Consequences of depleting TNRC6, AGO, and DROSHA proteins on expression of microRNAs.

The potential for microRNAs (miRNAs) to regulate gene expression remains incompletely understood. DROSHA initiates the biogenesis of miRNAs while variants of Argonaute (AGO) and trinucleotide repeat containing six (TNRC6) family proteins form complexes with miRNAs to facilitate RNA recognition and gene regulation. Here we investigate the fate of miRNAs in the absence of these critical RNAi protein factors. Knockout of DROSHA expression reduces levels of some miRNAs annotated in miRBase but not others. The identity of miRNAs with reduced expression matches the identity of miRNAs previously identified by experimental approaches. The MirGeneDB resource offers the closest alignment with experimental results. In contrast, the loss of TNRC6 proteins had much smaller effects on miRNA levels. Knocking out AGO proteins, which directly contact the mature miRNA, decreased expression of the miRNAs most strongly associated with AGO2 as determined from enhanced crosslinking immunoprecipitation (AGO2-eCLIP). Evaluation of miRNA binding to endogenously expressed AGO proteins revealed that miRNA:AGO association was similar for AGO1, AGO2, AGO3, and AGO4. Our data emphasize the need to evaluate annotated miRNAs based on approximate cellular abundance, DROSHA-dependence, and physical association with AGO when forming hypotheses related to their function.

Recommendations for data collection in cohort studies of preterm born individuals - The RECAP Preterm Core Dataset.

BACKGROUND: Preterm birth (before 37 completed weeks of gestation) is associated with an increased risk of adverse health and developmental outcomes relative to birth at term. Existing guidelines for data collection in cohort studies of individuals born preterm are either limited in scope, have not been developed using formal consensus methodology, or did not involve a range of stakeholders in their development. Recommendations meeting these criteria would facilitate data pooling and harmonisation across studies. OBJECTIVES: To develop a Core Dataset for use in longitudinal cohort studies of individuals born preterm. METHODS: This work was carried out as part of the RECAP Preterm project. A systematic review of variables included in existing core outcome sets was combined with a scoping exercise conducted with experts on preterm birth. The results were used to generate a draft core dataset. A modified Delphi process was implemented using two stages with three rounds each. Three stakeholder groups participated: RECAP Preterm project partners; external experts in the field; people with lived experience of preterm birth. The Delphi used a 9-point Likert scale. Higher values indicated greater importance for inclusion. Participants also suggested additional variables they considered important for inclusion which were voted on in later rounds. RESULTS: An initial list of 140 data items was generated. Ninety-six participants across 22 countries participated in the Delphi, of which 29% were individuals with lived experience of preterm birth. Consensus was reached on 160 data items covering Antenatal and Birth Information, Neonatal Care, Mortality, Administrative Information, Organisational Level Information, Socio-economic and Demographic information, Physical Health, Education and Learning, Neurodevelopmental Outcomes, Social, Lifestyle and Leisure, Healthcare Utilisation and Quality of Life. CONCLUSIONS: This core dataset includes 160 data items covering antenatal care through outcomes in adulthood. Its use will guide data collection in new studies and facilitate pooling and harmonisation of existing data internationally.

The early educational environment at five years of age in a European cohort of children born very preterm: challenges and opportunities for research.

BACKGROUND: Early childhood education offers opportunities for stimulation in multiple developmental domains and its positive impact on long-term outcomes and wellbeing for children is well documented. Few studies have explored early education in children born very preterm (VPT; <32 weeks of gestation) who are at higher risk of neurodevelopmental disorders and poor educational outcomes than their term-born peers. The purpose of the study is to describe and compare the educational environment of children born VPT in European countries at 5 years of age according to the degree of perinatal risk. METHODS: Data originated from the population-based Screening to Improve Health In very Preterm infants (SHIPS) cohort of children born VPT in 2011/2012 in 19 regions from 11 European countries. Perinatal data were collected from medical records and the 5-year follow-up was conducted using parental questionnaires. Outcomes at 5 years were participation in early education (any, type, intensity of participation) and receipt of special educational support, which were harmonized across countries. RESULTS: Out of 6,759 eligible children, 3,687 (54.6%) were followed up at 5 years (mean gestational age 29.3 weeks). At 5 years, almost all children (98.6%) were in an educational program, but type (preschool/primary), attendance (full-time/part-time) and use and type of school support/services differed by country. In some countries, children with high perinatal risk were more likely to be in full-time education than those with low risk (e.g. Estonia: 97.9% vs. 87.1%), while the inverse pattern was observed elsewhere (e.g. Poland: 78.5% vs. 92.8%). Overall, 22.8% of children received special educational support (country range: 12.4-34.4%) with more support received by children with higher perinatal risk. Large variations between countries remained after adjustment for socio-demographic characteristics. CONCLUSIONS: There are marked variations in approaches to early education for children born VPT in Europe, raising opportunities to explore its impact on their neurodevelopment and well-being.

Mental health, pain and tiredness in adults born very preterm or with very low birthweight.

AIM: Adults born preterm have increased risk of mental health problems and other neurodevelopmental conditions. We aimed to investigate associations of mental health with pain and tiredness in adults born very preterm (VP; <32 weeks) or very low birthweight (VLBW; <1500 g) and at term, and whether these associations are influenced by physical activity. METHODS: As part of an EU Horizon 2020 project, individual participant data from six prospective cohort studies were harmonised for 617 VP/VLBW and 1122 term-born participants. Mental health was assessed by the Achenbach System of Empirically Based Assessment Adult Self-Report. Pain and tiredness were harmonised based on specific items from self-reported questionnaires. Associations between mental health and pain or tiredness were explored by linear regression. RESULTS: An increase in the mental health scales internalising, externalising and total problems was associated with increased pain and tiredness in the preterm and term group alike. Results were maintained when adjusting for physical activity. CONCLUSION: The findings indicate that associations between mental health, pain and tiredness in adults are independent of gestation or birthweight. Future research should explore other potential mechanisms that may underlie the increased risk of mental health problems in the preterm population.

Impact of scaffolding protein TNRC6 paralogs on gene expression and splicing.

TNRC6 is a scaffolding protein that bridges interactions between small RNAs, argonaute (AGO) protein, and effector proteins to control gene expression. There are three paralogs in mammalian cells, TNRC6A, TNRC6B, and TNRC6C These paralogs have ∼40% amino acid sequence identity and the extent of their unique or redundant functions is unclear. Here, we use knockout cell lines, enhanced crosslinking immunoprecipitation (eCLIP), and high-throughput RNA sequencing (RNA-seq) to explore the roles of TNRC6 paralogs in RNA-mediated control of gene expression. We find that the paralogs are largely functionally redundant and changes in levels of gene expression are well-correlated with those observed in AGO knockout cell lines. Splicing changes observed in AGO knockout cell lines are also observed in TNRC6 knockout cells. These data further define the roles of the TNRC6 isoforms as part of the RNA interference (RNAi) machinery.

Risk factors for cerebral palsy and movement difficulties in 5-year-old children born extremely preterm.

BACKGROUND: Motor impairment is common after extremely preterm (EPT, <28 weeks' gestational age (GA)) birth, with cerebral palsy (CP) affecting about 10% of children and non-CP movement difficulties (MD) up to 50%. This study investigated the sociodemographic, perinatal and neonatal risk factors for CP and non-CP MD. METHODS: Data come from a European population-based cohort of children born EPT in 2011-2012 in 11 countries. We used multinomial logistic regression to assess risk factors for CP and non-CP MD (Movement Assessment Battery for Children - 2nd edition ≤5th percentile) compared to no MD (>15th percentile) among 5-year-old children. RESULTS: Compared to children without MD (n = 366), young maternal age, male sex and bronchopulmonary dysplasia were similarly associated with CP (n = 100) and non-CP MD (n = 224) with relative risk ratios (RRR) ranging from 2.3 to 3.6. CP was strongly related to severe brain lesions (RRR >10), other neonatal morbidities, congenital anomalies and low Apgar score (RRR: 2.4-3.3), while non-CP MD was associated with primiparity, maternal education, small for GA (RRR: 1.6-2.6) and severe brain lesions, but at a much lower order of magnitude. CONCLUSION: CP and non-CP MD have different risk factor profiles, with fewer clinical but more sociodemographic risk factors for non-CP MD. IMPACT: Young maternal age, male sex and bronchopulmonary dysplasia similarly increased risks of both cerebral palsy and non-cerebral palsy movement difficulties. Cerebral palsy was strongly related to clinical risk factors including severe brain lesions and other neonatal morbidities, while non-cerebral palsy movement difficulties were more associated with sociodemographic risk factors. These results on the similarities and differences in risk profiles of children with cerebral palsy and non-cerebral palsy movement difficulties raise questions for etiological research and provide a basis for improving the identification of children who may benefit from follow-up and early intervention.

Antenatal and neonatal exposure to SARS-CoV-2 and children's development: a systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review of the impact of antenatal and neonatal exposure to SARS-CoV-2 on developmental outcomes in preterm and term-born infants. METHODS: We searched Embase, Emcare, MEDLINE, PsycINFO, Web of Science and grey literature on May 27, 2022 and updated on May 8, 2023. Studies defining exposure with a positive SARS-CoV-2 protein or genetic material, used a contemporaneous non-exposed cohort, and reported developmental outcomes up to 2 years of age were included. RESULTS: Four out of 828 screened studies were included. Meta-analysis included 815 infants screened for developmental delay (n = 306 exposed; n = 509 non-exposed) between 3- and 11-months of age. Among term-born infants, we did not find an increased risk of delay in communication (odd's ratio: 0.73 (95% CI: 0.24-2.24)), gross motor (1.50 (0.62, 3.62)), fine motor (2.90 (0.58, 14.43)), problem-solving (1.19 (0.54, 2.66)) or personal-social development (1.93 (0.78, 4.75)) in exposed infants. The number of preterm-born infants in the exposed (n = 37) and comparison cohorts (n = 41) were too few to report meaningful comparisons. CONCLUSION: Evidence regarding the potential impact of antenatal or neonatal exposure to SARS-CoV-2 infection on developmental outcomes in early infancy is limited and inconsistent. Larger cohorts with outcomes beyond the first year of life are needed. IMPACT: The current evidence examining associations between SARS-CoV-2 exposure during the neonatal period and developmental outcomes in infancy is limited by there being few studies with extremely small sample sizes. Based on sparse data there was no consistent association between antenatal or neonatal exposure to SARS-CoV-2 infection and an adverse impact on developmental outcomes below 12 months of age for babies born preterm or at term. This study highlights that larger cohorts with outcomes assessed beyond the first year are needed to determine the potential longer-term impact of SARS-CoV-2 infection exposure on child development.

ADHD symptoms and diagnosis in adult preterms: systematic review, IPD meta-analysis, and register-linkage study.

BACKGROUND: This study examined differences in ADHD symptoms and diagnosis between preterm and term-born adults (≥18 years), and tested if ADHD is related to gestational age, birth weight, multiple births, or neonatal complications in preterm borns. METHODS: (1) A systematic review compared ADHD symptom self-reports and diagnosis between preterm and term-born adults published in PubMed, Web of Science, and PROQUEST until April 2021; (2) a one-stage Individual Participant Data(IPD) meta-analysis (n = 1385 preterm, n = 1633 term; born 1978-1995) examined differences in self-reported ADHD symptoms[age 18-36 years]; and (3) a population-based register-linkage study of all live births in Finland (01/01/1987-31/12/1998; n = 37538 preterm, n = 691,616 term) examined ADHD diagnosis risk in adulthood (≥18 years) until 31/12/2016. RESULTS: Systematic review results were conflicting. In the IPD meta-analysis, ADHD symptoms levels were similar across groups (mean z-score difference 0.00;95% confidence interval [95% CI] -0.07, 0.07). Whereas in the register-linkage study, adults born preterm had a higher relative risk (RR) for ADHD diagnosis compared to term controls (RR = 1.26, 95% CI 1.12, 1.41, p < 0.001). Among preterms, as gestation length (RR = 0.93, 95% CI 0.89, 0.97, p < 0.001) and SD birth weight z-score (RR = 0.88, 95% CI 0.80, 0.97, p < 0.001) increased, ADHD risk decreased. CONCLUSIONS: While preterm adults may not report higher levels of ADHD symptoms, their risk of ADHD diagnosis in adulthood is higher. IMPACT: Preterm-born adults do not self-report higher levels of ADHD symptoms, yet are more likely to receive an ADHD diagnosis in adulthood compared to term-borns. Previous evidence has consisted of limited sample sizes of adults and used different methods with inconsistent findings. This study assessed adult self-reported symptoms across 8 harmonized cohorts and contrasted the findings with diagnosed ADHD in a population-based register-linkage study. Preterm-born adults may not self-report increased ADHD symptoms. However, they have a higher risk of ADHD diagnosis, warranting preventive strategies and interventions to reduce the presentation of more severe ADHD symptomatology in adulthood.

Heterogeneity of design features in studies included in systematic reviews with meta-analysis of cognitive outcomes in children born very preterm.

BACKGROUND: Meta-analyses of the voluminous scientific literature on the impact of very preterm (VPT, <32 weeks' gestation) birth on cognition find a marked deficit in intelligence quotient (IQ) among children born VPT relative to term-born peers, but with unexplained between-study heterogeneity in effect size. OBJECTIVES: To conduct an umbrella review to describe the design and methodology of primary studies and to assess whether methodological heterogeneity affects the results of meta-analyses. DATA SOURCES: Primary studies from five systematic reviews with meta-analysis on VPT birth and childhood IQ. STUDY SELECTION AND DATA EXTRACTION: Information on study design, sample characteristics and results was extracted from studies. Study features covered study type, sample size, follow-up rates, adjustment for social context, management of severe impairments and test type. SYNTHESIS: We used random-effects subgroup meta-analyses and meta-regressions to investigate the contribution of study features to between-study variance in standardised mean differences (SMD) in IQ between groups. RESULTS: In 58 cohorts (56%), children with severe impairments were excluded, while 23 (22%) cohorts accounted for social factors. The least reported feature was the follow-up rate (missing in 38 cohorts). The largest difference in SMDs was between studies using full scale IQ tests (61 cohorts, SMD -0.89, 95% CI -0.96, -0.82) versus short-form tests (27 cohorts, SMD -0.68, 95% CI -0.79, -0.57). The proportion of between-study variance explained by the type of test was 14%; the other features explained less than 1% of the variance. CONCLUSIONS: Study design and methodology varied across studies, but most of them did not affect the variance in effect size, except the type of cognitive test. Key features, such as the follow-up rate, were not consistently reported limiting the evaluation of their potential contribution. Incomplete reporting limited the evaluation of the full impact of this methodological diversity.

Developmental motor problems and health-related quality of life in 5-year-old children born extremely preterm: A European cohort study.

AIM: To measure the association between cerebral palsy (CP) and non-CP-related movement difficulties and health-related quality of life (HRQoL) among 5-year-old children born extremely preterm (<28 weeks gestational age). METHOD: We included 5-year-old children from a multi-country, population-based cohort of children born extremely preterm in 2011 to 2012 in 11 European countries (n = 1021). Children without CP were classified using the Movement Assessment Battery for Children, Second Edition as having significant movement difficulties (≤5th centile of standardized norms) or being at risk of movement difficulties (6th-15th centile). Parents reported on a clinical CP diagnosis and HRQoL using the Pediatric Quality of Life Inventory. Associations were assessed using linear and quantile regressions. RESULTS: Compared to children without movement difficulties, children at risk of movement difficulties, with significant movement difficulties, and CP had lower adjusted HRQoL total scores (ß [95% confidence interval] = -5.0 [-7.7 to -2.3], -9.1 [-12.0 to -6.1], and - 26.1 [-31.0 to -21.2]). Quantile regression analyses showed similar decreases in HRQoL for all children with CP, whereas for children with non-CP-related movement difficulties, reductions in HRQoL were more pronounced at lower centiles. INTERPRETATION: CP and non-CP-related movement difficulties were associated with lower HRQoL, even for children with less severe difficulties. Heterogeneous associations for non-CP-related movement difficulties raise questions for research about mitigating and protective factors.

Prediction of movement difficulties at 5 years from parent report at 2 years in children born extremely preterm.

AIM: To assess the predictive validity of parent-reported gross motor impairment (GMI) at age 2 years to detect significant movement difficulties at age 5 years in children born extremely preterm. METHOD: Data were from 556 children (270 males, 286 females) born at less than 28 weeks' gestation in 2011 to 2012 in 10 European countries. Parent report of moderate/severe GMI was defined as walking unsteadily or unable to walk unassisted at 2 years corrected age. Examiners assessed significant movement difficulties (score ≤ 5th centile on the Movement Assessment Battery for Children, Second Edition) and diagnoses of cerebral palsy (CP) were collected by parent report at 5 years chronological age. RESULTS: At 2 years, 66 (11.9%) children had moderate/severe GMI. At 5 years, 212 (38.1%) had significant movement difficulties. Parent reports of GMI at age 2 years accurately classified CP at age 5 years in 91.0% to 93.2% of children. Classification of moderate/severe GMI at age 2 years had high specificity (96.2%; 95% confidence interval 93.6-98.0) and positive predictive value (80.3%; 68.7-89.1) for significant movement difficulties at age 5 years. However, 74.5% of children with significant movement difficulties at 5 years were not identified with moderate/severe GMI at age 2 years, resulting in low sensitivity (25.1%; 19.4-31.5). INTERPRETATION: This questionnaire may be used to identify children born extremely preterm who at age 2 years have a diagnosis of CP or movement difficulties that are likely to have a significant impact on their functional outcomes at age 5 years.

Evaluating interventions to improve ethical decision making in clinical practice: a review of the literature and reflections on the challenges posed.

Since the 1980s, there has been an increasing acknowledgement of the importance of recognising the ethical dimension of clinical decision-making. Medical professional regulatory authorities in some countries now include ethical knowledge and practice in their required competencies for undergraduate and post graduate medical training. Educational interventions and clinical ethics support services have been developed to support and improve ethical decision making in clinical practice, but research evaluating the effectiveness of these interventions has been limited. We undertook a systematic review of the published literature on measures or models of evaluation used to assess the impact of interventions to improve ethical decision making in clinical care. We identified a range of measures to evaluate educational interventions, and one tool used to evaluate a clinical ethics support intervention. Most measures did not evaluate the key impact of interest, that is the quality of ethical decision making in real-world clinical practice. We describe the results of our review and reflect on the challenges of assessing ethical decision making in clinical practice that face both developers of educational and support interventions and the regulatory organisations that set and assess competency standards.

Impaired pulmonary function mediates inattention in young adults born extremely preterm.

AIM: To test whether poor childhood pulmonary function explains the relationship between extremely preterm (EP) birth and attention-deficit/hyperactivity disorder (ADHD) symptoms in young adulthood. METHODS: EPICure birth cohort participants include children born <26 weeks' gestation in the United Kingdom and Ireland in 1995 and their term-born classmates. Predictor was EP birth. Outcomes were inattention/hyperactivity subscale z-scores at 19 years. Forced expiratory volume (FEV1) z-scores in childhood and young adulthood were mediators. We used recursive path analysis to determine the direct effect of EP birth on inattention/hyperactivity and its indirect effect through pulmonary function. RESULTS: Ninety EP and 47 term-born participants had pulmonary function testing at 11 and 19 years. Inattention z-scores were higher in the EP group (mean difference 0.55 [95% CI 0.11, 0.99]) but not hyperactivity. Compared to term-born peers, EP participants had lower FEV1 z-scores at 11 (mean difference-1.35 [95% CI -1.72, -0.98]) and 19 (mean difference-1.29 [95% CI -1.65, -0.92]). Path models revealed that childhood pulmonary function explained the relationship between EP birth and inattention. CONCLUSIONS: Extremely preterm young adults have increased risk for inattention compared to term-born peers. Poor pulmonary function appears to underlie this risk. The mechanisms responsible remain unclear and warrant further study.

Comparing behavioural outcomes in children born extremely preterm between 2006 and 1995: the EPICure studies.

BACKGROUND: Children born extremely preterm (EP) are at increased risk of neurocognitive and behavioural morbidity. Here, we investigate whether behavioural outcomes have changed over time concomitant with increasing survival following EP birth. METHODS: Comparison of outcomes at 11 years of age for two prospective national cohorts of children born EP in 1995 (EPICure) and 2006 (EPICure2), assessed alongside term-born children. Behavioural outcomes were assessed using the parent-completed Strengths and Difficulties Questionnaire (SDQ), DuPaul Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS), and Social Communication Questionnaire (SCQ). RESULTS: In EPICure, 176 EP and 153 term-born children were assessed (mean age: 10.9 years); in EPICure2, 112 EP and 143 term-born children were assessed (mean age: 11.8 years). In both cohorts, EP children had higher mean scores and more clinically significant difficulties than term-born children on almost all measures. Comparing outcomes for EP children in the two cohorts, there were no significant differences in mean scores or in the proportion of children with clinically significant difficulties after adjustment for confounders. Using term-born children as reference, EP children in EPICure2 had significantly higher SDQ total difficulties and ADHD-RS hyperactivity impulsivity z-scores than EP children in EPICure. CONCLUSIONS: Behavioural outcomes have not improved for EP children born in 2006 compared with those born in 1995. Relative to term-born peers, EP children born in 2006 had worse outcomes than those born in 1995. There is an ongoing need for long-term clinical follow-up and psychological support for children born EP.

Perspectives on long-acting injectable HIV antiretroviral therapy at an alternative care site: a qualitative study of people with HIV experiencing substance use and/or housing instability.

INTRODUCTION: Adherence to daily oral antiretroviral therapy (ART) and regular clinic appointments can be challenging for individuals who experience adverse social determinants of health. Long-acting injectable ART administered outside of traditional clinic settings may be a promising solution to adherence barriers, but additional research is needed to assess patients' perspectives. This study assessed perspectives of people living with HIV (PLWH) who had difficulty with adherence to traditional HIV care models and evaluated feasibility and acceptability of receiving a long-acting ART injection at a location outside of a traditional HIV clinic to address barriers to HIV care. METHODS: Qualitative interviews (n = 26) were conducted with PLWH who had experienced barriers to adherence. Participants were referred to the study by staff from Project Trust, a drop in harm reduction and sexually transmitted infection/HIV clinic. The interviews were conducted between May and November 2021. Interviews were recorded, professionally transcribed, coded, and analyzed qualitatively using the integrated-Promoting Action on Research Implementation in Health Services framework. RESULTS: We identified 6 main themes regarding the acceptability of receiving a long-acting injection to treat HIV, and the acceptability and feasibility of receiving injections at an alternative care site. Participants specified that they: (1) have a general understanding about their HIV care and the importance of ART adherence, (2) prefer a long-acting injection over a daily pill regimen, (3) expressed concerns about injection safety and efficacy, (4) had specific logistical aspects around the delivery of long-acting injections, including location of injection administration, that they believed would improve their ability to adhere, (5) have confidence that they can become undetectable and then complete the oral lead-in required to begin receiving the injection, and (6) see potential barriers that remain a concern for successful adherence to long-acting injections. CONCLUSION: To better treat HIV among people who are living with challenging social determinants of health, interventions that include a long-acting injection in a non-traditional care setting may prove to be a promising treatment option.

Resilient pedagogy: experiences of kinesiology faculty during COVID-19.

The COVID-19 pandemic required an emergency shift to remote teaching. Despite their limited previous experience with online or hybrid teaching, our cohort of kinesiology faculty (n = 112) had high confidence in their ability to deliver quality educational experiences for their students during the pandemic. With support from their institutions, technology departments, and teaching and learning centers, faculty developed new skills and organizational strategies. To achieve this, 81% of faculty reported needing extra course preparation time to deliver high-quality remote teaching, with 51% needing up to 5 extra hours per week per course. There is a fraction of faculty from this study excited about the prospect of teaching online in the future. These newfound online teaching skills should be leveraged to modernize course offerings in kinesiology departments, supporting student recruitment, retention, and success.NEW & NOTEWORTHY The COVID-19 pandemic caused temporary and permanent changes to higher education, specifically kinesiology programs. This article highlights the resiliency of faculty in kinesiology programs, how they adapted, where they felt supported, and what they hope to bring with them into their future pedagogy practices.

Methods for Constructing Normalised Reference Scores: An Application for Assessing Child Development at 24 Months of Age.

The use of the lambda-mu-sigma (LMS) method for estimating centiles and producing reference ranges has received much interest in clinical practice, especially for assessing growth in childhood. However, this method may not be directly applicable where measures are based on a score calculated from question response categories that is bounded within finite intervals, for example, in psychometrics. In such cases, the main assumption of normality of the conditional distribution of the transformed response measurement is violated due to the presence of ceiling (and floor) effects, leading to biased fitted centiles when derived using the common LMS method. This paper describes the methodology for constructing reference intervals when the response variable is bounded and explores different distribution families for the centile estimation, using a score derived from a parent-completed assessment of cognitive and language development in 24 month-old children. Results indicated that the z-scores, and thus the extracted centiles, improved when kurtosis was also modeled and that the ceiling effect was addressed with the use of the inflated binomial distribution. Therefore, the selection of the appropriate distribution when constructing centile curves is crucial.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).

Development of a data classification system for preterm birth cohort studies: the RECAP Preterm project.

BACKGROUND: The small sample sizes available within many very preterm (VPT) longitudinal birth cohort studies mean that it is often necessary to combine and harmonise data from individual studies to increase statistical power, especially for studying rare outcomes. Curating and mapping data is a vital first step in the process of data harmonisation. To facilitate data mapping and harmonisation across VPT birth cohort studies, we developed a custom classification system as part of the Research on European Children and Adults born Preterm (RECAP Preterm) project in order to increase the scope and generalisability of research and the evaluation of outcomes across the lifespan for individuals born VPT. METHODS: The multidisciplinary consortium of expert clinicians and researchers who made up the RECAP Preterm project participated in a four-phase consultation process via email questionnaire to develop a topic-specific classification system. Descriptive analyses were calculated after each questionnaire round to provide pre- and post- ratings to assess levels of agreement with the classification system as it developed. Amendments and refinements were made to the classification system after each round. RESULTS: Expert input from 23 clinicians and researchers from the RECAP Preterm project aided development of the classification system's topic content, refining it from 10 modules, 48 themes and 197 domains to 14 modules, 93 themes and 345 domains. Supplementary classifications for target, source, mode and instrument were also developed to capture additional variable-level information. Over 22,000 individual data variables relating to VPT birth outcomes have been mapped to the classification system to date to facilitate data harmonisation. This will continue to increase as retrospective data items are mapped and harmonised variables are created. CONCLUSIONS: This bespoke preterm birth classification system is a fundamental component of the RECAP Preterm project's web-based interactive platform. It is freely available for use worldwide by those interested in research into the long term impact of VPT birth. It can also be used to inform the development of future cohort studies.