DNA methylation in relation to gestational age and brain dysmaturation in preterm infants.

Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from the saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes or regions. We tested the hypothesis that variation in DNA methylation could underpin the association between low gestational age at birth and atypical brain development by linking differentially methylated probes with measures of white matter connectivity derived from diffusion MRI metrics: peak width skeletonized mean diffusivity, peak width skeletonized fractional anisotropy and peak width skeletonized neurite density index. Gestational age at birth was associated with widespread differential methylation at term equivalent age, with genome-wide significant associations observed for 8870 CpG probes (P < 3.6 × 10-8) and 1767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell-cell contacts and cell-extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component that explained 23.5% of the variance in DNA methylation, and this was negatively associated with gestational age at birth. The first principal component was associated with peak width of skeletonized mean diffusivity (ß = 0.349, P = 8.37 × 10-10) and peak width skeletonized neurite density index (ß = 0.364, P = 4.15 × 10-5), but not with peak width skeletonized fraction anisotropy (ß = -0.035, P = 0.510); these relationships mirrored the imaging metrics' associations with gestational age at birth. Low gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome that is apparent at term equivalent age. Enriched gene ontology terms related to cell-cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNA methylation and image markers of white matter tract microstructure suggest that variation in DNA methylation may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterizes atypical brain development in preterm infants.

Trends in Europe storm surge extremes match the rate of sea-level rise.

Coastal communities across the world are already feeling the disastrous impacts of climate change through variations in extreme sea levels1. These variations reflect the combined effect of sea-level rise and changes in storm surge activity. Understanding the relative importance of these two factors in altering the likelihood of extreme events is crucial to the success of coastal adaptation measures. Existing analyses of tide gauge records2-10 agree that sea-level rise has been a considerable driver of trends in sea-level extremes since at least 1960. However, the contribution from changes in storminess remains unclear, owing to the difficulty of inferring this contribution from sparse data and the consequent inconclusive results that have accumulated in the literature11,12. Here we analyse tide gauge observations using spatial Bayesian methods13 to show that, contrary to current thought, trends in surge extremes and sea-level rise both made comparable contributions to the overall change in extreme sea levels in Europe since 1960 . We determine that the trend pattern of surge extremes reflects the contributions from a dominant north-south dipole associated with internal climate variability and a single-sign positive pattern related to anthropogenic forcing. Our results demonstrate that both external and internal influences can considerably affect the likelihood of surge extremes over periods as long as 60 years, suggesting that the current coastal planning practice of assuming stationary surge extremes1,14 might be inadequate.

Eye-tracking for longitudinal assessment of social cognition in children born preterm.

BACKGROUND AND OBJECTIVES: Preterm birth is associated with atypical social cognition in infancy, and cognitive impairment and social difficulties in childhood. Little is known about the stability of social cognition through childhood, and its relationship with neurodevelopment. We used eye-tracking in preterm and term-born infants to investigate social attentional preference in infancy and at 5 years, its relationship with neurodevelopment and the influence of socioeconomic deprivation. METHODS: A cohort of 81 preterm and 66 term infants with mean (range) gestational age at birth 28+5 (23+2 -33+0 ) and 40+0 (37+0 -42+1 ) respectively, completed eye-tracking at 7-9 months, with a subset re-assessed at 5 years. Three free-viewing social tasks of increasing stimulus complexity were presented, and a social preference score was derived from looking time to socially informative areas. Socioeconomic data and the Mullen Scales of Early Learning at 5 years were collected. RESULTS: Preterm children had lower social preference scores at 7-9 months compared with term-born controls. Term-born children's scores were stable between time points, whereas preterm children showed a significant increase, reaching equivalent scores by 5 years. Low gestational age and socioeconomic deprivation were associated with reduced social preference scores at 7-9 months. At 5 years, preterm infants had lower Early Learning Composite scores than controls, but this was not associated with social attentional preference in infancy or at 5 years. CONCLUSIONS: Preterm children have reduced social attentional preference at 7-9 months compared with term-born controls, but catch up by 5 years. Infant social cognition is influenced by socioeconomic deprivation and gestational age. Social cognition and neurodevelopment have different trajectories following preterm birth.

Increasing mitigation ambition to meet the Paris Agreement's temperature goal avoids substantial heat-related mortality in U.S. cities.

Current greenhouse gas mitigation ambition is consistent with ~3°C global mean warming above preindustrial levels. There is a clear need to strengthen mitigation ambition to stabilize the climate at the Paris Agreement goal of warming of less than 2°C. We specify the differences in city-level heat-related mortality between the 3°C trajectory and warming of 2° and 1.5°C. Focusing on 15 U.S. cities where reliable climate and health data are available, we show that ratcheting up mitigation ambition to achieve the 2°C threshold could avoid between 70 and 1980 annual heat-related deaths per city during extreme events (30-year return period). Achieving the 1.5°C threshold could avoid between 110 and 2720 annual heat-related deaths. Population changes and adaptation investments would alter these numbers. Our results provide compelling evidence for the heat-related health benefits of limiting global warming to 1.5°C in the United States.

Early breast milk exposure modifies brain connectivity in preterm infants.

Preterm infants are at increased risk of alterations in brain structure and connectivity, and subsequent neurocognitive impairment. Breast milk may be more advantageous than formula feed for promoting brain development in infants born at term, but uncertainties remain about its effect on preterm brain development and the optimal nutritional regimen for preterm infants. We test the hypothesis that breast milk exposure is associated with improved markers of brain development and connectivity in preterm infants at term equivalent age. We collected information about neonatal breast milk exposure and brain MRI at term equivalent age from 47 preterm infants (mean postmenstrual age [PMA] 29.43 weeks, range 23.28-33.0). Network-Based Statistics (NBS), Tract-based Spatial Statistics (TBSS) and volumetric analysis were used to investigate the effect of breast milk exposure on white matter water diffusion parameters, tissue volumes, and the structural connectome. Twenty-seven infants received exclusive breast milk feeds for ≥75% of days of in-patient care and this was associated with higher connectivity in the fractional anisotropy (FA)-weighted connectome compared with the group who had < 75% of days receiving exclusive breast milk feeds (NBS, p = 0.04). Within the TBSS white matter skeleton, the group that received ≥75% exclusive breast milk days exhibited higher FA within the corpus callosum, cingulum cingulate gyri, centrum semiovale, corticospinal tracts, arcuate fasciculi and posterior limbs of the internal capsule compared with the low exposure group after adjustment for PMA at birth, PMA at image acquisition, bronchopulmonary dysplasia, and chorioamnionitis (p < 0.05). The effect on structural connectivity and tract water diffusion parameters was greater with ≥90% exposure, suggesting a dose effect. There were no significant groupwise differences in brain volumes. Breast milk feeding in the weeks after preterm birth is associated with improved structural connectivity of developing networks and greater FA in major white matter fasciculi.

Biogeophysical Impacts of Land-Use Change on Climate Extremes in Low-Emission Scenarios: Results From HAPPI-Land.

The impacts of land use have been shown to have considerable influence on regional climate. With the recent international commitment to limit global warming to well below 2°C, emission reductions need to be ambitious and could involve major land-use change (LUC). Land-based mitigation efforts to curb emissions growth include increasing terrestrial carbon sequestration through reforestation, or the adoption of bioenergy crops. These activities influence local climate through biogeophysical feedbacks, however, it is uncertain how important they are for a 1.5° climate target. This was the motivation for HAPPI-Land: the half a degree additional warming, prognosis, and projected impacts-land-use scenario experiment. Using four Earth system models, we present the first multimodel results from HAPPI-Land and demonstrate the critical role of land use for understanding the characteristics of regional climate extremes in low-emission scenarios. In particular, our results show that changes in temperature extremes due to LUC are comparable in magnitude to changes arising from half a degree of global warming. We also demonstrate that LUC contributes to more than 20% of the change in temperature extremes for large land areas concentrated over the Northern Hemisphere. However, we also identify sources of uncertainty that influence the multimodel consensus of our results including how LUC is implemented and the corresponding biogeophysical feedbacks that perturb climate. Therefore, our results highlight the urgent need to resolve the challenges in implementing LUC across models to quantify the impacts and consider how LUC contributes to regional changes in extremes associated with sustainable development pathways.

Diffusion MRI parameters of corpus callosum and corticospinal tract in neonates: Comparison between region-of-interest and whole tract averaged measurements.

PURPOSE: Measures of white matter (WM) microstructure inferred from diffusion magnetic resonance imaging (dMRI) are useful for studying brain development. There is uncertainty about agreement between FA and MD values obtained from region-of-interest (ROI) versus whole tract approaches. We investigated agreement between dMRI measures using ROI and Probabilistic Neighbourhood Tractography (PNT) in genu of corpus callosum (gCC) and corticospinal tracts (CST). MATERIALS AND METHODS: 81 neonates underwent 64 direction DTI at term equivalent age. FA and MD values were extracted from a 8 mm3 ROI placed within the gCC, right and left posterior limbs of internal capsule. PNT was used to segment gCC and CSTs to calculate whole tract-averaged FA and MD. Agreement between values obtained by each method was compared using Bland-Altman statistics and Pearson's correlation. RESULTS: Across the 3 tracts the mean difference in FA measured by PNT and ROI ranged between 0.13 and 0.17, and the 95% limits of agreement did not include the possibility of no difference. For MD, the mean difference in values obtained from PNT and ROI ranged between 0.101 and 0.184 mm2/s × 10-3 mm2/s: the mean difference in gCC was 0.101 × 10-3 mm2/s with 95% limits of agreement that included the possibility of no difference, but there was significant disagreement in MD values measured in the CSTs. CONCLUSION: Agreement between dMRI measures of neonatal WM microstructure calculated from ROI and whole tract averaged methods is weak. ROI approaches may not provide sufficient representation of tract microstructure at the level of neural systems in newborns.

Ensemble of European regional climate simulations for the winter of 2013 and 2014 from HadAM3P-RM3P.

Large data sets used to study the impact of anthropogenic climate change on the 2013/14 floods in the UK are provided. The data consist of perturbed initial conditions simulations using the Weather@Home regional climate modelling framework. Two different base conditions, Actual, including atmospheric conditions (anthropogenic greenhouse gases and human induced aerosols) as at present and Natural, with these forcings all removed are available. The data set is made up of 13 different ensembles (2 actual and 11 natural) with each having more than 7500 members. The data is available as NetCDF V3 files representing monthly data within the period of interest (1st Dec 2013 to 15th February 2014) for both a specified European region at a 50 km horizontal resolution and globally at N96 resolution. The data is stored within the UK Natural and Environmental Research Council Centre for Environmental Data Analysis repository.

Alterations in glucose concentrations affect DNA methylation at Lrg1 in an ex vivo rat cortical slice model of preterm brain injury.

Preterm birth affects 5-18% of all babies and is associated with neurodevelopmental impairment and increased neuropsychiatric disease risk. Although preterm birth associates with differential DNA methylation at neurodevelopmental genes in buccal DNA, including leucine-rich alpha-2-glycoprotein 1 (LRG1), it is not known whether these differences also occur in the brain, or whether they persist. Thus, there is a need for animal models or in vitro systems in which to undertake longitudinal and mechanistic studies. We used a combination of in vivo rat studies and ex vivo experiments in rat cortical slices to explore their utility in modelling the human preterm brain. We identified temporal changes in DNA methylation at LRG1 in human buccal DNA over the first year of life and found persistent differences in LRG1 methylation between preterm and term infants at 1 year. These developmental changes also occurred in rat brains in vivo, alongside changes in global DNA hydroxymethylation and expression of the ten-eleven translocation (Tet1) enzyme, and were reproducible in ex vivo rat cortical slices. On the basis of the observation that neonatal glucose homeostasis can modify neurodevelopmental outcome, we studied whether glucose concentration affects Lrg1 methylation using cortical slices. Culture of slices in lower glucose concentration was associated with lower Lrg1 methylation, lower global 5hmC and Tet1 expression. Our results suggest that ex vivo organotypic cultures may be useful in the study of biological and environmental influences on the epigenome and that perturbations during early life including glucose concentration can affect methylation at specific genes implicated in neurodevelopment.

Reducing Antibiotic Exposure in Suspected Neonatal Sepsis.

Prolonged antibiotic therapy is associated with antimicrobial resistance and increased mortality in preterm infants. We evaluated the impact of an automatic stop order (ASO) and C-reactive protein (CRP) on the duration of antibiotics and level of intervention in infants screened for early-onset sepsis who had negative cultures. We introduced an ASO for low-risk infants, then, consequently, for all infants treated for suspected sepsis. We subsequently introduced a single CRP measurement at 36 hours. Between 2011 and 2014, 4 time periods were studied, at baseline and after each intervention. The proportion of infants receiving ≤48 hours of antibiotics increased from 19% to 72.5% ( P < .0001), whereas that of infants receiving avoidable doses (>48 hours and <5 days) fell from 50% to 0.8% ( P < .0001). The use of an ASO decreased the proportion receiving avoidable doses from 26/92 (28.3%) to 9/293 (3.1%); P < .0001. There was a reduction in lumbar punctures performed, from 35% to 20%; P = .015.

A latent measure explains substantial variance in white matter microstructure across the newborn human brain.

A latent measure of white matter microstructure (g WM) provides a neural basis for information processing speed and intelligence in adults, but the temporal emergence of g WM during human development is unknown. We provide evidence that substantial variance in white matter microstructure is shared across a range of major tracts in the newborn brain. Based on diffusion MRI scans from 145 neonates [gestational age (GA) at birth range 23+2-41+5 weeks], the microstructural properties of eight major white matter tracts were calculated using probabilistic neighborhood tractography. Principal component analyses (PCAs) were carried out on the correlations between the eight tracts, separately for four tract-averaged water diffusion parameters: fractional anisotropy, and mean, radial and axial diffusivities. For all four parameters, PCAs revealed a single latent variable that explained around half of the variance across all eight tracts, and all tracts showed positive loadings. We considered the impact of early environment on general microstructural properties, by comparing term-born infants with preterm infants at term equivalent age. We found significant associations between GA at birth and the latent measure for each water diffusion measure; this effect was most apparent in projection and commissural fibers. These data show that a latent measure of white matter microstructure is present in very early life, well before myelination is widespread. Early exposure to extra-uterine life is associated with altered general properties of white matter microstructure, which could explain the high prevalence of cognitive impairment experienced by children born preterm.

SEGMA: An Automatic SEGMentation Approach for Human Brain MRI Using Sliding Window and Random Forests.

Quantitative volumes from brain magnetic resonance imaging (MRI) acquired across the life course may be useful for investigating long term effects of risk and resilience factors for brain development and healthy aging, and for understanding early life determinants of adult brain structure. Therefore, there is an increasing need for automated segmentation tools that can be applied to images acquired at different life stages. We developed an automatic segmentation method for human brain MRI, where a sliding window approach and a multi-class random forest classifier were applied to high-dimensional feature vectors for accurate segmentation. The method performed well on brain MRI data acquired from 179 individuals, analyzed in three age groups: newborns (38-42 weeks gestational age), children and adolescents (4-17 years) and adults (35-71 years). As the method can learn from partially labeled datasets, it can be used to segment large-scale datasets efficiently. It could also be applied to different populations and imaging modalities across the life course.

Association between preterm brain injury and exposure to chorioamnionitis during fetal life.

Preterm infants are susceptible to inflammation-induced white matter injury but the exposures that lead to this are uncertain. Histologic chorioamnionitis (HCA) reflects intrauterine inflammation, can trigger a fetal inflammatory response, and is closely associated with premature birth. In a cohort of 90 preterm infants with detailed placental histology and neonatal brain magnetic resonance imaging (MRI) data at term equivalent age, we used Tract-based Spatial Statistics (TBSS) to perform voxel-wise statistical comparison of fractional anisotropy (FA) data and computational morphometry analysis to compute the volumes of whole brain, tissue compartments and cerebrospinal fluid, to test the hypothesis that HCA is an independent antenatal risk factor for preterm brain injury. Twenty-six (29%) infants had HCA and this was associated with decreased FA in the genu, cingulum cingulate gyri, centrum semiovale, inferior longitudinal fasciculi, limbs of the internal capsule, external capsule and cerebellum (p < 0.05, corrected), independent of degree of prematurity, bronchopulmonary dysplasia and postnatal sepsis. This suggests that diffuse white matter injury begins in utero for a significant proportion of preterm infants, which focuses attention on the development of methods for detecting fetuses and placentas at risk as a means of reducing preterm brain injury.

Parcellation of the Healthy Neonatal Brain into 107 Regions Using Atlas Propagation through Intermediate Time Points in Childhood.

Neuroimage analysis pipelines rely on parcellated atlases generated from healthy individuals to provide anatomic context to structural and diffusion MRI data. Atlases constructed using adult data introduce bias into studies of early brain development. We aimed to create a neonatal brain atlas of healthy subjects that can be applied to multi-modal MRI data. Structural and diffusion 3T MRI scans were acquired soon after birth from 33 typically developing neonates born at term (mean postmenstrual age at birth 39(+5) weeks, range 37(+2)-41(+6)). An adult brain atlas (SRI24/TZO) was propagated to the neonatal data using temporal registration via childhood templates with dense temporal samples (NIH Pediatric Database), with the final atlas (Edinburgh Neonatal Atlas, ENA33) constructed using the Symmetric Group Normalization (SyGN) method. After this step, the computed final transformations were applied to T2-weighted data, and fractional anisotropy, mean diffusivity, and tissue segmentations to provide a multi-modal atlas with 107 anatomical regions; a symmetric version was also created to facilitate studies of laterality. Volumes of each region of interest were measured to provide reference data from normal subjects. Because this atlas is generated from step-wise propagation of adult labels through intermediate time points in childhood, it may serve as a useful starting point for modeling brain growth during development.

Preterm birth is associated with atypical social orienting in infancy detected using eye tracking.

BACKGROUND: Preterm birth is closely associated with neurocognitive impairment in childhood including increased risk for social difficulties. Eye tracking objectively assesses eye-gaze behaviour in response to visual stimuli, which permits inference about underlying cognitive processes. We tested the hypothesis that social orienting in infancy is altered by preterm birth. METHODS: Fifty preterm infants with mean (range) gestational age (GA) at birth of 29(+1) (23(+2) -33(+0) ) weeks and 50 term infants with mean (range) GA at birth 40(+2) (37(+0) -42(+3) ) weeks underwent eye tracking at median age of 7 months. Infants were presented with three categories of social stimuli of increasing complexity. Time to first fixate (TFF) and looking time (LT) on areas of interest (AoIs) were recorded using remote eye tracking. RESULTS: Preterm infants consistently fixated for a shorter time on social content than term infants across all three tasks: face-scanning (fixation to eyes minus mouth 0.61s vs. 1.47s, p = .013); face pop-out task (fixation to face 0.8s vs. 1.34s, p = .023); and social preferential looking (1.16s vs. 1.5s p = .02). Time given to AoIs containing social content as a proportion of LT at the whole stimulus was lower in preterm infants across all three tasks. These results were not explained by differences in overall looking time between the groups. CONCLUSIONS: Eye tracking provides early evidence of atypical cognition after preterm birth, and may be a useful tool for stratifying infants at risk of impairment for early interventions designed to improve outcome.

Accurate Learning with Few Atlases (ALFA): an algorithm for MRI neonatal brain extraction and comparison with 11 publicly available methods.

Accurate whole-brain segmentation, or brain extraction, of magnetic resonance imaging (MRI) is a critical first step in most neuroimage analysis pipelines. The majority of brain extraction algorithms have been developed and evaluated for adult data and their validity for neonatal brain extraction, which presents age-specific challenges for this task, has not been established. We developed a novel method for brain extraction of multi-modal neonatal brain MR images, named ALFA (Accurate Learning with Few Atlases). The method uses a new sparsity-based atlas selection strategy that requires a very limited number of atlases 'uniformly' distributed in the low-dimensional data space, combined with a machine learning based label fusion technique. The performance of the method for brain extraction from multi-modal data of 50 newborns is evaluated and compared with results obtained using eleven publicly available brain extraction methods. ALFA outperformed the eleven compared methods providing robust and accurate brain extraction results across different modalities. As ALFA can learn from partially labelled datasets, it can be used to segment large-scale datasets efficiently. ALFA could also be applied to other imaging modalities and other stages across the life course.

Tract shape modeling detects changes associated with preterm birth and neuroprotective treatment effects.

Preterm birth is associated with altered connectivity of neural circuits. We developed a tract segmentation method that provides measures of tract shape and integrity (probabilistic neighborhood tractography, PNT) from diffusion MRI (dMRI) data to test the hypotheses: 1) preterm birth is associated with alterations in tract topology (R), and tract-averaged mean diffusivity (〈D〉) and fractional anisotropy (FA); 2) neural systems are separable based on tract-averaged dMRI parameters; and 3) PNT can detect neuroprotective treatment effects. dMRI data were collected from 87 preterm infants (mean gestational age 29(+1) weeks, range 23(+2) -34(+6)) at term equivalent age and 24 controls (mean gestational age 39(+6) weeks). PNT was used to segment eight major fasciculi, characterize topology, and extract tract-averaged〈D〉and FA. Tract topology was altered by preterm birth in all tracts except the splenium (p < 0.05, false discovery rate [FDR] corrected). After adjustment for age at scan, tract-averaged〈D〉was increased in the genu and splenium, right corticospinal tract (CST) and the left and right inferior longitudinal fasciculi (ILF) in preterm infants compared with controls (p < 0.05, FDR), while tract-averaged FA was decreased in the splenium and left ILF (p < 0.05, FDR). Specific fasciculi were separable based on tract-averaged〈D〉and FA values. There was a modest decrease in tract-averaged〈D〉in the splenium of preterm infants who had been exposed to antenatal MgSO4 for neuroprotection (p = 0.002). Tract topology is a biomarker of preterm brain injury. The data provide proof of concept that tract-averaged dMRI parameters have utility for evaluating tissue effects of perinatal neuroprotective strategies.

Heat acclimatization and hydration status of American football players during initial summer workouts.

This investigation evaluated the new National Collegiate Athletic Association model of heat acclimatization for football players using physiological, psychological, fluid balance, anthropometric, and nutritional variables. Eleven football players (20 +/- 1 year, 1.88 +/- 0.05 m, and 115.36 +/- 18.85 kg) from a Division I football team were observed for the first 8 days of preseason practices. Measurements such as heart rate and gastrointestinal temperature (T(GI)) via telemetric sensor were taken before, 3 times during, and after practice daily. An average 1.39-kg (1.2%) decrease of body mass occurred from prepractice to postpractice (p < 0.01). Consistent with mild body mass losses, urinary indices of hydration status (i.e., color, specific gravity, and osmolality) indicated mild fluid deficits. A significant increase (p < 0.05) from pre- to postpractice was observed in urine color and urine specific gravity, but chronic hypohydration over the 8 days was not noted. The Environmental Symptoms Questionnaire (ESQ) postpractice score was significantly higher (p < 0.05) than the prepractice score was, but averages did not differ across practice days. There was no difference in postpractice T(GI) measurements across days (p < 0.05). Heart rate, T(GI), and ESQ measurements indicated that football players experienced gradual heat acclimatization and enhanced heat tolerance, despite progressive increases of exercise variables, clothing, and environmental stressors.

Personality characteristics associated with susceptibility to false memories.

This study examined whether certain personality characteristics are associated with susceptibility to false memories. Participants first answered questions from the Myers-Briggs Type Indicator in order to measure various personality characteristics. They then watched a video excerpt, the simulated eyewitness event. They were next encouraged to lie about the videotaped event during an interview. A week later, some participants recognized confabulated events as being from the video. Two personality characteristics in particular--the introversion-extroversion and thinking-feeling dimensions--were associated with susceptibility to false memories.