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.

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.

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.

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.

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.

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.

Combining qualitative and quantitative operational research methods to inform quality improvement in pathways that span multiple settings.

BACKGROUND: Improving integration and continuity of care across sectors within resource constraints is a priority in many health systems. Qualitative operational research methods of problem structuring have been used to address quality improvement in services involving multiple sectors but not in combination with quantitative operational research methods that enable targeting of interventions according to patient risk. We aimed to combine these methods to augment and inform an improvement initiative concerning infants with congenital heart disease (CHD) whose complex care pathway spans multiple sectors. METHODS: Soft systems methodology was used to consider systematically changes to services from the perspectives of community, primary, secondary and tertiary care professionals and a patient group, incorporating relevant evidence. Classification and regression tree (CART) analysis of national audit datasets was conducted along with data visualisation designed to inform service improvement within the context of limited resources. RESULTS: A 'Rich Picture' was developed capturing the main features of services for infants with CHD pertinent to service improvement. This was used, along with a graphical summary of the CART analysis, to guide discussions about targeting interventions at specific patient risk groups. Agreement was reached across representatives of relevant health professions and patients on a coherent set of targeted recommendations for quality improvement. These fed into national decisions about service provision and commissioning. CONCLUSIONS: When tackling complex problems in service provision across multiple settings, it is important to acknowledge and work with multiple perspectives systematically and to consider targeting service improvements in response to confined resources. Our research demonstrates that applying a combination of qualitative and quantitative operational research methods is one approach to doing so that warrants further consideration.

Upper Limb Evaluation in Duchenne Muscular Dystrophy: Fat-Water Quantification by MRI, Muscle Force and Function Define Endpoints for Clinical Trials.

OBJECTIVE: A number of promising experimental therapies for Duchenne muscular dystrophy (DMD) are emerging. Clinical trials currently rely on invasive biopsies or motivation-dependent functional tests to assess outcome. Quantitative muscle magnetic resonance imaging (MRI) could offer a valuable alternative and permit inclusion of non-ambulant DMD subjects. The aims of our study were to explore the responsiveness of upper-limb MRI muscle-fat measurement as a non-invasive objective endpoint for clinical trials in non-ambulant DMD, and to investigate the relationship of these MRI measures to those of muscle force and function. METHODS: 15 non-ambulant DMD boys (mean age 13.3 y) and 10 age-gender matched healthy controls (mean age 14.6 y) were recruited. 3-Tesla MRI fat-water quantification was used to measure forearm muscle fat transformation in non-ambulant DMD boys compared with healthy controls. DMD boys were assessed at 4 time-points over 12 months, using 3-point Dixon MRI to measure muscle fat-fraction (f.f.). Images from ten forearm muscles were segmented and mean f.f. and cross-sectional area recorded. DMD subjects also underwent comprehensive upper limb function and force evaluation. RESULTS: Overall mean baseline forearm f.f. was higher in DMD than in healthy controls (p<0.001). A progressive f.f. increase was observed in DMD over 12 months, reaching significance from 6 months (p<0.001, n = 7), accompanied by a significant loss in pinch strength at 6 months (p<0.001, n = 9) and a loss of upper limb function and grip force observed over 12 months (p<0.001, n = 8). CONCLUSIONS: These results support the use of MRI muscle f.f. as a biomarker to monitor disease progression in the upper limb in non-ambulant DMD, with sensitivity adequate to detect group-level change over time intervals practical for use in clinical trials. Clinical validity is supported by the association of the progressive fat transformation of muscle with loss of muscle force and function.

Identifying improvements to complex pathways: evidence synthesis and stakeholder engagement in infant congenital heart disease.

OBJECTIVES: Many infants die in the year following discharge from hospital after surgical or catheter intervention for congenital heart disease (3-5% of discharged infants). There is considerable variability in the provision of care and support in this period, and some families experience barriers to care. We aimed to identify ways to improve discharge and postdischarge care for this patient group. DESIGN: A systematic evidence synthesis aligned with a process of eliciting the perspectives of families and professionals from community, primary, secondary and tertiary care. SETTING: UK. RESULTS: A set of evidence-informed recommendations for improving the discharge and postdischarge care of infants following intervention for congenital heart disease was produced. These address known challenges with current care processes and, recognising current resource constraints, are targeted at patient groups based on the number of patients affected and the level and nature of their risk of adverse 1-year outcome. The recommendations include: structured discharge documentation, discharging certain high-risk patients via their local hospital, enhanced surveillance for patients with certain (high-risk) cardiac diagnoses and an early warning tool for parents and community health professionals. CONCLUSIONS: Our recommendations set out a comprehensive, system-wide approach for improving discharge and postdischarge services. This approach could be used to address challenges in delivering care for other patient populations that can fall through gaps between sectors and organisations.

Death and Emergency Readmission of Infants Discharged After Interventions for Congenital Heart Disease: A National Study of 7643 Infants to Inform Service Improvement.

BACKGROUND: Improvements in hospital-based care have reduced early mortality in congenital heart disease. Later adverse outcomes may be reducible by focusing on care at or after discharge. We aimed to identify risk factors for such events within 1 year of discharge after intervention in infancy and, separately, to identify subgroups that might benefit from different forms of intervention. METHODS AND RESULTS: Cardiac procedures performed in infants between 2005 and 2010 in England and Wales from the UK National Congenital Heart Disease Audit were linked to intensive care records. Among 7976 infants, 333 (4.2%) died before discharge. Of 7643 infants discharged alive, 246 (3.2%) died outside the hospital or after an unplanned readmission to intensive care (risk factors were age, weight-for-age, cardiac procedure, cardiac diagnosis, congenital anomaly, preprocedural clinical deterioration, prematurity, ethnicity, and duration of initial admission; c-statistic 0.78 [0.75-0.82]). Of the 7643, 514 (6.7%) died outside the hospital or had an unplanned intensive care readmission (same risk factors but with neurodevelopmental condition and acquired cardiac diagnosis and without preprocedural deterioration; c-statistic 0.78 [0.75-0.80]). Classification and regression tree analysis were used to identify 6 subgroups stratified by the level (3-24%) and nature of risk for death outside the hospital or unplanned intensive care readmission based on neurodevelopmental condition, cardiac diagnosis, congenital anomaly, and duration of initial admission. An additional 115 patients died after planned intensive care admission (typically following elective surgery). CONCLUSIONS: Adverse outcomes in the year after discharge are of similar magnitude to in-hospital mortality, warrant service improvements, and are not confined to diagnostic groups currently targeted with enhanced monitoring.

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.

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.

Cognitive deficit and poverty in the first 5 years of childhood in Bangladesh.

OBJECTIVE: We aimed to determine the timing and size of the cognitive deficit associated with poverty in the first 5 years of life and to examine the role of parental characteristics, pre- and postnatal growth, and stimulation in the home in Bangladeshi children. We hypothesized that the effect of poverty on cognition begins in infancy and is mainly mediated by these factors. METHODS: We enrolled 2853 singletons, a subsample from a pregnancy supplementation trial in a poor rural area. We assessed mental development at 7, 18, and 64 months; anthropometry at birth, 12, 24, and 64 months; home stimulation at 18 and 64 months; and family's socioeconomic background. In multiple regression analyses, we examined the effect of poverty at birth on IQ at 64 months and the extent that other factors mediated the effect. RESULTS: A mean cognitive deficit of 0.2 (95% confidence interval -0.4 to -0.02) z scores between the first and fifth wealth quintiles was apparent at 7 months and increased to 1.2 (95% confidence interval -1.3 to -1.0) z scores of IQ by 64 months. Parental education, pre- and postnatal growth in length, and home stimulation mediated 86% of the effects of poverty on IQ and had independent effects. Growth in the first 2 years had larger effects than later growth. Home stimulation had effects throughout the period. CONCLUSIONS: Effects of poverty on children's cognition are mostly mediated through parental education, birth size, growth in the first 24 months, and home stimulation in the first 5 years.

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.

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.

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 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.

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.