Correlation of gastroesophageal reflux disease symptoms characteristics with long-segment Barrett's esophagus.

Thus far, there has been a paucity of studies that have assessed the value of the different gastroesophageal reflux disease (GERD) symptom characteristics in identifying patients with long-segment Barrett's esophagus versus those with short-segment Barrett's esophagus. To determine if any of the symptom characteristics of GERD correlates with long-segment Barrett's esophagus versus short-segment Barrett's esophagus. Patients seen in our Barrett's clinic were prospectively approached and recruited into the study. All patients underwent an endoscopy, validated GERD symptoms questionnaire and a personal interview. Of the 88 Barrett's esophagus patients enrolled into the study, 47 had short-segment Barrett's esophagus and 41 long-segment Barrett's esophagus. Patients with short-segment Barrett's esophagus reported significantly more daily heartburn symptoms (84.1%) than patients with long-segment Barrett's esophagus (63.2%, P = 0.02). There was a significant difference in reports of severe to very severe dysphagia in patients with long-segment Barrett's esophagus versus those with short-segment Barrett's esophagus (76.9%vs. 38.1%, P = 0.02). Longer duration in years of chest pain was the only symptom characteristic of gastroesophageal reflux disease associated with longer lengths of Barrett's mucosa. Reports of severe or very severe dysphagia were more common in long-segment Barrett's esophagus patients. Only longer duration of chest pain was correlated with longer lengths of Barrett's esophagus.

Characterization of plant beta-ureidopropionase and functional overexpression in Escherichia coli.

Pyrimidine bases are rapidly catabolized in growing plant tissues. The final enzyme of the catabolic pathway, beta-ureidopropionase (beta-UP; EC 3.5.1.6), was partially purified from the shoots of etiolated maize (Zea mays) seedlings. The enzyme had a K(m) for beta-ureidopropionate (the substrate derived from uracil) of 11 microM. Only one enantiomer of racemic beta-ureidoisobutyrate (derived from thymine) was processed with a K(m) of 6 microM. The enzyme was inactivated by dialysis against 1,10-phenanthroline and activity could be partially restored by addition of Zn(2+). Maize beta-UP was very sensitive to inactivation by iodoacetamide. This could be prevented by addition of substrate, indicating the presence of an active site Cys. The enzyme was strongly inhibited by short chain aliphatic acids and aryl propionates, the most potent inhibitor of which was 2-(2, 6-dinitrophenoxy)-propionate (I(50) = 0.5 microM). A gene for Arabidopsis beta-UP encodes a polypeptide of 405 amino acids and has about 55% homology with the enzymes from other eukaryotic organisms. Several highly conserved residues link the plant beta-UP with a larger class of prokaryotic and eukaryotic amidohydrolases. An Arabidopsis cDNA truncated at the N terminus by 14 residues was cloned and overexpressed in Escherichia coli. The recombinant enzyme (43.7 kD) was soluble, functional, and purified to homogeneity with yields of 15 to 20 mg per 30 g fresh weight of E. coli cells. The recombinant enzyme from Arabidopsis and the native enzyme from maize had molecular masses of approximately 440 kD, indicating the enzyme is a decamer at pH 7.

Carbohydrate supplementation attenuates muscle glycogen loss during acute bouts of resistance exercise.

The effects of carbohydrate (CHO) supplementation on muscle glycogen and resistance exercise performance were examined with eight highly resistance trained males (mean +/- SEM, age: 24.3 +/- 1.1 years, height: 171.9 +/- 2.0 cm, body mass: 85.7 +/- 3.5 kg; experience 9.9 +/- 2.0 years). Subjects participated in a randomized, double blind protocol with testing sessions separated by 7 days. Testing consisted of an initial isokinetic leg exercise before and after an isotonic resistance exercise (IRT) session consisting of 3 leg exercises lasting approximately 39 min. Subjects consumed a CHO (1.0 g CHO.kg body mass(-1)) or placebo treatment (PLC), prior to and every 10-min (0.5 g CHO.kg body mass(-1)) during the IRT. Muscle tissue was obtained from the m vastus lateralis after a supine rest (REST) immediately after the initial isokinetic test (POST-ISO) and immediately after the IRT (POST-IRT). The CHO treatment elicited significantly less muscle glycogen degradation from the POST-ISO to POST-IRT (126.9 +/- 6.5 to 109.7 +/- 7.1 mmol.kg wet weight(-1)) compared to PLC (121.4 +/- 8.1 to 88.3 +/- 6. 0 mmol.kg wet weight(-1)). There were no differences in isokinetic performance between the treatments. The results of this investigation indicate that the consumption of a CHO beverage can attenuate the decrease in muscle glycogen associated with isotonic resistance exercise but does not enhance the performance of isokinetic leg exercise.

Hypothesis testing in clinical trials.

In designing and analyzing any clinical trial, two issues related to patient heterogeneity must be considered: (1) the effect of chance and (2) the effect of bias. These issues are addressed by enrolling adequate numbers of patients in the study and using randomization for treatment assignment. An "intention-to-treat" analysis of outcome data includes all individuals randomized and counted in the group to which they are randomized. There is an increased risk of spurious results with a greater number of subgroup analyses, particularly when these analyses are data derived. Factorial designs are sometimes appropriate and can lead to efficiencies by addressing more than one comparison of interventions in a single trial.

How young children spend their time: television and other activities.

Time-use diaries were collected over a 3-year period for 2 cohorts of 2- and 4-year-old children. TV viewing declined with age. Time spent in reading and educational activities increased with age on weekdays but declined on weekends. Time-use patterns were sex-stereotyped, and sex differences increased with age. As individuals' time in educational activities, social interaction, and video games increased, their time watching entertainment TV declined, but time spent playing covaried positively with entertainment TV. Educational TV viewing was not related to time spent in non-TV activities. Maternal education and home environment quality predicted frequent viewing of educational TV programs and infrequent viewing of entertainment TV. The results do not support a simple displacement hypothesis; the relations of TV viewing to other activities depend on the program content, the nature of the competing activity, and the environmental context.

Malignant glioma: who benefits from adjuvant chemotherapy?

We combined two randomized prospective Brain Tumor Study Group data sets to analyze the effects of prognostic factors on survival by treatment group. Adjuvant chemotherapy increased long-term survival regardless of prognostic factors. Pathological review revealed that oligo dendrogliomas were overrepresented among long-term survivors independent of therapy. Prognostic factors do not predict benefit from adjuvant nitrosourea in malignant gliomas, and long-term survival with chemotherapy is not explained by oligodendroglial tumors.

Effects of split exercise sessions on excess postexercise oxygen consumption and resting metabolic rate.

This study involved examining how splitting a 30-min exercise bout on a cycle ergometer into two equal sessions affects excess postexercise oxygen consumption (EPOC) and resting metabolic rate (RMR). In this study, 10 male volunteers (age = 23+/-3.8) participated in two exercise trials, which were randomly assigned in a counterbalanced design and separated by 40 hr. One trial was 30 min of exercise at 70% VO(2)max (CONT), followed by a 40-min measurement of EPOC. The second trial was divided into two 15-min sessions (SPLIT), separated by 6 hr. A 20-min measurement of EPOC followed each SPLIT session. Results indicated that the combined magnitude of EPOCs from SPLIT (7,410+/-1,851 ml) was significantly greater than that from CONT (5,278+/-1305 ml). Data indicate that dividing a 30-min exercise session in to two parts for these individuals significantly increases magnitude of EPOC but does not affect RMR.

State laws on youth access to tobacco in the United States: measuring their extensiveness with a new rating system.

OBJECTIVE: To develop and implement a rating system evaluating the extensiveness of state laws restricting youth access to tobacco. DESIGN: State laws on youth access to tobacco were analysed and assigned ratings on nine items. Six items addressed specific tobacco-control provisions, and three related to enforcement provisions. For each item, a target was specified reflecting public health objectives. Achieving the target resulted in a rating of +4 points; for three items, a rating of +5 was possible if the target was exceeded. Criteria for lower ratings were established for situations when the target was not met. SETTING: United States. RESULTS: State scores (sum of the ratings across all nine items) ranged from 0-18 in 1993, 2-21 in 1994, and 1-21 in 1995 and 1996, out of a possible total of 39. The average score across states was 7.2 in 1993, 7.9 in 1994, 8.2 in 1995, and 9.0 in 1996. The overall mean rating (per item) was 0.80 in 1993, 0.88 in 1994, 0.91 in 1995, and 1.00 in 1996, on a scale where 4.0 indicates that the target goals (per item) were met. From 1993 to 1996, scores increased for 20 states, decreased for one state, and remained unchanged for the others. The number of states for which state preemption of local tobacco regulation was a factor doubled from 10 states in 1993 to 20 states in 1996. CONCLUSIONS: Although all states have laws addressing youth access to tobacco, this analysis reveals that, as of the end of 1996, the progress towards meeting health policy targets is slow, and state legislation that preempts local tobacco regulation is becoming more common.

A Monte Carlo Investigation of Methods for Controlling Type I Errors with Specification Searches in Structural Equation Modeling.

A standard strategy in structural equation modeling is to conduct multiple Lagrange multiplier (LM) tests after rejection of an initial model. Controlling for Type 1 error across these tests minimizes the likelihood of including unnecessary additional parameters in the model. Three methods for controlling Type I errors are evaluated using simulated data for factor analytic models: the standard approach which involves testing each parameter at the .05 level, a Bonferroni approach, and a simultaneous test procedure (STP). In the first part of the study, all samples were generated from a population in which all null hypotheses associated with the LM tests were correct. Three factors were manipu1,~ted: factor weights, sample size, and number of parameters in the specification search. The standard and the STP approaches yielded overly liberal and overly conservative familywise error rates, respectively, while the Bonferroni approach yielded error rates closer to the nominal level. In the second part of the study, data were generated in which one or more null hypotheses associated with the LM test were incorrect, and the number of parameters in the search was manipulated. Again the Bonferroni method was the best approach in controlling familywise: error rate, particularly when the alpha level was adjusted for the number of parameters evaluated at each step.

The advantages of community-randomized trials for evaluating lifestyle modification.

Observational studies may provide suggestive evidence for the results of behavior change and lifestyle modification, but they do not replace randomized trials for comparing interventions. To obtain a valid comparison of competing intervention strategies, randomized trials of adequate size are the recommended approach. Randomization avoids bias, achieves balance (on average) of both known and unknown predictive factors between intervention and comparison groups, and provides the basis of statistical tests. The value of randomization is as relevant when investigating community interventions as it is for studies that are directed at individuals. Randomization by group is less efficient statistically than randomization by individual, but there are reasons why randomization by group (such as community) may be chosen, including feasibility of delivery of the intervention, political and administrative considerations, avoiding contamination between individuals allocated to competing interventions, and the very nature of the intervention. One example is the Community Intervention Trial for Smoking Cessation (COMMIT), which involved 11 matched pairs of communities and randomized within these pairs to active community-level intervention versus comparison. For analysis of results, community-level permutation tests (and corresponding test-based confidence intervals) can be designed based on the randomization distribution. The advantages of this approach are that it is robust, and the unit of randomization is the unit of analysis, yet it can incorporate individual-level covariates. Such covariates can play a role in imputation for missing values, adjustment for imbalances, and separate analyses in demographic subsets (with appropriate tests for interaction). A community-randomized trial can investigate a multichannel community-based approach to lifestyle modification, thus providing generalizability coupled with a rigorous evaluation of the intervention.

Does assessment of quality of life in comparative cancer trials make a difference? A discussion.

This paper discusses two accompanying manuscripts addressing the question whether the assessment of quality of life in comparative cancer trials makes a difference. A number of thoughts and comments stimulated by the manuscripts are presented. It is concluded that, when comparing treatment regimens for a disease such as cancer, three measures can be considered in turn. First, the primary endpoint must remain: How long do patients survive? The logical next question is: How well do patients function? Then we have the third question: How well do patients feel? Certainly, these questions are interrelated, but our decisions will be the most rational (and we will provide the most useful information to patients) if we keep these distinctions in mind. Whatever the endpoint of interest, however, the appropriate way to compare different therapeutic interventions reliably is the randomized trial.

The efficiency of the matched-pairs design of the Community Intervention Trial for Smoking Cessation (COMMIT).

The Community Intervention Trial for Smoking Cessation (COMMIT) was a randomized trial to evaluate the effects of a community-wide smoking cessation intervention on smoking behavior. The statistical design involved 22 pair-matched communities and the randomization of one community in each of the 11 pairs to the intervention, with the other community in the pair acting as a comparison. Communities were matched on the basis of their geographical proximity and similarity of demographic composition. In this paper, we use the data on the rates of quitting smoking among cohorts of heavy and light/moderate smokers in each community to estimate the gains in efficiency achieved by the matched-pairs design compared to an unmatched randomized trial. We find evidence of some gain in efficiency, although the data are not extensive enough to give estimates of efficiency gain that have good precision.

Control of Type I Errors with Multiple Tests of Constraints in Structural Equation Modeling.

Two contrasting views toward the evaluation of multiple tests of constraints and control of Type 1 errors in structural equation modeling are presented. (a) Exploring; data helps researchers make decisions about inclusion of relevant model parameters and control of Type 1 errors hinders this process. (b) Exploring data is not likely to yield meaningful models unless we can limit the process on the basis of methods and theory, and controlling Type I errors is a useful device: to force us to limit our searches. Also, in evaluating multiple tests of constraints for applications other than exploratory analyses, we should control for Type I errors as we do in testing multiple comparisons in analysis of variance. We argue for the second perspective and present examples to illustrate methods for controlling Type 1 errors when making model comparisons.

On design considerations and randomization-based inference for community intervention trials.

This paper discusses design considerations and the role of randomization-based inference in randomized community intervention trials. We stress that longitudinal follow-up of cohorts within communities often yields useful information on the effects of intervention on individuals, whereas cross-sectional surveys can usefully assess the impact of intervention on group indices of health. We also discuss briefly special design considerations, such as sampling cohorts from targeted subpopulations (for example, heavy smokers), matching the communities, calculating sample size, and other practical issues. We present randomization tests for matched and unmatched cohort designs. As is well known, these tests necessarily have proper size under the strong null hypothesis that treatment has no effect on any community response. It is less well known, however, that the size of randomization tests can exceed nominal levels under the 'weak' null hypothesis that intervention does not affect the average community response. Because this weak null hypothesis is of interest in community intervention trials, we study the size of randomization tests by simulation under conditions in which the weak null hypothesis holds but the strong null hypothesis does not. In unmatched studies, size may exceed nominal levels under the weak null hypothesis if there are more intervention than control communities and if the variance among community responses is larger among control communities than among intervention communities; size may also exceed nominal levels if there are more control than intervention communities and if the variance among community responses is larger among intervention communities. Otherwise, size is likely near nominal levels. To avoid such problems, we recommend use of the same numbers of control and intervention communities in unmatched designs. Pair-matched designs usually have size near nominal levels, even under the weak null hypothesis. We have identified some extreme cases, unlikely to arise in practice, in which even the size of pair-matched studies can exceed nominal levels. These simulations, however, tend to confirm the robustness of randomization tests for matched and unmatched community intervention trials, particularly if the latter designs have equal numbers of intervention and control communities. We also describe adaptations of randomization tests to allow for covariate adjustment, missing data, and application to cross-sectional surveys. We show that covariate adjustment can increase power, but such power gains diminish as the random component of variation among communities increases, which corresponds to increasing intraclass correlation of responses within communities. We briefly relate our results to model-based methods of inference for community intervention trials that include hierarchical models such as an analysis of variance model with random community effects and fixed intervention effects. Although we have tailored this paper to the design of community intervention trials, many of the ideas apply to other experiments in which one allocates groups or clusters of subjects at random to intervention or control treatments.

Representation of African-Americans, Hispanics, and whites in National Cancer Institute cancer treatment trials.

BACKGROUND: The National Cancer Institute (NCI)-sponsored clinical trials cooperative groups place more than 25 000 American patients in treatment trials every year. Equal access and proportional representation of all races/ethnicities is desired. PURPOSE: Our objectives were to evaluate the inclusion of African-Americans, Hispanics, and non-Hispanic whites in NCI-sponsored treatment trials and to determine if there is proportional racial/ethnic representation. METHODS: During the period of January 1, 1991, through June 30, 1994, 99 495 cancer patients were enrolled in clinical trials and declared themselves as non-Hispanic black, non-Hispanic white, or Hispanic (of any race). In the analysis, participants in NCI treatment trials were subdivided into three age groups: birth to 19 years, 20-49 years, and 50 or more years. The racial/ethnic composition of each of these age groups was compared with the racial/ethnic makeup of the American population with cancer. Estimates of the number of incident cancer cases per year were made for each racial/ethnic group within each age group using data from the Surveillance, Epidemiology, and End Results (SEER) Program and the 1990 Census. The percentage of all cancer patients who were in each racial/ethnic group were compared with the population that entered clinical trials. Comparisons are also made separately for patients with leukemia and breast, colorectal, lung, and prostate cancers. RESULTS: Among patients 0-19 years old, 20-49 years old, and 50 years old or older there is relatively proportional representation of non-Hispanic blacks, Hispanics, and non-Hispanic whites in trials. It is noted that more than 70% of cancer patients aged 0-19 years are estimated to enter cooperative group clinical trials compared with 4.0% of cancer patients aged 20-49 years and 1.5% of patients aged 50 years or older. CONCLUSIONS: Accrual of American cancer patients to NCI-sponsored treatment trials generally parallels the incident burden of disease among non-Hispanic African-Americans, Hispanics, and non-Hispanic whites. IMPLICATIONS: This study shows that the NCI clinical trials are, as a whole, racially/ethnically representative of the American population and suggests that there is equal access to NCI clinical trials.

Interplay between design and analysis for behavioral intervention trials with community as the unit of randomization.

This paper outlines an approach for the design and analysis of randomized controlled trials investigating community-based interventions for behavioral change aimed at health promotion. The approach is illustrated using the Community Intervention Trial for Smoking Cessation (COMMIT), conducted from 1988 to 1993, involving 11 pairs of communities in North America, matched on geographic location, size, and sociodemographic factors. The situation discussed is when assignment to intervention is done at the community level; for COMMIT, the very nature of the intervention required this. The number of communities as a key determinant of the statistical power of the trial. The use of matched pairs of communities can achieve a gain in statistical efficiency. Randomization is used to obtain an unbiased assessment of the intervention effect; randomization also provides the basis for statistical analysis. Permutation tests (and corresponding test-based confidence intervals), using community as the unit of analysis, follow directly from the randomization distribution. Within this framework, individual-level covariates can be used for imputation of missing values and for adjusting analyses of intervention effect.

Results of a randomized trial comparing intra-arterial cisplatin and intravenous PCNU for the treatment of primary brain tumors in adults: Brain Tumor Cooperative Group trial 8420A.

PURPOSE: To test the efficacy of intra-arterial (IA) cisplatin versus intravenous (IV) PCNU for treating primary brain tumors, in a randomized trial (Brain Tumor Cooperative Group [BTCG] Trial 8420A). METHODS: 311 adult patients (ages 19-79 years; median 45) with supratentorial tumors (confirmed histologically) were randomized by nine participating institutions. Patients were required to have completed radiotherapy (4500-6020 cGy to the tumor bed) before randomization. Patients were stratified as either nonprogressive (clinically and radiologically stable) or progressive. Results were analyzed for the 311 patients in the randomized population (RP), and for the 281 patients in the Valid Study Group (VSG) meeting protocol eligibility requirements. 56% of patients in the VSG had glioblastoma multiforme, 33% had other malignant glioma, and 11% had low-grade glioma. 64% were stratified as progressive. 12% had received prior chemotherapy. RESULTS: The group randomized to PCNU had the longer survival (p = 0.06 for the RP, p = 0.07 for the VSG). In the VSG, median survival was 10 months for the cisplatin group, 13 months for the PCNU group. The difference between treatment groups was significant (p < or = 0.02) when adjusted for important prognostic factors. PCNU lead to greater hematotoxicity; cisplatin lead to greater renal toxicity and some ototoxicity. Some cisplatin patients experienced complications associated with IA administration, including six cases of encephalopathy. CONCLUSION: The trial showed a survival advantage to the group randomized to PCNU, although the difference was modest. Coupled with previous BTCG results, these trails suggest that PCNU is an active drug for brain tumors.