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Concept: Area

306

Background Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. Methods We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. Results A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. Conclusions Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

Concepts: Signal transduction, Brain tumor, Magnetic resonance imaging, Neurology, Area, Neurofibromatosis, Neurofibroma, Dermal and subcutaneous growths

233

Smoking is a major public health problem. As smokers age and die prematurely, the tobacco industry must continue to recruit new, young smokers. Survey data indicate that currently in the UK around 207 000 children aged 11-15 start smoking every year. We used local data on adult smoking rates to apportion national data on child smoking uptake to specific areas. The presentation of data for individual local authorities, which now have responsibility for public health, can be used to focus attention locally. For example, this analysis demonstrates that each day, 67 children, more than two classrooms full, start smoking in London.

Concepts: Age, Tobacco, Tobacco smoking, United Kingdom, Child, Ageing, Area, Local government

182

The aim of this longitudinal study was to assess whether correction of unilateral posterior crossbite in the primary dentition results in improvement of facial symmetry and increase of palatal surface area and palatal volume. A group of 60 Caucasian children in the primary dentition, aged 5.3 ± 0.7 years, were collected at baseline. The group consisted of 30 children with a unilateral posterior crossbite with midline deviation of at least 2 mm (CB) and 30 without malocclusion (NCB). The CB group was treated using an acrylic plate expander. The children’s faces and dental casts were scanned using a three-dimensional laser scanning device. Non-parametric tests were used for data analysis to assess differences over the 30 months period of follow-up. The CB children had statistically significantly greater facial asymmetry in the lower part of the face (P < 0.05) and a significantly smaller palatal volume (P < 0.05) than the NCB children at baseline. There were no statistically significant differences between the two groups at 6, 12, 18, and 30 months follow-ups. Treatment of unilateral posterior crossbite in the primary dentition period resulted in an improvement of facial symmetry in the lower part of the face (P < 0.05) and increase of the palatal surface area and palatal volume (P < 0.001). At 30 months, relapse was observed in eight children (26.7 per cent). Treatment of unilateral posterior crossbite in the primary dentition improves facial symmetry and increases the palatal surface area and the palatal volume, though it creates normal conditions for normal occlusal development and skeletal growth.

Concepts: Statistical significance, Sociology, Group theory, Area, Asymmetry, Facial symmetry

172

Recent evidence has indicated an association between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis. Small internal jugular veins (IJVs) (with a cross-sectional area of less than 0.4 cm2) have been previously described as difficult to catheterize, and their presence may potentially affect cerebrospinal venous drainage. In this blinded extracranial color-Doppler study we had two principal aims: first, to assess prevalence of CCSVI among Serbian MS patients compared to healthy controls; and second, to assess prevalence of small IJVs (with a CSA <= 0.4 cm2) among MS patients and controls.

Concepts: Multiple sclerosis, Internal jugular vein, Jugular vein, Common facial vein, Area, Sclerotherapy, Chronic cerebrospinal venous insufficiency, Veins of the head and neck

167

BACKGROUND: Despite the extensive ownership and use of insecticide-treated nets (ITNs) over the last decade, the effective lifespan of these nets, especially their physical integrity, under true operational conditions is not well-understood. Usefulness of nets declines primarily due to physical damage or loss of insecticidal activity. METHODS: A community based cross-sectional survey was used to determine the physical condition and to identify predictors of poor physical condition for bed nets owned by individuals from communities in Kwale County, coastal Kenya. A proportionate hole index (pHI) was used as a standard measure, and the cut-offs for an ‘effective net’ (offer substantial protection against mosquito bites) and ‘ineffective nets’ (offer little or no protection against mosquito bites) were determined (pHI <= 88 (about <= 500 cm2 of holes surface area) and pHI of >88 (>=500 cm2 of holes surface area), respectively). RESULTS: The vast majority (78%) of the surveyed nets had some holes. The median pHI was 92 (range: 1–2,980). Overall, half of the nets were categorized as ‘effective nets’ or ‘serviceable nets’. Physical deterioration of nets was associated with higher use and washing frequency. Young children and older children were found to use ineffective bed nets significantly more often than infants, while the physical integrity of nets owned by pregnant women was similar to those owned by infants. Estuarine environment inhabitants owned nets with the worst physical condition, while nets owned by the coastal slope inhabitants were in fairly good physical condition. The results suggest that bed nets are optimally utilized when they are new and physically intact. Thereafter, bed net utilization decreases gradually with increasing physical deterioration, with most net owners withdrawing physically damaged nets from routine use.This withdrawal commonly happens following 1.5 years of use, making bed net use the most important predictor of physical integrity. On average, the nets were washed twice within six months prior to the survey. Washing frequency was significantly influenced by the bed net colour and bed net age. Lack of knowledge on reasons for net retreatment and the retreatment procedure was evident, while net repair was minimal and did not seem to improve the physical condition of the nets. The “catch-up” bed net distribution strategies are sufficient for ensuring adequate ownership and utilization of ‘effective nets’ in the targeted groups, but bi-annual mass distribution is necessary to provide similar ownership and utilization for the other groups not targeted by “catch-up” strategies. CONCLUSIONS: Monitoring and maintenance strategies that will deliver locally appropriate education messages on net washing and repair will enhance the effectiveness of malaria control programmes, and further research to assess ineffective nets need is needed.

Concepts: Malaria, Mosquito, Yellow fever, .NET Framework, Area, Insect repellent, Mosquito net

163

Physical activity is recommended for skeletal health because bones adapt to mechanical loading. The young skeleton shows greatest plasticity to physical activity-related mechanical loads, but bones are most at risk of failure later in life. The discrepancy raises the question of whether the skeletal benefits of physical activity completed when young persist with aging. Here we present a unique case wherein the cortical bone benefit of physical activity completed over five decades earlier could be established within an individual aged in their tenth decade of life. Specifically, we compared bone properties at the midshaft humerus between the throwing and nonthrowing arms of a 94-year-old former Major League Baseball player who ceased throwing 55 years earlier. By performing analyses within-subject, the long-term skeletal benefit of physical activity completed when young could be assessed independent of inherited and systemic traits. Also, as the subject threw left-handed during his throwing career, but was right-hand dominant in all other activities throughout life, any lasting skeletal benefits in favor of the throwing arm could not be attributable to simple arm dominance. Analyses indicated that any cortical bone mass, area and thickness benefits of throwing-related physical activity completed when young were lost with aging, possibly due to accelerated intracortical remodeling. In contrast, the subject’s throwing (nondominant) arm had greater total cross-sectional area and estimated strength (polar moment of inertia) than in his dominant arm, despite muscle indices favoring the latter. These data indicate that physical activity completed when young can have lasting benefits on bone size and strength, independent of the maintenance of bone mass benefits.

Concepts: Bone, Skeletal system, Ageing, Intramembranous ossification, Area, Moment of inertia, Skeleton, Major League Baseball

144

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) typically arises as an autonomic neuropathy primarily affecting small fibres and it occurs in adult patients in their second or third decades of life. It progresses rapidly and can lead to death in approximately 10 years. Other phenotypes have been described in non-endemic areas.

Concepts: Evolution, Life, Amyloid, Amyloidosis, Area, Neurological disorders, Familial amyloid polyneuropathy, Transthyretin

133

Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas. Making an accurate areal map has been a century-old objective in neuroscience. Using multi-modal magnetic resonance images from the Human Connectome Project (HCP) and an objective semi-automated neuroanatomical approach, we delineated 180 areas per hemisphere bounded by sharp changes in cortical architecture, function, connectivity, and/or topography in a precisely aligned group average of 210 healthy young adults. We characterized 97 new areas and 83 areas previously reported using post-mortem microscopy or other specialized study-specific approaches. To enable automated delineation and identification of these areas in new HCP subjects and in future studies, we trained a machine-learning classifier to recognize the multi-modal ‘fingerprint’ of each cortical area. This classifier detected the presence of 96.6% of the cortical areas in new subjects, replicated the group parcellation, and could correctly locate areas in individuals with atypical parcellations. The freely available parcellation and classifier will enable substantially improved neuroanatomical precision for studies of the structural and functional organization of human cerebral cortex and its variation across individuals and in development, aging, and disease.

Concepts: Neuroanatomy, Brain, Cerebral cortex, Cortical column, Area, Cortical area

69

Lakes are key components of biogeochemical and ecological processes, thus knowledge about their distribution, volume and residence time is crucial in understanding their properties and interactions within the Earth system. However, global information is scarce and inconsistent across spatial scales and regions. Here we develop a geo-statistical model to estimate the volume of global lakes with a surface area of at least 10 ha based on the surrounding terrain information. Our spatially resolved database shows 1.42 million individual polygons of natural lakes with a total surface area of 2.67 × 10(6) km(2) (1.8% of global land area), a total shoreline length of 7.2 × 10(6) km (about four times longer than the world’s ocean coastline) and a total volume of 181.9 × 10(3) km(3) (0.8% of total global non-frozen terrestrial water stocks). We also compute mean and median hydraulic residence times for all lakes to be 1,834 days and 456 days, respectively.

Concepts: Time, Volume, Earth, Parametric surface, Sphere, Cylinder, Area, Surface area

64

Socioeconomic disparities are associated with differences in cognitive development. The extent to which this translates to disparities in brain structure is unclear. We investigated relationships between socioeconomic factors and brain morphometry, independently of genetic ancestry, among a cohort of 1,099 typically developing individuals between 3 and 20 years of age. Income was logarithmically associated with brain surface area. Among children from lower income families, small differences in income were associated with relatively large differences in surface area, whereas, among children from higher income families, similar income increments were associated with smaller differences in surface area. These relationships were most prominent in regions supporting language, reading, executive functions and spatial skills; surface area mediated socioeconomic differences in certain neurocognitive abilities. These data imply that income relates most strongly to brain structure among the most disadvantaged children.

Concepts: Family, Brain, Cognition, Area, Executive functions