Biomedical subjects

M D Hughes

Publications and source records attributed to M D Hughes.

At least 55 records · Page 3Linked to original sources

PubMed1996

Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators.

OBJECTIVE: To study the addition of a third human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, nevirapine, to the combination of zidovudine and didanosine. DESIGN: A 48-week, randomized, double-blind, placebo-controlled trial at 16 AIDS (acquired immunodeficiency syndrome) Clinical Trials Units. PATIENTS: 398 adults who had HIV-1 infection, had 350 or fewer CD4+ T lymphocytes/mm3, and had had more than 6 months of previous nucleoside therapy. INTERVENTION: 1) Either nevirapine or placebo (200 mg/d for 2 weeks, then 400 mg/d thereafter) and 2) open-label zidovudine (600 mg/d) and didanosine (400 mg/d for patients weighing > or = 60 kg). MEASUREMENTS: CD4+ T lymphocyte counts, time to first HIV-1 disease progression event or death, adverse events, and nevirapine levels in plasma samples taken at random were measured in all patients. Plasma levels of HIV-1 RNA HIV-1 infectivity titer in peripheral blood mononuclear cells; serum p24 antigen levels; and plasma levels of zidovudine and didanosine were measured in patients enrolled at half the study sites. RESULTS: After 48 weeks of study treatment the patients assigned to the triple-combination regimen (nevirapine, zidovudine, and didanosine) had an 18% higher mean absolute CD4 cell count (95% Cl, 7% to 29%; P = 0.001), a 0.32 log10 lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (Cl, 0.05 to 0.59 log10 infectious units per million cells; P = 0.023), and a 0.25 log10 lower mean plasma HIV-1 RNA level (Cl, 0.03 to 0.48 log10 RNA copies/mL; P = 0.028) than did patients assigned to the double-combination regimen (zidovudine and didanosine). Severe rashes were more common among patients assigned to receive the triple combination (9% compared with 2%; P = 0.002). Risk for disease progression did not differ between the two groups (relative hazard of the triple-combination group, 1.24 [Cl, 0.75 to 2.06]; P > 0.2), although the study had only moderate power to detect a major difference. CONCLUSIONS: Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy and was associated with severe rash among the patients studied, who had had extensive previous therapy. These results support 1) the continuing development of combinations of more than two antiretroviral drugs to increase and prolong HIV-1 suppression and 2) the potential utility of nevirapine in combination regimens.

Adult↗

PubMed1995

CT-guided aspiration of suspected pancreatic infection: bacteriology and clinical outcome.

We have performed CT-guided percutaneous needle aspiration in 104 patients with severe pancreatitis strongly suspected of harboring pancreatic infection on the basis of systemic toxicity and CT findings (Balthazar CT grade D or E). Of these 104 patients, 51 (49%) were documented with pancreatic infection. Gram stain was positive in 54 of 58 infected aspirates, and culture was positive in all 58. Klebsiella, Escherichia coli, and Staphylococcus aureus were the most frequent organisms. Eighty-six percent of infected processes contained only one organism. Overall, pancreatic infection was documented by GPA within the first 2 wk in approx one-half of patients. There were no complications. The overall rate of infection decreased from 60 (1980-1987) to 34% (1988-1995) (p = 0.011). This change was caused by a reduction in the rate of infected necrosis from 67 to 32% (p = 0.015). The overall mortality rate remained at 20%. The mortality of sterile pancreatitis was not different from infected pancreatitis (p = 0.14). We conclude that GPA is a safe, accurate method of diagnosis of pancreatic infection. The rate of pancreatic infection appears to be decreasing. The overall mortality of severe pancreatitis among patients suspected of harboring pancreatic infection has remained unchanged because of the high mortality associated with both infected necrosis and severe sterile necrosis.

Adult↗

PubMed1995

Use of historical marker data for assessing treatment effects in phase I/II trials when subject selection is determined by baseline marker level.

Although the primary focus of Phase I clinical trials is to assess clinical pharmacology and possible toxicities, any information on the potential effect of treatment would be useful in helping to determine priorities between treatments for further study. We consider the scenario where data are routinely collected on a marker of disease progression on all patients attending a clinic, but the trial is restricted to patients who have a marker level within a defined range at study baseline. Using a two-step approach to estimation, the marker histories are used to give predictions of marker values during trial follow up, assuming no treatment effect and adjusted for the regression to the mean effect, for those subjects selected for the trial. Comparison between the observed responses and the predicted values then forms the basis for moment-based estimation and hypothesis testing for the treatment effect. The method is easily extended to compare summary measures for repeated measurements during follow up in the trial to predicted summary measures. An example using CD4 cell counts in an AIDS study is given.

Biometry↗

PubMed1995

Evaluating surrogate markers.

We discuss approaches for efficiently evaluating potential surrogate markers; in particular, we focus on case-cohort designs in which marker evaluation is undertaken only for a random sample of subjects within a randomized trial and for all other subjects who develop a major clinical outcome. These designs will be useful in clinical trials in which a highly significant treatment difference on clinical outcome has been obtained. In addition, we describe a method for using data from all available studies using a meta-analysis to explore the association of treatment effects on the potential marker and on clinical outcome. This may be the most effective approach for marker evaluation because it uses data from both large and small trials and incorporates information from trials in which nonsignificant treatment differences on the major clinical outcome are obtained.

Biomarkers↗

PubMed1994

Within-subject variation in CD4 lymphocyte count in asymptomatic human immunodeficiency virus infection: implications for patient monitoring.

Changes in CD4 lymphocyte counts are widely used in monitoring human immunodeficiency virus (HIV)-infected patients for disease progression. However, random fluctuations may obscure clinically significant changes. CD4 cell counts from 1020 untreated subjects with asymptomatic HIV infection monitored by standardized methods for up to 2 years were assessed. The within-subject coefficient of variation averaged 25% but was higher in subjects with lower counts; in 6% of subjects the count was half or double the one obtained 8 weeks before. Proportionate rates of decline, which had negligible correlation with the baseline count, averaged 14.3%/year but varied considerably between subjects: An estimated 29% had increasing trends. Declines were greater in HIV p24-positive subjects and those with higher lymphocyte percentages or lower platelet counts or hemoglobin levels. With such high variation, changes between single counts should be interpreted cautiously. Using multiple counts and other markers may provide more precise assessment of immune status.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Identification and purification of a protein that induces production of the Lactobacillus acidophilus bacteriocin lactacin B.

Lactacin B is a heat-stable bacteriocin produced by Lactobacillus acidophilus N2 that is active against closely related lactobacilli, including Lactobacillus delbrueckii subsp. lactis (formerly Lactobacillus leichmannii) ATCC 4797. Pure producer cultures propagated in MRS broth (initial pH 6.5) contain no lactacin B; it is detected only in cultures maintained at pH 5.0 to 6.0 and produced optimally at pH 6.0 S. F. Barefoot and T. R. Klaenhammer, Antimicrob. Agents Chemother. 26:328-334, 1984). Associative growth of producer and indicator, L. delbrueckii subsp. lactis ATCC 4797, resulted in production of an inhibitor identical to lactacin B. Associative growth increased lactacin B production from nondetectable levels (< 100 activity units [AU]/ml) to between 3,200 and 6,400 AU/ml in MRS broth (initial pH 6.5) and resulted in early but equal production of lactacin B (approximately 25,600 AU/ml) in broth maintained at pH 6.0. Indicator cells, but not spent culture filtrates, induced lactacin B production. Indicator cells disrupted by a French pressure cell yielded cell-free filtrates containing inducing activity. Chromatofocusing and gel filtration high-performance liquid chromatography of cell-free filtrates yielded a protein with a pI of 4.1 and a molecular size of approximately 58 kDa that induced lactacin B production. Analytical isoelectric focusing yielded a single protein band. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels contained a 28-kDa protein suggesting a two-subunit structure. Protein sequencing identified an N-terminal serine and 18 additional amino acids. To our knowledge, there are not previous descriptions of proteins that induce bacteriocin production in lactic acid bacteria.

Amino Acid Sequence↗

PubMed1994

Remission of childhood asthma after long-term treatment with an inhaled corticosteroid (budesonide): can it be achieved? Dutch CNSLD Study Group.

This study was undertaken in order to determine whether long-term treatment with inhaled corticosteroid can induce a remission in childhood asthma, and to decide when stabilization of airway responsiveness occurred. We therefore carried out, an extended follow-up of 28-36 months in one of two groups of children who participated in a long-term intervention study. This former study had shown that long-term (median follow-up 22 months) treatment with inhaled corticosteroid plus beta 2-agonist improves symptoms, airway calibre and airway responsiveness in children with asthma, compared with beta 2-agonist alone. On treatment with inhaled corticosteroid plus beta 2-agonist, airway calibre did not further improve after 4 months, whereas the provocative dose of histamine which causes a 20% fall in forced expiratory volume in one second (PD20) histamine showed gradual improvement without reaching an apparent plateau. Remission was defined as being symptom free during any 8 month period. Of the 58 children originally randomized to receive 0.2 mg salbutamol, plus 0.2 mg budesonide, t.i.d., five children withdrew: three due to lack of motivation, one for psychological reasons, and one due to a deterioration of asthma. One patient was hospitalized because of an asthma exacerbation. Airway calibre showed no improvement after 4 months up to 36 months. Mean PD20 histamine stabilized after 20 months at 2.1 doubling doses above baseline, but at a subnormal level of 80 micrograms. Symptoms improved during the first 18 months, and may have been improving further, but slowly, during the period between 18 and 36 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1993

Reporting Bayesian analyses of clinical trials.

Many clinicians wrongly interpret p-values as probabilities that treatment has an adverse effect and confidence intervals as probability intervals. Such inferences can be validly drawn from Bayesian analyses of trial results. These analyses use the data to update the prior (or pre-trial) beliefs to give posterior (or post-trial) beliefs about the magnitude of a treatment effect. However, for these methods to gain acceptance in the medical literature, understanding between statisticians and clinicians of the issues involved in choosing appropriate prior distributions for trial reporting needs to be reached. I focus on two types of prior that deserve consideration. The first is the non-informative prior giving standardized likelihood distributions as post-trial probability distributions. Their use is unlikely to be controversial among statisticians whilst being intuitively appealing to clinicians. The second type of prior has a spike of probability mass at the point of no treatment effect. Varying the magnitude of the spike illustrates the sensitivity of the conclusions drawn to the degree of prior scepticism in a treatment effect. With both, graphical displays provide clinical readers with the opportunity to explore the results more fully. An example of how a clinical trial might be reported in the medical literature using these methods is given.

Adrenergic beta-Antagonists↗

PubMed1993

Stopping guidelines for clinical trials with multiple treatments.

Stopping guidelines are widely used in long-term clinical trials involving two treatments. These allow planned interim analyses of the accumulating data to be undertaken whilst preserving the type I error rate for the treatment comparison. Their philosophy is extended to the case of trials with multiple treatments so that at any interim analysis, treatments may be considered for dropping from the trial if they are significantly inferior to all treatments that will remain. The proposed guidelines are designed to preserve the error rate in determining that treatment or group of treatments which is, in reality, best. Using simulation studies, stopping guidelines developed for two-arm trials are shown to be directly usable in multiple-arm studies when the treatments studied are all experimental and so in direct competition. When one treatment is the standard of care, a modification gives a better ethical perspective by also permitting treatments to be dropped when they are deemed inferior to the standard. Results are presented for normally distributed responses in trials involving three or four treatments and using stopping boundaries of the form proposed by O'Brien and Fleming. In conclusion, I discuss some of the additional considerations that are important in employing stopping guidelines in trials with multiple treatments.

Bias↗

PubMed1993

Cessation of long-term treatment with inhaled corticosteroid (budesonide) in children with asthma results in deterioration. The Dutch CNSLD Study Group.

Inhaled corticosteroid has been shown to be effective in the management of asthma. However, there is a lack of studies that assess the effect of cessation after long-term treatment with inhaled corticosteroid. This question was addressed in 28 children with stable asthma, aged 11 to 18 yr of age, who had completed 28 to 36 months of treatment with inhaled corticosteroid (budesonide 200 micrograms 3 times/day) and inhaled beta-2-agonist (salbutamol 200 micrograms 3 times/day). The children were randomized in a 1:2 ratio in a double-blind study either to continue budesonide (n = 8) during a period of 6 months or to decrease the dose of budesonide (n = 20) within 2 months, followed by placebo for 4 months. Treatment with salbutamol 600 micrograms daily was continued in both groups. Eight children from the tapering-off group withdrew, mainly due to symptoms of asthma, compared with none in the continuous treatment group. Five patients in the tapering-off group experienced exacerbations for which prednisolone was given, compared with none in the continuous treatment group. After tapering-off, symptoms of asthma and additional bronchodilator use increased, and both FEV1% predicted and PD20 histamine (provocation dose of histamine causing a 20% fall in FEV1) decreased, whereas these all remained unchanged in the group that continued treatment with inhaled corticosteroid. We conclude that in this study long-term treatment with 600 micrograms budesonide daily suppressed underlying mechanisms of asthma, but did not cure the disease.

Administration, Inhalation↗

PubMed1993

Regression dilution in the proportional hazards model.

The problem of regression dilution arising from covariate measurement error is investigated for survival data using the proportional hazards model. The naive approach to parameter estimation is considered whereby observed covariate values are used, inappropriately, in the usual analysis instead of the underlying covariate values. A relationship between the estimated parameter in large samples and the true parameter is obtained showing that the bias does not depend on the form of the baseline hazard function when the errors are normally distributed. With high censorship, adjustment of the naive estimate by the factor 1 + lambda, where lambda is the ratio of within-person variability about an underlying mean level to the variability of these levels in the population sampled, removes the bias. As censorship increases, the adjustment required increases and when there is no censorship is markedly higher than 1 + lambda and depends also on the true risk relationship.

Analysis of Variance↗

PubMed1992

A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. Dutch Chronic Non-Specific Lung Disease Study Group.

BACKGROUND: The morbidity from obstructive airways disease (asthma and chronic obstructive pulmonary disease) is considerable, and the mortality rate is rising in several countries. It has been hypothesized that long-term improvement in prognosis might result from vigorous bronchodilator or antiinflammatory therapy. METHODS: In a multicenter trial we compared three inhalation regimens in which a beta 2-agonist (terbutaline, 2000 micrograms daily) was combined with a corticosteroid (beclomethasone, 800 micrograms daily), an anticholinergic bronchodilator (ipratropium bromide, 160 micrograms daily), or placebo. Patients with airways hyperresponsiveness and obstruction who were 18 to 60 years old were followed for 2 1/2 years. RESULTS: Of the 274 patients enrolled, 56 percent had allergies. The mean forced expiratory volume in one second (FEV1) was 64 percent of the predicted value. The mean PC20 (the concentration of inhaled histamine causing a 20 percent decrease in FEV1, a measure of hyperresponsiveness) was 0.26 mg per milliliter. Withdrawal from the study, due mainly to pulmonary symptoms, was less frequent in the corticosteroid group (12 of 91 patients) than in the anticholinergic-drug group (45 of 92 patients) or the placebo group (44 of 91 patients; P < 0.001). The mean FEV1 (+/- SE) increased by 10.3 +/- 1.3 percent of the predicted value in the corticosteroid group within three months and remained stable thereafter, whereas it did not change in the other two groups (P < 0.001). The PC20 increased by 2.0 doubling concentrations in the corticosteroid group but did not change in the other groups (P < 0.001). In the corticosteroid group, patients who did not smoke, who had allergies, or who were less than 40 years old benefited more from their treatment than did those who smoked, did not have allergies, or were over 40, but all subgroups of the corticosteroid group had improvement as compared with the anticholinergic-drug or placebo group. CONCLUSIONS: The addition of an inhaled corticosteroid--but not an inhaled anticholinergic agent--to maintenance treatment with a beta 2-agonist (terbutaline) substantially reduced morbidity, hyperresponsiveness, and airways obstruction in patients with a spectrum of obstructive airways disease.

Administration, Inhalation↗

PubMed1992

Prediction of short-term survival with an application in primary biliary cirrhosis.

Many long-term follow-up studies for survival accumulate repeated measurements of prognostic factors. Survival models which include only covariate values at baseline do not use all available information, and do not relate to survival predictions for times other than at that baseline. Time-dependent covariate models (which update covariate values as measurements occur through time) might be used, though limitations of software for estimating the underlying hazard functions and difficulty in relating hazard function changes to survival prediction present serious drawbacks. By dividing each patient's follow-up into successive intervals of equal length (using a length of interest for prediction) and with measurements available at the start of each, we describe how an analysis taking person-intervals as the observation units can be undertaken using readily available software to produce short-term survival models. We show that this approach is related to both the baseline and time-dependent covariate models. The method is illustrated using data from a long-term study of patients with primary biliary cirrhosis, where interest is in short-term survival predictions to aid the decision when to undertake liver transplantation.

Humans↗

PubMed1992

Within-subject diastolic blood pressure variability: implications for risk assessment and screening.

Because of variability in diastolic blood pressure within an individual, repeated measurements increase precision in assessing an individual's underlying mean pressure and so also aid risk classification. Data from a cohort of 11,299 middle-aged men is used to model the variability in diastolic pressure between annual measurements. A simple model with pressure normally distributed about an underlying mean with standard deviation increasing with level fits the data very well. In modelling risk of cardiovascular mortality, a strong association is found with observed diastolic pressure level but not to trends in or variability between observed values. The effect of regression dilution is clear with the risk relationship appearing greater as one uses the mean of an increasing number of measurements. A method of adjusting for this regression dilution is described so giving an estimate of the relationship with underlying mean diastolic pressure. Using this survival model and the model for blood pressure variability, a method is presented for estimating both underlying mean pressure and absolute risk of cardiovascular disease given a sequence of blood pressure measurements from screening. This allows a sequential strategy for determining whether (a) antihypertensive intervention is desirable, (b) no further screening is necessary, or (c) further screening would aid the assessment, and emphasizes the need to consider blood pressure in the context of multiple risk factors.

Adult↗

PubMed1992

Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. The Dutch Chronic Non-specific Lung Disease Study Group.

In a randomized double-blind multicenter clinical study, 116 children with asthma were randomly assigned to treatment with an inhaled beta-2-agonist (salbutamol 0.2 mg) plus an inhaled corticosteroid (budesonide 0.2 mg) three times a day (BA+CS) or to an inhaled beta-2-agonist (salbutamol 0.2 mg) plus a placebo three times a day (BA+PL). After a median follow-up time of 22 months, 26 patients receiving BA+PL (45%) had withdrawn from randomized treatment, mainly because of asthma symptoms, compared with three withdrawals in the patients receiving BA+CS (p less than 0.0001). The FEV1, expressed as a percentage of the predicted value for age, sex, and height, showed an absolute increase of 7.0% after 2 months of BA+CS compared with a decrease of 4.0% after 2 months of BA+PL. This 11% difference in percent predicted FEV1 (95% confidence interval, 7 to 15%; p less than 0.0001) was then maintained after a median follow-up period of 22 months. Postbronchodilator FEV1 showed an absolute increase of 3.7% predicted within 2 months in patients receiving BA+CS and an absolute decrease of 1.1% predicted in children receiving BA+PL (p = 0.0005). Thereafter, this difference between the two treatment groups was maintained. Average peak expiratory flow rate (PEFR) increased from baseline by 36.6 L/min in the BA+CS group compared with 3.7 L/min in the BA+PL group (p = 0.003). This difference then remained for the median follow-up time of 22 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1992

The impact of stopping rules on heterogeneity of results in overviews of clinical trials.

This paper explores the extent to which application of statistical stopping rules in clinical trials can create an artificial heterogeneity of treatment effects in overviews (meta-analyses) of related trials. For illustration, we concentrate on overviews of identically designed group sequential trials, using either fixed nominal or O'Brien and Fleming two-sided boundaries. Some analytic results are obtained for two-group designs and simulation studies are otherwise used, with the following overall findings. The use of stopping rules leads to biased estimates of treatment effect so that the assessment of heterogeneity of results in an overview of trials, some of which have used stopping rules, is confounded by this bias. If the true treatment effect being studied is small, as is often the case, then artificial heterogeneity is introduced, thus increasing the Type I error rate in the test of homogeneity. This could lead to erroneous use of a random effects model, producing exaggerated estimates and confidence intervals. However, if the true mean effect is large, then between-trial heterogeneity may be underestimated. When undertaking or interpreting overviews, one should ascertain whether stopping rules have been used (either formally or informally) and should consider whether their use might account for any heterogeneity found.

Analysis of Variance↗

PubMed1990

Estimation issues in clinical trials and overviews.

There is a general move towards greater emphasis on point and interval estimates of treatment effect in reporting of clinical trials, so that significance testing plays a lesser role. In this article we examine a number of issues which affect the use and interpretation of conventional estimation methods. Should we accept or avoid the stereotypes of 95 per cent confidence? Should the abstract of a trial report include confidence intervals for major endpoints? Are frequentist confidence intervals being interpreted correctly, and should Bayesian probability intervals be more widely used in trial reports? Does the timing of publication, such as early stopping because of a large observed treatment difference, lead to exaggerated point and interval estimates? How can we produce realistic estimates from subgroup analyses? Is publication bias seriously affecting our ability to obtain unbiased estimates? Is the emphasis on estimation methods a powerful tool for encouraging larger sample sizes? Can we resolve the controversy concerning fixed or random effects models for estimation in overviews of related trials? Our arguments are illustrated by results from recent trials in cardiovascular disease.

Bayes Theorem↗

PubMed1990

Randomized, double-blind, placebo-controlled trial of somatostatin for variceal bleeding. Emergency control and prevention of early variceal rebleeding.

A randomized, double-blind, placebo-controlled trial of somatostatin was conducted among 120 patients admitted for bleeding esophageal varices (59 placebo, 61 somatostatin). An initial 250-micrograms bolus of somatostatin followed by a 5-day continuous infusion of 250 micrograms/h and an identical administration of placebo were evaluated for both the control of bleeding and prevention of early rebleeding from varices. Failure to control bleeding occurred in 22 (36%) somatostatin patients vs. 35 (59%) placebo patients, with time to failure occurring earlier with placebo (P = 0.036). blood and plasma transfused per hour during drug infusion of trial drug was reduced in the somatostatin group: median 0.033 vs. 0.105 unit/h (P = 0.025). Use of balloon tamponade was halved in somatostatin-treated patients. The average effect of somatostatin was a 41% reduction in the hazard of failure (95% confidence interval, -1% to 65%, P = 0.0545) after adjustment for the severity of liver disease, which was the only other variable having a significant influence on time to failure. There was no difference in 30-day mortality per admission (7 placebo, 9 somatostatin) or complications. It is concluded that somatostatin is safe and more effective than placebo for the control of variceal bleeding.

Adolescent↗