Neonatal Care

Purpose: Over the last 10 years, recommendations regarding the ideal level of oxygen for resuscitation in preterm infants have changed from 100 percent, down to low levels of oxygen (\<30 percent), up to moderate concentration (30-65 percent). In addition, in 2010, oxygen saturation targeting was recommended as standard of care and this contributed to a change in clinical practice as clinicians were more likely and comfortable to start resuscitation at either 21percent (room air) or titrated levels of oxygen such as 30-40 percent. When the guidelines were again revised in 2015, the International Liaison Committee on Resuscitation (ILCOR) acknowledged that a critical knowledge gap continued to exist for the resuscitation of the preterm infants \<37 weeks, highlighting the need to provide more concrete guidelines. This leaves clinicians in a challenging position. Despite the advances that have been achieved in perinatal and neonatal care, neonates are still vulnerable to the consequences of the oxidative effects from hyperoxia as well as the deleterious effects from hypoxia. A large, multi-centre international trial of sufficient sample size that is powered to look at safety outcomes such as mortality and adverse neurodevelopmental outcomes is required to provide the necessary evidenced to guide clinical practice with confidence. Hypothesis: the null hypothesis for this study is that the incidence of mortality or abnormal neurodevelopmental outcomes at 24+/- 6 months corrected age will be no different by using either higher initial oxygen concentration of 60 percent compared to using lower initial oxygen concentration of 30 percent for resuscitation of preterm infants of 23 0/7- 28 6/7 weeks gestation. Justification: The use of supplementary oxygen may be crucial, but also potentially detrimental to premature infants at birth. High oxygen levels may lead to organ damage through oxidative stress, while low oxygen levels may lead to increased mortality. Excess oxygen exposure during the early post-birth period is associated with many complications and morbidities of preterm birth. Preterm infants have lower levels of anti-oxidant pathways consistent with their expected fetal environment of low oxygen exposure. Excess of oxygen free-radicals in infants intrinsically deficient in enzymatic antioxidants and non-enzymatic antioxidants may contribute to these morbidities. Pulmonary oxygen toxicity, through the generation of reactive oxygen and nitrogen species in excess of antioxidant defenses, is believed to be a major contributor to the development of bronchopulmonary dysplasia (BPD). Using lower oxygen concentrations at birth results in decreased oxidative stress markers and a decrease risk of developing BPD compared to higher oxygen concentrations. Other organs that may be damaged by such oxidative stress include kidneys, myocardium and the retina. There is equally growing evidence that using lower oxygen concentrations will lead to lower oxygen saturation levels and bradycardia, which may lead to increased rates of mortality in this vulnerable group of infants. An individual patient analysis of clinical trials reported that 46% of preterm infants resuscitated with initial low oxygen concentration did not reach SpO2 of 80% at 5 min. This was associated with increased risk of major intraventricular hemorrhage (IVH), and an almost five times higher risk of death in this vulnerable group of infants. These data provide a warning note for the use of higher vs. lower initial oxygen concentration during delivery room resuscitation. As the investigator proceed in determining a safe range for resuscitation of ELBW/ELGA infants, it is highly likely that the optimum level of oxygen concentration is between the two extremes of 21 percent and 100 percent. Objectives: To determine whether initial resuscitation of preterm neonates with 60 percent versus 30 percent oxygen results in better neurodevelopmental outcomes at 24+/- 6 months. Research Method/Procedures: This will be a cluster crossover design, unmasked randomized controlled trial (RCT) comparing two oxygen concentrations at initiation of resuscitation. Infants will be placed on the resuscitation table with the initial steps of resuscitation carried out as per standard of care at each centre which usually follows current resuscitation guidelines. All centres will make every effort to establish adequate lung expansion using CPAP or positive pressure ventilation as needed. Enrolled infants will have a pulse oximeter sensor placed on the right arm in the first minute of life. Their resuscitation will be initiated with an oxygen concentration of 30 or 60 percent depending on the randomization sequence at the centre at the given time. Infants in the 30 percent group will remain in 30 percent oxygen until 5 min of age unless the infant's heart rate (HR) remains 100/min or less and does not show a tendency towards progressive increase before reaching 5 min of age or infant needs chest compression and/or epinephrine. No alteration in oxygen concentration will be made for an infant who is responding to resuscitation efforts with HR progressively increasing as minutes go by. At 5 min of age, the clinical team will assess oxygen saturation. If the saturation is less than 85 percent, oxygen should be increased by 10-20 percent every 60 sec to achieve saturations of 85 percent or greater or a saturation of 90-95 percent at 10 min of age. If saturations are greater than 95 percent at or before 5 min of age, oxygen should be decreased stepwise (every 60 sec) with an aim to maintain saturations of 85 percent or greater during 5-10 min of age or 90-95 percent at and beyond 10 min of age. The procedure for infants in the 60 percent group will be identical. The intervention duration for the trial will be the first 5 min after birth followed by initial monitoring/action for the next 5 min where titration in oxygen concentration will be made to achieve stability making a total of 10 min for study intervention. Titration of oxygen before 5 min after birth will only be made if the infant remains bradycardic (HR less than 100) and does not show a tendency towards a sustained increase in HR or if the oxygen saturation exceeds 95 percent. If the infant does not respond to ventilation with increasing HR in the first 5 min after birth, steps to ensure effective ventilation should be done before oxygen is titrated. Plan for Data Analysis: Generalized linear mixed model with binary outcome and maximum likelihood estimate will be used to evaluate the effect of an oxygen concentration on the primary outcome (as a composite at 24+/- 6 months corrected age of all-cause mortality or the presence of a major neurodevelopmental outcome). To account for cluster crossover design of the study, effects of centers (clusters) and a period (oxygen concentration) within center will be considered random, and effects of a period (oxygen concentration) will be entered as a fixed effect. This hierarchical model allows for the correlation of patients within periods and within clusters. The model will be adjusted for gestational age and whether or not infant required mask ventilation as potential confounding variables. Similar generalized linear mixed models will be performed to evaluate the effect of group on secondary outcomes. In addition, three subgroup analysis will be performed: i) Gestational age will be categorized into 2 categories: 23+0- 25+6 vs. 26+0-28+6 weeks; ii) Breathing support will be categorized by infants supported only with CPAP vs. received mask ventilation; iii) Sex/Gender will be categorized into 2 categories: female vs. male. For subgroup analysis baseline characteristics will be compared using linear and generalized linear mixed models. Sensitivity analysis will be performed to analyze the missing data; however, a very low number of missing values are expected due to the design of the study.

The goal of this clinicial trial is to test the acceptability and feasibility of linear cognitive aid intervention to support EMS teams in responding to pediatric emergencies. We are testing the hypothesis that cognitive aids with linear logic will be feasible to use and acceptable to EMS teams in urban and rural areas. Researchers will compare technical performance, teamwork, and self-assessed cognitive load of participants to see the difference between performing resuscitations using their current standard with existing cognitive aids and using our linear cognitive aid. Participants' teams will: * perform in situ high-fidelity simulation of two critical children's resuscitation scenarios * be randomized to 1) perform both resuscitations with their current standard with existing cognitive aids or 2) perform both resuscitations using our linear cognitive aid.

This project is based on a predictive alghorithm (Multifactorial Dynamic Perfusion Index-MDPI) already published and covered by a patent. The MDPI is based on a dynamic collection of 7 different variables during cardiopulmonary bypass (CPB) and provides a probability index for postoperative acute kidney injury. Multicenter observational prospective trial developed through 3 work packages, addressing (1) external validation of the MDPI in a series of 800 adult cardiac surgery patients collected in 2 Institutions (2) development of a novel MDPI to be applied in infants \< 20 kg undergoing cardiac surgery (200 patients) and (3) verification of of other possible outcomes that may be predicted by the MDPI. Since many of the predictive variables are modifiable by the perfusionist/anesthesiologist during CPB, it is a tool that allows therapeutic manouvres. Ultimately, the MDPI will be incorporated in a dedicated monitor to provide an on-line "flight control" during CPB. Cardiac surgery associated acute kidney injury (CSA-AKI) is one of the most common postoperative complications, associated with an increased mortality risk. Several risk scores for CSA-AKI exist. They are based on preoperative risk factors and severity of the procedure. They define a static risk (SR) based on non-modifiable risk factors. As so, they do not consider intraoperative variables, that include potentially modifiable risk factors (dynamic risk, DR). In a previous study we have developed a new model for prediction of CSA-AKI that is inclusive of the SR and the DR, producing the Multifactorial Dynamic Perfusion Index (MDPI). The MDPI is based on 7 factors collected during cardiopulmonary bypass (CPB): oxygen delivery time spent on a low oxygen delivery, hematocrit, time on CPB, mean arterial pressure, transfusions and lactate values. The MDPI showed a better discrimination (AUC 0.769) than the other existing models, and a good calibration until a risk of 60%. Of notice 5 out of the 7 predictors composing the MDPI are modifiable risk factors and therefore can be considered as a ¿flight control¿, on-line measure of the quality of perfusion, to prompt interventions by the perfusionist and the anesthesiologist. The MDPI is covered by an Italian patent (n. 102022000012893) owned by the IRCCS Policlinico San Donato with Marco Ranucci as inventor. The patent covers the inclusion of the MDPI into a dedicated monitor collecting the variables on CPB and producing the MDPI. The activities are separated into 3 work-packages (WP). WP 1: The MDPI has been developed in a single Institution. Additionally, its validation was performed on the same development series using a bootstrap technique. To make this algorithm exportable in different Institutions, a different new series of patients is required (internal validation) and a new series collected in an external Institution (external validation). Additionally, it cannot be excluded that additional risk factors may be identified and included in the MDPI algorithm; moreover, there is the hypothesis that other outcome measures of morbidity and even mortality may be predicted by the MDPI. WP 1 includes the operative Units 1 and 2 and is based on the collection of a new series of consecutive adult patients requiring cardiac surgery with CPB. The study protocol has been already submitted to the Ethics Committee (166/int/2022) and Clinical Trial. Gov for the internal validation at the operative unit 1 and includes 400 patients. An additional amount of 400 patients will be collected at the operative unit 2. In this series, the MDPI parameters will be collected and assessed for discrimination and calibration properties in predicting CSA-AKI (defined as AKI of any kind, AKI stage and AKI stage 2 or greater). Appropriate tools will be applied to define discrimination (ROC analysis) and calibration (calibration plot using LOWESS) properties of the MDPI. This WP is essentially a validation of the existing MDPI as patented by IRCCS Policlinico San Donato WP2: The MDPI has been develop in the adult patient population. There is little information available in the literature about the CSA-AKI risk factors in infants and newborns weighing \< 20 kgs. However, CSA-AKI in this segment of population is present at a rate that is equal or even higher than in the adults. It can be hypothesized that above 20 kgs, the patient is probably comparable to the adult patient, whereas there is a gap in knowledge in infants and newborns. WP2 is intended to cover this gap in knowledge by addressing a series of 200 patients weighing \< 20 kgs and receiving cardiac surgery with CPB for palliation or correction of congenital heart defects, producing an MDPI for infants (I MDPI). This WP will be totally performed at the operative unit 2, that is the largest congenital heart center in Italy. A new patent on the I-MDPI is anticipated. WP3: This WP is based on the same patient population of WP 1, but has a complementary aim. It is in fact possible that (a) other factors apart from the seven included in the MDPI may be associated with CSA-AKI, therefore deserving to be included in the model (MDPI 2.0) and (b) other outcomes, and namely 30-days mortality may be predicted by the MDPI. Once defined these aims, this WP (that includes the 2 operative units) includes the preliminary steps for the implementation of the MDPI into existing or newly developed monitoring systems for CPB. Dedicated patents are anticipated for MDPI 2.0.

The goal of this nationwide multicenter observational study is to comprehensively investigate the severity of Small Vulnerable Newborns (SVN) issues across China and to propose further preventive and intervention measures. The primary aim is to provide a thorough description of SVN problems using a unified definition and framework, and to develop targeted prevention strategies. Participating centers across the country will collect clinical data on vulnerable newborns under their care and complete detailed questionnaires to support this research.

The study will include all newborns in Normandie region for 3 years (about 105,000 births) for whom signed consent by one (or two) parents will be collected. Based on our previous pilot study (2011) assessing MCAD and PKU using tandem mass spectrometry-based method in Normandie region in which informed consents have been signed for all newborns (43,000) but we are expecting a great willingness to participate to this project. Thus, we are aiming to include 100,000 newborns, and the study will be continued until we reach at least this target. The primary objective is to evaluate the epidemiology of MPS1 and Pompe disease using dried blood samples in the first cohort of neonates tested in France (Normandie region).

Many newborn infants have breathing difficulty after birth, particularly when they are born prematurely. Many of these infants are supported with nasal continuous positive airway pressure (NCPAP). Some of the infants deteriorate despite treatment with NCPAP and have a thin catheter inserted into their trachea for the administration of surfactant, which is then immediately removed (often referred to as "less-invasive surfactant administration" or LISA). Insertion of a thin catheter is usually performed by doctors who are experienced at intubation (i.e. inserting endotracheal tubes, ETTs). They look directly into the the infants mouth using a standard laryngoscope to identify the opening of the airway (i.e. perform direct laryngoscopy). More recently video laryngoscopes have been developed. These devices display a magnified image of the airway on a screen that can be viewed indirectly by the doctor attempting to insert the ETT or thin catheter, and also by others. A single centre study reported that more infants were successfully intubated at the first attempt when doctors performed indirect video laryngoscopy compared to direct laryngoscopy. It is possible to independently verify when a doctor has correctly inserted and ETT, for example by detecting carbon dioxide coming out of the tube or seeing condensation in the tube during exhalation, or by hearing breath sounds by listening to the chest during positive pressure inflations. It is not possible to independently verify whether a doctor has correctly inserted a thin catheter under direct laryngoscopy, by these or other means. The standard (and to date only) way of confirming that a thin catheter has been correctly inserted is to rely on the report of the operator. Video laryngoscopy, in contrast, allows the independent verification of the tip of a thin catheter by one or more people observing the screen. The investigators are performing NEU-VODE, a stepped wedge cluster randomised study of the introduction of video laryngoscopy versus direct laryngoscopy for the intubation of newborn infants. Alongside this study, the investigators are performing a study of infants who have a thin endotracheal catheter inserted under video laryngoscopy versus direct laryngoscopy. As it is not possible to measure the outcome of successful insertion of the thin catheter equally in both groups, this is a prospective observational cohort study. The investigators will record information on infants who have a thin catheter inserted into the trachea for the purpose of surfactant administration at centres participating in the NEU-VODE study. The type of laryngoscope used for thin catheter insertion attempts will not be mandated; instead, the investigators will compare the information of groups within the cohort who have their first attempt made using the video laryngoscope to the group who have their first attempt made with direct laryngoscopy.

INTRODUCTION Many newborn infants have difficulty breathing after birth. Some of these babies have a tube inserted into their "windpipe" (trachea) - an endotracheal tube (ETT) - through which they are given breathing support (ventilation). When clinicians attempt to intubate (insert an ETT), they use an instrument called a laryngoscope to view the airway in order to identify the entrance to the trachea (larynx). Standard laryngoscopes have a "blade" (which, despite its name, is not sharp) with a light at the tip. Doctors insert the blade into the baby's mouth to view the larynx. Traditionally, clinicians used a standard laryngoscope to look directly into the baby's mouth to view the larynx (direct laryngoscopy, DL). When clinicians attempt to intubate newborns with DL, less than half of first attempts are successful. Also adverse effects - such as falls in the blood oxygen levels (fall in oxygen saturation (SpO2), or "desaturation"), slowing down of the heart rate (bradycardia), oral trauma - are relatively common. In recent years, video laryngoscopes (VL) have been developed. In addition to a light, VL have a video camera at the tip of the blade. This camera acquires a view of the larynx and displays it on a screen that the clinician views when attempting intubation (indirect laryngoscopy). In a randomised study performed at the National Maternity Hospital, Dublin, Ireland, more infants were successfully intubated at the first attempt when clinicians used VL compared to DL \[79/107 (74%) versus 48/107 (45%), P\<0.001\]. While this study was large enough to show that VL resulted infants being successfully intubated at the first attempt in one hospital, it couldn't give information about how it might work in a range of hospitals, and it wasn't large enough to see what effect VL had on adverse events. There is a large difference in cost between a standard laryngoscope (approx. €300) and a video laryngoscope (approx. €21,000). This is a matter of concern for all hospitals, particularly in settings where resources are more limited. The investigators aim to assess whether VL compared to DL results in more infants being intubated at the first attempt without physiological instability. STUDY DESIGN A recent single centre study reported that that more newborn infants were successfully intubated at the first attempt when VL was used to indirectly view the airway compared to DL. This study was not large enough to determine the effect of VL on adverse effects that are seen commonly (e.g. desaturation) or more rarely (e.g. bradycardia, receipt of chest compressions or adrenaline, oral trauma) during intubation attempts. For the current study, the investigators chose a stepped-wedge cluster randomised controlled design, where the participating centre, rather than the individual infant, will be the unit of randomisation. This design has been found appropriate to test the effects of an intervention that encompasses a behavioural aspect and to implement interventions while studying them at the same time. In this study, all centres will begin in the "control group"; where clinicians will routinely attempt intubation with DL, as is their usual practice. At specified intervals, centres will be randomly assigned to cross over to the "intervention group", where clinicians will routinely attempt intubation with VL. All participating centers will have included patients in both arms by the end of the study. SAMPLE SIZE ESTIMATION To determine the intra-cluster correlation (that means the correlation between two observations from the same centre), the investigators used the dataset of the MONITOR trial that included infants from 7 delivery rooms worldwide. In this trial, the intra-cluster correlation for intubation in the delivery room was reported as 0.1. This complete stepped-wedge cluster-randomized design includes 21 time periods (including the baseline) and 20 centres that will be including patients, with each randomised to a unique sequence. Each time period lasts a fortnight. Each time period, 1 centre will switch their treatment from DL to VL. With all centres including 2 patients each time period, 42 patients will be included per centre which will provide a total sample size of 840 patients. Assuming a control proportion of 0.4, this sample will achieve 90% power (0.9091) to detect a treatment proportion of 0.55, assuming a conservative ICC of 0.05. The power is not very sensitive to ICC values up to 0.1 (power of \>90% to detect difference 40% versus 56%). The test statistic used is the two-sided Wald Z-Test. TREATMENT OF SUBJECTS DIRECT LARYNGOSCOPY (DL, control period) At the start of the study, clinicians at participating centres will attempt intubation using a standard laryngoscope to perform DL as is their normal practice. VIDEO LARYNGOSCOPY (VL, intervention period) For each centre, a lot will be drawn which indicates the month in which endotracheal intubation will be routinely attempted with VL rather than DL. In the month before the switch, centres will be provided with a C-MAC VL by the manufacturers, Karl Storz-Endoskop (Tuttlingen, Germany). The system will be provided on loan for the duration of the study and will consist of an 8" high-definition monitor with connecting cable and reusable straight Miller type blades size 0 and size 1. The equipment will be demonstrated by representatives from Karl Storz, and clinicians who intubate babies at participating hospitals will be encouraged to practice with the equipment on mannequins. We will have an virtual meeting with each centre in the week before they are due to switch to review the protocol, data collection and to answer any queries that they may have. All other procedures in the delivery room and NICU will be performed according to international and local guidelines. All other aspects of the approach to intubation at the participating centre are at the discretion of the local clinicians and should remain the same for the duration of the study; e.g.: * The drugs used before intubation attempts (e.g. opiate, atropine, curare-like drug) * The route by which intubation is usually attempted (i.e. oral or nasal) * Whether they use a stylet is routinely used * Whether supplemental oxygen is given during attempts

Improvements in treatments for people with CF have meant that more are becoming pregnant. CFTR modulators (CFTRm) are one of these treatments. They work by tackling the underlying cause of CF. These changes have created a need and an opportunity for research into the health and experiences of people with CF and their children in the CFTRm era. The study is called 'MATRIARCH\_CF' and includes 3 related sub-studies: 'Mama' is enrolling participants aged 16 years or older with CF under the care of the Royal Brompton Hospital (RBH) adult CF Unit who are planning a pregnancy or pregnant. The aim is to describe the impact of pregnancy and the first 12-24 months of parenthood in females with CF on their physical and psychological health. Investigations in eight visits include blood tests, lung function, imaging, and interviews. 'Mini' is enrolling biological offspring of people with CF (mothers and fathers) cared for by the RBH Adult CF Service, from birth to age two. The aim is to collect information that will allow for assessment of health outcomes in offspring of parents with CF in the short term. There will be up to four visits over two years with investigations including blood tests, sweat tests, and brain ultrasound. 'Midi' explores the same question as 'Mini' but in the longer term for those aged three-to-six. There will be up to two visits, and they include lung function testing and a lung MRI. This study is described as 'observational' as investigators will not provide or change any treatment. Participant's health will be monitored with a range of investigations, many of which are optional. Knowledge gained from this study will be used to create guidelines to help families with CF and their medical teams make decisions around pregnancy and their offspring.

This is an observational study to collect data from Japanese babies with retinopathy of prematurity (ROP) who will be treated with Eylea. In observational studies, only observations are made without specified advice or interventions. ROP is a condition that affects the eye and occurs only in babies who are born too early. Most cases of ROP are mild and get better without treatment, but more serious cases need to be treated in time. ROP happens when the blood vessels in the "retina" grow abnormally. The retina is the layer of tissue at the back of the eye that picks up light and sends messages to the brain. In babies with ROP, these abnormal blood vessels can leak. This causes damage to the retina and can sometimes move it out of place causing medical problems such as blindness. Eylea is received as an injection into the eye. It works by blocking a certain protein (VEGF) that can cause blood vessels in the retina to grow abnormally. Eylea is already available in Japan and is approved for doctors to prescribe to babies with ROP. The participants in this study are Japanese babies with ROP that their doctors decided to treat with Eylea before the start of this study. Babies with ROP that were already prescribed Eylea by their doctors may also be included. The main purpose of this study is to collect more data on how safe the treatment with Eylea is in babies with ROP under a real-world setting. Another purpose of this study is to collect more data on how well Eylea works in these participants. To see how safe Eylea is, the study doctors will collect all medical problems that the participants treated with Eylea have. These medical problems are called adverse events. Doctors keep track of all the adverse events that happen, even if they do not think that they might be related to the treatment. To see how well Eylea works, the study doctors will check the number of participants: * with no active ROP after starting treatment * where ROP came back up to 6 months after start of treatment In this study, the study doctor will: * collect past data of the participants from medical records * interview the participants * collect treatment-related data during routine visits. The study duration is 6 months with 3 planned visits. One visit will be at start of treatment, one at one month and one at 6 months after start of treatment. All data required for this study will be collected during routine visits. Besides this data collection, no further tests or examinations are planned in this study.

The overall objective of the trial is to determine the efficacy, safety, and tolerability of administration of aficamten in adolescents (12 to \< 18 years old) and children (6 to \< 12 years old) with symptomatic oHCM. Adolescents and children will be studied in a staged approach involving established favorable pharmacodynamic and safety profiles of aficamten in adolescents followed by further pharmacokinetic modeling to inform the dosing regimen in children. Only the 12 to \<18 years old cohort is currently open for enrollment. The trial will consist of 3 periods: 1. Period 1 is the randomized, double-blind, placebo-controlled treatment period that will assess the efficacy, safety and tolerability of aficamten in pediatric participants. Duration: 12 weeks. 2. Period 2 is the open-label extension trial that will assess the long-term safety of aficamten in pediatric participants, and further assess efficacy and tolerability. Duration: 52 weeks. 3. Period 3 is the long-term extension trial that will assess the long-term safety of aficamten in pediatric participants, and further assess efficacy and tolerability. Duration: 144 weeks.