Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases α, δ, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 10 nucleotides/min with an error rate of less than one per million nucleotides polymerized. The majority of DNA replication of undamaged DNA is conducted by DNA polymerases δ and ε. The DNA polymerase α-primase complex performs limited synthesis to initiate the replication process, along with Okazaki-fragment synthesis on the discontinuous lagging strand. An increasing number of human disorders caused by defects in different components of the DNA-replication apparatus have been described to date. These are clinically diverse and involve a wide range of features, including variable combinations of growth delay, immunodeficiency, endocrine insufficiencies, lipodystrophy, and cancer predisposition. Here, by using various complementary approaches, including classical linkage analysis, targeted next-generation sequencing, and whole-exome sequencing, we describe distinct missense and splice-impacting mutations in POLA1 in five unrelated families presenting with an X-linked syndrome involving intellectual disability, proportionate short stature, microcephaly, and hypogonadism. POLA1 encodes the p180 catalytic subunit of DNA polymerase α-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals. Our findings describe the presentation of pathogenic mutations in a catalytic component of a B family DNA polymerase member, DNA polymerase α.
Background
Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome‐wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response.
Objective
We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings.
Methods
A meta‐analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10−6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations.
Results
A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10−6). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10−3) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10−3). Additionally, the reported association of the L3MBTL4‐ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified.
Conclusions and clinical relevance
This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.
Our hypothesis was that children with mutations in genes coding for Glutathione S-transferases (GST) have worse asthma outcomes compared to children with active type genotype. Data were collected in five populations. The rs1695 single nucleotide polymorphism (GSTP1) was determined in all cohorts (3692 children) and GSTM1 and GSTT1 null genotype were determined in three (2362 children). GSTT1 null (but not other genotypes) was associated with a minor increased risk for asthma attack and there were no significant associations between GST genotypes and asthma severity. Interactions between GST genotypes and SHS exposure or asthma severity with the study outcomes were non-significant. We find no convincing evidence that the GST genotypes studied are related to asthma outcomes.
This study aimed to determine whether there are seasonal changes in the performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) assays, an interferon-gamma release assay widely used for the diagnosis of tuberculosis infection. Results of 31,932 QFT-GIT assays performed at a large independent, accredited diagnostic service provider in London, UK over a 4.5-year-period were analysed. The proportion of positive results was significantly lower in autumn (14.8%) than in spring (16.0%; p=0.0366) and summer (17.5%; p < 0.0001), but similar to winter (15.2%; p=0.4711). The proportion of indeterminate results was significantly higher in autumn (8.2%)than in spring (6.2%; p < 0.0001), summer (4.8%; p < 0.0001), and winter (6.2%; p < 0.0001). The highest proportions of indeterminate results were observed in October (8.4%) and November (8.8%), the lowest in June (4.5%). Our data show that significant seasonal variation occurs in the performance of QFT-GIT assays in a
temperate climate setting. Potential underlying mechanisms, including host and environmental factors, are discussed.
The identification of suitable outcome measures will improve the evaluation of integrated NHS care for the large number of children affected by neurodisability, and has the potential to encourage the provision of more appropriate and effective health care. This research sought to appraise the potential of patient-reported outcome measures (PROMs) for children and young people with neurodisability. This research aimed (i) to identify key outcomes of health care for children with neurodisability, beyond morbidity and mortality, from the perspectives of children, parents and professionals; (ii) to critically appraise existing generic multidimensional PROMs; and (iii) to examine whether or not the key outcomes might be measured by existing PROMs. We also sought agreement on a definition of neurodisability. Data were gathered in three main ways, (i) a systematic review identified eligible generic multidimensional PROMs and peer-reviewed studies evaluating psychometric performance using English-language questionnaires. Studies were appraised for methodological quality and psychometric performance was appraised using standard criteria. (ii) Focus groups and interviews with children and young people with neurodisability, and separately with parents, sought to identify important outcomes of NHS care, and their feedback on example PROM questionnaires. (iii) An online Delphi survey was conducted with a multidisciplinary sample of health professionals to seek agreement on appropriate NHS outcomes. In addition, we convened a consensus meeting with a small nominal group of young people, parents and professionals; the group sought agreement on a core set of important health outcomes. From the systematic review, we identified 126 papers that reported eligible evidence regarding the psychometric performance of 25 PROMs. Evidence of psychometric robustness was more favourable for a small number of PROMs: KIDSCREEN (generic), DISABKIDS (chronic-generic) and Child Health Utility 9D (preference-based measure). The Pediatric Quality of Life Inventory and KINDL offer both self-report and a proxy report version for a range of age bands, but evidence of their psychometric performance was weaker. Evidence was lacking in one or more respects for all candidate PROMs, in both general populations and those with neurodisability. Proxy reporting was found generally to be poorly correlated with self-report. Focus groups and interviews included 54 children and young people, and 53 parents. The more important health outcomes were felt to be communication, emotional well-being, pain, mobility, independence/self-care, worry/mental health, social activities and sleep. In addition, parents of children with intellectual impairment identified behaviour, toileting and safety as important outcomes. Participants suggested problems with the face validity of example PROM questionnaires for measuring NHS care. In the Delphi survey, 276 clinicians from a wide range of professions contributed to at least one of four rounds. Professionals rated pain, hearing, seeing, sleep, toileting, mobility and communication as key goals for the NHS but also identified treating neurological symptoms as important. Professionals in the Delphi survey and parents working with the research team agreed a proposed definition for neurodisability. The consensus meeting confirmed overlap between the outcomes identified as important by young people, parents and professionals, but not complete agreement. There was agreement between young people, parents and professionals regarding a core suite of more important health outcomes: communication, emotional well-being, pain, mobility, independence/self-care, worry/mental health, social activities and sleep. In addition, behaviour, toileting and safety were identified as important by parents. This research suggests that it would be appropriate to measure these constructs using PROMs to assess health care. None of the candidate PROMs in the review adequately captures all of the identified constructs, and there is inadequate evidence that candidate PROMs are psychometrically robust for use across children with neurodisability. Further consultation with young people, families and professionals is warranted to support the use of PROMs to measure NHS outcomes. Research to test potential PROMs with different age groups and conditions would be valuable. The National Institute for Health Research Health Services and Delivery Research programme.
AIM: To review the qualitative and quantitative evidence of the benefits of peer support for parents of children with disabling conditions in the context of health, well-being, impact on family, and economic and service implications. Method: We comprehensively searched multiple databases. Eligible studies evaluated parent-to-parent support and reported on the psychological health and experience of giving or receiving support. There were no limits on the child's condition, study design, language, date, or setting. We sought to aggregate quantitative data; findings of qualitative studies were combined using thematic analysis. Qualitative and quantitative data were brought together in a narrative synthesis. Results: Seventeen papers were included: nine qualitative studies, seven quantitative studies, and one mixed-methods evaluation. Four themes were identified from qualitative studies: (1) shared social identity, (2) learning from the experiences of others, (3) personal growth, and (4) supporting others. Some quantitative studies reported a positive effect of peer support on psychological health and other outcomes; however, this was not consistently confirmed. It was not possible to aggregate data across studies. No costing data were identified. Conclusion: Qualitative studies strongly suggest that parents perceive benefit from peer support programmes, an effect seen across different types of support and conditions. However, quantitative studies provide inconsistent evidence of positive effects. Further research should explore whether this dissonance is substantive or an artefact of how outcomes have been measured. © The Authors © 2013 Mac Keith Press.
Background: Parents of disabled children are encouraged to seek peer support. Delivering one-to-one support requires resources; therefore, investigating how these services may impact on families and those providing the service is important when evaluating such services. Methods: We carried out a qualitative study involving semi-structured interviews and focus groups. Participants were 12 parents and 23 befrienders who had contact with the Face2Face one-to-one befriending service in Devon and Cornwall during a 12-month period, and 10 professionals from health, social care and education services. Findings: Shared experience was perceived central to successful peer support and was a catalyst for other elements of support, enabling parents to (i) learn from the experience of others; (ii) speak freely in a safe and non-judgemental environment; and (iii) receive support and encouragement from their befriender. These elements underpinned perceived outcomes for both parents providing and receiving support. Outcomes for parents receiving support centred on emotional stability, personal growth and reduced isolation. Supporting parents experienced positive outcomes through their training, mutual support and the feeling that they were helping others. Parents and befrienders appeared to benefit through expanding their social network. Nevertheless providing support was reported to create emotional burden and concerns for befrienders around their performance, and also required a substantial time commitment. Conclusions: Befrienders as well as parents perceived positive outcomes from their involvement in peer support although there is also potential for less positive impact on those offering support. © 2014 John Wiley & Sons Ltd.
Background: Parents of disabled children often seek support from their peers. The shared experience between parents appears to be a crucial mediating factor. Understanding how a sense of shared experience is fostered can help to design and evaluate services that seek to provide peer support. Methods: We carried out a qualitative study involving semi-structured interviews and focus groups. Participants were 12 parents and 23 befrienders who had contact with the Face2Face one-to-one befriending service in Devon and Cornwall during a 12-month period, and 10 professionals from health, social care and education. Findings: Formal structures and processes in place such as training and ongoing supervision and support were highly valued as was the highly personalized, confidential, flexible, one-to-one at-home nature of the service. Crucial to establishing rapport was putting the right people together and ensuring a good match between befrienders and parents. Clearly, the befriending parent has to be emotionally prepared to provide help. However, if the parent being offered support was not ready to accept help at the time it was offered or the type of support was not right for them, they are less likely to engage with the service. Conclusion: Organizational and process factors as well as characteristics of the parents offering and receiving support contribute to the sense of shared experience in one-to-one peer support. These factors interact to influence whether peer support is effective and should be explicitly considered when designing and evaluating services. © 2015 John Wiley & Sons Ltd.
OBJECTIVES: To investigate recruitment processes across a range of clinical trials and from the perspective of parents, young people and practitioners to identify strategies to improve recruitment and its conduct across the spectrum of trials of medicines for children. DESIGN: Qualitative interview and observational study. SETTING: Eleven paediatric clinical trial centres recruiting to four trials. PARTICIPANTS: Members of 60 families approached to consider entry to one of the participating trials and 31 practitioners. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Data were verbatim transcripts of (1) audio-recorded trial recruitment discussions between practitioners and families (n = 41) and (2) semi-structured interviews with parents (n = 62), young people (n = 22) and practitioners (19 doctors and 12 research nurses). Analyses were interpretive, following the general principles of the constant comparative method. RESULTS: Practitioners were concerned to avoid overburdening parents and some indicated that they found approaching families about trials to be aversive. By contrast, even in the most difficult situations, parents did not mind being asked about trials and they did not describe the approach as burdensome. Some parents viewed the trial approach as a positive or exciting opportunity. Parents and young people took little active part in the trial discussions and asked few questions. Despite this, they were satisfied with how they had been approached, and spoke of how they had felt involved, valued, cared for and comfortable to interject during the discussion. However, we identified several parents who had important misunderstandings about the trial. There were few differences between parents who consented and those who declined a trial. Regardless of whether they consented or declined, parents' trial decisions were influenced by their perceptions of the trial in relation to their child's safety and well-being, potential benefits to the child and family, potential benefits to others and the practicality of participation. Of these, parents' paramount consideration was safety. Parents', young people's and practitioners' views of what was important when considering a trial were broadly convergent, although families gave greater importance than practitioners to the trial's practical requirements. All parties valued the face-to-face trial discussion highly and wanted shorter and less complex written information. Parents did not feel pressured by the trial team to participate, but some described how their personal values made them reluctant to decline, and several parents who did decline described a passing sense of discomfort. CONCLUSIONS: The concerns of some practitioners that families would be overburdened were unfounded, as parents did not object to being asked about research. Practitioners may benefit from support that helps them feel personally more at ease in approaching families about trials. Parents and young people often described the trial discussions in strongly positive terms and emphasised the importance of the social and emotional aspects of these encounters. Informed consent training could be enhanced if it similarly emphasised these aspects of recruitment; the misunderstandings we identified indicate how this training could also help practitioners to improve the clarity of their trial discussions with families. Guidelines on informed consent documents should take account of findings that all groups thought that these documents should be shorter and more straightforward. FUNDING: This research was commissioned by the National Institute for Health Research Health Technology Assessment programme.
BACKGROUND: Health services are increasingly focused on measuring and monitoring outcomes, particularly those that reflect patients' priorities. To be meaningful, outcomes measured should be valued by patients and carers, be consistent with what health professionals seek to achieve, and be robust in terms of measurement properties. The aim of this study was (i) to seek a shared vision between families and clinicians regarding key aspects of health as outcomes, beyond mortality and morbidity, for children with neurodisability, and (ii) to appraise which multidimensional patient reported outcome measures (PROMs) could be used to assess salient health domains.
METHODS: Relevant outcomes were identified from (i) qualitative research with children and young people with neurodisability and parent carers, (ii) Delphi survey with health professionals, and (iii) systematic review of PROMs. The International Classification of Functioning Disability and Health provided a common language to code aspects of health. A subset of stakeholders participated in a prioritisation meeting incorporating a Q-sorting task to discuss and rank aspects of health.
RESULTS: A total of 33 pertinent aspects of health were identified. Fifteen stakeholders from the qualitative and Delphi studies participated in the prioritisation meeting: 3 young people, 5 parent carers, and 7 health professionals. Aspects of health that emerged as more important for families and targets for health professionals were: communication, emotional wellbeing, pain, sleep, mobility, self-care, independence, mental health, community and social life, behaviour, toileting and safety. Whilst available PROMs measure many aspects of health in the ICF, no single PROM captures all the key domains prioritised as for children and young people with neurodisability. The paucity of scales for assessing communication was notable.
CONCLUSIONS: We propose a core suite of key outcome domains for children with neurodisability that could be used in evaluative research, audit and as health service performance indicators. Future work could appraise domain-specific PROMs for these aspects of health; a single measure assessing the key aspects of health that could be applied across paediatric neurodisability remains to be developed.
BACKGROUND: Assent is used to take children's wishes into account when they are invited into clinical trials, but the concept has attracted considerable criticism. We investigated children's accounts of decision-making with the aim of informing practice in supporting children when invited to join a clinical trial. METHODS: We audio-recorded qualitative, semi-structured interviews with 22 children aged 8-16 years about being invited to take part in a clinical trial. Most children were interviewed with their parents. Analysis of the transcribed interviews examined the content of participants' accounts thematically, whilst also drawing on principles of discourse analysis, which examines how individuals use talk to achieve certain effects or social practices. RESULTS: It was not possible to separate children's knowledge of the clinical trial, or their decision-making processes from that of their parents, with parents taking a substantial mediating role in producing their children's decisions. Decision-making gradually unfolded across time and events and was interwoven within the family context, rather than happening in one moment or in the clinical setting. Whilst children valued their parents' role, a case study of child-parent disagreement indicated how children can struggle to be heard. CONCLUSIONS: Decisions happen within a process of family dynamics, in contrast to ideas of assent that isolate it from this context. Parents have a substantial role in children's decisions, and thus how families come to provide consent. Reflecting this we argue that assent practices need to focus on supporting parents to support their children in learning and deliberating about trials. However, this needs to be accompanied by practitioners being alert to the possibility of divergence in child and parent views and enabling children's perspectives to be heard.
OBJECTIVES: To identify key health outcomes, beyond morbidity and mortality, regarded as important in children and young people with neurodisability, and their parents. DESIGN: Qualitative research incorporating a thematic analysis of the data supported by the Framework Approach; the International Classification of Functioning, Disability and Health (ICF) provided a theoretical foundation. SETTING: The study was conducted in community settings. PARTICIPANTS: Participants were 54 children and young people with neurodisability: 50 participated in focus groups, and 4 in interviews; 53 parents participated: 47 in focus groups and 6 in interviews. Children/young people and parents were recruited through different networks, and were not related. RESULTS: Children/young people and parents viewed health outcomes as inter-related. Achievement in some outcomes appeared valued to the extent that it enabled or supported more valued domains of health. Health outcomes prioritised by both young people and parents were: communication, mobility, pain, self-care, temperament, interpersonal relationships and interactions, community and social life, emotional well-being and gaining independence/future aspirations. Parents also highlighted their child's sleep, behaviour and/or safety. CONCLUSIONS: Those responsible for health services for children/young people with neurodisability should take account of the aspects of health identified by families. The aspects of health identified in this study provide a basis for selecting appropriate health indicators and outcome measures.
Ensuring parents make an informed decision about their child's participation in a clinical trial is a challenge for practitioners as a parent's comprehension of a trial may differ from that intended by the practitioners responsible for recruitment. We explored what issues parents consider important when making a decision about participation in a paediatric clinical trial and their comprehension of these issues to inform future recruitment practice. This qualitative interview and observational study examined recruitment in four placebo-controlled, double-blind randomised clinical trials of medicines for children. Audio-recorded trial recruitment discussions between practitioners and parents (N = 41) were matched with semi-structured interviews with parents (N = 41). When making a decision about trial entry parents considered clinical benefit, child safety, practicalities of participation, research for the common good, access to medication and randomisation. Within these prioritised issues parents had specific misunderstandings, which had the potential to influence their decisions. While parents had many questions and concerns about trial participation which influenced their decision-making, they rarely voiced these during discussions about the trials with practitioners. Those involved in the recruitment of children to clinical trials need to be aware of parents' priorities and the sorts of misunderstandings that can arise with parents. Providing trial information that is tailored to what parents consider important in making a decision about a clinical trial may improve recruitment practice and ultimately benefit evidence-based paediatric medicine. © 2013 Woolfall et al.
BACKGROUND: Recruiting children to clinical trials is perceived to be challenging. To identify ways to optimise recruitment and its conduct, we compared how parents and practitioners described their experiences of recruitment to clinical trials. METHODS AND FINDINGS: This qualitative study ran alongside four children's clinical trials in 11 UK research sites. It compared analyses of semi-structured interviews with analyses of audio-recordings of practitioner-family dialogue during trial recruitment discussions. Parents from 59 families were interviewed; 41 had participated in audio-recorded recruitment discussions. 31 practitioners were interviewed. Parents said little in the recruitment discussions contributing a median 16% of the total dialogue and asking a median of one question. Despite this, parents reported a positive experience of the trial approach describing a sense of comfort and safety. Even if they declined or if the discussion took place at a difficult time, parents understood the need to approach them and spoke of the value of research. Some parents viewed participation as an 'exciting' opportunity. By contrast, practitioners often worried that approaching families about research burdened families. Some practitioners implied that recruiting to clinical trials was something which they found aversive. Many were also concerned about the amount of information they had to provide and believed this overwhelmed families. Whilst some practitioners thought the trial information leaflets were of little use to families, parents reported that they used and valued the leaflets. However, both parties agreed that the leaflets were too long and wanted them to be more reader-friendly. CONCLUSIONS: Parents were more positive about being approached to enter their child into a clinical trial than practitioners anticipated. The concerns of some practitioners, that parents would be overburdened, were unfounded. Educating practitioners about how families perceive clinical trials and providing them with 'moral' support in approaching families may benefit paediatric research and, ultimately, patients.
Background: As the number of randomised controlled trials of medicines for children increases,
it becomes progressively more important to understand the experiences of parents who are asked
to enrol their child in a trial. This paper presents a narrative review of research evidence on
parents' experiences of trial recruitment focussing on qualitative research, which allows them to
articulate their views in their own words.
Discussion: Parents want to do their best for their children, and socially and legally their role is
to care for and protect them yet the complexities of the medical and research context can
challenge their fulfilment of this role. Parents are simultaneously responsible for their child and
cherish this role yet they are dependent on others when their child becomes sick. They are keen
to exercise responsibility for deciding to enter a child in a trial yet can be fearful of making the
'wrong' decision. They make judgements about the threat of the child's condition as well as the risks
of the trial yet their interpretations often differ from those of medical and research experts.
Individual parents will experience these and other complexities to a greater or lesser degree
depending on their personal experiences and values, the medical situation of their child and the
nature of the trial. Interactions at the time of trial recruitment offer scope for negotiating these
complexities if practitioners have the flexibility to tailor discussions to the needs and situation of
individual parents. In this way, parents may be helped to retain a sense that they have acted as good
parents to their child whatever decision they make.
Summary: Discussing randomised controlled trials and gaining and providing informed consent is
challenging. The unique position of parents in giving proxy consent for their child adds to this
challenge. Recognition of the complexities parents face in making decisions about trials suggests
lines for future research on the conduct of trials, and ultimately, may help improve the experience
of trial recruitment for all parties.
There are a number of different cardiac emergencies that can face the neonatologist. Many of these relate to the initial presentation of congenital cardiac lesions (incidence 6–13 per 1,000 live births) (Reller et al. 2008; Ishikawa et al. 2011; Ferencz et al. 1985). Rarer causes also include cardiac arrhythmias (1 in 25,000 for supraventricular tachycardia) (Dubin 2000) and cardiomyopathies (5–9 per 100,000 infants) (Nugent et al. 2003; Lipshultz et al. 2003) which can lead to hemodynamic decompensation in the neonate. Furthermore, iatrogenic injuries caused by interventions can lead to emergencies such as cardiac tamponade. These particular pathologies can present acutely and require prompt treatment by the attending physician. For the purposes of this chapter, the pathologies are split into four common presentations with the aim of providing a practical approach to cardiac emergencies in newborns.
• Shock/circulatory failure
• Cyanosis
• Acute heart failure
• Arrhythmias
Background: Guidelines published by the International Liaison Committee for Resuscitation and by the World Health Organization recommend delaying cord clamping at birth as part of routine care for infants. Objective: To study the use of milking of the cord 4 times as an alternative to enhance the redistribution of placental blood into the baby. Methods: This is a prospective cohort study of neurodevelopmental assessment by the Bayley III method of very preterm infants who had participated in a trial of delayed cord clamping versus cord milking at birth that was conducted in a neonatal tertiary care hospital. The primary outcomes were differences in cognitive, motor and language development at 2 and 3.5 years. Two-tailed analyses were performed with the χ2 test, Fisher's exact test, t test, Mann-Whitney U test and ANCOVA. Results: Out of the 58 infants enrolled in the original study, 39 infants (67%) were assessed at 2 years and 29 (50%) at 3.5 years of age. Neurodevelopmental outcomes at 2 and 3.5 years did not significantly differ between the two groups for the three Bayley III composite scores. At 3.5 years there was a trend towards higher scores for girls in the language composite scores (girls: mean = 121.6, SD = 15.22; boys: mean = 101.07, SD = 19.84) and on the motor scale (girls: mean = 124.60, SD = 18.15; boys: mean = 97.86, SD = 17.23). Conclusions: In this small number of participants followed up at 2 and 3.5 years of age, milking of the cord 4 times did not have any long-term adverse effect on neurodevelopmental outcome, suggesting that cord milking could be used as an alternative to delayed cord clamping.
OBJECTIVE: To summarize evidence regarding the effectiveness of MTX in the treatment of childhood autoimmune chronic uveitis (ACU).
METHODS: A systematic search of articles between January 1990 and June 2011 was conducted using EMBASE, Ovid MEDLINE, Evidence-Based Medicine Reviews-ACP Journal Club, the Cochrane Library and EBM Reviews. Studies investigating the efficacy of MTX as a single immunosuppressant medication in the treatment of ACU refractory to therapy with topical treatment and/or systemic treatment in children (≤16 years) were eligible for inclusion. The primary outcome measure was the improvement of intraocular inflammation, expressed as Tyndall, as defined by the Standardization of Uveitis Nomenclature working group criteria. The effect measure for each study was the proportion of people classified as responders. We determined a combined estimate of the proportion of children in the eligible studies responding to MTX.
RESULTS: The initial search identified 246 articles of which 52 were potentially eligible. Nine eligible articles, all retrospective chart reviews, remained in the analysis. The number of children in studies ranged from 3 to 25, and the dose of MTX varied from 7.5 to 30 mg/m2. Altogether, 95 of 135 children responded to MTX. The pooled analysis suggested that MTX has a favourable effect in the improvement of intraocular inflammation: the proportion of responding subjects was 0.73 (95% CI 0.66, 0.81).
CONCLUSION: Although randomized controlled trials are needed, the available evidence supports the use of MTX in the treatment of childhood ACU: approximately three-quarters of patients on MTX can expect improvement in intraocular inflammation.
The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS.
The case has been made for introducing a rights-based, public health approach to child protection in England. A continuum of prevention is proposed, with multi-agency responses calibrated more carefully to the level of risk identified by children, parents and practitioners. The
aim was to allocate inter-professional authority and resources in such a way as to ensure the safeguarding response is proportionate to the nature and level of concerns expressed and reliable in achieving good
outcoSmes for children and parents alike. Recent research findings confirm the need for new models of service alignment and interprofessional responsibility at the interface of ‘primary’ and ‘specialist’ health-care services and ‘children’s social care’, where significant
safeguarding concerns are raised. This paper reports the findings of a scoping study, designed to establish the extent to which innovative practice methodologies have been implemented and evaluated in England to date. While the evidence to support the effectiveness of specific practice methodologies and contrasting logics of service design and implementation is shown to be very limited still, achieving
reliability and legitimacy in the safeguarding elationships established at the service interface seems to depend on the integrity of the dialogue facilitated in each case.
Background Although an increased concentration of
degraded elastin products in patients with chronic
obstructive pulmonary disease (COPD) has been reported
for many years, its clinical validity and utility remain
uncertain due to technical difficulties, small study groups
and the unknown relationship between exacerbation and
elastin degradation. The objectives of this study were to
determine the validity of urinary and blood total
desmosine/isodesmosine in patients with COPD and
asthma and to evaluate their relationship to exacerbation
status and lung function.
There is emerging evidence that cystic fibrosis lung disease begins early in infancy. Newborn screening allows early detection and surveillance of pulmonary disease and the possibility of early intervention in this life-shortening condition.We report two children with cystic fibrosis who underwent a comprehensive assessment from diagnosis that included measurement of lung function, limited-slice high-resolution CT and BAL performed annually. Early aggressive surveillance enabled significant lung disease and bronchiectasis to be detected during the first few years of life and led to a change in management, highlighting a clinical role for CT scanning during the preschool years in children with cystic fibrosis.
Rationale Wheezing is common in preschool children but objective evidence for airway obstruction and its reversibility are rarely available in clinical practice We assessed whether abnormalities of lung function and bronchodilator response can be detected in preschool children using the forced oscillation technique and measurements of specific airway resistance Methods Fifty nine children with a history of wheeze and 24 healthy controls aged 3-6 years were recruited Resistance and reactance at 6 and 8 Hz (Rrs6 Rrs8 Xrs6 and Xrs8 respectively) were measured using the forced oscillation technique and specific airway resistance was measured in a plethysmograph z Scores were calculated from published reference data Tests were repeated 15 min after 400 mcg salbutamol Bronchodilator response was expressed as the log transformed ratio of postbronchodilator/prebronchodilator values Results Technically acceptable measurements using the forced oscillation technique were obtained in n = 77 (93%) of children and in n = 56 (68%) using plethysmography There was no significant difference in baseline lung function or bronchodilator response assessed by either technique between those with a history of wheeze and healthy controls Conclusion Measurement of lung function is feasible in preschool children but neither of these techniques was able to identify diminished lung function or reversibility to bronchodilator in children with a history of wheeze Pediatr Pulmonol 2010, 45 1049-1056
Introduction Improved nutrition is the major proven
benefit of newborn screening programmes for cystic
fibrosis (CF) and is associated with better clinical
outcomes. It was hypothesised that early pulmonary
inflammation and infection in infants with CF is
associated with worse nutrition.
Methods Weight, height and pulmonary inflammation
and infection in bronchoalveolar lavage (BAL) were
assessed shortly after diagnosis in infants with CF and
again at 1, 2 and 3 years of age. Body mass index (BMI)
was expressed as z-scores. Inflammatory cells and
cytokines (interleukin 1b (IL-1b), IL-6, IL-8 and tumour
necrosis factor a (TNFa)), free neutrophil elastase
activity and myeloperoxidase were measured in BAL.
Mixed effects modelling was used to assess longitudinal
associations between pulmonary inflammation,
pulmonary infection (Staphylococcus aureus and
Pseudomonas aeruginosa) and BMI z-score after
adjusting for potential confounding factors.
Results Forty-two infants were studied (16 (38%) male;
39 (93%) pancreatic insufficient); 36 were diagnosed by
newborn screening (at median age 4 weeks) and six by
early clinical diagnosis (meconium ileus). Thirty-one
(74%) received antistaphylococcal antibiotics. More than
two-thirds were asymptomatic at each assessment.
Mean BMI z-scores were
Rationale: Better understanding of evolution of lung function in infants with cystic fibrosis (CF) and its association with pulmonary inflammation and infection is crucial in informing both early intervention studies aimed at limiting lung damage and the role of lung function as outcomes in such studies.
Objectives: To describe longitudinal change in lung function in infants with CF and its association with pulmonary infection and inflammation.
Methods: Infants diagnosed after newborn screening or clinical presentation were recruited prospectively. FVC, forced expiratory volume in 0.5 seconds (FEV0.5), and forced expiratory flows at 75% of exhaled vital capacity (FEF75) were measured using the raised-volume technique, and z-scores were calculated from published reference equations. Pulmonary infection and inflammation were measured in bronchoalveolar lavage within 48 hours of lung function testing.
Measurements and Main Results: Thirty-seven infants had at least two successful repeat lung function measurements. Mean (SD) z-scores for FVC were 130.8 (1.0), 130.9 (1.1), and 131.7 (1.2) when measured at the first visit, 1-year visit, or 2-year visit, respectively. Mean (SD) z-scores for FEV0.5 were 131.4 (1.2), 132.4 (1.1), and 134.3 (1.6), respectively. In those infants in whom free neutrophil elastase was detected, FVC z-scores were 0.81 lower (P = 0.003), and FEV0.5 z-scores 0.96 lower (P = 0.001), respectively. Significantly greater decline in FEV0.5 z-scores occurred in those infected with Staphylococcus aureus (P = 0.018) or Pseudomonas aeruginosa (P = 0.021).
Conclusions: In infants with CF, pulmonary inflammation is associated with lower lung function, whereas pulmonary infection is associated with a greater rate of decline in lung function. Strategies targeting pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF.
Background
Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema.
Methods and Findings
We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen(n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27–4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79–32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24–1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13–3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35–10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16–2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation.
Conclusions
We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life.
My research takes a social work perspective to investigate the concept of the child with ‘additional needs’. This concept arose out of the Labour Government’s programme ‘Every Child Matters’ (HM Government, 2003) which proposed that children’s needs for support should be picked up at an earlier point by an integrated Children’s Services consisting of social care, health and education. This would stop them from ‘falling through the net’ of services. A focus on ‘additional needs’ should mean that children in distress are helped at an early stage before problems became critical, improving the ‘well-being’ of children and their families.
The research has traced the cases of twelve children with ‘additional needs’ through their contacts with Children’s Services, using an interactionist methodology to interrogate the meaning-making between respondents. Further, following Hacking (2004), a Foucauldian approach to discourse allowed me investigate the discourses which shape formal diagnosis and categorization. Focusing on the ways that the child is positioned and perceived has allowed me to address the question of whose ‘need’ is prioritized when the child enters the professional gaze. In doing so it has examined the role of formal and informal labels in constructing the child, the emotional content that goes into creating the ‘meaning-labels’ of the child, and the ways that failures in knowing about the child affect the ways that a child becomes pictured.
It concludes that in the shifting practices that make up Children’s Services, the child with additional needs can become lost in the complex interaction between adult needs and emotions. The informal ‘meaning-labels’ which arise out of this complexity often identify the child as carrying a ‘spoiled identity’. This can be carried through into practice with the child, including the processes of formal diagnosis and categorization. Adult emotions need to be managed better if children are to get fitting and timely help to allow them to thrive.