Does switching from oral extended-release methylphenidate to the methylphenidate transdermal system affect health-related quality-of-life and medication satisfaction for children with attention-deficit/hyperactivity disorder?

Background: To evaluate health-related quality of life (HRQL) and medication satisfaction after switching from a stable dose of oral extended-release methylphenidate (ER-MPH) to methylphenidate transdermal system (MTS) via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD). Methods: In a 4-week, multisite, open-label study, 171 children (164 in the intent-to-treat [ITT] population) aged 6-12 years diagnosed with ADHD abruptly switched from a stable dose of oral ER-MPH to MTS nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. Subjects remained on the scheduled dose for the first week, after which the dose was then titrated to an optimal effect. The ADHD Impact Module-Children (AIM-C), a disease-specific validated HRQL survey instrument measuring child and family impact, was used to assess the impact of ADHD symptoms on the lives of children and their families at baseline and study endpoint. Satisfaction with MTS use was assessed via a Medication Satisfaction Survey (MSS) at study endpoint. Both the AIM-C and MSS were completed by a caregiver (parent/legally authorized representative). Tolerability was monitored by spontaneous adverse event (AE) reporting. Results: AIM-C child and family HRQL mean scores were above the median possible score at baseline and were further improved at endpoint across all MTS doses. Similar improvements were noted for behavior, missed doses, worry, and economic impact AIM-C item scores. Overall, 93.8% of caregivers indicated a high level of satisfaction with their child's use of the study medication. The majority of treatment-emergent AEs (> 98%) were mild to moderate in intensity, and the most commonly reported AEs included headache, decreased appetite, insomnia, and abdominal pain. Seven subjects discontinued the study due to intolerable AEs (n = 3) and application site reactions (n = 4). Conclusion: This study demonstrates that MTS, when carefully titrated to optimal dose, may further improve child and family HRQL, as well as behavioral, medication worry, and economic impact item scores, as measured by the AIM-C in subjects switching to MTS from a stable dose of routinely prescribed oral ER-MPH after a short treatment period. Furthermore, following the abrupt conversion from oral ER-MPH to MTS, the majority of caregivers reported being highly satisfied with MTS as a treatment option for their children with ADHD. Trial Registration: NCT0015198

Effects of methylphenidate on attention in Wistar rats treated with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)

The aim of this study was to assess the effects of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on attention in rats as measured using the 5-choice-serial-reaction-time task (5CSRTT) and to investigate whether methylphenidate has effects on DSP4-treated rats. Methylphenidate is a noradrenaline and dopamine reuptake inhibitor and commonly used in the pharmacological treatment of individuals with attention deficit/hyperactivity disorder (ADHD). Wistar rats were trained in the 5CSRTT and treated with one of three doses of DSP4 or saline. Following the DSP4 treatment rats were injected with three doses of methylphenidate or saline and again tested in the 5CSRTT. The treatment with DSP4 caused a significant decline of performance in the number of correct responses and a decrease in response accuracy. A reduction in activity could also be observed. Whether or not the cognitive impairments are due to attention deficits or changes in explorative behaviour or activity remains to be investigated. The treatment with methylphenidate had no beneficial effect on the rats’ performance regardless of the DSP4 treatment. In the group without DSP4 treatment, methylphenidate led to a reduction in response accuracy and bidirectional effects in regard to parameters related to attention. These findings support the role of noradrenaline in modulating attention and call for further investigations concerning the effects of methylphenidate on attentional processes in rats

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Measurement error in time-series analysis: a simulation study comparing modelled and monitored data.

BACKGROUND: Assessing health effects from background exposure to air pollution is often hampered by the sparseness of pollution monitoring networks. However, regional atmospheric chemistry-transport models (CTMs) can provide pollution data with national coverage at fine geographical and temporal resolution. We used statistical simulation to compare the impact on epidemiological time-series analysis of additive measurement error in sparse monitor data as opposed to geographically and temporally complete model data. METHODS: Statistical simulations were based on a theoretical area of 4 regions each consisting of twenty-five 5 km × 5 km grid-squares. In the context of a 3-year Poisson regression time-series analysis of the association between mortality and a single pollutant, we compared the error impact of using daily grid-specific model data as opposed to daily regional average monitor data. We investigated how this comparison was affected if we changed the number of grids per region containing a monitor. To inform simulations, estimates (e.g. of pollutant means) were obtained from observed monitor data for 2003-2006 for national network sites across the UK and corresponding model data that were generated by the EMEP-WRF CTM. Average within-site correlations between observed monitor and model data were 0.73 and 0.76 for rural and urban daily maximum 8-hour ozone respectively, and 0.67 and 0.61 for rural and urban loge(daily 1-hour maximum NO2). RESULTS: When regional averages were based on 5 or 10 monitors per region, health effect estimates exhibited little bias. However, with only 1 monitor per region, the regression coefficient in our time-series analysis was attenuated by an estimated 6% for urban background ozone, 13% for rural ozone, 29% for urban background loge(NO2) and 38% for rural loge(NO2). For grid-specific model data the corresponding figures were 19%, 22%, 54% and 44% respectively, i.e. similar for rural loge(NO2) but more marked for urban loge(NO2). CONCLUSION: Even if correlations between model and monitor data appear reasonably strong, additive classical measurement error in model data may lead to appreciable bias in health effect estimates. As process-based air pollution models become more widely used in epidemiological time-series analysis, assessments of error impact that include statistical simulation may be useful

Structural and functional analysis of cell wall-anchored polypeptide adhesin BspA in <em>Streptococcus agalactiae</em>

\ua9 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Streptococcus agalactiae (group B Streptococcus, GBS) is the predominant cause of early-onset infectious disease in neonates and is responsible for life-threatening infections in elderly and immunocompromised individuals. Clinical manifestations of GBS infection include sepsis, pneumonia, and meningitis. Here, we describe BspA, a deviant antigen I/II family polypeptide that confers adhesive properties linked to pathogenesis in GBS. Heterologous expression of BspA on the surface of the non-adherent bacterium Lactococcus lactis confers adherence to scavenger receptor gp340, human vaginal epithelium, and to the fungus Candida albicans. Complementary crystallographic and biophysical characterization of BspA reveal a novel →-sandwich adhesion domain and unique asparagine-dependent super-helical stalk. Collectively, these findings establish a new bacterial adhesin structure that has in effect been hijacked by a pathogenic Streptococcus species to provide competitive advantage in human mucosal infections