Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): Statistical analysis plan

Background: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth with short-term and long-term adverse consequences. Although the glucocorticoid dexamethasone has been proven to be beneficial for the prevention of BPD, there are concerns about an increased risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. The aim of the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (SToP-BPD) trial is to assess the efficacy and safety of postnatal hydrocortisone administration for the reduction of death or BPD in ventilator-dependent preterm infants. Methods/design: The SToP-BPD study is a multicentre, double-blind, placebo-controlled hydrocortisone trial in preterm infants at risk for BPD. After parental informed consent is obtained, ventilator-dependent infants are randomly allocated to hydrocortisone or placebo treatment during a 22-day period. The primary outcome measure is the composite outcome of death or BPD at 36 weeks postmenstrual age. Secondary outcomes are short-term effects on pulmonary condition and long-term neurodevelopmental sequelae assessed at 2 years corrected age. Complications of treatment, other serious adverse events and suspected unexpected serious adverse reactions are reported as safety outcomes. This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data

Impact of chronic obstructive pulmonary disease and dyspnoea on clinical outcomes in ticagrelor treated patients undergoing percutaneous coronary intervention in the randomized GLOBAL LEADERS trial

AIMS: To evaluate long-term safety and efficacy of ticagrelor monotherapy in patients undergoing percutaneous coronary interventions (PCIs) in relation to chronic obstructive pulmonary disease (COPD) at baseline and the occurrence of dyspnoea reported as adverse event (AE) that may lead to treatment non-adherence. METHODS AND RESULTS: This is a non-prespecified, post hoc analysis of the randomized GLOBAL LEADERS trial (n = 15 991), comparing the experimental strategy of 23-month ticagrelor monotherapy following 1-mo

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

No association between glucocorticoid receptor polymorphisms and long-term respiratory outcome after very preterm birth

Developmen

Gender differences in respiratory symptoms in 19-year-old adults born preterm

Objective: To study the prevalence of respiratory and atopic symptoms in (young) adults born prematurely, differences between those who did and did not develop Bronchopulmonary Disease (BPD) at neonatal age and differences in respiratory health between males and females. Methods: Design: Prospective cohort study. Setting: Nation wide follow-up study, the Netherlands. Participants: 690 adults (19 year old) born with a gestational age below 32 completed weeks and/or with a birth weight less than 1500g. Controls were Dutch participants of the European Community Respiratory Health Survey (ECRHS). Main outcome measures: Presence of wheeze, shortness of breath, asthma, hay fever and eczema using the ECRHS-questionnaire

Brain imaging and neurodevelopmental outcome at school age in preterm-born infants: Effects of neonatal hydrocortisone treatment

A 2-year cohort of 236 preterm-born infants (gestational age < 32 weeks and/or birth weight < 1500 grams), born between March 1, 1991 and March 1, 1993 and admitted to the NICU of the Wilhelmina Children's Hospital, was evaluated at school age. This cohort represented 83.4% of the surviving population of this time period. A normal neonatal cranial ultrasound excluded the occurrence of major abnormalities on later MRI in 99% of cases. Those with a normal or mildly abnormal cranial ultrasound had an approximately 50% chance of being in the corresponding MRI group. Over 70% of the children with a severely abnormal cranial ultrasound had major abnormalities on later MRI. MRI findings correlated better with outcome than ultrasound, although statistically significant, these differences were clinically not relevant. The mean total cross-sectional corpus callosum (CC) area, measured at school age, was significantly smaller in preterm-born infants compared with their term-born controls The preterm children with cerebral palsy (CP) had significantly smaller mean corpus callosum areas compared with the preterms who did not develop CP. The preterms without CP also had significantly smaller body, posterior and total CC areas compared with term-born controls. There was a significant inverse association between the total impairment score (TIS) and the areas of the CC. Higher TIS (indicating poorer motor function) was strongly related to smaller total CC area. A larger CC was strongly related to better scores on the VMI test. In the second part of the thesis, the impact of neonatal hydrocortisone administration, to treat chronic lung disease in ventilator-dependent preterm-born infants, on long-term outcome was investigated. The most commonly used corticosteroid worldwide to treat these infants is dexamethasone, but the adverse side-effects on long-term development are alarming. The Wilhelmina Children's Hospital has always used the much milder steroid hydrocortisone. At a median age of 8.1 years, neurocognitive assessment included an IQ test, a Visual-Motor Integration test and a memory test (15-word recall). Motor performance was assessed with the Movement Assessment Battery for Children. A MRI of the brain was obtained and in the last 60 children, three-dimensional MRI with advanced image-processing and proton magnetic resonance spectroscopy of the hippocampus were added to the protocol. Sixty-two hydrocortisone-treated preterm-born children were compared with 164 non-treated preterm-born children. Adjustments for gestational age, birth weight, gender, mechanical ventilation and small for gestational age was made. Adjusted mean IQ, VMI and memory test results were the same in the hydrocortisone and the non-steroid group. Motor function and incidence of CP in both groups was not different. Occurrence of brain lesions on MRI was identical for the two groups. Hydrocortisone-treated children had very similar volumes of gray matter, white matter, and cerebrospinal fluid, compared with non-treated infants. The volumes and proton spectroscopy ratios of the hippocampus were not significantly different between the hydrocortisone group and the non-steroid group. There was no relation between NAA/(Cho+Cr) ratios and memory nor between NAA/(Cho+Cr) ratios and IQ. Neonatal hydrocortisone treatment for BPD had no long-term effects on neurodevelopment

Brain imaging and neurodevelopmental outcome at school age in preterm-born infants: Effects of neonatal hydrocortisone treatment

A 2-year cohort of 236 preterm-born infants (gestational age < 32 weeks and/or birth weight < 1500 grams), born between March 1, 1991 and March 1, 1993 and admitted to the NICU of the Wilhelmina Children's Hospital, was evaluated at school age. This cohort represented 83.4% of the surviving population of this time period. A normal neonatal cranial ultrasound excluded the occurrence of major abnormalities on later MRI in 99% of cases. Those with a normal or mildly abnormal cranial ultrasound had an approximately 50% chance of being in the corresponding MRI group. Over 70% of the children with a severely abnormal cranial ultrasound had major abnormalities on later MRI. MRI findings correlated better with outcome than ultrasound, although statistically significant, these differences were clinically not relevant. The mean total cross-sectional corpus callosum (CC) area, measured at school age, was significantly smaller in preterm-born infants compared with their term-born controls The preterm children with cerebral palsy (CP) had significantly smaller mean corpus callosum areas compared with the preterms who did not develop CP. The preterms without CP also had significantly smaller body, posterior and total CC areas compared with term-born controls. There was a significant inverse association between the total impairment score (TIS) and the areas of the CC. Higher TIS (indicating poorer motor function) was strongly related to smaller total CC area. A larger CC was strongly related to better scores on the VMI test. In the second part of the thesis, the impact of neonatal hydrocortisone administration, to treat chronic lung disease in ventilator-dependent preterm-born infants, on long-term outcome was investigated. The most commonly used corticosteroid worldwide to treat these infants is dexamethasone, but the adverse side-effects on long-term development are alarming. The Wilhelmina Children's Hospital has always used the much milder steroid hydrocortisone. At a median age of 8.1 years, neurocognitive assessment included an IQ test, a Visual-Motor Integration test and a memory test (15-word recall). Motor performance was assessed with the Movement Assessment Battery for Children. A MRI of the brain was obtained and in the last 60 children, three-dimensional MRI with advanced image-processing and proton magnetic resonance spectroscopy of the hippocampus were added to the protocol. Sixty-two hydrocortisone-treated preterm-born children were compared with 164 non-treated preterm-born children. Adjustments for gestational age, birth weight, gender, mechanical ventilation and small for gestational age was made. Adjusted mean IQ, VMI and memory test results were the same in the hydrocortisone and the non-steroid group. Motor function and incidence of CP in both groups was not different. Occurrence of brain lesions on MRI was identical for the two groups. Hydrocortisone-treated children had very similar volumes of gray matter, white matter, and cerebrospinal fluid, compared with non-treated infants. The volumes and proton spectroscopy ratios of the hippocampus were not significantly different between the hydrocortisone group and the non-steroid group. There was no relation between NAA/(Cho+Cr) ratios and memory nor between NAA/(Cho+Cr) ratios and IQ. Neonatal hydrocortisone treatment for BPD had no long-term effects on neurodevelopment

Early versus late treatment of posthaemorrhagic ventricular dilatation: results of a retrospective study from five neonatal intensive care units in The Netherlands.

Item does not contain fulltextPosthaemorrhagic ventricular dilatation (PHVD) in very preterm infants carries a poor prognosis. As earlier studies have failed to show a benefit of early intervention, it is recommended that PHVD be first treated when head circumference is rapidly increasing and/or when symptoms of raised intracranial pressure develop. Infants with PHVD, admitted to 5 of the 10 Dutch neonatal intensive care units were studied retrospectively, to investigate whether there was a difference in the time of onset of treatment of PHVD and, if so, whether this was associated with a difference in the requirement of a ventriculo-peritoneal (VP) shunt and/or neurodevelopmental outcome. The surviving infants with a gestational age <34 wk, born between 1992 and 1996, diagnosed as having a grade III haemorrhage according to Papile on cranial ultrasound and who developed PHVD were included in the study. PHVD was defined as a ventricular index (VI) exceeding the 97th percentile according to Levene (1981), and severe PHVD as a VI crossing the p 97 + 4 mm line. Ninety-five infants met the entry criteria. Intervention was not deemed necessary in 22 infants, because of lack of progression. In 31 infants lumbar punctures (LP) were done before the p 97 + 4 mm line was crossed (early intervention). In 20/31 infants, stabilization occurred. In 9 a subcutaneous reservoir was placed, with subsequent stabilization in 6. In 5/31 infants a VP shunt was eventually inserted. In 42 infants treatment was started once the p 97 + 4 mm line was crossed (late intervention). In 30 infants LPs were performed and in 17 of these a VP shunt was eventually inserted. In 11 infants a subcutaneous reservoir was immediately inserted and in 8 of these infants a VP shunt was needed. In one infant a VP shunt was immediately inserted, without any other form of treatment. Infants with late intervention crossed the p 97 + 4 mm earlier (p 0.03) and needed a shunt (26/42; 62%) more often than those with early intervention (5/31; 16%). Early LP was associated with a strongly reduced risk of VP-shunting (odds ratio = 0.22, 95% confidence interval: 0.08-0.62). The number of infants who developed a moderate or severe handicap was also higher (11/42; 26%) in the late intervention group, compared with those not requiring any intervention (3/22; 14%) or treated early (5/31; 16%). CONCLUSION: In this retrospective study, infants receiving late intervention required shunt insertion significantly more often than those treated early. A randomized prospective intervention study, comparing early and late drainage, is required to further assess the role of earlier intervention