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Biomedical subjects

A Whitehead

Publications and source records attributed to A Whitehead.

At least 19 recordsLinked to original sources
PubMed2006

The effect of selective decontamination of the digestive tract on mortality in multiple trauma patients: a multicenter randomized controlled trial.

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. CONCLUSION: This study demonstrates that SDD significantly reduces infection in multiple trauma, although this RCT in 401 patients was underpowered to detect a mortality benefit.

Adult↗
PubMed2003

Dynamical synaptic plasticity: a model and connection to some experiments.

Using a modified version of a phenomenological model for the dynamics of synaptic plasticity, we examine some recent experiments of Wu et al. [(2001) J Physiol 533:745-755]. We show that the model is quantitatively consistent with their experimental protocols producing long-term potentiation (LTP) and long-term depression (LTD) in slice preparations of rat hippocampus. We also predict the outcome of similar experiments using different frequencies and depolarization levels than reported in their results.

Action Potentials↗
PubMed2003

A pilot study of zafirlukast as an anti-inflammatory agent in the treatment of adults with cystic fibrosis.

BACKGROUND: Persistent endobronchial inflammation is in part responsible for the attrition of lung function seen in cystic fibrosis. Leukotrienes act as pro-inflammatory mediators. The aim of this study was to assess the efficacy of the leukotriene receptor antagonist zafirlukast as a potential anti-inflammatory agent in the treatment of adult patients with cystic fibrosis. METHODS: Clinically stable patients were enrolled in the study if they had no history or clinical evidence of asthma, bronchial hyper-reactivity, or aspergillosis. They were randomised to receive zafirlukast 20 mg twice daily with all routine treatment for four months or routine treatment alone in an open cross-over design. Primary endpoints were changes in respiratory function tests and a modified NIH clinical score. RESULTS: Thirty patients were enrolled and 25 completed. There was a significant improvement in the modified NIH clinical score but no significant increase in respiratory function with zafirlukast. CONCLUSIONS: Patients receiving a leukotriene receptor antagonist in addition to routine treatments showed significant improvement in a clinical score which is a composite of clinical wellbeing, chest radiograph appearance, and physical examination. Respiratory function showed a non-significant trend towards improvement with treatment. Zafirlukast may benefit patients with CF. An adequately powered study is justified on the basis of these results.

Adult↗
PubMed2002

The effect of selegiline in the treatment of people with Alzheimer's disease: a meta-analysis of published trials.

OBJECTIVE: To evaluate the effect of selegiline in the treatment of patients with Alzheimer's disease, in terms of cognitive performance, functional ability, emotional state (including behaviour and mood) and global response. Data Sources The Cochrane database of trials, Embase, Medline and Psychlit. Study Selection Unconfounded, double-blind, randomised trials of selegiline compared with placebo reported before 31 December 1998. Data Extraction The reviewers selected trials for inclusion. Individual patient data were sought, but when these could not be retrieved summary data were extracted from published papers. RESULTS: Of 27 identified trials, 14 met the inclusion criteria. Individual patient data were retrieved from eight trials on 821 patients. Summary data were extracted from five trials on 240 patients. No data were available from one trial on 12 patients, which was therefore excluded from the meta-analysis. Fixed and random effects meta-analyses were performed on standardised mean differences. For cognition there was a statistically significant difference between selegiline and placebo at 4-6 weeks and 8-17 weeks after randomisation (at 8-17 weeks: smd=0.45 [95% confidence interval 0.03 to 0.88]), but this disappeared at later assessments. The size of the treatment difference was considered unlikely to be of clinical importance. Although there was a statistically significant difference at 4-6 weeks for activities of daily living, this disappeared at later assessments (at 8-17 weeks: smd=0.33 [-0.33, 0.69]). There were no statistically significant differences or clinically relevant differences between selegiline and placebo in terms of emotional state or global response. CONCLUSION: Although there was some evidence of improvement with selegiline in the short term in cognition and activities of daily living, the magnitude of the effect did not reach clinical importance. There was no evidence of long term effects.

Aged↗
PubMed2002

Once-daily tobramycin in the treatment of adult patients with cystic fibrosis.

The aim of this study was to test the equivalence of once- and thrice-daily dosing with tobramycin by comparing efficacy and safety in adult patients with cystic fibrosis. Sixty adult patients with an acute respiratory exacerbation were randomized to receive either 10 mg x kg(-1) tobramycin once-daily or 3.3 mg x kg(-1) tobramycin thrice-daily. Primary efficacy and safety endpoints were defined as changes in respiratory function and changes in renal function and hearing. Both groups showed a significant increase in respiratory function without a clinically significant change in renal function. For changes in forced vital capacity % predicted and serum potassium and magnesium levels, equivalence was demonstrated. For the variables forced expiratory volume in one second and forced mid-expiratory flow % pred and serum creatinine levels, there was insufficient power to demonstrate equivalence. One patient in each group showed bilateral impairment in pure tone audiogram after treatment. This study demonstrated significant clinical improvement with both once- and thrice-daily tobramycin dosing. Equivalence between the two regimens was shown for some, but not all primary endpoints. Once-daily dosing should be used with careful monitoring of safety and efficacy until large multicentre studies confirm these encouraging results.

Adolescent↗
PubMed2002

Statistical evaluation of the revised fixed-dose procedure.

The fixed-dose procedure (FDP) was introduced as OECD Test Guideline 420 in 1992, as an alternative to the conventional median lethal dose (LD50) test for the assessment of acute oral toxicity (OECD Test Guideline 401). The FDP uses fewer animals and causes less suffering than the conventional test, while providing information on the acute toxicity to allow substances to be ranked according to the EU hazard classification system. Recently the FDP has been revised, with the aim of providing further reductions and refinements, and classification according to the criteria of the Globally Harmonized Hazard Classification and Labelling scheme (GHS). This paper describes the revised FDP and analyses its properties, as determined by a statistical modelling approach. The analysis shows that the revised FDP classifies substances for acute oral toxicity generally in the same, or a more stringent, hazard class as that based on the LD50 value, according to either the GHS or the EU classification scheme. The likelihood of achieving the same classification is greatest for substances with a steep dose-response curve and median toxic dose (TD50) close to the LD50. The revised FDP usually requires five or six animals with two or fewer dying as a result of treatment in most cases.

Algorithms↗
PubMed2001

Meta-analysis of continuous outcome data from individual patients.

Meta-analyses using individual patient data are becoming increasingly common and have several advantages over meta-analyses of summary statistics. We explore the use of multilevel or hierarchical models for the meta-analysis of continuous individual patient outcome data from clinical trials. A general framework is developed which encompasses traditional meta-analysis, as well as meta-regression and the inclusion of patient-level covariates for investigation of heterogeneity. Unexplained variation in treatment differences between trials is considered as random. We focus on models with fixed trial effects, although an extension to a random effect for trial is described. The methods are illustrated on an example in Alzheimer's disease in a classical framework using SAS PROC MIXED and MLwiN, and in a Bayesian framework using BUGS. Relative merits of the three software packages for such meta-analyses are discussed, as are the assessment of model assumptions and extensions to incorporate more than two treatments.

Alzheimer Disease↗
PubMed2001

Meta-analysis of ordinal outcomes using individual patient data.

Meta-analyses are being undertaken in an increasing diversity of diseases and conditions, some of which involve outcomes measured on an ordered categorical scale. We consider methodology for undertaking a meta-analysis on individual patient data for an ordinal response. The approach is based on the proportional odds model, in which the treatment effect is represented by the log-odds ratio. A general framework is proposed for fixed and random effect models. Tests of the validity of the various assumptions made in the meta-analysis models, such as a global test of the assumption of proportional odds between treatments, are presented. The combination of studies with different definitions or numbers of response categories is discussed. The methods are illustrated on two data sets, in a classical framework using SAS and MLn and in a Bayesian framework using BUGS. The relative merits of the three software packages for such meta-analyses are discussed.

Alzheimer Disease↗
PubMed2001

Mid-trial design reviews for sequential clinical trials.

When sequential clinical trials are conducted by plotting a statistic measuring treatment difference against another measuring information, power is guaranteed regardless of nuisance parameters. However, values need to be assigned to nuisance parameters in order to gain an impression of the sample size distribution. Each interim analysis provides an opportunity to re-evaluate the relationship between sample size and information. In this paper we discuss such mid-trial design reviews. In the special cases of trials with a relatively short recruitment phase followed by a longer period of follow-up, and of normally distributed responses, mid-trial design reviews are particularly important. Examples are given of the various situations considered, and extensive simulations are reported demonstrating the validity of the review procedure in the case of normally distributed responses.

Cardiovascular Diseases↗
PubMed2001

Autosomal dominant peripheral cystic retinal patches and non-cystic retinal tufts associated with peripapillary crescents, retinal breaks and uveitis.

PURPOSE: To characterise an Irish kindred with apparent autosomal dominant peripheral retinal lesions and peripapillary crescents associated with retinal breaks and uveitis and assess whether these findings were associated with altered homocysteine metabolism. METHODS: Family members were followed prospectively and regularly examined. Molecular genetic analysis was performed on family members to detect cystathionine beta-synthase (CBS) 307G-S and 5,10-methylenetetrahydrofolate (MTHFR) 677C-T mutations. RESULTS: Over 11 years, 25 family members in four generations were examined, none of whom had significant refractive errors. Fifteen affected individuals had peripheral cystic retinal patches and in some cases non-cystic retinal tufts, associated with peripapillary pigmentation. Mean age at first examination of affected and non-affected individuals was the same. During follow-up the fundal findings remained unchanged in the affected group and no clinical characteristics developed in the unaffected individuals. Two affected siblings had associated uveitis and rhegmatogenous retinal detachment, which were successfully treated, while a third affected individual had a pigmented retinal break not requiring treatment. Heterozygosity for the CBS 307G-S mutation did not segregate with affected individuals while the MTHFR 677C-T mutation was not detected. CONCLUSIONS: This family has previously undescribed fundal findings inherited in an apparent autosomal dominant pattern associated with retinal breaks and uveitis. There is no associated inherited alteration of homocysteine metabolism.

Adolescent↗
PubMed2001

Stopping rules for phase II studies.

This paper, the second in a series of three papers concerned with the statistical aspects of interim analyses in clinical trials, is concerned with stopping rules in phase II clinical trials. Phase II trials are generally small-scale studies, and may include one or more experimental treatments with or without a control. A common feature is that the results primarily determine the course of further clinical evaluation of a treatment rather than providing definitive evidence of treatment efficacy. This means that there is more flexibility available in the design and analysis of such studies than in phase III trials. This has led to a range of different approaches being taken to the statistical design of stopping rules for such trials. This paper briefly describes and compares the different approaches. In most cases the stopping rules can be described and implemented easily without knowledge of the detailed statistical and computational methods used to obtain the rules.

Antineoplastic Agents↗
PubMed2001

Learning from previous responses in phase I dose-escalation studies.

Dose escalation in phase I studies is generally performed on the basis of clinical experience and judgement. In this paper some of the statistical approaches that have been proposed for the formalization of the procedure are described. Apart from the use of the Continual Reassessment Method in oncology studies, such formal methods have received little implementation. The purpose of presenting them here is to promote their further exploration and appropriate implementation. Certain limitations are discussed, which will be best overcome by collaboration between clinical pharmacologists and statisticians.

Antineoplastic Agents↗
PubMed2001

Interim analyses and sequential designs in phase III studies.

Recruitment of patients to a clinical trial usually occurs over a period of time, resulting in the steady accumulation of data throughout the trial's duration. Yet, according to traditional statistical methods, the sample size of the trial should be determined in advance, and data collected on all subjects before analysis proceeds. For ethical and economic reasons, the technique of sequential testing has been developed to enable the examination of data at a series of interim analyses. The aim is to stop recruitment to the study as soon as there is sufficient evidence to reach a firm conclusion. In this paper we present the advantages and disadvantages of conducting interim analyses in phase III clinical trials, together with the key steps to enable the successful implementation of sequential methods in this setting. Examples are given of completed trials, which have been carried out sequentially, and references to relevant literature and software are provided.

Clinical Trials, Phase III as Topic↗
PubMed2001

The development of a protocol for the use of 5-HT3 antagonists in chemotherapy-induced nausea and vomiting.

The purpose of this study was to evaluate the effectiveness of three 5-HT3 antagonists in routine clinical practice. The ultimate aim was to develop an antiemetic protocol, selecting a single 5-HT3 antagonist. Each of the drugs was studied for a 4-month period and data was collected from patients on nausea, vomiting (both acute and delayed) and side-effects by means of a diary card. A total of 274 patients were enrolled into the study. Success rates for acute emesis seen over the study period were in excess of 90%. There were no statistically significant differences between any of the three drugs investigated with respect to both acute and delayed nausea and vomiting. Similarly, there was no difference between the three groups for the incidence of constipation, diarrhoea and headache. Granisetron demonstrated a lesser deviation from the protocol in respect of the number of intravenous doses given to patients. The study allowed an effective 5-HT3 antagonist protocol to be developed for use in the management of nausea and vomiting in cancer patients.

Adolescent↗
PubMed2000

Diltiazem in acute myocardial infarction treated with thrombolytic agents: a randomised placebo-controlled trial. Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis post-Thrombolysis (INTERCEPT)

BACKGROUND: Diltiazem reduces non-fatal reinfarction and refractory ischaemia after non-Q-wave myocardial infarction, an acute coronary syndrome similar to the incomplete infarction that occurs after successful reperfusion. We postulated that this agent would reduce cardiac events in patients after acute myocardial infarction treated initially with thrombolytic agents-a clinical application previously unexplored with heart-rate-lowering calcium antagonists. METHODS: A prospective, randomised, double-blind, sequential trial was done in 874 patients with acute myocardial infarction, but without congestive heart failure, who first received thrombolytic agents. Patients received either 300 mg oral diltiazem once daily, or placebo, initiated within 36-96 h of infarct onset, and given for up to 6 months. The trial primary endpoint was the cumulative first event rate of cardiac death, non-fatal reinfarction, or refractory ischaemia. Additional prespecified endpoints included several composites of non-fatal cardiac events (non-fatal reinfarction combined with refractory ischaemia, all recurrent ischaemia, or the need for myocardial revascularisation). The diagnosis of ischaemia, whether refractory or recurrent, and the need for myocardial revascularisation, was always based on objective electrocardiographical evidence of ischaemia, either at rest or on exertion. RESULTS: For the trial primary endpoint, 131 events occurred in the 444 placebo patients and 97 events in the 430 diltiazem patients (hazard ratio 0.79; 95% CI, 0.61-1.02; p=0.07). For non-fatal cardiac events, diltiazem treatment was associated with a relative decrease (0.76; 0.58-1.00) in the combined event rate of non-fatal reinfarction and refractory ischaemia. There was a similar decrease in the composite non-fatal endpoints of non-fatal reinfarction combined with all recurrent ischaemia (0.80; 0.64-1.00) and non-fatal reinfarction combined with the need for myocardial revascularisation (0.67; 0.46-0.96). The need for myocardial revascularisation alone was significantly reduced by 42% (0.61; 0.39-0.96). No major safety issues were encountered. CONCLUSIONS: Diltiazem did not reduce the cumulative occurrence of cardiac death, non-fatal reinfarction, or refractory ischaemia during a 6-month follow-up, but did reduce all composite endpoints of non-fatal cardiac events, especially the need for myocardial revascularisation.

Calcium Channel Blockers↗
PubMed1999

Combining summaries of binary outcomes with those of continuous outcomes in a meta-analysis.

We present a methodology for combining trials some of which report continuous outcome measures and others binary outcomes created by a dichotomy of the continuous measurement. This was motivated by a series of controlled clinical trials investigating the effect of prophylactic use of oxytocics on postpartum blood loss during labor. Data were available in the form of summary statistics from published papers. The log-odds ratio is used as a common measure of treatment difference across all trials. We discuss the general applicability of this approach.

Female↗