Modelling of submerged gas injecting lance design parameters

Submerged gas injecting bottom lance design parameters are modelled by applying the theory of compressible flow of gas under irreversible-adiabatic conditions. Using the criterion of onsetting the jetting mode of injection of gas into liquid the lance design paramters such as upstream stagnation pressure and Mach number, length of the lance for a given diameter and material, gas injection rate etc. are determined. Nomograms are presented to determine the above mentioned lance design parameters. The derived parameters are discussed in relation to submerged gas injection practice.     

The design and implementation of trials of host modulation agents

Over the last two decades it has become more evident that although oral microorganisms are essential agents of periodontal pathogenesis, interpatient variability in the host response is a major determinant of the expression of periodontal disease extent and severity. Data from animal models and human studies have identified many of the components of the host inflammatory response which serve as critical mediators of clinical inflammation, attachment loss, and bone resorption. Studies suggest that certain pharmacologic agents, which act at a molecular level to block specific inflammatory mediators, appear to attenuate disease progression. These promising findings herald a new era in periodontal medicine. Anti-infective therapies may soon be supplemented with anti-inflammatory pharmacological agents. However, there are many unanswered issues regarding formulation design, clinical application, potential indication claims, and clinical study design. Furthermore, current considerations of fundamental mechanisms of pathogenesis, as well as new data from epidemiologic studies emphasizing the multifactorial nature of disease, are changing the underlying assumptions which have served to guide our design of anti-infective drug trials over the last two decades. There are new questions regarding appropriate outcome measurements which are to be reconsidered. For example, the measurement of a change in periodontal disease status, either during progression or in response to therapy, is fundamentally unidimensional and may be only mildly informative when one considers that the disease is multifactorial by nature. Using an example from intensive care medicine, pathophysiologic studies of septic shock have demonstrated that the microbial dose and the host inflammatory mediator response are far better predictors of patient morbidity and mortality than any combination of clinical signs associated with clinical shock. Clinical trials of anti-cytokine and anti-inflammatory drugs to treat shock are now designed and conducted taking strategic advantage of this knowledge by including measurements of microbial dose and host response. It appears prudent that the design and implementation of clinical trials of host modulation agents also benefit from our current insights into pathogenesis and not represent a template-driven adaptation of historical, anti-infective clinical trial protocols.     

Statistical power and optimal design for multisite randomized trials.

The multisite trial, widely used in mental health research and education, enables experimenters to assess the average impact of a treatment across sites, the variance of treatment impact across sites, and the moderating effect of site characteristics on treatment efficacy. Key design decisions include the sample size per site and the number of sites. To consider power implications, this article proposes a standardized hierarchical linear model and uses rules of thumb similar to those proposed by J. Cohen (1988) for small, medium, and large effect sizes and for small, medium, and large treatment-by-site variance. Optimal allocation of resources within and between sites as a function of variance components and costs at each level are also considered. The approach generalizes to quasiexperiments with a similar structure. These ideas are illustrated with newly developed software. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Statistical analysis and optimal design for cluster randomized trials.

In many intervention studies, therapy outcome evaluations, and educational field trials, random treatment assignment of clusters rather than persons is desirable for political feasibility, logistics, or ecological validity. However, cluster randomized designs are widely regarded as lacking statistical precision. This article considers when and to what extent using a pretreatment covariate can increase experimental precision. To answer this question, the author first optimizes allocation of resources within and between clusters for the no-covariate case. Optimal sample sizes at each level depend on variation within and between clusters and on the cost of sampling at each level. Next, the author considers optimal allocation when a covariate is added. In this case, the explanatory power of the covariate at each level becomes highly relevant for choosing optimal sample sizes. A key conclusion is that statistical analysis that fully uses information about the covariate-outcome relationship can substantially increase the efficiency of the cluster randomized trial, especially when the cost of sampling clusters is high and the covariate accounts for substantial variation between clusters. Recent multilevel studies indicate that these conditions are common. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Guidelines for the design and conduct of clinical trials on dentine hypersensitivity

Clinical trials on dentine hypersensitivity have been numerous and protocols varied. To date there is little consensus as to the conduct of studies on this poorly-understood yet common and painful dental condition. A committee of interested persons from academia and industry was convened to discuss the subject of clinical trials on dentine hypersensitivity and a consensus report is presented. A double-blind randomized parallel groups design is recommended, although cross-over designs may be used for the preliminary screening of agents. Subjects may have multiple sites scored. Sample size will be determined by estimating the variability in the study population, the effect to be detected and the power of the statistical test to be used. Subject selection is based on a clinical diagnosis of dentine hypersensitivity, excluding those with conflicting characteristics such as currently-active medical or dental therapy. The vestibular surfaces of incisors, cuspids and bicuspids are preferred as sites to be tested. A range of sensitivity levels should be included. Tactile, cold and evaporative air stimuli should be applied. Negative and benchmark controls should be incorporated. Most trials should last 8 weeks. Sensitivity may be assessed either in terms of the stimulus intensity required to evoke pain or the subjective evaluation of pain produced by a stimulus using a visual analog or other appropriate scale. The subject's overall assessment may be determined by questionnaire. Outcomes should be expressed in terms of clinically significant changes in symptoms. Follow-up evaluation is required to determine the persistence of changes. At least 2 independent trials should be conducted before a product receives approval.     

Research design for patient selection in clinical trials phase II

Phase II trials play a key role in the development of a treatment, because they are crucial in deciding whether or not to proceed to phase III. In the event of the evaluation of a new treatment given to only one group of subjects, multi-stage designs were developed to include subjects in phase II trials. Gehan's two stage designs stop inclusion of subjects if no success is observed among the first n1 subjects. They are easy to use, but have the disadvantage of exposing many subjects to an inefficient treatment at the second stage. Fleming's multi-stage designs and Simon's two stage designs permit the early termination of a trial when the intermediate results are extreme, either in favor of the efficiency or in favor of the inefficiency of the treatment. Simon's plans minimize either the average or the maximum number of subjects exposed to ineffective treatment. Ensign's three stage designs combine the first stage of Gehan with the two stages of Simon. These plans are interesting because they can reject a treatment quickly after a long run of failures which minimizes the average number of subjects exposed to an ineffective treatment.     

Optimal two-stage design for a series of pilot trials of new agents

An approach to determine the appropriate sample sizes for a series of screening trials to identify promising new therapeutic agents was presented by Yao, Begg, and Livingston (1996, Biometrics 52, 992-1001). This approach is now improved to a two-stage design that further minimizes the time to identify a promising agent under fixed error rates. When applied to data from the historical experience of exploratory vaccination trials at Memorial Sloan-Kettering Cancer Center, the method demonstrates that relatively small individual screening trials are optimal. The reliability of the results is evaluated using the bootstrap.     

Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials

Nodular hepatocellular carcinoma (HCC) is characterized by the presence of a pseudocapsule (constructed usually from connective fibrous tissue) that appears hypointense on T1- and T2-weighted spin-echo (SE) and gradient-echo (GE) MR imaging sequences without a contrast medium. The presence of vascular structures inside the tumor, which are verified by histological exam, affects enhancement of the PC after administrating the contrast medium: The impregnation is more evident in the dynamic study but also persists on the delayed T1-weighted SE images. The accuracy of MR in detecting the pseudocapsule of HCC and contrast enhancement of the pseudocapsule during dynamic studies were evaluated and related to pathological findings. Thirty-seven HCC were examined in 33 patients and afterwards resected. In capsulated nodules, besides usual hematoxylin, eosin, and trichrome stainings, histochemical and immunohistochemical methods were performed. On a 1.5-T MR unit, T1- and T2-weighted SE and GE FLASH 2D sequences after intravenous injection of Gd-DTPA (dynamic study) were used. In a later phase, T1-weighted SE sequences were repeated. Histologically, the pseudocapsule (thickness 0.2-6 mm) was present in 26 of 37 nodules (70%). The dynamic study was the most suitable technique to show the pseudocapsule, which was recognized in 80.7% (21 of 26 nodules). In 5 of 26 cases, the pseudocapsule, not demonstrated by MR, was thinner than 0.4 mm. In 16 of 21 cases, in the early portal phase (30-60 s), the pseudocapsule had an early enhancement, which was more evident later; in 5 of 21 cases the enhancement was observed only in the late portal phase (1-2 min). At histological examination, 14 of 16 pseudocapsules with early enhancement showed a more prominent vasculature than those with enhancement in the equilibrium phase. Magnetic resonance was a reliable tool in demonstrating the pseudocapsule of HCC. The histological examination demonstrated a good correlation between the enhancement behavior and the vessel number of the pseudocapsule.     

Use of the repeated cross-over designs in assessing bioequivalence

We consider applications of the repeated 2 x 2 cross-over design to evaluating bioequivalence between the two formulations. The repeated 2 x 2 cross-over design allows us not only to assess bioequivalence on average bioavailability and to examine the subject-by-formulation interaction but also to obtain independent unbiased estimates of intrasubject variability. One consequence of unequal intrasubject variabilities is that the sum of squares of intersubject residuals and the sum of squares of subject-by-formulation residuals are not independent. We also discuss the relative merits of this design as compared to the standard 2 x 2 cross-over design without repeated measurements in terms of precision and sample size with respect to the ratio of the number of subjects to the repeated measurements per subject. We investigate other uses of the 2 x 2 cross-over in examining the bioequivalence between the two different dosing regimens. Possible applications of other repeated cross-over designs to bioequivalence for more than two formulations are explored. A numerical example illustrates the proposed procedure.     

A review of the design of vaccine efficacy trials and a proposal for the design of the VA Cooperative Study of Active Immunotherapy of HIV Infection

We review the design of vaccine trials based on a search of the medical literature over the past four years, and present the proposed design of a therapeutic HIV vaccine efficacy study by the Department of Veterans Affairs Cooperative Studies Program. We explore the reasons for the atypical design of many vaccine trials, particularly the analysis of efficacy and how it differs from the more usual intent-to-treat analysis used in nonvaccine trials.     

Clinical trials with multiple outcomes: a statistical perspective on their design, analysis, and interpretation

This article tackles both practical and statistical issues in the handling of multiple outcomes in clinical trials, with relevance to trial design, analysis, and reporting. Specific topics illustrated by examples include: the advantage of prespecifying priorities amongst outcomes and analyses, corrections for multiple significance testing and their limited value, problems with adverse event data, the use of a single global test of significance for clinically related outcomes, the use of a combined outcome for clinical event data, and the value of exploring interrelationships amongst outcomes. The problems in handling multiple outcomes are enhanced by trials being too small, dichotomous attitudes (is the trial "positive" or not?), obsession with p-values, and the manipulative instincts of human nature. While predeclarations of priorities in analysis and reporting of multiple outcomes are important in suppressing distortive claims, it would be unfortunate if too inflexible an approach suppressed unpredictable findings from being seriously considered.     

Rapid diagnosis and identification of cross-over sites in patients with glucocorticoid remediable aldosteronism

Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant cause of primary aldosteronism and high blood pressure resulting from a chimeric 11beta-hydroxylase/aldosterone synthase gene. Abnormal expression of aldosterone synthase causes primary aldosteronism, which can be inhibited by glucocorticoids. Diagnosis of GRA has depended on the identification of a restriction enzyme product in genomic DNA of affected individuals. Recently, a two-tube long PCR method was described that allowed diagnosis of GRA in a kindred in Australia. A similar long PCR method confirmed the diagnosis of GRA in members of five northeastern Scotland families previously identified by Southern blotting and detected affected members of five GRA families previously identified in Glasgow. A multiplex PCR protocol is described here that allows the control aldosterone synthase amplification and chimeric gene amplification to be carried out in the same tube. We describe the regions of cross-over in each of 10 kindreds identified in Scotland. To identify cross-over regions in each of the kindreds, the chimeric long PCR product was cloned and sequenced. Five cross-over sites were identified ranging from intron 2 to exon 4, indicating the reliability of the method in identifying chimeric genes resulting from different sites of cross-over.     

Ipsilateral neglect: reversal of bias or exaggerated cross-over phenomenon?

We have shown previously that plating primary cultures of rat hepatocytes under low density, which stimulates hepatocytes to shift from the G0 to the G1 phase of the cell cycle, resulted in increased levels of glutathione (GSH) and cysteine, and increased activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis (Lu et al., Am. J. Physiol. 1992;263:C1181-C1189). In the current work we examined changes in GSH homeostasis after two-thirds partial hepatectomy (PH). Male Sprague-Dawley rats underwent two-thirds PH or sham operation. GSH, oxidized glutathione (GSSG), cysteine, GSH efflux, DNA synthesis, changes in GCS subunit messenger RNA (mRNA), and protein levels were measured 12 and 24 hours after PH. Both liver GSH and cysteine levels were doubled at 12 hours and remained elevated at 24 hours after PH. GSSG levels also increased, but the ratio of GSH to GSSG levels remained unchanged. The increase in GSH and cysteine levels preceded the increase in DNA synthesis. Sinusoidal GSH efflux was unchanged after two-thirds PH, but biliary GSH efflux decreased. However, total GSH efflux was minimally altered after two-thirds PH. The increase in GSH can be largely accounted for by the increase in both cysteine availability and the activity of GCS. The steady-state mRNA and protein levels of the GCS heavy subunit were increased at 12 hours after PH. The mRNA level of the GCS light subunit was unchanged. In summary, early in the course of liver regeneration the steady-state hepatic GSH levels double because of an increase in the biosynthesis of GSH.     

拆除爆破的建模与仿真

通过总结文献资料,提出了拆除爆破建模与仿真的原理、方法和步骤,并介绍了国内外的工程爆破数学模型发展概况,探讨了数值模型在建（构）筑物拆除爆破模拟方面的应用。