Detailed statistical analysis plan for ALBINO: effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome - a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).

BACKGROUND: Despite therapeutic hypothermia (TH) and neonatal intensive care, 45-50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol - a xanthine oxidase inhibitor - reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE. METHODS/DESIGN: The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years. RESULTS: The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and ."will be stratified for the two treatment groups. DISCUSSION: The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT03162653. Registered on 22 May 2017.

Craniofacial risk factors for obstructive sleep apnea-systematic review and meta-analysis.

Obstructive sleep apnea (OSA) is caused by temporary partial or complete constriction of the upper airway during sleep which leads to reduced blood oxygen and cardiovascular risks. Main symptoms vary between adults and children leading to misdiagnosis or delayed patient identification. To improve early diagnosis, lateral cephalograms can provide craniofacial measurements associated with a higher risk of OSA. In order to identify the most relevant craniofacial measurements, a systematic literature review with meta-analysis was conducted combining the terms 'orthodontic*', 'craniofacial', 'cephalometr*', 'cephalogram', 'OSA*', 'UARS', 'SDB', 'sleep disordered breathing', 'sleep apnea' and 'sleep apnoea'. Of 3016 publications, 19 were included in the systematic review and meta-analysis, 15 with adult patients and four with children. A total of 16 measurements (six angles, 10 distances) were compared, nine showed a possible influence in patients with OSA compared to controls: NSBa angle (-0.28°), ANB angle (+0.33°), ML-NSL angle (+0.34°), Me-Go-Ar angle (+0.33°), SN distance (-0.70 mm), N-ANS distance (-0.36 mm), MP-H distance (+1.18 mm), uvula length (+1.07 mm) and thickness (+0.96 mm). Posterior airway measurements were not sufficiently described or comparably measured to be statistically analysed. There is some evidence for altered craniofacial anatomy in patients with OSA compared to controls. Lateral cephalograms should be screened for these aspects routinely to improve early diagnosis of OSA and craniofacial orthopaedics should complement the interdisciplinary treatment plan for young patients with OSA.

Determination of tissue tracer transit of Technetium-99m-mercaptoacetyltriglycine diuretic renography in infants with suspected ureteropelvic junction obstruction - A multicenter prospective observational study.

INTRODUCTION: There is an ongoing controversy regarding management of ureteropelvic junction obstruction in infants, with a shift towards a non-operative approach. However, precise predictors of outcome are lacking. Recent studies postulated a high prognostic value of Technetium-99m-mercaptoacetyltriglycine tissue tracer transit with regard to the development of an impaired differential renal function and its potential improvement following pyeloplasty. OBJECTIVE: To evaluate the prognostic value of Technetium-99m-mercaptoacetyltriglycine tissue tracer transit for the occurrence of changes in differential renal function in infants with suspected unilateral ureteropelvic junction obstruction in a prospective observational multicenter study. STUDY DESIGN: Infants below 3 months of age with a unilateral isolated hydronephrosis ≥ grade 3 received ultrasound and Technetium-99m-mercaptoacetyltriglycine diuretic renography at two different time points (timepoint 1 and timepoint 2). Data were analyzed at local centers and at the study center and were collected in an internet-based database system. Tissue tracer transit was determined for each diuretic renography, inter-observer variation for tissue tracer transit and standard parameters for judgement of differential renal function development were assessed. RESULTS: Thirty-seven patients were analyzed. Median age was 11 weeks (7-15) at timepoint 1 and 26 weeks (19-33) at timepoint 2. A delayed tissue tracer transit at timepoint 1 was not associated with deterioration of differential renal function at timepoint 2 in both, locally (10/37 cases) and centrally (4/37) analyzed cases. However, sensitivity and specificity were poor. The intraclass correlation coefficient comparing local and central findings of tissue tracer transit and renal drainage demonstrated poor or fair agreement. Analysis of standard parameters for differential renal function development revealed a prognostic value only for the dichotomized anteroposterior renal pelvic diameter (APD, p = 0.03, 95%-CI 1.2-22.2). DISCUSSION: Regarding the primary endpoint of our study, we could not confirm the hypothesis that delayed tissue tracer transit reliably predicts a subsequent decline in differential renal function in the cohort of patients studied. Whether the low age of the patients, technical problems in the correct assessment of tissue tracer transit by the investigator in early infancy, the study design, or the parameter itself played a role is debated. CONCLUSION: In the presented setting tissue tracer transit was not useful as a predictive parameter for deterioration of differential renal function in infants with suspected unilateral ureteropelvic junction obstruction. Sensitivity and specificity of tissue tracer transit were not sufficient for risk stratification. Improved utility of tissue tracer transit as a marker might be achieved using a different study setting.

Antibody Binding and Angiotensin-Converting Enzyme 2 Binding Inhibition Is Significantly Reduced for Both the BA.1 and BA.2 Omicron Variants.

BACKGROUND: The rapid emergence of the Omicron variant and its large number of mutations led to its classification as a variant of concern (VOC) by the World Health Organization. Subsequently, Omicron evolved into distinct sublineages (eg, BA.1 and BA.2), which currently represent the majority of global infections. Initial studies of the neutralizing response toward BA.1 in convalescent and vaccinated individuals showed a substantial reduction. METHODS: We assessed antibody (immunoglobulin G [IgG]) binding, ACE2 (angiotensin-converting enzyme 2) binding inhibition, and IgG binding dynamics for the Omicron BA.1 and BA.2 variants compared to a panel of VOCs/variants of interest, in a large cohort (N = 352) of convalescent, vaccinated, and infected and subsequently vaccinated individuals. RESULTS: While Omicron was capable of efficiently binding to ACE2, antibodies elicited by infection or immunization showed reduced binding capacities and ACE2 binding inhibition compared to wild type. Whereas BA.1 exhibited less IgG binding compared to BA.2, BA.2 showed reduced inhibition of ACE2 binding. Among vaccinated samples, antibody binding to Omicron only improved after administration of a third dose. CONCLUSIONS: Omicron BA.1 and BA.2 can still efficiently bind to ACE2, while vaccine/infection-derived antibodies can bind to Omicron. The extent of the mutations within both variants prevents a strong inhibitory binding response. As a result, both Omicron variants are able to evade control by preexisting antibodies.

Long COVID symptoms in exposed and infected children, adolescents and their parents one year after SARS-CoV-2 infection: A prospective observational cohort study.

BACKGROUND: Long COVID in children and adolescents remains poorly understood due to a lack of well-controlled studies with long-term follow-up. In particular, the impact of the family context on persistent symptoms following SARS-CoV-2 infection remains unknown. We examined long COVID symptoms in a cohort of infected children, adolescents, and adults and their exposed but non-infected household members approximately 1 year after infection and investigated clustering of persistent symptoms within households. METHODS: 1267 members of 341 households (404 children aged <14 years, 140 adolescents aged 14-18 years and 723 adults) were categorized as having had either a SARS-CoV-2 infection or household exposure to SARS-CoV-2 without infection, based on three serological assays and history of laboratory-confirmed infection. Participants completed questionnaires assessing the presence of long COVID symptoms 11-12 months after infection in the household using online questionnaires. FINDINGS: The prevalence of moderate or severe persistent symptoms was statistically significantly higher in infected than in exposed women (36.4% [95% CI: 30.7-42.4%] vs 14.2% [95% CI: 8.7-21.5%]), infected men (22.9% [95% CI: 17.9-28.5%] vs 10.3% [95% CI: 5.8-16.9%]) and infected adolescent girls (32.1% 95% CI: 17.2-50.5%] vs 8.9% [95%CI: 3.1-19.8%]). However, moderate or severe persistent symptoms were not statistically more common in infected adolescent boys aged 14-18 (9.7% [95% CI: 2.8-23.6%] or in infected children <14 years (girls: 4.3% [95% CI: 1.2-11.0%]; boys: 3.7% [95% CI: 1.1-9.6%]) than in their exposed counterparts (adolescent boys: 0.0% [95% CI: 0.0-6.7%]; girls < 14 years: 2.3% [95% CI: 0·7-6·1%]; boys < 14 years: 0.0% [95% CI: 0.0-2.0%]). The number of persistent symptoms reported by individuals was associated with the number of persistent symptoms reported by their household members (IRR=1·11, p=·005, 95% CI [1.03-1.20]). INTERPRETATION: In this controlled, multi-centre study, infected men, women and adolescent girls were at increased risk of negative outcomes 11-12 months after SARS-CoV-2 infection. Amongst non-infected adults, prevalence of negative outcomes was also high. Prolonged symptoms tended to cluster within families, suggesting family-level interventions for long COVID could prove useful. FUNDING: Ministry of Science, Research and the Arts, Baden-Württemberg, Germany.

Role of ABO Blood Group in SARS-CoV-2 Infection in Households.

An association between certain ABO/Rh blood groups and susceptibility to SARS-CoV-2 infection has been proposed for adults, although this remains controversial. In children and adolescents, the relationship is unclear due to a lack of robust data. Here, we investigated the association of ABO/Rh blood groups and SARS-CoV-2 in a multi-center study comprising 163 households with 281 children and 355 adults and at least one SARS-CoV-2 seropositive individual as determined by three independent assays as a proxy for previous infection. In line with previous findings, we found a higher frequency of blood group A (+ 6%) and a lower frequency of blood group O (-6%) among the SARS-CoV-2 seropositive adults compared to the seronegative ones. This trend was not seen in children. In contrast, SARS-CoV-2 seropositive children had a significantly lower frequency of Rh-positive blood groups. ABO compatibility did not seem to play a role in SARS-CoV-2 transmission within the families. A correction for family clusters was performed and estimated fixed effects of the blood group on the risk of SARS-CoV-2 seropositivity and symptomatic infection were determined. Although we found a different distribution of blood groups in seropositive individuals compared to the reference population, the risk of SARS-CoV-2 seropositivity or symptomatic infection was not increased in children or in adults with blood group A or AB versus O or B. Increasing age was the only parameter positively correlating with the risk of SARS-CoV-2 infection. In conclusion, specific ABO/Rh blood groups and ABO compatibility appear not to predispose for SARS-CoV-2 susceptibility in children.

MRI-based brain volumes of preterm infants at term: a systematic review and meta-analysis.

BACKGROUND: MRI allows a detailed assessment of brain structures in preterm infants, outperforming cranial ultrasound. Neonatal MR-based brain volumes of preterm infants could serve as objective, quantitative and reproducible surrogate parameters of early brain development. To date, there are no reference values for preterm infants' brain volumes at term-equivalent age. OBJECTIVE: Systematic review of the literature to determine reference ranges for MRI-based brain volumes of very preterm infants at term-equivalent age. METHODS: PubMed Database was searched on 6 April 2020 for studies reporting MR-based brain volumes on representative unselected populations of very preterm and/or very low birthweight infants examined at term equivalent age (defined as 37-42 weeks mean postmenstrual age at MRI). Analyses were limited to volumetric parameters reported in >3 studies. Weighted mean volumes and SD were both calculated and simulated for each parameter. RESULTS: An initial 367 publications were identified. Following application of exclusion criteria, 13 studies from eight countries were included for analysis, yielding four parameters. Weighted mean total brain volume was 379 mL (SD 72 mL; based on n=756). Cerebellar volume was 21 mL (6 mL; n=791), cortical grey matter volume 140 mL (47 mL; n=572) and weighted mean volume of unmyelinated white matter was 195 mL (38 mL; n=499). CONCLUSION: This meta-analysis reports pooled data on several brain and cerebellar volumes which can serve as reference for future studies assessing MR-based volumetric parameters as a surrogate outcome for neurodevelopment and for the interpretation of individual or cohort MRI-based volumetric findings.

Robust and durable serological response following pediatric SARS-CoV-2 infection.

The quality and persistence of children's humoral immune response following SARS-CoV-2 infection remains largely unknown but will be crucial to guide pediatric SARS-CoV-2 vaccination programs. Here, we examine 548 children and 717 adults within 328 households with at least one member with a previous laboratory-confirmed SARS-CoV-2 infection. We assess serological response at 3-4 months and 11-12 months after infection using a bead-based multiplex immunoassay for 23 human coronavirus antigens including SARS-CoV-2 and its Variants of Concern (VOC) and endemic human coronaviruses (HCoVs), and additionally by three commercial SARS-CoV-2 antibody assays. Neutralization against wild type SARS-CoV-2 and the Delta VOC are analysed in a pseudotyped virus assay. Children, compared to adults, are five times more likely to be asymptomatic, and have higher specific antibody levels which persist longer (96.2% versus 82.9% still seropositive 11-12 months post infection). Of note, symptomatic and asymptomatic infections induce similar humoral responses in all age groups. SARS-CoV-2 infection occurs independent of HCoV serostatus. Neutralization responses of children and adults are similar, although neutralization is reduced for both against the Delta VOC. Overall, the long-term humoral immune response to SARS-CoV-2 infection in children is of longer duration than in adults even after asymptomatic infection.

Catheter insertion depths in less-invasive surfactant administration.

INTRODUCTION: Less-invasive surfactant administration (LISA) under continuous positive airway pressure is increasingly used for the treatment of neonatal respiratory distress. Different procedures are described, but data on the optimal catheter insertion depth are sparse. OBJECTIVE: To generate data for recommending an optimal catheter insertion depth in LISA. METHODS: We examined 112 anterior-posterior chest X-rays from intubated infants and determined the carina's vertebral projection, whenever possible. After that, distances between the middle of cervical vertebra 4 (C4) and thoracic vertebra 2 and the middle of C4 to thoracic vertebra 3, respectively, were measured. Results were plotted against infant's weight. RESULTS: A weight-based chart and recommendations for the optimal intratracheal catheter position in infants with a body weight between 350 and 4000 g were created. CONCLUSIONS: Generated data offer standardisation and may thus help to find a balance between risk of surfactant reflux and unilateral surfactant administration.

Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 in Households with Children, Southwest Germany, May-August 2020.

Resolving the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in households with members from different generations is crucial for containing the current pandemic. We conducted a large-scale, multicenter, cross-sectional seroepidemiologic household transmission study in southwest Germany during May 11-August 1, 2020. We included 1,625 study participants from 405 households that each had ≥1 child and 1 reverse transcription PCR-confirmed SARS-CoV-2-infected index case-patient. The overall secondary attack rate was 31.6% and was significantly higher in exposed adults (37.5%) than in children (24.6%-29.2%; p = <0.015); the rate was also significantly higher when the index case-patient was >60 years of age (72.9%; p = 0.039). Other risk factors for infectiousness of the index case-patient were SARS-CoV-2-seropositivity (odds ratio [OR] 27.8, 95% CI 8.26-93.5), fever (OR 1.93, 95% CI 1.14-3.31), and cough (OR 2.07, 95% CI 1.21-3.53). Secondary infections in household contacts generate a substantial disease burden.

Evaluating the Effect of a Neonatal Care Bundle for the Prevention of Intraventricular Hemorrhage in Preterm Infants.

Germinal matrix intraventricular hemorrhage (IVH) remains a severe and common complication in preterm infants. A neonatal care bundle (NCB) was implemented as an in-house guideline at a tertiary neonatal intensive care unit to reduce the incidence of IVH in preterm infants. The NCB was applied either to preterm infants <1250 g birth weight or <30 weeks gestational age or both, and standardized patient positioning, nursing care, and medical procedures within the first week of life. A retrospective cohort study was performed to investigate the effect of the NCB and other known risk factors on the occurrence and severity of IVH. Data from 229 preterm infants were analyzed. The rate of IVH was 26.2% before and 27.1% after implementing the NCB. The NCB was associated neither with reducing the overall rate of IVH (odds ratio (OR) 1.02; 95% confidence interval (CI) 0.57-1.84; p = 0.94) nor with severe IVH (OR 1.0; 95% CI 0.67-1.55; p = 0.92). After adjustment for group differences and other influencing factors, amnion infection syndrome and early intubation were associated with an increased risk for IVH. An NCB focusing on patient positioning, nursing care, and medical interventions had no impact on IVH in preterm infants. Known risk factors for IVH were confirmed.

Prevalence of SARS-CoV-2 Infection in Children and Their Parents in Southwest Germany.

Importance: School and daycare closures were enforced as measures to confine the novel coronavirus disease 2019 (COVID-19) pandemic, based on the assumption that young children may play a key role in severe acute respiratory coronavirus 2 (SARS-CoV-2) spread. Given the grave consequences of contact restrictions for children, a better understanding of their contribution to the COVID-19 pandemic is of great importance. Objective: To describe the rate of SARS-CoV-2 infections and the seroprevalence of SARS-CoV-2 antibodies in children aged 1 to 10 years, compared with a corresponding parent of each child, in a population-based sample. Design, Setting, and Participants: This large-scale, multicenter, cross-sectional investigation (the COVID-19 BaWü study) enrolled children aged 1 to 10 years and a corresponding parent between April 22 and May 15, 2020, in southwest Germany. Exposures: Potential exposure to SARS-CoV-2. Main Outcomes and Measures: The main outcomes were infection and seroprevalence of SARS-CoV-2. Participants were tested for SARS-CoV-2 RNA from nasopharyngeal swabs by reverse transcription-polymerase chain reaction and SARS-CoV-2 specific IgG antibodies in serum by enzyme-linked immunosorbent assays and immunofluorescence tests. Discordant results were clarified by electrochemiluminescence immunoassays, a second enzyme-linked immunosorbent assay, or an in-house Luminex-based assay. Results: This study included 4964 participants: 2482 children (median age, 6 [range, 1-10] years; 1265 boys [51.0%]) and 2482 parents (median age, 40 [range, 23-66] years; 615 men [24.8%]). Two participants (0.04%) tested positive for SARS-CoV-2 RNA. The estimated SARS-CoV-2 seroprevalence was low in parents (1.8% [95% CI, 1.2-2.4%]) and 3-fold lower in children (0.6% [95% CI, 0.3-1.0%]). Among 56 families with at least 1 child or parent with seropositivity, the combination of a parent with seropositivity and a corresponding child with seronegativity was 4.3 (95% CI, 1.19-15.52) times higher than the combination of a parent who was seronegative and a corresponding child with seropositivity. We observed virus-neutralizing activity for 66 of 70 IgG-positive serum samples (94.3%). Conclusions and Relevance: In this cross-sectional study, the spread of SARS-CoV-2 infection during a period of lockdown in southwest Germany was particularly low in children aged 1 to 10 years. Accordingly, it is unlikely that children have boosted the pandemic. This SARS-CoV-2 prevalence study, which appears to be the largest focusing on children, is instructive for how ad hoc mass testing provides the basis for rational political decision-making in a pandemic.

Clinical evaluation of an application aid for less-invasive surfactant administration (LISA).

BACKGROUND: Less-invasive surfactant administration (LISA) is increasingly used. We investigated the feasibility of a new LISA-device (Neofact®) in neonates. DESIGN: Prospective observational pilot study with open-label LISA in two tertiary neonatal intensive care units. PATIENTS: 20 infants with a gestational age of ≥26+0/7 weeks and an indication for LISA (Respiratory Severity Score (RSS)≥5 or fraction of inspired oxygen (FiO2) ≥0.30). Infants with respiratory tract malformations or unavailability of an instructed neonatologist were excluded. MAIN OUTCOME MEASURES: Success of LISA, defined as laryngoscopy-confirmed intratracheal catheter position or a decrease in FiO2 by ≥0.05 or to 0.21, accompanied by an RSS decrease of ≥2; number of attempts needed for tracheal catheterisation. RESULTS: 20/57 screened infants were enrolled. Successful application occurred in 19/20 (95%). One application failed after three attempts. No device-related adverse events occurred. The median number of attempts was 2, success rate per attempt 19/31 (61%). CONCLUSION: LISA via Neofact® appears feasible.

Application of two different nasal CPAP levels for the treatment of respiratory distress syndrome in preterm infants-"The OPTTIMMAL-Trial"-Optimizing PEEP To The IMMAture Lungs: study protocol of a randomized controlled trial.

BACKGROUND: Nasal continuous positive airway pressure (CPAP) applies positive end-expiratory pressure (PEEP) and has been shown to reduce the need for intubation and invasive mechanical ventilation in very low birth weight infants with respiratory distress syndrome. However, CPAP failure rates of 50% are reported in large randomized controlled trials. A possible explanation for these failure rates is the application of insufficient low levels of PEEP during nasal CPAP treatment to maintain adequate functional residual capacity shortly after birth. The optimum PEEP level to treat symptoms of respiratory distress in very low birth weight infants has not been assessed in clinical studies. The aim of the study is to compare two different PEEP levels during nasal CPAP treatment in preterm infants. METHODS: In this randomized multicenter trial, 216 preterm infants born at 26 + 0-29 + 6 gestational weeks will be allocated to receive a higher (6-8 cmH2O) or a lower (3-5 cmH2O) PEEP during neonatal resuscitation and the first 120 h of life. The PEEP level within each group will be titrated throughout the intervention based on the FiO2 (fraction of inspired oxygen concentration) requirements to keep oxygenation within the target range. The primary outcome is defined as the need for intubation and mechanical ventilation for > 1 h or being not ventilated but reaching one of the two pre-defined CPAP failure criteria (FiO2 > 0.5 for > 1 h or pCO2 ≥ 70 mmHg in two consecutive blood gas analyses at least 2 h apart). DISCUSSION: Based on available data from the literature, the optimum level of PEEP that most effectively treats respiratory distress syndrome in preterm infants is unknown, since the majority of large clinical trials applied a wide range of PEEP levels (4-8 cmH2O). The rationale for our study hypothesis is that the early application of a higher PEEP level will more effectively counteract the collapsing properties of the immature and surfactant-deficient lungs and that the level of inspired oxygen may serve as a surrogate marker to guide PEEP titration. Finding the optimum noninvasive continuous distending pressure during early nasal CPAP is required to improve CPAP efficacy and as a consequence to reduce the exposure to ventilator-induced lung injury and the incidence of chronic lung disease in this vulnerable population of very preterm infants. TRIAL REGISTRATION: drks.de DRKS00019940 . Registered on March 13, 2020.

Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial.

Importance: Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds. Objective: To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability. Design, Setting, and Participants: Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018. Interventions: Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants' postnatal age and current health state. Main Outcome and Measures: The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth. Results: Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, -4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of -0.7% (95% CI, -4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, -3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of -1.3% (95% CI, -4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups. Conclusions and Relevance: Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age. Trial Registration: ClinicalTrials.gov Identifier: NCT01393496.

Nasal insertion depths for neonatal intubation.

AIM: Data on the depth of nasal intubation in neonates are rare, although this is the preferred route in some countries. Therefore, recommendations on optimal nasal intubation depths based on gestational age (GA) and weight are desirable. METHODS: We determined the distances between the middle of thoracic vertebrae 2 (T2) and the tip of the endotracheal tube in 116 X-rays from nasally intubated neonates. The intubation depth (tip to nostril distance) that was documented in the digital patient's file was then corrected for this distance to reach an optimal nasal insertion depth. Results were plotted against the infant's GA and weight. RESULTS: GA-based and birthweight-based charts and formulas for the nasal intubation depth in infants with a GA between 24 and 43 weeks and body weight between 400 and 4500 g were created. CONCLUSIONS: Generated data may help in predicting optimal insertion depths for nasal intubation in neonates.

Calculating Protein Content of Expressed Breast Milk to Optimize Protein Supplementation in Very Low Birth Weight Infants with Minimal Effort-A Secondary Analysis.

Breast milk does not meet the nutritional needs of preterm infants, necessitating fortification. Breast milk is particularly variable in protein content, hence standardized (fixed dosage) supplementation results in inadequate supply. This was a secondary analysis of 589 breast milk protein content measurements of 51 mothers determined by mid-infrared spectroscopy during a clinical trial of higher versus lower protein supplementation in very low birth weight infants. Mothers (and breast milk samples) were divided into a test (41 mothers) and a validation cohort (10 mothers). In the test cohort, the decrease in protein content by day of lactation was modeled resulting in the breast milk-equation (BME)). In the validation cohort, five supplementation strategies to optimize protein supply were compared: standardized supplementation (adding 1.0 g (S1) or 1.42 g protein/100 mL (S2)) was compared with 'adapted' supplementation, considering variation in protein content (protein content according to Gidrewicz and Fenton (A1), to BME (A2) and to BME with adjustments at days 12 and 26 (A3)). S1 and S2 achieved 5% and 24% of adequate protein supply, while the corresponding values for A1-A3 were 89%, 96% and 95%. Adapted protein supplementation based on calculated breast milk protein content is easy, non-invasive, inexpensive and improves protein supply compared to standardized supplementation.

The impact of inhaled bronchodilators on bronchopulmonary dysplasia: a nonrandomized comparison from the NEuroSIS trial.

Background: Inhaled bronchodilators improve pulmonary function. Their effects on bronchopulmonary dysplasia (BPD) are uncertain. We assessed the efficacy of early inhaled bronchodilators on the risk of BPD and death in extremely preterm infants.Methods: We performed a post-hoc analysis of prospectively collected data from the Neonatal European Study of Inhaled Steroids (NEuroSIS). In NEuroSIS, 863 extremely preterm infants were randomly assigned to receive early inhaled budesonide or placebo. We now performed nonrandomized comparisons between infants that participated in the NEUROSIS trial and either received early (within the first 48 h of life) bronchodilators or no bronchodilators. Groups were assembled according to predefined criteria stated in the study protocol and we used the same prespecified primary outcome as in the main study, a composite of BPD and death at a postmenstrual age of 36 weeks.Results: Treatment groups did not differ significantly in the composite outcome of BPD and death at 36 weeks postmenstrual age: bronchodilator group (20/46; 43.5%), versus 349/810 (43.1%) in the no bronchodilator group; (p = .97). Analyzed by individual components, there were no significant differences in BPD and death rates between the groups.Discussion: Based on our analyses, early inhaled bronchodilators did not reduce the risk of BPD and death in extremely preterm infants.