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Biomedical subjects

J Whitehead

Publications and source records attributed to J Whitehead.

At least 19 recordsLinked to original sources
PubMed2006

Dietetic guidelines on food and nutrition in the secondary prevention of cardiovascular disease - evidence from systematic reviews of randomized controlled trials (second update, January 2006).

AIM: To update dietetic guidelines based on systematic review evidence on dietary advice to prevent further events in people with existing cardiovascular disease (CVD) (secondary prevention). METHODS: The Cochrane Library, MEDLINE and EMBASE were comprehensively searched to January 2005 for systematic reviews on aspects of diet and heart health. Reviews were included if they searched systematically for randomized controlled trials relating to diet and secondary prevention of CVD. Each review was critically appraised by at least two members of the UK Heart Health and Thoracic Dietitians Group. The quality and results of each review were discussed and summarized at a group meeting. RESULTS: Evidence-based strategies that reduce cardiovascular events in those with CVD include reduction in saturated fat and substitution with unsaturated fats. Individuals who have suffered a myocardial infarction may also benefit from adopting a Mediterranean type diet and increasing intake of omega 3 fats, but it is not clear whether they are beneficial for all patients with CVD. There is no systematic review evidence to support the use of antioxidant vitamins supplements, low glycaemic index diets, or homocysteine lowering therapies in this group. CONCLUSION: There remains good evidence that reducing saturated fat reduces morbidity in patients with CVD. This advice is consistent for most manifestations of CVD, with the addition of Mediterranean dietary advice and increased omega 3 fats for those who have had a myocardial infarction.

Antioxidants↗
PubMed2004

Dietetic guidelines: diet in secondary prevention of cardiovascular disease (first update, June 2003).

AIM: To update dietetic guidelines summarizing the systematic review evidence on dietary advice to prevent further events in people with existing cardiovascular disease (CVD) (secondary prevention). METHODS: The Cochrane Library, MEDLINE and EMBASE were comprehensively searched to November 2002 for systematic reviews on aspects of diet and heart health. Reviews were included if they searched systematically for randomised controlled trials relating to diet and secondary prevention of CVD. Two members of the UK Heart Health and Thoracic Dietitians Group critically appraised each review. The quality and results of each review were discussed and summarized in a meeting of the whole group. RESULTS: Providing evidence-based dietary information (including increasing omega-3 fat intake) to all people who have had a myocardial infarction will save more lives than concentrating dietary advice on just those in need of weight loss or lipid lowering. The practice of prioritizing dietetic time in secondary prevention to those with raised lipids is out of date since the advent of statin therapy. However, effective dietary advice for those with angina, stroke, peripheral vascular disease or heart failure is less clear. CONCLUSION: There is good systematic review evidence that dietary advice to those with coronary heart disease can reduce mortality and morbidity as well as modify some risk factors. Dietary advice that does this most effectively should be prioritized.

Cardiovascular Diseases↗
PubMed2002

Genomic sequencing of the bovine T cell receptor beta locus.

The T cell, which plays an integral role in the coordination of the immune system, has a heterodimer receptor (TCR) that can exist in one of the two forms: alpha/beta or gamma/delta. Cells displaying the gamma/delta TCR comprise less than 5% of T cell populations in humans and mice. In the bovine system, however, gamma/delta populations can reach as high as 60%. Differences in T cell populations make the bovine system an excellent candidate for genomic TCR sequencing and multi-species comparisons. In an effort to characterize the bovine TCR loci, a genomic library was screened for the beta TCR gene. A shotgun sequencing library was constructed and preliminary analysis demonstrates that the organization of the bovine TCR beta constant regions is different from both humans and mice. The bovine beta locus appears to have a third constant region. Overall, the genomic characterization of the bovine TCR genes will provide insight into the evolution of T cell receptor.

Animals↗
PubMed2002

Glucose uptake and insulin action in human adipose tissue--influence of BMI, anatomical depot and body fat distribution.

OBJECTIVE: To examine and compare in vitro basal and insulin-stimulated glucose uptake in human omental and subcutaneous adipose tissue derived from lean, overweight or obese individuals, and in those with central or peripheral obesity. DESIGN: In vitro study of basal and insulin-stimulated 2-deoxyglucose uptake in human omental and subcutaneous adipose tissue explants derived from patients undergoing elective abdominal surgery. SUBJECTS: Fourteen lean (average age 47 y, average body mass index (BMI) 22 kg/m(2)), 12 overweight (average age 51 y, average BMI 27 kg/m(2)), and 15 obese subjects (average age 45 y, average BMI 39 kg/m(2)). Ten peripherally obese (average age 43 y, average WHR 0.76) and 17 centrally obese (average age 50 y, average waist-to-hip ratio (WHR) 0.92). MEASUREMENTS: Fatness and fat distribution parameters (by anthropometry), basal and insulin stimulated [(3)H]-2-deoxyglucose uptake in omental and subcutaneous adipose tissue explants. RESULTS: In adipose tissue from lean subjects transport of 2-deoxyglucose over basal was stimulated approximately two-fold by insulin. In contrast, 2-deoxyglucose transport in adipose tissue of obese or overweight subjects was not responsive to insulin. Following incubation with 100-nM insulin for 35 min, insulin-stimulated 2-deoxyglucose transport was significantly lower in both omental and subcutaneous adipose tissue of obese and overweight compared to lean subjects. Basal 2-deoxyglucose uptake was also significantly reduced in omental and subcutaneous tissue in obese compared to lean subjects. Depot-specific differences in 2-deoxyglucose uptake were also seen. Overall 2-deoxyglucose uptake was greater in omental than subcutaneous adipose tissue but this was due to increased basal levels rather than increased insulin action. The reduction in insulin-stimulated 2-deoxyglucose uptake seen in overweight and obese subjects was relatively similar in both depots. However, insulin responsive 2-deoxyglucose transport was significantly lower in the omental adipose tissue of subjects with central obesity, as compared to that of subjects with peripheral obesity. No difference in insulin induced 2-deoxyglucose transport was observed in the subcutaneous adipose tissue explants of subjects with either central or peripheral obesity. CONCLUSION: In lean individuals insulin responsiveness of omental and subcutaneous adipose tissue was similar, but basal glucose uptake was significantly higher in omental adipose tissue. Adipose tissue obtained from overweight as well as obese individuals is insulin resistant. This insulin resistance occurs at a lower BMI than previously expected and is not adipose-depot specific. However, in obese subjects with a central distribution of adiposity insulin resistance occurs at the site of omental adipose tissue, in contrast to those with peripheral obesity.

Adipose Tissue↗
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

Monotherapy trials: sequential design.

In a sequential clinical trial, the accumulating data are subjected to a series of interim analyses, each of which involves a comparison of the treatments under study in respect of the primary efficacy criterion. The trial is stopped as soon as it is evident that one treatment is superior to the other, or that no such difference is going to be found. The stopping rule is devised to ensure that the required significance level and power are achieved and that valid statistical inference can be drawn at the end of the study. The methodology will be presented by means of a case study. This is the SEReNE study, which was completed last year and compared remacemide with carbamazepine in the treatment of newly diagnosed epilepsy. The study employed a double triangular test: an efficient form of sequential design for the comparison of two active treatments. The primary efficacy response was time from randomisation to the first seizure following dose titration. Details will be given of the stopping rule employed, the number of patients forecasted, the progress of the trial and its final analysis. The procedure adopted will be reviewed, and its suitability for future trials assessed.

Anticonvulsants↗
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

Easy-to-implement Bayesian methods for dose-escalation studies in healthy volunteers.

In phase I clinical trials, experimental drugs are administered to healthy volunteers in order to establish their safety and to explore the relationship between the dose taken and the concentration found in plasma. Each volunteer receives a series of increasing single doses. In this paper a Bayesian decision procedure is developed for choosing the doses to give in the next round of the study, taking into account both prior information and the responses observed so far. The procedure seeks the optimal doses for learning about the dose-concentration relationship, subject to a constraint which reduces the risk of administering dangerously high doses. Individual volunteers receive more than one dose, and the pharmacokinetic responses observed are, after logarithmic transformation, treated as approximately normally distributed. Thus data analysis can be achieved by fitting linear mixed models. By expressing prior information as 'pseudo-data', and by maximizing over posterior distributions rather than taking expectations, a procedure which can be implemented using standard mixed model software is derived. Comparisons are made with existing approaches to the conduct of these studies, and the new method is illustrated using real and simulated data.To whom correspondence should be addressed.

Journal Article↗
PubMed2001

Histology of lichen sclerosus varies according to site and proximity to carcinoma.

To investigate why vulvar but not extragenital lichen sclerosus is associated with squamous cell carcinoma, we performed a histologic study of extragenital lichen sclerosus, vulvar lichen sclerosus without carcinoma, and vulvar lichen sclerosus with carcinoma adjacent to and distant from the carcinoma. We compared epidermal thickness, rete ridge length, mitotic activity, atypia, dermal collagen change, dermal inflammation, and presence of other dermatoses in 30 women in each group. Extragenital lichen sclerosus showed thinner epidermis (mean thickness of 0.13 mm versus 0.41 mm; P < 0.0005), shorter rete ridges (P = 0.0001), more dermal edema (P = 0.16), and absence of associated dermatoses of spongiotic dermatitis and lichen planus (P < 0.005) compared with vulvar lichen sclerosus. The epidermal thickening seen in vulvar lichen sclerosus was indistinguishable from lichen simplex chronicus. Vulvar lichen sclerosus without carcinoma was generally similar to that distant from carcinoma. Vulvar lichen sclerosus adjacent to carcinoma showed increased epidermal thickness (0.61 mm versus 0.26 mm; P < 0.005), more dermal fibrosis (P < 0.0005), more inflammation (P < 0.0005), and more simplex (differentiated) vulvar intraepithelial neoplasia (18 cases versus 1 case; P < 0.0005) compared with that distant from carcinoma. We concluded that (1) the classic histologic features of lichen sclerosus are seen in both vulvar and extragenital sites; (2) vulvar lichen sclerosus without associated carcinoma has a mean epidermal thickness more than three times that of extragenital lichen sclerosus; (3) the epidermal thickening is histologically indistinguishable from lichen simplex chronicus; (4) there is a tendency for vulvar lichen sclerosus to have a more sclerotic and inflamed dermis; (5) lichen sclerosus 10 mm from cancer is more similar to vulvar lichen sclerosus without carcinoma than lichen sclerosus 1 mm from carcinoma; and (6) lichen sclerosus adjacent to carcinoma tends to show exaggerated epidermis thickness, basal atypia, and loss of the edematous-hyaline layer.

Adolescent↗
PubMed2001

Classification of ovarian endometriotic cysts.

Current literature describes 3 different pathogenetic types of ovarian endometriotic cysts. Cortical invagination cysts arise when surface ovarian endometriotic deposits adhere to another structure (such as the broad ligament), blocking the egress of menstrual fluid produced by cycling endometriosis, which then collects and causes the ovarian cortex to invaginate. Surface inclusion cyst-related endometriotic cysts develop when endometriotic tissue colonizes preexisting inclusion cysts. Physiological cyst-related endometriotic cysts occur when endometriosis gains access to a follicle, such as at the time of ovulation. To determine whether routine histological examination is of use in the classification of endometriotic cysts, and if so, whether such classification is of clinical relevance, we reviewed the histology of endometriotic cysts of 29 women under 35 years of age. Young women were chosen so that ovarian cortex surrounding the endometriotic lining in invagination cysts could be identified by the finding of oocytes. Ten women (34%) had cortical invagination endometriotic cysts, but no inclusion or physiological cyst-related endometriomas were found. The remaining 19 women (66%) had unclassified endometriotic cysts, of which 14 (48% of total) had a fibrous wall between the endometriotic lining and medulla and 5 had extensive destruction of ovarian tissue. We concluded that cortical invagination cysts were the only common diagnosable sort of the 3 types currently being investigated and that unclassified cysts required further study to determine their pathogenesis. Our study highlights the need for a prospective study using standardized pathological and clinical methods.

Adult↗
PubMed2001

Rapid real time PCR to distinguish between high risk human papillomavirus types 16 and 18.

AIMS: To assess the validity and practicality of real time polymerase chain reaction (PCR) for human papillomavirus (HPV) testing in combination with liquid based cytology samples for cervical screening. METHODS: Real time PCR using consensus (GPS+/6+) and type specific primers was developed to detect genital HPV types. This provides rapid, efficient amplification followed by denaturation of the product and computer analysis of the kinetics data that are generated. Liquid based cytology samples were obtained from patients attending routine cervical screening clinics. DNA was extracted from the residual cellular suspension after cytology using spin columns. RESULTS: Real time PCR successfully distinguished between HPV-16 and HPV-18 on the basis of amplification with consensus primers followed by DNA melting temperature (Tm) analysis. Sensitivities of one to 10 copies of HPV-16 (mean Tm = 79.4 degrees C; 2 SD, 0.8) and four to 40 copies of HPV-18 (mean Tm = 80.4 degrees C; 2 SD, 0.4) were obtained. In a mixed population of SiHa and HeLa cells containing known copy numbers of HPV-16 and HPV-18 genomes, HPV-16 and HPV-18 products were clearly separated by Tm analysis in mixtures varying from equivalence to 111000. Together with detailed melt analysis, type specific primers from the same region of the L1 gene confirmed the differential ability of this system. The method was applied to 100 liquid based cytology samples where HPV status using conventional GP5+/6+ PCR was already known. There was 95% agreement between the methods, with 55 positives detected by conventional PCR and 59 with real time PCR. The method was then tested on 200 routine liquid based cytology samples. Approximately 10% were positive by real time PCR, most of which were classified as HPV-16 by detailed melt analysis. Thirteen (6.8%) HPV positives were identified in 189 samples showing no evidence of cervical cytological abnormality. CONCLUSIONS: Real time PCR is a rapid, efficient method for the detection of HPV with the separation of HPV-16 and HPV-18 on the basis of differential Tm. Preliminary results suggest it could prove

Cell Line↗
PubMed2000

Formal approaches to safety monitoring of clinical trials in life-threatening conditions.

Large clinical trials in life-threatening conditions are usually conducted under the surveillance of a Data and Safety Monitoring Board (DSMB), whose remit is to protect the ethical and safety interests of the patients. The purpose of this paper is to describe a formal approach to safety monitoring, using a sequential safety procedure to aid the decisions made by the DSMB. This procedure is designed to recommend termination of the study as soon as evidence that the experimental treatment is worse than the control in terms of the primary safety response is so strong that it is unethical to proceed. The use of this formal sequential procedure enables probabilities of the study stopping erroneously and stopping correctly, under various degrees of experimental treatment disadvantage, to be examined. Also scenarios depicting data sets which lead to continuing or stopping can be presented. Such explorations are useful in encouraging all DSMB members to consider carefully, prior to the start of a study, the conditions under which they would seriously wish to consider termination. The implementation of these methods is described for three recently completed trials in which it has been used. Finally, our current recommendations for the design of these procedures, arising from these and other similar experiences, are given.

Clinical Trials as Topic↗
PubMed2000

Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators.

BACKGROUND: Early treatment may improve acute ischaemic stroke outcome. Gavestinel is a selective antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor, and is neuroprotective in animal models of ischaemic stroke. METHODS: We did a randomised, double-blind, placebo-controlled trial to test whether gavestinel could improve functional outcome after acute stroke in human beings. Conscious patients with stroke involving limb weakness received either gavestinel at an intravenous loading dose of 800 mg followed by 200 mg every 12 h for five doses, or matching placebo, within 6 h of stroke onset. Stratification variables were age and stroke severity. A computed tomography brain scan within 18 h of stroke onset identified the primary efficacy population with ischaemic stroke. Outcome was assessed by an independent observer with the Barthel index at 3 months. Three outcome categories were applied: good (Barthel index 95-100), moderate (60-90), and poor (0-55 or dead). Analysis was by intention to treat. FINDINGS: Of 1804 patients randomised, 16 received no treatment, and 333 had primary intracranial haemorrhage. 891 patients received gavestinel and 897 received placebo. Outcome in 721 patients who received gavestinel and were analysed for the primary endpoint at 3 months was good in 246 (34.1%), moderate in 136 (18.8%), and poor in 339 (47.0%), compared with 256 (34.9%), 133 (18.1%), and 345 (47.0%), respectively, of 734 patients who received placebo (p=0.8). Mortality at 3 months was 147 (20.4%) in the gavestinel group and 138 (18.8%) in the placebo group. Outcomes within preplanned subgroup and secondary analyses were also neutral. There were no significant differences in serious side-effects between the groups. INTERPRETATION: Treatment with gavestinel within 6 h of acute ischaemic stroke did not improve outcome.

Acute Disease↗
PubMed2000

Monitoring and evaluating clinical trials data.

This paper presents an overview of recent developments in statistical methods for the design of clinical trials. Whilst the methods are suitable for application in a wide range of therapeutic areas, they are of particular value in intensive care medicine due to its high levels of mortality and short periods of follow-up. The paper reviews the calculation of the sample size necessary to achieve a given power requirement, and then describes the operation of a Data and Safety Monitoring Board, the mid-trial reassessment of sample size and the use of stopping rules to terminate a study as soon as sufficient evidence is available. The purpose of the paper is to encourage investigators to consider the wide range of design options which have recently become available, when planning a new clinical study.

Clinical Trials as Topic↗
PubMed1999

On being the statistician on a Data and Safety Monitoring Board.

Data and Safety Monitoring Boards (DSMBs) are commonly appointed to monitor emerging data from major clinical trials. This paper describes their organization and remit, and their relationship with other trial committees and structures. The operation of formal stopping rules for safety and efficacy by a DSMB is discussed. The duties of a DSMB, from pre-trial planning through to stopping a study are described in detail, with emphasis on the reporting of information to the DSMB and the reporting of conclusions by the DSMB. The issue of blindness is given prominence and the role of the statistician on the DSMB is explored in detail.

Adverse Drug Reaction Reporting Systems↗