Southampton Children's Hospital

BACKGROUND: The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with ∼20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points. METHODS: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate. RESULTS: These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines. CONCLUSIONS: These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modern management strategies while maintaining vigilance around appropriate outcomes and safety issues.

BACKGROUND: Peanut allergy (PA) is known to impact on quality of life (QoL) of the sufferer, but little research has focused on all family members. We therefore sought to establish the impact of PA on QoL and reported anxiety of children with clinically confirmed PA, their parents and older siblings. METHODS: Forty-six families, who had a child with PA, completed QoL (PedsQL or WHOQOL-BREF), anxiety (SCAS or STAI) and perceived stress (PSS) scales. PA children completed a PA specific QoL questionnaire (Pediatr Allergy Immunol 2003;14:378). Parents and sibling also completed QoL proxy questionnaires for the PA child (PedsQL, Pediatr Allergy Immunol 2003;14:378). RESULTS: Mothers rated their own psychological (P < 0.01) and physical (P < 0.05) QoL significantly worse than fathers rated theirs, and had higher scores than fathers for anxiety (P < 0.05) and stress (P < 0.001). Children with PA had significantly poorer physical health-related QoL (P < 0.05), QoL within school (P < 0.01) and general QoL (P < 0.05) than their siblings did, and greater separation anxiety (P < 0.05). The majority of differences were between girls with PA and female siblings. Mothers felt that there was a greater impact on QoL for their PA child, compared with that reported by siblings, fathers or the PA children themselves (P < 0.01). CONCLUSIONS: Mothers report that they have significantly poorer QoL and suffer more anxiety and stress than fathers do; this inter-parental difference may be an important feature of family stress caused by PA. Siblings have a similar view of how QoL affects the PA child as the PA child does, while mothers may possibly overestimate this impact.

Sleep is crucial to children's health and development. Reduced physical activity and increased screen time adversely impact older children's sleep, but little is known about these associations in children under 5 y. This systematic review examined the association between screen time/movement behaviors (sedentary behavior, physical activity) and sleep outcomes in infants (0-1 y); toddlers (1-2 y); and preschoolers (3-4 y). Evidence was selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and synthesized using vote counting based on the direction of association. Quality assessment and a Grading of Recommendations, Assessment, Development and Evaluation was performed, stratified according to child age, exposure and outcome measure. Thirty-one papers were included. Results indicate that screen time is associated with poorer sleep outcomes in infants, toddlers and preschoolers. Meta-analysis confirmed these unfavorable associations in infants and toddlers but not preschoolers. For movement behaviors results were mixed, though physical activity and outdoor play in particular were favorably associated with most sleep outcomes in toddlers and preschoolers. Overall, quality of evidence was very low, with strongest evidence for daily/evening screen time use in toddlers and preschoolers. Although high-quality experimental evidence is required, our findings should prompt parents, clinicians and educators to encourage sleep-promoting behaviors (e.g., less evening screen time) in the under 5s.

Autoimmune diseases are chronic, multifactorial conditions. Through machine learning (ML), a branch of the wider field of artificial intelligence, it is possible to extract patterns within patient data, and exploit these patterns to predict patient outcomes for improved clinical management. Here, we surveyed the use of ML methods to address clinical problems in autoimmune disease. A systematic review was conducted using MEDLINE, embase and computers and applied sciences complete databases. Relevant papers included "machine learning" or "artificial intelligence" and the autoimmune diseases search term(s) in their title, abstract or key words. Exclusion criteria: studies not written in English, no real human patient data included, publication prior to 2001, studies that were not peer reviewed, non-autoimmune disease comorbidity research and review papers. 169 (of 702) studies met the criteria for inclusion. Support vector machines and random forests were the most popular ML methods used. ML models using data on multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease were most common. A small proportion of studies (7.7% or 13/169) combined different data types in the modelling process. Cross-validation, combined with a separate testing set for more robust model evaluation occurred in 8.3% of papers (14/169). The field may benefit from adopting a best practice of validation, cross-validation and independent testing of ML models. Many models achieved good predictive results in simple scenarios (e.g. classification of cases and controls). Progression to more complex predictive models may be achievable in future through integration of multiple data types.

Primary ciliary dyskinesia (PCD) is an inherited autosomal-recessive disorder of motile cilia characterised by chronic lung disease, rhinosinusitis, hearing impairment and subfertility. Nasal symptoms and respiratory distress usually start soon after birth, and by adulthood bronchiectasis is invariable. Organ laterality defects, usually situs inversus, occur in ∼50% of cases. The estimated prevalence of PCD is up to ∼1 per 10,000 births, but it is more common in populations where consanguinity is common. This review examines who to refer for diagnostic testing. It describes the limitations surrounding diagnosis using currently available techniques and considers whether recent advances to genotype patients with PCD will lead to genetic testing and screening to aid diagnosis in the near future. It discusses the challenges of monitoring and treating respiratory and ENT disease in children with PCD.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

Twenty children who presented with severe and communication difficulties at age 2 underwent a comprehensive assessment for autism, and were reassessed at age 4-5. In common with other recent studies, diagnosis of autistic spectrum disorders at age 2 was found to be reliable and stable. The communication and social skills of the children showed little change overall by the second assessment. However, children whose scores deteriorated in the social domain tended to have presented initially with more significant behaviour problems. Few repetitive behaviours were observed at age 2, whereas these were more apparent by age 4-5. The finding that early diagnosis of autism is reliable and stable has led to the development of an early diagnostic service in Southampton, which is described. The importance of early diagnosis is that it opens the door to early intervention programmes, which in turn prevent many problems from occurring in later life.

BACKGROUND AND AIM: Acute severe colitis (ASC) is one of the few emergencies in pediatric gastroenterology. Tight monitoring and timely medical and surgical interventions may improve outcomes and minimize morbidity and mortality. We aimed to standardize daily treatment of ASC in children through detailed recommendations and practice points which are based on a systematic review of the literature and consensus of experts. METHODS: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Fifteen predefined questions were addressed by working subgroups. An iterative consensus process, including 2 face-to-face meetings, was followed by voting of the national representatives of ECCO and all members of the Paediatric Inflammatory Bowel Disease (IBD) Porto group of ESPGHAN (43 voting experts). RESULTS: A total of 24 recommendations and 43 practice points were endorsed with a consensus rate of at least 91% regarding diagnosis, monitoring, and management of ASC in children. A summary flowchart is presented based on daily scoring of the Paediatric Ulcerative Colitis Activity Index. Several topics have been altered since the previous 2011 guidelines and from those published in adults. DISCUSSION: These guidelines standardize the management of ASC in children in an attempt to optimize outcomes of this intensive clinical scenario.

There is good evidence that morbidity and mortality increase for young persons (YP) following the move from paediatric to adult services. Studies show that effective transition between paediatric and adult care improves long-term outcomes. Many of the issues faced by young people across subspecialties with a long-term condition are generic. This article sets out some of the obstacles that have delayed the implementation of effective transition. It reports on a successful generic transition programme 'Ready Steady Go' that has been implemented within a large National Health Service teaching hospital in the UK, with secondary and tertiary paediatric services, where it is now established as part of routine care.

SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs∗18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657∗]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway. SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs∗18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657∗]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway. SHORT syndrome (MIM 269880) is a rare disorder characterized by short stature, hyperextensibility of joints and/or hernias, ocular depression, Rieger anomaly, and delays of tooth eruption.1Gorlin R.J. Cervenka J. Moller K. Horrobin M. Witkop Jr., C.J. Malformation syndromes. A selected miscellany.Birth Defects Orig. Artic. Ser. 1975; 11: 39-50PubMed Google Scholar Although these features provide the condition’s acronym, they do not capture the full range of clinical features, which can include a recognizable facial gestalt (triangular facies, lack of facial fat, and hypoplastic nasal alae with overhanging columella), a near universal partial lipodystrophy, insulin resistance, nephrophrocalcinosis, and hearing deficits, among many others.2Lipson A.H. Cowell C. Gorlin R.J. The SHORT syndrome: further delineation and natural history.J. Med. Genet. 1989; 26: 473-475Crossref PubMed Scopus (27) Google Scholar, 3Koenig R. Brendel L. Fuchs S. SHORT syndrome.Clin. Dysmorphol. 2003; 12: 45-49Crossref PubMed Scopus (25) Google Scholar, 4Aarskog D. Ose L. Pande H. Eide N. Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes.Am. J. Med. Genet. 1983; 15: 29-38Crossref PubMed Scopus (48) Google Scholar, 5Reardon W. Temple I.K. Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome.Am. J. Med. Genet. A. 2008; 146A: 1296-1298Crossref PubMed Scopus (11) Google Scholar, 6Brodsky M.C. Whiteside-Michel J. Merin L.M. Rieger anomaly and congenital glaucoma in the SHORT syndrome.Arch. Ophthalmol. 1996; 114: 1146-1147Crossref PubMed Scopus (15) Google Scholar, 7Schwingshandl J. Mache C.J. Rath K. Borkenstein M.H. SHORT syndrome and insulin resistance.Am. J. Med. Genet. 1993; 47: 907-909Crossref PubMed Scopus (27) Google Scholar Notably, both developmental milestones and cognition are normal for individuals with SHORT syndrome.3Koenig R. Brendel L. Fuchs S. SHORT syndrome.Clin. Dysmorphol. 2003; 12: 45-49Crossref PubMed Scopus (25) Google Scholar The first description of SHORT syndrome was of a sibling pair whose parents displayed no obvious features.1Gorlin R.J. Cervenka J. Moller K. Horrobin M. Witkop Jr., C.J. Malformation syndromes. A selected miscellany.Birth Defects Orig. Artic. Ser. 1975; 11: 39-50PubMed Google Scholar This has been followed by several reports of sporadic occurrences, suggesting an autosomal-recessive or de novo dominant mode of inheritance.6Brodsky M.C. Whiteside-Michel J. Merin L.M. Rieger anomaly and congenital glaucoma in the SHORT syndrome.Arch. Ophthalmol. 1996; 114: 1146-1147Crossref PubMed Scopus (15) Google Scholar However, there have also been several reports of parent-child transmissions, including male-to-male transmission, consistent with an autosomal-dominant inheritance pattern for SHORT syndrome.3Koenig R. Brendel L. Fuchs S. SHORT syndrome.Clin. Dysmorphol. 2003; 12: 45-49Crossref PubMed Scopus (25) Google Scholar, 4Aarskog D. Ose L. Pande H. Eide N. Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes.Am. J. Med. Genet. 1983; 15: 29-38Crossref PubMed Scopus (48) Google Scholar, 8Bankier A. Keith C.G. Temple I.K. Absent iris stroma, narrow body build and small facial bones: a new association or variant of SHORT syndrome?.Clin. Dysmorphol. 1995; 4: 304-312Crossref PubMed Scopus (15) Google Scholar, 9Sorge G. Ruggieri M. Polizzi A. Scuderi A. Di Pietro M. SHORT syndrome: a new case with probable autosomal dominant inheritance.Am. J. Med. Genet. 1996; 61: 178-181Crossref PubMed Scopus (54) Google Scholar The majority of affected individuals still appear to be simplex cases,3Koenig R. Brendel L. Fuchs S. SHORT syndrome.Clin. Dysmorphol. 2003; 12: 45-49Crossref PubMed Scopus (25) Google Scholar suggesting a significant contribution for de novo dominant mutations. Specific genes have been suggested to play a role in the etiology of SHORT syndrome. PITX2 (MIM 601542) was highlighted in an individual with Rieger anomaly and syndromic features including lipoatrophy, hyperextensibility, a ventricular septal heart defect, and dysmorphic facial features.10Karadeniz N.N. Kocak-Midillioglu I. Erdogan D. Bökesoy I. Is SHORT syndrome another phenotypic variation of PITX2?.Am. J. Med. Genet. A. 2004; 130A: 406-409Crossref PubMed Scopus (14) Google Scholar This individual had a familial chromosomal translocation involving PITX2.10Karadeniz N.N. Kocak-Midillioglu I. Erdogan D. Bökesoy I. Is SHORT syndrome another phenotypic variation of PITX2?.Am. J. Med. Genet. A. 2004; 130A: 406-409Crossref PubMed Scopus (14) Google Scholar Another individual with eye anomalies and short stature was found by microarray to have a large deletion spanning PITX2 and several other genes.11Lines M.A. Kozlowski K. Kulak S.C. Allingham R.R. Héon E. Ritch R. Levin A.V. Shields M.B. Damji K.F. Newlin A. Walter M.A. Characterization and prevalence of PITX2 microdeletions and mutations in Axenfeld-Rieger malformations.Invest. Ophthalmol. Vis. Sci. 2004; 45: 828-833Crossref PubMed Scopus (59) Google Scholar BMP4 (MIM 112262) is associated with microphthalmia and has been reported to be deleted, along with 14 other genes at 14q22.2, in a single individual diagnosed with SHORT syndrome.12Reis L.M. Tyler R.C. Schilter K.F. Abdul-Rahman O. Innis J.W. Kozel B.A. Schneider A.S. Bardakjian T.M. Lose E.J. Martin D.M. et al.BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome.Hum. Genet. 2011; 130: 495-504Crossref PubMed Scopus (85) Google Scholar Although they appear to have a syndrome related to Axenfield-Rieger anomaly, affected individuals with PITX2 and BMP4 mutations10Karadeniz N.N. Kocak-Midillioglu I. Erdogan D. Bökesoy I. Is SHORT syndrome another phenotypic variation of PITX2?.Am. J. Med. Genet. A. 2004; 130A: 406-409Crossref PubMed Scopus (14) Google Scholar, 12Reis L.M. Tyler R.C. Schilter K.F. Abdul-Rahman O. Innis J.W. Kozel B.A. Schneider A.S. Bardakjian T.M. Lose E.J. Martin D.M. et al.BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome.Hum. Genet. 2011; 130: 495-504Crossref PubMed Scopus (85) Google Scholar do not have the characteristic facial gestalt shared by the individuals in the original and subsequent descriptions of SHORT syndrome.1Gorlin R.J. Cervenka J. Moller K. Horrobin M. Witkop Jr., C.J. Malformation syndromes. A selected miscellany.Birth Defects Orig. Artic. Ser. 1975; 11: 39-50PubMed Google Scholar, 2Lipson A.H. Cowell C. Gorlin R.J. The SHORT syndrome: further delineation and natural history.J. Med. Genet. 1989; 26: 473-475Crossref PubMed Scopus (27) Google Scholar, 3Koenig R. Brendel L. Fuchs S. SHORT syndrome.Clin. Dysmorphol. 2003; 12: 45-49Crossref PubMed Scopus (25) Google Scholar, 4Aarskog D. Ose L. Pande H. Eide N. Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes.Am. J. Med. Genet. 1983; 15: 29-38Crossref PubMed Scopus (48) Google Scholar, 6Brodsky M.C. Whiteside-Michel J. Merin L.M. Rieger anomaly and congenital glaucoma in the SHORT syndrome.Arch. Ophthalmol. 1996; 114: 1146-1147Crossref PubMed Scopus (15) Google Scholar, 7Schwingshandl J. Mache C.J. Rath K. Borkenstein M.H. SHORT syndrome and insulin resistance.Am. J. Med. Genet. 1993; 47: 907-909Crossref PubMed Scopus (27) Google Scholar, 13Haan E. Morris L. SHORT syndrome: distinctive radiographic features.Clin. Dysmorphol. 1998; 7: 103-107Crossref PubMed Scopus (6) Google Scholar The FORGE (Finding of Rare Disease Genes) Canada Consortium is a collaborative project with the goal of identifying genetic mutations for rare childhood diseases.14Majewski J. Schwartzentruber J.A. Caqueret A. Patry L. Marcadier J. Fryns J.P. Boycott K.M. Ste-Marie L.G. McKiernan F.E. Marik I. et al.FORGE Canada ConsortiumMutations in NOTCH2 in families with Hajdu-Cheney syndrome.Hum. Mutat. 2011; 32: 1114-1117Crossref PubMed Scopus (82) Google Scholar, 15Bernier F.P. Caluseriu O. Ng S. Schwartzentruber J. Buckingham K.J. Innes A.M. Jabs E.W. Innis J.W. Schuette J.L. Gorski J.L. et al.FORGE Canada ConsortiumHaploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.Am. J. Hum. Genet. 2012; 90: 925-933Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 16Hood R.L. Lines M.A. Nikkel S.M. Schwartzentruber J. Beaulieu C. Nowaczyk M.J. Allanson J. Kim C.A. Wieczorek D. Moilanen J.S. et al.FORGE Canada ConsortiumMutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome.Am. J. Hum. Genet. 2012; 90: 308-313Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar We ascertained individuals with SHORT syndrome by contacting the members of the FORGE Canada Consortium and selected international colleagues and asking whether the physicians were aware of any individual(s) diagnosed with SHORT syndrome. Affected individuals and family members were recruited from Medical Genetics Clinics in North America, Israel, and the United Kingdom. Approval of the study design was obtained from the institutional research ethics board at the Children’s Hospital of Eastern Ontario, and free and informed consent was obtained from each study subject (or parent, if appropriate) prior to enrollment. Each individual was assessed by a medical geneticist, ophthalmologist, and/or pediatrician. Affected individuals 2 and 5 were previously published as cases of SHORT syndrome with associated nephrocalcinosis.5Reardon W. Temple I.K. Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome.Am. J. Med. Genet. A. 2008; 146A: 1296-1298Crossref PubMed Scopus (11) Google Scholar The clinical description of the affected individuals is presented in Table 1. DNA was extracted according to standard protocols. Paternity was confirmed by the genotyping of nine polymorphic simple-tandem-repeat markers.Table 1Clinical Characteristics of Individuals with SHORT SyndromeAffected Individual 1Affected Individual 2Affected Individual 3Affected Individual 4Affected Individual 5Affected Individual 6Affected Individual 7Age at assessment2 years10 years10.4 yearsbirth to 18 years4 years32 yearsat birthGenderfemalemalemalemalemalefemalemalePIK3R1 mutationc.1906_1907insC-c.1971T>Gc.1945C>Tc.1945C>Tc.1945C>Tc.1945C>TGrowthBirth weight1.556 kg at 365Reardon W. Temple I.K. Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome.Am. J. Med. Genet. A. 2008; 146A: 1296-1298Crossref PubMed Scopus (11) Google Scholar weeks0.760 kg at 32 weeks2.22 kg at 40 weeks2.52 kg at 38 weeks2.27 kg at term2.55 kg at term2.18 kg at termHeight (percentile)76.5 cm (<3rd)120 cm (<3rd)126 cm (3rd)132.5 cm at 11 years (5th); 160 cm at 18 years (<3rd)122.3 cm at 11 years (<3rd)148.5 cm (<3rd)45 cmWeight (percentile)8 kg (<3rd)not reported21.8 kg (<3rd)23.5 kg at 11 years (<3rd); 43 kg at 18 years (<3rd)17.9 kg at 11 years (<3rd)44 kg (3rd)2.18 kgHead circumference (percentile)43 cm (<3rd)not reported51.5 cm (25th)45.5 cm at 20 months (3rd)49 cm (25th)49.5 cm (<3rd)34 cmBone agenormaldelayed by 2.5 yearsdelayed by 24 monthsdelayednot reportednot reportednot reportedConnective TissueHyperextensibilitynoyes; especially small jointsyes; especially small jointsnonone reportednoNAHerniasnoinguinal hernianononone reportednonoFaciesTriangular faciesyesyesyesyesyesyesyesOcular depressionyesyesyesyesyesyesyesAged appearanceyesyesyesyesyesto handsto handsDimpleyesnonoyesyesnonoHypoplastic ala anterior-chamber with hypoplastic on of iris on delays or of and of with with and or narrow narrow to reported in the W. Temple I.K. Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome.Am. J. Med. Genet. A. 2008; 146A: 1296-1298Crossref PubMed Scopus (11) Google W. Temple I.K. Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome.Am. J. Med. Genet. A. 2008; 146A: 1296-1298Crossref PubMed Scopus (11) Google A. Keith C.G. Temple I.K. Absent iris stroma, narrow body build and small facial bones: a new association or variant of SHORT syndrome?.Clin. Dysmorphol. 1995; 4: 304-312Crossref PubMed Scopus (15) Google A. Keith C.G. Temple I.K. Absent iris stroma, narrow body build and small facial bones: a new association or variant of SHORT syndrome?.Clin. Dysmorphol. 1995; 4: 304-312Crossref PubMed Scopus (15) Google are not septal and ventricular septal in a new The are not septal and ventricular septal We capture and sequencing of for affected individual and two unaffected parents and for affected individual 2 for the was with the of variant and were as for FORGE M. Schwartzentruber J.A. Patry L. S. G. E. et al.FORGE Canada ConsortiumMutations in cause syndrome in Med. Genet. 2012; PubMed Scopus Google Scholar with a on the and We and by the and a to that with both were subsequently were to with H. R. and short with PubMed Scopus Google Scholar and was with the A. M. E. A. K. A. K. D. S. M. M.A. The a for DNA sequencing PubMed Scopus Google Scholar were with and from downstream We assessed of by the which showed that had of by at 20 each and short and were with H. A. J. N. G. G. R. and PubMed Scopus Google Scholar with the and were that at of the variant We by both K. M. H. of genetic from sequencing PubMed Scopus Google Scholar and to identify whether they and whether they are in the the in the and 2012; or in previously at the and we the from affected individual and unaffected de novo were in the affected and they were found to be in both The in is to be a by The frameshift c.1906_1907insC in exon 14 of a in the encoding and is to of the by PIK3R1. genes with two obvious from each we assessed the sequencing of affected individual 2 for any rare in a were in PIK3R1 or for affected individual several were highlighted as rare and were confirmed by Sanger were found to be and were for SHORT syndrome in this affected individual. was for PIK3R1 and no of any PIK3R1 was by Sanger sequencing in affected individuals exon 14 of affected individual 3 was found to have a mutation (c.1971T>G in both and affected individual was found to have a mutation in both parents and to be by Affected individual W. Temple I.K. Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome.Am. J. Med. Genet. A. 2008; 146A: 1296-1298Crossref PubMed Scopus (11) Google Scholar as as affected and A. Keith C.G. Temple I.K. Absent iris stroma, narrow body build and small facial bones: a new association or variant of SHORT syndrome?.Clin. Dysmorphol. 1995; 4: 304-312Crossref PubMed Scopus (15) Google Scholar has been previously three affected individuals were found to have the mutation, c.1945C>T (p.Arg649Trp), as affected individual and this mutation the of a mutations are not in or the The of rare mutations in the exon of PIK3R1 in of affected the of the mutation in two affected and a consistent inheritance pattern in a family and de novo cases provide genetic that we have identified the molecular cause of SHORT syndrome. The of a mutation in a disorder as SHORT syndrome can be a the of affected individuals and clinical the clinical we not identify a PIK3R1 mutation in affected individual the affected individuals in study features of SHORT syndrome of the phenotype of affected individual 2 confirmed that several of the features of SHORT syndrome stature, hernias, delayed a lack of fat, and an anterior-chamber ocular Table However, facial features appear from of the individuals The facial features in the individuals include a alae and a that individual 2 not have SHORT syndrome the lack of a PIK3R1 mutation and the recognizable facial This that SHORT syndrome is a and that on the facial PIK3R1 the of the as as the and G. a family of Sci. Full Text PDF PubMed Scopus Google Scholar The two are in the and D. and in of Genet. 26: PubMed Scopus Google Scholar is and to kinase for to first 2 to be This can by to by to a or by phosphorylation the in insulin 7: PubMed Scopus Google Scholar are two in and the identified in the individuals with SHORT syndrome are in the This is also in the and A lymphoblastoid cell was to be from affected individual c.1906_1907insC for were not for affected individuals 3 or or for individuals from the family of individual showed that the of the were in in in from individuals with by mutations in and were and the findings were consistent with a truncating PIK3R1 mutation a identified a in of affected individual they were consistent in with the to of the in with the and we found that of and were in from the of affected individual in from of in the PI3K-AKT-mTOR from from Individuals with SHORT and full The in from the individual and two previously individuals with The two individuals mutations in encoding the of and encoding the of M. J.L. Kim S. A. E. K.J. A. et novo mutations in of the cause Genet. 2012; PubMed Scopus Google Scholar The the of a of the by as as by and by A was in from individual and and The a to in from individual of of S6 S6 which is by is a of of that to from individual S6 phosphorylation on and from an individual with a mutation and show S6 as previously M. J.L. Kim S. A. E. K.J. A. et novo mutations in of the cause Genet. 2012; PubMed Scopus Google Scholar are of signaling this in the of individual The in from the individual and two previously individuals with The two individuals mutations in encoding the of and encoding the of M. J.L. Kim S. A. E. K.J. A. et novo mutations in of the cause Genet. 2012; PubMed Scopus Google Scholar The the of a of the by as as by and by A was in from individual and and The a to in from individual of of S6 S6 which is by is a of of that to from individual S6 phosphorylation on and from an individual with a mutation and show S6 as previously M. J.L. Kim S. A. E. K.J. A. et novo mutations in of the cause Genet. 2012; PubMed Scopus Google Scholar are of signaling this in the of individual 1. Another that has been in is a the in an individual with and insulin C.A. G. R. M. H. S. J.P. of in insulin a variant with kinase PubMed Scopus Google Scholar, I. J. M. of 2008; PubMed Scopus Google Scholar there has been a of an individual with and a of and from a mutation in exon of A.M. A. E. A.M. and cells in a the of Med. 2012; PubMed Scopus Google Scholar However, and were still the mutation was of the and A.M. A. E. A.M. and cells in a the of Med. 2012; PubMed Scopus Google Scholar findings suggest phenotypic for mutations this mutations in PIK3R1 in the multisystem phenotype of SHORT syndrome Although insulin might be to be an of is not universal among individuals with SHORT syndrome and is not a of the affected individuals reported this might with with a deletion of show a in insulin and of S. H. K. A. K. K. et insulin and in the of Genet. PubMed Scopus Google Scholar was that the other by were in these and the in insulin S. H. K. A. K. K. et insulin and in the of Genet. PubMed Scopus Google Scholar of and also in and in suggesting that the is for normal D. and in of Genet. 26: PubMed Scopus Google Scholar of the phosphorylation of phosphatidylinositol and an important that the of important downstream including and as part of the a in to by to the and of at a Sci. 2012; PubMed Scopus Google Scholar of in the of the at a Sci. 2012; PubMed Scopus Google Scholar mutations in (MIM are in disorders as syndrome (MIM and syndrome (MIM which are characterized by and a to or mutations in of this have been in syndrome (MIM M. D. R.L. J. Schwartzentruber J.A. Nikkel S.M. et of Rare Disease Canada novo and mutations in and cause a of related Genet. 2012; PubMed Scopus Google Scholar (MIM M. D. R.L. J. Schwartzentruber J.A. Nikkel S.M. et of Rare Disease Canada novo and mutations in and cause a of related Genet. 2012; PubMed Scopus Google Scholar (MIM and M. J.L. Kim S. A. E. K.J. A. et novo mutations in of the cause Genet. 2012; PubMed Scopus Google Scholar, M. D. R.L. J. Schwartzentruber J.A. Nikkel S.M. et of Rare Disease Canada novo and mutations in and cause a of related Genet. 2012; PubMed Scopus Google Scholar the of a single with a truncating mutation in PIK3R1 that the mechanism SHORT syndrome in an to the that the phosphorylation of S6 to that there is of the signaling by the PI3K-AKT-mTOR as in as syndrome (MIM and of this are associated with cell and Although further of cell from other individuals with SHORT syndrome be for the of PIK3R1 mutations on the of the PI3K-AKT-mTOR of a single cell a we have shown that dominant mutations in PIK3R1 cause SHORT a recognizable syndrome. The findings also suggest that the molecular mechanism of the disease might involve downregulation of the PI3K-AKT-mTOR which is important for and is that of other members of this in The to the study and this not have been This was by the of Canada the of and the was by and is a whose is by the Medical and is by a and are the of a from the of This was selected for study by the FORGE Canada of J. J. M. M. and S. The for presented are as of in SHORT with to 3 et of phosphatidylinositol 3 kinase (PI3K) as proliferation, and survival. A component in this is the by PIK3R1. we identified a PIK3R1 mutation in two unrelated families affected by partial lipodystrophy, body short stature, and Rieger anomaly This mutation to and and insulin signaling in from affected and in PDF with et of stature, hyperextensibility of joints and/or ocular depression, Rieger anomaly, and syndrome is a developmental disorder with an genetic cause and that include insulin and lack of We ascertained two unrelated individuals with SHORT that the phenotype was to de novo mutations in the and sequencing in the two and unaffected PDF

CONTEXT: Nonoperative treatment (NOT) with antibiotics alone of acute uncomplicated appendicitis (AUA) in children has been proposed as an alternative to appendectomy. OBJECTIVE: To determine safety and efficacy of NOT based on current literature. DATA SOURCES: Three electronic databases. STUDY SELECTION: All articles reporting NOT for AUA in children. DATA EXTRACTION: Two reviewers independently verified study inclusion and extracted data. RESULTS: Ten articles reporting 413 children receiving NOT were included. Six, including 1 randomized controlled trial, compared NOT with appendectomy. The remaining 4 reported outcomes of children receiving NOT without a comparison group. NOT was effective as the initial treatment in 97% of children (95% confidence interval [CI] 96% to 99%). Initial length of hospital stay was shorter in children treated with appendectomy compared with NOT (mean difference 0.5 days [95% CI 0.2 to 0.8]; P = .002). At final reported follow-up (range 8 weeks to 4 years), NOT remained effective (no appendectomy performed) in 82% of children (95% CI 77% to 87%). Recurrent appendicitis occurred in 14% (95% CI 7% to 21%). Complications and total length of hospital stay during follow-up were similar for NOT and appendectomy. No serious adverse events related to NOT were reported. LIMITATIONS: The lack of prospective randomized studies limits definitive conclusions to influence clinical practice. CONCLUSIONS: Current data suggest that NOT is safe. It appears effective as initial treatment in 97% of children with AUA, and the rate of recurrent appendicitis is 14%. Longer-term clinical outcomes and cost-effectiveness of NOT compared with appendicectomy require further evaluation, preferably in large randomized trials, to reliably inform decision-making.

OBJECTIVE: To conduct a meta-analysis of resting-state functional magnetic resonance imaging (R-fMRI) studies in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and in adults with ADHD to assess spatial convergence of findings from available studies. METHOD: Based on a preregistered protocol in PROSPERO (CRD42019119553), a large set of databases were searched up to April 9, 2019, with no language or article type restrictions. Study authors were systematically contacted for additional unpublished information/data. Resting-state functional magnetic resonance imaging studies using seed-based connectivity (SBC) or any other method (non-SBC) reporting whole-brain results of group comparisons between participants with ADHD and typically developing controls were eligible. Voxelwise meta-analysis via activation likelihood estimation with cluster-level familywise error (voxel-level: p < .001; cluster-level: p < .05) was used. RESULTS: Thirty studies (18 SBC and 12 non-SBC), comprising 1,978 participants (1,094 with ADHD; 884 controls) were retained. The meta-analysis focused on SBC studies found no significant spatial convergence of ADHD-related hyperconnectivity or hypoconnectivity across studies. This nonsignificant finding remained after integrating 12 non-SBC studies into the main analysis and in sensitivity analyses limited to studies including only children or only non-medication-naïve patients. CONCLUSION: The lack of significant spatial convergence may be accounted for by heterogeneity in study participants, experimental procedures, and analytic flexibility as well as in ADHD pathophysiology. Alongside other neuroimaging meta-analyses in other psychiatric conditions, the present results should inform the conduct and publication of future neuroimaging studies of psychiatric disorders.

Paediatric inflammatory bowel disease (PIBD), comprising Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBDU) is a complex and multifactorial condition with increasing incidence. An accurate diagnosis of PIBD is necessary for a prompt and effective treatment. This study utilises machine learning (ML) to classify disease using endoscopic and histological data for 287 children diagnosed with PIBD. Data were used to develop, train, test and validate a ML model to classify disease subtype. Unsupervised models revealed overlap of CD/UC with broad clustering but no clear subtype delineation, whereas hierarchical clustering identified four novel subgroups characterised by differing colonic involvement. Three supervised ML models were developed utilising endoscopic data only, histological only and combined endoscopic/histological data yielding classification accuracy of 71.0%, 76.9% and 82.7% respectively. The optimal combined model was tested on a statistically independent cohort of 48 PIBD patients from the same clinic, accurately classifying 83.3% of patients. This study employs mathematical modelling of endoscopic and histological data to aid diagnostic accuracy. While unsupervised modelling categorises patients into four subgroups, supervised approaches confirm the need of both endoscopic and histological evidence for an accurate diagnosis. Overall, this paper provides a blueprint for ML use with clinical data.

OBJECTIVE: To determine accuracy, safety and acceptability of the FreeStyle Libre Flash Glucose Monitoring System in the paediatric population. DESIGN, SETTING AND PATIENTS: Eighty-nine study participants, aged 4-17 years, with type 1 diabetes were enrolled across 9 diabetes centres in the UK. A factory calibrated sensor was inserted on the back of the upper arm and used for up to 14 days. Sensor glucose measurements were compared with capillary blood glucose (BG) measurements. Sensor results were masked to participants. RESULTS: Clinical accuracy of sensor results versus BG results was demonstrated, with 83.8% of results in zone A and 99.4% of results in zones A and B of the consensus error grid. Overall mean absolute relative difference (MARD) was 13.9%. Sensor accuracy was unaffected by patient factors such as age, body weight, sex, method of insulin administration or time of use (day vs night). Participants were in the target glucose range (3.9-10.0 mmol/L) ∼50% of the time (mean 12.1 hours/day), with an average of 2.2 hours/day and 9.5 hours/day in hypoglycaemia and hyperglycaemia, respectively. Sensor application, wear/use of the device and comparison to self-monitoring of blood glucose were rated favourably by most participants/caregivers (84.3-100%). Five device related adverse events were reported across a range of participant ages. CONCLUSIONS: Accuracy, safety and user acceptability of the FreeStyle Libre System were demonstrated for the paediatric population. Accuracy of the system was unaffected by subject characteristics, making it suitable for a broad range of children and young people with diabetes. TRIAL REGISTRATION NUMBER: NCT02388815.

Abstract Rationale The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children &amp;lt;30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97–2.60) compared with 0.02 units (95% CI, −0.29 to 0.34) in children given placebo (between-group treatment difference, −2.26 units; 95% CI, −2.71 to −1.81; P &amp;lt; 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, −51.2 mmol/L; 95% CI, −55.3 to −47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9–15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0–10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

UK good practice recommendations for outpatient parenteral antimicrobial therapy (OPAT) were published in 2012 and 2015 for adult and paediatric patients, respectively. Here we update the initial good practice recommendations in a combined document based on a further review of the OPAT literature and an extensive consultation process. As with the previous good practice recommendations, these updated recommendations are intended to provide pragmatic guidance for new and established OPAT services across a range of settings and to act as a set of quality indicators for service evaluation and quality improvement.

BACKGROUND AND AIM Acute severe colitis (ASC) is one of the few emergencies in pediatric gastroenterology. Tight monitoring and timely medical and surgical interventions may improve outcomes and minimize morbidity and mortality. We aimed to standardize daily treatment of ASC in children through detailed recommendations and practice points which are based on a systematic review of the literature and consensus of experts. METHODS These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Fifteen predefined questions were addressed by working subgroups. An iterative consensus process, including 2 face-to-face meetings, was followed by voting of the national representatives of ECCO and all members of the Paediatric Inflammatory Bowel Disease (IBD) Porto group of ESPGHAN (43 voting experts). RESULTS A total of 24 recommendations and 43 practice points were endorsed with a consensus rate of at least 91% regarding diagnosis, monitoring, and management of ASC in children. A summary flowchart is presented based on daily scoring of the Paediatric Ulcerative Colitis Activity Index. Several topics have been altered since the previous 2011 guidelines and from those published in adults. DISCUSSION These guidelines standardize the management of ASC in children in an attempt to optimize outcomes of this intensive clinical scenario.

Summary Detailed contemporary knowledge of the characteristics of the surgical population, national anaesthetic workload, anaesthetic techniques and behaviours are essential to monitor productivity, inform policy and direct research themes. Every 3–4 years, the Royal College of Anaesthetists, as part of its National Audit Projects (NAP), performs a snapshot activity survey in all UK hospitals delivering anaesthesia, collecting patient‐level encounter data from all cases under the care of an anaesthetist. During November 2021, as part of NAP7, anaesthetists recorded details of all cases undertaken over 4 days at their site through an online survey capturing anonymous patient characteristics and anaesthetic details. Of 416 hospital sites invited to participate, 352 (85%) completed the activity survey. From these, 24,177 reports were returned, of which 24,172 (99%) were included in the final dataset. The work patterns by day of the week, time of day and surgical specialty were similar to previous NAP activity surveys. However, in non‐obstetric patients, between NAP5 (2013) and NAP7 (2021) activity surveys, the estimated median age of patients increased by 2.3 years from median (IQR) of 50.5 (28.4–69.1) to 52.8 (32.1–69.2) years. The median (IQR) BMI increased from 24.9 (21.5–29.5) to 26.7 (22.3–31.7) kg.m –2 . The proportion of patients who scored as ASA physical status 1 decreased from 37% in NAP5 to 24% in NAP7. The use of total intravenous anaesthesia increased from 8% of general anaesthesia cases to 26% between NAP5 and NAP7. Some changes may reflect the impact of the COVID‐19 pandemic on the anaesthetic population, though patients with confirmed COVID‐19 accounted for only 149 (1%) cases. These data show a rising burden of age, obesity and comorbidity in patients requiring anaesthesia care, likely to impact UK peri‐operative services significantly.

BACKGROUND: The National Confidential Enquiry describes the epidemiology of children admitted to hospital with head injury. METHOD: Children (<15 years old) who died or were admitted for >4 h with head injury were identified from 216 UK hospitals (1 September 2009 to 28 February 2010). Data were collected using standard proformas and entered on to a database. A descriptive analysis of the causal mechanisms, child demographics, neurological impairment, CT findings, and outcome at 72 h are provided. RESULTS: Details of 5700 children, median age 4 years (range 0-14.9 years), were analysed; 1093 (19.2%) were <1 year old, 3500 (61.4%) were boys. There was a significant association of head injury with social deprivation 39.7/100 000 (95% CI 37.0 to 42.6) in the least deprived first quintile vs. 55.1 (95% CI 52.1 to 58.2) in the most deprived fifth quintile (p<0.01). Twenty-four children died (0.4%). Most children were admitted for one night or less; 4522 (79%) had a Glasgow Coma Scale score of 15 or were Alert (on AVPU (Alert, Voice, Pain, Unresponsive)). The most common causes of head injury were falls (3537 (62.1%); children <5 years), sports-related incidents (783 (13.7%); median age 12.4 years), or motor vehicle accidents (MVAs) (401 (7.1%); primary-school-aged children). CT scans were performed in 1734 (30.4%) children; 536 (30.9%) were abnormal (skull fracture and/or intracranial injury or abnormality): 269 (7.6%) were falls, 82 (10.5%) sports related and 100 (25%). A total of 357 (6.2%) children were referred to social care because of child protection concerns (median age 9 months (range 0-14.9 years)). CONCLUSIONS: The data described highlight priorities for targeted age-specific head injury prevention and have the potential to provide a baseline to evaluate the effects of regional trauma networks (2012) and National Institute of Health and Care Excellence (NICE) head injury guidelines (2014), which were revised after the study was completed.

AIM: To evaluate long-term cognitive and behavioural outcomes of children with neonatal hypoxic-ischaemic encephalopathy (HIE) in the absence of cerebral palsy (CP). METHODS: A systematic search was performed on five databases (EMBASE, Medline, PubMed, Web of Science, PsycInfo). Randomised controlled trials, non-randomised controlled trials, or observational studies, published between 1990 and 2017, that reported long-term (age greater than or equal to four years) cognitive and/or behavioural outcomes of neonatal HIE without CP were included. RESULTS: Seven articles met the inclusion criteria (n = 352 total participants, n = 53 treated with therapeutic hypothermia). Studies reporting cognitive outcome demonstrate impairment of general cognitive abilities in 25-63% of participants with HIE without CP. Specific cognitive difficulties were reported in two studies for attention, executive functioning, memory function and language. Results regarding behavioural outcome possibly indicate a higher risk of difficulties. CONCLUSION: A substantial proportion of children with neonatal HIE who survive without CP are at increased risk of general and/or specific cognitive impairments. Behavioural problems may be more common, but evidence is limited. Results highlight the importance of comprehensive long-term follow-up to identity difficulties and enable intervention to optimise educational achievement and behavioural adjustment.