In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

Objective-Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.Methods-We designed and implemented a multi-center trial with an adaptive, two-stage, biasadjusted, randomized, placebo-controlled, double-blind, Phase II design (n=185). The primary outcome in both stages was decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo.Results-Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an Kaufmann et al. Page 2Ann Neurol. Author manuscript; available in PMC 2010 August 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript accompanying pre-specified sensitivity test, and further supplementary analyses. Pre-specified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns.Interpretation-CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial.ALS is an orphan disease with an average annual incidence rate of 1 to 2 per 100,000 person-years, 1-3 and, because the disease typically leads to death within 2 to 4 years of onset, 4 a relatively low prevalence of 4-6 per 100,000 people. 5 About 10% of ALS cases are familial, and about 15 to 20% of autosomal dominant familial ALS patients have mutations the superoxide dismutase 1 (SOD1) gene. 6 The pathogenesis remains incompletely understood, but several lines of evidence suggest that oxidative stress plays an important role. SOD 1 is an enzyme that plays a role in detoxifying free radicals 7 . In a transgenic mouse model of familial ALS, there is increased oxidative stress. 8 In patients with sporadic ALS, oxidative stress indicators were found in plasma, urine, and CSF. 9-13 Mitochondrial impairment in ALS is supported by several findings in vitro, animal studies, and patients. In an ALS cell culture model, motor neuron cell lines harboring SOD1 mutations have morphologically abnormal mitochondria and impaired respiratory chain function. 14 Respiratory chain dysfunction has also been described in an ALS mouse model. 15 In spinal cord tissue of ALS patients, mutant mtDNA molecules were incre...

We wished to determine whether the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) is reliable when used as primary outcome measure in a multicenter clinical trial. To establish inter-rater reliability, we randomly assigned 19 primary raters and 11 back-up raters to score nine amyotrophic lateral sclerosis (ALS) patients using the ALSFRS-R. To assess intra-rater reliability and reliability of telephone administration, we randomly assigned consecutive participants of the Clinical Trial of High Dose Coenzyme Q10 in ALS (QALS) to have in-person ALSFRS-R interviews at both screening and baseline visits (n=41 patients) or to have the ALSFRS-R interview by telephone at screening and in person at the baseline visit (n=27). An intraclass correlation coefficient (ICC) of reliability was calculated using a one-way random effects analysis of variance model. In the inter-rater reliability assessment, the primary raters performed 54 ratings on nine patients with ICC=0.93 (95% CI 0.84-0.98). For back-up raters, 32 ratings on nine patients resulted in ICC=0.93 (95% CI 0.82-0.98). The intra-rater reliability for in-person interviews was ICC = 0.95 (95% CI 0.92-0.98). The reliability of telephone administration compared to in-person interviews was ICC=0.97 (95% CI 0.93-0.98). We conclude that the ALSFRS-R shows excellent inter- and intra-rater reliability, and reliability of telephone administration when used as primary outcome measure in a multicenter ALS trial.

LUTS that are excluded from the IPSS, most notably incontinence, were prevalent even among mildly symptomatic participants. Since storage symptoms appear to drive treatment seeking, identifying, and treating these symptoms is essential when caring for patients with LUTS.

Several features of the Clinical Trial of High Dose Coenzyme Q10 in ALS study design promote efficiency. These features may be beneficial in phase II trials in amyotrophic lateral sclerosis and other fields.

Objectives To assess the prevalence of neurocognitive impairment (NCI) in childhood-onset systemic lupus erythematosus (cSLE) comparing published classification criteria, and to examine associations between NCI, disease characteristics, psychosocial-well being and intelligence. Methods cSLE patients and ethnicity- and age-matched healthy controls completed a neuropsychological research battery, and results were categorized by three different NCI classification criteria with different cutoff scores (e.g., >2, 1.5, or 1 SD below mean) and number of required abnormal tests or domains. Results Forty-one cSLE subjects and 22 controls were included. Subjects were predominantly female (70%) and Hispanic (70%). Executive functioning, psychomotor and fine-motor speed were most commonly affected. Method 1 classified 34.1% of cSLE subjects with NCI, compared to Method 2 (14.6% with decline and 7.3 % with NCI) and Method 3 (63.4% with NCI). Prevalence of NCI was not significantly different between controls and patients using any of the categorization methods. NCI was not associated with SLE disease activity or characteristics, or with depression. Using Method 3, patients in the cognitive impairment group reported significantly lower quality of life estimates (69.7 vs 79.3, p=0.03). Below average intellectual functioning (IQ < 90) differentiated the number of test scores >1 and >1.5 SD, but not >2 SD below the mean. Conclusions NCI was prevalent in cSLE, but varied according to chosen categorization method. A similar proportion of cSLE patients and controls had NCI, reinforcing the importance of studying an appropriate control group. Categorical classification (i.e. impaired/nonimpaired) may oversimplify the commonly observed deficits in cSLE.

Background: Scoliosis is a frequent complication of pediatric neuromuscular disease (NMD). Scoliosis surgery in children with NMD is thought to carry greater morbidity and mortality. Objectives: To study demographics, comorbidities, outcomes, and hospitalization expenditures among children with NMD undergoing scoliosis surgery. Design: Using the Kids Inpatient Database, a large allpayer US database of hospital discharges among children and adults younger than 20 years, we studied children undergoing scoliosis surgery between January 1, 1997, and December 31, 2003. Continuous variables were compared by t test, and categorical variables were compared by Pearson product moment correlation 2 test. Setting: National database of pediatric hospital discharges. Patients: Children with and without NMD. Main Outcome Measures: Demographics, hospital length of stay, and in-hospital mortality associated with scoliosis surgery. Results: Of 17 780 reported hospitalizations owing to scoliosis surgery, 437 children (2.5%) had NMD. Compared with children undergoing scoliosis surgery for other indications, children with NMD were more likely to be younger (12.4 vs 14.2 years), male (73.5% vs 38.3%), and insured by Medicaid (35.6% vs 20.3%). Comorbidities that were more common among children with NMD included pulmonary complications (lung disease not classified, pulmonary collapse, pulmonary insufficiency, chronic respiratory failure, and ventilator requirement) and cardiovascular complications (cardiomyopathy, hypotension, and tachycardia). Scoliosis surgery in children with NMD was associated with increased hospital length of stay (10.3 vs 7.7 days) and hospitalization expenditures ($80 251 vs $62 154), and higher in-hospital mortality (1.6% vs 0.2%). Conclusion: Children with NMD have increased hospital length of stay and higher in-hospital mortality associated with scoliosis surgery, highlighting the need for further study of measures that could reduce complications and improve outcomes in this population.

Tampering with opioid medications to get high is associated with substantial loss of productivity and health care use. Technologies that reduce users' ability to tamper may reduce the burden of opioid abuse on the health care system.