Validation of the Brief Developmental Assessment in pre-school children with heart disease.

Introduction The objective of this study was to prospectively validate the "Brief Developmental Assessment", which is a new early recognition tool for neurodevelopmental abnormalities in children with heart disease that was developed for use by cardiac teams. METHODS: This was a prospective validation study among a representative sample of 960 pre-school children with heart disease from three United Kingdom tertiary cardiac centres who were analysed grouped into five separate age bands. RESULTS: The "Brief Developmental Assessment" was successfully validated in the older four age bands, but not in the youngest representing infants under the age of 4 months, as pre-set validation thresholds were met - lower 95% confidence limit for the correlation coefficient above 0.75 - in terms of agreement of scores between two raters and with an external measure the "Mullen Scales of Early Learning". On the basis of American Association of Pediatrics Guidelines, which state that the sensitivity and specificity of a developmental screening tool should fall between 70 and 80%, "Brief Developmental Assessment" outcome of Red meets this threshold for detection of Mullen scores >2 standard deviations below the mean. CONCLUSION: The "Brief Developmental Assessment" may be used to improve the quality of assessment of children with heart disease. This will require a training package for users and a guide to action for abnormal results. Further research is needed to determine how best to deploy the "Brief Developmental Assessment" at different time points in children with heart disease and to determine the management strategy in infants younger than 4 months old.

Prognostic significance of computed tomography criteria for pulmonary veno-occlusive disease in systemic sclerosis-pulmonary arterial hypertension.

Objectives: SSc-pulmonary arterial hypertension (SSc-PAH) is associated with worse response to therapy and survival when compared with idiopathic PAH. It is suggested that the vasculopathy in SSc may involve postcapillary pulmonary venules resulting in pulmonary veno-occlusive disease (PVOD). This may underlie the lower gas transfer and worse outcome on therapy. We sought to test whether CT signs of PVOD (CTS-PVOD) were frequent in SSc-PAH and whether they were associated with pulmonary oedema on therapy and worse survival. Methods: CT thorax of 66 SSc patients with precapillary pulmonary hypertension (PH) were blindly scored by two radiologists for CTS-PVOD (⩽1 or ⩾ 2). Case note and radiograph review determined the presence of pulmonary oedema on therapy. Results: Fifty-nine patients (89%) had ⩽1 CTS-PVOD and only 7 (11%) had ⩾2 CTS-PVOD. Pulmonary oedema on therapy was relatively common in those with ⩾2 CTS-PVOD. On univariate analysis ⩾2 CTS-PVOD were associated with a trend towards worse survival. Conclusion: CTS-PVOD were less frequent in this SSc-PAH cohort than in previous reports but the presence of at least two of these signs is associated with pulmonary oedema on therapy and a trend towards worse survival on univariate analysis.

Expanding the phenotype in argininosuccinic aciduria: need for new therapies.

OBJECTIVES: This UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs. METHODS: Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping. RESULTS: Fifty-six patients were defined as early-onset (n = 23) if symptomatic < 28 days of age, late-onset (n = 23) if symptomatic later, or selectively screened perinatally due to a familial proband (n = 10). The median follow-up was 12.4 years (range 0-53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n = 19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients. CONCLUSIONS: Our study further defines the natural history of argininosuccinic aciduria and genotype-phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.

The 1-Year Follow-Up Clinic for Neonates and Children After Respiratory Extracorporeal Membrane Oxygenation Support: A 10-Year Single Institution Experience.

OBJECTIVES: To establish the effectiveness of a "1-year extracorporeal membrane oxygenation follow-up clinic" and to characterize any neurodevelopmental concerns identified. DESIGN: Single-center retrospective cohort of respiratory extracorporeal membrane oxygenation survivors over 10 years. SETTING: Nationally commissioned center for neonatal and pediatric (> 28 d of life) respiratory extracorporeal membrane oxygenation. PATIENTS: Children attending the follow-up clinic 1 year after receiving respiratory extracorporeal membrane oxygenation between 2003 and 2013. INTERVENTIONS: Standardized follow-up 1 year after extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: In 10 years, 290 children received extracorporeal membrane oxygenation, 194 (67%) survived; all were offered 1-year follow-up, and 98 (51%) attended the clinic. Among these, 51 of 98 (52%) had meconium aspiration syndrome, and 74 of 98 (75%) were on veno-arterial extracorporeal membrane oxygenation with a median (interquartile range) duration of 6 days (4-8 d). Neurodevelopmental problems were identified in 30 of 98 (30%). The specific abnormalities noted included neurologic (seizures, motor, or vision abnormalities) (n = 8), hearing with/without language delay (n = 8), and behavioral problems (as reported by parents) (n = 6), with eight of 30 (27%) having difficulties spanning these domains. An acute neurologic event on extracorporeal membrane oxygenation was found to be the only risk factor for neurodevelopmental concerns (p = 0.006 with odds ratio 5.4 [95% CI, 1.63-17.92]). Despite having neither a cardiac arrest nor an acute neurologic event documented, 18 of 74 (24.3%), 95% CI (15.1-35.7), had neurodevelopmental concerns at 1-year follow-up. Among the nonattenders, 30 (15%) had local follow-up, and 66 (34%) were lost to follow-up. CONCLUSIONS: All extracorporeal membrane oxygenation survivors need follow-up either at the extracorporeal membrane oxygenation center or in their community, as evidenced by the 1-year follow-up data. Our 1-year extracorporeal membrane oxygenation follow-up clinic provides an opportunity to engage with families, identify neurodevelopmental concerns, and signpost to appropriate services. Of concern, one third of survivors are lost to follow-up, some with an acute neurologic event on extracorporeal membrane oxygenation, a significant risk factor. A consensus-based standardized national follow-up program is vital.

Brain weight in sudden unexpected death in infancy: experience from a large single-centre cohort.

AIMS: Published reports of brain weight in sudden infant death syndrome (SIDS) are contradictory, although several have concluded that brain weight is increased in SIDS compared with controls or reference data. This is important as, if brain weight is significantly different, it may be of diagnostic use or provide insights into the aetiology of SIDS. The aim of this study was to use a large series of well-characterized sudden unexpected infant deaths from a single centre to provide definitive data regarding this issue. METHODS: A retrospective review identified 1100 infants who had died suddenly and undergone a comprehensive autopsy at Great Ormond Street Hospital between 1996 and 2011. They were split into two groups: those in whom death could be explained and those whose deaths remained unexplained despite full investigation (SIDS/unexplained sudden unexpected death in infancy). RESULTS: There were 1100 cases of whom 573 (52%) were unexplained and 527 (48%) explained. Multiple regression analysis, which adjusted for sex, age and post-mortem interval, showed no difference in the ratio of brain weight : body weight between those infants dying of explained causes and those in whom no cause could be found. This finding remained true when restricting analysis to those with macroscopically normal brains. CONCLUSIONS: In this large series of infants dying of both explained and unexplained causes, brain weight, once corrected for body weight, did not vary consistently with the cause of death. Brain weight cannot be used as a diagnostic indicator of the cause of death or to inform hypothetical models of the pathogenesis of SIDS.

The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials.

OBJECTIVE: With the emergence of experimental therapies for Duchenne muscular dystrophy (DMD), it is fundamental to understand the natural history of this disorder to properly design clinical trials. The aims of this study were to assess the effects produced on motor function by different DMD genotypes and early initiation of glucocorticoids. METHODS: Through the NorthStar Network, standardised clinical data including the NorthStar Ambulatory Assessment score (NSAA) on 513 ambulant UK boys with DMD were analysed from 2004 to 2012. For the analysis of the genetic subpopulation, we also included data from 172 Italian boys with DMD. NSAA raw scores were converted into linear scores. RESULTS: On the linearised NSAA, we observed an average decline of 8 units/year (4 units on raw NSAA analysis) after age 7. The median age at loss of ambulation (LOA) was 13 years (95% CI 12.1 to 13.5); 2 years prior to LOA, the estimated mean linearised NSAA score was 42/100 (13/34 raw scale). Starting glucocorticoids between 3 and 5 years conferred an additional gain in motor function of 3 units/year (1.3 raw units) up to age 7. When analysing the effect of genotype in the UK and Italian cumulative cohorts, individuals with deletions amenable to exons 44 and 46 skipping declined at a slower rate over 2 years (9 units (4 raw units), p<0.001), while 53 and 51 skippable deletions showed a faster decline of 14 (4.5; p<0.001) and 5 linearised units (2.4 NSAA units; p=0.02), respectively. CONCLUSIONS: Our study provides a novel insight on the current natural history of DMD, which will be instrumental for the design of future clinical trials.

Comparison of three different timeframes for pediatric index of mortality data collection in transported intensive care admissions*.

OBJECTIVE: To identify the most appropriate timeframe for Pediatric Index of Mortality-2 data collection in patients transported to PICUs by specialist teams. DESIGN: Retrospective cohort study. SETTING: A regional PICU transport team in London, United Kingdom. PATIENTS: Children admitted for intensive care to a tertiary children's hospital PICU following transport by a PICU transport team between January 1, 2007, and December 31, 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data on case mix and outcome from children transferred to the tertiary PICU during the study period were analyzed. The "standard" timeframe used in calculating Pediatric Index of Mortality-2 was compared with Pediatric Index of Mortality-2 calculated using data from two other 1-hour timeframes (during "retrieval" and during "admission"). A total of 759 transported admissions were studied. Eighty-three children died (mortality rate, 10.9%). Data were missing in up to 42.7% of admissions for some Pediatric Index of Mortality-2 variables from transport. However, missing data persisted even after the first hour of PICU admission in most cases. There was significant improvement in some physiological variables following transport (p < 0.01), but Pediatric Index of Mortality-2 did not change significantly. Pediatric Index of Mortality-2 from all three timeframes exhibited good discrimination (area under the receiver-operating characteristic curve ≥ 0.77). Calibration across deciles of mortality risk was poor for the "admission" Pediatric Index of Mortality-2 (Hosmer-Lemeshow goodness-of-fit test p = 0.04) but good for the other two calculated Pediatric Index of Mortality-2 models (p > 0.20). CONCLUSIONS: The findings of our single-center study do not support the need for different timeframes for Pediatric Index of Mortality-2 data collection in transported and direct PICU admissions. Uniformity in scoring procedure may simplify data collection and improve data quality.

Republished: creating a safe, reliable hospital at night handover: a case study in implementation science.

BACKGROUND: We developed protocols to handover patients from day to hospital at night (H@N) teams. SETTING: NHS paediatric specialist hospital. METHOD: We observed four handover protocols (baseline, Phases 1, 2 and 3) over 2 years. A mixed-method study (observation, interviews, task analysis, prospective risk assessment, document and case note review) explored the impact of different protocols on performance. INTERVENTION: In Phase 1, a handover protocol was introduced to resolve problems with the baseline H@N handover. Following this intervention, two further revisions to the handover occurred, driven by staff feedback (Phases 2 and 3). RESULTS: Variations in performance between handover protocols on three process measures, start time efficiency, total length of handover, and number of distractions and interruptions, were identified. Univariate regression analysis showed statistically significant differences between handover protocols on two surrogate outcome measures: number of flagging omissions and the number of out of hours deteriorations (p=0.04 for Phase 3 vs Phase 1 for both measures (CI 1.04 to 4.08; CI 1.03 to 4.33), and for Phase 3 vs Phase 2 (p=0.006 and p=0.001 (CI 1.22 to 5.15; CI 1.62 to 9.0)), respectively). The Phase 1 and 2 handover protocols were effective at identifying patients whose clinical condition warranted review overnight. Performance on both surrogate outcome measures, length of handover and distractions, deteriorated in Phase 3. CONCLUSIONS: A carefully designed prioritisation process within the H@N handover can be effective at flagging acutely unwell patients. However, the protocol we introduced was unsustainable. In a complex healthcare system, sustainable implementation of new processes may be threatened by conflicting goals.

Long-term benefits and adverse effects of intermittent versus daily glucocorticoids in boys with Duchenne muscular dystrophy.

OBJECTIVE: To assess the current use of glucocorticoids (GCs) in Duchenne muscular dystrophy in the UK, and compare the benefits and the adverse events of daily versus intermittent prednisolone regimens. DESIGN: A prospective longitudinal observational study across 17 neuromuscular centres in the UK of 360 boys aged 3-15 years with confirmed Duchenne muscular dystrophy who were treated with daily or intermittent (10 days on/10 days off) prednisolone for a mean duration of treatment of 4 years. RESULTS: The median loss of ambulation was 12 years in intermittent and 14.5 years in daily treatment; the HR for intermittent treatment was 1.57 (95% CI 0.87 to 2.82). A fitted multilevel model comparing the intermittent and daily regiments for the NorthStar Ambulatory Assessment demonstrated a divergence after 7 years of age, with boys on an intermittent regimen declining faster (p<0.001). Moderate to severe side effects were more commonly reported and observed in the daily regimen, including Cushingoid features, adverse behavioural events and hypertension. Body mass index mean z score was higher in the daily regimen (1.99, 95% CI 1.79 to 2.19) than in the intermittent regimen (1.51, 95% CI 1.27 to 1.75). Height restriction was more severe in the daily regimen (mean z score -1.77, 95% CI -1.79 to -2.19) than in the intermittent regimen (mean z score -0.70, 95% CI -0.90 to -0.49). CONCLUSIONS: Our study provides a framework for providing information to patients with Duchenne muscular dystrophy and their families when introducing GC therapy. The study also highlights the importance of collecting longitudinal natural history data on patients treated according to standardised protocols, and clearly identifies the benefits and the side-effect profile of two treatment regimens, which will help with informed choices and implementation of targeted surveillance.

Psychosocial stimulation benefits development in nonanemic children but not in anemic, iron-deficient children.

Young children with iron deficiency anemia (IDA) usually have poor development, but there is limited information on their response to psychosocial intervention. We aimed to compare the effects of psychosocial stimulation on the development of children with IDA and children who were neither anemic nor iron deficient (NANI). NANI (n = 209) and IDA (n = 225) children, aged 6-24 mo, from 30 Bangladeshi villages were enrolled in the study. The villages were then randomized to stimulation or control, and all children with IDA received 30 mg iron daily for 6 mo. Stimulation comprised 9 mo weekly play sessions at home. We assessed children's development at baseline and after 9 mo by using the Psychomotor Development Index (PDI) and the Mental Development Index (MDI) of the Bayley Scales of Infant Development-II, and rated their behavior during the test. When we controlled for socioeconomic background, the IDA and NANI groups did not differ in their Bayley scores and behavior at baseline. After 9 mo, the IDA group had improved in iron status compared with baseline but had lower PDI scores and were less responsive to the examiner than the NANI group. Random-effects multilevel regressions of the final Bayley scores of the IDA and NANI groups showed that stimulation improved children's MDI [B ± SE = 5.7 ± 1.9 (95% CI: 2.0, 9.4), P = 0.003], and the interaction between iron status and stimulation showed a suggestive trend (P = 0.10), indicating that children with IDA and NANI responded differently to stimulation, with the NANI group improving more than the IDA group. In addition to iron treatment, children with IDA may require more intense or longer interventions than NANI children.

Long-term survival outcomes and causes of late death in neonates, infants, and children treated with extracorporeal life support.

OBJECTIVES: Extracorporeal life support is a resource-intense treatment offered to the sickest patients. We aimed to investigate long-term survival rates and late deaths. DESIGN: Retrospective cohort study. SETTING: Tertiary referral center for extracorporeal life support. PATIENTS: All patients who required extracorporeal life support from 1992 to 2010 at our center. The U.K. National Health Service number was used to trace survival status of all patients who received extracorporeal life support at our center, grouped by diagnosis. Death more than 90 days after extracorporeal life support was defined as late, and these medical records were reviewed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 741 children with 272 early deaths (36.7%) and 46 late deaths (6.2%) were included. Median follow-up time in survivors was 7.1 (interquartile range, 3.0-11.9) years. Five-year survival estimates were highest for meconium aspiration syndrome 88.0% (95% CI, 80.6-92.7%) and lowest for congenital heart disease 32.3% (95% CI, 25.1-39.8%). Five-year survival estimates conditional on being alive at 90 days were highest for meconium aspiration syndrome 97.9% (95% CI, 92.0-99.5%) and lowest for congenital diaphragmatic hernia 73.6% (52.3-86.5%). There was increased risk of late death in congenital diaphragmatic hernia, congenital heart disease, and acquired heart disease (p < 0.001, p < 0.01, p = 0.01) in comparison with the risk in meconium aspiration syndrome. For 46 late deaths, 17 had a cardiac cause, 16 had a respiratory cause, 10 had a comorbid cause, one died of sepsis, and in two, causation was unknown. CONCLUSIONS: Although the majority of deaths were early, late mortality was observed following extracorporeal life support. Late deaths were more prevalent in children with underlying complex long-term conditions, particularly heart disease and congenital diaphragmatic hernia. Evaluation of longer term survival is an important component of audit for extracorporeal life support outcomes.

The impact of mechanical ventilation time before initiation of extracorporeal life support on survival in pediatric respiratory failure: a review of the Extracorporeal Life Support Registry.

OBJECTIVE: To evaluate the relationship between duration of mechanical ventilation before the initiation of extracorporeal life support and the survival rate in children with respiratory failure. Extracorporeal life support has been used as a rescue therapy for >30 yrs in children with severe respiratory failure. Previous studies suggest patients who received >7-10 days of mechanical ventilation were not acceptable extracorporeal life support candidates as a result of irreversible lung damage. DESIGN: A retrospective review encompassing the past 10 yrs of the International Extracorporeal Life Support Organization Registry (January 1, 1999, to December 31, 2008). SETTING: Extracorporeal Life Support Organization Registry database. PATIENTS: A total of 1325 children (≥ 30 days and ≤ 18 yrs) met inclusion criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The following pre-extracorporeal life support variables were identified as independently and significantly related to the chance of survival: 1) >14 days of ventilation vs. 0-7 days was adverse (odds ratio, 0.32; p < .001); 2) the presence of a cardiac arrest was adverse (odds ratio, 0.56; p = .001); 3) pH per 0.1-unit increase was protective (odds ratio, 1.15; p < .001); 4) oxygenation index, per 10-unit increase was adverse (odds ratio, 0.95; p = .002); and 5) any diagnosis other than sepsis was related to a more favorable outcome. Patients requiring >7-10 or >10-14 days of pre-extracorporeal life support ventilation did not have a statistically significant decrease in survival as compared with patients who received 0-7 days. CONCLUSIONS: There was a clear relationship between the number of mechanical ventilation days before the initiation of extracorporeal life support and survival. However; there was no statistically significant decrease in survival until >14 days of pre-extracorporeal life support ventilation was reached regardless of underlying diagnosis. We found no evidence to suggest that prolonged mechanical ventilation should be considered as a contraindication to extracorporeal life support in children with respiratory failure before 14 days.

Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy: A 30-Month Nonrandomized Controlled Open-Label Extension Trial.

Importance: Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups. Objective: To investigate outcomes after 30 months of open-label vamorolone treatment. Design, Setting, and Participants: This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021. Interventions: Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d. Main Outcomes and Measures: Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone. Results: Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time. Conclusions and Relevance: This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD. Trial Registration: ClinicalTrials.gov Identifier: NCT03038399.

Determining Real Change in Conditioned Pain Modulation: A Repeated Measures Study in Healthy Volunteers.

Conditioned pain modulation (CPM) is a potentially useful biomarker in pain populations; however, a statistically robust interpretation of change scores is required. Currently, reporting of CPM does not consider measurement error. Hence, the magnitude of change representing a "true" CPM effect is unknown. This study determined the standard error of measurement (SEM) and proportion of healthy participants showing a "true" CPM effect with a standard CPM paradigm. Fifty healthy volunteers participated in an intersession reliability study using pressure pain threshold (PPT) test stimulus and contact heat, cold water, and sham conditioning stimuli. Baseline PPTs were used to calculate SEM and >±2 × SEM to determine CPM effect. SEM for PPT was .21 kg/cm2. An inhibitory CPM effect (>+2 SEM) was elicited in 59% of subjects in response to cold stimulus; in 44% to heat. Intrasession and intersession reliability of within-subject CPM response was poor (kappa coefficient <.36). Measurement error is important in determining CPM effect and change over time. Even when using reliable test stimuli, and incorporating measures to limit bias and error, CPM intersession reliability was fair and demonstrated a large degree of within-subject variation. Determining "true" change in CPM will underpin future interrogations of intraindividual differences in CPM. PERSPECTIVE: This study used a distribution-based statistical approach to identify real change in CPM, based on the SEM for the test stimulus. Healthy volunteers demonstrate substantial within-subject variation; CPM effect was paradigm dependent at intrasession testing and unstable to the same paradigm at intersession testing.

New-onset heart failure due to heart muscle disease in childhood: a prospective study in the United kingdom and Ireland.

BACKGROUND: We undertook the first prospective, national, multicenter study to describe the incidence and outcome of heart muscle disease-induced heart failure in children. METHODS AND RESULTS: Data were collected on patients admitted to a hospital through 2003 with a first episode of heart failure in the absence of congenital heart disease. All 17 pediatric cardiac centers in the United Kingdom and Ireland participated. Follow-up data were obtained to a minimum of 1 year. The incidence was 0.87/100,000 population <16 years (n=104; 53 girls; 95% confidence interval 0.71 to 1.05 per 100,000). Median age at presentation was 1 year, with 82% in New York Heart Association class III to IV. Causes of heart failure included dilated cardiomyopathy (50 idiopathic, 8 familial), probable myocarditis (23), occult arrhythmia (7), anthracycline toxicity (5), metabolic disease (4), left ventricular noncompaction (3), and other (4). Overall 1-year survival was 82%, and event (death or transplantation)-free survival was 66%. Regression analysis showed older age and reduced systolic function on admission echocardiogram increased the event risk. Only 8% of event-free survivors (n=69) remained in New York Heart Association class III to IV, but 35 required readmission during the study period, and all but 8 remained on medication. CONCLUSIONS: This first national prospective study of new-onset heart failure in children has shown an incidence of 0.87/100,000. Multivariable analysis of survival data indicates a better outcome for younger children and for those with better systolic function at presentation, but overall, one third of children die or require transplantation within 1 year of presentation.

The likelihood of an indeterminate test result from a whole-blood interferon-gamma release assay for the diagnosis of Mycobacterium tuberculosis infection in children correlates with age and immune status.

BACKGROUND: Interferon-gamma release assays for the diagnosis of infection with Mycobacterium tuberculosis have been increasingly used in recent years and are endorsed by national guidelines, but experience regarding their use in children is still limited. METHODS: We retrospectively evaluated the routine use of the QuantiFERON-TB Gold In-Tube assay (QFT-IT) in a pediatric tertiary care center with a high prevalence of immunocompromising conditions. The relationship between age, immune status, and likelihood of an indeterminate test result was analyzed using logistic regression analysis and fractional polynomials. RESULTS: Two hundred thirty-seven tests from 237 children were included in the analysis. Fifty-nine children (25%) were immunocompromised by our definition. An indeterminate test result was obtained in 83 children (35%). The likelihood of an indeterminate test result was inversely correlated with age (P < 0.001) for children who were not known to be immunocompromised, and decreased by 13% per year of age. Impaired immunity (P < 0.001) was independently associated with a higher probability of an indeterminate QFT-IT. Among 161 children with a documented tuberculin skin test, 89% had a concordant QFT-IT (kappa = 0.71). Twelve of 16 patients with culture-proven TB had a positive QFT-IT. CONCLUSION: These data suggest that QFT-IT may not provide a determinate test result in a substantial proportion of children in a tertiary care setting due to the combination of young age and primary and acquired immune deficiencies.

Chronic kidney disease in children following lung and heart-lung transplantation.

CKD is a major co-morbidity in pediatric lung transplant recipients. We report the prevalence of renal impairment post-lung transplant at a single center, using a modified, age-adjusted eGFR for the best approximation of true GFR, and investigated associations and possible predictors of decline in renal function post-transplant. Renal function was assessed by eGFR pre-transplant, three and 12 months post-transplant, and at last follow-up. Decline in renal function was analyzed as percentage fall in eGFR in two phases (0-3 and 3-12). Furthermore, we investigated impact of gender, age, pre-transplant diagnosis and renal function, transplant type, early post-transplant dialysis, and tacrolimus trough levels on decline in eGFR using multivariate analysis. Over a five-yr period, 30 transplants were performed. Mean eGFR pretransplant was 117 mL/min/1.73 m(2) (s.d. 35) with mean decline in eGFR during the first three months post-transplant of 33% (s.d. 31, p < 0.001). Thereafter, mean decline in eGFR was 8% (s.d. 18, p = 0.02). None of the factors assessed were significantly associated with decline in eGFR post-transplant. In conclusion, many children have decline in renal function following lung transplantation, particularly early post-transplant. Unlike in adults, we were unable to detect any predictors of renal impairment in pediatric lung transplant recipients.

Predictors of outcome for children requiring respiratory extra-corporeal life support: implications for inclusion and exclusion criteria.

OBJECTIVES: A range of children receive extra-corporeal life support (ECLS) for respiratory failure, but there is little published data on this group. Our aims were: (1) to analyse predictors of outcome and (2) comment on inclusion and exclusion criteria. DESIGN: Retrospective review. SETTING: Tertiary ECLS centre. PATIENTS: A total of 124 children categorised as 'paediatric respiratory ECLS' from July 1992 to December 2005. RESULTS: Fifty-three percent of children had one or more co-morbid conditions; the median age was 10.1 (IQR 3-34) months; the median ECLS duration was 9 (IQR 5-17) days; survival to discharge was 62% and at 1 year was 59%. Although survival varied according to primary reason for ECLS (range 36-100%), after adjustment for this, the presence of a co-morbid condition was unrelated to mortality (OR = 1.49, 95% CI 0.65, 3.42, P = 0.34) Predictors of mortality were increased pre-ECLS oxygenation index (OR = 1.09, 95% CI 1.00, 1.18, P = 0.05) and shock (OR 2.53, 95% CI 1.21, 5.28, P = 0.01). The relationship between mortality and end organ dysfunction (OR 2.12, 95% CI 0.89, 5.02, P = 0.09) and greater number of pre-ECLS ventilator days (OR 1.10, 95% CI 0.99, 1.22, P = 0.08) was less conclusive. CONCLUSIONS: Pre-existing co-morbid conditions may predispose children to develop severe respiratory failure but with careful case selection, do not appear to reduce the chance of survival. Severity of pulmonary dysfunction determined by OI and shock were key predictors of outcome and should remain important determinants of referral for ECLS.

Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer.

Argininosuccinate lyase (ASL) belongs to the hepatic urea cycle detoxifying ammonia, and the citrulline-nitric oxide (NO) cycle producing NO. ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia, multiorgan disease and neurocognitive impairment despite treatment aiming to normalise ammonaemia without considering NO imbalance. Here we show that cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress independent of hyperammonaemia. Intravenous injection of AAV8 vector into adult or neonatal ASL-deficient mice demonstrates long-term correction of the hepatic urea cycle and the cerebral citrulline-NO cycle, respectively. Cerebral disease persists if ammonaemia only is normalised but is dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This correlates with behavioural improvement and reduced cortical cell death. Thus, neuronal oxidative/nitrosative stress is a distinct pathophysiological mechanism from hyperammonaemia. Disease amelioration by simultaneous brain and liver gene transfer with one vector, to treat both metabolic pathways, provides new hope for hepatocerebral metabolic diseases.

Risk factors for sudden cardiac death in childhood hypertrophic cardiomyopathy: A systematic review and meta-analysis.

Aims To perform a systematic literature review and meta-analysis of clinical risk factors for sudden cardiac death (SCD) in childhood hypertrophic cardiomyopathy. Methods Medline and PubMed databases were searched for original articles published in English from 1963 through to December 2015 that included patients under 18 years of age with a primary or secondary end-point of either SCD or SCD-equivalent events (aborted cardiac arrest or appropriate implantable cardioverter-defibrillator discharge) or cardiovascular death (CVD). Results Twenty-five studies (3394 patients) met the inclusion criteria. We identified four conventional major risk factors that were evaluated in at least four studies and that we found to be statistically associated with an increased risk of death in at least two studies: previous adverse cardiac event (pooled hazard ratio [HR] 5.4, 95% confidence interval [CI] 3.67-7.95, p < 0.001); non-sustained ventricular tachycardia (pooled HR 2.13, 95% CI 1.21-3.74, p = 0.009); unexplained syncope (pooled HR 1.89, 95% CI 0.69-5.16, p = 0.22); and extreme left ventricular hypertrophy (pooled HR 1.80, 95% CI 0.75-4.32, p = 0.19). Left atrial diameter did not meet the major risk factor criteria; however, this is likely to be an additional significant risk factor. 'Minor' risk factors included a family history of SCD, gender, age, symptoms, electrocardiogram changes, abnormal blood pressure response to exercise and left ventricular outflow tract obstruction. Conclusions A lack of well-designed, large, population-based studies in childhood hypertrophic cardiomyopathy means that the evidence base for individual risk factors is not robust. We have identified four clinical parameters that are likely to be associated with increased risk of SCD, SCD-equivalent events or CVD. Multi-centre prospective studies are needed in order to further determine the relevance of these factors in predicting SCD in childhood hypertrophic cardiomyopathy and to identify novel risk markers. Condensed abstract A systematic review and meta-analysis of clinical risk factors predicting sudden cardiac death in childhood hypertrophic cardiomyopathy was performed, identifying four 'major' factors: previous adverse cardiac event; non-sustained ventricular tachycardia; syncope; and extreme left ventricular hypertrophy. Well-designed multi-centre studies are required in the future in order to confirm these findings.