Association of low hemoglobin at birth and neurodevelopmental outcomes in preterm neonates ≤28 weeks' gestation: a retrospective cohort study.

OBJECTIVE: To compare neurodevelopmental outcomes at 18-24 months corrected age (CA) for preterm infants who had hemoglobin levels <120 g/l versus those with hemoglobin level ≥120 g/l at birth. METHODS: We included infants of ≤28 weeks gestational age (GA) born between January 2009 and June 2018. The primary outcome was neurodevelopmental impairment (NDI) at 18-24 months. Multivariable logistic regression was applied to determine the association. RESULTS: Of the 2351 eligible neonates, 351 (14.9%) had hemoglobin levels <120 g/L at birth. Of the 2113 surviving infants, 1534 (72.5%) underwent developmental follow-up at 18-24 months CA. There was no statistically significant difference in ND outcomes between the two groups. The composite outcome of death or NDI was significantly higher in the low hemoglobin group. CONCLUSION: In preterm infants ≤28 weeks GA, initial hemoglobin <120 g/L at birth was not associated with neurodevelopmental impairment at 18-24 months CA among survivors.

Hyperbilirubinemia Among Infants Born Preterm: Peak Levels and Association with Neurodevelopmental Outcomes.

OBJECTIVE: To describe the distribution of peak bilirubin levels among infants born before 29 weeks of gestation in the first 14 days of life and to study the association between quartiles of peak bilirubin levels at different gestational ages and neurodevelopmental outcomes. STUDY DESIGN: Multicenter, retrospective, nationwide cohort study of neonatal intensive care units in the Canadian Neonatal Network and Canadian Neonatal Follow-Up Network, including neonates born preterm at 220/7 to 286/7 weeks of gestation born between 2010 and 2018. Peak bilirubin levels were recorded during the first 14 days of age. Main outcome was significant neurodevelopmental impairment, defined as cerebral palsy with Gross Motor Function Classification System ≥3, or Bayley III-IV scores of <70 in any domain, or visual impairment, or bilateral hearing loss requiring hearing aids. RESULTS: Among 12 554 included newborns, median gestational age was 26 weeks (IQR 25-28) and birth weight was 920 g (IQR 750-1105 g). The median peak bilirubin values increased as gestational age increased (112 mmol/L [6.5 mg/dL] at 22 weeks and 156 mmol/L [9.1 mg/dL] at 28 weeks). Significant neurodevelopmental impairment was identified in 1116 of 6638 (16.8%) of children. Multivariable analyses identified an association between peak bilirubin in the highest quartile and neurodevelopmental impairment (aOR 1.27, 95% CI 1.01-1.60) and receipt of hearing aid/cochlear implant (aOR 3.97, 95%CI: 2.01-7.82) compared with the lowest quartile. CONCLUSION: In this multicenter cohort study, peak bilirubin levels in neonates of <29 weeks of gestation increased with gestational age. Peak bilirubin values in the highest gestational age-specific quartile were associated with significant neurodevelopmental and hearing impairments.

Automated Movement Analysis to Predict Cerebral Palsy in Very Preterm Infants: An Ambispective Cohort Study.

The General Movements Assessment requires extensive training. As an alternative, a novel automated movement analysis was developed and validated in preterm infants. Infants < 31 weeks' gestational age or birthweight ≤ 1500 g evaluated at 3−5 months using the general movements assessment were included in this ambispective cohort study. The C-statistic, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for a predictive model. A total of 252 participants were included. The median gestational age and birthweight were 274/7 weeks (range 256/7−292/7 weeks) and 960 g (range 769−1215 g), respectively. There were 29 cases of cerebral palsy (11.5%) at 18−24 months, the majority of which (n = 22) were from the retrospective cohort. Mean velocity in the vertical direction, median, standard deviation, and minimum quantity of motion constituted the multivariable model used to predict cerebral palsy. Sensitivity, specificity, positive, and negative predictive values were 55%, 80%, 26%, and 93%, respectively. C-statistic indicated good fit (C = 0.74). A cluster of four variables describing quantity of motion and variability of motion was able to predict cerebral palsy with high specificity and negative predictive value. This technology may be useful for screening purposes in very preterm infants; although, the technology likely requires further validation in preterm and high-risk term populations.

Automated movement recognition to predict motor impairment in high-risk infants: a systematic review of diagnostic test accuracy and meta-analysis.

AIM: To assess the sensitivity and specificity of automated movement recognition in predicting motor impairment in high-risk infants. METHOD: We searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Scopus databases and identified additional studies from the references of relevant studies. We included studies that evaluated automated movement recognition in high-risk infants to predict motor impairment, including cerebral palsy (CP) and non-CP motor impairments. Two authors independently assessed studies for inclusion, extracted data, and assessed methodological quality using the Quality Assessment of Diagnostic Accuracy Studies-2. Meta-analyses were performed using hierarchical summary receiver operating characteristic models. RESULTS: Of 6536 articles, 13 articles assessing 59 movement variables in 1248 infants under 5 months corrected age were included. Of these, 143 infants had CP. The overall sensitivity and specificity for motor impairment were 0.73 (95% confidence interval [CI] 0.68-0.77) and 0.70 (95% CI 0.65-0.75) respectively. Comparatively, clinical General Movements Assessment (GMA) was found to have sensitivity and specificity of 98% (95% CI 74-100) and 91% (95% CI 83-93) respectively. Sensor-based technologies had higher specificity (0.88, 95% CI 0.80-0.93). INTERPRETATION: Automated movement recognition technology remains inferior to clinical GMA. The strength of this study is its meta-analysis to summarize performance, although generalizability of these results is limited by study heterogeneity.

Automated movement analysis to predict motor impairment in preterm infants: a retrospective study.

OBJECTIVE: To apply automated movement analysis to the general movements assessment (GMA) to build a predictive model for motor impairment (MI). STUDY DESIGN: A retrospective cohort study including infants ≤306/7 weeks GA or BW ≤1500 g seen at 3-5 months was conducted. Automated video analysis was used to develop a multivariable model to identify MI, defined as Bayley motor composite score <85 or cerebral palsy (CP). RESULTS: One hundred and fifty two videos were analyzed. Median GA and BW were 275/7 weeks and 955 g, respectively. MI and CP rates were 22% (N = 33) and 14% (N = 22). Minimum, mean, and mean vertical velocity of the infant's silhouette correlated significantly with MI. Sensitivity, specificity, positive and negative predictive values, and accuracy of automated GMA were 79%, 63%, 37%, 91%, and 66%, respectively. C-statistic indicated good fit (C = 0.77). CONCLUSIONS: Automated movement analysis predicts MI in preterm infants. Further refinement of this technology is required for clinical application.

Neurodevelopmental outcomes in infants treated with intravitreal bevacizumab versus laser.

OBJECTIVE: To compare neurodevelopmental and visual outcomes in preterm infants treated with intravitreal bevacizumab (IVB) to laser ablation at 18-24 months corrected age. STUDY DESIGN: A retrospective study was performed. The primary outcome was neurodevelopmental impairment (NDI). Secondary neurodevelopmental outcomes were significant NDI (sNDI), cerebral palsy, hearing loss, and composite scores of the Bayley Scales of Infant Development, Third edition. Visual outcomes included structural and refractive outcomes. Adjusted odds ratios (AOR) were calculated controlling for GA, sex, and ROP severity and confounding baseline characteristics using a cutoff of p < 0.20. RESULTS: Thirty-four (60 eyes) infants receiving IVB and 30 (51 eyes) laser were included. No significant differences were identified in NDI (AOR 1.77, 95% CI 0.46, 6.73) or sNDI (AOR 2.31, 95% CI 0.75, 7.14). There were no other differences in outcomes. CONCLUSIONS: Larger randomized trials are required to establish long-term efficacy and safety of IVB in preterm neonates.

Adenovirus-Associated Central Nervous System Disease in Children.

OBJECTIVE: To characterize the spectrum and salient clinical features of adenovirus-associated neurologic disease in immunocompetent children. STUDY DESIGN: Previously healthy children (aged 1 month-18 years) with central nervous system (CNS) disease associated with adenovirus infection were identified via the Encephalitis Registry (1996-2016) and Microbiology Database (2000-2016) at The Hospital for Sick Children, Toronto, and by systematic review of the literature. The data were pooled and analyzed to identify the spectrum of illness, clinical outcome, and risk factors for death or neurologic impairment. RESULTS: Neurologic complications associated with adenovirus infection in our institution included febrile seizures, encephalitis, acute disseminated encephalomyelitis, and aseptic meningitis. A total of 48 immunocompetent children with adenovirus-associated CNS disease were included in the pooled analysis-38 from the literature and 10 from our institution. In 85% of cases, the virus was detected in the respiratory or gastrointestinal tract, but not the cerebrospinal fluid. Eighteen of the 48 (38%) patients either died or suffered permanent neurologic sequelae. Predictors of adverse outcome included younger age, coagulopathy, the absence of meningismus, serotype 2 virus, and the presence of seizures. After multivariable adjustment, only seizures remained a significant risk factor. CONCLUSION: Adenovirus is a rare cause of CNS disease in immunocompetent children. Disease spectrum is variable, ranging from mild aspetic meningitis and fully reversible encephalopathy to severe, potentially fatal, acute necrotizing encephalopathy.

Detection of Atypical and Typical Infant Movements using Computer-based Video Analysis.

The diagnosis of cerebral palsy (CP) is difficult before 2 years of age. The general movements assessment (GMA) is a method for predicting CP from the spontaneous movements of infants in the first months of life. This assessment has shown high accuracy in predicting CP, but its use is limited by a lack of trained clinicians and its subjective nature. An objective and cost-effective alternative is the automatic videobased assessment of infant movements. Retrospective videos with clinical GMA outcomes were evaluated against eligibility criteria for the automatic analysis consisting of a skin model for segmentation and large displacement optical flow (LDOF) for motion tracking. Kinematic features were extracted to classify the movements as typical or atypical using different classification algorithms. Preliminary classification results obtained from the analysis of 127 videos of preterm infants showed up to 92% of accuracy in predicting CP. A computerbased assessment would provide clinicians with an objective tool for early diagnosis of CP, to facilitate early intervention and improve functional outcomes.

Inhaled corticosteroids in ventilated preterm neonates: a non-randomized dose-ranging study.

BACKGROUND: Inhaled corticosteroids (ICS) offer targeted treatment for bronchopulmonary dysplasia (BPD) with minimal systemic effects compared to systemic steroids. However, dosing of ICS in the management of infants at high-risk of developing BPD is not well established. The objective of this study was to determine an effective dose of ICS for the treatment of ventilator-dependent infants to facilitate extubation or reduce fractional inspired oxygen concentration. METHODS: Forty-one infants born at < 32 weeks gestational age (GA) or < 1250 g who were ventilator-dependent at 10-28 days postnatal age were included. A non-randomized dose-ranging trial was performed using aerosolized inhaled beclomethasone with hydrofluoralkane propellant (HFA-BDP). Four dosing groups (200, 400, 600 and 800 µg twice daily for 1 week) with 11, 11, 10 and 9 infants in each group, respectively, were studied. The primary outcome was therapeutic efficacy (successful extubation or reduction in FiO2 of > 75% from baseline) in ≥60% of infants in the group. Oxygen requirements, complications and long-term neurodevelopmental outcomes were also assessed. RESULTS: The median age at enrollment was 22 (10-28) postnatal days. The primary outcome, therapeutic efficacy as defined above, was not achieved in any group. However, there was a significant reduction in post-treatment FiO2 at a dose of 800 µg bid. No obvious trends were seen in long-term neurodevelopmental outcomes. CONCLUSIONS: Therapeutic efficacy was not achieved with all studied doses of ICS. A significant reduction in oxygen requirements was noted in ventilator-dependent preterm infants at 10-28 days of age when given 800 µg of HFA-BDP bid. Larger randomized trials of ICS are required to determine efficacy for the management of infants at high-risk for development of BPD. TRIAL REGISTRATION: This clinical trial was registered retrospectively on clinicaltrials.gov. The registration number is NCT03503994 .

Head Growth Trajectory and Neurodevelopmental Outcomes in Preterm Neonates.

OBJECTIVES: To evaluate the association between head growth (HG) during neonatal and postdischarge periods and neurodevelopmental outcomes of preterm neonates of <29 weeks gestational age. METHODS: We conducted a retrospective cohort study of infants <29 weeks gestationalage admitted between 2009 and 2011 to participating Canadian Neonatal Networkunits and followed by Canadian Neonatal Follow-Up Network clinics. Differences in head circumference (ΔHC) z score were calculated for 3 time periods, which include admission to discharge, discharge to follow-up at 16-36 months, and admission to follow-up. These were categorized in 1 reference group (ΔHC z score between -1 and +1) and 4 study groups (ΔHC z score of <-2, between -2 to -1, +1 to +2, and >+2). Neurodevelopmental outcomes were compared with the reference group. RESULTS: 1973 infants met the inclusion criteria. Poor HG occurred frequently during the NICU admission (ΔHC z score <-2 in 24% infants versus 2% infants post-discharge) with a period of "catch-up" growth postdischarge. Significant neurodevelopmental impairment was higher in infants with the poorest HG from admission to follow-up (adjusted odds ratio 2.18, 95% confidence interval 1.50-3.15), specifically cognitive and motor delays. Infants with poor initial HG and catch-up postdischarge have a lower adjusted odds ratio of significant neurodevelopmental impairment (0.35, 95% CI 0.16-0.74). Infants with poor HG received a longer duration of parenteral nutrition and mechanical ventilation and had poor weight gain. CONCLUSIONS: Poor HG during the neonatal and postdischarge periods was associated with motor and cognitive delays at 16 to 36 months.

Mammalian Cell Encapsulation in Alginate Beads Using a Simple Stirred Vessel.

Cell encapsulation in alginate beads has been used for immobilized cell culture in vitro as well as for immunoisolation in vivo. Pancreatic islet encapsulation has been studied extensively as a means to increase islet survival in allogeneic or xenogeneic transplants. Alginate encapsulation is commonly achieved by nozzle extrusion and external gelation. Using this method, cell-containing alginate droplets formed at the tip of nozzles fall into a solution containing divalent cations that cause ionotropic alginate gelation as they diffuse into the droplets. The requirement for droplet formation at the nozzle tip limits the volumetric throughput and alginate concentration that can be achieved. This video describes a scalable emulsification method to encapsulate mammalian cells in 0.5% to 10% alginate with 70% to 90% cell survival. By this alternative method, alginate droplets containing cells and calcium carbonate are emulsified in mineral oil, followed by a decrease in pH leading to internal calcium release and ionotropic alginate gelation. The current method allows the production of alginate beads within 20 min of emulsification. The equipment required for the encapsulation step consists in simple stirred vessels available to most laboratories.

Impact of flap reconstruction on perineal wound complications following ablative surgery for advanced and recurrent rectal cancers.

BACKGROUND: To determine the effect of flap reconstruction on perineal complications in locally advanced rectal cancers (LARC) and locally recurrent rectal cancers (LRRC). Prior studies have suggested that flap reconstruction may decrease wound complications after ablative surgery for rectal cancer but are limited by small sample sizes, heterogeneity of pathologies, and lack of comparison groups. METHODS: A retrospective cohort study (1999-2010) was performed on consecutive patients undergoing abdominoperineal resection (APR) or pelvic exenteration for locally advanced/locally recurrent rectal cancers. Differences in perineal complications between patients treated with and without perineal flap reconstruction were analyzed by using univariable, multivariable, and propensity score regression analyses. RESULTS: Flap reconstruction was performed in 52 of 177 patients (29 %). Patients receiving flap reconstruction had multiple risk factors for perineal morbidity, including longer operative times and more complex procedures. In our final multivariable analyses that were stratified by type of ablative procedure, we found a trend toward lower odds of perineal complications in patients receiving flaps (p = 0.065) compared with primary closure after pelvic exenteration. Although operative time and sacrectomy were significant determinants of perineal morbidity for pelvic exenteration patients, no significant predictors of perineal outcomes were identified for patients undergoing APR. CONCLUSIONS: This study suggests that flap reconstruction may provide some protective effect against perineal complications in patients undergoing pelvic exenteration, although this was not observed for APR. The most important determinants of perineal complications after pelvic exenteration were operative time and sacral resection, but no predictive factors for post-APR perineal outcomes were identified.

Genotypic and functional diversity of phenotypically defined primitive hematopoietic cells in patients with chronic myeloid leukemia.

Much progress has been made in the management of chronic-phase chronic myeloid leukemia (CP-CML), but there is a continuing imperative to develop curative treatments, predict patient responses to specific modalities, and anticipate disease relapse or progression. These needs underlie continuing interest in methods to detect and quantify the relevant leukemic cells in clinical samples with improved reliability and specificity. We report the results of comparing three methods to enumerate primitive CP-CML cells in the same samples: genotyping CD34(+)38(-) cells directly by fluorescence in situ hybridization, and measuring BCR-ABL1 transcript-genotyped colony-forming cell outputs in either 5-week long-term cultures (LTCs) containing non-engineered mouse fibroblasts or in 6-week LTCs containing mouse fibroblasts engineered to produce human Steel factor, granulocyte colony-stimulating factor, and IL-3. The results demonstrate that the first two methods significantly overestimate the prevalence of primitive CP-CML cells by comparison to the third. In additional studies, we found that CML-CD34(+) cells can repopulate the marrow and spleen of serially transplanted adult NOD/SCID-IL-2Rγ chain-null mice for more than 1 year with an almost exclusive myeloid differentiation in primary and secondary recipients and without evidence of disease progression. These findings underscore the importance of long-term functional in vitro and in vivo endpoints to identify and characterize CP-CML stem cells.

Barriers and facilitators to implementation of a metabolic monitoring protocol in hospital and community settings for second-generation antipsychotic-treated youth.

OBJECTIVE: 1) Assess perceived barriers associated with metabolic monitoring in second-generation antipsychotic (SGA)-treated youth; and 2) Propose a metabolic monitoring protocol (MMP) and implementation strategies. METHOD: Online surveys were created for community mental health teams (CMHTs) and BC Children's Hospital (BCCH) with questions designed to evaluate knowledge of physical health care, confidence, communication with primary care, and practical issues. RESULTS: 26/50 (52%) of CMHT and 44/111 (40%) of BCCH surveys were completed. While both groups agreed that monitoring is their responsibility, 26% of CMHTs and 35% of BCCH professionals agreed that providing information about SGA side-effects would influence medication adherence. CMHTs reported lower overall confidence and more practical issues as monitoring barriers. While higher overall confidence was reported at BCCH, there was still a substantial proportion (23%) of hospital professionals who reported not knowing what parameters to monitor and how frequently. Communication with primary care, including inadequate systems for sharing results and identifying responsibility for acting on abnormal results, appear to be common barriers shared by both settings. CONCLUSIONS: Barriers to metabolic monitoring were more frequently reported by CMHTs who had limited access to nursing staff. We propose hands-on training, educational resources, pre-printed orders, and regular quality assurance evaluation as facilitators to promote MMP uptake.

Pancreatic cell immobilization in alginate beads produced by emulsion and internal gelation.

Alginate has been used to protect transplanted pancreatic islets from immune rejection and as a matrix to increase the insulin content of islet progenitor cells. The throughput of alginate bead generation by the standard extrusion and external gelation method is limited by the rate of droplet formation from nozzles. Alginate bead generation by emulsion and internal gelation is a scaleable alternative that has been used with biological molecules and microbial cells, but not mammalian cells. We describe the novel adaptation of this process to mammalian cell immobilization. After optimization, the emulsion process yielded 90 ± 2% mouse insulinoma 6 (MIN6) cell survival, similar to the extrusion process. The MIN6 cells expanded at the same rate in both bead types to form pseudo-islets with increased glucose stimulation index compared to cells in suspension. The emulsion process was suitable for primary pancreatic exocrine cell immobilization, leading to 67 ± 32 fold increased insulin expression after 10 days of immobilized culture. Due to the scaleability and broad availability of stirred mixers, the emulsion process represents an attractive option for laboratories that are not equipped with extrusion-based cell encapsulators, as well as for the production of immobilized or encapsulated cellular therapeutics on a clinical scale.