The history of diapers and their environmental impact.

IMPACT: This article examines diaper practices around the world throughout history. This article reviews the innovation of the modern diaper and the environmental effects of disposable diapers.

Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

The effect of early postnatal auditory stimulation on outcomes in preterm infants.

Preterm infants are deprived of in utero sensory stimulation during the third trimester, an important period of central nervous system development. As a result, maturational trajectories are often reduced in infants born preterm. One such system affected is the brain including the auditory and respiratory control pathways. During normal pregnancy the intrauterine environment attenuates external auditory stimuli while exposing the fetus to filtered maternal voice, intra-abdominal sounds, and external stimuli. In contrast, during the third trimester of development, preterm infants are exposed to a vastly different soundscape including non-attenuated auditory sounds and a lack of womb related stimuli, both of which may affect postnatal brain maturation. Therefore, fostering a nurturing postnatal auditory environment during hospitalization may have a significant impact on related outcomes of preterm infants. Studies using a range of postnatal auditory stimulations have suggested that exposure to sounds or lack thereof can have a significant impact on outcomes. However, studies are inconsistent with sound levels, duration of exposure to auditory stimuli, and the gestational age at which infants are exposed. IMPACT: Auditory stimulation can provide a low cost and low risk intervention to stabilize respiration, improve neuronal maturation and reduce long-term sequelae in preterm infants. The potential benefits of auditory stimulation are dependent on the type of sound, the duration of exposure and age at time of exposure. Future studies should focus on the optimal type and duration of sound exposure and postnatal developmental window to improve outcomes.

Choline supplementation mitigates effects of bilirubin in cerebellar granule neurons in vitro.

BACKGROUND: Premature infants may suffer from high levels of bilirubin that could lead to neurotoxicity. Bilirubin has been shown to decrease L1-mediated ERK1/2 signaling, L1 phosphorylation, and L1 tyrosine 1176 dephosphorylation. Furthermore, bilirubin redistributes L1 into lipid rafts (LR) and decreases L1-mediated neurite outgrowth. We demonstrate that choline supplementation improves L1 function and signaling in the presence of bilirubin. METHODS: Cerebellar granule neurons (CGN) were cultured with and without supplemental choline, and the effects on L1 signaling and function were measured in the presence of bilirubin. L1 activation of ERK1/2, L1 phosphorylation and dephosphorylation were measured. L1 distribution in LR was quantified and neurite outgrowth of CGN was determined. RESULTS: Forty µM choline significantly reduced the effect of bilirubin on L1 activation of ERK1/2 by 220% (p = 0.04), and increased L1 triggered changes in tyrosine phosphorylation /dephosphorylation of L1 by 34% (p = 0.026) and 35% (p = 0.02) respectively. Choline ameliorated the redistribution of L1 in lipid rafts by 38% (p = 0.02) and increased L1-mediated mean neurite length by 11% (p = 0.04). CONCLUSION: Choline pretreatment of CGN significantly reduced the disruption of L1 function by bilirubin. The supplementation of pregnant women and preterm infants with choline may increase infant resilience to the effects of bilirubin. IMPACT: This article establishes choline as an intervention for the neurotoxic effects of bilirubin on lipid rafts. This article provides clear evidence toward establishing one intervention for bilirubin neurotoxicity, where little is understood. This article paves the way for future investigation into the mechanism of the ameliorative effect of choline on bilirubin neurotoxicity.

The DO-KB Knowledgebase: a 20-year journey developing the disease open science ecosystem.

In 2003, the Human Disease Ontology (DO, https://disease-ontology.org/) was established at Northwestern University. In the intervening 20 years, the DO has expanded to become a highly-utilized disease knowledge resource. Serving as the nomenclature and classification standard for human diseases, the DO provides a stable, etiology-based structure integrating mechanistic drivers of human disease. Over the past two decades the DO has grown from a collection of clinical vocabularies, into an expertly curated semantic resource of over 11300 common and rare diseases linking disease concepts through more than 37000 vocabulary cross mappings (v2023-08-08). Here, we introduce the recently launched DO Knowledgebase (DO-KB), which expands the DO's representation of the diseaseome and enhances the findability, accessibility, interoperability and reusability (FAIR) of disease data through a new SPARQL service and new Faceted Search Interface. The DO-KB is an integrated data system, built upon the DO's semantic disease knowledge backbone, with resources that expose and connect the DO's semantic knowledge with disease-related data across Open Linked Data resources. This update includes descriptions of efforts to assess the DO's global impact and improvements to data quality and content, with emphasis on changes in the last two years.

Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series).

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

Modeling the enigma of complex disease etiology.

BACKGROUND: Complex diseases often present as a diagnosis riddle, further complicated by the combination of multiple phenotypes and diseases as features of other diseases. With the aim of enhancing the determination of key etiological factors, we developed and tested a complex disease model that encompasses diverse factors that in combination result in complex diseases. This model was developed to address the challenges of classifying complex diseases given the evolving nature of understanding of disease and interaction and contributions of genetic, environmental, and social factors. METHODS: Here we present a new approach for modeling complex diseases that integrates the multiple contributing genetic, epigenetic, environmental, host and social pathogenic effects causing disease. The model was developed to provide a guide for capturing diverse mechanisms of complex diseases. Assessment of disease drivers for asthma, diabetes and fetal alcohol syndrome tested the model. RESULTS: We provide a detailed rationale for a model representing the classification of complex disease using three test conditions of asthma, diabetes and fetal alcohol syndrome. Model assessment resulted in the reassessment of the three complex disease classifications and identified driving factors, thus improving the model. The model is robust and flexible to capture new information as the understanding of complex disease improves. CONCLUSIONS: The Human Disease Ontology's Complex Disease model offers a mechanism for defining more accurate disease classification as a tool for more precise clinical diagnosis. This broader representation of complex disease, therefore, has implications for clinicians and researchers who are tasked with creating evidence-based and consensus-based recommendations and for public health tracking of complex disease. The new model facilitates the comparison of etiological factors between complex, common and rare diseases and is available at the Human Disease Ontology website.

Sexual dimorphic vulnerability of respiratory control in a neonatal rodent model of fetal alcohol spectrum disorder.

Fetal alcohol spectrum disorder (FASD) has been linked to numerous poor neurological outcomes as well as impairments in respiratory neural control. Females are known to metabolize ethanol (EtOH) differently than males suggesting a sexual dimorphic sensitivity to EtOH exposure. We used a rodent model of FASD to investigate whether EtOH disrupts respiratory neural control. Rat pups received a single intraperitoneal injection of 2 different doses (0.8 mg/g or 4.4 mg/g) of EtOH. Whole-body plethysmography was used ∼24 h later to assess ventilatory responses to acute hypoxia (HVR) and hypercapnia (HCVR). Females treated with 4.4 mg/g of EtOH exhibited an attenuated HVR and HCVR, but there was no effect on males, and no effect of 0.8 mg/g on either sex. There was unexpected mortality of unknown causes, especially in females, that occurred 2-3 days after EtOH administration. These data suggest that important ventilatory defense responses in females are impaired following developmental EtOH exposure, and this may be associated with increased risk of later death.

Neuroprotective therapies in the NICU in term infants: present and future.

Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.