Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial

Background Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement. Methods Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36–43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155. Findings The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference −0·01, 95% CI −0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded. Interpretation Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia

Safety and efficacy of 2% chlorhexidine gluconate aqueous versus 2% chlorhexidine gluconate in 70% isopropyl alcohol for skin disinfection prior to percutaneous central venous catheter insertion in preterm neonates:The ARCTIC randomised-controlled feasibility trial protocol

Introduction Catheter-related sepsis is one of the most dangerous complications of neonatal intensive care and is associated with significant morbidity and mortality. Use of catheter-care € bundles' has reduced the incidence of catheter-related sepsis, although individual components have not been well studied. Better evidence is needed to guide selection of the most appropriate antiseptic solution for skin disinfection in preterm neonates. This study will inform the feasibility and design of the first randomised controlled trial to examine the safety and efficacy of alcohol-based versus aqueous-based chlorhexidine antiseptic formulations for skin disinfection prior to percutaneous central venous catheterisation in preterm neonates. The antiseptics to be compared are 2% chlorhexidine gluconate (CHG) aqueous and 2% CHG in 70% isopropyl alcohol. Methods and analysis The Antiseptic Randomised Controlled Trial for Insertion of Catheters (ARCTIC) is a two-centre randomised-controlled feasibility trial. At least 100 preterm infants born at <34 weeks' gestation and due to undergo percutaneous insertion of a central venous catheter will be randomly allocated to receive prior skin disinfection with one of the two antiseptic solutions. Outcomes include: i) recruitment and retention rates; ii) completeness of data collection; iii) numbers of enrolled infants meeting case definitions for definite catheter-related sepsis, catheter-associated sepsis and catheter colonisation and iv) safety outcomes of skin morbidity scores recorded daily from catheter insertion until 48 hours post removal. The key feasibility metrics will be reported as proportions with 95% CIs. Estimated prevalence of catheter colonisation will allow calculation of sample size for the large-scale trial. The data will inform whether it will be feasible to progress to a large-scale trial. Ethics and dissemination ARCTIC has been approved by the National Health Service Health Research Authority National Research Ethics Service Committee East of England (Cambridge South) (IRAS ID 163868), was adopted onto the National Institute of Health Research Clinical Research Network portfolio (CPMS ID 19899) and is registered with an International Standard Randomised Control Trials Number (ISRCTN: 82571474; Pre-results) and European Clinical Trials Database number 2015-000874-36. Dissemination plans include presentations at scientific conferences, scientific publications and sharing of the findings with parents via the support of Bliss baby charity

Emotional responses to the experience of cancer 'alarm' symptoms

To qualitatively explore associations between emotional responses to experience of cancer 'alarm' symptoms and help-seeking in a community sample of adults

Prediction of neurodevelopmental outcome in children born extremely preterm

Background: The survival rate of preterm children has risen steadily due to advances in obstetric and neonatal intensive care. Children born extremely preterm (≤28 weeks of gestation) are at high risk of long term developmental problems, including cerebral palsy, motor and cognitive impairment, visual and auditory deficits and behavioural problems. This can have serious implications for their quality of life and that of their family and carers. These children take up a disproportionate amount of neonatal intensive care unit resources and overall costs, and as they grow up are more likely to require additional health and social care services beyond routine care to compensate for their functional limitations. The early identification and management of factors that mediate long term outcome is necessary to assist healthcare professionals in selecting appropriate treatment pathways, and to develop, target and evaluate interventions. Many risk factor analyses for neurodevelopmental impairment have been published in preterm populations, but this vast literature has not been formally summarised. Furthermore, there is a dearth of studies reporting longitudinal analysis of neurodevelopmental trajectories from early childhood to adulthood. Objectives: The first aim of this thesis was to perform a comprehensive systematic review of the world literature over the last two decades, to consolidate the evidence about the prognosis of neurodevelopmental outcome in children born very preterm or with very low birth weight. The second aim was to conduct a longitudinal analysis of a cohort of extremely preterm participants followed up into early adulthood to investigate the trajectories of long term sequelae over time, and to examine the association of neurodevelopmental course in relation to the predictive factors identified in the systematic review. Methods: A systematic review was conducted using MEDLINE, EMBASE and PyscINFO databases to identify studies published between January 1 1990 and June 1 2014 reporting multivariable prediction models for the neurodevelopment of children born ≤32 weeks of gestation or with a birth weight ≤1250 grams (protocol registration number CRD42014006943). Seventy-eight studies reporting 222 risk factor models for neurodevelopmental outcome were identified. Two independent reviewers extracted key information about study design, outcome definition, risk factor selection, model development, reporting, and conducted a risk of bias assessment. To address the second objective of the study, a longitudinal analysis of cognitive and behavioural trajectories was conducted using a prospective, population-based cohort study in the United Kingdom and the Republic of Ireland. Three hundred and fifteen surviving infants born less than 26 completed weeks of gestation recruited at birth in 1995 and 160 term-born classroom peers recruited at age six were followed-up to 19 years. Participants were invited for up to four standardized, blinded cognitive assessments and the parent-completed Strengths and Difficulties Questionnaire was used to assess behavioural problems. Results: The systematic review of risk factors for motor impairment in children born very preterm or with very low birth weight provided strong evidence that neonatal brain injury is a robust prognostic factor for cerebral palsy, and some evidence that the use of postnatal steroids increases the risk and the use of antenatal steroids reduces the risk of cerebral palsy. There was moderate evidence that male sex was prognostic for motor impairment at school age in children free of major disability. The systematic review of risk factors for cognitive impairment identified male sex, non-white ethnicity, lower levels of parental education and lower birth weight as significant predictors of global cognitive dysfunction in early infancy, with parental education having a sustained impact after five years of age. There was also evidence that male sex was predictive of delayed language development in early infancy. Gestational age was found to be of limited use as prognostic factor for cerebral palsy, motor and cognitive impairment in cohorts restricted to ≤32 weeks of gestation. There was a dearth of good quality studies investigating risk factors for behavioural problems and psychiatric disorders and the findings of this review were inconclusive. The only factors that appeared to be consistent predictors of general behavioural problems were markers of socio-economic deprivation, neurodevelopmental or cognitive delay, and an abnormal behavioural screen in early infancy. In the longitudinal analysis of the prospective, population-based cohort of extremely preterm children, cognitive trajectories were stable in both the extremely preterm and term-born groups over time with persistent deficit in the extremely preterm group of 25.2 IQ points (95% CI: -27.8 to -22.6, p&LT;0.001) and only minimal catch-up over time. Participants with neonatal brain injury and of male sex had the largest deficits, but a lower level of maternal education and earlier gestational age at birth were also associated with reduced IQ scores. Behavioural problems were also more prevalent among the extremely preterm participants who had a mean Total Difficulties Score of 4.81 points above their term-born peers (95% CI: 3.76 to 5.87, p&LT;0.001) and which persisted over the time period. Behavioural difficulties were mainly due to hyperactivity, inattention and peer problems and were strongly associated with a positive behavioural screen in early infancy. Conclusions: The most robust predictors of poor neurodevelopmental outcome identified by the systematic review were neonatal brain injury, male sex, and markers of social disadvantage. The unclear findings for many risk factors may reflect differences in study design, study population, methodological quality and lack of standardization of measures. Or it may simply reflect the fact that prognostic modelling in such a heterogeneous population is challenging and complex, with multiple risk factors acting sequentially over time, and often with the existence of multiple impairments within the same individual. The main conclusions from the longitudinal analysis of children born extremely preterm is that being born too soon appears to place limits on brain plasticity and function which is not recovered over time; with the most vulnerable being males and those with evidence of brain injury early in life. These structural abnormalities may disturb neurodevelopmental processes and impede the brain from maintaining a normal developmental trajectory. If extremely preterm children fail to achieve optimum levels of cognitive function and are still experiencing behavioural problems once they have reached maturity, then this has implications for health and well-being in later adulthood and old age. Cognitive test scores in infancy and early childhood reflect early adult outcomes and a positive behavioural screen in infancy is strongly associated with early adult behavioural outcomes. Recommendations: The systematic review revealed some shortcomings in methodology and reporting that could be improved in future studies, and confirmed that that there is a dearth of properly designed and well-conducted prognostic modelling studies in this field. The findings and recommendations of this critical review should be used as a basis for the design, analysis and reporting of future studies seeking to develop multivariate risk factor or prognostic models in this population. There is an urgent need for larger population cohorts followed up routinely beyond two years as subtle outcomes such as impairment of executive function and fine motor skills cannot be reliably assessed at this age, and the natural course of some disorders may have their onset later in childhood. Studies with larger sample sizes and greater power are needed for studying less common conditions in preterm populations and there should be more standardisation of outcome and risk factor measurements, particularly with the use of standard diagnostic evaluations to assess psychiatric disorders. Future studies should include a term-born comparison group and adopt appropriate statistical analysis techniques to analyse longitudinal outcome data and the impact of risk factors on these trajectories. Additional research is required to improve the prediction of individual differences, and to identify the neuropathological differences underlying different developmental trajectories and their interaction with environmental influences over time

Hand Preference Develops Across Childhood and Adolescence in Extremely Preterm Children: The EPICure Study.

AIM: To determine how handedness changes with age and its relation to brain injury and cognition following birth before 26 weeks of gestation. METHODS: We used data from the EPICure study of health and development following birth in the British Isles in 1995. Handedness was determined by direct observation during standardized testing at age 2.5, six, and 11 years and by self-report using the Edinburgh Handedness Inventory at 19 years. Control data from term births were included at six, 11, and 19 years. RESULTS: In extremely preterm children left handedness increased from 9% to 27% between 2.5 and 19 years, with a progressive reduction in mixed handedness from 59% to 13%. Although individual handedness scores varied over childhood, the between-group effects were consistent through 19 years, with greatest differences in females. In extremely preterm participants, neonatal brain injury was associated with lower right handedness scores at each age and left-handed participants had lower cognitive scores at 19 years after controlling for confounders, but not at other ages. CONCLUSION: Increasing hand lateralization is seen over childhood in extremely preterm survivors, but consistently more have non-right preferences at each age than controls

The Birthplace in England national prospective cohort study: further analyses to enhance policy and service delivery decision-making for planned place of birth

Background: Evidence from the Birthplace in England Research Programme supported a policy of offering ‘low risk’ women a choice of birth setting, but a number of unanswered questions remained. Aims: This project aimed to provide further evidence to support the development and delivery of maternity services and inform women’s choice of birth setting: specifically, to explore maternal and organisational factors associated with intervention, transfer and other outcomes in each birth setting in ‘low risk’ and ‘higher risk’ women. Design: Five component studies using secondary analysis of the Birthplace prospective cohort study (studies 2–5) and ecological analysis of unit/NHS trust-level data (studies 1 and 5). Setting: Obstetric units (OUs), alongside midwifery units (AMUs), freestanding midwifery units (FMUs) and planned home births in England. Participants: Studies 1–4 focused on ‘low risk’ women with ‘term’ pregnancies planning vaginal birth in 43 AMUs (n = 16,573), in 53 FMUs (n = 11,210), at home in 147 NHS trusts (n = 16,632) and in a stratified, random sample of 36 OUs (n = 19,379) in 2008–10. Study 5 focused on women with pre-existing medical and obstetric risk factors (‘higher risk’ women). Main outcome measures: Interventions (instrumental delivery, intrapartum caesarean section), a measure of low intervention (‘normal birth’), a measure of spontaneous vaginal birth without complications (‘straightforward birth’), transfer during labour and a composite measure of adverse perinatal outcome (‘intrapartum-related mortality and morbidity’ or neonatal admission within 48 hours for > 48 hours). In studies 1 and 3, rates of intervention/maternal outcome and transfer were adjusted for maternal characteristics. Analysis: We used (a) funnel plots to explore variation in rates of intervention/maternal outcome and transfer between units/trusts, (b) simple, weighted linear regression to evaluate associations between unit/trust characteristics and rates of intervention/maternal outcome and transfer, (c) multivariable Poisson regression to evaluate associations between planned place of birth, maternal characteristics and study outcomes, and (d) logistic regression to investigate associations between time of day/day of the week and study outcomes. Results: Study 1 – unit-/trust-level variations in rates of interventions, transfer and maternal outcomes were not explained by differences in maternal characteristics. The magnitude of identified associations between unit/trust characteristics and intervention, transfer and outcome rates was generally small, but some aspects of configuration were associated with rates of transfer and intervention. Study 2 – ‘low risk’ women planning non-OU birth had a reduced risk of intervention irrespective of ethnicity or area deprivation score. In nulliparous women planning non-OU birth the risk of intervention increased with increasing age, but women of all ages planning non-OU birth experienced a reduced risk of intervention. Study 3 – parity, maternal age, gestational age and ‘complicating conditions’ identified at the start of care in labour were independently associated with variation in the risk of transfer in ‘low risk’ women planning non-OU birth. Transfers did not vary by time of day/day of the week in any meaningful way. The duration of transfer from planned FMU and home births was around 50–60 minutes; transfers for ‘potentially urgent’ reasons were quicker than transfers for ‘non-urgent’ reasons. Study 4 – the occurrence of some interventions varied by time of the day/day of the week in ‘low risk’ women planning OU birth. Study 5 – ‘higher risk’ women planning birth in a non-OU setting had fewer risk factors than ‘higher risk’ women planning OU birth and these risk factors were different. Compared with ‘low risk’ women planning home birth, ‘higher risk’ women planning home birth had a significantly increased risk of our composite adverse perinatal outcome measure. However, in ‘higher risk’ women, the risk of this outcome was lower in planned home births than in planned OU births, even after adjustment for clinical risk factors. Conclusions: Expansion in the capacity of non-OU intrapartum care could reduce intervention rates in ‘low risk’ women, and the benefits of midwifery-led intrapartum care apply to all ‘low risk’ women irrespective of age, ethnicity or area deprivation score. Intervention rates differ considerably between units, however, for reasons that are not understood. The impact of major changes in the configuration of maternity care on outcomes should be monitored and evaluated. The impact of non-clinical factors, including labour ward practices, staffing and skill mix and women’s preferences and expectations, on intervention requires further investigation. All women planning non-OU birth should be informed of their chances of transfer and, in particular, older nulliparous women and those more than 1 week past their due date should be advised of their increased chances of transfer. No change in the guidance on planning place of birth for ‘higher risk’ women is recommended, but research is required to evaluate the safety of planned AMU birth for women with selected relatively common risk factors. Funding: The National Institute for Health Research Health Services and Delivery Research programme

Diffuse oesophageal spasm and related disorders.

A significant proportion of patients with non cardiac chest pain and/or dysphagia may have diffuse oesophageal spasm. Conventional techniques of endoscopy and barium studies had a low diagnostic yield for oesophageal motility disorders. Baseline oesophageal manometry using intraoesophageal microtransducers (Gaeltec) diagnosed diffuse oesophageal spasm in 66% of the patients. In view of the intermittent nature of the symptoms, provocative testing during manometry with a Bernstein acid perfusion test and edrophonium injection was used to increase the diagnostic accuracy. The edrophonium provocation test increased diagnostic yield by 34%. Treatment was initially conservative and if this failed then balloon dilatation of the oesophagus was performed. Balloon dilatation relieved symptoms but reduced lower oesophageal sphincter pressure. Success was obtained in the absence of pathological reflux. Dilatation did not result in increased gastro-oesophageal reflux. Many patients with the globus symptom have organic disease accounting for their symptoms. Spasm of the upper oesophageal sphincter secondary to gastro-oesophageal reflux and motility disorders of the oesophageal body have been postulated as causes for the globus sensation. Using the microtransducer system, it was possible to examine the upper oesophageal sphincter with greater accuracy. Patients with the globus symptom as a presenting symptom and normal pan­ endoscopy were investigated with cine-barium, oesophageal manometry and ambulatory pH recording to assess oesophageal motility and reflux. The upper oesophageal sphincter complex was examined but all features, including coordination, were normal. An association between globus and gastro-oesophageal reflux has been demonstrated. No link could be shown between acid perfusion and upper oesophageal sphincter dysfunction. When compared to controls, the globus patients did not have increased psychological abnormality on two psychometry questionnaires. This suggests that the basis for globus may be related to a sensory abnormality in the pharynx in relation to reflux disease

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

The views of older women towards mammographic screening: a qualitative and quantitative study

Purpose: Mammographic screening has improved breast cancer survival in the screened age group. This improved survival has not been seen in older women (>70 years) where screening uptake is low. This study explores the views, knowledge and attitudes of older women towards screening. Methods: Women (>70) were interviewed about breast screening. Interview findings informed the development of a questionnaire which was sent to 1000 women (>70) to quantify their views regarding screening. Results: Twenty-six women were interviewed and a questionnaire designed. The questionnaire response rate was 48.3% (479/992). Over half (52.9%, 241/456) of respondents were unaware they could request mammography by voluntary self-referral and were unaware of how to arrange this. Most (81.5% 383/470) had not attended breast screening since turning 70. Most (75.6%, 343/454) felt screening was beneficial and would attend if invited. Most, (90.1%, 412/457) felt screening should be offered to all women regardless of age or health. Conclusions: There is a lack of knowledge about screening in older women. The majority felt that invitation to screening should be extended to the older age group regardless of age or health. The current under-utilised system of voluntary self referral is not supported by older women

Manipulatives and multiplicative thinking

This small study sought to determine students’ knowledge of multiplication and division and whether they are able to use sets of bundling sticks to demonstrate their knowledge. Manipulatives are widely used in primary and some middle school classrooms, and can assist children to connect multiplicative concepts to physical representations. Qualitative data were generated from semi-structured interviews with 32 primary and middle school children aged nine to eleven years. Participants were asked to work out the answer to multiplication and division examples and explain their thinking using bundling sticks. Results suggest that the majority of participant students may have a limited knowledge of aspects of the multiplication process and even less knowledge of the division process. The study also identified that many of the students appeared uncomfortable and/or unfamiliar with using bundling sticks and a number of them had difficulty in using bundling sticks to explain the multiplication and division processes. We conclude that manipulatives such as bundling sticks do not magically lead children to mathematical learning but are sufficiently powerful to warrant teachers familiarising themselves with how manipulatives can be used to develop conceptual understanding