Late outcomes of a randomized trial of high-frequency oscillation in neonates

BACKGROUND: Results from an observational study involving neonates suggested that high-frequency oscillatory ventilation (HFOV), as compared with conventional ventilation, was associated with superior small-airway function at follow-up. Data from randomized trials are needed to confirm this finding. METHODS: We studied 319 adolescents who had been born before 29 weeks of gestation and had been enrolled in a multicenter, randomized trial that compared HFOV with conventional ventilation immediately after birth. The trial involved 797 neonates, of whom 592 survived to hospital discharge. We compared follow-up data from adolescents who had been randomly assigned to HFOV with follow-up data from those who had been randomly assigned to conventional ventilation, with respect to lung function and respiratory health, health-related quality of life, and functional status, as assessed with the use of questionnaires completed when the participants were 11 to 14 years of age. The primary outcome was forced expiratory flow at 75% of the expired vital capacity (FEF(75)). RESULTS: The HFOV group had superior results on a test of small-airway function (z score for FEF(75), −0.97 with HFOV vs. −1.19 with conventional therapy; adjusted difference, 0.23 [95% confidence interval, 0.02 to 0.45]). There were significant differences in favor of HFOV in several other measures of respiratory function, including forced expiratory volume in 1 second, forced vital capacity, peak expiratory flow, diffusing capacity, and impulse-oscillometric findings. As compared with the conventional-therapy group, the HFOV group had significantly higher ratings from teachers in three of eight school subjects assessed, but there were no other significant differences in functional outcomes. CONCLUSIONS: In a randomized trial involving children who had been born extremely prematurely, those who had undergone HFOV, as compared with those who had received conventional ventilation, had superior lung function at 11 to 14 years of age, with no evidence of poorer functional outcomes. (Funded by the National Institute for Health Research Health Technology Assessment Programme and others.

Postnatal dexamethasone, respiratory and neurodevelopmental outcomes at two years in babies born extremely preterm.

IMPORTANCE: Postnatal dexamethasone is associated with reduction in bronchopulmonary dysplasia. There remains, however, concern that its short-term benefits are accompanied by long-term adverse effects e.g. poorer neurodevelopmental outcomes. OBJECTIVE: Our aim was to determine the effects of administration of postnatal dexamethasone on respiratory and neurodevelopmental outcome at two years of age after adjusting for neonatal and infant risk factors. MATERIALS AND METHODS: The study included 412 infants born at 23-28 weeks of gestation, 29% had received postnatal dexamethasone. Two outcomes were examined, respiratory hospital admissions in the past 12 months and neurodevelopmental impairment. Logistic regression, adjusted for sex, birthweight z-score, gestation, maternal smoking, oxygen dependency at 36 weeks, airleak, patent ductus arteriosus, pulmonary haemorrhage, major ultrasound abnormality, mode of ventilation and age at assessment, was undertaken. RESULTS: After adjustment, postnatal dexamethasone was associated with significantly increased proportions of both respiratory hospital readmission: (0.35 vs 0.15, difference = 0.20; 95% CI: 0.08, 0.31) and neurodevelopmental impairment (0.59 vs 0.45, difference = 0.14; 95% CI: 0.02, 0.26). CONCLUSIONS: Postnatal dexamethasone use in extremely preterm infants is associated with increased risks of respiratory hospital admissions and neurodevelopmental impairment. These associations were not explained by excess neonatal morbidities

Altered versican cleavage in ADAMTS5 deficient mice : a novel etiology of myxomatous valve disease

AbstractIn fetal valve maturation the mechanisms by which the relatively homogeneous proteoglycan-rich extracellular matrix (ECM) of endocardial cushions is replaced by a specialized and stratified ECM found in mature valves are not understood. Therefore, we reasoned that uncovering proteases critical for ‘remodeling’ the proteoglycan rich (extracellular matrix) ECM may elucidate novel mechanisms of valve development. We have determined that mice deficient in ADAMTS5, (A Disintegrin-like And Metalloprotease domain with ThromboSpondin-type 1 motifs) which we demonstrated is expressed predominantly by valvular endocardium during cardiac valve maturation, exhibited enlarged valves. ADAMTS5 deficient valves displayed a reduction in cleavage of its substrate versican, a critical cardiac proteoglycan. In vivo reduction of versican, in Adamts5−/− mice, achieved through Vcan heterozygosity, substantially rescued the valve anomalies. An increase in BMP2 immunolocalization, Sox9 expression and mesenchymal cell proliferation were observed in Adamts5−/− valve mesenchyme and correlated with expansion of the spongiosa (proteoglycan-rich) region in Adamts5−/− valve cusps. Furthermore, these data suggest that ECM remodeling via ADAMTS5 is required for endocardial to mesenchymal signaling in late fetal valve development. Although adult Adamts5−/− mice are viable they do not recover from developmental valve anomalies and have myxomatous cardiac valves with 100% penetrance. Since the accumulation of proteoglycans is a hallmark of myxomatous valve disease, based on these data we hypothesize that a lack of versican cleavage during fetal valve development may be a potential etiology of adult myxomatous valve disease

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Lung function and respiratory outcomes in teenage boys and girls born very prematurely:Prematurity, sex and respiratory outcome

OBJECTIVES: Male sex in prematurely born infants has been associated with worse respiratory outcomes in early childhood. WORKING HYPOTHESIS: Respiratory outcomes at 11 to 14 years of age in children born very prematurely and routinely exposed to antenatal corticosteroids and postnatal surfactant would differ according to sex. STUDY DESIGN: Analysis of follow‐up data. PATIENT-SUBJECT SELECTION: Three hundred and nineteen children born before 29 weeks of gestational age from the United Kingdom Oscillation Study. METHODOLOGY: Spirometry was used to assess forced expiratory flow at 75%, 50%, and 25% of expired vital capacity (FEF_{75}, FEF_{50}, and FEF_{25}), forced expiratory volume in 1 second (FEV_{1}), peak expiratory flow (PEF), and forced vital capacity (FVC). Lung volumes were measured using a helium dilution technique (FRC_{He}) and by plethysmography (FRC_{pleth}). Total lung capacity (TLC) and residual volume (RV) were calculated. Mean lung function measurements were compared using linear mixed models and reported as unadjusted and adjusted for neonatal and age 11 to 14 years factors. The participants also completed health questionnaires and provided a urine sample for assessment of passive or active smoking. RESULTS: Three (FEF_{25}, FEF_{25‐75}, FEV_{1}) lung function measures showed significant differences in favor of females after adjustment. The percentage of children with abnormal lung function (below 5th centile for normal) had adjusted differences between 10 and 30 percentage points, for example, for FEF25 15% females compared with 26% males. CONCLUSIONS: Among extremely prematurely born school children airway function was significantly worse in males

United Kingdom Oscillation Study: long-term outcomes of a randomised trial of two modes of neonatal ventilation

BACKGROUND: One in 200 infants in the UK is born extremely prematurely, i.e. before 29 weeks of gestation. Seventy-five per cent of such infants survive, but many have long-term respiratory and/or functional problems. OBJECTIVES: To compare respiratory and functional outcomes of school-age children born extremely prematurely who received either high-frequency oscillation (HFO) or conventional ventilation (CV) immediately after birth to test the hypothesis that the use of HFO would be associated with superior small airway function at school age without adverse effects. DESIGN: Follow-up of a randomised trial, the United Kingdom Oscillation Study, in which infants were randomised to receive HFO or CV within 1 hour of birth. SETTING: King's College Hospital NHS Foundation Trust, London, UK. PARTICIPANTS: Three hundred and nineteen children aged between 11 and 14 years were recruited (160 had received HFO); the planned sample size was 320. INTERVENTIONS: HFO versus CV. MAIN OUTCOME MEASURES: The results of comprehensive lung function assessments (primary outcome small airway function), echocardiographic examinations and respiratory, health-related quality of life and functional assessment questionnaires. RESULTS: Significant baseline differences in maternal and neonatal characteristics between the two groups favoured the CV group, who had a higher mean birthweight (56 g) and were born later (0.3 weeks), and a greater proportion of whom had received surfactant. There were no significant differences between the two groups in their characteristics when assessed at 11-14 years of age. The children who had received HFO had significantly superior small airway function; their forced expiratory flow at 75% vital capacity z-score was 0.23 higher than that of the CV group [95% confidence interval (CI) 0.02 to 0.45]. Thirty-seven per cent of the HFO group and 46% of the CV group had small airway function results that were below the tenth centile. There were significant differences between ventilation groups in favour of HFO for other lung function results as expressed by z-scores {forced expiratory volume at 1 minute (FEV1) [difference 0.35 (95% CI 0.09 to 0.60)], the ratio of FEV1 to forced vital capacity [0.58 (95% CI 0.16 to 0.99)], diffusing capacity of the lung for carbon monoxide [0.31 (95% CI 0.04 to 0.58)], maximum vital capacity [0.31 (95% CI 0.05 to 0.57)]} and expressed as % predicted {peak expiratory flow rate [5.85 (95% CI 2.21 to 9.49)] and respiratory resistance at 5 Hz [-7.13 Hz (95% CI -2.50 to -1.76 Hz)]}. There were no significant differences between ventilation groups with regard to the echocardiographic results, respiratory morbidity in the last 12 months, health problems, Health Utilities Index scores or Strengths and Difficulties Questionnaire (SDQ) scores. When SDQ scores were dichotomised, there was a significant finding for one subscale: a greater proportion of HFO children reported emotional symptoms. This finding was not replicated by parents' or teachers' reports. Two hundred and twenty-four teachers completed questionnaires regarding the children's educational attainment and provision. There were statistically significant differences in attainment in three subjects in favour of HFO: art and design, information technology, and design and technology. The HFO children had lower risk of receiving special education needs support [odds ratio 0.56 (95% CI 0.32 to 1.00)], but the difference was not significant. CONCLUSIONS: Follow-up at 11-14 years of age of extremely prematurely born infants entered into a randomised trial of HFO versus CV has demonstrated significant differences in lung function in favour of HFO. There was no evidence that this was offset by poorer functional outcomes; indeed, HFO children did better in some school subjects. It will be important to determine whether or not these differences are maintained after puberty as this is the last positive effect on lung function. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98436149