Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1.

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. RESULTS: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. INTERPRETATION: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

Mixture is better: enhanced electrochemical performance of phenyl selenosulfide in rechargeable lithium batteries.

Phenyl selenosulfide (PhS-SePh) is synthesized by an exchange reaction between phenyl disulfide and diselenide. PhS-SePh possesses average values of lattice parameters, bond character, and the lowest unoccupied molecular orbital as expected, but displays a higher discharge voltage plateau and much better cycling stability than the two precursors in rechargeable lithium batteries.

Exploration of US men's professional sport organization concussion policies.

Concussion policies are increasingly being developed and adopted among professional sports organizations. We sought to compare the policies of the National Hockey League (NHL), the National Basketball Association (NBA), the National Football League (NFL), and Major League Baseball (MLB). Our objective was to summarize each policy and evaluate the extent to which each policy is organization-specific and/or consistent with medical guidelines. We visited websites for the NHL, NBA, NFL, and MLB. We searched media articles reporting concussion policy. We utilized only publically available data. We collected information on each league's approach to the definition of concussion, education provided about concussion, baseline testing requirements, minimum return to play time and return to play protocol. We found that concussion policies vary across these organizations. Most organizations utilize the Concussion in Sport Group (CISG) definition (2013) to define concussion. The NFL and NBA mandate preseason education. All organizations require some type of baseline testing. All organizations require sideline evaluation after suspected concussion. The NFL and MLB require Sport Concussion Assessment Tool (SCAT) testing for sideline evaluation of suspected concussion. MLB is the only organization to require minimum time before return to play. There is a return to play protocol in place for each organization. The NFL and MLB require independent neurologic consultation as part of their return to play protocol. There is variability in concussion policy among the professional sports organizations. The most pronounced variation from the CISG consensus statement is the variability in the minimum time to return to play. Further, the rules of the individual sports have a role in how concussion policy can be designed and implemented. Professional sports set an example for thousands of recreational sports enthusiasts so their publically available policies on concussion have a large impact.

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1.

OBJECTIVE: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). METHODS: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. RESULTS: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. CONCLUSIONS: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. CLINICALTRIALSGOV IDENTIFIER: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.