Integration of EpiSign, facial phenotyping, and likelihood ratio interpretation of clinical abnormalities in the re-classification of an ARID1B missense variant.

Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome-wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome-specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype-driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype-phenotype has been expanded through an extended analysis of missense variation through genome-wide methylation signatures, ML facial phenotyping, and likelihood-ratio gene prioritization.

Improving the prescribing of palivizumab.

AIM: Palivizumab prevents respiratory syncytial virus (RSV) in children at high risk of severe disease. This paper reviews the use and effectiveness of palivizumab at two tertiary paediatric hospitals (hospitals A and B) in New South Wales, Australia. METHODS: Children prescribed palivizumab during the pre-intervention period, 1 January 2013 until 31 December 2014, were compared with children under 2 years of age who were admitted to paediatric intensive care units (PICUs) with an RSV infection. Eligibility for palivizumab was determined. To improve evidence-based utilisation of palivizumab, a 'streamlined palivizumab individual patient use' (IPU) pro forma was introduced at hospital A during 2015, and its applicability was reviewed. RESULTS: In the 2 years prior to implementing the streamlined IPU, 47 children received palivizumab, with 87% at hospital A. Of the children at hospital A, 32% did not meet the guidelines, and 32% did not complete the course. While 13% of children admitted to PICU for RSV infection were eligible for palivizumab, none received it prior to admission. In 2015, 16 streamlined IPUs were submitted, and 11 patients received palivizumab. Of these patients, 27% did not meet the guidelines, and 63% did not complete the course. Of the children who received palivizumab during the three RSV seasons, one developed an RSV infection, and none were admitted to PICU. CONCLUSIONS: Palivizumab is often prescribed without meeting recognised best practice guidelines, and patients eligible are frequently not prescribed palivizumab. The streamlined IPU, implemented in hospital A, excluded patients who did not meet guidelines. The pro forma needs further refinement, and complementary strategies introduced to improve compliance.

Temporal trends in paediatric bacterial meningitis in a tropical Australian region: 1992-2014.

AIM: The epidemiology of community-acquired bacterial meningitis has changed following the introduction of routine immunisation against common causative organisms. Indigenous children living in the Northern Territory, Australia, have high rates of bacterial infections. This study describes changes in the epidemiology of childhood bacterial meningitis and the distribution of the burden of disease in the Top End. METHODS: A retrospective review of cases derived from hospital medical records and laboratory data was performed. Inclusion criteria were children aged 3 months to 14 years of age, admitted to Royal Darwin Hospital between 1992 and 2014 and diagnosed with bacterial meningitis. Annual incidence of bacterial meningitis and the distribution of causative pathogens are described. Demographic data, investigations, treatment and outcomes were compared between Indigenous and non-Indigenous children. RESULTS: There were 137 cases of childhood bacterial meningitis identified over the 23-year period. The incidence reduced from 21 per 100 000 children per year for 1992-2002 to 11 per 100 000 per year for 2003-2014 (P = 0.0025). Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitidis were the most common causative organisms, with a reduction in cases for each pathogen observed across the study period. Indigenous children were over-represented (104/137, 76%). Case fatality rate was 8% (11/137); 91% of fatal cases presented to a remote facility. CONCLUSIONS: The incidence of childhood bacterial meningitis has declined in the Northern Territory of Australia, but Indigenous children are disproportionately affected. Routine immunisation is beneficial for all, although further efforts to 'Close the Gap' between health outcomes in Indigenous and non-Indigenous Australians is required.

Paediatric antimicrobial stewardship and safe prescribing: an assessment of medical staff knowledge and behaviour.

OBJECTIVE: Determine baseline knowledge of antimicrobial stewardship, and safe prescribing among junior medical officers, monitor their level of participation in interactive education during protected teaching time and assess day-to-day prescribing behaviours over the subsequent 3-month period. METHODS: A voluntary and anonymous survey of all non-consultant level medical officers was conducted with the use of an audience response system during mandatory face-to-face orientation sessions at a tertiary paediatric hospital. Routine prescribing audits monitored compliance with national and locally derived quality use of medicines indicators. RESULTS: Eighty-six percent of medical officers participated by responding to at least one question (171/200). Response rate for individual questions ranged between 31% and 78%. Questions that addressed adverse drug reactions, documentation and monitoring for empiric antibiotics and the error-prone abbreviations IU and U were correctly answered by over 90% of participants. Other non-standard and error-prone abbreviations were less consistently identified. In practice, 68% of patients had complete adverse drug reaction documentation (113/166). Error-prone abbreviations were identified on 5% of audited medication orders (47/976), approximately half included a documented indication and intended dose. CONCLUSIONS: Participants demonstrated a good understanding of safe prescribing and antimicrobial stewardship. Audits of prescribing identified potential discrepancies between prescribing knowledge and behaviours.