Colin Powell

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD)

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.

Prospective cohort study to test the predictability of the Cardiff and Vale paediatric early warning system

Objective: To develop and test the predictability of a paediatric early warning score to identify children at risk of developing critical illness. Design: Prospective cohort study. Setting: Admissions to all paediatric wards at the University Hospital of Wales. Outcome measures: Respiratory arrest, cardiac arrest, paediatric high-dependency unit admission, paediatric intensive care unit admission and death. Results: Data were collected on 1000 patients. A single abnormal observation determined by the Cardiff and Vale paediatric early warning system (C&VPEWS) had a 89.0% sensitivity (95% CI 80.5 to 94.1), 63.9% specificity (95% CI 63.8 to 63.9), 2.2% positive predictive value (95% CI 2.0 to 2.3) and a 99.8% negative predictive value (95% CI 99.7 to 99.9) for identifying children who subsequently had an adverse outcome. The area under the receiver operating characteristic curve for the C&VPEWS score was 0.86 (95% CI 0.82 to 0.91). Conclusion: Identifying children likely to develop critical illness can be difficult. The assessment tool developed from the advanced paediatric life support guidelines on identifying sick children appears to be sensitive but not specific. If the C&VPEWS was used as a trigger to activate a rapid response team to assess the child, the majority of calls would be unnecessary.

Comparison of complementary and alternative medicine use: reasons and motivations between two tertiary children’s hospitals

Aims: To compare prevalence, reasons, motivations, initiation, perceived helpfulness, and communication of complementary and alternative medicine (CAM) use between two tertiary children’s hospitals. Methodology: A study, using a face-to-face questionnaire, of 500 children attending the University Hospital of Wales, Cardiff, UK was compared to an identical study of 503 children attending the Royal Children’s Hospital, Melbourne, Australia. Results: One year CAM use in Cardiff was lower than Melbourne (41% v 51%; OR = 0.67, 95% CI 0.52–0.85), reflected in non-medicinal use (OR = 0.41, 95% CI 0.29–0.58) and general paediatric outpatients (OR = 0.38, 95% CI 0.21–0.67). Compared to Melbourne, factors associated with lower CAM use in Cardiff included families born locally (father: OR = 0.58, 95% CI 0.44–0.77) or non-tertiary educated parents (mother: OR = 0.54, 95% CI 0.38–0.77). Cardiff participants used less vitamin C (OR = 0.31, 95% CI 0.18–0.51) and herbs (OR = 0.49, 95% CI 0.34–0.71), attended less chiropractors (OR = 0.25, 95% CI 0.06–0.37) and naturopaths (OR = 0.08, 95% CI 0.02–0.33), but saw more reflexologists (OR = 3.33, 95% CI 1.08–10.29). In Cardiff, CAM was more popular for relaxation (OR = 1.92, 95% CI 1.03–3.57) but less for colds/coughs (OR = 0.4, 95% CI 0.27–0.73). Most CAM was self-initiated (by parent) in Cardiff and Melbourne (74% v 70%), but Cardiff CAM users perceived it less helpful (OR = 0.46, 95% CI 0.31–0.68). Non-disclosure of CAM use was high in Cardiff and Melbourne (66% v 63%); likewise few doctors/nurses documented recent medicinal CAM use in inpatient notes (0/21 v 2/22). Conclusions: The differences in CAM use may reflect variation in sociocultural factors influencing reasons, motivations, attitudes, and availability. The regional variation in use and poor communication highlights the importance of local policy development.

A parent completed questionnaire to describe the patterns of wheezing and other respiratory symptoms in infants and preschool children

Aim: To develop a standardised and validated respiratory symptom questionnaire for use in epidemiological or follow up studies in infants and preschool children. Methodology: After initial design and development, the questionnaire was administered to two cohorts of subjects, one recruited from a respiratory clinic and the other from a postnatal ward. The two cohorts then repeated the questionnaire, two weeks apart. The qualities of the questionnaire were assessed. Results: Response rate to the initial questionnaire was 100% for the clinic based cohort and 64% for postnatally recruited families (total number of subjects 114). Questions showed good to moderate short term reliability (weighted kappa scores 0.47–0.7; average correct classification rates 0.74–0.91). Four domain concept scores showed excellent internal consistency (Cronbach alpha scores 0.87–0.95). Using principal component factor analysis, four new domains were devised showing acceptable construct validity and internal consistency. Criterion validity was assessed using a respiratory physician based diagnosis of asthma (RPBDA) as the gold standard for comparison. All eight scales in the questionnaire could significantly distinguish between infants with RPBDA and well or mildly symptomatic subjects. Conclusion: We have developed a practical, acceptable questionnaire with eight concept domains for use in infants and preschool children. The questionnaire has strong construct validity and internal consistency with good short term reliability of questions. More detailed study of criterion validity and the responsiveness of the questionnaire is required using a larger population and including children with the different phenotypes of wheezy illness.

Assessing the potential for outcome reporting bias in a review: a tutorial

BackgroundOutcome reporting bias (ORB) occurs when variables are selected for publication based on their results. This can impact upon the results of a meta-analysis, biasing the pooled treatment effect estimate.The aim of this paper is to show how to assess a systematic review and corresponding trial reports for ORB using an example review of intravenous and nebulised magnesium in the treatment of asthma.MethodsThe review was assessed for ORB by 1) checking the reasons, when available, for excluding studies to ensure that no studies were excluded because they did not report the outcomes of interest in the review; 2) assessing the eligible studies as to whether the review outcomes of interest were reported. Each study was classified using a system developed in the ORBIT (Outcome Reporting Bias In Trials) project to indicate whether ORB was suspected and a reason for the suspicion. Authors of trials that did not report the outcomes of interest were contacted for information. A sensitivity analysis was performed to assess the robustness of the conclusions of the review to this potential source of bias.ResultsTwenty-four studies were included in the review; two studies had been excluded for not reporting either of the two outcomes of interest. Six included studies did not report hospital admission and two did not report pulmonary function. There was high suspicion of outcome reporting bias in four studies. Results from the sensitivity analysis indicate that review conclusions were not overturned.ConclusionThis paper demonstrates, with the example of the magnesium review, how to assess a review for outcome reporting bias. A review should not exclude studies if they have not reported the outcomes of interest and should consider the potential for outcome reporting bias in all included studies.

A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)

Congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders identified by pathological erythroid precursors with perinuclear mitochondrial iron deposition in bone marrow. An international collaborative group of physicians and laboratory scientists collated clinical information on cases of CSA lacking known causative mutations, identifying a clinical subgroup of CSA associated with B immunodeficiency, periodic fevers, and development delay. Twelve cases from 10 families were identified. Median age at presentation was 2 months. Anemia at diagnosis was sideroblastic, typically severe (median hemoglobin, 7.1 g/dL) and markedly microcytic (median mean corpuscular volume, 62.0 fL). Clinical course involved recurrent febrile illness and gastrointestinal disturbance, lacking an infective cause. Investigation revealed B-cell lymphopenia (CD19⁺ range, 0.016-0.22 × 10⁹/L) and panhypogammaglobulinemia in most cases. Children displayed developmental delay alongside variable neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem features. Most required regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement. Median survival was 48 months, with 7 deaths caused by cardiac or multiorgan failure. One child underwent bone marrow transplantation aged 9 months, with apparent cure of the hematologic and immunologic manifestations. We describe and define a novel CSA and B-cell immunodeficiency syndrome with additional features resembling a mitochondrial cytopathy. The molecular etiology is under investigation.

Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial

BACKGROUND Little evidence is available for the effect of nebulised magnesium sulphate (MgSO(4)) in acute asthma in children. We assessed the effect of MgSO(4) treatment in children with severe acute asthma. METHODS In this randomised placebo-controlled, multi-centre, parallel trial, we enrolled children (aged 2-16 years) with severe acute asthma who did not respond to standard inhaled treatment from 30 hospitals in the UK. Children were randomly allocated (1:1) to receive nebulised salbutamol and ipratropium bromide with either 2·5 mL of isotonic MgSO(4) (250 mmol/L; 151 mg per dose; MgSO(4) group) or 2·5 mL of isotonic saline (placebo group) on three occasions at 20-min intervals. Randomisation was done with a computer-generated randomisation sequence, with random block sizes of two to four. Both patients and researchers were masked to treatment allocation. The primary outcome measure was the Yung Asthma Severity Score (ASS) at 60 min post-randomisation. We used a statistical significance level of p<0·05 for a between-group difference, but regarded a between-group difference in ASS of 0·5 as the minimal clinically significant treatment effect. Analysis was done by intention to treat. This trial is registered with controlled-trials.com, number ISRCTN81456894. FINDINGS Between Jan 3, 2009, and March 20, 2011, we recruited and randomly assigned 508 children to treatment: 252 to MgSO(4) and 256 to placebo. Mean ASS at 60 min was lower in the MgSO(4) group (4·72 [SD 1·37]) than it was in the placebo group (4·95 [SD 1·40]; adjusted difference -0·25, 95% CI -0·48 to -0·02; p=0·03). This difference, however, was not clinically significant. The clinical effect was larger in children with more severe asthma exacerbation (p=0·03) and those with symptoms present for less than 6 h (p=0·049). We detected no difference in the occurrence of adverse events between groups. INTERPRETATION Overall, nebulised isotonic MgSO(4), given as an adjuvant to standard treatment, did not show a clinically significant improvement in mean ASS in children with acute severe asthma. However, the greatest clinical response was seen in children with more severe attacks (SaO(2)<92%) at presentation and those with preceding symptoms lasting less than 6 h. FUNDING National Institute for Health Research Health Technology Assessment Programme.

Use of paediatric early warning systems in Great Britain: has there been a change of practice in the last 7 years?

Objective To determine the use of paediatric early warning systems (PEWS) and rapid response teams (RRTs) in paediatric units in Great Britain. Design Cross sectional survey. Setting All hospitals with inpatient paediatric services in Great Britain. Outcome measures Proportion of units using PEWS, origin of PEWS used, criterion included in PEWS, proportion of units with an RRT and membership of RRT. Results The response rate was 95% (149/157). 85% of units were using PEWS and 18% had an RRT in place. Tertiary units were more likely than district general hospital to have implemented PEWS, 90% versus 83%, and an RRT, 52% versus 10%. A large number of PEWS were in use, the majority of which were unpublished and unvalidated systems. Conclusions Despite the inconclusive evidence of effectiveness, the use of PEWS has increased since 2005. The implementation has been inconsistent with large variation in the PEWS used, the activation criteria used, availability of an RRT and the membership of the RRT. There must be a coordinated national evaluation of the implementation, impact and effectiveness of a standardised PEWS programme in the various environments where acutely sick children are managed.

How to implement change in clinical practice.

Changing clinical practice is a major challenge. It is not acceptable simply to send out a new clinical guideline or care pathway and expect there to be a change in practice. This paper addresses the problems associated with the development of a clinical guideline and sets out a clear strategy for dissemination, implementation and evaluation in a way that should promote the successful change of practice. The first section examines the development of the guideline. National or international guidelines may well exist but local adaptation and refinement of those guidelines are required, along with a local summary document. Valid, reproducible, evidence-based, clear, logical, easily accessible guidelines need to be available after widespread local, multi-professional consultation. Second, prior to dissemination, there needs to be promotion among all the health professionals and families involved with the change in practice. Appropriate educational and multi-disciplinary interventions, highlighting and informing in workshops and preparing people for the changes are recommended. Recognising the barriers to implementation and change and addressing these locally is important. Once the guideline has been disseminated and implemented and the change in practice has occurred, full evaluation and ongoing audit of the changes in practice are required to sustain the changes.

Safety incidents in the primary care office setting

BACKGROUND: In the United Kingdom, 26% of child deaths have identifiable failures in care. Although children account for 40% of family physicians’ workload, little is known about the safety of care in the community setting. Using data from a national patient safety incident reporting system, this study aimed to characterize the pediatric safety incidents occurring in family practice. METHODS: We undertook a retrospective, cross-sectional, mixed methods study of pediatric reports submitted to the UK National Reporting and Learning System from family practice. Analysis involved detailed data coding using multiaxial frameworks, descriptive statistical analysis, and thematic analysis of a special-case sample of reports. Using frequency distributions and cross-tabulations, the relationships between incident types and contributory factors were explored. RESULTS: Of 1788 reports identified, 763 (42.7%) described harm to children. Three crosscutting priority areas were identified: medication management, assessment and referral, and treatment. The 4 incident types associated with the most harmful outcomes are errors associated with diagnosis and assessment, delivery of treatment and procedures, referrals, and medication provision. Poor referral and treatment decisions in severely unwell or vulnerable children, along with delayed diagnosis and insufficient assessment of such children, featured prominently in incidents resulting in severe harm or death. CONCLUSION: This is the first analysis of nationally collected, family practice–related pediatric safety incident reports. Recommendations to mitigate harm in these priority areas include mandatory pediatric training for all family physicians; use of electronic tools to support diagnosis, management, and referral decision-making; and use of technological adjuncts such as barcode scanning to reduce medication errors.