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Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant's phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed. What is Known: • Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation. What is New: • This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES). • In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.

To compare neurodevelopmental outcomes of preterm infants at 18–21 months corrected age (CA) whose mothers smoked during pregnancy to those whose mothers did not smoke. Preterm infants born at

Preterm infants are at higher risk of developing hypothermia and complications from cold stress, resulting in high mortality and short-term morbidity. Our objective is to evaluate the association between admission temperatures of extremely low-gestational age neonates (ELGAN) (

BackgroundHuman studies investigating the link between postnatal polyunsaturated fatty acids and preterm brain growth are limited, despite emerging evidence of potential effects on outcomes.MethodsSixty preterm neonates

To compare the neurodevelopmental outcomes at 18 to 21 months corrected age (CA) of infants born at29 weeks that received room air, an intermediate oxygen concentration or 100% oxygen at the initiation of resuscitation.In this retrospective cohort study, we compared neonatal and neurodevelopmental outcomes at 18 to 21 months CA among inborn infants born before 29 weeks' gestation that received room air, intermediate oxygen concentration or 100% oxygen at the initiation of resuscitation.Of 1509 infants, 445 received room air, 483 received intermediate oxygen concentrations and 581 received 100% oxygen. Compared to infants that received room air, the primary outcome of death or neurodevelopmental impairment (NDI) was not different in intermediate oxygen (adjusted odds ratio (aOR) 1.01; 95% confidence interval (CI) 0.77, 1.34) or 100% oxygen (aOR 1.03; 95% CI 0.78, 1.35). Compared to room air, there was no difference in odds of death or severe NDI in intermediate oxygen (aOR 1.14; 95% CI 0.82, 1.58) or 100% oxygen group (aOR 1.22; 95% CI 0.90, 1.67). The odds of severe NDI among survivors were significantly higher in infants that received 100% oxygen as compared to room air (aOR 1.57, 95% CI 1.05, 2.35).We observed no significant difference in the primary composite outcomes of death or NDI and death or severe NDI at 18 to 21 months CA between infants that received room air, intermediate oxygen concentration or 100% oxygen at the initiation of resuscitation. However, use of 100% oxygen was associated with increased odds of severe NDI among survivors as compared to room air.

BackgroundHospitalized infants undergo multiple painful procedures daily. Despite the significant evidence, procedural pain assessment and management continues to be suboptimal. Repetitive and untreated pain at this vital developmental juncture is associated with negative behavioral and neurodevelopmental consequences. To address this knowledge to practice gap, we developed the web-based Implementation of Infant Pain Practice Change (ImPaC) Resource to guide change in healthcare professionals’ pain practice behaviors. This protocol describes the evaluation of the intervention effectiveness and implementation of the Resource and how organizational context influences outcomes.MethodsAn effectiveness-implementation hybrid type 1 design, blending a cluster randomized clinical trial and a mixed-methods implementation study will be used. Eighteen Neonatal Intensive Care Units (NICUs) across Canada will be randomized to intervention (INT) or standard practice (SP) groups. NICUs in the INT group will receive the Resource for six months; those in the SP group will continue with practice as usual and will be offered the Resource after a six-month waiting period. Data analysts will be blinded to group allocation. To address the intervention effectiveness, the INT and SP groups will be compared on clinical outcomes including the proportion of infants who have procedural pain assessed and managed, and the frequency and nature of painful procedures. Data will be collected at baseline (before randomization) and at completion of the intervention (six months). Implementation outcomes (feasibility, fidelity, implementation cost, and reach) will be measured at completion of the intervention. Sustainability will be assessed at six and 12 months following the intervention. Organizational context will be assessed to examine its influence on intervention and implementation outcomes.DiscussionThis mixed-methods study aims to determine the effectiveness and the implementation of a multifaceted online strategy for changing healthcare professionals’ pain practices for hospitalized infants. Implementation strategies that are easily and effectively implemented are important for sustained change. The results will inform healthcare professionals and decision-makers on how to address the challenges of implementing the Resource within various organizational contexts.Trial registrationClinicalTrials.gov,NCT03825822. Registered 31 January 2019.

Background Orally administered sucrose is effective and safe in reducing pain intensity during single, tissue-damaging procedures in neonates, and is commonly recommended in neonatal pain guidelines. However, there is wide variability in sucrose doses examined in research, and more than a 20-fold variation across neonatal care settings. The aim of this study was to determine the minimally effective dose of 24% sucrose for reducing pain in hospitalized neonates undergoing a single skin-breaking heel lance procedure. Methods A total of 245 neonates from 4 Canadian tertiary neonatal intensive care units (NICUs), born between 24 and 42 weeks gestational age (GA), were prospectively randomized to receive one of three doses of 24% sucrose, plus non-nutritive sucking/pacifier, 2 min before a routine heel lance: 0.1 ml (Group 1; n = 81), 0.5 ml (Group 2; n = 81), or 1.0 ml (Group 3; n = 83). The primary outcome was pain intensity measured at 30 and 60 s following the heel lance, using the Premature Infant Pain Profile-Revised (PIPP-R). The secondary outcome was the incidence of adverse events. Analysis of covariance models, adjusting for GA and study site examined between group differences in pain intensity across intervention groups. Results There was no difference in mean pain intensity PIPP-R scores between treatment groups at 30 s (P = .97) and 60 s (P = .93); however, pain was not fully eliminated during the heel lance procedure. There were 5 reported adverse events among 5/245 (2.0%) neonates, with no significant differences in the proportion of events by sucrose dose (P = .62). All events resolved spontaneously without medical intervention. Conclusions The minimally effective dose of 24% sucrose required to treat pain associated with a single heel lance in neonates was 0.1 ml. Further evaluation regarding the sustained effectiveness of this dose in reducing pain intensity in neonates for repeated painful procedures is warranted. Trial registration ClinicalTrials.gov: NCT02134873. Date: May 5, 2014 (retrospectively registered).

Preterm birth has a dramatic impact on polyunsaturated fatty acid exposures for the developing brain. This study examined the association between postnatal fatty acid levels and measures of brain injury and development, as well as outcomes. A cohort of 60 preterm newborns (24–32 wk gestational age) was assessed using early and near-term magnetic resonance imaging (MRI) studies. Red blood cell fatty acid composition was analyzed coordinated with each scan. Outcome at a mean of 33 mo corrected age was assessed using the Bayley Scales of Infant Development, 3rd edition. Adjusting for confounders, a 1% increase in postnatal docosahexaenoic acid (DHA) levels at early MRI was associated with 4.3-fold decreased odds of intraventricular hemorrhage, but was not associated with white matter injury or cerebellar haemorrhage. Higher DHA and lower linoleic acid (LA) levels at early MRI were associated with lower diffusivity in white matter tracts and corresponding improved developmental scores in follow-up. Higher DHA and lower LA levels in the first few weeks of life are associated with decreased intraventricular haemorrhage, improved microstructural brain development, and improved outcomes in preterm born children. Early and possibly antenatal interventions in high-risk pregnancies need to be studied for potential benefits in preterm developmental outcomes.

Background Evidence supports magnesium sulphate (MgSO4) for women at risk of imminent birth at 95% power to detect an increase in optimal MgSO4 use for fetal NP from

The recent approval of several oral disease-modifying drugs (DMDs) for multiple sclerosis (MS) brings promise of improved clinical effectiveness as well as greater drug compliance compared to the existing non-oral DMDs, and substantially increases patient choice and therapeutic options in the effective management of MS. However, for men and women with MS of childbearing age, concerns about the effect of oral DMDs on pregnancy and the fetus may arise. Some limited data from animal reproductive studies of oral DMDs suggest a potential increased risk of early pregnancy loss, impaired growth and birth defects. Although active surveillance mechanisms exist, there is limited data to inform clinical practice. Using existing information from published clinical trials and drug monographs, as well as recent conference proceedings, this review summarizes the mechanism of action (in relation to embryogenesis and pregnancy) and existing animal or human pregnancy-related data for approved (fingolimod, teriflunomide and dimethyl fumarate) and investigational (laquinimod and firategrast) oral DMDs for MS.

To examine whether early inflammation is related to cortisol levels at 18 months corrected age (CA) in children born very preterm.Infants born ≤ 32 weeks of gestational age were recruited in the neonatal intensive care unit (NICU), and placental histopathology, magnetic resonance imaging (MRI) and chart review were obtained. At 18 months CA, developmental assessment and collection of three salivary cortisol samples were carried out. Generalized least squares was used to analyze data from 85 infants providing 222 cortisol samples.Infants exposed to chorioamnionitis with funisitis had a significantly different pattern of cortisol across the samples compared with infants with chorioamnionitis alone or no prenatal inflammation (F(4, 139)=7.3996, P0.0001). Postnatal infections, necrotizing enterocolitis and chronic lung disease were not significantly associated with the cortisol pattern at 18 months CA.In children born very preterm, prenatal inflammatory stress may contribute to altered programming of the hypothalamic-pituitary-adrenal (HPA) axis.

The lack of a standard format for storing data generated within the smart environments research domain is limiting the opportunity for researchers to compare and share datasets. The opportunity to ...

Infection is a risk factor for adverse neurodevelopmental outcome in preterm newborns. Our objective was to characterize the association of postnatal infection with adverse microstructural and metabolic brain development in premature newborns. In 34/117 newborns studied, clinical signs were accompanied by positive cultures whereas 17 had clinical signs of sepsis alone. White matter injury (WMI) was identified in 34 newborns. In multivariate regression models, infected newborns had brain imaging measures indicative of delayed brain development: lower N-acetylaspartate/choline, elevated average diffusivity (DAV), and decreased white matter fractional anisotropy. These widespread brain abnormalities were found in both newborns with positive-culture infection and in those with clinical infection. These findings suggest that postnatal infection, even without a positive culture, is an important risk factor for widespread abnormalities in brain development. These abnormalities extend beyond brain injuries apparent with conventional magnetic resonance injury (MRI). 117 preterm newborns (24–32 wk gestation) were studied prospectively at a median of 32.0 and 40.3 wk ostmenstrual age with MRI (WMI, hemorrhage), magnetic resonance (MR) spectroscopy (metabolism), and diffusion tensor imaging (microstructure). Newborns were categorized as having “no infection,” “clinical infection,” or “positive-culture infection.” We compared brain injuries as well as metabolic and microstructural development across these infection groups.

Resting cortical activity is characterized by a distinct spectral peak in the alpha frequency range. Slowing of this oscillatory peak toward the upper theta-band has been associated with a variety of neurological and neuropsychiatric conditions, and has been attributed to altered thalamocortical dynamics. Children born very preterm exhibit altered development of thalamocortical systems. To test the hypothesis that peak oscillatory frequency is slowed in children born very preterm, we recorded resting magnetoencephalography (MEG) from school age children born very preterm (≤32 weeks gestation) without major intellectual or neurological impairment and age-matched full term controls. Very preterm children exhibit a slowing of peak frequency toward the theta-band over bilateral frontal cortex, together with reduced alpha-band power over bilateral frontal and temporal cortex, suggesting that mildly dysrhythmic thalamocortical interactions may contribute to altered spontaneous cortical activity in children born very preterm.

To describe the incidence trend and long-term visual outcomes of infants diagnosed with stages 3 to 4 retinopathy of prematurity (ROP) or laser-treated ROP born in British Columbia (Canada).Data from all (n=1384) neonates with birth weight (BW)1250 g, admitted to British Columbia Children's Hospital between period 1 (January 1992 to December 1996) and period 2 (January 1997 to December 2001) were analyzed. Ophthalmologic records of infants with stages 3 to 4 ROP or laser-treated ROP were abstracted. chi(2)- and t-test were used to compare neonatal characteristics between periods. Logistic regression was used to identify risk factors associated with visual impairment (defined as visual acuityor=20/60 or visual field restriction of 20 degrees binocularly).Of 1159 surviving infants, 887 were examined for acute ROP (473 in period 1, 414 in period 2). Stages 3 to 4 ROP or laser-treated ROP were present in 35 infants in period 1 (7%) and 59 in period 2 (14%), Por=0001. Infants born in period 2 had lower mean BW and gestational age. Among infants who developed severe ROP or laser-treated ROP, binocular visual impairment was present in eight children in period 1 and seven in period 2. Refractive errors, including myopia and astigmatism, were increased in period 2. Children who developed periventricular leucomalacia had the highest risk of visual impairment at 4 to 6 years of age.During the 10-year study period, a significant increase in rates of stages 3 to 4 or laser-treated ROP was not associated with increases in visual impairment rates.

Long-term outcomes of preterm infants have been extensively studied, but few studies have examined long-term outcomes of term infants who require neonatal intensive care unit (NICU). Our objectives were to assess perinatal characteristics and health status of preschool age term babies using data from a population-based study of NICU graduates. Retrospective cross-sectional survey. All babies were born in 1996 to 1997 in BC (Canada). The Health Status Classification System Preschool (HSCS-PS) questionnaire was completed by parents at 42 months of age. HSCS-PS was grouped in four categories (neurosensory, learning, motor and quality of life). Logistic regression was used to identify perinatal risk factors associated with moderate/severe problems at 42 months of age. Completed surveys were received for 261 term NICU survivors and 393 control children. Term infants represent 32% of all NICU admissions. Mean birth weight of NICU graduates was 3458 g (s.d.=600 g). Median length-of-stay in NICU was 5 days. At 42 months, the NICU group had significantly more problems on the HSCS-PS as compared to the full-term healthy infants in neurosensory, motor and learning/remembering. Moderate/severe health status problems were associated with congenital anomalies (odds ratio (OR), 3.2; confidence interval (CI): 1.3 to 7.8); smoking status (OR, 2.7, CI: 1.1 to 6.6) and SNAP score (OR, 1.04; CI: 1.0 to 1.1). Term babies admitted to NICUs may have significant health issues in childhood. Greater attention needs to be paid to long-term outcomes of term NICU graduates. Further study is warranted to address which NICU term survivors warrant secondary and/or tertiary-level neurodevelopmental follow-up.

Accelerating technological development has made it possible for humans to reach to one of the most remote parts of the Earth, the deepest areas of the sea, also called the Earth’s last frontier. Rare, previously hidden ecosystems with vast biological diversity can be found here. These communities and their inhabitants are starting to feel the pressure of human impact, being regarded as having an enormous potential in the development of new products such as pharmaceuticals, molecular probes, enzymes, cosmetics, nutritional supplements, and agrichemicals. However, compared to the bioprospecting activity of these areas, an increasing pressure on deep-sea fisheries is probably an even more serious threat for the deep-sea communities, and a recent publication reports that deep-sea fishes qualify as endangered. Sustainable use of the deep sea and the organisms that inhabit it should thus be aimed for.

Background This multicenter prospective study of invasive candidiasis (IC) was carried out to determine the risk factors for, incidence of, clinical and laboratory features, treatment and outcome of IC in infants of birth weight

Background There is limited information in the literature on the presentation and prognosis of candidal urinary tract infection (UTI) in infants in the neonatal intensive care unit (NICU). Methods This was a prospective cohort study performed in 13 Canadian NICUs. Infants with candidal UTI without extra-renal candidal infection at presentation were enrolled. Results Thirty infants fit the study criteria. Median birth weight and gestational age were 2595 grams (range 575-4255) and 35 weeks (range 24-41) with 10 infants being < 30 weeks gestation. The most common primary underlying diagnosis was congenital heart disease (n = 10). The median age at initial diagnosis was 16 days (range 6-84 days). Renal ultrasonography findings were compatible with possible fungal disease in 15 of the 26 infants (58%) in whom it was performed. Treatment was variable, but fluconazole and either amphotericin B deoxycholate or lipid-based amphotericin B in combination or sequentially were used most frequently. Extra-renal candidiasis subsequently developed in 4 infants. In 2 of these 4 infants, dissemination happened during prolonged courses of anti-fungal therapy. Three of 9 deaths were considered to be related to candidal infection. No recurrences of candiduria or episodes of invasive candidiasis following treatment were documented. Conclusion Candidal UTI in the NICU population occurs both in term infants with congenital abnormalities and in preterm infants, and is associated with renal parenchymal disease and extra-renal dissemination. A wide variation in clinical approach was documented in this multicenter study. The overall mortality rate in these infants was significant (30%). In one third of the deaths, Candida infection was deemed to be a contributing factor, suggesting the need for antifungal therapy with repeat evaluation for dissemination in infants who are slow to respond to therapy.

BackgroundThe increased survival of preterm and very low birth weight infants in recent years has been well documented but continued surveillance is required in order to monitor the effects of new therapeutic interventions. Gestation and birth weight specific survival rates most accurately reflect the outcome of perinatal care. Our aims were to determine survival to discharge for a large Canadian cohort of preterm infants admitted to the neonatal intensive care unit (NICU), and to examine the effect of gender on survival and the effect of increasing postnatal age on predicted survival.MethodsOutcomes for all 19,507 infants admitted to 17 NICUs throughout Canada between January 1996 and October 1997 were collected prospectively. Babies with congenital anomalies were excluded from the study population. Gestation and birth weight specific survival for all infants with birth weight ResultsSurvival to discharge at 24 weeks gestation was 54%, compared to 82% at 26 weeks and 95% at 30 weeks. In infants with birth weights 600–699, survival to discharge was 62%, compared to 79% at 700–799 g and 96% at 1,000–1,099 g. In infants born at 24 weeks gestational age, survival was higher in females but there were no significant gender differences above 24 weeks gestation. Actuarial analysis showed that risk of death was highest in the first 5 days. For infants born at 24 weeks gestation, estimated survival probability to 48 hours, 7 days and 4 weeks were 88 (CI 84,92)%, 70 (CI 64, 76)% and 60 (CI 53,66)% respectively. For smaller birth weights, female survival probabilities were higher than males for the first 40 days of life.ConclusionActuarial analysis provides useful information when counseling parents and highlights the importance of frequently revising the prediction for long term survival particularly after the first few days of life.

Checkpoint mechanisms prevent cell cycle transitions until previous events have been completed or damaged DNA has been repaired. In fission yeast, checkpoint mechanisms are known to regulate entry into mitosis, but so far no checkpoint inhibiting S phase entry has been identified. We have studied the response of germinating Schizosaccharomyces pombe spores to UV irradiation in G1. When germinating spores are irradiated in early G1 phase, entry into S phase is delayed. We argue that the observed delay is caused by two separate mechanisms. The first takes place before entry into S phase, does not depend on the checkpoint proteins Rad3, Cds1 and Chk1 and is independent of Cdc2 phosphorylation. Furthermore, it is not dependent upon inhibiting the Cdc10-dependent transcription required for S phase entry, unlike a G1/S checkpoint described in budding yeast. We show that expression of Cdt1, a protein essential for initiation of DNA replication, is delayed upon UV irradiation. The second part of the delay occurs after entry into S phase and depends on Rad3 and Cds1 and is probably due to the intra-S checkpoint. If the germinating spores are irradiated in late G1, they enter S phase without delay and arrest in S phase, suggesting that the delay we observe upon UV irradiation in early G1 is not caused by nonspecific effects of UV irradiation. We have studied the response of germinating S. pombe spores to UV irradiation in G1 and shown that S phase entry is delayed by a mechanism that is different from classical checkpoint responses. Our results point to a mechanism delaying expression of proteins required for S phase entry.