Household energy poverty and trajectories of emotional and behavioural difficulties in children and adolescents: findings from two prospective cohort studies.

PURPOSE: The aim of this study is to examine the association between household energy poverty (EP) and trajectories of emotional and behavioural difficulties during childhood. METHODS: The Growing up in Ireland study is two nationally representative prospective cohorts of children. The Infant Cohort (n = 11,134) were recruited at age 9 months (9 m) and followed up at 3, 5, 7 and 9 years (y). The Child Cohort (n = 8,538) were recruited at age 9 y and followed up at 13 y and 17/18 y. EP was a composite of two relative measures of EP. Emotional and behavioural difficulties were repeatedly measured using the strengths and difficulties questionnaire (SDQ). Linear spline multilevel models were used, adjusted for confounders to examine the association between (1) EP (9 m or 3 y) and trajectories of emotional and behavioural difficulties from 3 to 9 y in the Infant Cohort and (2) EP at 9 y and the same trajectories from 9 to 18 y in the Child Cohort. RESULTS: In adjusted analyses, EP at 9 m or 3 y of age was associated with higher total difficulties score at 3 y (0.66, 95% CI 0.41, 0.91) and 5 y (0.77, 95% CI 0.48, 1.05) but not at 7 y or 9 y. EP at 9 y was associated with higher total difficulties score at 9 y (1.73, 95% CI 1.28, 2.18), with this difference reducing over time leading to 0.68 (95% CI 0.19, 1.17) at 17/18 y. CONCLUSIONS: Our study demonstrates a potential association between early life EP and emotional and behavioural difficulties that may be transient and attenuate over time during childhood. Further studies are required to replicate these findings and to better understand if these associations are causal.

The Australian Health Informatics Competency Framework: Conceptual Design, Framework Development, and Certification Delivery.

The Australian Health Informatics Competency Framework (AHICF) guides the healthcare workforce in identifying the required competencies to perform as a health informatician, and more definitively defines the foundational body of knowledge on which the discipline is based. The aim of this paper is to describe the conceptual foundations in developing the AHICF v1.0, detail the methods used to revise and publish AHICF v2.0, and explore the certification and workforce outcomes achieved. This paper contributes to the competency framework and certification discourse, and knowledge of the increasing importance and recognition of health informaticians through certification. Further, implications for workforce training and education, career advancement and recruitment strategies, are also discussed.

An Exploration of the Certified Health Informatician Australasia (CHIA) Participants.

The Certified Health Informatician Australasian (CHIA) is an assessment of a candidate's capabilities measured using a core set of health informatics competencies. The aim of this paper is to describe the outcomes of the first eight years since the program's launch. This paper contributes to the competency framework and certification discourse, and knowledge of the increasing importance and recognition of health informaticians through certification. An analysis of results and possible contributing factors is discussed.

Melatonin Alters Innate Immune Function in Infants with Neonatal Encephalopathy.

INTRODUCTION: Melatonin has been suggested an adjunctive therapy in neonatal encephalopathy (NE). Melatonin reduces oxidative stress and neutrophil activation; however, the immunological effects in NE have not been studied. METHODS: Infants with NE and neonatal controls were prospectively recruited. Whole blood was sampled in the first week of life. Following endotoxin and or melatonin treatment, diurnal variation was measured by RT PCR for circadian rhythm genes (brain and Muscle Arnt-Like protein [BMAL1], circadian locomotor output cycles kaput [CLOCK], Nuclear Receptor Subfamily 1 Group D Member 2 [REV Erß], and cryptochrome circadian clock [CRY]). Neutrophil and monocyte cell surface markers of activation CD11b, reactive oxygen intermediates (ROIs), and Toll-like receptor (TLR)-4 were also examined by flow cytometry in matching samples. RESULTS: Serum and RNA samples from forty infants were included (controls n = 20; NE n = 20) over the first week of life. Melatonin reduced neutrophil CD11b and TLR-4 expression in response to LPS in infants with NE compared to controls. There were no differences in ROIs. BMAL1 and CLOCK baseline gene expression levels were similar. BMAL1 was significantly decreased with LPS stimulation in NE. There was no significant diurnal variation in melatonin, neutrophil, and monocyte function or circadian genes. CONCLUSIONS: Melatonin alters immune function ex vivo in infants with NE. Infants with NE have altered immune circadian responses following LPS stimulation, which have potential for modulation.

Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in neonatal sepsis.

BACKGROUND: Efficient and accurate diagnosis of neonatal sepsis is challenging. The potential impact for a reduction in morbidity and mortality as well as antibiotic usage has stimulated the ongoing search for biomarkers of early sepsis. The objective of this pilot study was to quantify the levels of sTREM-1 and correlate with blood cultures and inflammatory markers in neonates evaluated for sepsis. METHODS: Neonates with suspected sepsis were enrolled (n = 83; Preterm n = 35; Term n = 48). Routine bloods for sepsis evaluation were included and plasma sTREM-1 levels were quantified by ELISA. RESULTS: Term and preterm neonates (n = 83; Preterm n = 35; Term n = 48) were enrolled and 16 neonates had positive blood cultures (preterm n = 15; term n = 1). sTREM-1 levels were not significantly different in infants with culture-positive or culture-negative sepsis (356 ± 218 pg/mL and 385 ± 254 pg/mL respectively). The immature-to-total granulocyte (I/T) ratio showed a significant positive correlation with sTREM-1 in the preterm group with positive blood cultures. Additionally, sTREM-1 showed a positive correlation with CRP in the preterm group with negative blood cultures. CONCLUSIONS: sTREM-1 was associated with traditional markers of inflammation (I/T ratio and CRP). However, in this cohort sTREM-1 did not improve the early detection of neonatal culture-positive sepsis.

Cannabidiol modulation of oxidative stress and signalling.

Cannabidiol (CBD), one of the primary non-euphoric components in the Cannabis sativa L. plant, has undergone clinical development over the last number of years as a therapeutic for patients with Lennox-Gastaut syndrome and Dravet syndromes. This phytocannabinoid demonstrates functional and pharmacological diversity, and research data indicate that CBD is a comparable antioxidant to common antioxidants. This review gathers the latest knowledge regarding the impact of CBD on oxidative signalling, with focus on the proclivity of CBD to regulate antioxidants and control the production of reactive oxygen species. CBD is considered an attractive therapeutic agent for neuroimmune disorders, and a body of literature indicates that CBD can regulate redox function at multiple levels, with a range of downstream effects on cells and tissues. However, pro-oxidant capacity of CBD has also been reported, and hence caution must be applied when considering CBD from a therapeutic standpoint. Such pro- and antioxidant functions of CBD may be cell- and model-dependent and may also be influenced by CBD dose, the duration of CBD treatment and the underlying pathology.

A systematic review protocol of quantitative instruments of income inequality in studies of children and adolescents.

Background: Income inequality is an important indicator of socioeconomic position which is a determinant of social, psychological, and physical health outcomes from childhood to adulthood. Different income inequality instruments (metrics) are used to investigate associations between income inequality and health outcomes (e.g. Gini coefficient). Income inequality instruments provide unique information on the construct of socioeconomic inequality. Albeit there is variation in studies as to the type and rationale for using a particular quantitative instrument of income inequality. The aim of this systematic review will be to investigate and identify the most used quantitative income inequality instrument in studies of children and adolescents up to 18 years of age.   Methods: The PRISMA-P framework will be applied to identify high quality articles (PROSPERO: CRD42021259114). A search will be conducted in PubMed, Embase, and PsycINFO. The search will include studies concerned with income inequality and/or socioeconomic inequality in children and adolescents. All articles will be independently reviewed, data extracted, and quality appraised by two reviewers and a third to arbitrate disputes. Articles will be reviewed by title and abstract using inclusion criteria. A data extraction form will be used. Three questions will assess the quality of the rationale for using a particular income inequality instrument and the Newcastle-Ottawa Scale will be used to assess bias and quality. The primary outcome of interest is the type and frequency of quantitative income inequality instruments used and the study outcome associated with that income inequality instrument.  Conclusions: This systematic review will aim to provide a summary of the different types of quantitative income inequality instruments used in studies of child and adolescent populations. This will help to guide researchers and policy makers on the use of income inequality metrics in future studies aimed at understanding associations with health and social outcomes in children and adolescents.

Type 1 IFN Induction by Cytosolic Nucleic Acid Is Intact in Neonatal Mononuclear Cells, Contrasting Starkly with Neonatal Hyporesponsiveness to TLR Ligation Due to Independence from Endosome-Mediated IRF3 Activation.

Two million infants die each year from infectious diseases before they reach 12 mo; many of these diseases are vaccine preventable in older populations. Pattern recognition receptors represent the critical front-line defense against pathogens. Evidence suggests that the innate immune system does not fully develop until puberty, contributing to impaired response to infection and impaired vaccine responses in neonates, infants, and children. The activity of the pattern recognition receptor family of cytosolic nucleic acid (CNA) sensors in this pediatric population has not been reported. We show that in direct contrast to weak TLR-induced type I IFN in human cord blood mononuclear cells, cord blood mononuclear cells are capable of initiating a potent response to CNA, inducing both antiviral type I IFN and, unexpectedly, proinflammatory TNF-α. A deficiency in Rab11-GTPase endosome formation and consequent lack of IRF3 activation in neonatal monocytes is at least in part responsible for the marked disparity in TLR-induced IFN production between neonatal and adult monocytes. CNA receptors do not rely on endosome formation, and therefore, these responses remain intact in neonates. Heightened neonatal responses to CNA challenge are maintained in children up to 2 y of age and, in marked contrast to TLR4/9 agonists, result in IL-12p70 and IFN-γ generation. CNA sensors induce robust antiviral and proinflammatory pathways in neonates and children and possess great potential for use as immunostimulants or vaccine adjuvants for targeted neonatal and pediatric populations to promote cell-mediated immunity against invasive infectious disease.

Gender disparities in preterm neonatal outcomes.

AIM: From birth to old age, males generally have poorer disease outcomes compared to females. Preterm infants display a marked gender disparity in disease outcomes, and the underlying mechanisms are not well delineated. Our aim was to review the literature on clinical outcomes between preterm infants of different genders and discuss the potential mechanisms underlying the differences observed. METHODS: A literature review was undertaken for experimental and clinical research related to gender differences in preterm outcomes. RESULTS: Preterm male infants appear to have consistently worse outcomes compared to females, and the aetiology of these differences, while mostly undetermined, is likely multifactorial. CONCLUSION: The male disadvantage in preterm outcomes is likely multifactorial with hormonal, genetic and immunological differences likely playing key roles. Gender is an important variable in preterm outcome and should be considered when designing clinical and experimental research.

Immune function? A missing link in the gender disparity in preterm neonatal outcomes.

INTRODUCTION: In neonatology, males exhibit a more severe disease course and poorer prognosis in many pathological states when compared to females. Perinatal brain injury, respiratory morbidity, and sepsis, among other complications, preferentially affect males. Preterm neonates (born <37 weeks gestation) display a particularly marked sexual disparity in pathology, especially at the borders of viability. The sex biases in preterm neonatal outcomes and underlying multifactorial mechanisms have been incompletely explored. Sex-specific clinical phenomena may be partially explained by intrinsic differences in immune function. The distinct immune system of preterm neonates renders this patient population vulnerable, and it is increasingly important to consider biological sex in disease processes and to strive for improved outcomes for both sexes. Areas covered: We discuss the cellular responses and molecular intermediates in immune function which are strongly dependent on sex-specific factors such as the genetic and hormonal milieu of premature birth and consider novel findings in a clinical context. Expert commentary: The role of immune function in the manifestation of sex-specific disease manifestations and outcomes in preterm neonates is a critical prognostic variable. Further mechanistic elucidation will yield valuable translational and clinical information of disease processes in preterm neonates which may be harnessed for modulation.

Expression of X-linked Toll-like receptor 4 signaling genes in female vs. male neonates.

BACKGROUND: Male neonates display poorer disease prognosis and outcomes compared with females. Immune genes which exhibit higher expression in umbilical cord blood (UCB) of females may contribute to the female immune advantage during infection and inflammation. The aim of this study was to quantify expression of Toll-like receptor (TLR) 4 signaling genes encoded on the X-chromosome in UCB from term female vs. male neonates. METHODS: UCB samples were collected from term neonates (n = 26) born by elective Caesarean section and whole blood was collected from adults (n = 20). Leukocyte RNA was isolated and used in quantitative PCR reactions for IκB kinase γ (IKKγ), Bruton's tyrosine kinase (BTK), and IL-1 receptor associated kinase (IRAK)1. IRAK1 protein was analyzed by Western blot and confocal microscopy. RESULTS: In neonates there was no significant difference in the relative expression of IKKγ or BTK mRNA between genders. IRAK1 gene and protein expression was significantly higher in female vs. male UCB, with increased cytosolic IRAK1 expression also evident in female UCB mononuclear cells. Adults had higher expression of all three genes compared with neonates. CONCLUSION: Increased expression of IRAK1 could be responsible, in part, for sex-specific responses to infection and subsequent immune advantage in female neonates.

Identification and Characterization of Stimulator of Interferon Genes As a Robust Adjuvant Target for Early Life Immunization.

Immunization is key to preventing infectious diseases, a leading cause of death early in life. However, due to age-specific immunity, vaccines often demonstrate reduced efficacy in newborns and young infants as compared to adults. Here, we combined in vitro and in vivo approaches to identify adjuvant candidates for early life immunization. We employed newborn and adult bone marrow-derived dendritic cells (BMDCs) to perform a screening of pattern recognition receptor agonists and found that the stimulator of interferon genes ligand 2'3'-cGAMP (hereafter cGAMP) induces a comparable expression of surface maturation markers in newborn and adult BMDCs. Then, we utilized the trivalent recombinant hemagglutinin (rHA) influenza vaccine, Flublok, as a model antigen to investigate the role of cGAMP in adult and early life immunization. cGAMP adjuvantation alone could increase rHA-specific antibody titers in adult but not newborn mice. Remarkably, as compared to alum or cGAMP alone, immunization with cGAMP formulated with alum (Alhydrogel) enhanced newborn rHA-specific IgG2a/c titers ~400-fold, an antibody subclass associated with the development of IFNγ-driven type 1 immunity in vivo and endowed with higher effector functions, by 42 days of life. Highlighting the amenability for successful vaccine formulation and delivery, we next confirmed that cGAMP adsorbs onto alum in vitro. Accordingly, immunization early in life with (cGAMP+alum) promoted IFNγ production by CD4+ T cells and increased the proportions and absolute numbers of CD4+ CXCR5+ PD-1+ T follicular helper and germinal center (GC) GL-7+ CD138+ B cells, suggesting an enhancement of the GC reaction. Adjuvantation effects were apparently specific for IgG2a/c isotype switching without effect on antibody affinity maturation, as there was no effect on rHA-specific IgG avidity. Overall, our studies suggest that cGAMP when formulated with alum may represent an effective adjuvantation system to foster humoral and cellular aspects of type 1 immunity for early life immunization.