Variability of neonatal premedication practices for endotracheal intubation and LISA in the UK (NeoPRINT survey).

OBJECTIVE: The NeoPRINT Survey was designed to assess premedication practices throughout UK NHS Trusts for both neonatal endotracheal intubation and less invasive surfactant administration (LISA). DESIGN: An online survey consisting of multiple choice and open answer questions covering preferences of premedication for endotracheal intubation and LISA was distributed over a 67-day period. Responses were then analysed using STATA IC 16.0. SETTING: Online survey distributed to all UK Neonatal Units (NNUs). PARTICIPANTS: The survey evaluated premedication practices for endotracheal intubation and LISA in neonates requiring these procedures. MAIN OUTCOME MEASURES: The use of different premedication categories as well as individual medications within each category was analysed to create a picture of typical clinical practice across the UK. RESULTS: The response rate for the survey was 40.8 % (78/191). Premedication was used in all hospitals for endotracheal intubation but overall, 50 % (39/78) of the units that have responded, use premedications for LISA. Individual clinician preference had an impact on premedication practices within each NNU. CONCLUSION: The wide variability on first-line premedication for endotracheal intubation noted in this survey could be overcome using best available evidence through consensus guidance driven by organisations such as British Association of Perinatal |Medicine (BAPM). Secondly, the divisive view around LISA premedication practices noted in this survey requires an answer through a randomised controlled trial.

Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variation.

The abnormal vascular structures of hereditary hemorrhagic telangiectasia (HHT) often cause severe anemia due to recurrent hemorrhage, but HHT causal genes do not predict the severity of hematological complications. We tested for chance inheritance and clinical associations of rare deleterious variants in which loss-of-function causes bleeding or hemolytic disorders in the general population. In double-blinded analyses, all 104 patients with HHT from a single reference center recruited to the 100 000 Genomes Project were categorized on new MALO (more/as-expected/less/opposite) sub-phenotype severity scales, and whole genome sequencing data were tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, or platelet, hemoglobin, erythrocyte enzyme, and erythrocyte membrane constituents. Rare variants (all gnomAD allele frequencies <0.003) were identified in 56 (75%) of these 75 HHT-unrelated genes. Deleteriousness assignments by Combined Annotation Dependent Depletion (CADD) scores >15 were supported by gene-level mutation significance cutoff scores. CADD >15 variants were identified in 38/104 (36.5%) patients with HHT, found for 1 in 10 patients within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to HHT vessels had more CADD-deleterious variants in platelet (Spearman ρ = 0.25; P = .008) and coagulation (Spearman ρ = 0.21; P = .024) genes. However, the HHT cohort had 60% fewer deleterious variants in platelet and coagulation genes than expected (Mann-Whitney test P = .021). In conclusion, patients with HHT commonly have rare variants in genes of relevance to their phenotype, offering new therapeutic targets and opportunities for informed, personalized medicine strategies.

DNA variant classification-reconsidering "allele rarity" and "phenotype" criteria in ACMG/AMP guidelines.

Recent guidance suggested modified DNA variant pathogenicity assignments based on genome-wide allele rarity. Different a priori probabilities of pathogenicity operate where patients already have clinical diagnoses, and are found to have a very rare variant in a gene known to cause their disease, compared to predictive testing of a clinically unaffected individual. We tested new recommendations from the ClinGen Sequence Variant Interpretation Working Group for ClinVar-listed, loss-of-function variants meeting the very strong evidence of pathogenicity criterion [PVS1] in genes for 3 specific diseases where causal gene identification can modify clinical care of an individual- Von Willebrand disease, cystic fibrosis and hereditary haemorrhagic telangiectasia. Across these diseases, current rules leave 20/1,278 (1.6%) of loss-of-function variants as variants of uncertain significance (VUS that may not be reported to clinicians), and 207/1,278 (17.2%) as likely pathogenic. Applying the new ClinGen rule enabling PVS1 and the allele rarity criterion PM2 to delineate likely pathogenicity still left 8/1,278 (0.9%) as VUS (reflecting non-PVS1 calls by the submitters), and the majority of null alleles meeting PVS1 as merely likely pathogenic. We favour an approach whereby, for PVS1 variants in patients who personally meet the phenotypic PP4 criterion for a disease where casual variants are commonly family-specific, that PM2 is upgraded to permit a pathogenic call. Of 1,278 ClinVar-listed frameshift, nonsense and canonical splice site variants that met PVS1 in the 3 conditions, 16.0% (204/1,278) would be newly designated as pathogenic, avoiding misinterpretation outside of clinical genetics communities. We suggest further discussion around variant assessment across different clinical applications, potentially guided by PP4 alerts to distinguish personal versus family phenotypic history.

Are neurocognitive factors associated with repetition of self-harm? A systematic review.

BACKGROUND: Prediction of self-harm is limited clinically. Early identification of individuals likely to repeat self-harm could improve outcomes and reduce suicide risk. Various neurocognitive deficits have been found in people who self-harm, but the ability of these to predict repetition has yet to be established AIMS: Identify neurocognitive factors that may predict repetition of self-harm. METHODS: Systematic narrative review of English language publications assessing neurocognitive functioning and self-harm repetition, searching multiple databases from inception to March 2015. Quality of studies was appraised. A narrative synthesis was performed. RESULTS: 7026 unique records were identified, and 169 full-texts assessed. 15 unique studies provided data. No imaging studies could be included. Most studies assessed cognitive control or problem solving, but neither factor was consistently associated with repetition. However, specific tasks may show promise. Two studies in adolescents suggest that value-based decision-making impairments could be predictive of repetition. There were too few results for memory to draw specific conclusions. CONCLUSIONS: Selected studies suggest promise for particular neurocognitive factors and specific cognitive tasks in terms of repetition of self-harm.

Is treatment for bipolar disorder more effective earlier in illness course? A comprehensive literature review.

BACKGROUND: We aimed to investigate a key element of the early intervention approach whether treatment at an earlier stage of bipolar disorder is more effective than later in its course. METHODS: A comprehensive literature review using Medline, Embase, Psychinfo, PsycArticle, and Web of Science, as data sources, with a subsequent narrative synthesis. Study quality was assessed using the Cochrane risk of bias method. RESULTS: Our search strategy yielded eight primary papers and two meta-analyses (of psychological therapies and Olanzapine) in total representing 8942 patients. Five studies focused on comparisons between first and multiple episodes, and the others on fewer vs more episode categories. There was a consistent finding, suggesting treatment in earlier illness stage resulted in better outcomes in terms of response, relapse rate, time to recurrence, symptomatic recovery, remission, psychosocial functioning, and employment. This effect was found for pharmacological (Lithium, Olanzapine, Divalproex) and psychological treatments. LIMITATIONS: There was high risk of selection, performance, and attrition bias in most studies. First admission or presentation is unlikely to equate to first episode, because of the duration of untreated illness. Some patients having experienced multiple episodes could be "treatment resistant". Study heterogeneity precluded meta-analysis. CONCLUSIONS: Psychological and pharmacological treatments in the early stages of illness are more effective than in the later stages of bipolar disorder across multiple domains. There is a first episode and the early phase effect. Consistent with the staging model of illness, findings provide evidence for the clinical utility of an early intervention approach in bipolar disorder to improve patient outcomes.