Definition of diaphragmatic sleep disordered breathing and clinical meaning in Duchenne muscular dystrophy.

BACKGROUND: Diaphragmatic sleep disordered breathing (dSDB) has been recently identified as sleep dysfunction secondary to diaphragmatic weakness in Duchenne muscular dystrophy (DMD). However, scoring criteria for the identification of dSDB are missing.This study aimed to define and validate dSDB scoring criteria and to evaluate whether dSDB severity correlates with respiratory progression in DMD. METHODS: Scoring criteria for diaphragmatic apnoea (dA) and hypopnoeas (dH) have been defined by the authors considering the pattern observed on cardiorespiratory polygraphy (CR) and the dSDB pathophysiology.10 sleep professionals (physiologists, consultants) blinded to each other were involved in a two-round Delphi survey to rate each item of the proposed dSDB criteria (Likert scale 1-5) and to recognise dSDB among other SDB. The scorers' accuracy was tested against the authors' panel.Finally, CR previously conducted in DMD in clinical setting were rescored and diaphragmatic Apnoea-Hypopnoea Index (dAHI) was derived. Pulmonary function (forced vital capacity per cent of predicted, FVC%pred), overnight oxygen saturation (SpO2) and transcutaneous carbon dioxide (tcCO2) were correlated with dAHI. RESULTS: After the second round of Delphi, raters deemed each item of dA and dH criteria as relevant as 4 or 5. The agreement with the panel in recognising dSDB was 81%, kappa 0.71, sensitivity 77% and specificity 85%.32 CRs from DMD patients were reviewed. dSDB was previously scored as obstructive. The dAHI negatively correlated with FVC%pred (r=-0.4; p<0.05). The total number of dA correlated with mean overnight tcCO2 (r 0.4; p<0.05). CONCLUSIONS: dSDB is a newly defined sleep disorder that correlates with DMD progression. A prospective study to evaluate dSDB as a respiratory measure for DMD in clinical and research settings is planned.

Startle responses in Duchenne muscular dystrophy: a novel biomarker of brain dystrophin deficiency.

Duchenne muscular dystrophy (DMD) is characterized by loss of dystrophin in muscle, however patients also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length dystrophin isoform (Dp427) is produced, multiple isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3' end of the gene, which disrupt expression of shorter Dp140 and Dp71 isoforms. A mouse model (mdx mouse) lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalize with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognized feature of DMD, and its characterization has implications for improved clinical management and translational research. To investigate startle responses in DMD, we used a novel fear-conditioning task in an observational study of 56 males aged 7-12 years (31 affected boys, mean age 9.7 ± 1.8 years; 25 controls, mean age 9.6 ± 1.4 years). Trials of two neutral visual stimuli were presented to participants: one 'safe' cue presented alone; one 'threat' cue paired with an aversive noise to enable conditioning of physiological startle responses (skin conductance response and heart rate). Retention of conditioned physiological responses was subsequently tested by presenting both cues without the aversive noise in an 'Extinction' phase. Primary outcomes were the initial unconditioned skin conductance and change in heart rate responses to the aversive 'threat' and acquisition and retention of conditioned responses after conditioning. Secondary and exploratory outcomes were neuropsychological measures and genotype associations. The mean unconditioned skin conductance response was greater in the DMD group than controls [mean difference 3.0 µS (1.0, 5.1); P = 0.004], associated with a significant threat-induced bradycardia only in the patient group [mean difference -8.7 bpm (-16.9, -0.51); P = 0.04]. Participants with DMD found the task more aversive than controls, with increased early termination rates during the Extinction phase (26% of DMD group versus 0% of controls; P = 0.007). This study provides the first evidence that boys with DMD show similar increased unconditioned startle responses to threat to the mdx mouse, which in the mouse respond to brain dystrophin restoration. Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in DMD and defines an objective measure of this CNS phenotype, which will be valuable for future CNS-targeted dystrophin-restoration studies.

The Impact of Morbidities Following Pediatric Cardiac Surgery on Family Functioning and Parent Quality of Life.

We previously selected and defined nine important post-operative morbidities linked to paediatric cardiac surgery, and prospectively measured their incidence following 3090 consecutive operations. Our aim was to study the impact of these morbidities on family functioning and parental quality of life over 6 months in a subset of cases. As part of a prospective case matched study in five of the ten children's cardiac centers in the UK, we compared outcomes for parents of children who had a 'single morbidity', 'multiple morbidities', 'extracorporeal life support (ECLS)' or 'no morbidity'. Outcomes were evaluated using the PedsQL Family impact module (FIM) at 6 weeks and 6 months post-surgery. Outcomes were modelled using mixed effects regression, with adjustment for case mix and clustering within centers. We recruited 340 patients with morbidity (60% of eligible patients) and 326 with no morbidity over 21 months. In comparison to the reference group of 'no morbidity', after adjustment for case mix, at 6 weeks parent health-related quality of life (HRQoL) and total FIM sores were lower (worse) only for ECLS (p < 0.005), although a higher proportion of parents in both the ECLS and multi-morbidity groups had low/very low scores (p < .05). At 6 months, parent outcomes had improved for all groups but parent HRQoL and total score for ECLS remained lower than the 'no morbidity' group (p < .05) and a higher proportion of families had low or very low scores in the ECLS (70%) group (p < .01). Post-operative morbidities impact parent HRQoL and aspects of family functioning early after surgery, with this impact lessening by 6 months. Families of children who experience post-operative morbidities should be offered timely psychological support.

Prospective evaluation of acute neurological events after paediatric cardiac surgery.

OBJECTIVES: Children with CHD are at heightened risk of neurodevelopmental problems; however, the contribution of acute neurological events specifically linked to the perioperative period is unclear. AIMS: This secondary analysis aimed to quantify the incidence of acute neurological events in a UK paediatric cardiac surgery population, identify risk factors, and assess how acute neurological events impacted the early post-operative pathway. METHODS: Post-operative data were collected prospectively on 3090 consecutive cardiac surgeries between October 2015 and June 2017 in 5 centres. The primary outcome of analysis was acute neurological event, with secondary outcomes of 6-month survival and post-operative length of stay. Patient and procedure-related variables were described, and risk factors were statistically explored with logistic regression. RESULTS: Incidence of acute neurological events after paediatric cardiac surgery in our population occurred in 66 of 3090 (2.1%) consecutive cardiac operations. 52 events occurred with other morbidities including renal failure (21), re-operation (20), cardiac arrest (20), and extracorporeal life support (18). Independent risk factors for occurrence of acute neurological events were CHD complexity 1.9 (1.1-3.2), p = 0.025, longer operation times 2.7 (1.6-4.8), p < 0.0001, and urgent surgery 3.4 (1.8-6.3), p < 0.0001. Unadjusted comparison found that acute neurological event was linked to prolonged post-operative hospital stay (median 35 versus 9 days) and poorer 6-month survival (OR 13.0, 95% CI 7.2-23.8). CONCLUSION: Ascertainment of acute neurological events relates to local measurement policies and was rare in our population. The occurrence of acute neurological events remains a suitable post-operative metric to follow for quality assurance purposes.

Surgical Management of Submucous Cleft Palate by Radical Muscle Dissection Veloplasty: Speech Outcomes in Patients with 22q11.2 Deletion Syndrome.

OBJECTIVE: To evaluate the benefit of anatomical muscle dissection repair for velopharyngeal insufficiency (VPI) in patients with submucous cleft palate (SMCP) with 22q11.2 deletion syndrome. DESIGN: Retrospective blinded randomised analysis of a surgeon's management over 10 years. SETTING: The study was performed at a specialised Paediatric hospital in the United Kingdom. PATIENTS: Children with SMCP and 22q11.2 deletion syndrome. INTERVENTIONS: All participants underwent radical muscle dissection veloplasty. OUTCOMES MEASURED: Pre- and post- operative measurements included severity of anatomical defect, speech samples and lateral images which were digitised, randomised then externally and blindly analysed using validated techniques. Stata software was used to perform statistical analysis. RESULTS: 57 children with 22q11.2 deletion syndrome were included in this analysis. Intra-operatively, the majority of cases were identified as SMCP Grade I anomalies. Post-operatively, a statistically significant improvement in hypernasality, resting palate length, palate length at maximum closure, palate excursion and gap size at maximum closure was observed. Secondary surgery was performed for 59% of patients by ten years. CONCLUSION: Muscle dissection repair improves hypernasality, palate closure function and the closure gap in patients with 22q11.2 deletion syndrome. Although over 50% of patients may require further surgery, muscle dissection repair should be a first step due to its utility at a younger age, when invasive investigations are impossible, its lower morbidity, speech and language benefits or altering the plans for less obstructive secondary surgery when it lead to reduced velo-pharyngeal gap and improved palate mobility even when adequate velo-pharyngeal closure was not achieved.

The Relationship Between Postoperative Complications and Children's Quality of Life: A Mediation Analysis to Explore the Role of Family Factors.

OBJECTIVES: To explore whether postoperative morbidities after pediatric cardiac surgery affected children's health-related quality of life (HRQOL) at 6 months, through potentially modifiable parental psychological factors. DESIGN: We undertook a mediation analysis, to explore the causal pathway, based on data from a prospective, case-matched cohort study. PATIENTS: Six hundred sixty-six children undergoing cardiac surgery. SETTING: Five centers in the United Kingdom. INTERVENTIONS: No intervention. MEASUREMENTS AND MAIN RESULTS: Cases of morbidity were identified early after pediatric cardiac surgery, and matched controls with no morbidities were identified at discharge. Four mediators were assessed at 6 weeks after surgery, using the PedsQL Family Impact Module (Parent HRQOL and Family Function) and the PHQ-4 (Anxiety and Depression). The study outcome of child HRQOL was assessed at 6 months with the PedsQL. Of 666 children, 408 (65% of those surviving) contributed to the primary outcome. Children who had extracorporeal life support (ECLS) ( n = 11) ( p < 0.05) and multiple morbidities ( n = 62) ( p < 0.01) had worse 6-month HRQOL than those with a single morbidity ( n = 125) or no morbidity ( n = 209). After adjustment for case mix complexity and sociodemographic variables, there were significant indirect effects of parent HRQOL at 6 weeks, on the PedsQL Total Score (ECLS, -5.1 [-8.4 to -1.8]; p = 0.003; multiple morbidities, -2.1 [-3.7 to -0.5]; p = 0.01), PedsQL Physical Score (ECLS, -5.1 [-8.7 to -1.4]; p = 0.007; multiple morbidities, -2.1 [-3.8 to -0.4]; p = 0.016), and PedsQL Psychosocial Score (ECLS: -5.3 [-8.7 to -1.8); p = 0.003; multiple morbidities, -2.2 [-3.9 to -0.5]; p = 0.01). The proportion of the total effect of ECLS and multiple morbidity on the study outcomes mediated through parent HRQOL ranges between 18% and 61%. There was no evidence that the other three mediators had indirect effects on the study outcome. CONCLUSIONS: Parental HRQOL at 6 weeks after surgery contributes to child HRQOL at 6 months, among those with the severest types of morbidity, and as such should be a target for future interventions.

Quality of Life and Social and Psychological Outcomes in Adulthood Following Allogeneic HSCT in Childhood for Inborn Errors of Immunity.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) is well established as a corrective treatment for many inborn errors of immunity (IEIs) presenting in childhood. Due to improved techniques, more transplants are undertaken and patients are living longer. However, long-term complications can significantly affect future health and quality of life. Previous research has focused on short-term medical outcomes and little is known about health or psychosocial outcomes in adulthood. OBJECTIVE: This project aimed to ascertain the long-term social and psychological outcomes for adults who underwent HSCT for IEI during childhood. METHODS: Adult patients, who had all undergone HSCT for IEI during childhood at two specialist immunology services at least 5 years previously, were invited to participate in the study. Questionnaires and practical tasks assessed their current functioning and circumstances. Information was also gathered from medical notes. Data was compared with population norms and a control group of participant-nominated siblings or friends. RESULTS: Eighty-three patients and 46 matched controls participated in the study. Patients reported significantly better physical health-related quality of life than the general population norm, but significantly worse than matched controls. Patient's self-reported physical health status and the perceived impact of their physical health on everyday life were worse than matched controls and patients reported higher levels of anxiety and lower mood than the general population. For those where their IEI diagnosis was not associated with a learning disability, cognitive function was generally within the normal range. CONCLUSIONS: Patients who have had a HSCT in childhood report mixed psychosocial outcomes in adulthood. More research is needed to establish screening protocols and targeted interventions to maximize holistic outcomes. CLINICAL IMPLICATIONS: Screening for holistic needs and common mental health difficulties should be part of routine follow-up. Information should be provided to patients and families in order to support decision-making regarding progression to transplant and the early identification of any difficulties.

Retrospective, Landmark Analysis of Long-term Adult Morbidity Following Allogeneic HSCT for Inborn Errors of Immunity in Infancy and Childhood.

PURPOSE: Allogeneic hematopoietic stem cell transplant (HSCT) remains the treatment of choice for patients with inborn errors of immunity (IEI). There is little published medical outcome data assessing late medical complications following transition to adult care. We sought to document event-free survival (EFS) in transplanted IEI patients reaching adulthood and describe common late-onset medical complications and factors influencing EFS. METHODS: In this landmark analysis, 83 adults surviving 5 years or more following prior HSCT in childhood for IEI were recruited. The primary endpoint was event-free survival, defined as time post-first HSCT to graft failure, graft rejection, chronic infection, life-threatening or recurrent infections, malignancy, significant autoimmune disease, moderate to severe GVHD or major organ dysfunction. All events occurring less than 5 years post-HSCT were excluded. RESULTS: EFS was 51% for the whole cohort at a median of 20 years post HSCT. Multivariable analysis identified age at transplant and whole blood chimerism as independent predictors of long-term EFS. Year of HSCT, donor, conditioning intensity and underlying diagnosis had no significant impact on EFS. 59 events occurring beyond 5 years post-HSCT were documented in 37 patients (45% cohort). A total of 25 patients (30% cohort) experienced ongoing significant complications requiring active medical intervention at last follow-up. CONCLUSION: Although most patients achieved excellent, durable immune reconstitution with infrequent transplant-related complications, very late complications are common and associated with mixed chimerism post-HSCT. Early intervention to correct mixed chimerism may improve long-term outcomes and adult health following HSCT for IEI in childhood.

Patterns of anxiety and distress over 12 months following participation in HPV primary screening.

OBJECTIVES: Many countries are now using primary human papillomavirus (HPV) testing for cervical screening, testing for high-risk HPV and using cytology as triage. An HPV-positive result can have an adverse psychological impact, at least in the short term. In this paper, we explore the psychological impact of primary HPV screening over 12 months. METHODS: Women were surveyed soon after receiving their results (n=1133) and 6 (n=762) and 12 months (n=537) later. Primary outcomes were anxiety (Short-Form State Anxiety Inventory-6) and distress (General Health Questionnaire-12). Secondary outcomes included concern, worry about cervical cancer and reassurance. Mixed-effects regression models were used to explore differences at each time point and change over time across four groups according to their baseline result: control (HPV negative/HPV cleared/normal cytology and not tested for HPV); HPV positive with normal cytology; HPV positive with abnormal cytology; and HPV persistent (ie, second consecutive HPV-positive result). RESULTS: Women who were HPV positive with abnormal cytology had the highest anxiety scores at baseline (mean=42.2, SD: 15.0), but this had declined by 12 months (mean=37.0, SD: 11.7) and was closer to being within the 'normal' range (scores between 34 and 36 are considered 'normal'). This group also had the highest distress at baseline (mean=3.3, SD: 3.8, scores of 3+ indicate case-level distress), but the lowest distress at 12 months (mean=1.9, SD: 3.1). At 6 and 12 months, there were no between-group differences in anxiety or distress for any HPV-positive result group when compared with the control group. The control group were less concerned and more reassured about their result at 6 and 12 months than the HPV-positive with normal cytology group. CONCLUSIONS: Our findings suggest the initial adverse impact of an HPV-positive screening result on anxiety and distress diminishes over time. Specific concerns about the result may be longer lasting and efforts should be made to address them.

Genotype-related respiratory progression in Duchenne muscular dystrophy-A multicenter international study.

INTRODUCTION/AIMS: Mutations amenable to skipping of specific exons have been associated with different motor progression in Duchenne muscular dystrophy (DMD). Less is known about their association with long-term respiratory function. In this study we investigated the features of respiratory progression in four DMD genotypes relevant in ongoing exon-skipping therapeutic strategies. METHODS: This was a retrospective longitudinal study including DMD children followed by the UK NorthStar Network and international AFM Network centers (May 2003 to October 2020). We included boys amenable to skip exons 44, 45, 51, or 53, who were older than 5 years of age and ambulant at first recorded visit. Subjects who were corticosteroid-naive or enrolled in interventional clinical trials were excluded. The progression of respiratory function (absolute forced vital capacity [FVC] and calculated as percent predicted [FVC%]) was compared across the four subgroups (skip44, skip45, skip51, skip53). RESULTS: We included 142 boys in the study. Mean (standard deviation) age at first visit was 8.6 (2.5) years. Median follow-up was 3 (range, 0.3-8.3) years. In skip45 and skip51, FVC% declined linearly from the first recorded visit. From the age of 9 years, FVC% declined linearly in all genotypes. Skip44 had the slowest (2.7%/year) and skip51 the fastest (5.9%/year) annual FVC% decline. The absolute FVC increased progressively in skip44, skip45, and skip51. In skip53, FVC started declining from 14 years of age. DISCUSSION: The progression of respiratory dysfunction follows different patterns for specific genotype categories. This information is valuable for prognosis and for the evaluation of exon-skipping therapies.

Peak functional ability and age at loss of ambulation in Duchenne muscular dystrophy.

AIM: To correlate the North Star Ambulatory Assessment (NSAA) and timed rise from floor (TRF) recorded at age of expected peak with age at loss of ambulation (LOA) in Duchenne muscular dystrophy (DMD). METHOD: Male children with DMD enrolled in the UK North Start Network database were included according to the following criteria: follow-up longer than 3 years, one NSAA record between 6 years and 7 years 6 months (baseline), at least one visit when older than 8 years. Data about corticosteroid treatment, LOA, genotype, NSAA, and TRF were analysed. Age at LOA among the different groups based on NSAA and TRF was determined by log-rank tests. Cox proportional hazard models were used for multivariable analysis. RESULTS: A total of 293 patients from 13 different centres were included. Mean (SD) age at first and last visit was 5 years 6 months (1 year 2 months) and 12 years 8 months (2 years 11 months) (median follow-up 7 years 4 months). Higher NSAA and lower TRF at baseline were associated with older age at LOA (p<0.001). Patients scoring NSAA 32 to 34 had a probability of 0.61 of being ambulant when older than 13 years compared with 0.34 for those scoring 26 to 31. In multivariable analysis, NSAA, TRF, and corticosteroid daily regimen (vs intermittent) were all independently associated with outcome (p=0.01). INTERPRETATION: Higher functional abilities at peak are associated with older age at LOA in DMD. This information is important for counselling families. These baseline measures should also be considered when designing clinical trials.

The association of sensory phenotype and concomitant mood, sleep and functional impairment with the outcome of carpal tunnel surgery.

BACKGROUND: Up to 25% of people who have had carpal tunnel release surgery (CTR) fail to report improvement; however, evidence for prognostic indicators in this surgical cohort is limited. To identify candidate prognostic factors, this study investigated the association of quantitative sensory testing (QST) derived sensory phenotype and attendant impairment with patient-reported surgical outcome. METHODS: With ethical approval and informed consent, this prospective observational longitudinal study recruited patients from two London hospitals. Multimodal phenotyping measures including quantitative sensory testing (QST), pain parameters, insomnia, pain-related worry, mood and function, were evaluated prior to; and at 3- and 6-months post-surgery. Pain in median nerve distribution with electrophysiologically confirmed conduction delay and DN4 score ≥ 4 was defined as neuropathic. Primary outcome was patient-rated change at 6 months, dichotomised as poor outcome; "worse" or "no change" and good outcome; "slightly better", "much better" or "completely cured". RESULTS: Seventy-six patients participated. Prior to surgery, substantial heterogeneity in established categories of somatosensory function was observed with 21% of participants categorised as having a healthy sensory phenotype; 29% with thermal hyperalgesia; 32% mechanical hyperalgesia and 18% sensory loss. Seventy six percent of participants were classified as having neuropathic pain, 33% with high levels of pain related worry and 64% with clinical insomnia. Observed differences in pain, sleep impairment, psychological factors and function, between sensory phenotypic groups, was not significant. At 3- and 6-months post-surgery there was significant improvement in all phenotyping measures with a moderate to large effect size. Thermal and mechanical measures of somatosensation improved (p < 0.001), as did functional ability (p < 0.001). Symptom severity diminished (p < 0.001), as did pain-related worry (p < 0.001), anxiety (p = 0.02) and insomnia (p < 0.001). Patient-rated surgical outcome was good in 92% of the cohort, poor in 8%. Baseline sensory phenotype category was not associated with surgical outcome however pain-related worry, anxiety and functional interference were significantly associated with outcome (p ≤ 0.05). CONCLUSION: In patients undergoing carpal tunnel surgery, pain-related worry, anxiety and pain functional interference are candidate prognostic outcome factors and require further elucidation.

Anxiety and distress following receipt of results from routine HPV primary testing in cervical screening: The psychological impact of primary screening (PIPS) study.

We used a cross-sectional survey to examine short-term anxiety and distress in women receiving different results following routine human papillomavirus (HPV) primary testing at cervical screening. Participants were women aged 24-65 (n = 1,127) who had attended screening at one of five sites piloting HPV primary screening in England, including a control group with normal cytology who were not tested for HPV. Women completed a postal questionnaire ~2 weeks after receiving their screening result. Unadjusted mean anxiety scores ranged from 32.9 (standard deviation [SD] = 12.2) in HPV-negative women to 42.1 (SD = 14.9) in women who were HPV-positive with abnormal cytology. In adjusted analyses, anxiety was significantly higher in women testing HPV-positive with either normal cytology (mean difference [MD] = 3.5, CI: 0.6-6.4) or abnormal cytology (MD = 7.2, CI: 3.7-10.6), than the control group. Distress was slightly higher in women who tested HPV-positive with abnormal cytology (MD = 0.9, CI: 0.02-1.8), than the control group. We also found increased odds of very high anxiety in women who tested HPV-positive with normal or abnormal cytology compared to the control group. This pattern of results was only observed among women receiving their first HPV-positive result, not among women found to have persistent HPV at 12-month follow-up. Testing HPV-positive with normal cytology for the first time, is associated with elevated anxiety despite carrying very low immediate cervical cancer risk. However, receiving the same test result at 12-month early recall does not appear to be associated with higher anxiety, suggesting anxiety may normalise with repeated exposure and/or over time.

Predicting developmental dysplasia of the hip in at-risk newborns.

BACKGROUND: The development of developmental dysplasia of the hip can be attributed to several risk factors and often in combination with each other. When predicting the likelihood of developing this condition, clinicians tend to over and underestimate its likelihood of occurring. Therefore, the study aim is to determine among at-risk newborns how to best predict developmental dysplasia of the hip (DDH) within 8 weeks post-partum. METHODS: Prospective cohort study in secondary care. Patient population included newborns at-risk for DDH - we assessed 13,276 consecutive newborns for the presence of DDH risk factors. Only newborns with at least one of the predefined risk factors and those showing an abnormal examination of the hip were enrolled (n = 2191). For the development of a risk prediction model we considered 9 candidate predictors and other variables readily available at childbirth. The main outcome measure was ultrasonography at a median age of 8 weeks using consensus diagnostic criteria; outcome assessors were blinded. RESULTS: The risk model includes four predictors: female sex (OR = 5.6; 95% CI: 2.9-10.9; P <  0.001); first degree family history of DDH (OR = 4.5; 95% CI: 2.3-9.0; P <  0.001), birthweight > 4000 g (OR = 1.6; 95% CI: 0.6-4.2; P = 0.34), and abnormal examination of hip (OR = 58.8; 95% CI: 31.9, 108.5; P <  0.001). This model demonstrated excellent discrimination (C statistic = 0.9) and calibration of observed and predicted risk (P = 0.35). A model without the variable 'hip examination' demonstrated similar performance. CONCLUSION: The risk model quantifies absolute risk of DDH within 8 weeks postpartum in at-risk newborns. Based on clinical variables readily available at the point of childbirth, the model will enhance parental counselling and could serve as the basis for real time decisions prior to discharge from maternity wards.

Cross-sectional study of a United Kingdom cohort of neonatal vein of galen malformation.

OBJECTIVE: Describe the course and outcomes in a UK national cohort of neonates with vein of Galen malformation identified before 28 days of life. METHODS: Neonates with angiographically confirmed vein of Galen malformation presenting to 1 of 2 UK treatment centers (2006-2016) were included; those surviving were invited to participate in neurocognitive assessment. Results in each domain were dichotomized into "good" and "poor" categories. Cross-sectional and angiographic brain imaging studies were systematically interrogated. Logistic regression was used to explore potential outcome predictors. RESULTS: Of 85 children with neonatal vein of Galen malformation, 51 had survived. Thirty-four participated in neurocognitive assessment. Outcomes were approximately evenly split between "good" and "poor" categories across all domains, namely, neurological status, general cognition, neuromotor skills, adaptive behavior, and emotional and behavioral development. Important predictors of poor cognitive outcome were initial Bicêtre score ≤ 12 and presence of brain injury, specifically white matter injury, on initial imaging; in multivariate analysis, only Bicêtre score ≤ 12 remained significant. INTERPRETATION: Despite modern supportive and endovascular treatment, more than one-third of unselected newborns with vein of Galen malformation did not survive. Outcome was good in around half of survivors. The importance of white matter injury suggests that abnormalities of venous as well as arterial circulation are important in the pathophysiology of brain injury. Ann Neurol 2018;84:547-555.

Extracorporeal Membrane Oxygenation for Pertussis: Predictors of Outcome Including Pulmonary Hypertension and Leukodepletion.

OBJECTIVE: The recent increase of pertussis cases worldwide has generated questions regarding the utility of extracorporeal membrane oxygenation for children with pertussis. We aimed to evaluate factors associated with extracorporeal membrane oxygenation outcome. DESIGN: The study was designed in two parts: a retrospective analysis of the Extracorporeal Life Support Organization Registry to identify factors independently linked to outcome, and an expanded dataset from individual institutions to examine the association of WBC count, pulmonary hypertension, and leukodepletion with survival. SETTING: Extracorporeal Life Support Organization Registry database from 2002 though 2015, and contributions from 19 international centers. PATIENTS: Two hundred infants from the Extracorporeal Life Support Organization Registry and expanded data on 73 children. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 200 infants who received extracorporeal membrane oxygenation for pertussis, only 56 survived (28%). In a multivariable logistic regression analysis, the following variables were independently associated with increased chance of survival: older age (odds ratio, 1.43 [1.03-1.98]; p = 0.034), higher PaO2/FIO2 ratio (odds ratio, 1.10 [1.03-1.17]; p = 0.003), and longer intubation time prior to the initiation of extracorporeal membrane oxygenation (odds ratio, 2.10 [1.37-3.22]; p = 0.001). The use of vasoactive medications (odds ratio, 0.33 [0.11-0.99]; p = 0.047), and renal neurologic or infectious complications (odds ratio, 0.21 [0.08-0.56]; p = 0.002) were associated with increased mortality. In the expanded dataset (n =73), leukodepletion was independently associated with increased chance of survival (odds ratio, 3.36 [1.13-11.68]; p = 0.03) while the presence of pulmonary hypertension was adverse (odds ratio, 0.06 [0.01-0.55]; p = 0.01). CONCLUSIONS: The survival rate for infants with pertussis who received extracorporeal membrane oxygenation support remains poor. Younger age, lower PaO2/FIO2 ratio, vasoactive use, pulmonary hypertension, and a rapidly progressive course were associated with increased mortality. Our results suggest that pre-extracorporeal membrane oxygenation leukodepletion may provide a survival advantage.

Development and preliminary testing of the Brief Developmental Assessment: an early recognition tool for children with heart disease.

Introduction Neurodevelopmental abnormalities are common in children with CHD and are the highest-priority concerns for parents and professionals following cardiac surgery in childhood. There is no additional routine monitoring of development for children with CHD in the United Kingdom; hence, neurodevelopmental concerns may be detected late, precluding early referral and intervention. METHODS: An early recognition tool - the "Brief Developmental Assessment" - was developed using quality improvement methodology involving several iterations and rounds of pilot testing. Our requirements were for a tool covering important developmental domains and practicable for use within inpatient and outpatient settings by paediatric cardiac health professionals who are non-developmental specialists, without specialised equipment and which involved direct observation, as well as parental report. RESULTS: Items were included in the tool based on existing developmental measures, covering the domains of gross and fine motor skills, daily living skills, communication, socialisation, and general understanding. Items were developed for five age bands - 0-16 weeks, 17-34 weeks, 35-60 weeks, 15 months-2.9 years, and 3-4.9 years - and the final versions included a traffic light scoring system for identifying children with possible delay in any or all domains. Preliminary testing indicated excellent inter-rater reliability, an ability to detect children with a diagnosis known to be associated with developmental delay, and largely acceptable internal reliability. CONCLUSION: We report the evolution and preliminary testing of an early recognition tool for assessing the development of children with heart disease; this was encouraging and sufficiently good to support further validation in a larger study.

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.