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

The Role of Carbonate Factories and Sea Water Chemistry on Basin-Wide Ramp to High-Relief Carbonate Platform Evolution: Triassic, Nanpanjiang Basin, South China

The end-Permian extinction and its aftermath altered carbonate factories globally for millions of years, but its impact on platform geometries remains poorly understood. Here, the evolution in architecture and composition of two exceptionally exposed platforms in the Nanpanjiang Basin are constrained and compared with geochemical proxies to evaluate controls on platform geometries. Geochemical proxies indicate elevated siliciclastic and nutrient fluxes in the basal Triassic, at the Induan—Olenekian boundary and in the uppermost Olenekian. Cerium/Ce* shifts from high Ce/Ce* values and a lack of Ce anomaly indicating anoxia during the Lower Triassic to a negative Ce anomaly indicating oxygenation in the latest Olenekian and Anisian. Uranium and Mo depletion represents widespread anoxia in the world\u27s oceans in the Early Triassic with progressive oxygenation in the Anisian. Carbonate factories shifted from skeletal in the Late Permian to abiotic and microbial in the Early Triassic before returning to skeletal systems in the Middle Triassic, Anisian coincident with declining anoxia. Margin facies shifted to oolitic grainstone in the Early Triassic with development of giant ooids and extensive marine cements. Anisian margins, in contrast, are boundstone with a diverse skeletal component. The shift in platform architecture from ramp to steep, high-relief, flat-topped profiles is decoupled from carbonate compositions having occurred in the Olenekian prior to the onset of basin oxygenation and biotic stabilisation of the margins. A basin-wide synchronous shift from ramp to high-relief platforms points to a combination of high subsidence rate and basin starvation coupled with high rates of abiotic and microbial carbonate accumulation and marine cement stabilisation of oolitic margins as the primary causes for margin up-building. High sea water carbonate saturation resulting from a lack of skeletal sinks for precipitation, and basin anoxia promoting an expanded depth of carbonate supersaturation, probably contributed to marine cement stabilisation of margins that stimulated the shift from ramp to high-relief platform architecture

Problematising international placements as a site of intercultural learning

This paper theorises some of the learning outcomes of a three-year project concerning student learning in international social work placements in Malaysia. The problematic issue of promoting cultural and intercultural competence through such placements is examined, where overlapping hegemonies are discussed in terms of isomorphism of social work models, that of the nation state, together with those relating to professional values and knowledge, and the tyrannies of received ideas. A critical discussion of cultural competence as the rationale for international placements is discussed in terms of the development of the graduating social worker as a self-reflexive practitioner. The development of sustainable international partnerships able to support student placement and the issue of non-symmetrical reciprocation, typical of wide socio-economic differentials across global regions, is additionally discussed

Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1:a study protocol for a randomised placebo-controlled crossover trial

INTRODUCTION: Dopamine dysregulation has been identified as a key modulator of behavioural impairment in neurofibromatosis type 1 (NF1) and a potential therapeutic target. Preclinical research demonstrates reduced dopamine in the brains of genetically engineered NF1 mouse strains is associated with reduced spatial-learning and attentional dysfunction. Methylphenidate, a stimulant medication that increases dopaminergic and noradrenergic neurotransmission, rescued the behavioural and dopamine abnormalities. Although preliminary clinical trials have demonstrated that methylphenidate is effective in treating attention deficit hyperactivity disorder (ADHD) symptoms in children with NF1, its therapeutic effect on cognitive performance is unclear. The primary aim of this clinical trial is to assess the efficacy of methylphenidate for reducing attention deficits, spatial working memory impairments and ADHD symptoms in children with NF1.METHODS AND ANALYSIS: A randomised, double-blind, placebo-controlled trial of methylphenidate with a two period crossover design. Thirty-six participants with NF1 aged 7-16 years will be randomised to one of two treatment sequences: 6 weeks of methylphenidate followed by 6 weeks of placebo or; 6 weeks of placebo followed by 6 weeks of methylphenidate. Neurocognitive and behavioural outcomes as well as neuroimaging measures will be completed at baseline and repeated at the end of each treatment condition (week 6, week 12). Primary outcome measures are omission errors on the Conners Continuous Performance Test-II (attention), between-search errors on the Spatial Working Memory task from the Cambridge Neuropsychological Test Automated Battery (spatial working memory) and the Inattentive and Hyperactivity/Impulsivity Symptom Scales on the Conners 3-Parent. Secondary outcomes will examine the effect of methylphenidate on executive functions, attention, visuospatial skills, behaviour, fine-motor skills, language, social skills and quality of life.ETHICS AND DISSEMINATION: This trial has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.TRIAL REGISTRATION NUMBER: ACTRN12611000765921.</p

Security Monitoring System for a Bulk Foodstuff Transport Container

A security monitoring system provides for the secure transport of a bulk foodstuff container. The system includes an electromechanical locking mechanism allowing access by only authorized persons, a positional locator for determining the geographical position of the bulk foodstuff transport container, and a controller associated with the transport container. The controller controls operation of the electromechanical locking mechanism, stores data received from the electromechanical locking mechanism and the positional locator, and communicates with a remote data processor in near real time. A handheld user interface device is configured to control operation of the controller, to process and store data received from the controller, and to communicate with the remote data processor. Unique identifiers are provided for the bulk foodstuff transport container, the transport vehicle, any storage container from which or into which a bulk foodstuff is transferred, and any authorized operator of the security monitoring system

Selectivity of mass extinctions: Patterns, processes, and future directions

A central question in the study of mass extinction is whether these events simply intensify background extinction processes and patterns versus change the driving mechanisms and associated patterns of selectivity. Over the past two decades, aided by the development of new fossil occurrence databases, selectivity patterns associated with mass extinction have become increasingly well quantified and their differences from background patterns established. In general, differences in geographic range matter less during mass extinction than during background intervals, while differences in respiratory and circulatory anatomy that may correlate with tolerance to rapid change in oxygen availability, temperature, and pH show greater evidence of selectivity during mass extinction. The recent expansion of physiological experiments on living representatives of diverse clades and the development of simple, quantitative theories linking temperature and oxygen availability to the extent of viable habitat in the oceans have enabled the use of Earth system models to link geochemical proxy constraints on environmental change with quantitative predictions of the amount and biogeography of habitat loss. Early indications are that the interaction between physiological traits and environmental change can explain substantial proportions of observed extinction selectivity for at least some mass extinction events. A remaining challenge is quantifying the effects of primary extinction resulting from the limits of physiological tolerance versus secondary extinction resulting from the loss of taxa on which a given species depended ecologically. The calibration of physiology-based models to past extinction events will enhance their value in prediction and mitigation efforts related to the current biodiversity crisis

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation

BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial

The Geozoic Supereon

Geological time units are the lingua franca of earth sciences: they are a terminological convenience, a vernacular of any geological conversation, and a prerequisite of geo-scientific writing found throughout in earth science dictionaries and textbooks. Time units include terms formalized by stratigraphic committees as well as informal constructs erected ad hoc to communicate more efficiently. With these time terms we partition Earth’s history into utilitarian and intuitively understandable time segments that vary in length over seven orders of magnitude: from the 225-year-long Anthropocene (Crutzen and Stoermer, 2000) to the ,4-billion-year-long Precambrian (e.g., Hicks, 1885; Ball, 1906; formalized by De Villiers, 1969)