Larry R. Muenz

Prognostic factors in lupus nephritis: Contribution of renal histologic data

The predictive value of laboratory results and renal histologic data was examined in 102 patients upon entry into prospective, randomized, therapeutic trials of lupus nephritis. Three clinical features at the time of entry into the study were individually associated with increased rates of renal failure: age less than 24 years, male gender, and an elevated serum creatinine level. Subjects with diffuse proliferative or membranoproliferative glomerulonephritis were at a modest but significantly increased risk for the development of end-stage renal disease compared with patients with other classes of lupus nephritis. Semiquantitative scores of histologic features (specified by activity and chronicity indexes) identified subgroups of patients with comparatively high renal failure rates. To address the controversial issue of whether renal histologic data significantly improve the outcome predictions in patients with lupus nephritis, multivariate survival models were generated, permitting simultaneous consideration of multiple prognostic factors. Outcome predictions based on the strongest clinical predictors (age, sex, and serum creatinine level) were significantly enhanced by the addition of activity and chronicity indexes. Only age and chronicity index contributed significantly to the five-variable model and together constituted a two-variable model, the predictions of which were similar to observed outcomes. In the context of the highly significant prognostic indicators (age and chronicity index), immunosuppressive agents appeared to provide a slight therapeutic advantage over oral corticosteroids alone.

A 1-Year Randomized Trial of Calcium Acetate Versus Sevelamer on Progression of Coronary Artery Calcification in Hemodialysis Patients With Comparable Lipid Control : The Calcium Acetate Renagel Evaluation-2 (CARE-2) Study

BACKGROUND Previous clinical trials showed that progression of coronary artery calcification (CAC) may be slower in hemodialysis patients treated with sevelamer than those treated with calcium-based phosphate binders. Because sevelamer decreases low-density lipoprotein cholesterol (LDL-C) levels, we hypothesized that intensive lowering of LDL-C levels with atorvastatin in hemodialysis patients treated with calcium acetate would result in CAC progression rates similar to those in sevelamer-treated patients. STUDY DESIGN Randomized, controlled, open-label, noninferiority trial with an upper bound for the noninferiority margin of 1.8. SETTING & PARTICIPANTS 203 prevalent hemodialysis patients at 26 dialysis centers with serum phosphorus levels greater than 5.5 mg/dL, LDL-C levels greater than 80 mg/dL, and baseline CAC scores of 30 to 7,000 units assessed by means of electron-beam computed tomography. INTERVENTIONS 103 patients were randomly assigned to calcium acetate, and 100 patients to sevelamer for 12 months to achieve phosphorus levels of 3.5 to 5.5 mg/dL. Atorvastatin was added to achieve serum LDL-C levels less than 70 mg/dL in both groups. OUTCOMES & MEASUREMENTS The primary end point was change in CAC score assessed by means of electron-beam computed tomography. RESULTS After 12 months, mean serum LDL-C levels decreased to 68.8 +/- 22.0 mg/dL in the calcium-acetate group and 62.4 +/- 23.0 mg/dL in the sevelamer group (P = 0.3). Geometric mean increases in CAC scores were 35% in the calcium-acetate group and 39% in the sevelamer group, with a covariate-adjusted calcium acetate-sevelamer ratio of 0.994 (95% confidence interval, 0.851 to 1.161). LIMITATIONS Treatment assignment was not blinded. The 1.8 a priori margin is large, CAC is a surrogate outcome, duration of treatment was short, and dropout rate was high. CONCLUSIONS With intensive lowering of LDL-C levels for 1 year, hemodialysis patients treated with either calcium acetate or sevelamer experienced similar progression of CAC.

Effect of Treatment on the Evolution of Renal Abnormalities in Lupus Nephritis

We retrospectively studied the evolution of histopathologic features in successive renal biopsies in patients with lupus nephritis, to evaluate the effects of various treatment regimens. Repeat renal biopsies had been performed in 62 patients after more than 18 months of observation (median interval, 44 months) in randomized therapeutic trials comparing prednisone with cytotoxic drugs. Renal histopathologic features were graded individually, and a composite score reflecting the number and severity of irreversible lesions was defined as a chronicity index. The chronicity index for patients treated with conventional high-dose prednisone increased linearly with the interval between biopsies, whereas the index in the group receiving cytotoxic-drug treatments did not increase over time. After statistical adjustment for important prognostic factors (age and initial chronicity index) identified by multiple linear regression, the difference in the slopes between the group receiving prednisone and the group receiving cytotoxic drugs was significant (P less than 0.0001). We conclude that cytotoxic-drug treatment reduces the likelihood of progressive renal scarring in lupus nephritis.

Standardized Mood Induction With Happy and Sad Facial Expressions

The feasibility of applying ecologically valid and socially relevant emotional stimuli in a standardized fashion to obtain reliable mood changes in healthy subjects was examined. The stimuli consisted of happy and sad facial expressions varying in intensity. Two mood-induction procedures (happy and sad, each consisting of 40 slides) were administered to 24 young healthy subjects, who were instructed to look at each slide (self-paced) and try to feel the happy or sad mood expressed by the person in the picture. On an emotional self-rating scale, subjects rated themselves as relatively happier during the happy mood-induction condition and as relatively sadder during the sad mood-induction condition. Conversely, they reported that they were less happy during the sad mood-induction condition and less sad during the happy mood-induction condition. The effects were generalized to positive and negative affect as measured by the Positive and Negative Affect Scale. The intraindividual variability in the effect was very small. In a retest study after 1 month, the mood-induction effects showed good stability over time. The results encourage the use of this mood-induction procedure as a neurobehavioral probe in physiologic neuroimaging studies for investigating the neural substrates of emotional experience.

Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study.

OBJECTIVE To investigate the efficacy of etanercept in improving the symptoms and underlying inflammation in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS Fifteen patients with TRAPS were enrolled in a prospective, open-label, dose-escalation study. Patients recorded attacks, symptom severity, and use of ancillary medications in a daily diary. Blood samples were collected during each period and measured for levels of acute-phase reactants. Between 7 years and 9 years after the conclusion of the initial study, patients completed a followup survey and were evaluated to determine the long-term outcome of etanercept treatment. RESULTS Etanercept treatment significantly attenuated the total symptom score and reduced the frequency of symptoms. Etanercept also reduced levels of acute-phase reactants, particularly during asymptomatic periods. During a 10-year followup period, patients continued to receive etanercept for a median of 3.3 years, with a number of patients switching to anti-interleukin-1β receptor therapy or not receiving biologic agents, most frequently citing injection site reactions and lack of efficacy as reasons for discontinuation. However, patients continuing to receive etanercept had reduced symptoms at followup. CONCLUSION Etanercept reduces symptoms and serum levels of inflammatory markers of TRAPS in a dose-dependent manner, but does not completely normalize symptoms or acute-phase reactant levels. Although long-term adherence to etanercept is poor, continuing to receive etanercept may provide continued symptomatic benefit.

Efficacy of Etanercept in the Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS)

OBJECTIVE To investigate the efficacy of etanercept in improving the symptoms and underlying inflammation in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS Fifteen patients with TRAPS were enrolled in a prospective, open-label, dose-escalation study. Patients recorded attacks, symptom severity, and use of ancillary medications in a daily diary. Blood samples were collected during each period and measured for levels of acute-phase reactants. Between 7 years and 9 years after the conclusion of the initial study, patients completed a followup survey and were evaluated to determine the long-term outcome of etanercept treatment. RESULTS Etanercept treatment significantly attenuated the total symptom score and reduced the frequency of symptoms. Etanercept also reduced levels of acute-phase reactants, particularly during asymptomatic periods. During a 10-year followup period, patients continued to receive etanercept for a median of 3.3 years, with a number of patients switching to anti-interleukin-1β receptor therapy or not receiving biologic agents, most frequently citing injection site reactions and lack of efficacy as reasons for discontinuation. However, patients continuing to receive etanercept had reduced symptoms at followup. CONCLUSION Etanercept reduces symptoms and serum levels of inflammatory markers of TRAPS in a dose-dependent manner, but does not completely normalize symptoms or acute-phase reactant levels. Although long-term adherence to etanercept is poor, continuing to receive etanercept may provide continued symptomatic benefit.

Impact of Tobacco-Related Health Warning Labels across Socioeconomic, Race and Ethnic Groups: Results from a Randomized Web-Based Experiment

Background The U.S. Family Smoking Prevention and Tobacco Control Act of 2009 requires updating of the existing text-only health warning labels on tobacco packaging with nine new warning statements accompanied by pictorial images. Survey and experimental research in the U.S. and other countries supports the effectiveness of pictorial health warning labels compared with text-only warnings for informing smokers about the risks of smoking and encouraging cessation. Yet very little research has examined differences in reactions to warning labels by race/ethnicity, education or income despite evidence that population subgroups may differ in their ability to process health information. The purpose of the present study was to evaluate the potential impact of pictorial warning labels compared with text-only labels among U.S. adult smokers from diverse racial/ethnic and socioeconomic subgroups. Methods/Findings Participants were adult smokers recruited from two online research panels (n = 3,371) into a web-based experimental study to view either the new pictorial warnings or text-only warnings. Participants viewed the labels and reported their reactions. Adjusted regression models demonstrated significantly stronger reactions for the pictorial condition for each outcome salience (b = 0.62, p<.001); perceived impact (b = 0.44, p<.001); credibility (OR = 1.41, 95% CI = 1.22−1.62), and intention to quit (OR = 1.30, 95% CI = 1.10−1.53). No significant results were found for interactions between condition and race/ethnicity, education, or income. The only exception concerned the intention to quit outcome, where the condition-by-education interaction was nearly significant (p = 0.057). Conclusions Findings suggest that the greater impact of the pictorial warning label compared to the text-only warning is consistent across diverse racial/ethnic and socioeconomic populations. Given their great reach, pictorial health warning labels may be one of the few tobacco control policies that have the potential to reduce communication inequalities across groups. Policies that establish strong pictorial warning labels on tobacco packaging may be instrumental in reducing the toll of the tobacco epidemic, particularly within vulnerable communities.

Effects of Memory Processing on Regional Brain Activation: Cerebral Blood Flow in Normal Subjects

The role of the temporal lobe in memory has been implicated in lesion studies, which have also suggested the hypothesis of greater left hemispheric involvement in verbal, and right hemispheric involvement in facial memory. We tested these hypotheses in a sample of 27 normal right-handed subjects using the 133Xenon clearance method for measuring cerebral blood flow (CBF). The CBF was measured during resting baseline, word recognition, and face recognition conditions in counterbalanced order. CBF increased during recognition compared to baseline, and for the midtemporal lobe this increase was asymmetric to the left hemisphere for words and to the right for faces. While overall CBF levels and task related increases in CBF were uncorrelated either with performance or with delta performance (excess performance relative to basal memory abilities), laterality of task-related CBF correlated with both performance indices, showing regional specificity of correlations. This neurobehavioral probe paradigm can be applied in the study of neural substrates of normal and disturbed memory.

Determination and Interpretation of the Optimal Operating Point for ROC Curves Derived Through Generalized Linear Models

Sensitivity and specificity summarize the performance of a diagnostic test with a positive/negative outcome determined by a gold standard. When the test is quantitative, receiver operating characteristic (ROC) curves are used to display the performance of all possible cutpoints of the quantitative diagnostic marker. The ROC curve offers a graphical interpretation of the trade-off between sensitivity and specificity of the range of possible cutpoints. Various methods are used to estimate the ROC curve including empirical, parametric, semiparametric, and regression methods. Similarly, various software packages provide ROC curve estimation. Regression methods based on using generalized linear models are discussed as well as their implementation with the SAS procedures PROC LOGISTIC and PROC GENMOD. Recent attention has been given to determining the optimal decision rule, also called the optimal operating point (OOP). Similar to the ROC curve, the OOP provides a graphical interpretation for decision making. T...

Early Prediction of Initiation of Abstinence from Cocaine: Use of a Craving Questionnaire

The authors administered a five-item craving questionnaire daily to 86 outpatients to determine whether initial craving scores predicted the likelihood of initiation of abstinence within a 30-day period. Patients with higher mean craving scores during the first 3 days of the study were less likely to initiate abstinence. However the relationship between craving and abstinence initiation was not linear. Rather, patients in the top quartile of craving scores were significantly less likely to abstain than were patients in the lower three quartiles. The findings suggest that this rapid, easily administered craving questionnaire may have short-term predictive validity.