With advances in neonatal care, preterm neonates are surviving with an evolving constellation of motor and cognitive disabilities that appear to be related to widespread cellular maturational ...disturbances that target cerebral gray and white matter. Whereas preterm infants were previously at high risk for destructive brain lesions that resulted in cystic white matter injury and secondary cortical and subcortical gray matter degeneration, contemporary cohorts of preterm survivors commonly display less severe injury that does not appear to involve pronounced glial or neuronal loss. Nevertheless, these milder forms of injury are also associated with reduced cerebral growth. Recent human and experimental studies support that impaired cerebral growth is related to disparate responses in gray and white matter. Myelination disturbances in cerebral white matter are related to aberrant regeneration and repair responses to acute death of premyelinating late oligodendrocyte progenitors (preOLs). In response to preOL death, early oligodendrocyte progenitors rapidly proliferate and differentiate, but the regenerated preOLs fail to normally mature to myelinating cells required for white matter growth. Although immature neurons appear to be more resistant to cell death from hypoxia–ischemia than glia, they display widespread disturbances in maturation of their dendritic arbors, which further contribute to impaired cerebral growth. These complex and disparate responses of neurons and preOLs thus result in large numbers of cells that fail to fully mature during a critical window in development of neural circuitry. These recently recognized forms of cerebral gray and white matter dysmaturation raise new diagnostic challenges and suggest new therapeutic directions centered on reversal of the processes that promote dysmaturation. Ann Neurol 2014;75:469–486
Neurodevelopmental outcomes are impaired in survivors of critical congenital heart disease (CHD) in several developmental domains including motor, cognitive and sensory outcomes. These deficits can ...extend into the adolescent and early adulthood years. The cause of these neurodevelopmental impairments is multi-factorial and includes patient specific risk factors, cardiac anatomy and physiology as well as brain changes seen on MRI. Advances in imaging techniques have identified delayed brain development in the neonate with critical CHD as well as acquired brain injury. These abnormalities are seen even before corrective neonatal cardiac surgery. This review focuses on describing brain changes seen on MRI in neonates with CHD, risk factors for these changes and the association with neurodevelopmental outcome. There is an emerging focus on the impact of cardiovascular physiology on brain health and the complex heart-brain interplay that influences ultimate neurodevelopmental outcome in these patients.
•Neurodevelopmental outcome is impaired in survivors of critical congenital heart disease.•Advances in neonatal brain imaging have identified delayed brain development beginning in the third trimester of fetal life.•Acquired brain injury is common in critical congenital heart disease.•The relationship between brain imaging abnormalities in CHD and neurodevelopmental outcome is complex.
We propose BrainNetCNN, a convolutional neural network (CNN) framework to predict clinical neurodevelopmental outcomes from brain networks. In contrast to the spatially local convolutions done in ...traditional image-based CNNs, our BrainNetCNN is composed of novel edge-to-edge, edge-to-node and node-to-graph convolutional filters that leverage the topological locality of structural brain networks. We apply the BrainNetCNN framework to predict cognitive and motor developmental outcome scores from structural brain networks of infants born preterm. Diffusion tensor images (DTI) of preterm infants, acquired between 27 and 46 weeks gestational age, were used to construct a dataset of structural brain connectivity networks. We first demonstrate the predictive capabilities of BrainNetCNN on synthetic phantom networks with simulated injury patterns and added noise. BrainNetCNN outperforms a fully connected neural-network with the same number of model parameters on both phantoms with focal and diffuse injury patterns. We then apply our method to the task of joint prediction of Bayley-III cognitive and motor scores, assessed at 18 months of age, adjusted for prematurity. We show that our BrainNetCNN framework outperforms a variety of other methods on the same data. Furthermore, BrainNetCNN is able to identify an infant's postmenstrual age to within about 2 weeks. Finally, we explore the high-level features learned by BrainNetCNN by visualizing the importance of each connection in the brain with respect to predicting the outcome scores. These findings are then discussed in the context of the anatomy and function of the developing preterm infant brain.
•First deep convolutional neural network architecture designed for connectomes.•Novel convolutional layers for leveraging topological locality in brain networks.•Prediction of neurodevelopmental outcomes in preterm infants.•Visualization of brain connections learned to be important for prediction.
Summary
The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and ...the burden of age‐related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro‐survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL‐xL, or plasminogen‐activated inhibitor‐2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM‐MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation‐exposed, and progeroid Ercc1−/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1−/∆ mice, delaying age‐related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
Altered brain development is evident in children born very preterm (24-32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence ...compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age.
42 right-handed children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling.
After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes.
In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.
In a multicohort study from 2022, brain volumetric trajectories were mapped across the lifespan—from the mid-gestation or preterm period to age 100 years—by pooling data collected in more than 100 ...000 individuals.2 Although this study provided insight into longitudinal brain volumetric trajectories, individual factors affecting brain maturation trajectories in early childhood, and how these trajectories relate to cognitive outcomes, are still unknown. A trial of cash transfer programmes (as a poverty reduction intervention) found changes in outcomes measuring infant brain activity.8 However, an important question to consider is whether social–environmental factors such as parental education, household income, and neighbourhood supports are determinants or modifiers of childhood cognitive outcomes. Understanding these interactions is important because socioeconomic status is a complex and multidimensional construct that is traditionally measured using parental education, family income, or employment, but it also intersects with broader social–environmental factors such as parenting behaviour, parental stress, the home environment, and neighbourhood resources.10 Findings from animal studies suggest that these individual social–environmental factors might all affect the developing brain through different pathways.10 Further research in animal models and clinical cohorts is warranted for development of effective, multidimensional, social–environmental interventions that will promote brain health in childhood.
Extremely preterm babies are at increased risk of less than optimal neurodevelopment compared with their term-born counterparts. Optimising nutrition is a promising avenue to mitigate the adverse ...neurodevelopmental consequences of preterm birth. In this narrative review, we summarize current knowledge on how nutrition, and in particular, protein intake, affects neurodevelopment in extremely preterm babies. Observational studies consistently report that higher intravenous and enteral protein intakes are associated with improved growth and possibly neurodevelopment, but differences in methodologies and combinations of intravenous and enteral nutrition strategies make it difficult to determine the effects of each intervention. Unfortunately, there are few randomized controlled trials of nutrition in this population conducted to determine neurodevelopmental outcomes. Substantial variation in reporting of trials, both of nutritional intakes and of outcomes, limits conclusions from meta-analyses. Future studies to determine the effects of nutritional intakes in extremely preterm babies need to be adequately powered to assess neurodevelopmental outcomes separately in boys and girls, and designed to address the many potential confounders which may have clouded research findings to date. The development of minimal reporting sets and core outcome sets for nutrition research will aid future meta-analyses.
Decades of research unequivocally demonstrates that no matter the society, socioeconomic resources are perhaps the most fundamental determinants of health throughout the life course, including during ...its very earliest stages. As a result, societies have implemented 'cash transfer' programmes, whichprovide income supplementation to reduce socioeconomic disadvantage among the poorest families with young children. Despite this being a common approach of societies around the world, research on effects of these programmes in low-income/middle-income countries, and those in high-income countries has been conducted as if they are entirely distinct phenomena. In this paper, we systematically review the international literature on the association between cash transfer programmes and health outcomes during the first year of life.
We conducted a systematic review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. Using a variety of relevant keywords, we searched MEDLINE, EMBASE, CINAHL, Cochrane Reviews, EconLit and Social Sciences Citations Index.
Our review yielded 14 relevant studies. These studies suggested cash transfer programmes that were not attached to conditions tended to yield positive effects on outcomes such as birth weight and infant mortality. Programmes that were conditional on use of health services also carried positive effects, while those that carried labour-force participation conditionalities tended to yield no positive effects.
Given several dynamics involved in determining whether children are healthy or not, which are common worldwide, viewing the literature from a global perspective produces novel insights regarding the tendency of policies and programmes to reduce or, to exacerbate, the effects of socioeconomic disadvantage on child health.
An organophosphorus-catalyzed method for the synthesis of unsymmetrical hydrazines by cross-selective intermolecular N-N reductive coupling is reported. This method employs a small ring phosphacycle ...(phosphetane) catalyst together with hydrosilane as the terminal reductant to drive reductive coupling of nitroarenes and anilines with good chemoselectivity and functional group tolerance. Mechanistic investigations support an autotandem catalytic reaction cascade in which the organophosphorus catalyst drives two sequential and mechanistically distinct reduction events via P
/P
═O cycling in order to furnish the target N-N bond.
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