The genetic architecture of sporadic congenital heart disease (CHD) is characterized by enrichment in damaging de novo variants in chromatin-modifying genes. To test the hypothesis that gene pathways ...contributing to de novo forms of CHD are distinct from those for recessive forms, we analyze 2391 whole-exome trios from the Pediatric Cardiac Genomics Consortium. We deploy a permutation-based gene-burden analysis to identify damaging recessive and compound heterozygous genotypes and disease genes, controlling for confounding effects, such as background mutation rate and ancestry. Cilia-related genes are significantly enriched for damaging rare recessive genotypes, but comparatively depleted for de novo variants. The opposite trend is observed for chromatin-modifying genes. Other cardiac developmental gene classes have less stratification by mode of inheritance than cilia and chromatin-modifying gene classes. Our analyses reveal dominant and recessive CHD are associated with distinct gene functions, with cilia-related genes providing a reservoir of rare segregating variation leading to CHD.
Elevated levels of neurotoxic methylmercury in Arctic food-webs pose health risks for indigenous populations that consume large quantities of marine mammals and fish. Estuaries provide critical ...hunting and fishing territory for these populations, and, until recently, benthic sediment was thought to be the main methylmercury source for coastal fish. New hydroelectric developments are being proposed in many northern ecosystems, and the ecological impacts of this industry relative to accelerating climate changes are poorly characterized. Here we evaluate the competing impacts of climate-driven changes in northern ecosystems and reservoir flooding on methylmercury production and bioaccumulation through a case study of a stratified sub-Arctic estuarine fjord in Labrador, Canada. Methylmercury bioaccumulation in zooplankton is higher than in midlatitude ecosystems. Direct measurements and modeling show that currently the largest methylmercury source is production in oxic surface seawater. Water-column methylation is highest in stratified surface waters near the river mouth because of the stimulating effects of terrestrial organic matter on methylating microbes. We attribute enhanced biomagnification in plankton to a thin layer of marine snow widely observed in stratified systems that concentrates microbial methylation and multiple trophic levels of zooplankton in a vertically restricted zone. Large freshwater inputs and the extensive Arctic Ocean continental shelf mean these processes are likely widespread and will be enhanced by future increases in water-column stratification, exacerbating high biological methylmercury concentrations. Soil flooding experiments indicate that near-term changes expected from reservoir creation will increase methylmercury inputs to the estuary by 25–200%, overwhelming climate-driven changes over the next decade.
We combined two existing datasets of vegetation aboveground biomass (AGB) (Proceedings of the National Academy of Sciences of the United States of America, 108, 2011, 9899; Nature Climate Change, 2, ...2012, 182) into a pan‐tropical AGB map at 1‐km resolution using an independent reference dataset of field observations and locally calibrated high‐resolution biomass maps, harmonized and upscaled to 14 477 1‐km AGB estimates. Our data fusion approach uses bias removal and weighted linear averaging that incorporates and spatializes the biomass patterns indicated by the reference data. The method was applied independently in areas (strata) with homogeneous error patterns of the input (Saatchi and Baccini) maps, which were estimated from the reference data and additional covariates. Based on the fused map, we estimated AGB stock for the tropics (23.4 N–23.4 S) of 375 Pg dry mass, 9–18% lower than the Saatchi and Baccini estimates. The fused map also showed differing spatial patterns of AGB over large areas, with higher AGB density in the dense forest areas in the Congo basin, Eastern Amazon and South‐East Asia, and lower values in Central America and in most dry vegetation areas of Africa than either of the input maps. The validation exercise, based on 2118 estimates from the reference dataset not used in the fusion process, showed that the fused map had a RMSE 15–21% lower than that of the input maps and, most importantly, nearly unbiased estimates (mean bias 5 Mg dry mass ha⁻¹ vs. 21 and 28 Mg ha⁻¹ for the input maps). The fusion method can be applied at any scale including the policy‐relevant national level, where it can provide improved biomass estimates by integrating existing regional biomass maps as input maps and additional, country‐specific reference datasets.
The traditional Inuit diet includes wild birds, fish and marine mammals, which can contain high concentrations of the neurotoxicant methylmercury (MeHg). Hydroelectric development may increase MeHg ...concentrations in traditional foods. Consumption advisories are often used to mitigate such risks and can result in reduced intake of traditional foods. Data from a dietary survey, MeHg exposure assessment and risk analysis for individuals in three Inuit communities in Labrador, Canada (n = 1145) in 2014 indicate reducing traditional food intake is likely to exacerbate deficiencies in n-3 polyunsaturated fatty acids and vitamins B12 and B2. Traditional foods accounted for < 5% of per-capita calories but up to 70% of nutrients consumed. Although consumption advisories could lower neurodevelopmental risks associated with an increase in MeHg exposure (90th-percentile ∆IQ = − 0.12 vs. − 0.34), they may lead to greater risks of cardiovascular mortality (90th-percentile increase: + 58% to + 116% vs. + 25%) and cancer mortality (90th-percentile increase + 2% to + 4% vs. no increase). Conversely, greater consumption of locally caught salmon mostly unaffected by hydroelectric flooding would lower all these risks (90th-percentile ∆IQ = + 0.4; cardiovascular risk: − 45%; cancer risk: − 1.4%). We thus conclude that continued consumption of traditional foods is essential for Inuit health in these communities.
•Traditional foods account for up to 70% of essential nutrients.•They account for the majority of bioaccumulative contaminant exposures.•Food advisories may increase median risk of cardiovascular mortality.•Advisories may also increase cancer risks associated with red meat consumption.
Developing Canadian hydroelectric resources is a key component of North American plans for meeting future energy demands. Microbial production of the bioaccumulative neurotoxin methylmercury (MeHg) ...is stimulated in newly flooded soils by degradation of labile organic carbon and associated changes in geochemical conditions. We find all 22 Canadian hydroelectric facilities being considered for near-term development are located within 100 km of indigenous communities. For a facility in Labrador, Canada (Muskrat Falls) with planned completion in 2017, we probabilistically modeled peak MeHg enrichment relative to measured baseline conditions in the river to be impounded, downstream estuary, locally harvested fish, birds and seals, and three Inuit communities. Results show a projected 10-fold increase in riverine MeHg levels and a 2.6-fold increase in estuarine surface waters. MeHg concentrations in locally caught species increase 1.3 to 10-fold depending on time spent foraging in different environments. Mean Inuit MeHg exposure is forecasted to double following flooding and over half of the women of childbearing age and young children in the most northern community are projected to exceed the U.S. EPA’s reference dose. Equal or greater aqueous MeHg concentrations relative to Muskrat Falls are forecasted for 11 sites across Canada, suggesting the need for mitigation measures prior to flooding.
Whilst an acute bout of exercise has been shown to enhance subsequent cognition, including in adolescents, the effects of team games (of which Football is the most popular) has received little ...attention. Therefore, this study examined: the effect of an acute bout of outdoor Football activity on information processing, inhibitory control, working memory and circulating brain-derived neurotrophic factor (BDNF) in adolescents; the effect of physical fitness on cognition and; the moderating effect of physical fitness on the acute exercise responses.
Following familiarisation, 36 adolescents (16 girls) took part in two trials (60-min Football and 60-min seated rest) separated by 7-d in a counterbalanced, crossover design. Information processing and inhibitory control (Stroop Test), and working memory (Sternberg Paradigm) were assessed 30-min before exercise/rest and immediately, 45- and 90-min post-exercise/rest. Capillary blood samples were obtained before exercise/rest and up to 120-min post-exercise/rest. The median split of distance covered on the MSFT was used to divide the group into high- and low-fit groups.
Performance on the cognitive function tasks was similar between Football and seated rest (trial*time interactions; all p > .05). However, the high-fit group had overall quicker response times on both levels of the Stroop Task and all three levels of the Sternberg Paradigm (main effect of fitness; all p < .001). Furthermore, the exercise-cognition relationship was moderated by physical fitness, with improvements in working memory response times seen post-exercise, only in the high-fit group (trial*time*fitness interaction, p < .05). Circulating BDNF was unaffected by the Football activity and physical fitness (p > .05).
The present study shows that higher levels of physical fitness are beneficial for cognitive function and provides novel evidence that an ecologically valid, and popular, form of exercise is beneficial for working memory following exercise, in high-fit participants only.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cystic fibrosis is a genetic disorder characterized by recurrent airway infections, inflammation, impaired mucociliary clearance and progressive decline in lung function. The disease may start in the ...small airways; however, this is difficult to prove due to limited accessibility of the small airways with the current single photon mucociliary clearance assay. Here, we developed a dynamic positron emission tomography assay with high spatial and temporal resolution. We tested that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Clearance of 68 Ga tagged macro-aggregated albumin from small airways started immediately after delivery and continued for the duration of the study. Initial clearance was fast but slowed down few minutes after delivery. Cystic fibrosis pig small airways cleared significantly less than non-CF pig small airways (non-CF 25.1±3.1% vs. CF 14.6±0.1%). Stimulation of the cystic fibrosis airways with the purinergic secretagogue UTP further impaired clearance (non-CF with UTP 20.9±0.3% vs. CF with UTP 13.0±1.8%). None of the cystic fibrosis pig treated with UTP (N = 6) cleared more than 20% of the delivered dose. These data indicate that mucociliary clearance in the small airways is fast and can easily be missed if the assay is not sensitive enough. The data also indicate that mucociliary clearance is impaired in the small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists.
Abstract
The aim of the present study was to determine the effect of 5-weeks participation in The Daily Mile on cognitive function, physical fitness, and adiposity in primary school children. In a ...quasi-experimental study, one class from each school completed The Daily Mile (n = 44) or acted as a control group (n = 35). Baseline measures included cognitive function tests (Stroop test, Sternberg paradigm, Flanker task), physical fitness (multi-stage fitness test) and body composition (BMI percentile, waist:hip circumference, sum of skinfolds). The intervention group completed 5-weeks of The Daily Mile. Follow-up measurements were completed within 48-h of the last training session. Data were analysed via ANCOVA, examining between group differences at follow-up, controlling for baseline values. Response times on the complex Stroop test were faster at follow-up in the intervention group (Intervention: 1357 ms 1280–1400 ms; Control: 1463 ms, 1410–1523 ms,
d
= 0.31
, p
= 0.048). There was no effect of The Daily Mile on the Sternberg paradigm or Flanker test. Physical fitness was greater at follow-up in the intervention group (Intervention: 880 m, 820–940 m; Control: 740 m, 680–800 m,
d
= 0.39,
p
= 0.002). There was no effect of the intervention on adiposity. In conclusion, five-weeks of The Daily Mile enhanced inhibitory control and physical fitness in children, but did not affect working memory, attention, or adiposity.
Unprofessional behaviour among hospital staff is common. Such behaviour negatively impacts on staff wellbeing and patient outcomes. Professional accountability programs collect information about ...unprofessional staff behaviour from colleagues or patients, providing this as informal feedback to raise awareness, promote reflection, and change behaviour. Despite increased adoption, studies have not assessed the implementation of these programs utilising implementation theory. This study aims to (1) identify factors influencing the implementation of a whole-of-hospital professional accountability and culture change program, Ethos, implemented in eight hospitals within a large healthcare provider group, and (2) examine whether expert recommended implementation strategies were intuitively used during implementation, and the degree to which they were operationalised to address identified barriers.
Data relating to implementation of Ethos from organisational documents, interviews with senior and middle management, and surveys of hospital staff and peer messengers were obtained and coded in NVivo using the Consolidated Framework for Implementation Research (CFIR). Implementation strategies to address identified barriers were generated using Expert Recommendations for Implementing Change (ERIC) strategies and used in a second round of targeted coding, then assessed for degree of alignment to contextual barriers.
Four enablers, seven barriers, and three mixed factors were found, including perceived limitations in the confidential nature of the online messaging tool ('Design quality and packaging'), which had downstream challenges for the capacity to provide feedback about utilisation of Ethos ('Goals and Feedback', 'Access to Knowledge and Information'). Fourteen recommended implementation strategies were used, however, only four of these were operationalised to completely address contextual barriers.
Aspects of the inner setting (e.g., 'Leadership Engagement', 'Tension for Change') had the greatest influence on implementation and should be considered prior to the implementation of future professional accountability programs. Theory can improve understanding of factors affecting implementation, and support strategies to address them.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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