Clinical aspects of incorporating cord clamping into stabilisation of preterm infants

Fetal to neonatal transition is characterised by major pulmonary and haemodynamic changes occurring in a short period of time. In the international neonatal resuscitation guidelines, comprehensive recommendations are available on supporting pulmonary transition and delaying clamping of the cord in preterm infants. Recent experimental studies demonstrated that the pulmonary and haemodynamic transition are intimately linked, could influence each other and that the timing of umbilical cord clamping should be incorporated into the respiratory stabilisation. We reviewed the current knowledge on how to incorporate cord clamping into stabilisation of preterm infants and the physiological-based cord clamping (PBCC) approach, with the infant's transitional status as key determinant of timing of cord clamping. This approach could result in optimal timing of cord clamping and has the potential to reduce major morbidities and mortality in preterm infants

Physiological-based cord clamping in very preterm infants — Randomised controlled trial on effectiveness of stabilisation

Aim: To test whether stabilising very preterm infants while performing physiological-based cord clamping (PBCC) is at least as effective as the standard approach of time-based delayed cord clamping (DCC). Methods: A randomised contr

Multi-site genetic analysis of diffusion images and voxelwise heritability analysis : a pilot project of the ENIGMA–DTI working group

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA–DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18–85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/)

Sex role similarity and sexual selection predict male and female song elaboration and dimorphism in fairy-wrens

Historically, bird song complexity was thought to evolve primarily through sexual selection on males; yet, in many species, both sexes sing and selection pressure on both sexes may be broader. Previous research suggests competition for mates and resources during short, synchronous breeding seasons leads to more elaborate male songs at high, temperate latitudes. Furthermore, we expect male–female song structure and elaboration to be more similar at lower, tropical latitudes, where longer breeding seasons and year-round territoriality yield similar social selection pressures in both sexes. However, studies seldom take both types of selective pressures and sexes into account. We examined song in both sexes in 15 populations of nine-fairy- wren species (Maluridae), a Southern Hemisphere clade with female song. We compared song elaboration (in both sexes) and sexual song dimorphism to latitude and life-history variables tied to sexual and social selection pressures and sex roles. Our results suggest that song elaboration evolved in part due to sexual competition in males: male songs were longer than female songs in populations with low male survival and less male provisioning. Also, female songs evolved independently of male songs: female songs were slower paced than male songs, although only in less synchronously breeding populations. We also found male and female songs were more similar when parental care was more equal and when male survival was high, which provides strong evidence that sex role similarity correlates with male–female song similarity. Contrary to Northern Hemisphere latitudinal patterns, male and female songs were more similar at higher, temperate latitudes. These results suggest that selection on song can be sex specific, with male song elaboration favored in contexts with stronger sexual selection. At the same time, selection pressures associated with sex role similarity appear to favor sex role similarity in song structure

Tau pathology as determinant of changes in atrophy and cerebral blood flow: a multi-modal longitudinal imaging study

PURPOSE: Tau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF. METHODS: We included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-β positive [Aβ +], 26 cognitively impaired [CI]) who underwent dynamic [18F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [18F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [18F]flortaucipir PET binding potential (BPND) and R1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in Aβ-  cognitively normal (CN) individuals and Aβ+  (CN and CI) individuals separately. RESULTS: In Aβ+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aβ+ or Aβ-  individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aβ + individuals. CONCLUSION: We showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal

Distinct amyloid-beta and tau-associated microglia profiles in Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-beta and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-beta and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-beta plaques or both amyloid-beta plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-beta load and localized to amyloid-beta plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes

Physiological-based cord clamping in very preterm infants:the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial

Background: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC. Methods: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data. Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth. Trial registration: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019.</p

Heritability of fractional anisotropy in human white matter: a comparison of Human Connectome Project and ENIGMA-DTI data

The degree to which genetic factors influence brain connectivity is beginning to be understood. Large-scale efforts are underway to map the profile of genetic effects in various brain regions. The NIH-funded Human Connectome Project (HCP) is providing data valuable for analyzing the degree of genetic influence underlying brain connectivity revealed by state-of-the-art neuroimaging methods. We calculated the heritability of the fractional anisotropy (FA) measure derived from diffusion tensor imaging (DTI) reconstruction in 481 HCP subjects (194/287 M/F) consisting of 57/60 pairs of mono- and dizygotic twins, and 246 siblings. FA measurements were derived using (Enhancing NeuroImaging Genetics through Meta-Analysis) ENIGMA DTI protocols and heritability estimates were calculated using the SOLAR-Eclipse imaging genetic analysis package. We compared heritability estimates derived from HCP data to those publicly available through the ENIGMA-DTI consortium, which were pooled together from five-family based studies across the US, Europe, and Australia. FA measurements from the HCP cohort for eleven major white matter tracts were highly heritable (h2 = 0.53–0.90, p < 10− 5), and were significantly correlated with the joint-analytical estimates from the ENIGMA cohort on the tract and voxel-wise levels. The similarity in regional heritability suggests that the additive genetic contribution to white matter microstructure is consistent across populations and imaging acquisition parameters. It also suggests that the overarching genetic influence provides an opportunity to define a common genetic search space for future gene-discovery studies. Uniquely, the measurements of additive genetic contribution performed in this study can be repeated using online genetic analysis tools provided by the HCP ConnectomeDB web application