ABSTRACT
OBJECTIVES: The objective of this study was to evaluate the impact and efficacy of pulse oximetry screening for CHD in a level-two neonatal unit without on-site access to paediatric echocardiography. METHODS: All neonatal unit admissions between 1 September, 2011 and 31 August, 2013 were reviewed to determine the outcomes of newborns identified by pulse oximetry screening. Record linkage with the National Congenital Heart Disease Audit allowed follow-up of newborns with a negative screening result. RESULTS: There were 11,233 live births during the study period, with 973 neonatal unit admissions unrelated to pulse oximetry screening. From the remaining screening population of 10,260 newborns, 23 were admitted on the basis of a screen-positive result; three of the 23 patients went on to have urgent echocardiograms, and two were found to have critical CHD. In the 21 newborns without critical CHD, an alternative diagnosis was made in 16 cases. Record linkage with the National Congenital Heart Disease Audit indicated that no newborns born in the hospital during the study period received surgery for critical CHD following negative screening. The estimated sensitivity of screening was 100% (95% confidence interval 15.81-100%) and specificity was 99.80% (95% confidence interval 99.69-99.87%), with a false-positive rate of 0.20% (95% confidence interval 0.13-0.31%). CONCLUSION: The introduction of pulse oximetry screening to a hospital where paediatric echocardiography services are not available is practical, results in very few referrals to the regional paediatric cardiology centre, and detects cases of CHD that would otherwise go undiagnosed. Record linkage with a national CHD database provides a straightforward method for tracking cases of CHD that may have been missed by screening.
Subject(s)
Heart Defects, Congenital/diagnosis , Neonatal Screening/methods , Oximetry , Echocardiography , Female , Hospitals , Humans , Infant, Newborn , Male , Sensitivity and Specificity , United KingdomABSTRACT
Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity â¼0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones.
Subject(s)
Clone Cells/metabolism , Down Syndrome/genetics , Mutation , Acute Disease , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Chromatography, High Pressure Liquid/methods , Clone Cells/pathology , DNA Mutational Analysis/methods , Down Syndrome/blood , GATA1 Transcription Factor , Genetic Testing/methods , High-Throughput Nucleotide Sequencing/methods , Humans , Infant, Newborn , Leukemia, Myeloid/blood , Leukemia, Myeloid/diagnosis , Leukemia, Myeloid/genetics , Myelopoiesis/genetics , Neonatal Screening/methods , Neoplastic Cells, Circulating/metabolism , Neoplastic Cells, Circulating/pathology , Preleukemia/blood , Preleukemia/diagnosis , Preleukemia/genetics , Reproducibility of Results , Risk Factors , Sensitivity and SpecificityABSTRACT
OBJECTIVE: Uncertainty exists regarding optimal supplemental diet for very preterm infants if the mother's own milk (MM) is insufficient. We evaluated feasibility for a randomised controlled trial (RCT) powered to detect important differences in health outcomes. METHODS: In this open, parallel, feasibility trial, we randomised infants 25+0-31+6 weeks of gestation by opt-out consent to one of three diets: unfortified human milk (UHM) (unfortified MM and/or unfortified pasteurised human donor milk (DM) supplement), fortified human milk (FHM) (fortified MM and/or fortified DM supplement), and unfortified MM and/or preterm formula (PTF) supplement from birth to 35+0 weeks post menstrual age. Feasibility outcomes included opt-outs, adherence rates, and slow growth safety criteria. We also obtained anthropometry, and magnetic resonance imaging body composition data at term and term plus 6 weeks (opt-in consent). RESULTS: Of 35 infants randomised to UHM, 34 to FHM, and 34 to PTF groups, 21, 19, and 24 infants completed imaging at term, respectively. Study entry opt-out rate was 38%; 6% of parents subsequently withdrew from feeding intervention. Two infants met predefined slow weight gain thresholds. There were no significant between-group differences in term total adipose tissue volume (mean [SD]: UHM: 0.870 L [0.35 L]; FHM: 0.889 L [0.31 L]; PTF: 0.809 L [0.25 L], p = 0.66), nor in any other body composition measure or anthropometry at either timepoint. CONCLUSIONS: Randomisation to UHM, FHM, and PTF diets by opt-out consent was acceptable to parents and clinical teams, associated with safe growth profiles and no significant differences in body composition. Our data provide justification to proceed to a larger RCT.
Subject(s)
Infant, Premature , Milk, Human , Infant, Newborn , Infant , Humans , Feasibility Studies , Infant, Very Low Birth Weight , Weight Gain , Infant FormulaABSTRACT
PURPOSE: Minzasolmin (UCB0599) is an orally administered, small molecule inhibitor of ASYN misfolding in development as a potential disease-modifying therapy for Parkinson's disease. Here we describe the preclinical development of a radiolabeled tracer and results from a phase 1 study using the tracer to investigate the brain distribution of minzasolmin. PROCEDURES: In the preclinical study, two radiolabeling positions were investigated on the S-enantiomer of minzasolmin (UCB2713): [11C]methylamine UCB2713 ([11C-N-CH3]UCB2713) and [11C]carbonyl UCB2713 ([11C-CO]UCB2713). Male C57 black 6 mice (N = 10) received intravenous [11C-N-CH3]UCB2713; brain homogenates were assessed for radioactivity and plasma samples analyzed by high-performance liquid chromatography. Positron emission tomography-computed tomography (PET-CT) was used to image brains in a subset of mice (n = 3). In the open-label, phase 1 study, healthy volunteers were scanned twice with PET-CT following injection with [11C]minzasolmin radiotracer (≤ 10 µg), first without, then with oral dosing with non-radiolabeled minzasolmin 360 mg. PRIMARY OBJECTIVE: to determine biodistribution of minzasolmin in the human brain; secondary objectives included minzasolmin safety/tolerability. RESULTS: Preclinical data supported the use of [11C]minzasolmin in clinical studies. In the phase 1 study, PET data showed substantial drug signal in the brain of healthy volunteers (N = 4). The mean estimated whole brain total distribution volume (VT) at equilibrium across all regions of interest was 0.512 mL/cm3, no difference in VT was observed following administration of minzasolmin 360 mg. Treatment-emergent adverse events (TEAEs) were reported by 75% (n = 3) of participants. No drug-related TEAEs, deaths, serious adverse events, or discontinuations were reported. CONCLUSION: Following positive preclinical results with the N-methyl labeled PET tracer, [11C]minzasolmin was used in the phase 1 study, which demonstrated that minzasolmin readily crossed the blood-brain barrier and was well distributed throughout the brain. Safety and pharmacokinetic findings were consistent with previous early-phase studies (such as UP0077, NCT04875962).
Subject(s)
Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Humans , Male , Mice , Animals , Tissue Distribution , Positron-Emission Tomography/methods , Brain , Blood-Brain BarrierABSTRACT
The aim of the study was to characterize performance of a complementary set of assays to measure antigen-specific immune responses in subjects immunized with a neoantigen. Healthy volunteers (HV) (n = 8) and patients with systemic lupus erythematosus (SLE) (n = 6) were immunized with keyhole limpet haemocyanin (KLH) on days 1 and 29. Serum antibodies were detected using a flow cytometric bead array (CBA) that multiplexed the KLH response alongside pre-existing anti-tetanus antibodies. Peripheral blood mononuclear cells were studied by B cell ELISPOT. These assays were built upon precedent assay development in cynomolgus monkeys, which pointed towards their utility in humans. Primary anti-KLH IgG responses rose to a mean of 65-93-fold above baseline for HV and SLE patients, respectively, and secondary responses rose to a mean of 260-170-fold above baseline. High levels of anti-tetanus IgG were detected in pre-immunization samples and their levels did not change over the course of study. Anti-KLH IgG1-4 subclasses were characterized by a predominant IgG1 response, with no significant differences in subclass magnitude or distribution between HV and SLE subjects. Anti-KLH IgM levels were detectable, although the overall response was lower. IgM was not detected in two SLE subjects whodid generate an IgG response. All subjects responded to KLH by B cell ELISPOT, with no significant differences observed between HV and SLE subjects. The CBA and B cell ELISPOT assays reliably measured anti-KLH B cell responses, supporting use of this approach and these assays to assess the pharmacodynamic and potential safety impact of marketed/investigational immune-therapeutics.
Subject(s)
Adjuvants, Immunologic/administration & dosage , B-Lymphocytes/immunology , Hemocyanins/administration & dosage , Lupus Erythematosus, Systemic/prevention & control , Vaccination , B-Lymphocytes/drug effects , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Hemocyanins/immunology , Humans , Immunoglobulin G/blood , Lupus Erythematosus, Systemic/immunologyABSTRACT
INTRODUCTION: Advances in foetal medicine and neonatology have enabled increased antenatal diagnosis of life-limiting conditions and improved preterm survival, escalating the debate surrounding the ethics of neonatal end-of-life care and withholding or withdrawing intensive care. SOURCES OF DATA: Literature search of MEDLINE and the Cochrane library databases using the search terms [neonatal palliative care] AND [neonatal AND withdrawal of intensive care and treatment]. Review of consensus statements and guidelines. AREAS OF AGREEMENT: UK practice is aided by Grade 3-4 evidence, consensus statements and practice frameworks. There is limited systematic evidence. AREAS OF CONTROVERSY: We illustrate UK practice with clinical cases and describe worldwide variations. GROWING POINTS: Neonatal end-of-life care incorporating withholding and withdrawing intensive care is not uncommon. The child's 'best interests' take precedent and clinical guidance has been published to support the joint decision-making partnership of clinicians and families. Withholding and withdrawing intensive care should be part of an overall end-of-life care plan incorporating the principles and standards of palliative care. AREAS TIMELY FOR DEVELOPING RESEARCH: Further guidance on standards and staff training with regard to communicating and delivering neonatal end-of-life care is required to ensure consistent practice of staff and choices for families. The recommended establishment of neonatal outcome databases should aid UK preterm decision-making (NHS and Department of Health Neonatal Taskforce, Toolkit for high-quality neonatal services, London, Department of Health 2009).
Subject(s)
Intensive Care, Neonatal/standards , Terminal Care/standards , Withholding Treatment/standards , Bereavement , Evidence-Based Medicine , Humans , Infant, Newborn , Infant, Premature , Palliative Care/standards , Practice Guidelines as Topic , Refusal to TreatABSTRACT
We describe a son of consanguineous parents with congenital scalp defects, transverse limb abnormalities, hypoplasia of the corpus callosum and bilateral falciform retinal folds. Aplasia cutis congenita with transverse limb defects are features of Adams-Oliver syndrome, which is usually inherited as an autosomal dominant condition. The association of bilateral retinal folds and brain abnormalities with scalp defects and terminal limb defects has only once been previously described. It is possible that these cases represent a severe variant of Adams-Oliver syndrome. We, however, suggest that they may characterize a new, distinct, autosomal recessive syndrome, involving vascular disruption.
Subject(s)
Ectodermal Dysplasia/pathology , Limb Deformities, Congenital/pathology , Retina/abnormalities , Vascular Diseases/pathology , Adult , Ectodermal Dysplasia/genetics , Female , Genes, Recessive , Humans , Infant , Limb Deformities, Congenital/genetics , Male , Retina/pathology , Syndrome , Vascular Diseases/geneticsABSTRACT
OBJECTIVES: To describe the impact on early-onset group B Streptococcus (EOGBS) infection rates following reversion from screening-based to risk-based intrapartum antimicrobial prophylaxis (IAP) for prevention. SETTING: Maternity services provided by secondary healthcare organisation in North West London. PARTICIPANTS: All women who gave birth in the healthcare organisation between April 2016 and March 2017. There were no exclusions. DESIGN: Observational study comparing EOGBS rates in the postscreening period (2016-2017) with prescreening (2009-2013) and screening periods (2014-2015). METHODS: Local guidelines for risk-based IAP were reintroduced in April 2016. Compliance with guidelines was audited. Gestational age, mode of delivery, maternal demographics and EOGBS rates in three time periods were compared using Poisson regression analysis. EOGBS was defined through GBS being cultured from blood, cerebrospinal fluid or other sterile fluids within 6 days of birth. PRIMARY OUTCOME: EOGBS rates/1000 live births in prescreening, screening and postscreening periods RESULTS: Incremental changes in maternity population were observed throughout the study period (2009 onwards), in particular the ethnic profile of mothers. Of the 5033 live births in postscreening period, 9 babies developed EOGBS infection. Only one of the mothers of affected babies had a risk factor indicating use of IAP. Comparison of postscreening period with screening period showed a fivefold increase in EOGBS rates after adjustment for ethnicity (1.79 vs 0.33/1000 live births; risk ratio =5.67, p=0.009). There was no significant difference between prescreening and postscreening periods with rates of infection reverting to their prescreening level. CONCLUSIONS: This study provides further evidence of efficacy of screening-based IAP compared with risk-based IAP in prevention of EOGBS in newborns in an area of high incidence.
Subject(s)
Infectious Disease Transmission, Vertical/prevention & control , Mass Screening , Post-Exposure Prophylaxis , Pre-Exposure Prophylaxis , Pregnancy Complications, Infectious/prevention & control , Streptococcal Infections/prevention & control , Streptococcus agalactiae , Adult , Female , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical/statistics & numerical data , London/epidemiology , Pregnancy , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/epidemiology , Pregnancy Complications, Infectious/microbiology , Streptococcal Infections/diagnosis , Streptococcal Infections/epidemiology , Streptococcal Infections/microbiology , Streptococcus agalactiae/growth & development , Young AdultABSTRACT
This is a case of a newborn male who was diagnosed in the first month of life with tuberous sclerosis following an incidental ultrasound finding of unilateral ventriculomegaly at 36+6 weeks gestation. The antenatal ultrasound scan at 36+6 weeks was performed to establish fetal lie. Subsequent fetal brain MRI showed lesions that were initially thought to be haemorrhages, but turned out to be features of tuberous sclerosis. The baby also had five cardiac rhabdomyomas and multiple ash leaf macules. This was an unusual presentation of tuberous sclerosis, which on average is diagnosed later (mean age of diagnosis is 5 years). It also illustrates two important points: that subependymal nodules and haemorrhage can have a similar radiological appearance on antenatal MRI and cranial ultrasound and that routine antenatal ultrasound screening will miss the majority of cardiac rhabdomyomas.
Subject(s)
Brain Neoplasms/diagnosis , Cerebral Hemorrhage/diagnosis , Heart Neoplasms/diagnosis , Hydrocephalus/diagnosis , Hypopigmentation/diagnosis , Rhabdomyoma/diagnosis , Tuberous Sclerosis/diagnosis , Diagnosis, Differential , Echocardiography , Echoencephalography , Female , Humans , Infant, Newborn , Magnetic Resonance Imaging , Male , Neoplasms, Multiple Primary/diagnosis , Pregnancy , Prenatal Diagnosis , Ultrasonography, PrenatalABSTRACT
BACKGROUND: Mothers with preterm infants may need to express milk for considerable periods. Research to improve breast pump design has focused on compression stimuli, frequencies, and vacuums. OBJECTIVE: This study aimed to compare the effectiveness of 2 electric pumps: Medela Symphony (pump S) and a novel pump (Philips AVENT Twin electronic pump; pump A). Both offer flexibility of rate and suction; pump A also incorporates petal compression cushions. Primary outcomes were (1) milk weight expressed during 10-day study period and (2) weight of milk expressed in a 15-minute test. METHODS: Seventy-one mothers with preterm infants < 34 weeks were randomized. Mothers completed 10-day diaries including weight of milk expressed. Milk weight expressed during a single 15-minute test period and data on pumping mode, skin-to-skin contact, breastfeeding at infant discharge, and mothers' opinions of the pump were recorded. RESULTS: There was no significant difference in milk expressed during the first 10 days between groups. Pump S mothers expressed significantly more milk during a fixed 15-minute period. Mothers using pump A awarded higher scores for certain characteristics of the pump, notably location of control button and ease of use. Similar proportions of infants received breast milk at discharge, but pump A mothers were more likely to be directly breastfeeding (odds ratio, 4.27 [95% confidence interval, 1.29, 14.1]). CONCLUSION: The breast pumps showed similar effectiveness in terms of milk expression and maternal opinions. The finding that breast pump design may influence breastfeeding at infant discharge merits further investigation.
Subject(s)
Breast Milk Expression/instrumentation , Intensive Care Units, Neonatal , Adult , Breast Feeding/statistics & numerical data , Comparative Effectiveness Research , Female , Humans , Infant, Newborn , Infant, Premature , Intention to Treat Analysis , Outcome Assessment, Health CareABSTRACT
BACKGROUND: Animal models and observations in human neonates suggest fetal exocrine pancreas vulnerability to reduced maternofetal blood flow. We investigated the relationship between superior mesenteric artery blood flow velocity (sma bfv) and exocrine pancreatic function, in a cohort of very low birth weight (VLBW) babies. Group 1: 9 babies < 3rd percentile for birth weight. Antenatally, all had absent or reversed diastolic flow on Doppler ultrasound of the umbilical artery (UA). Group 2: 18 babies > 10th percentile for birth weight. FINDINGS: All had Doppler ultrasound scan of the superior mesenteric artery (sma), by same operator (RMN), on day 1 of life before commencement of enteral feeding. Stool samples assayed for faecal chymotrypsin and weekly serum samples assayed for amylase and lipase (kinetic colorimetric assay) from days 1 to 14 of life.Growth restricted babies had significantly lower sma bfv values compared with appropriately grown preterm babies. Faecal chymotrypsin levels were also lower but this difference did not achieve statistical significance. Both groups had serum lipase levels detectable in adult concentrations. Serum amylase was undetectable in either group. CONCLUSION: Babies with previous in-utero blood flow redistribution may exhibit altered gut ontogeny with re-setting of mesenteric blood flow velocities and altered exocrine pancreatic function.