A human importin-ß-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-ß protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-ß signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8-/- mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-ß signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8-/- mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-ß signaling pathway in TAA development. Because importin 8 is the most downstream TGF-ß-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.

Characterisation of infantile cardiomyopathy in Alström syndrome using ALMS1 knockout induced pluripotent stem cell derived cardiomyocyte model.

Alström syndrome (AS) is an inherited rare ciliopathy characterised by multi-organ dysfunction and premature cardiovascular disease. This may manifest as an infantile-onset dilated cardiomyopathy with significant associated mortality. An adult-onset restrictive cardiomyopathy may also feature later in life. Loss of function pathogenic variants in ALMS1 have been identified in AS patients, leading to a lack of ALMS1 protein. The biological role of ALMS1 is unknown, particularly in a cardiovascular context. To understand the role of ALMS1 in infantile cardiomyopathy, the reduction of ALMS1 protein seen in AS patients was modelled using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), in which ALMS1 was knocked out. MuscleMotion analysis and calcium optical mapping experiments suggest that ALMS1 knockout (KO) cells have increased contractility, with altered calcium extrusion and impaired calcium handling dynamics compared to wildtype (WT) counterparts. Seahorse metabolic assays showed ALMS1 knockout iPSC-CMs had increased glycolytic and mitochondrial respiration rates, with ALMS1 knockout cells portraying increased energetic demand and respiratory capacity than WT counterparts. Using senescence associated ß-galactosidase (SA-ß gal) staining assay, we identified increased senescence of ALMS1 knockout iPSC-CMs. Overall, this study provides insights into the molecular mechanisms in AS, particularly the role of ALMS1 in infantile cardiomyopathy in AS, using iPSC-CMs as a 'disease in a dish' model to provide insights into multiple aspects of this complex disease.

Acute Cardiovascular Manifestations in 286 Children With Multisystem Inflammatory Syndrome Associated With COVID-19 Infection in Europe.

BACKGROUND: The aim of the study was to document cardiovascular clinical findings, cardiac imaging, and laboratory markers in children presenting with the novel multisystem inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) infection. METHODS: This real-time internet-based survey has been endorsed by the Association for European Paediatric and Congenital Cardiologists Working Groups for Cardiac Imaging and Cardiovascular Intensive Care. Children 0 to 18 years of age admitted to a hospital between February 1 and June 6, 2020, with a diagnosis of an inflammatory syndrome and acute cardiovascular complications were included. RESULTS: A total of 286 children from 55 centers in 17 European countries were included. The median age was 8.4 years (interquartile range, 3.8-12.4 years) and 67% were boys. The most common cardiovascular complications were shock, cardiac arrhythmias, pericardial effusion, and coronary artery dilatation. Reduced left ventricular ejection fraction was present in over half of the patients, and a vast majority of children had raised cardiac troponin when checked. The biochemical markers of inflammation were raised in most patients on admission: elevated C-reactive protein, serum ferritin, procalcitonin, N-terminal pro B-type natriuretic peptide, interleukin-6 level, and D-dimers. There was a statistically significant correlation between degree of elevation in cardiac and biochemical parameters and the need for intensive care support (P<0.05). Polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 was positive in 33.6%, whereas immunoglobulin M and immunoglobulin G antibodies were positive in 15.7% cases and immunoglobulin G in 43.6% cases, respectively, when checked. One child in the study cohort died. CONCLUSIONS: Cardiac involvement is common in children with multisystem inflammatory syndrome associated with the Covid-19 pandemic. The majority of children have significantly raised levels of N-terminal pro B-type natriuretic peptide, ferritin, D-dimers, and cardiac troponin in addition to high C-reactive protein and procalcitonin levels. In comparison with adults with COVID-19, mortality in children with multisystem inflammatory syndrome associated with COVID-19 is uncommon despite multisystem involvement, very elevated inflammatory markers, and the need for intensive care support.

Vitamin D status of children with paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS).

Coronavirus disease 2019 (COVID-19) has caused mild illness in children, until the emergence of the novel hyperinflammatory condition paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS). PIMS-TS is thought to be a post-SARS-CoV-2 immune dysregulation with excessive inflammatory cytokine release. We studied 25 hydroxyvitamin D (25OHD) concentrations in children with PIMS-TS, admitted to a tertiary paediatric hospital in the UK, due to its postulated role in cytokine regulation and immune response. Eighteen children (median (range) age 8·9 (0·3-14·6) years, male = 10) met the case definition. The majority were of Black, Asian and Minority Ethnic (BAME) origin (89 %, 16/18). Positive SARS-CoV-2 IgG antibodies were present in 94 % (17/18) and RNA by PCR in 6 % (1/18). Seventy-eight percentage of the cohort were vitamin D deficient (< 30 nmol/l). The mean 25OHD concentration was significantly lower when compared with the population mean from the 2015/16 National Diet and Nutrition Survey (children aged 4-10 years) (24 v. 54 nmol/l (95 % CI -38·6, -19·7); P < 0·001). The paediatric intensive care unit (PICU) group had lower mean 25OHD concentrations compared with the non-PICU group, but this was not statistically significant (19·5 v. 31·9 nmol/l; P = 0·11). The higher susceptibility of BAME children to PIMS-TS and also vitamin D deficiency merits contemplation. Whilst any link between vitamin D deficiency and the severity of COVID-19 and related conditions including PIMS-TS requires further evidence, public health measures to improve vitamin D status of the UK BAME population have been long overdue.

Paediatric Inflammatory Multisystem Syndrome: Temporally Associated with SARS-CoV-2 (PIMS-TS): Cardiac Features, Management and Short-Term Outcomes at a UK Tertiary Paediatric Hospital.

Children were relatively spared during COVID-19 pandemic. However, the recently reported hyperinflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome-"Paediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2" (PIMS-TS) has caused concern. We describe cardiac findings and short-term outcomes in children with PIMS-TS at a tertiary children's hospital. Single-center observational study of children with PIMS-TS from 10th April to 9th May 2020. Data on ECG and echocardiogram were retrospectively analyzed along with demographics, clinical features and blood parameters. Fifteen children with median age of 8.8 (IQR 6.4-11.2) years were included, all were from African/Afro-Caribbean, South Asian, Mixed or other minority ethnic groups. All showed raised inflammatory/cardiac markers (CRP, ferritin, Troponin I, CK and pro-BNP). Transient valve regurgitation was present in 10 patients (67%). Left Ventricular ejection fraction was reduced in 12 (80%), fractional shortening in 8 (53%) with resolution in all but 2. Fourteen (93%) had coronary artery abnormalities, with normalization in 6. ECG abnormalities were present in 9 (60%) which normalized in 6 by discharge. Ten (67%) needed inotropes and/or vasopressors. None needed extracorporeal life support. Improvement in cardiac biochemical markers was closely followed by improvement in ECG/echocardiogram. All patients were discharged alive and twelve (80%) have been reviewed since. Our entire cohort with PIMS-TS had cardiac involvement and this degree of involvement is significantly more than other published series and emphasizes the need for specialist cardiac review. We believe that our multi-disciplinary team approach was crucial for the good short-term outcomes.

Cardiac, bone and growth plate manifestations in hypocalcemic infants: revealing the hidden body of the vitamin D deficiency iceberg.

BACKGROUND: Whilst hypocalcemic complications from vitamin D deficiency are considered rare in high-income countries, they are highly prevalent among Black, Asian and Minority Ethnic (BAME) group with darker skin. To date, the extent of osteomalacia in such infants and their family members is unknown. Our aim was to investigate clinical, cardiac and bone histomorphometric characteristics, bone matrix mineralization in affected infants and to test family members for biochemical evidence of osteomalacia. CASE PRESENTATION: Three infants of BAME origin (aged 5-6 months) presented acutely in early-spring with cardiac arrest, respiratory arrest following seizure or severe respiratory distress, with profound hypocalcemia (serum calcium 1.22-1.96 mmol/L). All infants had dark skin and vitamin D supplementation had not been addressed during child surveillance visits. All three had severely dilated left ventricles (z-scores + 4.6 to + 6.5) with reduced ejection fraction (25-30%; normal 55-70), fractional shortening (7 to 15%; normal 29-40) and global hypokinesia, confirming hypocalcemic dilated cardiomyopathy. They all had low serum levels of 25 hydroxyvitamin D (25OHD < 15 nmol/L), and elevated parathyroid hormone (PTH; 219-482 ng/L) and alkaline phosphatase (ALP; 802-1123 IU/L), with undiagnosed rickets on radiographs. One infant died from cardiac arrest. At post-mortem examination, his growth plate showed a widened, irregular zone of hypertrophic chondrocytes. Histomorphometry and backscattered electron microscopy of a trans-iliac bone biopsy sample revealed increased osteoid thickness (+ 262% of normal) and osteoid volume/bone volume (+ 1573%), and extremely low bone mineralization density. Five of the nine tested family members had vitamin D deficiency (25OHD < 30 nmol/L), three had insufficiency (< 50 nmol/L) and 6/9 members had elevated PTH and ALP levels. CONCLUSIONS: The severe, hidden, cardiac and bone pathology described here exposes a failure of public health prevention programs, as complications from vitamin D deficiency are entirely preventable by routine supplementation. The family investigations demonstrate widespread deficiency and undiagnosed osteomalacia in ethnic risk groups and call for protective legislation.

Assessment of myocardial function in preterm infants with patent ductus arteriosus using tissue Doppler imaging.

OBJECTIVE: To assess myocardial function in preterm infants with different degrees of ductal patency in the first week of life using tissue Doppler imaging. STUDY DESIGN: Infants <30 weeks of gestation underwent echocardiography on day 3. A total of 72 infants were recruited into the study and categorised into three groups (i) haemodyamically significant ductus arteriosus, (ii) patent ductus arteriosus and (iii) no patent ductus arteriosus. Those with haemodynamically significant ductus arteriosus were treated with indometacin and echocardiography was repeated after 48-72 hours following treatment. Peak systolic and diastolic myocardial velocities were obtained using tissue Doppler imaging, and myocardial performance index was calculated. RESULTS: Initial myocardial velocities were significantly lower and myocardial performance index significantly higher in the haemodynamically significant ductus arteriosus group compared with other groups. For the haemodynamically significant ductus arteriosus group, post-treatment myocardial velocities were higher and myocardial performance index lower than pre-treatment. CONCLUSION: Preterm infants with haemodynamically significant ductus arteriosus had lower myocardial velocities and higher myocardial performance index, suggesting relative systolic and diastolic myocardial dysfunction. Babies whose patent ductus arteriosus remained open despite indometacin had lower pre-treatment myocardial velocities and higher myocardial performance index than those babies whose patent ductus arteriosus closed, suggesting worse myocardial function in this group. Measurement of myocardial function using tissue Doppler imaging in preterm infants is feasible and may prove to be helpful in the management of babies with patent ductus arteriosus.

COVID-19 in congenital heart disease (COaCHeD) study.

BACKGROUND: COVID-19 has caused significant worldwide morbidity and mortality. Congenital heart disease (CHD) is likely to increase vulnerability and understanding the predictors of adverse outcomes is key to optimising care. OBJECTIVE: Ascertain the impact of COVID-19 on people with CHD and define risk factors for adverse outcomes. METHODS: Multicentre UK study undertaken 1 March 2020-30 June 2021 during the COVID-19 pandemic. Data were collected on CHD diagnoses, clinical presentation and outcomes. Multivariable logistic regression with multiple imputation was performed to explore predictors of death and hospitalisation. RESULTS: There were 405 reported cases (127 paediatric/278 adult). In children (age <16 years), there were 5 (3.9%) deaths. Adjusted ORs (AORs) for hospitalisation in children were significantly lower with each ascending year of age (OR 0.85, 95% CI 0.75 to 0.96 (p<0.01)). In adults, there were 24 (8.6%) deaths (19 with comorbidities) and 74 (26.6%) hospital admissions. AORs for death in adults were significantly increased with each year of age (OR 1.05, 95% CI 1.01 to 1.10 (p<0.01)) and with pulmonary arterial hypertension (PAH; OR 5.99, 95% CI 1.34 to 26.91 (p=0.02)). AORs for hospitalisation in adults were significantly higher with each additional year of age (OR 1.03, 95% CI 1.00 to 1.05 (p=0.04)), additional comorbidities (OR 3.23, 95% CI 1.31 to 7.97 (p=0.01)) and genetic disease (OR 2.87, 95% CI 1.04 to 7.94 (p=0.04)). CONCLUSIONS: Children were at low risk of death and hospitalisation secondary to COVID-19 even with severe CHD, but hospital admission rates were higher in younger children, independent of comorbidity. In adults, higher likelihood of death was associated with increasing age and PAH, and of hospitalisation with age, comorbidities and genetic disease. An individualised approach, based on age and comorbidities, should be taken to COVID-19 management in patients with CHD.

Cardiac care of children with dystrophinopathy and females carrying DMD-gene variations.

OBJECTIVE: We provide succinct, evidence-based and/or consensus-based best practice guidance for the cardiac care of children living with Duchenne muscular dystrophy (DMD) as well as recommendations for screening and management of female carriers of mutations in the DMD-gene. METHODS: Initiated by an expert working group of UK-based cardiologists, neuromuscular clinicians and DMD-patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK-cardiologists, consensus was reached on these best-practice recommendations for cardiac care in DMD. RESULTS: The resulting recommendations are presented in the form of a succinct care pathway flow chart with brief justification. The guidance signposts evidence on which they are based and acknowledges where there have been differences in opinion. Guidelines for cardiac care of patients with more advanced cardiac dystrophinopathy at any age have also been considered, based on the previous published work of Quinlivan et al and are presented here in a similar format. The recommendations have been endorsed by the British Cardiovascular Society. CONCLUSION: These guidelines provide succinct, reasoned recommendations for all those managing paediatric patients with early or advanced stages of cardiomyopathy as well as females with cardiac dystrophinopathy. The hope is that this will result in more uniform delivery of high standards of care for children with cardiac dystrophinopathy, so improving heart health into adulthood through timely earlier interventions across the UK.

Critical Care Course of Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 and Response to Immunomodulation.

We describe the critical care course of children with a novel hyperinflammatory syndrome associated with coronavirus disease 2019 (COVID-19) pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with focus on trajectory before and after immunomodulation. Overall, 10 patients who met the U.K. Royal College of Pediatrics and Child Health case definition during a 2-month study period were analyzed. All tested positive for SARS-CoV-2 IgG antibody. Although only 20% were ventilated, 100% required inotropic or vasopressor support. All children had significantly raised inflammatory markers with a median C-reactive protein of 248 (175-263) mg/L, ferritin of 1,561 (726-2,255) µg/L, and troponin-I of 723 (351-2,235) ng/L. Six patients had moderately impaired myocardial function and two had severe impairment. None needed extracorporeal membrane oxygenation. Despite severe illness only a brief period of critical care support of 3 to 5 days was required. Eight received at least one dose of intravenous immunoglobulin. Six received high-dose steroids. Clinical improvement including cardiovascular stability and reduction in inflammatory markers may have occurred with and without immunomodulation.

Transcatheter interventions in the early postoperative period after the Fontan procedure.

OBJECTIVE: To analyze the safety and clinical impact of interventional cardiac catheter procedures in the management of early postoperative problems after completion of an extracardiac Fontan procedure. BACKGROUND: The mortality after Fontan procedure has consistently decreased over the last decade. The role of interventional catheterization to address early postoperative problems in this setting has not been studied systematically. METHODS: Over a 9.7-year period, 289 patients underwent an extracardiac fenestrated Fontan procedure with two early deaths (0.7%) and takedown in four (1.4%). Twenty-seven patients (9.3%) underwent 32 interventional cardiac catheter procedures at a median interval of 12.2 (1-30) days. The median weight was 14.5 (13.5-25) kg. The case notes and procedure records were reviewed retrospectively. RESULTS: Fontan pathway obstructions were treated in 11 patients with stent implantation with good results and no complications. Stent fenestration of the Fontan circulation was performed in 16 patients with one episode of transient hemiparesis and one episode of pericardial effusion. Three patients underwent initial balloon dilatation of branch pulmonary arteries or fenestration with little effect and underwent stent treatment 6 (5-9) days later. One patient had device closure of a large atrial fenestration. In one patient, residual anterograde pulmonary blood flow was occluded using a device. There were no deaths and in-hospital course was improved in all. CONCLUSION: Interventional cardiac catheter procedures can be performed safely and effectively in the early postoperative period after Fontan completion to address hemodynamic problems. These techniques contribute significantly to achieve a very low mortality and address morbidity after Fontan completion.

Association of Ethnicity With Multisystem Inflammatory Syndrome in Children Related to SARS-CoV-2 Infection: An International Case-Referent Study.

Background: It has been suggested that children and infants can develop multisystem inflammatory syndrome in children (MIS-C) in response to a SARS-CoV-2 infection and that Black children are overrepresented among cases. The aim of the current study was to quantify the association between Black, Asian, or other non-White genetic background and COVID-19-related MIS-C in children and infants. Methods: Eight different research groups contributed cases of MIS-C, potentially related to SARS-CoV-2 infection. Several sensitivity analyses were performed, including additional data available from the literature. Analyses were stratified by geographical region. Results: Seventy-three cases from nine distinct geographical regions were included in the primary analyses. In comparison to White children, the relative risk for developing MIS-C after SARS-CoV-2 infection was 15 [95% confidence interval (CI): 7.1 to 32] for Black children, 11 (CI: 2.2 to 57) for Asian, and 1.6 (CI: 0.58 to 4.2) for other ethnic background. Conclusion: Pediatricians should be aware of the fact that the risk of COVID-19-related MIS-C is severely increased in Black children.

The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells, with increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL-6 may be preferable to IL-1 or TNF-α. We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease.

Serology confirms SARS-CoV-2 infection in PCR-negative children presenting with Paediatric Inflammatory Multi-System Syndrome.

BACKGROUND: During the COVID-19 outbreak, reports have surfaced of children who present with features of a multisystem inflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome - Paediatric Inflammatory Multisystem Syndrome- temporally associated with SARS-CoV-2 pandemic (PIMS-TS). Initial reports find that many of the children are PCR-negative for SARS-CoV-2, so it is difficult to confirm whether this syndrome is a late complication of viral infection in an age group largely spared the worst consequences of this infection, or if this syndrome reflects enhanced surveillance. METHODS: Children hospitalised for symptoms consistent with PIMS-TS between 28 April and 8 May 2020, and who were PCR-negative for SARS-CoV-2, were tested for antibodies to viral spike glycoprotein using an ELISA test. RESULTS: Eight patients (age range 7-14 years, 63% male) fulfilled case-definition for PIMS-TS during the study period. Six of the eight patients required admission to intensive care. All patients exhibited significant IgG and IgA responses to viral spike glycoprotein. Further assessment showed that the IgG isotypes detected in children with PIMS-TS were of the IgG1 and IgG3 subclasses, a distribution similar to that observed in samples from hospitalised adult COVID-19 patients. In contrast, IgG2 and IgG4 were not detected in children or adults. IgM was not detected in children, which contrasts with adult hospitalised adult COVID-19 patients of whom all had positive IgM responses. CONCLUSIONS: Strong IgG antibody responses can be detected in PCR-negative children with PIMS-TS. The low detection rate of IgM in these patients is consistent with infection having occurred weeks previously and that the syndrome onset occurs well after the control of SARS-CoV-2 viral load. This implies that the disease is largely immune-mediated. Lastly, this indicates that serology can be an appropriate diagnostic tool in select patient groups.

Prostaglandin E 2 in a preterm infant with coarctation of the aorta.

Prostaglandins are widely used in aortic coarctation to maintain ductal patency and preserve systemic perfusion until surgical intervention can be performed. Although the short-term use of prostaglandins to ameliorate aortic narrowing in neonates with a closed ductus has been reported, it has not been described as a longer term therapy in extremely preterm neonates. A 27-week gestation baby weighing 560 g presented at 40 days of age with coarctation and a closed ductus arteriosus. He was successfully treated with a 7-week course of prostaglandin E2 therapy because surgical intervention was not deemed feasible in view of his size. Treatment resulted in a relaxation of the aortic constriction and improvement in aortic blood flow velocity profile, highlighting the value of long-term prostaglandin therapy in this population and supporting the hypothesis that the presence of ductal tissue contributes to the development of juxtaductal aortic constriction in some extremely preterm infants.

Randomised placebo-controlled trial of combination ACE inhibitor and beta-blocker therapy to prevent cardiomyopathy in children with Duchenne muscular dystrophy? (DMD Heart Protection Study): a protocol study.

INTRODUCTION: Although cardiologists were 'late-comers' to the multidisciplinary team-contributing to the complex care of patients with Duchenne muscular dystrophy (DMD), they now recognise the importance of systematic cardiac surveillance and timely therapy to prolonged survival in patients with DMD. Empirical deployment of cardioactive medications has already improved outcomes, but the evidence base for clinical decision making is weak. Fundamental questions remain as to whether prophylactic therapy is justified and convincingly superior to prompt deployment of the same therapies once left ventricular (LV) dysfunction is detected. Even if it were, at what age should therapy be introduced and with what specific drugs? METHODS AND ANALYSIS: We are conducting a multicentre, parallel group, randomised, placebo-controlled study of combination therapy with an ACE inhibitor (perindopril) and a beta-blocker (bisoprolol) in boys with DMD aged 5-13 years, with normal LV function by echocardiographic criteria at the time of recruitment. Boys are being followed-up for a minimum of 3 years and a maximum of 5 years and undergo repeat assessments of LV function, heart rate and ECG, forced expiratory volume in the 1 s and forced vital capacity, adverse event reporting and quality of life at 6 monthly intervals.The primary outcome is change in LV function between active and placebo-treated participants over the course of the study. ETHICS AND DISSEMINATION: The study was approved by 'NRES Committee East Midlands - Derby'. The results will be disseminated through manuscript publications, an international workshop and presentations to scientific meetings and parent forums. TRANSLATIONAL ASPECTS: The study seeks to establish the evidence for prophylactic heart therapies for children with DMD, define the optimum age for their introduction and identify any safety concerns. ARTICLE SUMMARY: The protocol describes the design of an ongoing multicentre, double-blind, randomised placebo-controlled study to establish the evidence for the use of prophylactic heart therapies in children with DMD, define the optimum age for their introduction and identify any safety concerns. TRIAL REGISTRATION NUMBERS: EudraCT2007-005932-10 and ISRCTN50395346; Pre-results.

Duchenne muscular dystrophy: the management of scoliosis.

This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group.

Predicting complications with pretreatment testing in infantile haemangioma treated with oral propranolol.

BACKGROUND: Since 2008, orally administered propranolol has rapidly gained acceptance as the preferred therapy for haemangiomas, and is usually initiated by ophthalmologists, dermatologists or plastic surgeons who do not routinely use propranolol for any other indication. During the initial years when experience was limited, most healthcare professionals justifiably adopted a cautious approach when initiating and monitoring treatment. A consensus recommendation from the American Society of Dermatologists suggests routine observation, monitoring and cardiology assessments prior to propranolol initiation. AIM: This study aims to analyse treatment initiation in a large tertiary children's hospital and investigate the value of pretreatment testing in predicting commonly seen adverse reactions of propranolol. METHOD: 104 eligible patients treated between January 2009 and July 2012 were included. All patients underwent pretesting either with protocol A (administration of test dose with routine observations) or protocol B (cardiology clinic assessment, including two-dimensional echocardiography without test dose). RESULTS: 38.5% (40/104) of patients developed adverse reactions during treatment; however, there were no severe or life-threatening reactions. Protocol A has a sensitivity of 0 (95% CI 0 to 0.17) and specificity of 0.95 (95% CI 0.83 to 0.99). Protocol B has a sensitivity of 0.07 (95% CI 0 to 0.34) and specificity of 0.86 (95% CI 0.63 to 0.96). CONCLUSIONS: The predictive values of both protocols for the commonly observed adverse reactions are low. In this series, there is no evidence to suggest that routine pretreatment testing before propranolol initiation is of any value in otherwise healthy children.

Twenty-year outcome of anomalous origin of left coronary artery from pulmonary artery: management of mitral regurgitation.

BACKGROUND: This study is a single-center experience with surgical repair of anomalous origin of left coronary artery from pulmonary artery (ALCAPA) with focus on the management of associated mitral regurgitation (MR). METHODS: We performed a retrospective analysis of cases presenting to a quaternary referral center between November 1990 and October 2011. RESULTS: In all, 25 patients (18 female) presented with a diagnosis of ALCAPA at a median age of 5 months (range, 1.5 to 102). Twenty-one patients (84%) had moderate to severe impairment of left ventricular function with median fractional shortening of 14% (range, 2% to 33%), and 19 patients (76%) had moderate to severe MR. Surgery was performed with direct coronary reimplantation in 16 patients (64%) and intrapulmonary tunnel (Takeuchi repair) in 9 (36%). Four patients had mitral valve repair at time of surgery, all for structural anomalies. Functional MR with a structurally normal mitral valve was not repaired. The median duration of postoperative follow-up was 93 months (range, 9 to 240). There were no early or late deaths, and no patient required mechanical support. Four patients (16%) required surgical or catheter reintervention. At last follow-up, 24 of 25 patients were asymptomatic; the left ventricular function was normal in 22 patients. Moderate MR was present in 4 patients. There was significant improvement in left ventricular function and MR (p < 0.01) during follow-up. CONCLUSIONS: Surgical repair of ALCAPA has good long-term results with low mortality and reintervention rates. The majority of MR is functional and will improve with reperfusion, but structural mitral valve abnormalities should be repaired at the time of surgery.