Common Core Assessments in follow-up studies of adults born preterm-Recommendation of the Adults Born Preterm International Collaboration

Background Of all newborns, 1%-2% are born very preterm (VP;Peer reviewe

Very Preterm Early Motor Repertoire and Neurodevelopmental Outcomes at 8 Years

BACKGROUND AND OBJECTIVES: Children born very preterm (<32 weeks' gestation) have more neurodevelopmental problems compared with term-born peers. Aberrant fidgety movements (FMs) are associated with adverse motor outcomes in children born very preterm. However, associations of aberrant FMs combined with additional movements and postures to give a motor optimality score-revised (MOS-R) with school-aged cognitive and motor outcomes are unclear. Our aim with this study was to determine those associations. METHODS: Of 118 infants born <30 weeks' gestation recruited into a randomized controlled trial of early intervention, 97 had a general movements assessment at 3 months' corrected age and were eligible for this study. Early motor repertoire including FMs and MOS-R were scored from videos of infant's spontaneous movement at 3 months' corrected age. At 8 years' corrected age, cognitive and motor performances were evaluated. Associations of early FMs and MOS-R with outcomes at 8 years were determined using linear regression. RESULTS: Seventy-eight (80%) infants with early motor repertoire data had neurodevelopmental assessments at 8 years. A higher MOS-R, and favorable components of the individual subscales of the MOS-R, including the presence of normal FMs, were associated with better performance for general cognition, attention, working memory, executive function and motor function at 8 years; eg, presence of normal FMs was associated with a 21.6 points higher general conceptual ability score (95% confidence interval: 12.8-30.5; P < .001) compared with absent FMs. CONCLUSIONS: Favorable early motor repertoire of infants born <30 weeks is strongly associated with improved cognitive and motor performance at 8 years

Long-term expiratory airflow of infants born moderate-late preterm:A systematic review and meta-analysis

Background: Moderate-late preterm (MLP; 32 to <37 weeks’ gestation) birth is associated with reduced expiratory airflow during child, adolescent and adult years. However, some studies have reported only minimal airflow limitation and hence it is unclear if clinical assessment in later life is warranted. Our aim was to compare maximal expiratory airflow in children and adults born MLP with term-born controls, and with expected norms. Methods: We systematically reviewed studies reporting z-scores for spirometric indices (forced expired volume in 1 second [FEV1], forced vital capacity [FVC], FEV1/FVC ratio and forced expiratory flow at 25-75% of FVC [FEF25-75%]) from participants born MLP aged five years or older, with or without a term-born control group from 4 databases (MEDLINE, CINAHL, Embase, Emcare). Publications were searched for between the 22nd of September 2021 to the 29th of September 2021. A meta-analysis of eligible studies was conducted using a random effects model. The study protocol was published in PROSPERO (CRD #42021281518). Findings: We screened 4970 articles and identified 18 relevant studies, 15 of which were eligible for meta-analysis (8 with term-born controls and 7 without). Compared with controls, MLP participants had lower z-scores (mean difference [95% confidence interval] I2) for FEV1: -0.22 [-0.35, -0.09] 49.3%, FVC: -0.23 [-0.4, -0.06] 71.8%, FEV1/FVC: -0.11 [-0.20 to -0.03] 9.3% and FEF25-75%: -0.27 [-0.41 to -0.12] 21.9%. Participants born MLP also had lower z-scores, on average, when compared with a z-score of 0 (mean [95% CI] I2) for FEV1: -0.26 [-0.40 to -0.11] 85.2%, FVC: -0.18 [-0.34 to -0.02] 88.3%, FEV1/FVC: -0.24 [-0.43 to -0.05] 90.5% and FEF25-75%: -0.33 [-0.54 to -0.20] 94.7%. Interpretation: Those born MLP had worse expiratory airflows than those born at term, and compared with norms, although reductions were modest. Clinicians should be aware that children and adults born MLP may be at higher risk of obstructive lung disease compared with term-born peers. Funding: This work is supported by grants from the National Health and Medical Research Council (Centre of Research Excellence #1153176, Project grant #1161304); Medical Research Future Fund (Career Development Fellowship to J.L.Y Cheong #1141354) and from the Victorian Government's Operational Infrastructure Support Programme. C. Du Berry's PhD candidature is supported by the Melbourne Research Scholarship and the Centre of Research Excellence in Newborn Medicine

Analysis of epigenetic changes in survivors of preterm birth reveals the effect of gestational age and evidence for a long term legacy

BACKGROUND: Preterm birth confers a high risk of adverse long term health outcomes for survivors, yet the underlying molecular mechanisms are unclear. We hypothesized that effects of preterm birth can be mediated through measurable epigenomic changes throughout development. We therefore used a longitudinal birth cohort to measure the epigenetic mark of DNA methylation at birth and 18 years comparing survivors of extremely preterm birth with infants born at term. METHODS: Using 12 extreme preterm birth cases and 12 matched, term controls, we extracted DNA from archived neonatal blood spots and blood collected in a similar way at 18 years of age. DNA methylation was measured at 347,789 autosomal locations throughout the genome using Infinium HM450 arrays. Representative methylation differences were confirmed by Sequenom MassArray EpiTYPER. RESULTS: At birth we found 1,555 sites with significant differences in methylation between term and preterm babies. At 18 years of age, these differences had largely resolved, suggesting that DNA methylation differences at birth are mainly driven by factors relating to gestational age, such as cell composition and/or maturity. Using matched longitudinal samples, we found evidence for an epigenetic legacy associated with preterm birth, identifying persistent methylation differences at ten genomic loci. Longitudinal comparisons of DNA methylation at birth and 18 years uncovered a significant overlap between sites that were differentially-methylated at birth and those that changed with age. However, we note that overlapping sites may either differ in the same (300/1,555) or opposite (431/1,555) direction during gestation and aging respectively. CONCLUSIONS: We present evidence for widespread methylation differences between extreme preterm and term infants at birth that are largely resolved by 18 years of age. These results are consistent with methylation changes associated with blood cell development, cellular composition, immune induction and age at these time points. Finally, we identified ten probes significantly associated with preterm individuals and with greater than 5% methylation discordance at birth and 18 years that may reflect a long term epigenetic legacy of preterm birth

Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial

Objective: To investigate the effects of hypothermia treatment on magnetic resonance imaging (MRI) patterns of brain injury in newborns with hypoxic-ischemic encephalopathy compared with normothermia, including the prognostic utility of MRI for death and/or disability at a postnatal age of 2 years

Desikan-Killiany-Tourville Atlas Compatible Version of M-CRIB Neonatal Parcellated Whole Brain Atlas: The M-CRIB 2.0

Our recently published M-CRIB atlas comprises 100 neonatal brain regions including 68 compatible with the widely-used Desikan-Killiany adult cortical atlas. A successor to the Desikan-Killiany atlas is the Desikan-Killiany-Tourville atlas, in which some regions with unclear boundaries were removed, and many existing boundaries were revised to conform to clearer landmarks in sulcal fundi. Our first aim here was to modify cortical M-CRIB regions to comply with the Desikan-Killiany-Tourville protocol, in order to offer: (a) compatibility with this adult cortical atlas, (b) greater labeling accuracy due to clearer landmarks, and (c) optimisation of cortical regions for integration with surface-based infant parcellation pipelines. Secondly, we aimed to update subcortical regions in order to offer greater compatibility with subcortical segmentations produced in FreeSurfer. Data utilized were the T2-weighted MRI scans in our M-CRIB atlas, for 10 healthy neonates (post-menstrual age at MRI 40–43 weeks, four female), and corresponding parcellated images. Edits were performed on the parcellated images in volume space using ITK-SNAP. Cortical updates included deletion of frontal and temporal poles and ‘Banks STS,’ and modification of boundaries of many other regions. Changes to subcortical regions included the addition of ‘ventral diencephalon,’ and deletion of ‘subcortical matter’ labels. A detailed updated parcellation protocol was produced. The resulting whole-brain M-CRIB 2.0 atlas comprises 94 regions altogether. This atlas provides comparability with adult Desikan-Killiany-Tourville-labeled cortical data and FreeSurfer-labeed subcortical data, and is more readily adaptable for incorporation into surface-based neonatal parcellation pipelines. As such, it offers the ability to help facilitate a broad range of investigations into brain structure and function both at the neonatal time point and developmentally across the lifespan

Comparative evaluation of the health utilities index mark 3 and the short form 6D : evidence from an individual participant data meta-analysis of very preterm and very low birthweight adults

Background The most appropriate preference-based health-related quality of life (HRQoL) instruments for trials or research studies that ascertain the consequences of individuals born very preterm and/or low birthweight (VP/VLBW) are not known. Agreement between the HUI3 and SF-6D multi-attribute utility measures have not been previously investigated for VP/VLBW and normal birthweight or term-born controls. This study examined the agreement between the outputs of the HUI3 and SF-6D measures among adults born VP/VLBW and normal birthweight or term born controls. Methods We used two prospective cohorts of individuals born VP/VLBW and controls contributing to the ‘Research on European Children and Adults Born Preterm’ (RECAP) consortium which assessed HRQoL using two preference-based measures. The combined dataset of individual participant data (IPD) included 407 adult VP/VLBW survivors and 367 controls, ranging in age from 18 to 26 years. Bland–Altman plots, intra-class correlation coefficients, and generalized linear mixed models in a one-step approach were used to examine agreement between the measures. Results There was significant discordance between the HUI3 and SF-6D multi-attribute utility measures in the VP/VLBW sample, controls, and in the combined samples. Agreement between the HUI3 and SF-6D multi-attribute utility measures was weaker in controls compared with VP/VLBW individuals. Conclusions and relevance The HUI3 and SF-6D each provide unique information on different aspects of health status across the groups. The HUI3 better captures preterm-related changes to HRQoL in adulthood compared to SF-6D. Studies focused on measuring physical or cognitive aspects of health will likely benefit from using the HUI3 instead of the SF-6D, regardless of gestational age at birth and birthweight status

Impact of hypercapnia on alveolar Na+-transport : Establishing a system for ENaC-protein detection

Acute respiratory distress syndrome is a life threatening condition triggered by a variety of pulmonary and extrapulmonary causes, that is characterized by pulmonary edema and subsequently impaired gas exchange. Due to lung protective ventilation strategies, its treatment is often associated with systemic accumulation of CO2, a condition termed permissive hypercapnia. Recent studies report a negative effect of CO2 on alveolar fluid clearance, a process mediated by its two key elements the Na+,K+-ATPase and epithelial Na+-channels (ENaCs). A reduced activity of the Na+,K+-ATPase during hypercapnia has already been demonstrated, but regulation of ENaC has never been directly linked to CO2. Many molecular signaling events that are activated during hypercapnia are known to regulate ENaC function, so the present study aimed to generate and subsequently apply techniques to investigate a possible contribution of ENaC to the reduction of alveolar epithelial fluid transport upon hypercapnia. ENaC function was studied in H441 cells by Ussing chamber experiments which revealed no significant regulation during short term hypercapnia, but a clear reduction of ENaC function during sustained hypercapnia. To identify the signaling mechanism on the molecular level, epitope-tagged human ENaC constructs for the &#945;-, &#946;- and &#947;-subunit were cloned and initially expressed in A549 cells. Exposition to hypercapnia up to 4 hours did not significantly reduce cell surface expression of the ENaC-subunits, but after 24 hours, a significant decrease of &#946;-ENaC was observed. Since the molecular sizes of &#945;- and &#947;-ENaC expressed in A549 cells were differing from previously published studies, transfection of ENaC was continued in other cells. H441 cells are commonly used for ENaC studies, so their transfection was established, yielding an efficiency of about 60 %. The molecular sizes of transfected ENaC subunits matched the pattern that was expected, but expression levels were evanescent and too low for further experiments. Since ENaC detection in these two cell lines remained problematic, a novel methodology was applied. Since the primary site of ENaC expression in the lung are epithelial cells, rat primary alveolar epithelial cells type II were used as recipients for ENaC plasmids. Non-viral transfection of ATII cells has been inefficient in the past, but during the present study a protocol was generated to efficiently deliver nucleic acids to exactly this cell type. ENaC expression was largely increased in ATII cells, compared to the cell lines used, indicating that established system might be extremely useful for further studies involving ENaC turnover. Thus, a new and highly relevant, non-viral transfection technique for primary alveolar epithelial type II cells was established, providing ground-breaking opportunities for future pulmonary research.Das Atemnotsyndrom des Erwachsenen ist eine lebensbedrohliche Erkrankung, ausgelöst durch eine Reihe von Faktoren, die direkt oder indirekt auf die Lunge einwirken . Charakteristisch für dieses Syndrom sind pulmonare Ödeme und daraus resultierend ein eingeschränkter Gasaustausch. Die daher benötigte künstliche Beatmung führt im Zuge von protektiven Beatmungsstrategien oft zu einer systemischen Anreicherung von CO2 (Hyperkapnie). Einige Studien zeigen, dass erhöhte CO2-Level den Flüssigkeitstransport der Lunge einschränken. Dieser aktive Prozess wird maßgeblich durch zwei Komponenten, die Na+,K+-ATPase und epitheliale Na+-Kanäle (ENaCs), kontrolliert. Eine Beeinträchtigung der Na+,K+-ATPase durch CO2 gezeigt, für ENaCs ist dies bislang nicht bekannt. Einige bekannte Regulatoren von ENaCs werden jedoch während Hyperkapnie aktiviert. Das Ziel der vorliegenden Arbeit war, Methoden zu etablieren und anzuwenden, die einen möglichen Einfluss von CO2 auf ENaC zeigen. Funktionelle Versuche wurden an H441-Zellen mit Ussing-Kammer-Messungen durchgeführt. Während akuter Hyperkapnie konnte keine signifikante Regulation von ENaC nachgewiesen werden, jedoch war die ENaC-Funktion bei anhaltender Hyperkapnie deutlich verringert. Um die Signalwege auf molekularer Ebene zu untersuchen, wurde die &#945;-, &#946;- und &#947;- Untereinheit des humanen ENaC kloniert, genetisch modifiziert und in A549 Zellen überexprimiert. Nach bis zu vierstündiger Hyperkapnie erfolgte keine Regulation von ENaC, jedoch wurde nach 24 Stunden eine deutlich verminderte Menge &#946;-ENaC in der Zellmembran nachgewiesen. Da die Größen von &#945;- und &#947;-ENaC von den bisher publizierten abwichen, wurden weitere Versuche in H441 Zellen durchgeführt. Die Transfektion dieser Zelllinie wurde etabliert und erreichte eine Effizienz von ungefähr 60 %. Die posttranslationale Regulation der &#945;- und &#947;-Untereinheiten, insbesondere die proteolytische Aktivierung funktionierten wie in der Literatur beschrieben, jedoch waren die Expressionslevel zu gering für weitere Versuche. In der Lunge werden ENaCs überwiegend in epithelialen Zellen exprimiert. Diese Zellen konnten bisher jedoch nicht effizient transfiziert werden, ohne Viren einzusetzen. In der vorliegenden Arbeit wurde jedoch eine effiziente Methode zur Transfektion von primären epithelialen Zellen der Ratte erarbeitet. Die Expression von transfizierten ENaC-Untereinheiten war in diesen Zellen deutlich erhöht, weswegen die Etablierung dieses Systems ausschlaggebend für weitere Versuche ist. Die vorliegende Arbeit beschreibt daher zum ersten Mal die nicht-virale, effiziente Transfektion von primären alveolaren Zellen und liefert damit ein bedeutendes neues Werkzeug für die Lungenforschung