32 resultados para discrete trial

em CentAUR: Central Archive University of Reading - UK


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Relatively little is known about the role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in extinction of appetitively motivated tasks. The benzodiazepine (BZ) chlordiazepoxide (CDP) was administered during extinction and re-acquisition of lever pressing by mice following food reinforced discrete-trial fixed-ratio 5 (FR-5) training. Typical FR behaviour was established during baseline training and persisted for several extinction sessions. There were 15 extinction sessions in all, followed by six re-acquisition sessions where food reinforcement was re-introduced. In a 2x2x2 between-group design, CDP (15 mg/kg) or vehicle injections were given prior to either the last two food reinforcement sessions and the first 10 extinction sessions, or the final five extinction sessions, or the six re-acquisition sessions. Initially CDP had no effect on the rate of extinction, but after several extinction sessions it significantly facilitated it. Surprisingly, if CDP was administered only after several sessions of extinction, it immediately produced facilitation. Thus the delayed effects of CDP are not due to drug accumulation. These data suggest that some neural change must occur before CDP can affect extinction processes. In re-acquisition sessions, CDP facilitated the reinstatement of food-reinforced lever pressing. Implications for neural and behavioural accounts of operant extinction are discussed.

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Several recent studies have shown that reducing gamma-aminobutyric acid (GABA)-mediated neurotransmission retards extinction of aversive conditioning. However, relatively little is known about the effect of GABA on extinction of appetitively motivated tasks. We examined the effect of chlordiazepoxide (CDP), a classical benzodiazepine (BZ) and two novel subtype-selective BZs when administered to male C57Bl/6 mice during extinction following training on a discrete-trial fixed-ratio 5 (FR5) food reinforced lever-press procedure. Initially CDP had no effect, but after several extinction sessions CDP significantly facilitated extinction, i.e. slowed responding, compared with vehicle-treated mice. This effect was not due to drug accumulation because mice switched from vehicle treatment to CDP late in extinction showed facilitation immediately. Likewise, this effect could not be attributed to sedation because the dose of CDP used (15 mg/kg i.p.) did not suppress locomotor activity. The two novel subtype-selective BZ partial agonists, L-838417 and TP13, selectively facilitated extinction in similar fashion to CDP. The non-GABAergic anxiolytic buspirone was also tested and found to have similar effects when administered at a non-sedating dose. These studies demonstrate that GABA-mediated processes are important during extinction of an appetitively motivated task, but only after the animals have experienced several extinction sessions.

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Long-term indicators of soil fertility were assessed by measuring grain yield, soil organic carbon (SOC) and soil Olsen phosphorous for a P-deficient soil. In one set of treatments, goat manure was applied annually for 13 years at 0, 5 and 10 t ha(-1), and intercrops of sorghum/cowpea, millet/green gram and maize/pigeonpea were grown. Yield depended on rainfall and trends with time were not identifiable. Manure caused an upward trend in SOC, but 10 t ha(-1) manure did not give significantly more SOC than 5 t ha(-1). Only 10 t ha(-1) manure increased Olsen P. Measurements of both SOC and Olsen P are recommended. In another set of treatments, manure was applied for four years; the residual effect lasted another seven to eight years when assessed by yield, SOC and Olsen P Treatment with mineral fertilizers provided the same rates of N and P as 5 t hat manure and yields from manure and fertilizer were similar. Fertilizer increased Olsen P but not SOC. Management systems with occasional manure application and intermediate fertilizer applications should be assessed. Inputs and offtakes of C, N and P were measured for three years. Approximately 16, 25 and 11% of C, N and P respectively were stabilized into soil organic matter from 5 t ha(-1) a(-1) manure. The majority of organic P was fixed as soil inorganic P.

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The sustainability of cereal/legume intercropping was assessed by monitoring trends in grain yield, soil organic C (SOC) and soil extractable P (Olsen method) measured over 13 years at a long-term field trial on a P-deficient soil in semi-arid Kenya. Goat manure was applied annually for 13 years at 0, 5 and 10 t ha(-1) and trends in grain yield were not identifiable because of season-to-season variations. SOC and Olsen P increased for the first seven years of manure application and then remained constant. The residual effect of manure applied for four years only lasted another seven to eight years when assessed by yield, SOC and Olsen P. Mineral fertilizers provided the same annual rates of N and P as in 5 t ha(-1) manure and initially ,gave the same yield as manure, declining after nine years to about 80%. Therefore, manure applications could be made intermittently and nutrient requirements topped-up with fertilizers. Grain yields for sorghum with continuous manure were described well by correlations with rainfall and manure input only, if data were excluded for seasons with over 500 mm rainfall. A comprehensive simulation model should correctly describe crop losses caused by excess water.

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Bone meal amendments are being considered as a remediation method for metal-contaminated wastes. In various forms (biogenic, geogenic or synthetic), apatite, the principal mineral constituent of bone, has shown promise as an amendment to remediate metal-contaminated soils via the formation of insoluble phosphates of Pb and possibly other metals. The efficacy of commercially available bovine bone meal in this role was investigated in a field trial at Nenthead, Cumbria with a mine waste derived soil contaminated with Zn, Pb and Cd. Two 5 m(2) plots were set up: the first as a control and the second, a treatment plot where the soil was thoroughly mixed with bone meal to a depth of 50 cm at a soil to amendment ratio of 25:1 by weight. An array of soil solution samplers (Rhizon SMS (TM)) were installed in both plots and the soil pore water was collected and analysed for Ca, Cd, Zn and Pb regularly over a period of 2 a. Concurrently with the field trial, a laboratory trial with 800 mm high and 100 mm wide leaching Columns Was conducted using identical samplers and with soil from the held site. A substantial release of Zn, Pb, Cd and Ca was observed associated with the bone meal treatment. This release was transient in the case of the leaching columns, and showed seasonal variation in the case of the field trial. It is proposed that this effect resulted from metal complexation with organic acids released during breakdown of the bone meal organic fraction and was facilitated by the relatively high soil pH of 7.6-8.0. Even after this transient release effect had subsided or when incinerated bone meal was substituted in order to eliminate the organic fraction, no detectable decrease in dissolved metals was observed and no P was detected in solution, in contrast with an earlier small column laboratory study. It is concluded that due to the relative insolubility of apatite at above-neutral pH, the rate of supply of phosphate to soil solution was insufficient to result in significant precipitation of metal phosphates and that this may limit the effectiveness of the method to more acidic soils. (c) 2008 Elsevier Ltd. All rights reserved.

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Objective: To evaluate CBTp delivered by non-expert therapists, using CBT relevant measures. Methods: Participants (N=74) were randomised into immediate therapy or waiting list control groups. The therapy group was offered six months of therapy and followed up three months later. The waiting list group received therapy after waiting nine months (becoming the delayed therapy group). Results: Depression improved in the combined therapy group at both the end of therapy and follow-up. Other significant effects were found in only one of the two therapy groups (positive symptoms; cognitive flexibility; uncontrollability of thoughts) or one of the two timepoints (end of therapy: PANSS general symptoms, anxiety, suicidal ideation, social functioning, resistance to voices; follow-up: power beliefs about voices, negative symptoms). There was no difference in costs between the groups. Conclusions: The only robust improvement was in depression. Nevertheless, there were further encouraging but modest improvements in both emotional and cognitive variables, in addition to psychotic symptoms.

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In clinical trials, situations often arise where more than one response from each patient is of interest; and it is required that any decision to stop the study be based upon some or all of these measures simultaneously. Theory for the design of sequential experiments with simultaneous bivariate responses is described by Jennison and Turnbull (Jennison, C., Turnbull, B. W. (1993). Group sequential tests for bivariate response: interim analyses of clinical trials with both efficacy and safety endpoints. Biometrics 49:741-752) and Cook and Farewell (Cook, R. J., Farewell, V. T. (1994). Guidelines for monitoring efficacy and toxicity responses in clinical trials. Biometrics 50:1146-1152) in the context of one efficacy and one safety response. These expositions are in terms of normally distributed data with known covariance. The methods proposed require specification of the correlation, ρ between test statistics monitored as part of the sequential test. It can be difficult to quantify ρ and previous authors have suggested simply taking the lowest plausible value, as this will guarantee power. This paper begins with an illustration of the effect that inappropriate specification of ρ can have on the preservation of trial error rates. It is shown that both the type I error and the power can be adversely affected. As a possible solution to this problem, formulas are provided for the calculation of correlation from data collected as part of the trial. An adaptive approach is proposed and evaluated that makes use of these formulas and an example is provided to illustrate the method. Attention is restricted to the bivariate case for ease of computation, although the formulas derived are applicable in the general multivariate case.

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Objective: Evaluation of selective decontamination of the digestive tract (SDD) on late mortality in ventilated trauma patients in an intensive care unit (ICU). Methods: A multicenter, randomized controlled trial was undertaken in 401 trauma patients with Hospital Trauma Index-Injury Severity Score of 16 or higher. Patients were randomized to control (n = 200) or SDD (n = 201), using polymyxin E, tobramycin, and amphotericin B in throat and gut throughout ICU treatment combined with cefotaxime for 4 days. Primary endpoint was late mortality excluding early death from hemorrhage or craniocerebral injury. Secondary endpoints were infection and organ dysfunction. Results: Mortality was 20.9% with SDD and 22.0% in controls. Overall late mortality was 15.3% (57/372) as 29 patients died from cerebral injury, 16 SDD and 13 control. The odds ratio (95% confidence intervals) of late mortality for SDD relative to control was 0.75 (0.40-1.37), corresponding to estimates of 13.4% SDD and 17.2% control. The overall infection rate was reduced in the test group (48.8% vs. 61.0%). SDD reduced lower airway infections (30.9% vs. 50.0%) and bloodstream infections due to aerobic Gram-negative bacilli (2.5% vs. 7.5%). No difference in organ dysfunction was found. Concluson: This study demonstrates that SDD significantly reduces infection in multiple trauma, although this RCT in 401 patients was underpowered to detect a mortality benefit.

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The aim of a phase H clinical trial is to decide whether or not to develop an experimental therapy further through phase III clinical evaluation. In this paper, we present a Bayesian approach to the phase H trial, although we assume that subsequent phase III clinical trials will hat,e standard frequentist analyses. The decision whether to conduct the phase III trial is based on the posterior predictive probability of a significant result being obtained. This fusion of Bayesian and frequentist techniques accepts the current paradigm for expressing objective evidence of therapeutic value, while optimizing the form of the phase II investigation that leads to it. By using prior information, we can assess whether a phase II study is needed at all, and how much or what sort of evidence is required. The proposed approach is illustrated by the design of a phase II clinical trial of a multi-drug resistance modulator used in combination with standard chemotherapy in the treatment of metastatic breast cancer. Copyright (c) 2005 John Wiley & Sons, Ltd.

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In a sequential clinical trial, accrual of data on patients often continues after the stopping criterion for the study has been met. This is termed “overrunning.” Overrunning occurs mainly when the primary response from each patient is measured after some extended observation period. The objective of this article is to compare two methods of allowing for overrunning. In particular, simulation studies are reported that assess the two procedures in terms of how well they maintain the intended type I error rate. The effect on power resulting from the incorporation of “overrunning data” using the two procedures is evaluated.

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Health care providers, purchasers and policy makers need to make informed decisions regarding the provision of cost-effective care. When a new health care intervention is to be compared with the current standard, an economic evaluation alongside an evaluation of health benefits provides useful information for the decision making process. We consider the information on cost-effectiveness which arises from an individual clinical trial comparing the two interventions. Recent methods for conducting a cost-effectiveness analysis for a clinical trial have focused on the net benefit parameter. The net benefit parameter, a function of costs and health benefits, is positive if the new intervention is cost-effective compared with the standard. In this paper we describe frequentist and Bayesian approaches to cost-effectiveness analysis which have been suggested in the literature and apply them to data from a clinical trial comparing laparoscopic surgery with open mesh surgery for the repair of inguinal hernias. We extend the Bayesian model to allow the total cost to be divided into a number of different components. The advantages and disadvantages of the different approaches are discussed. In January 2001, NICE issued guidance on the type of surgery to be used for inguinal hernia repair. We discuss our example in the light of this information. Copyright © 2003 John Wiley & Sons, Ltd.