A pregnancy lifestyle intervention to prevent gestational diabetes risk factors in overweight Hispanic women: a feasibility randomized controlled trial.

AIMS: To pilot the feasibility of a prenatal lifestyle intervention to modify physical activity and diet among pregnant overweight and obese Hispanic women, with the aim of reducing risk factors for gestational diabetes mellitus. METHODS: Women were randomized either to a lifestyle intervention (n = 33, 48.5%), consisting of a culturally and linguistically modified, motivationally targeted, individually tailored 6-month prenatal programme, or to standard care (n = 35, 51.5%). Bilingual and bicultural health educators encouraged women to achieve guidelines for physical activity, decrease saturated fat and increase dietary fibre. Outcomes included gestational weight gain, infant birth weight and biomarkers associated with insulin resistance. RESULTS: Patient retention up to delivery was 97% in both study groups. The lifestyle intervention attenuated the pregnancy-associated decline in moderate-intensity physical activity, but differences between groups were not significant (mean ± se -23.4 ± 16.6 vs -27.0 ± 16.2 metabolic equivalent of task h/week; P = 0.88). Vigorous-intensity activity increased during the course of pregnancy in the lifestyle intervention group (mean ± se 1.6 ± 0.8 metabolic equivalent of task h/week) and declined in the standard care group (-0.8 ± 0.8 metabolic equivalent of task h/week; P = 0.04). The lifestyle intervention group also had slightly lower gestational weight gain and infant birth weights compared with the standard care group; however, these differences were not statistically significant. There were no statistically significant differences in biomarkers of insulin resistance between groups. CONCLUSIONS: Findings suggest that a motivationally matched lifestyle intervention is feasible and may help attenuate pregnancy-related decreases in vigorous physical activity in a population of overweight and obese Hispanic women. The intervention protocol can readily be translated into clinical practice in underserved and minority populations.

Estimation of finite population parameters with auxiliary information and response error.

We use a finite population mixed model that accommodates response error in the survey variable of interest and auxiliary information to obtain optimal estimators of population parameters from data collected via simple random sampling. We illustrate the method with the estimation of a regression coefficient and conduct a simulation study to compare the performance of the empirical version of the proposed estimator (obtained by replacing variance components with estimates) with that of the least squares estimator usually employed in such settings. The results suggest that when the auxiliary variable distribution is skewed, the proposed estimator has a smaller mean squared error.

Providing patients with pharmacogenetic test results affects adherence to statin therapy: results of the Additional KIF6 Risk Offers Better Adherence to Statins (AKROBATS) trial.

Despite the clinical benefit of statin therapy and the numerous strategies used to improve adherence, no strategy has used direct communication of genetic test results to the patient as an adherence and persistence motivator. We investigated in a real-world setting the effect of a process of providing KIF6 test results and risk information directly to 647 tested patients on 6-month statin adherence (proportion of days covered (PDC)) and persistence compared with concurrent non-tested matched controls. Adjusted 6-month statin PDC was significantly greater in tested patients: 0.77 (95% confidence interval (CI) 0.72-0.82) vs controls 0.68 (95% CI 0.63-0.73), P<0.0001. Significantly more tested patients were adherent (PDC⩾0.80) (63.4% (59.6-67.1%) vs 45.0% (41.1-48.8%), P<0.0001) and persisted on therapy (69.1% (65.4-72.5%) vs 53.3% (49.4-57.1%), P<0.0001). Similar results were observed in a secondary comparison with 779 unmatched patients who declined testing. The Additional KIF6 Risk Offers Better Adherence to Statins trial provides the first evidence that pharmacogenetic testing may modify patient adherence.

Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey.

To develop a benchmark measure of US physicians' level of knowledge and extent of use of pharmacogenomic testing, we conducted an anonymous, cross-sectional, fax-based, national survey. Of 397,832 physicians receiving the survey questionnaire, 10,303 (3%) completed and returned it; the respondents were representative of the overall US physician population. The factors associated with the decision to test were evaluated using χ(2) and multivariate logistic regression. Overall, 97.6% of responding physicians agreed that genetic variations may influence drug response, but only 10.3% felt adequately informed about pharmacogenomic testing. Only 12.9% of physicians had ordered a test in the previous 6 months, and 26.4% anticipated ordering a test in the next 6 months. Early and future adopters of testing were more likely to have received training in pharmacogenomics, but only 29.0% of physicians overall had received any education in the field. Our findings highlight the need for more effective physician education on the clinical value, availability, and interpretation of pharmacogenomic tests.

Aspirin reduces cutaneous flushing after administration of an optimized extended-release niacin formulation.

OBJECTIVE: Niacin is an effective treatment for dyslipidemia due to its favorable effects on multiple lipid parameters. Clinical utility of niacin is sometimes limited, however, because of cutaneous flushing. A once-daily, extended-release (ER) niacin formulation has been shown to significantly reduce flushing compared to immediate-release niacin. An optimized (reformulated) version of niacin ER has recently been developed and was shown in a previous study to significantly reduce flushing intensity (severity) compared to the non-optimized (commercial) formulation. The current study was designed to evaluate the effect of aspirin on various indices of flushing when administered with the optimized niacin ER formulation. METHOD: This was a randomized, double-blind, double-dummy, placebo-controlled flush provocation crossover study in healthy males. To increase the probability of flushing, subjects received a single dose of reformulated niacin ER 2,000 mg, which is the upper limit of the approved dosage range. Subjects received 650 mg aspirin orally either 30 minutes before or concomitantly with niacin ER, or placebo with niacin ER, in 3-way crossover fashion. The primary endpoint was the number of subjects who reported at least one flushing event. Secondary endpoints included the perceived intensity and duration of flushing symptoms. RESULTS: In the 148 men who completed all treatments, aspirin significantly reduced flushing incidence (the primary endpoint) following administration of niacin ER compared with placebo. Among subjects receiving placebo, 77% of subjects reported flushing with niacin ER. Among subjects receiving aspirin, 53-61% of subjects reported flushing (pretreatment and concomitant treatment, respectively, both p < 0.001 compared with placebo) with niacin ER. Aspirin also significantly reduced intensity and duration of flushing (by 30-40%) compared with no aspirin. The two aspirin-containing treatments (i.e. pre- or concomitant treatment) were similar in their effects on flushing incidence, intensity and duration. Median intensity on a 100 mm visual analogue scale (VAS) was reduced from 33 mm with placebo to 19-23 mm with aspirin. Median duration was reduced from approximately 1 hour with placebo to 37-48 minutes with aspirin. CONCLUSION: Aspirin significantly reduced the incidence, intensity and duration of flushing associated with reformulated niacin ER. These results support the administration of aspirin prophylactically to decrease niacin-induced cutaneous flushing and to improve patient adherence and acceptability of chronic niacin treatment at therapeutic doses.

Improved control of niacin-induced flushing using an optimized once-daily, extended-release niacin formulation.

INTRODUCTION: Niacin is a recognized treatment for dyslipidemia due to its favorable effects on all lipid parameters. However, the clinical use of niacin has been limited by its adverse effects, particularly cutaneous flushing. A newly reformulated 1,000 mg niacin ER tablet has been designed to reduce flushing relative to the original commercial niacin ER formulation. The aim of this study is to compare the incidence, intensity and duration of flushing between the 1,000 mg reformulated niacin ER and the 1,000 mg commercially available formulation, when administered as a single 2,000 mg dose to healthy male volunteers. METHODS: This was a double-blind, double-dummy, placebo-controlled, 3-way crossover, flush provocation study conducted at a single center. To increase the probability of flushing, subjects were administered niacin ER at the upper limit of the approved dosage range (2,000 mg), and were precluded from using aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) during the study. Subjects received reformulated niacin ER, commercial niacin ER or placebo in a 3-way crossover fashion. The primary flushing variable was the occurrence of a flushing event. Secondary flushing variables included the number of flushing episodes, intensity and duration of flushing for both overall flushing events and for individual symptoms of flushing (redness, warmth, tingling and itching). RESULTS: A total of 156 subjects were enrolled in the study. Of 133 subjects who received at least 1 dose of study medication in at least 2 study periods, 89% of subjects experienced flushing during treatment with reformulated niacin ER, and 98% of subjects experienced flushing during treatment with commercial niacin ER. This difference was statistically significant (p - 0.0027). Reformulated niacin ER resulted in a 42% reduction in median flush intensity (p < 0.0001) and a 43% reduction in median flush duration (p < 0.0001) relative to commercial niacin ER. The duration of first flushing event was more than 1 hour shorter with reformulated niacin ER. During the study, 29% of subjects (45/156) experienced treatment-emergent adverse events, which were mostly mild in intensity and considered to be remotely related or unrelated to the study drug. CONCLUSION: The 1,000 mg reformulated niacin ER tablet substantially decreases the incidence, intensity and duration of flushing relative to the commercially available 1,000 mg niacin ER tablet, and represents an improved niacin therapy option.

Low doses of dietary lead are associated with a profound reduction in the time to the onset of puberty in female mice.

We report results from a replication in second and third generation female mice of accelerated time to puberty associated with low Pb exposure levels . Mice in the 2nd generation study are offspring of mice from the initial study; the 3rd generation mice are offspring from mice in the 2nd generation study. For each generation the time to puberty onset was markedly influenced by exposure to dietary lead. Modest increases in blood lead concentration from a normal background of 2-3 to 8-13 micro g/dl delayed the onset of puberty by 10-20% from a normal of 33-35 days to about 40-43 days; reducing blood lead from 2-3 to 0.7 micro g/dl was associated with profound acceleration of puberty to 21 days, an enhancement by over 30%. This dose-response relationship, which replicates previous novel findings, has possible ecological as well as public health significance and indicates that lead is able to induce biologically significant changes at blood lead levels previously thought to be without effect.

Below background levels of blood lead impact cytokine levels in male and female mice.

A number of studies have documented that Pb exerts immunotoxic effects on T lymphocytes. In studies designed to explore this general response over a broad dose range, female Swiss mice were administered six different diets containing Pb acetate 1 day after mating. During lactation, the mothers received the same feed given during pregnancy, and the same diets were administered to the offspring for 9 months after weaning. At the end of exposure, blood Pb level in the offspring was determined, and possible changes in two type 1 cytokines (IL-2, INF-gamma) and one type 2 cytokine (IL-4) in the serum were measured. At higher dietary Pb levels (40 and 400 ppm), a significant increase in IL-4 production was associated with a profound decrease in INF-gamma and IL-2 production. At the lowest Pb diet level (0.02 ppm), which resulted in a blood lead level of (0.8 microg/dL), which is below background (2-3 microg/dL) values in humans, increases in INF-gamma and IL-2 production along with a significant decrease in IL-4 production were observed. The findings provide evidence of a reversal of lead-induced cytokine skewing depending on the blood lead concentration. As blood lead concentration increases, there is a notable skewing toward Th2, while the pattern is reversed favoring Th1 development at lower blood lead values. The present findings are also notable since they indicate the potential for dietary Pb to have significant biological effects below normal background concentrations.

Effects of low doses of dietary lead on puberty onset in female mice.

Female Swiss mice typically display signs of puberty at about 33-37 days of age. In the present investigation (96 female mice tested in 8 Pb exposure levels, n=12 per exposure level), the time to puberty onset was markedly influenced by exposure to dietary lead. While modest increases in blood lead concentrations from a normal background of 2-3 to 13.2 microg/dl delayed the onset of puberty by 15-20% to about 40-43 days, reducing blood lead from 2-3 to 0.7 microg/dl was associated with an acceleration of puberty to 21 days, an enhancement by over 30%. This dose-response relationship represents novel findings of possible ecological as well as public health significance and indicates that lead is able to induce biologically significant changes at blood lead levels previously thought to be without effect.

Effects of low doses of dietary lead on red blood cell production in male and female mice.

The effect of lead (Pb) ingestion on hematological parameters in male and female Swiss mice was assessed. Eight different doses of Pb were administered through preparation of different feeds. The levels of Pb in the diet were designed to provide exposure below (0.6 to <2.0 microg/dl) and above (>2.0-13 microg/dl) normal background. One litter of mice was exposed to each Pb dose, with the mother given the feed 1 day after mating, and the mother and offspring continuing to receive the feed until the litter was 90 days old. Male and female mice receiving below normal background levels of dietary Pb displayed enhanced red blood cell (RBC) production as measured by increased numbers of RBC and increased hemoglobin and hematocrit values. However, as the blood Pb levels approached 10 microg/dl there was a marked decrease in RBC production. These findings are significant since Pb was biologically active in a stimulating manner below typical background levels (2.0 microg/dl) while adversely effecting red cell synthesis at above background levels (7.0-13 microg/dl) encountered in the environment by humans.

Effects of per os lead acetate administration on mouse hepatocyte survival.

Previously published studies indicate that hepatotoxicity is associated with high blood lead (Pb) levels in animal models and humans. The present investigation evaluated the effects of in vivo Pb exposure via drinking water on mouse hepatocyte survival in vitro when blood Pb concentrations reflected those seen in children in urban and rural settings (2-15 microg/dl). The findings indicated a biphasic dose-response with low concentrations associated with a modest decrease in hepatocyte survival, while at the highest concentration, survival was significantly enhanced (60%). Since these responses were associated with concentrations normally encountered by children, follow-up investigations are warranted.

Seasonal variation in household, occupational, and leisure time physical activity: longitudinal analyses from the seasonal variation of blood cholesterol study.

The authors examined seasonal variation in physical activity in longitudinal analyses of 580 healthy adults from Worcester, Massachusetts (the Seasonal Variation of Blood Cholesterol Study, 1994-1998). Three 24-hour physical activity recalls administered five times during 12 months of follow-up were used to estimate household, occupational, leisure time, and total physical activity levels in metabolic equivalent (MET)-hours/day. Trigonometric models were used to estimate the peak-to-trough amplitude and phase of the peaks in activity during the year. Total activity increased by 1.4 MET-hours/day (121 kcal/day) in men and 1.0 MET-hours/day (70 kcal/day) in women during the summer in comparison with winter. Moderate intensity nonoccupational activity increased by 2.0-2.4 MET-hours/day in the summer. During the summer, objectively measured mean physical activity increased by 51 minutes/day (95% confidence interval: 20, 82) in men and by 16 minutes/day (95% confidence interval: -12, 45) in women. The authors observed complex patterns of seasonal change that varied in amplitude and phase by type and intensity of activity and by subject characteristics (i.e., age, obesity, and exercise). These findings have important implications for clinical research studies examining the health effects of physical activity and for health promotion efforts designed to increase population levels of physical activity.

Daily soil ingestion estimates for children at a Superfund site.

Ingestion of contaminated soil by children may result in significant exposure to toxic substances at contaminated sites. Estimates of such exposure are based on extrapolation of short-term-exposure estimates to longer time periods. This article provides daily estimates of soil ingestion on 64 children between the ages of 1 and 4 residing at a Superfund site; these values are employed to estimate the distribution of 7-day average soil ingestion exposures (mean, 31 mg/day; median, 17 mg/day) at a contaminated site over different time periods. Best linear unbiased predictors of the 95th-percentile of soil ingestion over 7 days, 30 days, 90 days, and 365 days are 133 mg/day, 112 mg/day, 108 mg/day and 106 mg/day, respectively. Variance components estimates (excluding titanium and outliers, based on Tukey's far-out criteria) are given for soil ingestion between subjects (59 mg/day)2, between days on a subject (95 mg/day)2, and for uncertainty on a subject-day (132 mg/day)2. These results expand knowledge of potential exposure to contaminants among young children from soil ingestion at contaminated sites. They also provide basic distributions that serve as a starting point for use in Monte Carlo risk assessments.

Preferences for treatment outcomes in patients with heart failure: symptoms versus survival.

BACKGROUND: Patient preferences for congestive heart failure therapy outcomes may vary depending on the goals of improving symptoms versus survival, but this has not been extensively investigated. Our objective was to analyze patient preferences for congestive heart failure therapy outcomes based on the goals of symptom versus survival improvement. METHODS AND RESULTS: This was a prospective, full-profile conjoint analysis study of individual preferences for congestive heart failure treatment outcomes. Conjoint analysis was based on ratings of 16 treatment-outcome profiles, each consisting of 4 attributes (tiredness, shortness of breath, depression, and survival) varied across 4 severity levels. Part-worths (utilities) and importance weights were calculated for each attribute to determine their relative contribution to the full-profile rating decision using standard full-profile conjoint analysis techniques. Fifty-one patients with congestive heart failure from our medical center (University of Pennsylvania Medical Center, Philadelphia, PA) and 47 age-, gender-, and race-matched control subjects were studied. Part-worths and importance weights were significantly different for shortness of breath and depression between patients and control subjects. Symptom-sensitive (n = 33) and survival-sensitive (n = 17) treatment outcome preference segments were identified within the patient group. Importance weights for symptom-sensitive versus survival-sensitive patients were as follows: tiredness 0.30+/-0.10 versus 0.16+/-0.09 (P < .01); shortness of breath 0.26+/-0.08 versus 0.21+/-0.08 (P = .07); depression 0.26+/-0.09 versus 0.19+/-0.09 (P = .01); and survival 0.18+/-0.07 versus 0.43+/-0.11 (P < .01). There were no significant predictors of which treatment outcome preference segment a patient belonged. Control subjects did not display similar preference segmentation. CONCLUSIONS: Symptomatic congestive heart-failure patients were clustered into symptom-sensitive and survival-sensitive segments in a manner suggesting that treatment outcomes of improved symptoms were of greater importance to the majority than longer survival. A full understanding of these individual preferences may have important implications for the design of therapy for heart-failure patients.

Children's emotional and behavioral disorders: attributions of parental responsibility by professionals.

In the wake of the neurobiological "revolution," do mental health professionals still assign etiological responsibility for emotional and behavioral disorders to deficient or harmful parenting? This study investigated differences in attributions of causality by theoretical orientation, professional discipline, areas of practice, familiarity with parent support groups, and demographic characteristics. Implications for policy, research, and practice are discussed.

Comparing physical activity assessment methods in the Seasonal Variation of Blood Cholesterol Study.

PURPOSE: This paper evaluated three measures of physical activity employed in the Seasonal Variation of Blood Cholesterol Study (Seasons), and it had two objectives: 1) To examine the laboratory validity of the Actillume activity monitor, and 2) To examine the relative validity of three 24-h physical activity recalls (24HR) in quantifying short-term physical activity behaviors. METHODS: Nineteen healthy middle-age adults completed seven activity trials (reading, typing, box moving, stepping, and walking (3.5, 4.25, 5.0 km x h(-1))) while oxygen consumption and Actillume measures were obtained. ANOVA, linear regression, and a scatter plot were employed to examine the validity of the Actillume. In relative validity analyses of the 24HR in the Seasons study, participants (N = 481) completed two or three 24HR (MET-h x d(-1)) and a modified Baecke Questionnaire. A subset of the cohort (N = 41) wore the Actillume for 3-8 d (counts x min(-1) x d(-1)). The relative validity of the 24HR method was examined by comparison to these criterion measures. RESULTS: In laboratory validation analyses, the monitor was found to discriminate between sedentary and moderate intensity activities, changes in walking speed, and to account for 79% of the variance in oxygen consumption across sedentary and walking trials. In relative validity analyses, correlations between the 24HR and the modified Baecke ranged from 0.29 to 0.52 (P < 0.01) across total, household, occupational, and leisure-time activities. CONCLUSIONS: In laboratory testing, the Actillume monitor discriminated between sedentary and moderate intensity activities and was highly correlated with oxygen consumption. Three 24HR of physical activity were observed to have a relative validity that was comparable to published data from other short-term activity assessments that also employed the Baecke Questionnaire and activity monitors as criterion measures.

Why not routinely use best linear unbiased predictors (BLUPs) as estimates of cholesterol, per cent fat from kcal and physical activity?

Measures of biologic and behavioural variables on a patient often estimate longer term latent values, with the two connected by a simple response error model. For example, a subject's measured total cholesterol is an estimate (equal to the best linear unbiased estimate (BLUE)) of a subject's latent total cholesterol. With known (or estimated) variances, an alternative estimate is the best linear unbiased predictor (BLUP). We illustrate and discuss when the BLUE or BLUP will be a better estimate of a subject's latent value given a single measure on a subject, concluding that the BLUP estimator should be routinely used for total cholesterol and per cent kcal from fat, with a modified BLUP estimator used for large observed values of leisure time activity. Data from a large longitudinal study of seasonal variation in serum cholesterol forms the backdrop for the illustrations. Simulations which mimic the empirical and response error distributions are used to guide choice of an estimator. We use the simulations to describe criteria for estimator choice, to identify parameter ranges where BLUE or BLUP estimates are superior, and discuss key ideas that underlie the results.

Intravenous nitroglycerin tolerance in patients with ischemic cardiomyopathy and congestive heart failure.

A daily nitrate-free interval (NFI) lasting 4-7 hours was instituted in four patients with severe congestive heart failure secondary to myocardial ischemia who were awaiting orthotopic heart transplantation. The duration of intravenous nitroglycerin therapy ranged from 14-55 days, and the maximum dosage was 50-400 microg/minute. Anginal events occurred more frequently during the NFI than during intravenous therapy. An NFI of 8-12 hours reduces tolerance in patients with congestive heart failure and stable angina. However, the experience in these patients with recurrent ischemia does not support its use to prevent ischemic events during hospitalization.

Treatment patterns for heart failure in a primary care environment.

Little published information regarding current pharmacotherapeutic treatment patterns for congestive heart failure (CHF) in nonacademic, ambulatory care settings is available. We sought to assess, in a nonacademic primary care environment, pharmacotherapeutic treatment patterns for CHF with respect to consistency with clinical trial evidence and published treatment guideline recommendations. Over an 18-month period, we examined CHF pharmacotherapy using a computerized, integrated clinical diagnoses and prescription database from an outpatient community healthcare center without academic affiliations. We identified adult patients meeting contact criteria and with diagnosis of CHF by International Classification of Diseases (ICD-9-CM) coding and assessed prescribed therapy as well as select comorbid conditions. Drugs of interest included those with known or suspected benefit or detriment and those with unproven benefit. An eligible group of 14,983 patients was identified, from which a cohort of 148 patients with CHF was selected. Forty-one percent of these 148 patients were prescribed an angiotensin converting enzyme (ACE) inhibitor, 34% digoxin, 12% diuretic, 12% hydralazine + nitrate, 20% inhaled beta-agonists, and 66% warfarin. Only 5% of patients were prescribed the combination of an ACE inhibitor, digoxin, and diuretic. Thirty-one percent had a comorbid diagnosis of atrial fibrillation, of whom 44% were prescribed digoxin, 22% diltiazem, 15% beta-blockers, 15% digoxin and diltiazem, 7% digoxin and a beta-blocker, and 33% warfarin. In general, recommended therapies for CHF appeared underutilized in this cohort, whereas those of unclear benefit and potential detriment appeared overutilized. Although these results may not be readily generalized to the entire healthcare system, they do suggest a need for additional analysis and potential intervention.

Patient preferences for thrombolytic therapy in acute myocardial infarction.

BACKGROUND: Despite extensive professional debate regarding the optimal thrombolytic therapy strategy in acute myocardial infarction (AMI), patient preferences have not been explored. METHODS: Preferences among patients with known or suspected coronary artery disease for treatment with tissue plasminogen activator (tPA) or streptokinase (SK) for AMI were determined using a questionnaire presenting GUSTO-1 trial and drug cost data. Preferences were based on consideration of 30-day mortality (M) alone, hemorrhagic stroke rate (SR) alone, overall preference (M + SR), drug acquisition costs, and the estimated annual costs of using a single agent to treat all AMIs. Cost-related responses were provided under payer designations of self, third-party insurance, and federal government. RESULTS: The response rate was 81% (101/125 patients). tPA was preferred by 84%, and SK by 66%, for M alone and SR alone, respectively (chi 2, p < 0.01). Overall preference (M + SR) favored tPA (78%, p < 0.01). tPA preference decreased to 43% considering drug acquisition costs under the self-pay option (p < 0.01 vs M + SR). Similar trends of lesser magnitude were also observed for the third-party and government-payer options. CONCLUSIONS: Under conditions of zero cost and consideration of mortality plus stroke-risk data, tPA were preferred overall due to its lower mortality. Introduction of drug-cost data significantly shifted the preference toward SK, particularly under the self-payer designation. Patient preferences for thrombolytic therapy in AMI indicate tradeoffs between clinical attributes and costs, and should assist in framing medical debate and decision making.