Use of atorvastatin in systemic lupus erythematosus in children and adolescents.

OBJECTIVE: Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. METHODS: A total of 221 participants with pediatric SLE (ages 10-21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n=113) or placebo (n=108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. RESULTS: Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P=0.24). The atorvastatin group achieved lower hsCRP (P=0.04), total cholesterol (P<0.001), and low-density lipoprotein (P<0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023-0.0144 mm/year; P<0.05). Serious adverse events and critical safety measures did not differ between groups. CONCLUSION: Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.

Effect of varying contrast material iodine concentration and injection technique on the conspicuity of hepatocellular carcinoma during 64-section MDCT of patients with cirrhosis.

OBJECTIVES: The aim of this study was to compare the intraindividual effects of contrast material with two different iodine concentrations on the conspicuity of hepatocellular carcinoma (HCC) and vascular and hepatic contrast enhancement during multiphasic, 64-section multidetector row CT (MDCT) in patients with cirrhosis using two contrast medium injection techniques. METHODS: Patients were randomly assigned to one of two groups with an equal iodine dose but different contrast material injection techniques: scheme A, fixed injection duration (25 s), and scheme B, fixed injection flow rate (4 ml s(-1)). For each group, patients were randomised to receive both moderate-concentration contrast medium (MCCM) and high-concentration contrast medium (HCCM) during two CT examinations within 3 months. Enhancement of the aorta, liver and portal vein and the tumour-to-liver contrast-to-noise ratio (CNR) were compared between MCCM and HCCM. RESULTS: 30 patients (mean age 59 years; range 45-80 years; 16 patients in scheme A and 14 in scheme B) with a total of 31 confirmed HCC nodules were prospectively enrolled. For scheme B, the mean contrast enhancement of the aorta and tumour-to-liver CNR were significantly higher with HCCM than with MCCM during the hepatic arterial phase (+350.5 HU vs +301.1 HU, p = 0.001, and +7.5 HU vs +5.5 HU, p = 0.004). For both groups, there was no significant difference between MCCM and HCCM for all other comparisons. CONCLUSION: For a constant injection flow rate, HCCM significantly improves the conspicuity of HCC lesions and aortic enhancement during the hepatic arterial phase on 64-section MDCT in patients with cirrhosis.

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

Observer detection limits for a dedicated SPECT breast imaging system.

An observer-based contrast-detail study is performed in an effort to evaluate the limits of object detectability using a dedicated CZT-based breast SPECT imaging system under various imaging conditions. A custom geometric contrast-resolution phantom was developed that can be used for both positive ('hot') and negative contrasts ('cold'). The 3 cm long fillable tubes are arranged in six sectors having equal inner diameters ranging from 1 mm to 6 mm with plastic wall thicknesses of <0.25 mm, on a pitch of twice their inner diameters. Scans of the activity filled tubes using simple circular trajectories are obtained in a 215 mL uniform water filled cylinder, varying the rod:background concentration ratios from 10:1 to 1:10 simulating a large range of biological uptake ratios. The rod phantom is then placed inside a non-uniformly shaped 500 mL breast phantom and scans are again acquired using both simple and complex 3D trajectories for similarly varying contrasts. Summed slice and contiguous multi-slice images are evaluated by five independent readers, identifying the smallest distinguishable rod for each concentration and experimental setup. Linear and quadratic regression is used to compare the resulting contrast-detail curves. Results indicate that in a moderately low-noise 500 mL background, using the SPECT camera having 2.5 mm intrinsic pixels, the mean detectable rod was approximately 3.4 mm at a 10:1 ratio, degrading to approximately 5.2 mm with the 2.5:1 concentration ratio. The smallest object detail was observed using a 45 degrees tilted trajectory acquisition. The complex 3D projected sine wave acquisition, however, had the most consistent combined intra- and inter-observer results, making it potentially the best imaging approach for consistent results.

Neuropsychological and psychiatric sequelae of pallidotomy for PD: clinical trial findings.

OBJECTIVE: To evaluate the neuropsychological and psychiatric sequelae of unilateral posterior pallidotomy for treatment of PD. METHODS: Patients with idiopathic PD completed baseline and 3- and 6-month assessments after random assignment to an immediate surgery (n = 17) or medical management (n = 16) group. RESULTS: Compared with the medical management group, the immediate surgery group with single lesions centered on the posterior internal pallidum showed superior naming and response inhibition, better verbal recall at 6 months, but greater distractibility, a tendency toward lower phonemic fluency, and a transient (3 months' only) semantic fluency deficit. The group with left lesions had more neuropsychological deficits than the group with right lesions or the medical management group, although these occurred mainly at 3 (but not 6) months. At 6 months, the patients with left lesions showed better verbal memory retention than the patients with right lesions. On most measures, the pattern of individual clinical change did not differ as a function of surgery or lesion laterality, with the exception of a higher frequency of decline in phonemic fluency in the patients with left lesions at 6 months. Although psychiatric status did not change overall, a history of depression tended to increase the risk of a depressive episode following surgery. CONCLUSIONS: Well-targeted, uncomplicated, unilateral pallidotomy does not produce overall neuropsychological or psychiatric change, although there are subtle changes on specific measures sensitive to frontal lobe function.

Modeling concordance correlation via GEE to evaluate reproducibility.

Clinical studies are often concerned with assessing whether different raters/methods produce similar values for measuring a quantitative variable. Use of the concordance correlation coefficient as a measure of reproducibility has gained popularity in practice since its introduction by Lin (1989, Biometrics 45, 255-268). Lin's method is applicable for studies evaluating two raters/two methods without replications. Chinchilli et al. (1996, Biometrics 52, 341-353) extended Lin's approach to repeated measures designs by using a weighted concordance correlation coefficient. However, the existing methods cannot easily accommodate covariate adjustment, especially when one needs to model agreement. In this article, we propose a generalized estimating equations (GEE) approach to model the concordance correlation coefficient via three sets of estimating equations. The proposed approach is flexible in that (1) it can accommodate more than two correlated readings and test for the equality of dependent concordant correlation estimates; (2) it can incorporate covariates predictive of the marginal distribution; (3) it can be used to identify covariates predictive of concordance correlation; and (4) it requires minimal distribution assumptions. A simulation study is conducted to evaluate the asymptotic properties of the proposed approach. The method is illustrated with data from two biomedical studies.

The impact of lesion laterality on neuropsychological change following posterior pallidotomy: a review of current findings.

This paper reviews seven studies evaluating the impact of lesion laterality on the neuropsychological sequelae of posterior pallidotomy for treatment of Parkinson's disease. Left lesions of the internal globus pallidus (GPi) were associated with subtle deficits on measures sensitive to frontal lobe function. The findings of a randomized clinical trial including a patient control group indicated that many of these deficits were transient, resolving by 6 months following surgery. Right GPi lesions were not consistently associated with neuropsychological deficit, except in one study that included a significant proportion of demented patients. It is hypothesized that when neuropsychological decline is present following surgery, this reflects impingement of posterior GPi lesions into proximal regions such as anterior GPi or the external pallidum that participate in cognitive basal ganglia-thalamocortical circuits. The findings from neuroimaging will be important for elucidating the relationship between lesion locus and neuropsychological sequelae.

Early childhood nutrition, education and fertility milestones in Guatemala.

Data on fertility milestones were collected in 1994 and linked to information collected in a trial conducted in eastern Guatemala between 1969 and 1977, to examine whether early childhood nutrition was associated with the timing of fertility milestones. In the original trial, two pairs of villages were randomly allocated to receive either a high energy, high protein supplement (Atole) or a low energy, no-protein supplement (Fresco). Mean age at follow-up was 23.47 y (n = 240). About 62% of women had experienced first birth (median age at first birth = 19.83 y). The median intervals from menarche to first intercourse and from first intercourse to first birth were 5.67 and 0.95 y; they were 1.68 and 0.06 y shorter, respectively, for the Atole group than for the Fresco group. Women who had received Atole in utero and/or during early childhood experienced earlier milestones even after adjusting for socioeconomic status (SES), education and age at the prior event. Median age at first birth was 1.17 y earlier for the Atole group. Better growth during early childhood (not severely stunted) led to earlier milestones (median age at first birth was 1.04 y earlier), primarily among women with illiterate fathers. Completion of primary school significantly delayed fertility milestones; the median age at first birth was 4.27 y later for those who completed primary school compared with those who did not (P < 0.05). In sum, improved nutrition during early childhood results in earlier fertility milestones, but the effects of schooling in delaying fertility milestones are greater in magnitude. Intervention programs that improve early childhood nutrition should be accompanied by investments in education that ensure that girls complete primary school.

Testing proportionality in the proportional odds model fitted with GEE.

Generalized estimating equations (GEE) methodology as proposed by Liang and Zeger has received widespread use in the analysis of correlated binary data. Miller et al. and Lipsitz et al. extended GEE to correlated nominal and ordinal categorical data; in particular, they used GEE for fitting McCullagh's proportional odds model. In this paper, we consider robust (that is, empirically corrected) and model-based versions of both a score test and a Wald test for assessing the assumption of proportional odds in the proportional odds model fitted with GEE. The Wald test is based on fitting separate multiple logistic regression models for each dichotomization of the response variable, whereas the score test requires fitting just the proportional odds model. We evaluate the proposed tests in small to moderate samples by simulating data from a series of simple models. We illustrate the use of the tests on three data sets from medical studies.

A regression model for multivariate random length data.

Multivariate random length data occur when we observe multiple measurements of a quantitative variable and the variable number of these measurements is also an observed outcome for each experimental unit. For example, for a patient with coronary artery disease, we may observe a number of lesions in that patient's coronary arteries, along with percentage of blockage of each lesion. Barnhart and Sampson first proposed the multiple population model to analyse multivariate random length data without covariates. This paper extends their approach to deal with multiple covariates. We propose a new multiple population regression model with covariates, and discuss the estimation issues. We analyse data from the TYPE II coronary intervention study to illustrate the methodology.

Molecular epidemiology of Campylobacter jejuni in broiler flocks using randomly amplified polymorphic DNA-PCR and 23S rRNA-PCR and role of litter in its transmission.

Poultry has long been cited as a reservoir for Campylobacter spp., and litter has been implicated as a vehicle in their transmission. Chicks were raised on litter removed from a broiler house positive for Campylobacter jejuni. Litter was removed from the house on days 0, 3, and 9 after birds were removed for slaughter. Chicks were raised on these three litters under controlled conditions in flocks of 25. None of these birds yielded C. jejuni in their cecal droppings through 7 weeks. Two successive flocks from the same Campylobacter-positive broiler house were monitored for Campylobacter colonization. Campylobacter jejuni prevalence rates were determined for each flock. Randomly amplified polymorphic DNA (RAPD)-PCR and 23S rRNA-PCR typing methods were used to group isolates. A high prevalence (60%) of C. jejuni in flock 1 coincided with the presence of an RAPD profile not appearing in flock 2, which had a lower rate of prevalence (28%). A 23S rRNA-PCR typing method was used to determine if strains with different RAPD profiles and different prevalence rates contained different 23S sequences. RAPD profiles detected with higher prevalence rates contained a spacer in the 23S rRNA region 100% of the time, while RAPD profiles found with lower prevalence rates contained an intervening sequence less than 2% of the time. Data suggest varying colonizing potentials of different RAPD profiles and a source other than previously used litter as a means of transmission of C. jejuni. These molecular typing methods demonstrate their usefulness, when used together, in this epidemiologic investigation.

Goodness-of-fit tests for GEE modeling with binary responses.

Analysis of data with repeated measures is often accomplished through the use of generalized estimating equations (GEE) methodology. Although methods exist for assessing the adequacy of the fitted models for uncorrelated data with likelihood methods, it is not appropriate to use these methods for models fitted with GEE methodology. We propose model-based and robust (empirically corrected) goodness-of-fit tests for GEE modeling with binary responses based on partitioning the space of covariates into distinct regions and forming score statistics that are asymptotically distributed as chi-square random variables with the appropriate degrees of freedom. The null distribution and the statistical power of the proposed goodness-of-fit tests were assessed using simulated data. The proposed goodness-of-fit tests are illustrated by two examples using data from clinical studies.

Antibiotic resistance of bacterial litter isolates.

Use of antibiotics in subtherapeutic doses as growth-promoting feed additives for animal production is widespread in the U.S. and throughout the world. Previous studies by our research group concluded that size fractionation of poultry (broiler) litter followed by storage facilitated reutilization of litter as a soil amendment or bedding supplement. However, litter microbial contamination, including antibiotic-resistant populations, and accumulation of metals and other elements may limit litter reutilization. Litter from four broiler houses was separated into a fine fraction for use as a soil amendment, and a coarse fraction for reutilization as a bedding supplement in growing subsequent flocks of broilers. Fractions and whole litter were stored in indoor piles simulating farm storage conditions for 4 mo with periodic analysis for metals, other elements, and culturable bacteria (including total and fecal coliform, Aeromonas hydrophila, Pseudomonas aeruginosa, Yersinia enterocolitica, and Campylobacter jejuni). Representative bacterial isolates were tested for their sensitivity to 12 common antibiotics (ampicillin, bacitracin, cephalothin, erythromycin, gentamicin, kanamycin, nalidixic acid, neomycin, penicillin, streptomycin, sulfisoxazole, and tetracycline) using the Kirby-Bauer technique. Pathogens and indicator bacteria tested were found to be resistant to multiple antibiotics. Data suggest that microbial contamination of litter should be reduced or eliminated prior to reutilization to minimize environmental health risks related to transfer of antibiotic-resistant bacteria to humans or other animals.

Self-report benefits of Tai Chi practice by older adults.

Older persons who are willing to begin exercise programs are often not willing to continue them. At the Atlanta FICSIT (Frailty and Injuries: Cooperative Studies of Intervention Techniques) site, individuals aged 70+ were randomized to Tai Chi (TC), individualized balance training (BT), and exercise control education (ED) groups for 15 weeks. In a follow-up assessment 4 months post-intervention, 130 subjects responded to exit interview questions asking about perceived benefits of participation. Both TC and BT subjects reported increased confidence in balance and movement, but only TC subjects reported that their daily activities and their overall life had been affected; many of these subjects had changed their normal physical activity to incorporate ongoing TC practice. The data suggest that when mental as well as physical control is perceived to be enhanced, with a generalized sense of improvement in overall well-being, older persons' motivation to continue exercising also increases.

A generalized estimating equation approach for modeling random length binary vector data.

A common measure in clinical trials and epidemiologic studies is the number of events such as seizures, hospitalizations, or bouts of disease. Frequently, a binary measure of severity for each event is available but is not incorporated in the analysis. This paper proposes methodology for jointly modeling the number of events and the vector of correlated binary severity measures. Our formulation exploits the notion that a given covariate may affect both outcomes in a similar way. We functionally link the regression parameters for the counts and binary means and discuss a generalized estimating equation (GEE) approach for parameter estimation. We discuss conditions under which the proposed joint modeling approach provides marked gains in efficiency relative to the common procedure of simply modeling the counts, and we illustrate the methodology with epilepsy clinical trial data.

Angioplasty or surgery for multivessel coronary artery disease: comparison of eligible registry and randomized patients in the EAST trial and influence of treatment selection on outcomes. Emory Angioplasty versus Surgery Trial Investigators.

The Emory Angioplasty versus Surgery Trial (EAST) showed that multivessel patients eligible for both percutaneous transluminal coronary angioplasty (PTCA) and coronary bypass surgery (CABG) had equivalent 3-year outcomes regarding survival, myocardial infarction, and major myocardial ischemia. Patients eligible for the trial who were not randomized because of physician or patient refusal were followed in a registry. This study compares the outcomes of the randomized and registry patients. Of the 842 eligible patients, 450 did not enter the trial. Their baseline features closely resembled those of the randomized patients and follow up was performed using the same methods. In the registry there was a bias toward selecting CABG in patients with 3-vessel disease (84%) and PTCA in patients with 2-vessel disease (54%). Three-year survival for the registry patients was 96.4%, which was better than the randomized patients, 93.4% (p = 0.044). Angina relief in the registry was equal for CABG and PTCA patients and was better for the PTCA registry (12.4%) than PTCA randomized patients (19.6%) (p = 0.079). Thus, the registry confirms that EAST is representative of all eligible patients and does not represent a low-risk subgroup. Since baseline differences were small, improved survival in the registry may be due to treatment selection. Physician judgment, even in patients judged appropriate for clinical trials, remains a potentially important predictor of outcomes.

The effect of Tai Chi Quan and computerized balance training on postural stability in older subjects. Atlanta FICSIT Group. Frailty and Injuries: Cooperative Studies on Intervention Techniques.

BACKGROUND AND PURPOSE: This study explored whether two exercise programs would affect the ability to minimize postural sway of 72 relatively inactive, older subjects who participated in the Atlanta FICSIT trial. SUBJECTS: Subjects were randomly assigned to (1) a computerized balance training group, (2) a tai chi group, or (3) an educational group serving as a control for exercise. Each group consisted of 24 members. METHODS: All subjects were evaluated under four postural conditions before, immediately after, and 4 months following their respective interventions, each of which was given over 15 weeks. RESULTS: Platform balance measures revealed greater stability after training among subjects in the balance training group but little change in stability among subjects in the tai chi and educational group. Subjects in the tai chi group were less afraid of falling after training compared with subjects in other groups with similar covariates. CONCLUSION AND DISCUSSION: Unlike computerized balance training, tai chi does not improve measures of postural stability. Because tai chi delayed onset to first or multiple falls in older individuals, this effect does not appear to be associated with measures of enhanced postural stability. Tai chi may gain its success, in part, from promoting confidence without reducing sway rather than primarily facilitating a reduction in sway-based measures.

Epidemiological study of Campylobacter spp. in broilers: source, time of colonization, and prevalence.

From October 1993 to August 1994, broiler chickens in four grow-out houses, two previously used (houses 1 and 2) and two newly constructed (houses 3 and 4), were used in a study to determine the source, time of infection, and prevalence of Campylobacter spp. Cecal droppings and cecal samples were obtained from the broilers. Samples were also obtained from water, feed, litter, soil, fans, and workers' boots. Samples were obtained from domestic animals and wildlife species (rectal swabs), including insects, on or near the premises. Broilers in houses 2, 3, and 4 became infected in the second or third week and were fully colonized by day 42. Campylobacter appeared in house 1 during week 2 in a low percentage of the birds, disappearing by the fourth week. Isolates were also recovered from domestic pigs and water on this farm. In house 3, the organism was isolated from workers' boots and a wild bird prior to isolation from the broilers. Following isolation from cecal droppings, the organism was isolated from water, feed, litter, feathers, flies, cattle, feces, and wild animals. In house 2, Campylobacter was isolated from cattle feces and wild birds prior to week 5, when the broilers first became infected, and thereafter from water, feed, insect, and wildlife, and cecal droppings. It was subsequently isolated from workers' boots, cattle feces, feathers, insects, and other wildlife. All ceca taken from 20 birds each from houses 2 and 3 were positive at time of slaughter (day 49). All ceca from house 1 were negative. No ceca were collected from birds originating in house 4. No specific source could be identified from the samples obtained, although apparently the organism permeates the environment and several potential sources are discussed in this paper.

Flagellin A gene restriction fragment length polymorphism patterns of Campylobacter spp. isolates from broiler production sources.

The purpose of this study was to determine the potential reservoirs for Campylobacter spp. that provide the initial sources involved with broiler chicken colonization during poultry production. We characterized the flagellin A gene (flaA) of the organism by restriction fragment length polymorphism (RFLP) for 59 isolates of the bacterium provided during an epidemiological study. Isolates were obtained from three broiler production houses existing at separate locations. They were cultured and isolated from other (nonbroiler) domestic farm animals, wild birds, rodents, feed, farmers' boots, chicken feathers, and chicken intestinal materials. Eight distinctive flaA types were found in two of the houses. In one house, at least five flaA types (4, 6, 8, 15, and 21) were characterized from the poultry production environment, with three types isolated and identified from the chicken intestinal tract. flaA type 15 was found in flies, on boots, and in chicken intestinal samples. In another house, a distinctive diversity of flaA types existed (4, 7, 43, and 53). At least three flaA types found in samples from chicken intestinal tracts were also found in warm-blooded animals outside of the poultry house (domesticated animals, wild birds, and vermin).

Virulence determinants invA and spvC in salmonellae isolated from poultry products, wastewater, and human sources.

The presence of two virulence foci, invA and spvC, in Salmonella isolates obtained from poultry, wastewater, and human sources was determined. All isolates (n = 245) were positive for the invA gene sequence. Differences in degree of invasiveness were apparent with the Madin Darby canine kidney cell line, as only 79 of 159 randomly selected isolates (49.7%) tested were invasive at > 0.1% of the inoculum. 25% were invasive between 0.1 and 1.0% of the inoculum, and 24.5% were invasive at > 1.0% of the inoculum. There was a significant correlation between degree of invasion and source from which the isolate was recovered but no correlation between geographic origin of poultry isolates and degree of invasion. Only 37 of 245 isolates (15.1%) hybridized with the spvC DNA probe. All isolates that were recovered from a commercial egg production environment and chicken eggs and whose sequences exhibited homology with the spvC gene sequence were determined to be either Salmonella enteritidis PT 23 or PT 13. The sequences of few isolates from ceca and none from wastewater or humans demonstrated homology with the spvC gene.