combination with paclitaxel.
Experimental Design: Adults with refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses
of 44 and 135 mg/m 2 , respectively. After increasing paclitaxel to 175 mg/m 2 , the STA-4783 dose was escalated as permitted by dose-limiting toxicity during the first 21-day cycle.
Results: Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving 175 mg/m 2 paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m 2 , and 438 mg/m 2 was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia
being dose limiting. Partial responses were achieved in one patient with Kaposi's sarcoma and another with ovarian cancer
that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid
elimination from plasma (biological half-life, 1.06 ± 0.24 h) and a low steady-state apparent volume of distribution (25.1
± 8.1 L/m 2 ). The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose.
Conclusions: The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced
systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity.
Objective responses in two heavily pretreated patients, both with taxane exposure, have encouraged further clinical evaluation
of this regimen.
The objective of our study was to determine the mechanism of action of the short-chain ceramide analog, C6-ceramide, and the breast cancer drug, tamoxifen, which we show coactively depress viability ...and induce apoptosis in human acute myelogenous leukemia cells. Exposure to the C6-ceramide-tamoxifen combination elicited decreases in mitochondrial membrane potential and complex I respiration, increases in reactive oxygen species (ROS), and release of mitochondrial proapoptotic proteins. Decreases in ATP levels, reduced glycolytic capacity, and reduced expression of inhibitors of apoptosis proteins also resulted. Cytotoxicity of the drug combination was mitigated by exposure to antioxidant. Cells metabolized C6-ceramide by glycosylation and hydrolysis, the latter leading to increases in long-chain ceramides. Tamoxifen potently blocked glycosylation of C6-ceramide and long-chain ceramides. N-desmethyltamoxifen, a poor antiestrogen and the major tamoxifen metabolite in humans, was also effective with C6-ceramide, indicating that traditional antiestrogen pathways are not involved in cellular responses. We conclude that cell death is driven by mitochondrial targeting and ROS generation and that tamoxifen enhances the ceramide effect by blocking its metabolism. As depletion of ATP and targeting the "Warburg effect" represent dynamic metabolic insult, this ceramide-containing combination may be of utility in the treatment of leukemia and other cancers.
Background:
Mental health impairments have been shown to negatively affect preoperative self-reported function in patients with various musculoskeletal disorders, including those with ...femoroacetabular impingement.
Hypothesis:
Those with symptoms of depression will have lower self-reported function, more pain, and less satisfaction on initial assessment and at 2-year follow-up than those without symptoms of depression.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
Patients who were enrolled in a multicenter hip arthroscopic surgery registry and had 2-year outcome data available were included in the study. Patients completed the 12-item International Hip Outcome Tool (iHOT-12), visual analog scale (VAS) for pain, and 12-item Short-Form Health Survey (SF-12) when consenting for surgery. At 2-year follow-up, patients were emailed the iHOT, the VAS, and a rating scale of surgical satisfaction. Initial SF-12 mental component summary (MCS) scores <46.5 and ≤36 were used to qualify symptoms of depression and severe depression, respectively, as previously described and validated. Repeated-measures analysis of variance was performed to compare preoperative and 2-year postoperative iHOT-12, VAS, and satisfaction scores between those with and without symptoms of depression.
Results:
A total of 781 patients achieved the approximate 2-year milestone (mean follow-up, 735 ± 68 days), with 651 (83%) having 2-year outcome data available. There were 434 (67%) female and 217 (33%) male patients, with a mean age of 35.8 ± 13.0 years and a mean body mass index of 25.4 ± 8.8 kg/m2. The most common procedures were femoroplasty (83%), followed by synovectomy (80%), labral repair (76%), acetabuloplasty (58%), acetabular chondroplasty (56%), femoral chondroplasty (23%), and labral reconstruction (19%). The mean initial SF-12 MCS score was 51.5 ± 10.3, with cutoff scores indicating symptoms of depression and severe depression in 181 (28%) and 71 (11%) patients, respectively. Patients with symptoms of depression scored significantly (P < .05) lower on the initial iHOT-12 and VAS and 2-year follow-up iHOT-12, VAS, and rating scale of surgical satisfaction.
Conclusion:
A large number of patients who underwent hip arthroscopic surgery presented with symptoms of depression, which negatively affected self-reported function, pain levels, and satisfaction on initial assessment and at 2-year follow-up. Surgeons who perform hip arthroscopic surgery may need to identify the symptoms of depression and be aware of the impact that depression can have on surgical outcomes.
Herein, we characterize transcription factor NF-κB from the demosponge Amphimedon queenslandica (Aq). Aq–NF–κB is most similar to NF-κB p100/p105 among vertebrate proteins, with an N-terminal ...DNA-binding domain, a C-terminal Ankyrin (ANK) repeat domain, and a DNA binding-site profile akin to human NF-κB proteins. Like mammalian NF-κB p100, C-terminal truncation allows nuclear translocation of Aq–NF–κB and increases its transcriptional activation activity. Expression of IκB kinases (IKKs) induces proteasome-dependent C-terminal processing of Aq–NF–κB in human cells, and processing requires C-terminal serines in Aq–NF–κB. Unlike NF-κB p100, C-terminal sequences of Aq–NF–κB do not inhibit its DNA-binding activity. Tissue of a black encrusting demosponge contains NF-κB site DNA-binding activity, as well as nuclear and processed NF-κB. Treatment of sponge tissue with LPS increases both DNA-binding activity and processing of NF-κB. A. queenslandica transcriptomes contain homologs to upstream NF-κB pathway components. This is first functional characterization of NF-κB in sponge, the most basal multicellular animal.
•Proteins in the immunity transcription factor NF-κB pathway are present in sponge.•Activities and regulation of sponge NF-κB proteins are characterized.•LPS treatment of sponge tissue activates NF-κB processing and DNA binding.•NF-κB likely has a role in immunity in sponges, the most basal multicellular animals.
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