Assessing and investigating children with suspected bone and abdominal tumours: an e-Delphi consensus process.

BACKGROUND: The incidence of childhood cancer has risen by 15% since the 1990s. Early diagnosis is key to optimising outcomes, however diagnostic delays are widely reported. Presenting symptoms are often non-specific causing a diagnostic dilemma for clinicians. This Delphi consensus process was conducted to develop a new clinical guideline for children and young people presenting with signs/symptoms suggestive of a bone or abdominal tumour. METHODS: Invitation emails were sent to primary and secondary healthcare professionals to join the Delphi panel. 65 statements were derived from evidence review by a multidisciplinary team. Participants were asked to rank their level of agreement with each statement on a 9-point Likert scale (1=strongly disagree, 9=strongly agree), with responses ≥7 taken to indicate agreement. Statements not reaching consensus were rewritten and reissued in a subsequent round. RESULTS: All statements achieved consensus after two rounds. 96/133 (72%) participants responded to round 1 (R1) and 69/96 (72%) completed round 2 (R2). 62/65 (94%) statements achieved consensus in R1 with 29/65 (47%) gaining more than 90% consensus. Three statements did not reach consensus scoring between 61% and 69%. All reached numerical consensus at the end of R2. Strong consensus was reached on best practice of conducting the consultation, acknowledging parental instinct and obtaining telephone advice from a paediatrician to decide the timing and place of review, rather than adult cancer urgent referral pathways. Dissensus in statements was due to unachievable targets within primary care and valid concerns over a potential overinvestigation of abdominal pain. CONCLUSIONS: This consensus process has consolidated statements that will be included in a new clinical guideline for suspected bone and abdominal tumours for use in both primary and secondary care. This evidence base will be translated into awareness tools for the public as part of the Child Cancer Smart national awareness campaign.

Observational cohort study of use of caffeine in preterm infants and association between early caffeine use and neonatal outcomes.

OBJECTIVE: To quantify trends in caffeine use in infants born at <32 weeks' gestational age (GA), and to investigate the effects of early vs late caffeine on neonatal outcomes. STUDY DESIGN: Retrospective propensity score matched cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks' GA admitted to neonatal units in England and Wales (2012-2020). RESULTS: 89% (58 913/66 081) of infants received caffeine. In 70%, caffeine was started early (on the day of birth or the day after), increasing from 55% in 2012 to 83% in 2020. Caffeine was given for a median (IQR) of 28 (17-43) days starting on day 2 (1-3) and continued up to 34 (33-34) weeks postmenstrual age.In the propensity score matched cohort of 13 045 pairs of infants, the odds of preterm brain injury (early caffeine, 2306/13 045 (17.7%) vs late caffeine, 2528/13 045 (19.4%), OR=0.89 (95% CI 0.84 to 0.95)) and bronchopulmonary dysplasia (BPD) (early caffeine, 4020/13 045 (32.8%) vs late caffeine, 4694/13 045 (37.7%), OR=0.81 (95% CI 0.76 to 0.85)) were lower in the group that received early caffeine compared with those who received it later. CONCLUSIONS: Early use of caffeine has increased in England and Wales. This is associated with reduced risks of BPD and preterm brain injury. Randomised trials are needed to find the optimal timing of caffeine use and the groups of infants who will benefit most from early administration of caffeine.

Management of patent ductus arteriosus in very preterm infants in England and Wales: a retrospective cohort study.

OBJECTIVE: To describe the diagnosis and treatment of patent ductus arteriosus (PDA) in infants born at <32 weeks' gestational age (GA) in England and Wales between 2010 and 2017. STUDY DESIGN: Retrospective cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks admitted to neonatal units in England and Wales from 2010 to 2017. RESULTS: Among 58 108 infants born at <32 weeks' GA, 28.3% (n=16 440) had a PDA diagnosed clinically or with echocardiographic confirmation. Of these, 34.8% (n=5721; 9.8% of total <32 weeks' infants included) had PDA treatment including 7.6% (n=1255) with indomethacin, 23.5% (n=3857) with ibuprofen and 5.6% (n=916) with surgical closure. The highest incidence of PDA was among infants born at 24 and 25 weeks' GA (70.2% and 70.8%, respectively), decreasing to 6.1% among infants born at 31 weeks' GA. The percentage of infants with a PDA increased over the study period (25.5% in 2010 to 28.5% in 2017). The percentage of infants who received ibuprofen or indomethacin or had PDA surgery decreased from 41.3% in 2010 to 33.7% in 2017, with an increase in use of ibuprofen from 20.2% to 27.3% while use of indomethacin decreased from 20.0% to 8.8%. Surgical closure of PDA decreased from 9.1% to 3.0%. Indomethacin was used for median (IQR) 3 (2-5) days while ibuprofen was given for 3 (2-4) days, at a median of 8 and 10 days after birth, respectively; surgical treatment was used later at 33 (24-45) days after birth. CONCLUSIONS: Ibuprofen is the preferred drug and surgical interventions are becoming less frequent for PDA closure among very preterm infants in England and Wales. TRIAL REGISTRATION NUMBER: NCT03773289.

Sedation and analgesia from prolonged pain and stress during mechanical ventilation in preterm infants: is dexmedetomidine an alternative to current practice?

Mechanical ventilation is an uncomfortable and potentially painful intervention. Opioids, such as morphine and fentanyl, are used for analgesia and sedation but there is uncertainty whether they reduce pain in mechanically ventilated infants. Moreover, there may be short-term and long-term adverse consequences such as respiratory depression leading to prolonged mechanical ventilation and detrimental long-term neurodevelopmental effects. Despite this, opioids are widely used, possibly due to a lack of alternatives.Dexmedetomidine, a highly selective alpha-2-adrenergic agonist with analgesic and sedative effects, currently approved for adults, has come into use in newborn infants. It provides analgesia and simulates natural sleep with maintenance of spontaneous breathing and upper airway tone. Although data on pharmacokinetics-pharmacodynamics in preterm infants are scant, observational studies report that using dexmedetomidine in conjunction with opioids/benzodiazepines or on its own can reduce the cumulative exposure to opioids/benzodiazepines. As it does not cause respiratory depression, dexmedetomidine could enable quicker weaning and extubation. Dexmedetomidine has also been suggested as an adjunct to therapeutic hypothermia in hypoxic ischaemic encephalopathy and others have used it during painful procedures and surgery. Dexmedetomidine infusion can cause bradycardia and hypotension although most report clinically insignificant effects.The increasing number of publications of observational studies and clinical use demonstrates that dexmedetomidine is being used in newborn infants but data on safety and efficacy are scant and not of high quality. Importantly, there are no data on long-term neurodevelopmental impact on preterm or term-born infants. The acceptance of dexmedetomidine in routine clinical practice must be preceded by clinical evidence. We need adequately powered and well-designed randomised controlled trials investigating whether dexmedetomidine alone or with opioids/benzodiazepines in infants on mechanical ventilation reduces the need for opioids/benzodiazepine and improves neurodevelopment at 24 months and later as compared with the use of opioids/benzodiazepines alone.

The natural history of ataxia-telangiectasia (A-T): A systematic review.

BACKGROUND: Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely reported, there are no studies that give a comprehensive picture of this intriguing condition. OBJECTIVES: Understand the natural history of ataxia-telangiectasia (A-T), as reported in scientific literature. SEARCH METHODS: 107 search terms were identified and divided into 17 searches. Each search was performed in PubMed, Ovid SP (MEDLINE) 1946-present, OVID EMBASE 1980 -present, Web of Science core collection, Elsevier Scopus, and Cochrane Library. SELECTION CRITERIA: All human studies that report any aspect of A-T. DATA COLLECTION AND ANALYSIS: Search results were de-duplicated, data extracted (including author, publication year, country of origin, study design, population, participant characteristics, and clinical features). Quality of case-control and cohort studies was assessed by the Newcastle-Ottawa tool. Findings are reported descriptively and where possible data collated to report median (interquartile range, range) of outcomes of interest. MAIN RESULTS: 1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia. 687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months). CONCLUSIONS: This review demonstrates the multi-system involvement in A-T, confirms that neurological symptoms are the most frequent presenting features in classical A-T but variants have diverse manifestations. We found that most individuals with A-T have life limited to teenage or early adulthood. Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T. We recommend population-based studies to fill this evidence gap.

The Childhood Cancer Diagnosis (CCD) Study: a UK observational study to describe referral pathways and quantify diagnostic intervals in children and young people with cancer.

INTRODUCTION: Childhood cancer is diagnosed in 400 000 children and young people (CYP) aged 0-19 years worldwide annually. In the UK, a child's cumulative cancer risk increases from 1 in 4690 from birth to aged 1, to 1 in 470 by age 15. Once diagnosed, access to treatments offers survival to adulthood for over 80%. Tumour diagnoses are at a later stage and mortality is higher when compared with those in other parts of Europe. This means higher risk, more intensive therapies for a cure. Some CYPs are known to experience delays to diagnosis which may further contribute to poor outcomes. This study aims to understand the current pathway of childhood cancer referrals and diagnosis and quantify diagnostic intervals in the UK. METHODS AND ANALYSIS: This is a prospective multicentre observational study including all tertiary childhood cancer treatment centres in the UK. CYP (0-18 years) with a new diagnosis of cancer over the study period will be invited to participate. Data will be collected at initial diagnosis and 5 years after diagnosis. Data will include demographic details, clinical symptoms, tumour location, stage and clinical risk group. In addition, key diagnostic dates and referral routes will be collected to calculate the diagnostic intervals. At 5 years' follow-up, data will be collected on refractory disease, relapse and 1-year and 5-year survival. Population characteristics will be presented with descriptive analyses with further analyses stratified by age, geographical region and cancer type. Associations between diagnostic intervals/delay and risk factors will be explored using multiple regression and logistic regression. ETHICS: The study has favourable opinion from the York and Humber, Leeds West REC (19/YH/0416). DISSEMINATION: Results will be presented at academic conferences, published in peer-reviewed journals and disseminated through public messaging in collaboration with our charity partners through a national awareness campaign (ChildCancerSmart). STUDY REGISTRATION: researchregistry.com (researchregistry5313).

Observational cohort study of changing trends in non-invasive ventilation in very preterm infants and associations with clinical outcomes.

OBJECTIVE: To determine the change in non-invasive ventilation (NIV) use over time in infants born at <32 weeks' gestation and the associated clinical outcomes. STUDY DESIGN: Retrospective cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks admitted to neonatal units in England and Wales from 2010 to 2017. RESULTS: In 56 537 infants, NIV use increased significantly between 2010 and 2017 (continuous positive airway pressure (CPAP) from 68.5% to 80.2% in 2017 and high flow nasal cannula (HFNC) from 14% to 68%, respectively) (p<0.001)). Use of NIV as the initial mode of respiratory support also increased (CPAP, 21.5%-28.0%; HFNC, 1%-7% (p<0.001)).HFNC was used earlier, and for longer, in those who received CPAP or mechanical ventilation. HFNC use was associated with decreased odds of death before discharge (adjusted OR (aOR) 0.19, 95% CI 0.17 to 0.22). Infants receiving CPAP but no HFNC died at an earlier median chronological age: CPAP group, 22 (IQR 10-39) days; HFNC group 40 (20-76) days (p<0.001). Among survivors, HFNC use was associated with increased odds of bronchopulmonary dysplasia (BPD) (aOR 2.98, 95% CI 2.81 to 3.15) and other adverse outcomes. CONCLUSIONS: NIV use is increasing, particularly as initial respiratory support. HFNC use has increased significantly with a sevenfold increase soon after birth which was associated with higher rates of BPD. As more infants survive with BPD, we need robust clinical evidence, to improve outcomes with the use of NIV as initial and ongoing respiratory support.

Feeding during neonatal therapeutic hypothermia, assessed using routinely collected National Neonatal Research Database data: a retrospective, UK population-based cohort study.

BACKGROUND: Therapeutic hypothermia is standard of care in high-income countries for babies born with signs of hypoxic ischaemic encephalopathy, but optimal feeding during treatment is uncertain and practice is variable. This study aimed to assess the association between feeding during therapeutic hypothermia and clinically important outcomes. METHODS: We did a population-level retrospective cohort study using the UK National Neonatal Research Database. We included all babies admitted to National Health Service neonatal units in England, Scotland, and Wales between Jan 1, 2010, and Dec 31, 2017, who received therapeutic hypothermia for 72 h or died during this period. For analysis, we created matched groups using propensity scores and compared outcomes in babies who were fed versus unfed enterally during therapeutic hypothermia. The primary outcome was severe necrotising enterocolitis, either confirmed at surgery or causing death. Secondary outcomes include pragmatically defined necrotising enterocolitis (a recorded diagnosis of necrotising enterocolitis in babies who received at least 5 consecutive days of antibiotics while also nil by mouth during their neonatal unit stay), late-onset infection (pragmatically defined as 5 consecutive days of antibiotic treatment commencing after day 3), survival to discharge, measures of breastmilk feeding, and length of stay in neonatal unit. FINDINGS: 6030 babies received therapeutic hypothermia, of whom 1873 (31·1%) were fed during treatment. Seven (0·1%) babies were diagnosed with severe necrotising enterocolitis and the number was too small for further analyses. We selected 3236 (53·7%) babies for the matched feeding analysis (1618 pairs), achieving a good balance for all recorded background variables. Pragmatically defined necrotising enterocolitis was rare in both groups (incidence 0·5%, 95% CI 0·2-0·9] in the fed group vs 1·1% [0·7-1·4] in the unfed group). The enterally fed group had fewer pragmatically defined late-onset infections (difference -11·6% [95% CI -14·0 to -9·3]; p<0·0001), higher survival to discharge (5·2% [3·9-6·6]; p<0·0001), higher proportion of breastfeeding at discharge (8·0% [5·1-10·8]; p<0·0001), and shorter neonatal unit stays (-2·2 [-3·0 to -1·2] days; p<0·0001) compared with the unfed group. INTERPRETATION: Necrotising enterocolitis is rare in babies receiving therapeutic hypothermia. Enteral feeding during hypothermia is safe and associated with beneficial outcomes compared with not feeding, although residual confounding could not be completely ruled out. Our findings support starting milk feeds during therapeutic hypothermia. FUNDING: UK National Institute for Health Research Health Technology Assessment programme 16/79/13.

Education of family members to support weaning to solids and nutrition in later infancy in term-born infants.

BACKGROUND: Education of family members about infant weaning practices could affect nutrition, growth, and development of children in different settings across the world. OBJECTIVES: To compare effects of family nutrition educational interventions for infant weaning with conventional management on growth and neurodevelopment in childhood. SEARCH METHODS: We used the standard strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 5), MEDLINE via PubMed (1966 to 26 June 2018), Embase (1980 to 26 June 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 26 June 2018). We searched clinical trials databases, conference proceedings, and references of retrieved articles. We ran an updated search from 1 January 2018 to 12 December 2019 in the following databases: CENTRAL via CRS Web, MEDLINE via Ovid, and CINAHL via EBSCOhost. SELECTION CRITERIA: We included randomised controlled trials that examined effects of nutrition education for weaning practices delivered to families of infants born at term compared to conventional management (standard care in the population) up to one year of age. DATA COLLECTION AND ANALYSIS: Two review authors independently identified eligible trial reports from the literature search and performed data extraction and quality assessments for each included trial. We synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 21 trials, recruiting 14,241 infants. Five of the trials were conducted in high-income countries and the remaining 16 were conducted in middle- and low-income countries. Meta-analysis showed that nutrition education targeted at improving weaning-related feeding practices probably increases both weight-for-age z scores (WAZ) (MD 0.15 standard deviations, 95% CI 0.07 to 0.22; 6 studies; 2551 infants; I² = 32%; moderate-certainty evidence) and height-for-age z scores (0.12 standard deviations, 95% CI 0.05 to 0.19; 7 studies; 3620 infants; I² = 49%; moderate-certainty evidence) by 12 months of age. Meta-analysis of outcomes at 18 months of age was heterogeneous and inconsistent in the magnitude of effects of nutrition education on WAZ and weight-for-height z score across studies. One trial that assessed effects of nutrition education on growth at six years reported an uncertain effect on change in height and body mass index z score. Two studies investigated effects of nutrition education on neurodevelopment at 12 to 24 months of age with conflicting results. No trials assessed effects of nutrition education on long-term neurodevelopmental outcomes. AUTHORS' CONCLUSIONS: Nutrition education for families of infants may reduce the risk of undernutrition in term-born infants (evidence of low to moderate certainty due to limitations in study design and substantial heterogeneity of included studies). Modest effects on growth during infancy may not be of clinical significance. However, it is unclear whether these small improvements in growth parameters in the first two years of life affect long-term childhood growth and development. Further studies are needed to resolve this question.

Investigating ataxia in childhood.

Ataxia is a common presentation to an acute paediatric unit and it can often be difficult to determine the cause. It is important to distinguish between serious causes, for example, brain tumours and encephalitis, and more benign causes in order to guide investigations and treatment. In this review, we describe the different types of ataxia, the causes associated with them, the examination findings and what investigations to perform in order to make a diagnosis.

Education of family members to support weaning to solids and nutrition in infants born preterm.

BACKGROUND: Weaning refers to the period of introduction of solid food to complement breast milk or formula milk. Preterm infants are known to acquire extrauterine growth restriction by the time of discharge from neonatal units. Hence, the postdischarge and weaning period are crucial for optimal growth. Optimisation of nutrition during weaning may have long-term impacts on outcomes in preterm infants. Family members of preterm infants may require nutrition education to promote ideal nutrition practices surrounding weaning in preterm infants who are at high risk of nutritional deficit. OBJECTIVES: To investigate the role of nutrition education of family members in supporting weaning in preterm infants with respect to their growth and neurodevelopment compared with conventional management. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 26 June 2018), Embase (1980 to 26 June 2018), and CINAHL (1982 to 26 June 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: RCTs and quasi-RCTs were eligible for inclusion if they examined the effects of nutrition education of family members as compared to conventional management for weaning of preterm infants up to one year of corrected gestational age. We defined prematurity as less than 37 completed weeks of gestation. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened potential studies for inclusion and planned to identify, extract data, and assess the quality of eligible studies. We resolved any differences in opinion through discussion with a third review author and consensus among all three review authors. MAIN RESULTS: No eligible trials looking at the impact of nutrition education of family members in weaning of preterm infants fulfilled the inclusion criteria of this systematic review. Two studies investigating the ideal timing for weaning in premature infants reported conflicting results, AUTHORS' CONCLUSIONS: We were unable to assess the impact of nutrition education of family members in weaning of preterm infants as there were no eligible studies. This may be due to the lack of evidence to determine the ideal weaning strategies for preterm infants with regards to the time of initiating weaning and type of solids to introduce. Trials are needed to assess the many aspects of infant weaning in preterm infants. Long-term neurodevelopment and metabolic outcomes should also be assessed in addition to growth parameters.

Newborn infants with bilious vomiting: a national audit of neonatal transport services.

OBJECTIVE: The precautionary approach to urgently investigate infants with bilious vomiting has increased the numbers referred to transport teams and tertiary surgical centres. The aim of this national UK audit was to quantify referrals and determine the frequency of surgical diagnoses with the purpose to inform the consequent inclusion of these referrals in the national 'time-critical' data set. METHODS: A prospective, multicentre UK-wide audit was conducted between 1 August, 2015 and 31 October, 2015. Term infants aged ≤7 days referred for transfer due to bilious vomiting were included. Data at the time of transport and outcomes at 7 days after transfer were collected by the local teams and transferred anonymously for analysis. RESULTS: Sixteen teams contributed data on 165 cases. Teams that consider such transfers as 'time-critical' responded significantly faster than those that do not classify bilious vomiting as time-critical. There was a surgical diagnosis in 22% cases, and 7% had a condition where delayed treatment may have caused bowel loss. Most surgical problems could be predicted by clinical and/or X-ray findings, but two infants with normal X-ray features were found to have a surgical problem. CONCLUSION: The results support the need for infants with bilious vomiting to be investigated for potential surgical pathologies, but the data do not provide evidence for the default designation of such referrals as 'time-critical.' Decisions should be made by clinical collaboration between the teams and, where appropriate, swift transfer provided.

Adult epicardial fat exhibits beige features.

CONTEXT: Human epicardial fat has been designated previously as brown-like fat. The supraclavicular fat depot in man has been defined as beige coexistent with classical brown based on its gene expression profile. OBJECTIVE: The aim of the study was to establish the gene expression profile and morphology of human epicardial and visceral paracardial fat compared with sc fat. SETTING: The study was conducted at a tertiary care hospital cardiac center. PATIENTS: Epicardial, visceral paracardial, and sc fat samples had been taken from middle-aged patients with severe coronary atherosclerosis or valvular heart disease. INTERVENTIONS: Gene expression was determined by reverse transcription-quantitative PCR and relative abundance of the mitochondrial uncoupling protein-1 (UCP-1) by Western blotting. Epicardial tissue sections from patients were examined by light microscopy, UCP-1 immunohistochemistry, and cell morphometry. MAIN OUTCOME MEASURES: We hypothesized that epicardial fat has a mixed phenotype with a gene expression profile similar to that described for beige cell lineage. RESULTS: Immunoreactive UCP-1 was clearly measurable in each epicardial sample analyzed but was undetectable in each of the 4 other visceral and sc depots. Epicardial fat exhibited high expression of genes for UCP-1, PRDM16, PGC-1α, PPARγ, and the beige adipocyte-specific marker CD137, which were also expressed in visceral paracardial fat but only weakly in sternal, upper abdominal, and lower extremity sc fat. Histology of epicardial fat showed small unilocular adipocytes without UCP-1 immunostaining. CONCLUSION: UCP-1 is relatively abundant in epicardial fat, and this depot possesses molecular features characteristic of those found in vitro in beige lineage adipocytes.