Seoul National University Children's Hospital

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy. Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1, which are restricted to Group 3. Medulloblastoma is the most common malignant brain tumour in children. Four papers published in the 2 August 2012 issue of Nature use whole-genome and other sequencing techniques to produce a detailed picture of the genetics and genomics of this condition. Notable findings include the identification of recurrent mutations in genes not previously implicated in medulloblastoma, with significant genetic differences associated with the four biologically distinct subgroups and clinical outcomes in each. Potential avenues for therapy are suggested by the identification of targetable somatic copy-number alterations, including recurrent events targeting TGFβ signalling in Group 3, and NF-κB signalling in Group 4 medulloblastomas.

Abstract Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3–6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.

Growth charts are curves or tables that facilitate the visualization of anthropometric parameters, and are widely used as an important indicator when evaluating the growth status of children and adolescents. The latest version of the Korean National Growth Charts released in 2007 has raised concerns regarding the inclusion of data from both breastfed and formula-fed infants, higher body mass index (BMI) values in boys, and smaller 3rd percentile values in height-for-age charts. Thus, new growth charts have been developed to improve the previous version. The 2006 World Health Organization Child Growth Standards, regarded as the standard for breastfed infants and children, were introduced for children aged 0–35 months. For children and adolescents aged 3–18 years, these new growth charts include height-for-age, weight-for-age, BMI-for-age, weight-for-height, and head circumference-for-age charts, and were developed using data obtained in 1997 and 2005. Data sets and exclusion criteria were applied differently for the development of the different growth charts. BMI-for-age charts were adjusted to decrease the 95th percentile values of BMI. Criteria for obesity were simplified and defined as a BMI of ≥95th percentile for age and sex. The 3rd percentile values for height-for-age charts were also increased. Additional percentile lines (1st and 99th) and growth charts with standard deviation lines were introduced. 2017 Korean National Growth Charts are recommended for the evaluation of body size and growth of Korean children and adolescents for use in clinics and the public health sector in Korea.

AIMS: The aim of this study was to investigate the causal relationship and evidence of an association between increased adiposity and the risk of incident cardiovascular disease (CVD) events or mortality. METHODS AND RESULTS: Observational (informing association) and Mendelian randomization (MR) (informing causality) studies were assessed to gather mutually complementary insights and elucidate perplexing epidemiological relationships. Systematic reviews and meta-analyses of observational and MR studies that were published until January 2021 and evaluated the association between obesity-related indices and CVD risk were searched. Twelve systematic reviews with 53 meta-analyses results (including over 501 cohort studies) and 12 MR studies were included in the analysis. A body mass index (BMI) increase was associated with higher risks of coronary heart disease, heart failure, atrial fibrillation, all-cause stroke, haemorrhagic stroke, ischaemic stroke, hypertension, aortic valve stenosis, pulmonary embolism, and venous thrombo-embolism. The MR study results demonstrated a causal effect of obesity on all indices but stroke. The CVD risk increase for every 5 kg/m2 increase in BMI varied from 10% [relative risk (RR) 1.10; 95% confidence interval (CI) 1.01-1.21; certainty of evidence, low] for haemorrhagic stroke to 49% (RR 1.49; 95% CI 1.40-1.60; certainty of evidence, high) for hypertension. The all-cause and CVD-specific mortality risks increased with adiposity in cohorts, but the MR studies demonstrated no causal effect of adiposity on all-cause mortality. CONCLUSION: High adiposity is associated with increased CVD risk despite divergent evidence gradients. Adiposity was a causal risk factor for CVD except all-cause mortality and stroke. Half (49%; 26/53) of the associations were supported by high-level evidence. The associations were consistent between sexes and across global regions. This study provides guidance on how to integrate evidence from observational (association) and genetics-driven (causation) studies accumulated to date, to enable a more reliable interpretation of epidemiological relationships.

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy that associates, in 70% of cases, with genetic or acquired disorders leading to dysregulation of the alternative pathway of complement. Autoantibody directed against Factor H causes at least 6% to 10% of aHUS cases, but only a few clinical reports are available. Here, we describe the clinical, biologic, genetic features, treatment, and outcome of 45 patients who presented with aHUS associated with anti-FH autoantibody. We found that this form of aHUS primarily affects children between 9 and 13 years old but it also affects adults. It presents with a high frequency of gastrointestinal symptoms and with extrarenal complications and has a relapsing course. Activation of the alternative pathway of complement at the onset of disease portends a poor prognosis. Early specific treatment may lead to favorable outcomes. These data should improve the recognition and diagnosis of this form of aHUS and help identify patients at high risk of a poor outcome.

BACKGROUND AND OBJECTIVES: With the increasing survival of preterm infants, pulmonary hypertension (PH) related to bronchopulmonary dysplasia (BPD) has become an important complication. The aim of this study was to investigate the characteristics and outcome of PH in preterm infants with BPD and to identify the risk factors for PH. SUBJECTS AND METHODS: We reviewed the records of 116 preterm infants with BPD cared for at a single tertiary center between 2004 and 2008. RESULTS: Twenty-nine (25%) infants had PH >2 months after birth. PH occurred initially at a median age of 65 days (range, 7-232 days). Severe BPD, a birth weight <800 g, long-term ventilator care and oxygen supplementation, a high ventilator setting, infection, and a patent ductus arteriosus (PDA) were related to PH based on univariate analysis (p<0.05). The infants who had longer oxygen supplementation were significantly more likely to have PH (odds ratio, 18.5; 95% confidence interval, 4.1-84.6; p<0.001). PH was improved in 76% of infants after a median of 85 days (range, 20-765 days). Four infants (14%) died. The death of 3 infants was attributed to PH. CONCLUSION: BPD was frequently complicated by PH. Although PH resolved in the majority of infants, PH in preterm infants with BPD can be fatal. Regular screening for PH and adequate management are required.

Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, hypoalbuminemia, and/or concomitant edema. Approximately 85-90% of patients attain complete remission of proteinuria within 4-6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70-80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given.

OBJECTIVE: There is no scale for rating the severity of autoimmune encephalitis (AE). In this study, we aimed to develop a novel scale for rating severity in patients with diverse AE syndromes and to verify the reliability and validity of the developed scale. METHODS: The key items were generated by a panel of experts and selected according to content validity ratios. The developed scale was initially applied to 50 patients with AE (development cohort) to evaluate its acceptability, reproducibility, internal consistency, and construct validity. Then, the scale was applied to another independent cohort (validation cohort, n = 38). RESULTS: A new scale consisting of 9 items (seizure, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness) was developed. Each item was assigned a value of up to 3 points. The total score could therefore range from 0 to 27. We named the scale the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The new scale showed excellent interobserver (intraclass correlation coefficient [ICC] = 0.97) and intraobserver (ICC = 0.96) reliability for total scores, was highly correlated with modified Rankin scale (r = 0.86, p < 0.001), and had acceptable internal consistency (Cronbach α = 0.88). Additionally, in the validation cohort, the scale showed high interobserver reliability (ICC = 0.99) and internal consistency (Cronbach α = 0.92). INTERPRETATION: CASE is a novel clinical scale for AE with a high level of clinimetric properties. It would be suitable for application in clinical practice and might help overcome the limitations of current outcome scales for AE. ANN NEUROL 2019;85:352-358.

OBJECTIVE: Moyamoya disease (MMD) is a cerebrovascular occlusive disease of the bilateral internal carotid arteries that causes a compensatory abnormal vascular network at the base of brain. The rare incidence and various surgical techniques applied have limited the clinical research on MMD. METHODS: We conducted a retrospective analysis of the surgical outcome of 410 pediatric MMD patients. All patients were treated in a relatively uniform scheme at a single institution. The surgical procedures consisted of bilateral encephaloduroarteriosynangiosis augmented by bifrontal encephalogaleo-/periosteal synangiosis. Logistic regression analyses were applied to reveal the prognostic factors for surgical outcome. RESULTS: The overall clinical outcome was excellent in 66%, good in 15%, fair in 15%, and poor in 4% of the patients. Therefore, 81% of the patients had a favorable clinical outcome (excellent and good). Multivariate analyses revealed that infarction on presentation was associated with unfavorable clinical outcome (odds ratio [OR], 2.85; 95% confidence interval [CI], 1.49-5.46; p < 0.01) and decreased vascular reserve only on single-photon emission computerized tomography (OR, 0.07; 95% CI, 0.01-0.52; p < 0.01), with favorable clinical outcome. INTERPRETATION: Our results indicate that an early diagnosis and active intervention before establishment of irreversible hemodynamic change are essential to achieve a favorable clinical outcome in children with MMD.

Importance: Overall, immunotherapy has been shown to improve outcomes and reduce relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear. Objective: To map the use and safety of immunotherapies in individuals with NMDARE, identify early predictors of poor functional outcome and relapse, evaluate changes in immunotherapy use and disease outcome over the 14 years since first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. Data Sources: Systematic search in PubMed from inception to January 1, 2019. Study Selection: Published articles including patients with NMDARE with positive NMDAR antibodies and available individual immunotherapy data. Data Extraction and Synthesis: Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcome (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models. Main Outcomes and Measures: The planned study outcomes were functional outcome at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset). Results: Data from 1550 patients from 652 articles were evaluated. Of these, 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors at first event that were significantly associated with good functional outcome included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Factors significantly associated with poor functional outcome were age younger than 2 years or age of 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Factors significantly associated with nonrelapsing disease were rituximab use or maintenance IVIG use for 6 months or more. Adolescent age at onset was significantly associated with relapsing disease. Rituximab use increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P < .001), concurrent with a falling relapse rate over the same period (22% [12 of 55] in 2008 and earlier; 10.9% [35 of 322] in 2017 and later; P = .006). Modified NEOS score (including 4 of 5 original NEOS items) was associated with probability of poor functional status at 1 year (20.1% [40 of 199] for a score of 0 to 1 points; 43.8% [77 of 176] for a score of 3 to 4 points; P = .05). Conclusions and Relevance: Factors influencing functional outcomes and relapse are different and need to be considered independently in development of evidence-based optimal management guidelines of patients with NMDARE.

Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. Because the etiology of MMD is unknown, its diagnosis is based on characteristic angiographic findings. Re-vascularization techniques (e.g., bypass surgery) are used to restore perfusion, and are the primary treatment for MMD. There is no specific treatment to prevent MMD progression. This review summarizes the recent advances in MMD pathophysiology, including the genetic and circulating factors related to disease development. Genetic and environmental factors may play important roles in the development of the vascular stenosis and aberrant angiogenesis in complex ways. These factors include the related changes in circulating endothelial/smooth muscle progenitor cells, cytokines related to vascular remodeling and angiogenesis, and endothelium, such as caveolin which is a plasma membrane protein. With a better understanding of MMD pathophysiology, nonsurgical approaches targeting MMD pathogenesis may be available to stop or slow the progression of this disease. The possible strategies include targeting growth factors, retinoic acid, caveolin-1, and stem cells.

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin beta2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin beta2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.

Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases.

OBJECTIVE: The prognosis for moyamoya disease (MMD) among young patients is known to be worse than that among older patients. The aim of this study was to investigate the clinical features and treatment outcomes of young patients with MMD. METHODS: A total of 204 patients with MMD who underwent encephaloduroarteriosynangiosis, with or without bifrontal encephalogaleosynangiosis, were categorized into three groups according to their ages at the time of surgery, i.e., Group A (n = 23, <3 yr of age), Group B (n = 50, 3-6 yr of age), and Group C (n = 131, >6 yr of age). For each group, patterns of presentation and the occurrence of subsequent preoperative or surgery-related infarctions were assessed. Clinical outcomes and postoperative hemodynamic status were analyzed. RESULTS: At initial presentation, infarctions were significantly more frequent in Group A (87%) and Group B (58%) than in Group C (46%). Subsequent preoperative infarctions occurred significantly more frequently in Group A (39%) than in Group B (6%) or Group C (0.8%). The median interval between the onset of symptoms and a subsequent preoperative infarction was 3 months (range, 1-14 mo). No significant difference in the rates of surgery-related infarctions among the three groups was observed. The rate of favorable clinical outcomes was significantly lower in Group A (58%) than in Group B (84%) or Group C (86%), although the rates of postoperative hemodynamic improvements were similar among the groups. The poor clinical outcomes for Group A were caused mainly by preoperative infarctions. CONCLUSION: Young-age MMD demonstrates rapid disease progression and results in poor clinical outcomes. These findings indicate the necessity of early surgery for young patients with MMD; however, the actual benefits should be verified with additional controlled studies, with long-term follow-up monitoring.

INTRODUCTION: Mycoplasma pneumoniae is an important cause of community-acquired pneumonia in children and young adolescents. Macrolides are recommended as the first-line therapy however, macrolide resistance rates in M. pneumoniae among children have been increasing substantially. Areas covered: This review focused on clinical characteristics and treatment of macrolide-resistant M. pneumoniae pneumonia in children. Expert commentary: Antibiotic choice should be based on in vitro activity, clinical efficacy and in consideration of potential adverse events. Macrolide resistance did not contribute to the clinical severity of M. pneumoniae pneumonia, but resistance may be an aggravating factor. Antibiotics may not be required for treatment in mild cases due to the self-resolving nature of M. pneumonia infection, regardless of macrolide resistance. In contrast, antibiotic treatment of severe cases of M. pneumoniae pneumonia is complicated. The clinical benefit of tetracyclines and fluoroquinolones has been shown in terms of shortening duration of symptoms and rapid defervescence in some reports. However, due to safety concerns regarding these two alternative antibiotics, clinicians should weigh the risks and benefits when choosing treatment options. Alternative antibiotics may be considered when patients remain febrile or when chest x-rays show deterioration at least 48-72 hours after macrolide treatment.

OBJECTIVE: To identify the prevalence, clinical characteristics, risk factors of hepatic complications after a Fontan operation. METHODS: This was a cross-sectional study of 139 Fontan patients who underwent cardiac CT scans out of a total of 204 patients who had undergone the Fontan procedure between 1986 and 2003. Mean age was 19.0 ± 6.3 years and mean elapsed time since the initial Fontan operation was 11.5 ± 4.7 years. Subjects' clinical features, echocardiograms, radiological features and biochemical test results were reviewed. Various non-invasive hepatic fibrosis blood markers were also evaluated. RESULTS: Fifty-seven patients had hepatic complications, including radiological features of liver cirrhosis (25.9%), thrombocytopenia (7.2%), hyperbilirubinaemia (20.9%) and hepatic masses (2.9%). Hepatic complications were also significantly associated with ventricular dysfunction (p=0.020), absence of fenestration (p=0.004), thrombus in the Fontan tract (p=0.027), sinus node dysfunction (p=0.034) and tachyarrhythmia (p<0.001). In a multivariate analysis, the elapsed time since the initial Fontan operation was the only measure that was correlated with hepatic complications; the odds ratio of the post-Fontan duration of 16-20 years to that of 0-5 years was 9.00 (CI 2.24 to 36.17). The non-invasive hepatic fibrosis blood marker (Forns index) was also correlated with the elapsed time since the initial Fontan operation (r=0.718, p<0.001). CONCLUSION: Late hepatic dysfunction and cirrhotic change were often seen in Fontan patients. Moreover, hepatic complications were correlated with the duration of Fontan circulation. Therefore, after a Fontan operation, regular evaluation of the hepatic condition is required--for which some non-invasive hepatic fibrosis markers can be effectively used.

Importance: Preterm infants must establish regular respirations at delivery. Sustained inflations may establish lung volume faster than short inflations. Objective: To determine whether a ventilation strategy including sustained inflations, compared with standard intermittent positive pressure ventilation, reduces bronchopulmonary dysplasia (BPD) or death at 36 weeks' postmenstrual age without harm in extremely preterm infants. Design, Setting, and Participants: Unmasked, randomized clinical trial (August 2014 to September 2017, with follow-up to February 15, 2018) conducted in 18 neonatal intensive care units in 9 countries. Preterm infants 23 to 26 weeks' gestational age requiring resuscitation with inadequate respiratory effort or bradycardia were enrolled. Planned enrollment was 600 infants. The trial was stopped after enrolling 426 infants, following a prespecified review of adverse outcomes. Interventions: The experimental intervention was up to 2 sustained inflations at maximal peak pressure of 25 cm H2O for 15 seconds using a T-piece and mask (n = 215); standard resuscitation was intermittent positive pressure ventilation (n = 211). Main Outcome and Measures: The primary outcome was the rate of BPD or death at 36 weeks' postmenstrual age. There were 27 prespecified secondary efficacy outcomes and 7 safety outcomes, including death at less than 48 hours. Results: Among 460 infants randomized (mean [SD] gestational age, 25.30 [0.97] weeks; 50.2% female), 426 infants (92.6%) completed the trial. In the sustained inflation group, 137 infants (63.7%) died or survived with BPD vs 125 infants (59.2%) in the standard resuscitation group (adjusted risk difference [aRD], 4.7% [95% CI, -3.8% to 13.1%]; P = .29). Death at less than 48 hours of age occurred in 16 infants (7.4%) in the sustained inflation group vs 3 infants (1.4%) in the standard resuscitation group (aRD, 5.6% [95% CI, 2.1% to 9.1%]; P = .002). Blinded adjudication detected an imbalance of rates of early death possibly attributable to resuscitation (sustained inflation: 11/16; standard resuscitation: 1/3). Of 27 secondary efficacy outcomes assessed by 36 weeks' postmenstrual age, 26 showed no significant difference between groups. Conclusions and Relevance: Among extremely preterm infants requiring resuscitation at birth, a ventilation strategy involving 2 sustained inflations, compared with standard intermittent positive pressure ventilation, did not reduce the risk of BPD or death at 36 weeks' postmenstrual age. These findings do not support the use of ventilation with sustained inflations among extremely preterm infants, although early termination of the trial limits definitive conclusions. Trial Registration: clinicaltrials.gov Identifier: NCT02139800.

OBJECTIVE: To document the expression patterns of various matrixins, cytokines and angiogenic factors in plasma to assess their involvement in the pathogenesis of moyamoya disease (MMD). METHODS: This study included plasma samples from 20 MMD patients and nine healthy individuals. The plasma concentration of five matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, MMP-12), monocyte chemoattractant protein-1 (MCP-1), resistin, three interleukins (IL-1beta, IL-6, IL-8), tumour necrosis factor-alpha, vascular endothelial growth factor (VEGF), platelet-derived growth factor BB (PDGF-BB) and basic fibroblast growth factor was determined using multianalyte profiling systems. The concentration of the tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2) was measured using ELISA. Gelatin zymography for MMP-2 and MMP-9 was also performed. RESULTS: MMD patients exhibited significantly higher plasma concentrations of MMP-9, MCP-1, IL-1beta, VEGF and PDGF-BB, and lower plasma concentrations of MMP-3, TIMP-1 and TIMP-2 compared with healthy controls. Significant correlations were found among MMP-9, MCP-1, VEGF, PDGF-BB and TIMP-2 in MMD patients. CONCLUSION: There were distinctive expression patterns of matrixins, cytokines and angiogenic factors in MMD patients, which seemed to correlate with disease pathogenesis. The balance between MMPs and TIMPs was disrupted in MMD and correlated with disease pathogenesis. Increased plasma levels of MCP-1 and VEGF in MMD patients may play a role in the recruitment of vascular progenitor cells and in the formation of collateral vessels.

Abstract BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 ( n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m − 2 once weekly; 600 mg maximum) in patients with BRAF -altered, relapsed/refractory pLGG. Arm 2 ( n = 60) is an extension cohort, which provided treatment access for patients with RAF -altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF -altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .