CRISPR/Cas9 targeted mutations of OsDSG1 gene enhanced salt tolerance in rice.

Salinization is one of the leading causes of arable land shrinkage and rice yield decline, recently. Therefore, developing and utilizing salt-tolerant rice varieties have been seen as a crucial and urgent strategy to reduce the effects of saline intrusion and protect food security worldwide. In the current study, the CRISPR/Cas9 system was utilized to induce targeted mutations in the coding sequence of the OsDSG1, a gene involved in the ubiquitination pathway and the regulation of biochemical reactions in rice. The CRISPR/Cas9-induced mutations of the OsDSG1 were generated in a local rice cultivar and the mutant inheritance was validated at different generations. The OsDSG1 mutant lines showed an enhancement in salt tolerance compared to wild type plants at both germination and seedling stages indicated by increases in plant height, root length, and total fresh weight as well as the total chlorophyll and relative water contents under the salt stress condition. In addition, lower proline and MDA contents were observed in mutant rice as compared to wild type plants in the presence of salt stress. Importantly, no effect on seed germination and plant growth parameters was recorded in the CRISRP/Cas9-induced mutant rice under the normal condition. This study again indicates the involvement of the OsDSG1 gene in the salt resistant mechanism in rice and provides a potential strategy to enhance the tolerance of local rice varieties to the salt stress.

Change in Volumes and Location of Preterm White Matter Injury over a Period of 15 Years.

OBJECTIVE: To evaluate whether white matter injury (WMI) volumes and spatial distribution, which are important predictors of neurodevelopmental outcomes in preterm infants, have changed over a period of 15 years. STUDY DESIGN: Five hundred and twenty-eight infants born <32 weeks' gestational age from 2 sequential prospective cohorts (cohort 1: 2006 through 2012; cohort 2: 2014 through 2019) underwent early-life (median 32.7 weeks postmenstrual age) and/or term-equivalent-age MRI (median 40.7 weeks postmenstrual age). WMI were manually segmented for quantification of volumes. There were 152 infants with WMI with 74 infants in cohort 1 and 78 in cohort 2. Multivariable linear regression models examined change in WMI volume across cohorts while adjusting for clinical confounders. Lesion maps assessed change in WMI location across cohorts. RESULTS: There was a decrease in WMI volume in cohort 2 compared with cohort 1 (ß = -0.6, 95% CI [-0.8, -0.3], P < .001) with a shift from more central to posterior location of WMI. There was a decrease in clinical illness severity of infants across cohorts. CONCLUSIONS: We found a decrease in WMI volume and shift to more posterior location in very preterm infants over a period of 15 years. This may potentially reflect more advanced maturation of white matter at the time of injury which may be related to changes in clinical practice over time.

Neonatal Hypoxic-Ischemic Encephalopathy Spectrum: Severity-Stratified Analysis of Neuroimaging Modalities and Association with Neurodevelopmental Outcomes.

OBJECTIVE: To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. STUDY DESIGN: This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and postrewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18 months of age. RESULTS: Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48 hours after birth were more common in the severe HIE group than the mild HIE group (81% vs 39% and 50% vs 0%, respectively; P < .001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted P < .001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (OR: 19.9, 95% CI: 4.0-98.1; P < .001). CONCLUSION: The present study shows the complementary utility of cUS in the first 48 hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.

Prognostic Indicators of Reorientation of Care in Perinatal Hypoxic-Ischemic Encephalopathy Spectrum.

OBJECTIVE: To investigate the clinical, electrographic, and neuroimaging characteristics in neonates with perinatal hypoxic-ischemic encephalopathy who underwent reorientation of care using standardized scoring systems. STUDY DESIGN: A nested observational substudy within a prospective hypoxic-ischemic encephalopathy cohort was conducted. Group 1 comprised infants whose parents received the medical recommendation for reorientation of care, while group 2 continued to receive standard care. Encephalopathy scores were monitored daily. Amplitude-integrated and continuous-video-integrated electroencephalogram during therapeutic hypothermia were analyzed. Standardized scoring systems for cranial ultrasonography and postrewarming brain magnetic resonance imaging were deployed. RESULTS: The study included 165 infants, with 35 in group 1 and 130 in Group 2. By day 3, all infants in group 1 were encephalopathic with higher Thompson scores (median 13 [IQR 10-19] vs 0 [IQR 0-3], P < .001). Electrographic background normalization within 48 hours occurred in 3% of group 1 compared with 46% of group 2 (P < .001). Sleep-wake cycling was not observed in group 1 and emerged in 63% of group 2 within the first 72 hours (P < .001). The number of antiseizure medications received was higher in group 1 (median 3 [IQR, 2-4] vs 0 [IQR, 0-1], respectively; P < .001). Group 1 had higher cranial ultrasound injury scores (median 4 [IQR 2-7] vs 1 [IQR 0-1], P < .001) within 48 hours and postrewarming brain magnetic resonance imaging injury scores (median 33 [range 20-51] vs 4 [range 0-28], P < .001). CONCLUSIONS: Neonates with perinatal hypoxic-ischemic encephalopathy who underwent reorientation of care presented with and maintained significantly more pronounced clinical manifestations, electrographic findings, and near-total brain injury as scored objectively on all modalities. TRIAL REGISTRATION: Registration of the study cohort: NCT04913324.

Umbilical artery eucapnic pH to assess fetal well-being.

BACKGROUND: Umbilical artery gas results help obstetricians assess fetal well-being during labor and guide screening decisions on eligibility for therapeutic hypothermia (ie, whole-body or head cooling). The accuracy of results, especially for the base deficit on arterial cord gas analysis, in predicting brain injury is questioned. A novel biomarker specifically calculated for fetal acid-base physiology and response to asphyxia-neonatal eucapnic pH as a marker of neonatal metabolic acidosis-has the potential to be an accurate predictor of hypoxic-ischemic encephalopathy. OBJECTIVE: We aimed to compare false-negative rates of hypoxic-ischemic encephalopathy for umbilical artery pH, base deficit, and neonatal eucapnic pH in assessing fetal acid-base balance as a marker of fetal well-being and predicting acute brain injury. STUDY DESIGN: This is a retrospective single-center cohort study of newborns ≥ 35 weeks of gestation diagnosed with hypoxic-ischemic encephalopathy. We compared false-negative rates for any grade of hypoxic-ischemic encephalopathy using unilateral paired chi-square statistical analysis based on cutoff values for umbilical artery pH ≤7.00, base deficit ≥16 mmol/L, base deficit ≥12 mmol/L and neonatal eucapnic pH ≤7.14. We performed an analysis of variance between umbilical artery pH, base deficit, and neonatal eucapnic pH for each hypoxic-ischemic encephalopathy grade. RESULTS: We included 113 newborns. False-negative rate for hypoxic-ischemic encephalopathy was significantly higher for base deficit <16 mmol/L (n=78/113; 69.0%) than <12 mmol/L (n=46/113; 40.7%), pH >7.00 (n=41/113; 36.3%), or neonatal eucpanic pH >7.14 (n=35/113; 31.0%) (P<.0001). All true-positive cases were identified using only umbilical artery pH and neonatal eucapnic pH. Base deficit ≥16 or ≥12 mmol/L did not add any value in identifying newborns with hypoxic-ischemic encephalopathy when using umbilical artery pH and neonatal eucapnic pH. No association emerged between any marker and hypoxic-ischemic encephalopathy severity grading. CONCLUSION: Our findings support the accuracy of neonatal eucapnic pH to assess fetal well-being during labor and to improve predictive performance for acute brain injury. Neonatal eucpanic pH, in addition to umbilical artery pH, may be a viable alternative in identifying newborns at risk for hypoxic-ischemic encephalopathy.

Neurodevelopmental outcomes at 18 months of children diagnosed with CHD compared to children born very preterm.

OBJECTIVE: To compare neurodevelopmental outcomes and parent behaviour ratings of children born term with CHD to children born very preterm. METHODS: A clinical research sample of 181 children (CHD [n = 81]; very preterm [≤32 weeks; n = 100]) was assessed at 18 months. RESULTS: Children with CHD and born very preterm did not differ on Bayley-III cognitive, language, or motor composite scores, or on expressive or receptive language, or on fine motor scaled scores. Children with CHD had lower ross motor scaled scores compared to children born very preterm (p = 0.047). More children with CHD had impaired scores (<70 SS) on language composite (17%), expressive language (16%), and gross motor (14%) indices compared to children born very preterm (6%; 7%; 3%; ps < 0.05). No group differences were found on behaviours rated by parents on the Child Behaviour Checklist (1.5-5 years) or the proportion of children with scores above the clinical cutoff. English as a first language was associated with higher cognitive (p = 0.004) and language composite scores (p < 0.001). Lower median household income and English as a second language were associated with higher total behaviour problems (ps < 0.05). CONCLUSIONS: Children with CHD were more likely to display language and motor impairment compared to children born very preterm at 18 months. Outcomes were associated with language spoken in the home and household income.

Association of Postnatal Growth Changes and Neurodevelopmental Outcomes in Preterm Neonates of <29 Weeks' Gestation.

OBJECTIVE: To examine associations between weight and head circumference (HC) changes and neurodevelopment in preterm infants. STUDY DESIGN: This retrospective cohort study of Canadian Neonatal Network and Canadian Neonatal Follow-Up Network sites included preterm infants born 2010-2018. Logistic regression and model diagnostics evaluated relationships between changes in z score and velocity of weight and HC from birth to discharge from a tertiary neonatal intensive care unit, discharge to 18-24 months corrected age (CA), and birth to 18-24 months CA and significant cognitive/motor impairment at 18-24 months CA classified using a Bayley Scales of Infant and Toddler Development-Third Edition cognitive or motor composite score <70. RESULTS: In total, 4530 infants (53.0% male) with a mean (SD) gestational age of 26.3 (1.4) weeks and birth weight of 920 (227) g were included. Weight and HC changes were associated with lower odds of significant cognitive/motor impairment including an OR of 0.87 (95% CI: 0.83, 0.91; P < .001) for a 1-g/d increase in weight from discharge to 18-24 months CA and 0.81 (95% CI: 0.75, 0.88; P < .001) for a 1-unit increase in HC z score from birth to 18-24 months CA. Associations were not statistically significant in morbidity-free neonates. Weight and HC gains poorly discriminated between infants with and without significant cognitive/motor impairment (areas under the receiver operating characteristic curve of <0.64). No growth measure had a clinically useful balance of sensitivity and specificity. CONCLUSIONS: Weight and HC changes were associated with significant cognitive/motor impairment but had poor discriminatory capability. Neonatal morbidities may make a larger contribution than postnatal growth to neurodevelopment.

Early-life exposure to analgesia and 18-month neurodevelopmental outcomes in very preterm infants.

BACKGROUND: We assessed variability of analgesic use across three tertiary neonatal intensive care units (NICUs) accounting for early-life pain, quantified as number of invasive procedures. We also determined whether analgesia exposure modifies associations between early-life pain and neurodevelopment. METHODS: Multicenter prospective study of 276 very preterm infants (born <24-32 weeks' gestational age [GA]). Detailed data of number of invasive procedures and duration of analgesia exposure were collected in initial weeks after birth. Eighteen-month neurodevelopmental assessments were completed in 215 children with Bayley Scales for Infant Development-Third edition. RESULTS: Multivariable linear regressions revealed significant differences in morphine use across sites, for a given exposure to early-life pain (interaction p < 0.001). Associations between early-life pain and motor scores differed by duration of morphine exposure (interaction p = 0.01); greater early-life pain was associated with poorer motor scores in infants with no or long (>7 days) exposure, but not short exposure (≤7 days). CONCLUSIONS: Striking cross-site differences in morphine exposure in very preterm infants are observed even when accounting for early-life pain. Negative associations between greater early-life pain and adverse motor outcomes were attenuated in infants with short morphine exposure. These findings emphasize the need for further studies of optimal analgesic approaches in preterm infants. IMPACT: In very preterm neonates, both early-life exposure to pain and analgesia are associated with adverse neurodevelopment and altered brain maturation, with no clear guidelines for neonatal pain management in this population. We found significant cross-site variability in morphine use across three tertiary neonatal intensive care units in Canada. Morphine use modified associations between early-life pain and motor outcomes. In infants with no or long durations of morphine exposure, greater early-life pain was associated with lower motor scores, this relationship was attenuated in those with short morphine exposure. Further trials of optimal treatment approaches with morphine in preterm infants are warranted.

Enhancing plant growth and biomass production by overexpression of GA20ox gene under control of a root preferential promoter.

Overexpression of GA20 oxidase gene has been a recent trend for improving plant growth and biomass. Constitutive expression of GA20ox has successfully improved plant growth and biomass in several plant species. However, the constitutive expression of this gene causes side-effects, such as reduced leaf size and stem diameter, etc. To avoid these effects, we identified and employed different tissue-specific promoters for GA20ox overexpression. In this study, we examined the utility of At1g promoter to drive the expression of GUS (ß-glucuronidase) reporter and AtGA20ox genes in tobacco and Melia azedarach. Histochemical GUS assays and quantitative real-time-PCR results in tobacco showed that At1g was a root-preferential promoter whose expression was particularly strong in root tips. The ectopic expression of AtGA20ox gene under the control of At1g promoter showed improved plant growth and biomass of both tobacco and M. azedarach transgenic plants. Stem length as well as stem and root fresh weight increased by up to 1.5-3 folds in transgenic tobacco and 2 folds in transgenic M. azedarach. Both tobacco and M. azedarach transgenic plants showed increases in root xylem width with xylem to phloem ratio over 150-200% as compared to WT plants. Importantly, no significant difference in leaf shape and size was observed between At1g::AtGA20ox transgenic and WT plants. These results demonstrate the great utility of At1g promoter, when driving AtGA20ox gene, for growth and biomass improvements in woody plants and potentially some other plant species.

Pulsed laser-induced dewetting and thermal dewetting of Ag thin films for the fabrication of Ag nanoparticles.

Two different dewetting methods, namely pulsed laser-induced dewetting (PLiD)-a liquid-state dewetting process and thermal dewetting (TD)-a solid-state dewetting process, have been systematically explored for Ag thin films (1.9-19.8 nm) on Si substrates for the fabrication of Ag nanoparticles (NPs) and the understanding of dewetting mechanisms. The effect of laser fluence and irradiation time in PLiD and temperature and duration in TD were investigated. A comparison of the produced Ag NP size distributions using the two methods of PLiD and TD has shown that both produce Ag NPs of similar size with better size uniformity for thinner films (<6 nm), whereas TD produced bigger Ag NPs for thicker films (≥8-10 nm) as compared to PLiD. As the film thickness increases, the Ag NP size distributions from both PLiD and TD show a deviation from the unimodal distributions, leading to a bimodal distribution. The PLiD process is governed by the mechanism of nucleation and growth of holes due to the formation of many nano-islands from the Volmer-Weber growth of thin films during the sputtering process. The investigation of thickness-dependent NP size in TD leads to the understanding of void initiation due to pore nucleation at the film-substrate interface. Furthermore, the linear dependence of NP size on thickness in TD provides direct evidence of fingering instability, which leads to the branched growth of voids.

Associations Between Age at Arterial Switch Operation, Brain Growth, and Development in Infants With Transposition of the Great Arteries.

BACKGROUND: Brain injury, impaired brain growth, and long-term neurodevelopmental problems are common in children with transposition of the great arteries. We sought to identify clinical risk factors for brain injury and poor brain growth in infants with transposition of the great arteries undergoing the arterial switch operation, and to examine their relationship with neurodevelopmental outcome. METHODS: The brains of 45 infants with transposition of the great arteries undergoing surgical repair were imaged pre- and postoperatively using magnetic resonance imaging. Brain weight z scores were calculated based on brain volume and autopsy reference data. Brain injury scores were determined as previously described. Neurodevelopment was assessed at 18 months using the Bayley-III scores of infant development. The relationships between clinical variables, brain injury, perioperative brain growth, and 18-month Bayley-III scores were analyzed. RESULTS: On preoperative imaging, moderate or severe white matter injury was present in 10 of 45 patients, whereas stroke was seen in 4 of 45. A similar prevalence of injury was seen on postoperative imaging, and we were unable to identify any clinical risk factors for brain injury. Brain weight z scores decreased perioperatively in 35 of 45 patients. The presence of a ventricular septal defect ( P=0.009) and older age at surgery ( P=0.007) were associated with impaired perioperative brain growth. When patients were divided into those undergoing surgery during the first 2 weeks of life (32/45) versus those being repaired later (13/45), infants repaired later had significantly worse perioperative brain growth (late repair postoperative brain weight z = -1.0±0.90 versus early repair z = -0.33±0.64; P=0.008). Bayley-III testing scores fell within the normal range for all patients, although age at repair ( P=0.03) and days of open chest ( P=0.03) were associated with a lower composite language score, and length of stay was associated with a lower composite cognitive score ( P=0.02). CONCLUSIONS: Surgery beyond 2 weeks of age is associated with impaired brain growth and slower language development in infants with transposition of the great arteries cared for at our center. Although the mechanisms underlying this association are still unclear, extended periods of cyanosis and pulmonary overcirculation may adversely impact brain growth and subsequent neurodevelopment.

The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease.

PURPOSE: This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease. METHODS: We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation. RESULTS: In 14 families (12.6%), we identified causative variants: seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene-disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis. CONCLUSION: This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene-disease associations.

Periventricular Hemorrhagic Infarction in Very Preterm Infants: Characteristic Sonographic Findings and Association with Neurodevelopmental Outcome at Age 2 Years.

OBJECTIVE: To describe the sonographic characteristics of periventricular hemorrhagic infarction (PVHI) and their association with mortality and neurodevelopmental disability in very preterm infants born in 2008-2013. STUDY DESIGN: Retrospective multicenter observational cohort study. Diagonal PVHI size was measured and severity score assessed. PVHI characteristics were scored and temporal trends were assessed. Neurodevelopmental outcome at 2 years of corrected age was assessed using either the Bayley Scales of Infant and Toddler Development, Third Edition or the Griffiths Mental Development Scales. Multigroup analyses were applied as appropriate. RESULTS: We enrolled 160 infants with median gestational age of 26.6 weeks. PVHI was mostly unilateral (90%), associated with an ipsilateral grade III intraventricular hemorrhage (84%), and located in the parietal lobe (51%). Sixty-four (40%) infants with PVHI died in the neonatal period. Of the survivors assessed at 2 years of corrected age, 65% had normal cognitive and 69% had normal motor outcomes. The cerebral palsy rate was 42%. The composite outcome of death or severe neurodevelopmental disability was observed in 58%, with no trends over the study period (P = .6). Increasing PVHI severity score was associated with death (P < .001). Increasing PVHI size and severity score were negatively associated with gross motor scores (P = .01 and .03, respectively). Trigone involvement was associated with cerebral palsy (41% vs 14%; P = .004). Associated posthemorrhagic ventricular dilation (36%) was an independent risk factor for poorer cognitive and motor outcomes (P < .001 for both). CONCLUSIONS: Increasing PVHI size and severity score were predictive of less optimal gross motor outcome and death in very preterm infants.

Implementation of amplitude-integrated electroencephalography in tertiary Canadian Neonatal Intensive Care Units-a longitudinal study.

AIM: To investigate the implementation of amplitude-integrated electroencephalography (aEEG) as bedside monitoring tool of cerebral function in tertiary Canadian Neonatal Intensive Care Units (NICU) over the past decade. METHODS: Longitudinal study consisting of online surveys of neonatologists on the use of aEEG in 2009 and 2018. RESULTS: The response rate to the survey was 72 of 149 (49%) in 2009 and 18 of 30 (60%) in 2018, respectively. aEEG has been implemented in almost all (2009: 62.5%; 2018: 94%) tertiary Canadian NICUs. Two-thirds (2009: 67%; 2018: 71%) of the respondents considered information from aEEG tracing helpful in clinical practice. The main indications for aEEG were term neonates with hypoxic ischemic encephalopathy (2009 and 2018: 76%) and seizure detection/surveillance (2009: 88%; 2018: 94%). Teaching on aEEG has been implemented for neonatologists (2018: 100%) and health care providers (2018: 50%) in tertiary Canadian NICUs but there is a lack of standardization of training. Use of aEEG in preterm neonates (2009: 37%, 2018: 33%) and application of aEEG in research (18% reported occasional use) is less common. CONCLUSION: aEEG is well established in tertiary Canadian NICUs to monitor cerebral function and detect seizure activity. There is a need to develop formalized aEEG training programs and methods to assess competence. Further implementation of aEEG in preterm neonates and research is desirable.

Outcomes of Surgical Ligation after Unsuccessful Pharmacotherapy for Patent Ductus Arteriosus in Neonates Born Extremely Preterm.

A retrospective cohort study of neonates born extremely preterm with persistent patent ductus arteriosus after unsuccessful pharmacologic closure compared outcomes between 166 surgically ligated and 142 nonligated neonates. After adjustment for confounders, ligation was not associated with the composite outcome of death or neurodevelopmental impairment, neurodevelopmental impairment alone, chronic lung disease, or retinopathy of prematurity among survivors.

Initiation of passive cooling at referring centre is most predictive of achieving early therapeutic hypothermia in asphyxiated newborns.

OBJECTIVE: To identify factors associated with early initiation and achievement of therapeutic hypothermia (TH) in newborns with hypoxic-ischemic encephalopathy (HIE). METHODS: Retrospective cohort study of newborns who received TH according to National Institute of Child Health and Human Development (NICHD) criteria in two academic level 3 Neonatal Intensive Care Units (NICU) between 2009 and 2013. All infants were transported by a neonatal transport team (NNTT). Multivariate linear regression including who initiated cooling and degree of resuscitation in the model was performed. RESULTS: Two hundred and seven infants were included. Waiting for advice from a tertiary care NICU was independently associated with a 50 minute delay in the median time of initiation of TH. The need for extensive resuscitation (cardiopulmonary resuscitation [CPR] or epinephrine) was independently associated with a reduction of 43 minutes in the median time to reach target core temperature. Log-transformed time to initiation of TH was associated with time to reach target core temperature (P<0.001). A doubling of time to initiation of TH corresponds to a 24% (95% CI 18% to 30%) increase in median time to reach target core temperature. CONCLUSIONS: Initiating passive cooling at the referring centre, before transfer, is critical to faster achievement of target core temperature in asphyxiated infants. Greater outreach education and development of clinical care pathways are needed to improve optimal delivery of TH to enhance outcome.

Effect of Supplemental Donor Human Milk Compared With Preterm Formula on Neurodevelopment of Very Low-Birth-Weight Infants at 18 Months: A Randomized Clinical Trial.

Importance: For many very low-birth-weight (VLBW) infants, there is insufficient mother's milk, and a supplement of pasteurized donor human milk or preterm formula is required. Awareness of the benefits of mother's milk has led to an increase in use of donor milk, despite limited data evaluating its efficacy. Objective: To determine if nutrient-enriched donor milk compared with formula, as a supplement to mother's milk, reduces neonatal morbidity, supports growth, and improves neurodevelopment in VLBW infants. Design, Setting, and Participants: In this pragmatic, double-blind, randomized trial, VLBW infants were recruited from 4 neonatal units in Ontario, Canada, within 96 hours of birth between October 2010 and December 2012. Follow-up was completed in July 2015. Interventions: Infants were fed either donor milk or formula for 90 days or to discharge when mother's milk was unavailable. Main Outcomes and Measures: The primary outcome was the cognitive composite score on the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 18 months' corrected age (standardized mean, 100 [SD, 15]; minimal clinically important difference, 5 points). Secondary outcomes included Bayley-III language and motor composite scores, growth, and a dichotomous mortality and morbidity index. Results: Of 840 eligible infants, 363 (43.2%) were randomized (181 to donor milk and 182 to preterm formula); of survivors, 299 (92%) had neurodevelopment assessed. Mean birth weight and gestational age of infants was 996 (SD, 272) g and 27.7 (2.6) weeks, respectively, and 195 (53.7%) were male. No statistically significant differences in mean Bayley-III cognitive composite score (adjusted scores, 92.9 in donor milk group vs 94.5 in formula group; fully adjusted mean difference, -2.0 [95% CI, -5.8 to 1.8]), language composite score (adjusted scores, 87.3 in donor milk group vs 90.3 in formula group; fully adjusted mean difference, -3.1 [95% CI, -7.5 to 1.3]), or motor composite score (adjusted scores, 91.8 in donor milk group vs 94.0 in formula group; fully adjusted mean difference, -3.7 [95% CI, -7.4 to 0.09]) were observed between groups. There was no statistically significant difference in infants positive for the mortality and morbidity index (43% in donor milk group, 40% in formula group) or changes in growth z scores. Conclusions and Relevance: Among VLBW infants, use of supplemental donor milk compared with formula did not improve neurodevelopment at 18 months' corrected age. If donor milk is used in settings with high provision of mother's milk, this outcome should not be considered a treatment goal. Trial Registration: isrctn.org Identifier: ISRCTN35317141.

Compliance monitoring in business processes: Functionalities, application, and tool-support.

In recent years, monitoring the compliance of business processes with relevant regulations, constraints, and rules during runtime has evolved as major concern in literature and practice. Monitoring not only refers to continuously observing possible compliance violations, but also includes the ability to provide fine-grained feedback and to predict possible compliance violations in the future. The body of literature on business process compliance is large and approaches specifically addressing process monitoring are hard to identify. Moreover, proper means for the systematic comparison of these approaches are missing. Hence, it is unclear which approaches are suitable for particular scenarios. The goal of this paper is to define a framework for Compliance Monitoring Functionalities (CMF) that enables the systematic comparison of existing and new approaches for monitoring compliance rules over business processes during runtime. To define the scope of the framework, at first, related areas are identified and discussed. The CMFs are harvested based on a systematic literature review and five selected case studies. The appropriateness of the selection of CMFs is demonstrated in two ways: (a) a systematic comparison with pattern-based compliance approaches and (b) a classification of existing compliance monitoring approaches using the CMFs. Moreover, the application of the CMFs is showcased using three existing tools that are applied to two realistic data sets. Overall, the CMF framework provides powerful means to position existing and future compliance monitoring approaches.

Size and Location of Preterm Brain Injury and Associations With Neurodevelopmental Outcomes.

BACKGROUND AND OBJECTIVES: We examined associations of white matter injury (WMI) and periventricular hemorrhagic infarction (PVHI) volume and location with 18-month neurodevelopment in very preterm infants. METHODS: A total of 254 infants born <32 weeks' gestational age were prospectively recruited across 3 tertiary neonatal intensive care units (NICUs). Infants underwent early-life (median 33.1 weeks) and/or term-equivalent-age (median 41.9 weeks) MRI. WMI and PVHI were manually segmented for quantification in 92 infants. Highest maternal education level was included as a marker of socioeconomic status and was defined as group 1 = primary/secondary school; group 2 = undergraduate degree; and group 3 = postgraduate degree. Eighteen-month neurodevelopmental assessments were completed with Bayley Scales of Infant and Toddler Development, Third Edition. Adverse outcomes were defined as a score of less than 85 points. Multivariable linear regression models were used to examine associations of brain injury (WMI and PVHI) volume with neurodevelopmental outcomes. Voxel-wise lesion symptom maps were developed to assess relationships between brain injury location and neurodevelopmental outcomes. RESULTS: Greater brain injury volume was associated with lower 18-month Motor scores (ß = -5.7, 95% CI -9.2 to -2.2, p = 0.002) while higher maternal education level was significantly associated with higher Cognitive scores (group 3 compared 1: ß = 14.5, 95% CI -2.1 to 26.9, p = 0.03). In voxel-wise lesion symptom maps, brain injury involving the central and parietal white matter was associated with an increased risk of poorer motor outcomes. DISCUSSION: We found that brain injury volume and location were significant predictors of motor, but not cognitive outcomes, suggesting that different pathways may mediate outcomes across domains of neurodevelopment in preterm infants. Specifically, assessing lesion size and location may allow for more accurate identification of infants with brain injury at highest risk of poorer motor outcomes. These data also highlight the importance of socioeconomic status in cognitive outcomes, even in preterm infants with brain injury.

Blood product transfusion practices in neonates with hypoxic-ischemic encephalopathy.

OBJECTIVE: Blood product transfusion is a common practice in infants with hypoxic-ischemic encephalopathy (HIE) undoing therapeutic hypothermia (TH). The advantages and disadvantages of conservative or liberal transfusion practices in this fragile population are unknown. Study aims to characterize the transfusion practices in infants with HIE and investigate the association with outcome. STUDY DESIGN: We conducted a retrospective cohort study at a single level IV NICU, evaluating transfusion thresholds, as well as the association between hematological abnormalities or blood product transfusions and outcomes in infants admitted with HIE. RESULT: By univariate analysis, FFP transfusion was associated with increased in-hospital death. However, multivariate analysis adjusting for HIE severity demonstrated no association between hematological abnormality or blood product transfusion and death, nor with neurodevelopmental impairment. CONCLUSION: No association was found between hematological blood product transfusion and death or neurodevelopmental impairment in a retrospective single NICU study of infants with HIE.