Erasmus MC - Sophia Children’s Hospital

OBJECTIVE: Sequelae of academic underachievement, behavioral problems, and poor executive function (EF) have been extensively reported for very preterm (<or=33 weeks' gestation) and/or very low birth weight (VLBW) (<or=1500 g) children. Great variability in the published results, however, hinders the field in studying underlying dysfunctions and developing intervention strategies. We conducted a quantitative meta-analysis of studies published between 1998 and 2008 on academic achievement, behavioral functioning, and EF with the aim of providing aggregated measures of effect size for these outcome domains. METHODS: Suitable for inclusion were 14 studies on academic achievement, 9 studies on behavioral problems, and 12 studies on EF, which compared a total of 4125 very preterm and/or VLBW children with 3197 term-born controls. Combined effect sizes for the 3 outcome domains were calculated in terms of Cohen's d. Q-test statistics were performed to test homogeneity among the obtained effect sizes. Pearson's correlation coefficients were calculated to examine the impact of mean birth weight and mean gestational age, as well as the influence of mean age at assessment on the effect sizes for academic achievement, behavioral problems, and EF. RESULTS: Combined effect sizes show that very preterm and/or VLBW children score 0.60 SD lower on mathematics tests, 0.48 SD on reading tests, and 0.76 SD on spelling tests than term-born peers. Of all behavioral problems stacked, attention problems were most pronounced in very preterm and/or VLBW children, with teacher and parent ratings being 0.43 to 0.59 SD higher than for controls, respectively. Combined effect sizes for parent and teacher ratings of internalizing behavior problems were small (<0.28) and for externalizing behavior problems negligible (<0.09) and not significant. Combined effect sizes for EF revealed a decrement of 0.57 SD for verbal fluency, 0.36 SD for working memory, and 0.49 SD for cognitive flexibility in comparison to controls. Mean age at assessment was not correlated with the strength of the effect sizes. Mathematics and reading performance, parent ratings of internalizing problems, teacher ratings of externalizing behavior, and attention problems, showed strong and positive correlations with mean birth weight and mean gestational age (all r values > 0.51). CONCLUSIONS: Very preterm and/or VLBW children have moderate-to-severe deficits in academic achievement, attention problems, and internalizing behavioral problems and poor EF, which are adverse outcomes that were strongly correlated to their immaturity at birth. During transition to young adulthood these children continue to lag behind term-born peers.

STUDY QUESTION: What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available evidence in the literature? SUMMARY ANSWER: The guideline development group (GDG) formulated 99 recommendations answering 31 key questions on the diagnosis and treatment of women with POI. WHAT IS KNOWN ALREADY: NA. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a multidisciplinary group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology (ESHRE) members and professional organizations were asked to review the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 17 recommendations on diagnosis and assessment of POI and 46 recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on puberty induction resulted in five recommendations. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the guideline is that, due to the lack of data, many of the recommendations are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome. WIDER IMPLICATIONS OF THE FINDINGS: Despite the limitations, the guideline group is confident that this document will be able to guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline group has formulated research recommendations on the gaps in knowledge identified in the literature searches, in an attempt to stimulate research on the key issues in POI. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. Dr Davies reports non-financial support from Novo Nordisk, outside the submitted work; the other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: NA.

The number of surviving children born prematurely has increased substantially during the last 2 decades. The major goal of enteral nutrient supply to these infants is to achieve growth similar to foetal growth coupled with satisfactory functional development. The accumulation of knowledge since the previous guideline on nutrition of preterm infants from the Committee on Nutrition of the European Society of Paediatric Gastroenterology and Nutrition in 1987 has made a new guideline necessary. Thus, an ad hoc expert panel was convened by the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition in 2007 to make appropriate recommendations. The present guideline, of which the major recommendations are summarised here (for the full report, see http://links.lww.com/A1480), is consistent with, but not identical to, recent guidelines from the Life Sciences Research Office of the American Society for Nutritional Sciences published in 2002 and recommendations from the handbook Nutrition of the Preterm Infant. Scientific Basis and Practical Guidelines, 2nd ed, edited by Tsang et al, and published in 2005. The preferred food for premature infants is fortified human milk from the infant's own mother, or, alternatively, formula designed for premature infants. This guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of approximately 1800 g, because most data are available for these infants. These recommendations are based on a considered review of available scientific reports on the subject, and on expert consensus for which the available scientific data are considered inadequate.

BACKGROUND: The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete. METHODS: We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm. RESULTS: The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy. CONCLUSIONS: These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.

BACKGROUND: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. METHODS: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. RESULTS: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. CONCLUSIONS: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.

Little is known about the epidemiology of pain in children. We studied the prevalence of pain in Dutch children aged from 0 to 18 years in the open population, and the relationship with age, gender and pain parameters. A random sample of 1300 children aged 0-3 years was taken from the register of population in Rotterdam, The Netherlands. In the Rotterdam area, 27 primary schools and 14 secondary schools were selected to obtain a representative sample of 5336 children aged 4-18 years. Depending on the age of the child, a questionnaire was either mailed to the parents (0-3 years) or distributed at school (4-18 years). Of 6636 children surveyed, 5424 (82%) responded; response rates ranged from 64 to 92%, depending on the subject age and who completed the questionnaire. Of the respondents, 54% had experienced pain within the previous 3 months. Overall, a quarter of the respondents reported chronic pain (recurrent or continuous pain for more than 3 months). The prevalence of chronic pain increased with age, and was significantly higher for girls (P<0.001). In girls, a marked increase occurred in reporting chronic pain between 12 and 14 years of age. The most common types of pain in children were limb pain, headache and abdominal pain. Half of the respondents who had experienced pain reported to have multiple pain, and one-third of the chronic pain sufferers experienced frequent and intense pain. These multiple pains and severe pains were more often reported by girls (P<0.001). The intensity of pain was higher in the case of chronic pain (P<0. 001) and multiple pains (P<0.001), and for chronic pain the intensity was higher for girls (P<0.001). These findings indicate that chronic pain is a common complaint in childhood and adolescence. In particular, the high prevalence of severe chronic pain and multiple pain in girls aged 12 years and over calls for follow-up investigations documenting the various bio-psycho-social factors related to this pain.

Turner syndrome affects 25-50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.

BACKGROUND: We have previously reported how the SCORAD index was designed. This cumulative index combines objective (extent and intensity of lesions) and subjective (daytime pruritus and sleep loss) criteria. AIMS: To study interobserver variability in scoring for objective SCORAD criteria and to optimize the scoring guidelines. MATERIAL AND METHODS: Three scoring sessions were organized in 1993-1994 in Hamburg, Bordeaux and Rotterdam totalizing 19 patients (14 children and 5 adults) and 23 physicians, among whom 12 participated in at least 2 scoring sessions; 169 evaluation sheets have been processed using the SCORAD File Marker Pro software. At each session, total body photographs and close-up views were taken of each patient, and this material was reviewed at the final evaluation. RESULTS: The extent of lesions according to the rule of nines showed interobserver variability mostly for patients with lesions of moderate intensity involving 20-60% of body surface. Intensity items were scored with more consistency overall, but variations subsided especially for oozing/crusts and lichenifications. Low and high scorer profiles and the benefit of training were noted. CONCLUSIONS: This study has allowed to optimize clinical scoring using the SCORAD system. A proposal has been made to grade the severity of atopic dermatitis according to objective criteria in three groups for inclusion in clinical trials. The SCORAD index remains the major criterion for follow-up in trials.

This position paper on complementary feeding summarizes evidence for health effects of complementary foods. It focuses on healthy infants in Europe. After reviewing current knowledge and practices, we have formulated these conclusions: Exclusive or full breast-feeding for about 6 months is a desirable goal. Complementary feeding (ie, solid foods and liquids other than breast milk or infant formula and follow-on formula) should not be introduced before 17 weeks and not later than 26 weeks. There is no convincing scientific evidence that avoidance or delayed introduction of potentially allergenic foods, such as fish and eggs, reduces allergies, either in infants considered at increased risk for the development of allergy or in those not considered to be at increased risk. During the complementary feeding period, >90% of the iron requirements of a breast-fed infant must be met by complementary foods, which should provide sufficient bioavailable iron. Cow's milk is a poor source of iron and should not be used as the main drink before 12 months, although small volumes may be added to complementary foods. It is prudent to avoid both early (<4 months) and late (>or=7 months) introduction of gluten, and to introduce gluten gradually while the infant is still breast-fed, inasmuch as this may reduce the risk of celiac disease, type 1 diabetes mellitus, and wheat allergy. Infants and young children receiving a vegetarian diet should receive a sufficient amount ( approximately 500 mL) of breast milk or formula and dairy products. Infants and young children should not be fed a vegan diet.

This position paper considers different aspects of complementary feeding (CF), focussing on healthy term infants in Europe. After reviewing current knowledge and practices, we have formulated these recommendations: Timing: Exclusive or full breast-feeding should be promoted for at least 4 months (17 weeks, beginning of the 5th month of life) and exclusive or predominant breast-feeding for approximately 6 months (26 weeks, beginning of the 7th month) is a desirable goal. Complementary foods (solids and liquids other than breast milk or infant formula) should not be introduced before 4 months but should not be delayed beyond 6 months. CONTENT: Infants should be offered foods with a variety of flavours and textures including bitter tasting green vegetables. Continued breast-feeding is recommended alongside CF. Whole cows' milk should not be used as the main drink before 12 months of age. Allergenic foods may be introduced when CF is commenced any time after 4 months. Infants at high risk of peanut allergy (those with severe eczema, egg allergy, or both) should have peanut introduced between 4 and 11 months, following evaluation by an appropriately trained specialist. Gluten may be introduced between 4 and 12 months, but consumption of large quantities should be avoided during the first weeks after gluten introduction and later during infancy. All infants should receive iron-rich CF including meat products and/or iron-fortified foods. No sugar or salt should be added to CF and fruit juices or sugar-sweetened beverages should be avoided. Vegan diets should only be used under appropriate medical or dietetic supervision and parents should understand the serious consequences of failing to follow advice regarding supplementation of the diet. METHOD: Parents should be encouraged to respond to their infant's hunger and satiety queues and to avoid feeding to comfort or as a reward.

The treatment of inflammatory bowel disease (IBD) has been revolutionised over the past decade by the increasing use of immunomodulators. With such immunomodulation, the potential for opportunistic infection is a key safety concern for patients with IBD. Opportunistic infections pose particular problems for the clinician: they are often difficult to recognise and are associated with appreciable morbidity or mortality, because they are potentially serious and hard to treat effectively. This led the European Crohn's and Colitis Organisation (ECCO) to update the previous Consensus meeting on opportunistic infections in IBD. To organise the work, infections were classified into six major topics. Guideline statements of 2009 were analysed systematically by the chairs and the working parties. In parallel, the working parties performed a systematic literature search of their topic with the appropriate key words using Medline/Pubmed and the Cochrane database, as well as their own files. The evidence level (EL) was graded according to the 2011 Oxford Centre for Evidence-Based Medicine (http://www.cebm.net/index.aspx?o=5653). Provisional update guideline statements were then posted on a weblog. Discussions and exchange of the literature evidence among the working party members was then performed on the weblog. The working parties then met in Lille on the 15th–16th of November 2012 to agree on the statements. Consensus was defined as agreement by > 80% of participants, termed a Consensus Statement and numbered for convenience in the document. This paper is the product of work by gastroenterologists, infectious disease experts and pediatricians. It provides guidance on the prevention, detection and management of opportunistic infections in patients of all age categories with IBD. After a section on definitions and risk factors for developing opportunistic infection, there are five sections on different infectious agents, followed by a section on information and guidance for patients with IBD travelling frequently or to less economically developed countries. In the final section, a systematic work up and vaccination programme is proposed for consideration in patients exposed to immunomodulator therapies. The final document on each topic was written by the workgroup leader and their working party. Statements are intended to be read in context with qualifying comments and not read in isolation. The final text was edited for consistency of style by JF Rahier, F Magro, R Eliakim and JF Colombel before being circulated and approved by the participants. In some areas the level of evidence is generally low, which reflects the paucity of randomised controlled trials. Consequently expert opinion is included where appropriate. An immunocompromised host has an alteration in phagocytic, cellular, or humoral immunity that increases the risk of an infectious complication or an opportunistic process. Patients may also be immunocompromised if they have a breach of their skin or mucosal defense barriers that permits microorganisms to cause either local or systemic infection.1 There is no clearcut definition of an immunocompromised state. Three categories are recognised by the Centers for Disease Control,2 depending on the severity of immunosuppression: Persons who are severely immunocompromised not as a result of HIV infection: Severe immunosuppression can be the result of congenital immunodeficiency, leukemia, lymphoma, generalised malignancy or therapy with alkylating agents, antimetabolites, radiation, or high doses of corticosteroids (2 mg/kg body weight, or > 20 mg/day of prednisolone, Section 2.4.1) Persons with HIV infection Persons with conditions that cause limited immune deficits (e.g. hyposplenism and renal failure) An opportunistic infection may be defined as a usually progressive infection by a microorganism that has limited (or no) pathogenic capacity under ordinary circumstances, but which is able to cause serious disease as a result of the predisposing effect of another disease or of its treatment.3 Patients with IBD should not be routinely considered to have altered immunocompetence [EL5] per se, despite evidence of impaired innate mucosal immunity. Different immunomodulators may alter immune responsiveness by different mechanisms and to varying degrees, but there is currently no single method of evaluating the effects of immunosuppression on the immune system [EL5] From genome wide association studies there is increasing evidence of an aberrant immune response in IBD.4 Susceptibility loci involve both the innate and adaptive immune response towards a diminished diversity of commensal microbiota.5 Description of the numerous mechanisms contributing to this dysimmunity is beyond the scope of this article. Despite evidence of defective mucosal immunity, there is no proof of a systemic immune defect in patients with IBD in the absence of concomitant immunomodulator therapy. Patients with IBD are therefore rendered immunocompromised through their treatment. Immunomodulators commonly used in inflammatory bowel disease are corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, anti-tumor necrosis factor agents, or other biologics. Their modes of action differ, but they all compromise to some extent the immune To there is no to immunosuppression in patients with IBD. IBD patients risk of opportunistic infections are with immunomodulators in and with In and a of serious infections should be is an risk factor for opportunistic infections in IBD factors not the to opportunistic infection, but the infection to and to an extent that is not are factors for developing an opportunistic In a were associated with and bowel was therefore also patients with disease and the have defined categories of that are to the to or and that are to the and The immunomodulators commonly used in IBD and associated with an risk of infections corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, and other corticosteroids, a to 20 of for is associated with an risk of infections and infections have all been associated with the use of immunomodulator therapy in IBD. Despite different mechanisms of of can to of a immunomodulator and a of infection has been and that use was commonly associated with with infections and therapy with or There are commonly the infectious be the of that immunomodulators as risk factors for opportunistic infection the are to risk of both and infections in for in were and with and > 20 In the the for all infectious was with > the risk of opportunistic infection There are no in the IBD that a associated with risk of The risk of infections has been to use of corticosteroids in IBD patients corticosteroids and therapy and in the of infectious in a of In this a has therapy to infectious in Crohn's disease but not a different of not an risk with therapy for all therapy is associated with of serious infection in in the of treatment of opportunistic serious infections and of were in patients as in the and for The an risk of serious infections with therapy in Crohn's disease less that for corticosteroids and of all randomised controlled in a risk of opportunistic infections with immunomodulator an risk of infection, to a varying that has not been is the that of immunomodulator therapy in IBD are associated with an in the risk of opportunistic infection risk if immunomodulator was increasing if or were used to microorganisms is a risk factor for opportunistic infection in the immunocompromised with potential of and to areas may the risk of infection in IBD patients on immunomodulators consideration should be to patients and patients who not to be to immunomodulators as that are is to is to high as a with a a with infection or of in an where or other such as or are increases the risk for an opportunistic infection in the who are on immunomodulator microorganisms have been to be of in In both and in have been the of of In less economically developed the immunocompromised may be to and is defined as the of immune that to an of the to infection and to disease and In this there is evidence of in the innate and adaptive immune there is evidence that immune has to the infections commonly in the of the other there are to that infections with such as and infections are to 20 in the in In infections are in with the with the of of and In IBD age has been as an risk factor for of patients age > as a predisposing factor for opportunistic infections to age This was by who also an of opportunistic infections in patients or the of infections and in patients with for IBD as with patients or is of to patients with agents, age has also been as a of infection in a with The evidence in the IBD literature that immunosuppression increases the risk for but infections usually a 20 on in IBD who to an infection In of of IBD are and may be with immune such as altered and patients are to such as have been as risk factors for infection in disease and In IBD have been in as an risk factor for is immunomodulator therapy in patients with the immune system is of the to an immune The immune response can in has a on and is associated with impaired immunity, as well as and and of the to opportunistic infections and to to with cause and of immune the of infections and the impaired response to is in Crohn's disease and as to or often is of is factors to in to of and renal of and of or altered with to bowel and disease or bowel immunity has been in both in and in the and risk of infection has not been in IBD. has been as an risk factor for an risk of in patients with an level It is this was cause or a often reflects as a of infection or disease and is not a of in IBD a or has been associated with opportunistic infection in patients with or of are the body and the of a to a of and is a is of the IBD a to an IBD and immunomodulator therapy in with a 20 be in for using should be should be by detection of This is to the potential risk of as a result of concomitant infection with other or by the effects of Immunomodulators may are not but should be used with The on the severity of IBD and the of the The risk that therapy or with IBD therapy IBD should be the for treatment The the of infection in patients with IBD and its to immunomodulator therapy in patients of were in patients with were to corticosteroids and in to The severity of was for for of This also and for the of an was the cause of In there is a agreement in patients as the of with the of in and In studies have that the The of corticosteroids on disease has been in patients in are associated with and the in this is the of to in IBD patients to be to that in of as is in not to have a effect on the of and not to disease for of with HIV in may In a systematic with on patients who were with agents, for of the evidence that therapy be for infection a of as an to and therapy for patients with to response to a therapy in of patients with with no effect treatment with to or infection are vaccination or for potential infection is not In previous European no agreement be for or in the of to immunomodulators. on in some a and effect with other to and should be can be used in IBD patients of concomitant the other treatment for infection in with Crohn's disease is generally not therapy may this This is in to where therapy not to have an and the inhibitors, are of the which is for the of both and It has been in that the of both and which to serious or In the of or the therapy and may of used for IBD the risk of IBD by therapy or with IBD therapy should be the of treatment and consideration on an There are no of infection developing immunomodulator therapy. of immunomodulator therapy is not IBD patients should be for of IBD to In patients with should also be vaccination is in all patients with IBD. of vaccination is impaired in by the disease and by response should be doses of the may be to of should be in patients risk and for immunomodulator treatment has patients who are should with high to of the of in to Patients with and may have of with therapy used in IBD should be but therapy is not is of is a complication of immunosuppression in the of or in up to if therapy is not of therapy in patients with is by the of immunomodulators on the of infection in IBD be The of of in IBD were treatment and have been the of were other immunomodulators such as corticosteroids or thiopurines, that immunosuppression may studies the of infection in IBD patients and its to therapy have been in to of IBD patients with In of of patients with with The information is the and of immunomodulators in IBD that used in therapy and in other inflammatory conditions immunomodulators. In this of the patients who were treatment with or immunomodulators for a of were for not treatment. was in a Crohn's disease with and with corticosteroids and of infection to be with the immunosuppression used in in to patients IBD patients have to be for infection to infection or vaccination In patients with evidence of infection, and should also be The by infection, in systematic vaccination of all patients In the for vaccination has been the the of as as not in with high but also in or The of infection in IBD is that in the the of to areas may a local In this the of and may cause of to to frequently with a of often The vaccination 20 single and is to in the of IBD in with The of followed by and a if no response is has a the to The response should be to the patients vaccination per of > are to if treatment is the other a has to immune response in patients who and is the in The of is not well but for or in with and high In treatment with is to the of immunomodulators and for their Patients with high should treatment to patients are according to for of and that are and in IBD patients on immunomodulator and are the for IBD patients to their of and of In a of infection is the of may not be In the of immunosuppression with a high and of is for may Crohn's disease but not and may cause may in patients who are but and as well as in with and that of in IBD for is not patients should be routinely for of as well as for in and to on immunomodulator therapy on There are no of infection immunomodulator or therapies. where expert opinion has there is no treatment for infection in in the of immunomodulators disease or the of This has been for corticosteroids which the of by effects on as well as of the immune In IBD patients with infection, immunomodulators should be or of the infection or In treatment is in infection as is for for HIV is for and patients with and should of immunomodulator on of risk and severity of infections in patients immunomodulator therapy immunomodulators are not in patients is for patients risk The effect of corticosteroids on the of HIV infection in IBD patients has been are used as therapy in the treatment of of HIV infections such as or that patients immune is if this which is that used to treat IBD has a effect in HIV disease It is to use corticosteroids for the therapy of IBD patients with HIV infection who have immune and but no are the use of and its effect on HIV infection in IBD patients is with a 20 HIV IBD patients with IBD in HIV patients in HIV patients were The of patients were has been in the of HIV infection, by contributing to HIV through of have also been associated with of HIV infection and the of infectious It has also been proposed that as a of a immune response to may the There some studies on the effects of therapy on the of HIV infection which have been and of IBD patients or patients with have that in HIV a in HIV in a the effect of a therapy with in HIV patients with and > The response to was or to a treatment is difficult to such a that therapy may be to IBD patients with HIV infection and not have the effects on HIV HIV patients may be with if by the of IBD but they should be and to HIV infection are appropriate. to by using and in is appropriate for exposed to or are to be and is appropriate. IBD patients immunomodulator or therapy are for HIV infection HIV and with if infection is to infection, because of the potential of such therapy in HIV It is to the risk of HIV into The of inflammatory bowel disease in patients should be and treatment in with appropriate to the on the effect of immune treatment with on the of concomitant HIV and no are It is to that and immune that IBD patients have infectious IBD therapy if they not The to infection of IBD patients HIV on the of the is the risk may be different to but less increases the the of a with for of was but was potential immunomodulators and of the of are There may be or effects of the different in of or effects HIV infection can immunomodulator therapy but its should be a with Crohn's disease who HIV infection therapy with with this for From a of HIV infection should be according to with appropriate of immunomodulator or therapy should be considered if there is no response to by or in for infection is not before immunomodulator therapy In patients with should be by or before increasing immunomodulator therapy In of with in the immunomodulator therapy should be and of immunomodulators considered In of systemic immunomodulator therapy be therapy is often associated with of This is usually or by a is It is appropriate to a infection by or and disease as have that is frequently in patients with with or but In their were in all patients and or in agree with previous studies that of immunomodulator or therapy is but if therapy is with the of infection immunomodulator treatment may be There is no different are therapy for infection, the potential for not a of infections to for infection in IBD patients is not the patients are Different for the of infection are The high in the that is of limited for the of infection, but detection of can be used to infection in or This patients risk and the are but have of if is and to or are but as an of are to infection and treatment in immunocompromised if of by is not with using are and for infection in or The commonly used for of infection and disease is detection of through in and in the The of are high the potential for and detection in a wide of and and in In patients with has been in in and in of The has been to be a of is the therapy of for After a to for the of the to may be considered if depending on the and local In of or (e.g. is an or not treatment or of immunomodulator therapy and usually or is but associated with a treatment with or other and of is associated with and are for infection is not to of immunomodulator therapy infection is not a to immunomodulator therapy The for therapy should be considered in patients with or infection or immunomodulator therapy there is a is by or as a cause of IBD before increasing immunomodulator therapy In the of disease immunomodulator therapy should be and immunomodulators or and may be and in immunocompromised In a IBD patients therapy skin or with patients on may cause systemic infections with morbidity and and has potential for in immunocompromised may be the of This but complication of is in immunocompromised There is no for Patients should be if they have a of or infection, to and should be for patients with to should be considered for patients with who are therapy. or are as of and infection with but is not and are for Patients with or should be for section for of in skin or the or in doses for often a not of immunomodulators or systemic immunomodulators should not be infection, may be or for is in a with or may cause or therapy for IBD. therapy with or and of are and other or of or treatment can be and the for consideration on a is in patients with but cause or an The risk of is of patients should be by for to a of or of doses of should be for patients should the of to of immunomodulator therapy can be a of all therapy patients should therapy should not be infection with or In the of infection immunomodulator treatment should be and immunomodulator therapy in if therapy can be all have over and has [EL5] is often or in immunocompromised or or In a of in five of 20 of IBD on an risk of for and in a is also with an risk of IBD patients with were thiopurines, as patients evidence of five with In with a of the is with a doses of of and should be by of (or for to the is or or the up in a or they should be for It is to a which may for by patients with IBD should doses of a or the before immunomodulators are should be of all high of (or for a or are to be on high as are prednisolone, or for or for immune should be an with IBD has to or on exposed After patients should be for and in the of the provides both and It is in and a single is routinely for of over of IBD patients immunomodulators before and as for to therapy with of or are not considered to safety and are not as for of that may be in patients with the and safety of this vaccination is not in IBD patients with immunomodulators should and are is not for of or can be in or a skin The of on the are and and can in no and are on the and of the and the of the or not and for have but work is to the and to for are not to to the or action in and therapy should be treatment doses and the or with are to therapy is Immunomodulators should not be or Patients should be and with It may be to immunomodulator therapy for infection before of immunomodulator therapy should be considered In infection immunomodulator therapy may be considered and immunomodulator therapy In the of disease immunomodulator the should be in with appropriate Immunomodulators should be In the in the with of by is the of and the risk of infection in the is associated with a risk of patients and with of infection and of In has an risk of among IBD on In the of therapy a of for of The risk to result in for of but to be with a for In patients on thiopurines, of the were usually of in patients not on therapy. infection may pose a particular among patients under in the infectious associated of infectious have been in patients on is with or renal has been to the risk of in renal but the risk of in IBD is to this should be considered before of immunomodulator then be used in to in patients the The and are for infection is by the detection and the with usually or has a high for or in high risk and but The limited IBD or increases in of associated and by a is to infectious and in to the of for is not an as are often not therapy not the of infectious in therapy may be for have no in the treatment of the limited infection with and and therapy should be or if In infection, therapy with or may be despite the of are for infection, but are should be for and management of of therapy may result in of In the absence of or of is the of therapy for may also be for is for with if with immunomodulators In patients with of immunomodulator therapy should be considered vaccination is for and according to or past infection with is not a for immunomodulator therapy It is immunomodulators can the of the but there are of in immunocompromised studies in an risk of infection and studies in by IBD also that were the risk of infection and a using of and is in In a of and was approved in are and high infection in on local vaccination is for before of In the of or local vaccination to in some depending on of The is in for with vaccination for a can be to immunocompromised IBD to to immunocompromised through age and who not or all doses they were with being with and in this doses of the were and of and to or is a of or and reflects infection the are for of infection, because not all patients and can a or to of is for of a infection, but infection is and usually is limited to the detection of in immunocompromised is as for the is to patients on immunomodulators they have a is not for in the because there is currently no evidence that or treatment the risk of to in this for or of infections are for and studies a of associated with and in with IBD to the The risk of an associated with and has also been to in patients on immunomodulator the a in not in of IBD and In all factors and are if with IBD and on immunomodulators are to have as high risk patients according to local or The that who are immunocompromised should be the of and may be considered for of their infection with is no to and in particular are considered of IBD in with Crohn's and may be associated with infection with of There are of an of in immunocompromised of immunomodulators may be in patients with with on immunomodulators not a there are of in patients who have been on for is with a but the risk of the IBD by has to be considered and with the in patients therapy have been in Patients on immunomodulator therapy are considered to an risk for the of infection vaccination with is an to The is not not to have an on the of inflammatory bowel disease vaccination of patients on immunomodulators is in with is in patients immunomodulator in on therapy patients with a of should treatment in the of or not an has been treatment should be on an in with on the of infection in patients with IBD. the of not in IBD patients immunosuppression is generally considered to the risk of vaccination is the method for infection and is therefore for patients on immunomodulators in the for Disease of are should be used for age and is not for patients on immunomodulators. In the may be used for on IBD patients on immunomodulators are considered to be risk and vaccination has been with and proof of is There is to that vaccination may be less in patients with IBD The use of may also response to the immune response to vaccination in patients with IBD and is not associated with a

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P &lt; 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P &lt; 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

This document summarises the conclusions of a European Respiratory Society Task Force on the diagnosis and management of obstructive sleep disordered breathing (SDB) in childhood and refers to children aged 2-18 years. Prospective cohort studies describing the natural history of SDB or randomised, double-blind, placebo-controlled trials regarding its management are scarce. Selected evidence (362 articles) can be consolidated into seven management steps. SDB is suspected when symptoms or abnormalities related to upper airway obstruction are present (step 1). Central nervous or cardiovascular system morbidity, growth failure or enuresis and predictors of SDB persistence in the long-term are recognised (steps 2 and 3), and SDB severity is determined objectively preferably using polysomnography (step 4). Children with an apnoea-hypopnoea index (AHI) >5 episodes·h(-1), those with an AHI of 1-5 episodes·h(-1) and the presence of morbidity or factors predicting SDB persistence, and children with complex conditions (e.g. Down syndrome and Prader-Willi syndrome) all appear to benefit from treatment (step 5). Treatment interventions are usually implemented in a stepwise fashion addressing all abnormalities that predispose to SDB (step 6) with re-evaluation after each intervention to detect residual disease and to determine the need for additional treatment (step 7).

Whole-genome sequencing of neuroblastoma, a childhood tumour of the nervous system, shows that chromothripsis (a local shredding of chromosomes) and mutations in genes regulating neurite growth are associated with the most aggressive tumours. Whole-genome sequencing is used here to identify genetic defects in 87 people with neuroblastoma, a childhood tumour of the peripheral sympathetic nervous system. Analyses revealed few recurrent amino-acid-changing mutations, but a series of genes functioning in neuritogenesis and extension of neuronal growth cones were deleted in aggressive high-stage tumours. Chromothripsis, the localized shattering of the chromosomes, was common in high-stage tumours and was generally associated with poor prognosis. Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour1. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%)2,3,4,5. Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma6. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization7,8,9. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.

Abstract Key questions in COVID-19 are the duration and determinants of infectious virus shedding. Here, we report that infectious virus shedding is detected by virus cultures in 23 of the 129 patients (17.8%) hospitalized with COVID-19. The median duration of shedding infectious virus is 8 days post onset of symptoms (IQR 5–11) and drops below 5% after 15.2 days post onset of symptoms (95% confidence interval (CI) 13.4–17.2). Multivariate analyses identify viral loads above 7 log 10 RNA copies/mL (odds ratio [OR] of 14.7 (CI 3.57-58.1; p &lt; 0.001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract. A serum neutralizing antibody titre of at least 1:20 (OR of 0.01 (CI 0.003-0.08; p &lt; 0.001) is independently associated with non-infectious SARS-CoV-2. We conclude that quantitative viral RNA load assays and serological assays could be used in test-based strategies to discontinue or de-escalate infection prevention and control precautions.

BACKGROUND: Clinical pathways are structured multidisciplinary care plans used by health services to detail essential steps in the care of patients with a specific clinical problem. They aim to link evidence to practice and optimise clinical outcomes whilst maximising clinical efficiency. OBJECTIVES: To assess the effect of clinical pathways on professional practice, patient outcomes, length of stay and hospital costs. SEARCH STRATEGY: We searched the Database of Abstracts of Reviews of Effectiveness (DARE), the Effective Practice and Organisation of Care (EPOC) Register, the Cochrane Central Register of Controlled Trials (CENTRAL) and bibliographic databases including MEDLINE, EMBASE, CINAHL, NHS EED and Global Health. We also searched the reference lists of relevant articles and contacted relevant professional organisations. SELECTION CRITERIA: Randomised controlled trials, controlled clinical trials, controlled before and after studies and interrupted time series studies comparing stand alone clinical pathways with usual care as well as clinical pathways as part of a multifaceted intervention with usual care. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all titles to assess eligibility and methodological quality. Studies were grouped into those comparing clinical pathways with usual care and those comparing clinical pathways as part of a multifaceted intervention with usual care. MAIN RESULTS: Twenty-seven studies involving 11,398 participants met the eligibility and study quality criteria for inclusion. Twenty studies compared stand alone clinical pathways with usual care. These studies indicated a reduction in in-hospital complications (odds ratio (OR) 0.58; 95% confidence interval (CI) 0.36 to 0.94) and improved documentation (OR 13.65: 95%CI 5.38 to 34.64). There was no evidence of differences in readmission to hospital or in-hospital mortality. Length of stay was the most commonly employed outcome measure with most studies reporting significant reductions. A decrease in hospital costs/ charges was also observed, ranging from WMD +261 US$ favouring usual care to WMD -4919 US$ favouring clinical pathways (in US$ dollar standardized to the year 2000). Considerable heterogeneity prevented meta-analysis of length of stay and hospital cost results. An assessment of whether lower hospital costs contributed to cost shifting to another health sector was not undertaken.Seven studies compared clinical pathways as part of a multifaceted intervention with usual care. No evidence of differences were found between intervention and control groups. AUTHORS' CONCLUSIONS: Clinical pathways are associated with reduced in-hospital complications and improved documentation without negatively impacting on length of stay and hospital costs.

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

In the absence of any overt task performance, it has been shown that spontaneous, intrinsic brain activity is expressed as systemwide, resting-state networks in the adult brain. However, the route to adult patterns of resting-state activity through neuronal development in the human brain is currently unknown. Therefore, we used functional MRI to map patterns of resting-state activity in infants during sleep. We found five unique resting-states networks in the infant brain that encompassed the primary visual cortex, bilateral sensorimotor areas, bilateral auditory cortex, a network including the precuneus area, lateral parietal cortex, and the cerebellum as well as an anterior network that incorporated the medial and dorsolateral prefrontal cortex. These results suggest that resting-state networks driven by spontaneous signal fluctuations are present already in the infant brain. The potential link between the emergence of behavior and patterns of resting-state activity in the infant brain is discussed.

This medical position article by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition summarises the current status of breast-feeding practice, the present knowledge on the composition of human milk, advisable duration of exclusive and partial breast-feeding, growth of the breast-fed infant, health benefits associated with breast-feeding, nutritional supplementation for breast-fed infants, and contraindications to breast-feeding. This article emphasises the important role of paediatricians in the implementation of health policies devised to promote breast-feeding.The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition recognises breast-feeding as the natural and advisable way of supporting the healthy growth and development of young children. This article delineates the health benefits of breast-feeding, reduced risk of infectious diarrhoea and acute otitis media being the best documented. Exclusive breast-feeding for around 6 months is a desirable goal, but partial breast-feeding as well as breast-feeding for shorter periods of time are also valuable. Continuation of breast-feeding after the introduction of complementary feeding is encouraged as long as mutually desired by mother and child.The role of health care workers, including paediatricians, is to protect, promote, and support breast-feeding. Health care workers should be trained in breast-feeding issues and counselling, and they should encourage practices that do not undermine breast-feeding. Societal standards and legal regulations that facilitate breast-feeding should be promoted, such as providing maternity leave for at least 6 months and protecting working mothers.

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.