A novel mixed-method approach to assess children's sedentary behaviours

Purpose: Accurately measuring sedentary behavior (SB) in children is challenging by virtue of its complex nature. While self-report questionnaires are susceptible to recall errors, accelerometer data lacks contextual information. This study aimed to explore the efficacy of using accelerometry combined with the Digitising Children’s Data Collection (DCDC) for Health application (app), to capture SB comprehensively. Methods: 74 children (9–10 years old) wore ActiGraph GT9X accelerometers for 7 days. Each received a SAMSUNG Galaxy Tab4 (SM-T230) tablet, with the DCDC app installed and a specially designed sedentary behavior study downloaded. The app uses four data collection tools: 1) Questionnaire, 2) Take a photograph, 3) Draw a picture, and 4) Record my voice. Children self-reported their SB daily. Accelerometer data were analyzed using R-package GGIR. App data were downloaded and individual participant profiles created. SBs reported were grouped into categories and reported as frequencies. Results: Participants spent, on average, 629 min (i.e., 73% of their waking time) sedentary. App data revealed most of their out-of-school SB consisted of screen time (112 photos, 114 drawings, and screen time mentioned 135 times during voice recordings). Playing with toys, reading, arts and crafts, and homework were also reported across all four data capturing tools on the app. On an individual level, data from the app often explained irregular patterns in physical activity and SB observed in accelerometer data. Conclusion: This mixed methods approach to assessing SB adds context to accelerometer data, providing researchers with information needed for intervention design

Validating the Sedentary Sphere method in children: does wrist or accelerometer brand matter?

This study aimed to validate the Sedentary Sphere posture classification method from wrist-worn accelerometers in children. Twenty-seven 9-10-year-old children wore ActiGraph GT9X (AG) and GENEActiv (GA) accelerometers on both wrists, and activPAL on the thigh while completing prescribed activities: five sedentary activities, standing with phone, walking (criterion for all 7: observation) and ten minutes free-living play (criterion: activPAL). In an independent sample, 21 children wore AG and GA accelerometers on the non-dominant wrist and activPAL for two days of free-living. Percent accuracy, pairwise 95% equivalence tests (±10% equivalence zone) and intra-class correlation coefficients (ICC) analyses were completed. Accuracy was similar, for prescribed activities irrespective of brand (non-dominant wrist: 77%-78%; dominant wrist: 79%). Posture estimates were equivalent between wrists within brand (±6%, ICC>0.81, lower 95% CI>0.75), between brands worn on the same wrist (±5%, ICC>0.84, lower 95% CI>0.80) and between brands worn on opposing wrists (±6%, ICC>0.78, lower 95% CI>0.72). Agreement with activPAL during free-living was 77%, but sedentary time was underestimated by 7% (GA) and 10% (AG). The Sedentary Sphere can be used to classify posture from wrist-worn AG and GA accelerometers for group-level estimates in children, but future work is needed to improve the algorithm for better individual-level results

Establishing Raw Acceleration Thresholds to Classify Sedentary and Stationary Behaviour in Children

This study aimed to: (1) compare acceleration output between ActiGraph (AG) hip and wrist monitors and GENEActiv (GA) wrist monitors; (2) identify raw acceleration sedentary and stationary thresholds for the two brands and placements; and (3) validate the thresholds during a free-living period. Twenty-seven from 9- to 10-year-old children wore AG accelerometers on the right hip, dominant- and non-dominant wrists, GA accelerometers on both wrists, and an activPAL on the thigh, while completing seven sedentary and light-intensity physical activities, followed by 10 minutes of school recess. In a subsequent study, 21 children wore AG and GA wrist monitors and activPAL for two days of free-living. The main effects of activity and brand and a significant activity × brand × placement interaction were observed (all p < 0.0001). Output from the AG hip was lower than the AG wrist monitors (both p < 0.0001). Receiver operating characteristic (ROC) curves established AG sedentary thresholds of 32.6 mg for the hip, 55.6 mg and 48.1 mg for dominant and non-dominant wrists respectively. GA wrist thresholds were 56.5 mg (dominant) and 51.6 mg (non-dominant). Similar thresholds were observed for stationary behaviours. The AG non-dominant threshold came closest to achieving equivalency with activPAL during free-living

Lead exposure in adult males in urban Transvaal Province, South Africa during the apartheid era

Human exposure to lead is a substantial public health hazard worldwide and is particularly problematic in the Republic of South Africa given the country’s late cessation of leaded petrol. Lead exposure is associated with a number of serious health issues and diseases including developmental and cognitive deficiency, hypertension and heart disease. Understanding the distribution of lifetime lead burden within a given population is critical for reducing exposure rates. Femoral bone from 101 deceased adult males living in urban Transvaal Province (now Gauteng Province), South Africa between 1960 and 1998 were analyzed for lead concentration by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Of the 72 black and 29 white individuals sampled, chronic lead exposure was apparent in nearly all individuals. White males showed significantly higher median bone lead concentration (ME = 10.04 µg·g−1), than black males (ME = 3.80 µg·g−1) despite higher socioeconomic status. Bone lead concentration covaries significantly, though weakly, with individual age. There was no significant temporal trend in bone lead concentration. These results indicate that long-term low to moderate lead exposure is the historical norm among South African males. Unexpectedly, this research indicates that white males in the sample population were more highly exposed to lead

Amyloid-Like Aggregates of the Yeast Prion Protein Ure2 Enter Vertebrate Cells by Specific Endocytotic Pathways and Induce Apoptosis

BACKGROUND: A number of amyloid diseases involve deposition of extracellular protein aggregates, which are implicated in mechanisms of cell damage and death. However, the mechanisms involved remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Here we use the yeast prion protein Ure2 as a generic model to investigate how amyloid-like protein aggregates can enter mammalian cells and convey cytotoxicity. The effect of three different states of Ure2 protein (native dimer, protofibrils and mature fibrils) was tested on four mammalian cell lines (SH-SY5Y, MES23.5, HEK-293 and HeLa) when added extracellularly to the medium. Immunofluorescence using a polyclonal antibody against Ure2 showed that all three protein states could enter the four cell lines. In each case, protofibrils significantly inhibited the growth of the cells in a dose-dependent manner, fibrils showed less toxicity than protofibrils, while the native state had no effect on cell growth. This suggests that the structural differences between the three protein states lead to their different effects upon cells. Protofibrils of Ure2 increased membrane conductivity, altered calcium homeostasis, and ultimately induced apoptosis. The use of standard inhibitors suggested uptake into mammalian cells might occur via receptor-mediated endocytosis. In order to investigate this further, we used the chicken DT40 B cell line DKOR, which allows conditional expression of clathrin. Uptake into the DKOR cell-line was reduced when clathrin expression was repressed suggesting similarities between the mechanism of PrP uptake and the mechanism observed here for Ure2. CONCLUSIONS/SIGNIFICANCE: The results provide insight into the mechanisms by which amyloid aggregates may cause pathological effects in prion and amyloid diseases

Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe