Royal Hospital for Sick Children

BACKGROUND: Crohn's disease and ulcerative colitis are complex disorders with some shared and many unique predisposing genes. Accurate phenotype classification is essential in determining the utility of genotype-phenotype correlation. The Montreal Classification of IBD has several weaknesses with respect to classification of children. The dynamic features of pediatric disease phenotype (change in disease location and behavior over time, growth failure) are not sufficiently captured by the current Montreal Classification. METHODS: Focusing on facilitating research in pediatric inflammatory bowel disease (IBD), and creating uniform standards for defining IBD phenotypes, an international group of pediatric IBD experts met in Paris, France to develop evidence-based consensus recommendations for a pediatric modification of the Montreal criteria. RESULTS: Important modifications developed include classifying age at diagnosis as A1a (0 to <10 years), A1b (10 to <17 years), A2 (17 to 40 years), and A3 (>40 years), distinguishing disease above the distal ileum as L4a (proximal to ligament of Treitz) and L4b (ligament of Treitz to above distal ileum), allowing both stenosing and penetrating disease to be classified in the same patient (B2B3), denoting the presence of growth failure in the patient at any time as G(1) versus G(0) (never growth failure), adding E4 to denote extent of ulcerative colitis that is proximal to the hepatic flexure, and denoting ever severe ulcerative colitis during disease course by S1. CONCLUSIONS: These modifications are termed the Paris Classification. By adhering to the Montreal framework, we have not jeopardized or altered the ability to use this classification for adult onset disease or by adult gastroenterologists.

OBJECTIVES: The ESPGHAN 2012 coeliac disease (CD) diagnostic guidelines aimed to guide physicians in accurately diagnosing CD and permit omission of duodenal biopsies in selected cases. Here, an updated and expanded evidence-based guideline is presented. METHODS: Literature databases and other sources of information were searched for studies that could inform on 10 formulated questions on symptoms, serology, HLA genetics, and histopathology. Eligible articles were assessed using QUADAS2. GRADE provided a basis for statements and recommendations. RESULTS: Various symptoms are suggested for case finding, with limited contribution to diagnostic accuracy. If CD is suspected, measurement of total serum IgA and IgA-antibodies against transglutaminase 2 (TGA-IgA) is superior to other combinations. We recommend against deamidated gliadin peptide antibodies (DGP-IgG/IgA) for initial testing. Only if total IgA is low/undetectable, an IgG-based test is indicated. Patients with positive results should be referred to a paediatric gastroenterologist/specialist. If TGA-IgA is ≥10 times the upper limit of normal (10× ULN) and the family agrees, the no-biopsy diagnosis may be applied, provided endomysial antibodies (EMA-IgA) will test positive in a second blood sample. HLA DQ2-/DQ8 determination and symptoms are not obligatory criteria. In children with positive TGA-IgA <10× ULN at least 4 biopsies from the distal duodenum and at least 1 from the bulb should be taken. Discordant results between TGA-IgA and histopathology may require re-evaluation of biopsies. Patients with no/mild histological changes (Marsh 0/I) but confirmed autoimmunity (TGA-IgA/EMA-IgA+) should be followed closely. CONCLUSIONS: CD diagnosis can be accurately established with or without duodenal biopsies if given recommendations are followed.

BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). INTERPRETATION: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

OBJECTIVE: We aimed to provide an evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn's disease [CD]. METHODS: We formed 10 working groups and formulated 17 PICO-structured clinical questions [Patients, Intervention, Comparator, and Outcome]. A systematic literature search from January 1, 1991 to March 19, 2019 was conducted by a medical librarian using MEDLINE, EMBASE, and Cochrane Central databases. A shortlist of 30 provisional statements were further refined during a consensus meeting in Barcelona in October 2019 and subjected to a vote. In total 22 statements reached ≥ 80% agreement and were retained. RESULTS: We established that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity, to reduce bowel damage. Patients with perianal disease, stricturing or penetrating behaviour, or severe growth retardation should be considered for up-front anti-tumour necrosis factor [TNF] agents in combination with an immunomodulator. Therapeutic drug monitoring to guide treatment changes is recommended over empirically escalating anti-TNF dose or switching therapies. Patients with low-risk luminal CD should be induced with exclusive enteral nutrition [EEN], or with corticosteroids when EEN is not an option, and require immunomodulator-based maintenance therapy. Favourable outcomes rely on close monitoring of treatment response, with timely adjustments in therapy when treatment targets are not met. Serial faecal calprotectin measurements or small bowel imaging [ultrasound or magnetic resonance enterography] are more reliable markers of treatment response than clinical scores alone. CONCLUSIONS: We present state-of-the-art guidance on the medical treatment and long-term management of children and adolescents with CD.

Background & aimsThe incidence of inflammatory bowel disease (IBD) is increasing internationally, particularly in nations with historically low rates. Previous reports of the epidemiology of pediatric-onset IBD identified a paucity of data. We systematically reviewed the global trends in incidence and prevalence of IBD diagnosed in individuals <21 years old over the first 2 decades of the 21st century.MethodsWe systematically reviewed studies indexed in MEDLINE, EMBASE, Airiti Library, and SciELO from January 2010 to February 2020 to identify population-based studies reporting the incidence and/or prevalence of IBD, Crohn’s disease, ulcerative colitis, and/or IBD-unclassified. Data from studies published before 2000 were derived from a previously published systematic review. We described the geographic distribution and trends in children of all ages and limiting to very early onset (VEO) IBD.ResultsA total of 131 studies from 48 countries were included. The incidence and prevalence of pediatric-onset IBD is highest in Northern Europe and North America and lowest in Southern Europe, Asia, and the Middle East. Among studies evaluating trends over time, most (31 of 37, 84%) studies reported significant increases in incidence and all (7 of 7) reported significant increases in prevalence. Data on the incidence and prevalence of VEO-IBD are limited to countries with historically high rates of IBD. Time trends in the incidence of VEO-IBD were visually heterogeneous.ConclusionsRates of pediatric-onset IBD continue to rise around the world and data are emerging from regions where it was not previously reported; however, there remains a paucity of data on VEO-IBD and on pediatric IBD from developing and recently developed countries. The incidence of inflammatory bowel disease (IBD) is increasing internationally, particularly in nations with historically low rates. Previous reports of the epidemiology of pediatric-onset IBD identified a paucity of data. We systematically reviewed the global trends in incidence and prevalence of IBD diagnosed in individuals <21 years old over the first 2 decades of the 21st century. We systematically reviewed studies indexed in MEDLINE, EMBASE, Airiti Library, and SciELO from January 2010 to February 2020 to identify population-based studies reporting the incidence and/or prevalence of IBD, Crohn’s disease, ulcerative colitis, and/or IBD-unclassified. Data from studies published before 2000 were derived from a previously published systematic review. We described the geographic distribution and trends in children of all ages and limiting to very early onset (VEO) IBD. A total of 131 studies from 48 countries were included. The incidence and prevalence of pediatric-onset IBD is highest in Northern Europe and North America and lowest in Southern Europe, Asia, and the Middle East. Among studies evaluating trends over time, most (31 of 37, 84%) studies reported significant increases in incidence and all (7 of 7) reported significant increases in prevalence. Data on the incidence and prevalence of VEO-IBD are limited to countries with historically high rates of IBD. Time trends in the incidence of VEO-IBD were visually heterogeneous. Rates of pediatric-onset IBD continue to rise around the world and data are emerging from regions where it was not previously reported; however, there remains a paucity of data on VEO-IBD and on pediatric IBD from developing and recently developed countries.

Abstract Objective : To investigate the role of sleeping arrangements as risk factors for the sudden infant death syndrome after a national risk reduction campaign. Design : Two year population based case-control study. Parental interviews were conducted for each infant who died and for four controls matched for age and date of interview. Setting : Three regions in England with a total population of 17 million people. Subjects : 195 babies who died and 780 matched controls. Results : Prone and side sleeping positions both carried increased risks of death compared with supine when adjusted for maternal age, parity, gestation, birth weight, exposure to smoke, and other relevant factors in the sleeping environment (multivariate odds ratio = 9.00 (95% confidence interval 2.84 to 28.47) and 1.84 (1.02 to 3.31), respectively). The higher incidence of side rather than prone sleeping led to a higher population attributable risk (side 18.4%, prone 14.2%). More of the infants who died were found with bed covers over their heads (21.58; 6.21 to 74.99). The use of a dummy had an apparent protective effect (0.38; 0.21 to 0.70). Bed sharing for the whole night was a significant risk factor for infants whose mothers smoked (9.25; 2.31 to 34.02). No protective effect of breast feeding could be identified on multivariate analysis. Conclusions : This study confirms the importance of certain risk factors for the sudden infant death syndrome and identifies others—for example, covers over the head, side sleeping position—which may be amenable to change by educating and informing parents and health care professionals. Key messages This large case-control study is the first after the national campaign to reduce the risk of the syndrome The risk of sudden infant death is increased by prone or side sleeping position; loose bedding (particularly duvets), which can slip over the baby's head; and bed sharing by mothers who smoke The risk may be reduced by supine sleeping position; placing the baby with feet at the foot of the cot (“feet to foot”); ensuring that bedding is securely tucked in; and avoiding the use of duvets

BACKGROUND AND OBJECTIVES: Epilepsy affects 0.5% to 1% of children and is the most frequent chronic neurologic condition in childhood. Incidence rates appear to be declining in high-income countries. The validity of epilepsy diagnoses from different data sources varies, and contemporary population-based incidence studies are needed. METHODS: The study was based on the Norwegian Mother and Child Cohort Study. Potential epilepsy cases were identified through registry linkages and parental questionnaires. Cases were validated through medical record reviews and telephone interviews of parents. RESULTS: The study population included 112 744 children aged 3 to 13 years (mean 7.4 years) at end of registry follow-up (December 31, 2012). Of these, 896 had registry recordings and/or questionnaire reports of epilepsy. After validation, 587 (66%) met the criteria for an epilepsy diagnosis. The incidence rate of epilepsy was 144 per 100 000 person-years in the first year of life and 58 per 100 000 for ages 1 to 10 years. The cumulative incidence of epilepsy was 0.66% at age 10 years, with 0.62% having active epilepsy. The 309 children (34%) with erroneous reports of epilepsy from the registry and/or the questionnaires had mostly been evaluated for nonepileptic paroxysmal events, or they had undergone electroencephalography examinations because of other developmental or neurocognitive difficulties. CONCLUSIONS: Approximately 1 out of 150 children is diagnosed with epilepsy during the first 10 years of life, with the highest incidence rate observed during infancy. Validation of epilepsy diagnoses in administrative data and cohort studies is crucial because reported diagnoses may not meet diagnostic criteria for epilepsy.

BACKGROUND: The achievement of glycaemic control remains challenging for patients with type 1 diabetes. We assessed the effectiveness of day-and-night hybrid closed-loop insulin delivery compared with sensor-augmented pump therapy in people with suboptimally controlled type 1 diabetes aged 6 years and older. METHODS: . The primary endpoint was the proportion of time that glucose concentration was within the target range of 3·9-10·0 mmol/L at 12 weeks post randomisation. Analyses of primary outcome and safety measures were done in all randomised patients. The trial is registered with ClinicalTrials.gov, number NCT02523131, and is closed to accrual. FINDINGS: percentages were significantly greater in the closed-loop group compared with the control group (mean difference in change 0·36%, 95% CI 0·19 to 0·53; p<0·0001). The time spent with glucose concentrations below 3·9 mmol/L (mean difference in change -0·83 percentage points, -1·40 to -0·16; p=0·0013) and above 10·0 mmol/L (mean difference in change -10·3 percentage points, -13·2 to -7·5; p<0·0001) was shorter in the closed-loop group than the control group. The coefficient of variation of sensor-measured glucose was not different between interventions (mean difference in change -0·4%, 95% CI -1·4% to 0·7%; p=0·50). Similarly, total daily insulin dose was not different (mean difference in change 0·031 U/kg per day, 95% CI -0·005 to 0·067; p=0·09) and bodyweight did not differ (mean difference in change 0·68 kg, 95% CI -0·34 to 1·69; p=0·19). No severe hypoglycaemia occurred. One diabetic ketoacidosis occurred in the closed-loop group due to infusion set failure. Two participants in each study group had significant hyperglycaemia, and there were 13 other adverse events in the closed-loop group and three in the control group. INTERPRETATION: Hybrid closed-loop insulin delivery improves glucose control while reducing the risk of hypoglycaemia across a wide age range in patients with suboptimally controlled type 1 diabetes. FUNDING: JDRF, NIHR, and Wellcome Trust.

BACKGROUND: For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). METHODS: We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. RESULTS: Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. CONCLUSIONS: Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.).

BACKGROUND: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. METHODS: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. FINDINGS: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. INTERPRETATION: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials. FUNDING: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

Over the last 15 years, various oncology groups throughout the world have used the PRETEXT system for staging malignant primary liver tumours of childhood. This paper, written by members of the radiology and surgery committees of the International Childhood Liver Tumor Strategy Group (SIOPEL), presents various clarifications and revisions to the original PRETEXT system.

OBJECTIVE: To investigate the effects of exposure to tobacco smoke and of parental consumption of alcohol and illegal drugs as risk factors for the sudden infant death syndrome after a national risk reduction campaign which included advice on prenatal and postnatal avoidance of tobacco smoke. DESIGN: Two year population based case-control study. Parental interviews were conducted for each infant who died and four controls matched for age and date of interview. SETTING: Three regions in England with a total population of 17 million people. SUBJECTS: 195 babies who died and 780 matched controls. RESULTS: More index than control mothers (62.6% v 25.1%) smoked during pregnancy (multivariate odds ratio = 2.10; 95% confidence interval 1.24 to 3.54). Paternal smoking had an additional independent effect when other factors were controlled for (2.50; 1.48 to 4.22). The risk of death rose with increasing postnatal exposure to tobacco smoke, which had an additive effect among those also exposed to maternal smoking during pregnancy (2.93; 1.56 to 5.48). The population attributable risk was over 61%, which implies that the numbers of deaths from the syndrome could be reduced by almost two third if parents did not smoke. Alcohol use was higher among index than control mothers but was strongly correlated with smoking and on multivariate analysis was not found to have any additional independent effect. Illegal drug use was more common among the index parents, and paternal use of illegal drugs remained significant in the multivariate model (4.68; 1.56 to 14.05). CONCLUSIONS: This study confirms the increased risk of the sudden infant death syndrome associated with maternal smoking during pregnancy and shows evidence that household exposure to tobacco smoke has an independent additive effect. Parental drug misuse has an additional small but significant effect.

Of 13 135 children followed up from birth to the age of 5 years, 303 (2.3%) had febrile convulsions. Prior neurological abnormality had been noted in 13. Of the 290 remaining children, 57 (20%) presented with a complex convulsion, and 103 children (35%) went on to have further febrile convulsions. The risk of further febrile convulsions varied with the age at first convulsion and the presence of a history of convulsive disorders in relatives. There were no significant differences between the sexes.

OBJECTIVE: To assess unexpected associations between childhood cancer and pethidine given in labour and the neonatal administration of vitamin K that had emerged in a study performed in the 1970 national birth cohort. DESIGN AND SETTING: 195 children with cancer diagnosed in 1971-March 1991 and born in the two major Bristol maternity hospitals in 1965-87 were compared with 558 controls identified from the delivery books for the use of pethidine during labour and administration of vitamin K. MAIN OUTCOME MEASURES: Odds ratios for cancer in the presence of administration of pethidine or of intramuscular vitamin K. Both logistic regression and Mantel-Haenszel techniques were used for statistical analyses. RESULTS: Children of mothers given pethidine in labour were not at increased risk of cancer (odds ratio 1.05, 95% confidence interval 0.7 to 1.5) after allowing for year and hospital of delivery, but there was a significant association (p = 0.002) with intramuscular vitamin K (odds ratio 1.97, 95% confidence interval 1.3 to 3.0) when compared with oral vitamin K or no vitamin K. There was no significantly increased risk for children who had been given oral vitamin K when compared with no vitamin K (odds ratio 1.15, 95% confidence interval 0.5 to 2.7). These results could not be accounted for by other factors associated with administration of intramuscular vitamin K, such as type of delivery or admission to a special care baby unit. CONCLUSIONS: The only two studies so far to have examined the relation between childhood cancer and intramuscular vitamin K have shown similar results, and the relation is biologically plausible. The prophylactic benefits against haemorrhagic disease are unlikely to exceed the potential adverse effects from intramuscular vitamin K. Since oral vitamin K has major benefits but no obvious adverse effects this could be the prophylaxis of choice.

<h3>Abstract</h3> <b>Objective:</b> To investigate the risks of the sudden infant death syndrome and factors that may contribute to unsafe sleeping environments. <b>Design:</b> Three year, population based case-control study. Parental interviews were conducted for each sudden infant death and for four controls matched for age, locality, and time of sleep. <b>Setting:</b> Five regions in England with a total population of over 17 million people. <b>Subjects:</b> 325 babies who died and 1300 control infants. <b>Results:</b> In the multivariate analysis infants who shared their parents9 bed and were then put back in their own cot had no increased risk (odds ratio 0.67; 95% confidence interval 0.22 to 2.00). There was an increased risk for infants who shared the bed for the whole sleep or were taken to and found in the parental bed (9.78; 4.02 to 23.83), infants who slept in a separate room from their parents (10.49; 4.26 to 25.81), and infants who shared a sofa (48.99; 5.04 to 475.60) The risk associated with being found in the parental bed was not significant for older infants (&gt;14 weeks) or for infants of parents who did not smoke and became non-significant after adjustment for recent maternal alcohol consumption (&gt;2 units), use of duvets (&gt;4 togs), parental tiredness (infant slept ≤4 hours for longest sleep in previous 24 hours), and overcrowded housing conditions (&gt;2 people per room of the house). <b>Conclusions:</b> There are certain circumstances when bed sharing should be avoided, particularly for infants under four months old. Parents sleeping on a sofa with infants should always be avoided. There is no evidence that bed sharing is hazardous for infants of parents who do not smoke. <h3>Key messsages</h3> Cosleeping with an infant on a sofa was associated with a particularly high risk of sudden infant death syndrome Sharing a room with the parents was associated with a lower risk There was no increased risk associated with bed sharing when the infant was placed back in his or her cot Among parents who do not smoke or infants older than 14 weeks there was no association between infants being found in the parental bed and an increased risk of sudden infant death syndrome The risk linked with bed sharing among younger infants seems to be associated with recent parental consumption of alcohol, overcrowded housing conditions, extreme parental tiredness, and the infant being under a duvet

SUMMARY Fourteen newborn babies of different gestational ages (33 to 40 weeks) but similar postnatal age (four to 19 days) were studied during bottle‐feeding using real‐time ultrasonography, combined with respiratory monitoring. Previously undescribed tongue movements and graded changes in the temporal relationships between tongue movements, swallowing and breathing were observed among infants of differing maturity. These were most marked in the least mature infants, but were occasionally seen in term infants. The results suggest that adequate neuromuscular co‐ordination is more a function of gestational maturity than of postnatal sucking experience. The pattern of intraoral events for infants of differing maturity described in this study provides a framework for the study of feeding problems of term and preterm infants. RÉSUMÉ Développement de la coordination, de la succion, de la déglutition et de la respiration chez les nourrissons nés à terme et chez les prématurés Quatorze nouveaux‐nés d'âges differents de gestation (33 à 40 semaines) mais d'âges post‐nataux semblables (quatre à 19 jours) on*** été étudiés durant l'alimentation au biberon en utilisant une échographie en temps reel combinée avec un contrôle respiratoire. Des mouvements de langue non décrits antérieurement et des modifications graduées dans les relations temporelles entre les mouvements de langue, la déglutition et la respiration ont été observés chez les nourrissons de differentes maturités. Ils étaient au plus élevé chez les moins matures des enfants étudiés mais observés occasionnellement chez les nourrissons à terme. Les résultats suggèrent que la coordination neuro‐musculaire adéquate est plus une fonction de la maturité de gestation que de l'expérience post‐natale de succion. La distribution des évènements intra‐oraux pour les nourrissons de differentes maturités décrites dans cette étude fournit une base de travail pour l'étude des problèmes d'alimentation chez les nourrissons à terme et prématurés. ZUSAMMENFASSUNG Koordinationsentwicklung von Saugen, Schlucken und Atmen bei reif‐ und frühgeborenen Kindern Bei 14 Neugeborenen mit verschiedenem Gestationsalter (33 bis 40 Wochen), aber etwa gleichem Lebensalter (vier bis 19 Tage) wurden während der Flaschenfütterung Real‐Zeit Ultraschalluntersuchungen mit gleichzeitigen Aufzeichnungen der Atmung durchgeführt. Es wurden bisher nicht beschriebene Zungenbewegungen und abgestufte Veränderungen in der zeitlichen Relation zwischen Zungenbewegungen, Schlucken und Atmen bei Kindern mit unterschiedlichem Reifegrad festgestellt. Diese waren bei den unreifsten Kindern am ausgeprägtesten, wurden aber auch bei einigen reifen Kindern beobachtet. Die Ergebnisse zeigen, daβ eine richtige neuromuskuläre Koordination eher eine Funktion der Gestationsreife als der postnatalen Saugerfahrung ist. Die Muster intra‐oraler Abläufe bei Kindern unterschiedlicher Reife, die in dieser Studie beschrieben werden, bilden die Basis für Untersuchungen von Fütterungsproblemen bei reif‐ und frühgeborenen Kindern. RESUMEN Desarrollo de la coordinación de la succión, deglución y respiración en lactantes a término y pretérmino Catorce reciàn nacidos de diferentes edades gestacionales (33 a 40 semanas) pero de edad postnatal similar (de cuatro a 19 dias) fueron estudiados durante la toma del biberón usando una ultrasonografia a tiempo real en combinaciòn con la monitorización de la respiración. Entre los lactantes con diferente madurez se observaron movimientos de lengua no descritos previamente, así como cambios graduales en las relaciones temporales entre los movimientos de la lengua, la deglución y la respiración. Esto era marcado sobre todo en los lactantes menos maduros mientras que se observaron raramente en los lactantes a término. Los resultados sugieren que la adecuada coordinación neuromuscular es más una función de la maduración gestacional que de la experiencia succional postnatal. El esquema de los acontecimientos intraorales en lactantes de diferente madurez descritos en este estudio proporciona un marco para el estudio de los problemas de alimentación de lactantes a término y a pretérmino.

Abstract The many conceptual and methodological difficulties involved in evaluating depression rating scales for children arc discussed. A clinical validation of the Depression Self Rating Scale for Children (DSRSC) is described. The instrument is easy to use and has a predictive value comparable with that of a psychiatric global rating of depressed appearance and history of depression obtained at interview. There was confirmation that the: DSRSC can tap an internal dimension of depression and that children are able lo evaluate their feeling stales. An examination of misclassified children pointed to diagnostic overlap and some unreliability of diagnosis by clinicians.

BACKGROUND: Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). METHODS: Children with standard-risk hepatoblastoma who were younger than 16 years of age were eligible for inclusion in the study. After they received one cycle of cisplatin (80 mg per square meter of body-surface area per 24 hours), we randomly assigned patients to receive cisplatin (every 14 days) or cisplatin plus doxorubicin administered in three preoperative cycles and two postoperative cycles. The primary outcome was the rate of complete resection, and the trial was powered to test the noninferiority of cisplatin alone (<10% difference in the rate of complete resection). RESULTS: Between June 1998 and December 2006, 126 patients were randomly assigned to receive cisplatin and 129 were randomly assigned to receive cisplatin plus doxorubicin. The rate of complete resection was 95% in the cisplatin-alone group and 93% in the cisplatin-doxorubicin group in the intention-to-treat analysis (difference, 1.4%; 95% confidence interval [CI], -4.1 to 7.0); these rates were 99% and 95%, respectively, in the per-protocol analysis. Three-year event-free survival and overall survival were, respectively, 83% (95% CI, 77 to 90) and 95% (95% CI, 91 to 99) in the cisplatin group, and 85% (95% CI, 79 to 92) and 93% (95% CI, 88 to 98) in the cisplatin-doxorubicin group (median follow-up, 46 months). Acute grade 3 or 4 adverse events were more frequent with combination therapy (74.4% vs. 20.6%). CONCLUSIONS: As compared with cisplatin plus doxorubicin, cisplatin monotherapy achieved similar rates of complete resection and survival among children with standard-risk hepatoblastoma. Doxorubicin can be safely omitted from the treatment of standard-risk hepatoblastoma. (ClinicalTrials.gov number, NCT00003912.)

PURPOSE: This study aimed to identify the nature and extent of receptive and expressive prosodic deficits in children with high-functioning autism (HFA). METHOD: Thirty-one children with HFA, 72 typically developing controls matched on verbal mental age, and 33 adults with normal speech completed the prosody assessment procedure, Profiling Elements of Prosodic Systems in Children. RESULTS: Children with HFA performed significantly less well than controls on 11 of 12 prosody tasks (p < .005). Receptive prosodic skills showed a strong correlation (p < .01) with verbal mental age in both groups, and to a lesser extent with expressive prosodic skills. Receptive prosodic scores also correlated with expressive prosody scores, particularly in grammatical prosodic functions. Prosodic development in the HFA group appeared to be delayed in many aspects of prosody and deviant in some. Adults showed near-ceiling scores in all tasks. CONCLUSIONS: The study demonstrates that receptive and expressive prosodic skills are closely associated in HFA. Receptive prosodic skills would be an appropriate focus for clinical intervention, and further investigation of prosody and the relationship between prosody and social skills is warranted.

BACKGROUND: Myxomatous dystrophy of the cardiac valves affects approximately 3% of the population and remains one of the most common indications for valvular surgery. Familial inheritance has been demonstrated with autosomal and X-linked transmission, but no specific molecular abnormalities have been documented in isolated nonsyndromic forms. We have investigated the genetic causes of X-linked myxomatous valvular dystrophy (XMVD) previously mapped to chromosome Xq28. METHODS AND RESULTS: A familial and genealogical survey led us to expand the size of a large, previously identified family affected by XMVD and to refine the XMVD locus to a 2.5-Mb region. A standard positional cloning approach identified a P637Q mutation in the filamin A (FLNA) gene in all affected members. Two other missense mutations (G288R and V711D) and a 1944-bp genomic deletion coding for exons 16 to 19 in the FLNA gene were identified in 3 additional, smaller, unrelated families affected by valvular dystrophy, which demonstrates the responsibility of FLNA as a cause of XMVD. Among carriers of FLNA mutation, the penetrance of the disease was complete in men and incomplete in women. Female carriers could be mildly affected, and the severity of the disease was highly variable among mutation carriers. CONCLUSIONS: Our data demonstrate that FLNA is the first gene known to cause isolated nonsyndromic MVD. This is the first step to understanding the pathophysiological mechanisms of the disease and to defining pathways that may lead to valvular dystrophy. Screening for FLNA mutations could be important for families affected by XMVD to provide adequate follow-up and genetic counseling.