Rationale and design of the granulocyte-macrophage colony stimulating factor in peripheral arterial disease (GPAD-3) study.

BACKGROUND: Lower extremity peripheral arterial disease (PAD) is a public health problem and many patients with PAD experience claudication despite adequate medical and/or surgical management. Mobilization of endogenous progenitor cells using Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is a novel therapeutic option that has shown promising results in experimental models and phase I/IIA clinical trials. The GPAD-3 trial will study the effect of two successive administrations of GM-CSF at 3-month interval for improving claudication among patients with lower extremity PAD. METHODS: We plan to recruit 176 patients in this ongoing randomized, double-blind, placebo-controlled Phase IIB trial. After screening for inclusion and exclusion criteria, eligible subjects undergo a 4-week screening phase where they perform subcutaneous placebo injections thrice weekly and walk at least three times a day until they develop claudication. After the screening phase, eligible subjects undergo baseline testing and are randomized 2:1 to receive 500 µg/day of GM-CSF subcutaneously thrice weekly for three weeks or placebo injections. After 3 months, follow-up endpoint testing is performed and subjects in the GM-CSF group receive the second administration of the drug for three weeks while subjects in placebo group receive matching placebo injections. All participants undergo endpoint testing at six-month and nine-month follow-up. The primary endpoint is change in 6-min walk distance between baseline and 6-month follow-up. CONCLUSION: GPAD-3 explores a novel approach to address the need for alternative therapies that can alleviate symptoms among patients with lower extremity PAD. If successful, this study will pave the way for a pivotal Phase III trial.

Response rate profiles for major depressive disorder: Characterizing early response and longitudinal nonresponse.

BACKGROUND: Definition of response is critical when seeking to establish valid predictors of treatment success. However, response at the end of study or endpoint only provides one view of the overall clinical picture that is relevant in testing for predictors. The current study employed a classification technique designed to group subjects based on their rate of change over time, while simultaneously addressing the issue of controlling for baseline severity. METHODS: A set of latent class trajectory analyses, incorporating baseline level of symptoms, were performed on a sample of 344 depressed patients from a clinical trial evaluating the efficacy of cognitive behavior therapy and two antidepressant medications (escitalopram and duloxetine) in patients with major depressive disorder. RESULTS: Although very few demographic and illness-related features were associated with response rate profiles, the aggregated effect of candidate genetic variants previously identified in large pharmacogenetic studies and meta-analyses showed a significant association with early remission as well as nonresponse. These same genetic scores showed a less compelling relationship with endpoint response categories. In addition, consistent nonresponse throughout the study treatment period was shown to occur in different subjects than endpoint nonresponse, which was verified by follow-up augmentation treatment outcomes. CONCLUSIONS: When defining groups based on the rate of change, controlling for baseline depression severity may help to identify the clinically relevant distinctions of early response on one end and consistent nonresponse on the other.

Brain Correlates of Mental Stress-Induced Myocardial Ischemia.

OBJECTIVE: Coronary artery disease (CAD) is a major cause of morbidity and mortality, and despite important advances in our understanding of this disorder, the underlying mechanisms remain under investigation. Recently, increased attention has been placed on the role of behavioral factors such as emotional stress on CAD risk. Brain areas involved in memory and the stress response, including medial prefrontal cortex, insula, and parietal cortex, also have outputs to the peripheral cardiovascular system. The purpose of this study was to assess the effects of mental stress on brain and cardiac function in patients with CAD. METHODS: CAD patients (N = 170) underwent cardiac imaging with [Tc-99m] sestamibi single-photon emission tomography at rest and during a public speaking mental stress task. On another day, they underwent imaging of the brain with [O-15] water positron emission tomography (PET) during mental stress (arithmetic and public speaking) and control conditions. RESULTS: Patients with mental stress-induced myocardial ischemia showed increased activation with stress in anterior cingulate, inferior frontal gyrus, and parietal cortex (p < .005). This was seen with both arithmetic stress and public speaking stress. Arithmetic stress was additionally associated with left insula activation, and public speaking with right pre/postcentral gyrus and middle temporal gyrus activation (p < .005). CONCLUSIONS: These findings suggest that mental stress-induced myocardial ischemia is associated with activation in brain areas involved in the stress response and autonomic regulation of the cardiovascular system. Altered brain reactivity to stress could possibly represent a mechanism through which stress leads to increased risk of CAD-related morbidity and mortality.

Melatonin supplementation to treat the metabolic syndrome: a randomized controlled trial.

BACKGROUND: Supplemental melatonin may ameliorate metabolic syndrome (MetS) components, but data from placebo-controlled trials are lacking. METHODS: We conducted a double-blind, placebo-controlled, crossover, Phase II randomized pilot clinical trial to estimate the effects of melatonin supplementation on MetS components and the overall prevalence of MetS. We randomized 39 subjects with MetS to receive 8.0 mg oral melatonin or matching placebo nightly for 10 weeks. After a 6-week washout, subjects received the other treatment for 10 more weeks. We measured waist circumference, triglycerides, HDL cholesterol, fasting glucose, and blood pressure (BP) in each subject at the beginning and end of both 10-week treatment periods. The primary outcome was the mean 10-week change in each MetS component, and a secondary outcome was the proportion of subjects free from MetS, after melatonin versus placebo. RESULTS: The mean 10-week change for most MetS components favored melatonin over placebo (except fasting glucose): waist circumference -0.9 vs. +1.0 cm (p = 0.15); triglycerides -66.3 vs. -4.2 mg/dL (p = 0.17); HDL cholesterol -0.2 vs. -1.1 mg/dL (p = 0.59); fasting glucose +0.3 vs. -3.1 mg/dL (p = 0.29); systolic BP -2.7 vs. +4.7 mmHg (p = 0.013); and diastolic BP -1.1 vs. +1.1 mmHg (p = 0.24). Freedom from MetS tended to be more common following melatonin versus placebo treatment (after the first 10 weeks, 35.3% vs. 15.0%, p = 0.25; after the second 10 weeks, 45.0% vs. 23.5%, p = 0.30). Melatonin was well-tolerated. CONCLUSIONS: Melatonin supplementation modestly improved most individual MetS components compared with placebo, and tended to increase the proportion of subjects free from MetS after treatment. TRIAL REGISTRATION: NCT01038921, clinicaltrials.gov.

Distal splenorenal shunt versus transjugular intrahepatic portal systematic shunt for variceal bleeding: a randomized trial.

BACKGROUND & AIMS: Variceal bleeding refractory to medical treatment with beta-blockers and endoscopic therapy can be managed by variceal decompression with either surgical shunts or transjugular intrahepatic portal systemic shunts (TIPS). This prospective randomized trial tested the hypothesis that patients receiving distal splenorenal shunts (DSRS) would have significantly lower rebleeding and encephalopathy rates than TIPS in management of refractory variceal bleeding. METHODS: A prospective randomized controlled clinical trial at 5 centers was conducted. One hundred forty patients with Child-Pugh class A and B cirrhosis and refractory variceal bleeding were randomized to DSRS or TIPS. Protocol and event follow-up for 2-8 years (mean, 46 +/- 26 months) for primary end points of variceal bleeding and encephalopathy and secondary end points of death, ascites, thrombosis and stenosis, liver function, need for transplant, quality of life, and cost were evaluated. RESULTS: There was no significant difference in rebleeding (DSRS, 5.5%; TIPS, 10.5%; P = .29) or first encephalopathy event (DSRS, 50%; TIPS, 50%). Survival at 2 and 5 years (DSRS, 81% and 62%; TIPS, 88% and 61%, respectively) were not significantly different (P = .87). Thrombosis, stenosis, and reintervention rates (DSRS, 11%; TIPS, 82%) were significantly (P < .001) higher in the TIPS group. Ascites, need for transplant, quality of life, and costs were not significantly different. CONCLUSIONS: DSRS and TIPS are similarly efficacious in the control of refractory variceal bleeding in Child-Pugh class A and B patients. Reintervention is significantly greater for TIPS compared with DSRS. Because both procedures have equivalent outcomes, the choice is dependent on available expertise and ability to monitor the shunt and reintervene when needed.

Reduction in fear of falling through intense tai chi exercise training in older, transitionally frail adults.

OBJECTIVES: To determine whether an intense tai chi exercise program could reduce fear of falling better than a wellness education (WE) program in older adults who had fallen previously and meet criteria for transitioning to frailty. DESIGN: Cluster-randomized, controlled trial of 48 weeks' duration. SETTING: Ten matched pairs of congregate living facilities in the greater Atlanta area. PARTICIPANTS: Sample of 291 women and 20 men, aged 70 to 97. MEASUREMENTS: Activity-related fear of falling using the Activities-Specific Balance Confidence Scale (ABC) and the Fall Efficacy Scale at baseline and every 4 months for 1 year. Demographics, time to first fall and all subsequent falls, functional measures, Centers for Epidemiologic Studies Depression Scale, medication use, level of physical activity, comorbidities, and adherence to interventions. RESULTS: Mean ABC was similar in both cohort groups at the time of randomization but became significantly higher (decreased fear) in the tai chi cohort at 8 months (57.9 vs 49.0, P<.001) and at study end (59.2 vs 47.9, P<.001). After adjusting for covariates, the mean ABC after 12 months of intervention was significantly greater in the tai chi group than in the WE group, with the differences increasing with time (mean difference at 12 months=9.5 points, 95% confidence interval=4.8-14.2, P<.001). CONCLUSION: Tai chi led to a significantly greater reduction in fear of falling than a WE program in transitionally frail older adults. The mean percentage change in ABC scores widened between tai chi and WE participants over the trial period. Tai chi should be considered in any program designed to reduce falling and fear of falling in transitionally frail older adults.

The Dialysis Outcomes and Practice Patterns Study (DOPPS): design, data elements, and methodology.

The Dialysis Outcomes and Practice Patterns Study (DOPPS) is a prospective, observational study designed to elucidate aspects of hemodialysis practice that are associated with the best outcomes for hemodialysis patients. In DOPPS I, 308 hemodialysis units from 7 countries participated, including 145 facilities from the United States (1996-2001), 62 facilities from Japan (1999-2001), and 101 facilities from France, Germany, Italy, Spain, and the United Kingdom (all 1998-2000). DOPPS II (2002-2004) has included 320 hemodialysis units and more than 12,400 hemodialysis patients from the 7 DOPPS I countries as well as Australia, Belgium, Canada, New Zealand, and Sweden. Dialysis units are chosen via a stratified random selection procedure to provide proportional sampling by region and type of facility within each country. In DOPPS I and II, longitudinal data have been collected from both a prevalent (cross-sectional) patient sample and an incident patient sample. Data have also been collected on numerous facility practice patterns. Most DOPPS analyses incorporate both facility- and patient-level data in regression-based analyses to investigate predictors of survival, hospitalization, quality of life, vascular access type, and other outcomes. DOPPS longitudinal data also help identify trends in subject characteristics, practice indicators, medication use, and outcomes. The DOPPS remains a unique source of data on hemodialysis patients and facilities. It continues to refine its methods of data collection and analysis with the goal of improving hemodialysis practice and end-stage renal disease patient lives worldwide.

Sleep-disordered breathing and nocturia in older adults.

OBJECTIVES: To investigate the relationship between sleep-disordered breathing (SDB) and nocturia episodes in community-dwelling older adults. DESIGN: A cross-sectional study. SETTING: Community. PARTICIPANTS: Community-dwelling older adults (N=72) recruited from independent living facilities and adult learning centers in Atlanta, Georgia. MEASUREMENTS: Three-day voiding diary, ambulatory sleep recording, focused physical examination, Epworth Sleepiness Scale, and Geriatric Depression Scale. RESULTS: Fifty-eight of the 72 subjects completed the study. The mean age+/-standard deviation was 77.7+/-6.7; 44 (76%) were female. Of the 58 subjects, 26 (45%) had an apnea-hypopnea index (AHI) of less than 10 per hour of sleep, 21 (36%) had an AHI between 10 and 24 per hour sleep, and 11 (19%) had an AHI of 25 or higher per hour of sleep. The mean nocturia episodes were 1.7+/-1.1, 1.6+/-0.9, and 2.6+/-1.4 for subjects in these groups, respectively (F=3.82; P=.028). Those with an AHI of 25 or higher had more nocturia episodes, higher mean arterial blood pressure, and higher body mass index than those with a lower AHI. CONCLUSION: These results suggest that older adults with severe SDB have a greater number of nocturia episodes. These findings underscore the importance of considering SDB as a differential diagnosis in the evaluation of older patients with nocturia.

Changes in nocturia from medical treatment of benign prostatic hyperplasia: secondary analysis of the Department of Veterans Affairs Cooperative Study Trial.

PURPOSE: We evaluate the efficacy of medical therapy on nocturia in men with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We performed a secondary analysis of data from the VA Cooperative Study Program Trial in which 1,229 men with BPH 45 to 80 years old were randomly assigned to receive terazosin, finasteride, combination or placebo. RESULTS: The 1,078 men who completed 12 months of the trial are included in this study. Of those men 1,040 (96.5%) had at least 1 episode of nocturia at baseline and 38 (3.5%) had less than 1 episode (baseline nocturia is an average of 2 measures). Of those 1,040 men 788 (75.8%) had 2 or more nocturia episodes. Overall, nocturia decreased from a baseline mean of 2.5 to 1.8, 2.1, 2.0 and 2.1 episodes in the terazosin, finasteride, combination and placebo groups, respectively. Of men with 2 or more episodes of nocturia 50% reduction in nocturia was seen in 39%, 25%, 32% and 22% in the terazosin, finasteride, combination and placebo groups, respectively. Changes in nocturia were correlated with changes in reported bother from nocturia (Pearson correlation 0.48), BPH impact index (0.32) and overall satisfaction with urinary symptoms (0.33). CONCLUSIONS: Terazosin and combination therapy reduced nocturia in men with BPH, yet the net advantage of terazosin over placebo was a net reduction of 0.3 nocturia episode. For a person to reach a 50% or greater reduction in nocturia, the advantage of terazosin over placebo was 17 percentage points. Changes in nocturia had a moderate impact on symptom specific quality of life measures.