Nucleic acid cytokine responses in obese children and infants of obese mothers

Almost a third of Irish children are now overweight and the country ranks 58th out of 200 countries for its proportion of overweight youths. With the rising obesity epidemic, and the impaired immune responses of this population, it is vital to understand the effects that obesity has on the immune system and to design future therapeutics, adjuvants and vaccines with overweight and obese populations in mind. Many current vaccines use adjuvants that have been found to be less effective at stimulating the immune response in children compared with adults and there is now substantial effort to design paediatric-focused adjuvants. Additionally, vaccine responses have been shown to be less effective in obese populations indicating that this is a particularly vulnerable population. We have recently identified cytosolic nucleic acids (CNAs), as novel candidate adjuvants for childhood vaccines. Here we investigated whether immune responses to these candidate adjuvants were adversely affected in infants born to overweight or obese mothers, and in overweight and obese children. Type I Interferon (IFN) and proinflammatory cytokines such as Tumor Necrosis Factor α (TNFα) are vital for driving innate and adaptive immune responses. We found that childhood obesity conferred no significant adverse effect on CNA-induced Type I IFN responses when compared with lean children. Similarly, Type I IFN responses were intact in the cord blood of babies delivered from overweight and obese mothers, when compared with lean mothers. There was also no significant impact of obesity on CNA-induced TNFα responses in children or from cord blood of infants born to overweight/obese mothers. In all cases, there was a tendency towards decreased production of innate cytokine Type I Interferon and TNFα, however there was no significant negative correlation. Interestingly, high maternal BMI showed weak and moderate positive correlation with IL-12p70 and IFNγ, respectively, in response to CNA stimulation. This study demonstrates that future adjuvants can be tailored for these populations through the use of activators of CNA sensors

Unexpected Widespread Hypophosphatemia and Bone Disease Associated with Elemental Formula Use in Infants and Children

OBJECTIVE: Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases. METHODS: A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism. RESULTS: Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product. CONCLUSION: The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop

Long-Term Follow-up of Hypophosphatemic Bone Disease Associated With Elemental Formula Use: Sustained Correction of Bone Disease After Formula Change or Phosphate Supplementation

In this article, we describe the long-term outcomes of children who were previously reported to have developed hypophosphatemic bone disease in association with elemental formula use. An extended chart review allowed for an updated report of 34 children with regard to severity/duration of bone disease, extent of recovery, and time to correction using radiology reports and biochemical data. After implementation of formula change and/or phosphate supplementation, we found that serum phosphorus concentration increased and serum alkaline phosphatase activity decreased in all patients, normalizing by 6.6 ± 4.0 (mean ± SD) months following diagnosis. The decrease in serum alkaline phosphatase from diagnosis to the time of correction was moderately correlated with the concurrent increase in serum phosphorus (R = 0.48, P < .05). Age at diagnosis significantly correlated with time to resolution (R = 0.51, P = .01). This study supports the earlier report that bone disease associated with hypophosphatemia during elemental formula use responds to formula change and/or phosphate supplementation

Assessing the impact of an Irish research funder’s recommendation to consider core outcome sets

The purpose of this study is to determine the impact of Health Research Board (HRB) Ireland call guidance on the use of available core outcome sets (COS) in trials and also the rationale behind outcome selection, where a COS was not available

Irish funder guidance increased searching for, and uptake of, Core Outcome Sets.

ObjectiveAssess the impact of the Health Research Board (HRB) Ireland guidance on the uptake of core outcome sets (COS).Study design and setting1. Information on COS use, searching of the Core Outcome Measures in Effectiveness Trials (COMET) database and rationale for outcome selection were extracted from HRB funding applications 2. COMET was searched for relevant COS availability at the time of application or developed since 3. PI choices were explored through online surveys.ResultsOut of 187 funding applications, 44% (n=82) searched the COMET database, and 13% (n=11) of those found a relevant COS to inform their outcomes. Four applicants proposed COS development. However, 84% (n=156) of applications had no relevant COS available at the time of submission, as identified by subsequent author COMET search. Among 84 Principal Investigators who participated in the surveys, 10 (12%) found and used a COS and 19 (42%) of the 45 respondents who did not reference COMET had searched the COMET database. A new question in the application form prompted a rise in those reporting a search of the COMET database from 6% to 99%.ConclusionThe study found low COS uptake in funding applications, but a new application question prompted an increase in reporting searches of the COMET database. Funder guidance promoted COS awareness and use, but more efforts are needed to facilitate COS development and adoption in clinical research

The Impact of Childhood Obesity on Inflammation, Innate Immune Cell Frequency, and Metabolic MicroRNA Expression

Background: Obesity is characterized by chronic inflammation, immune dysregulation, and alteration of gene expression, associated with type 2 diabetes mellitus and cardiovascular disease. The degree to which these changes occur in childhood obesity is not fully defined. Aims and Methods: The aim was to investigate the effect of childhood obesity on immune cell frequency, macrophage activation, cytokine production, and specific regulators of metabolic gene expression. Profiling was performed on peripheral blood from 29 obese and 20 nonobese children using real-time PCR, ELISA, and flow cytometry. Results: Fasting glucose was similar in both groups, but there was a higher degree of insulin resistance in obese subjects (homeostasis model of assessment for insulin resistance, 4.8 vs 0.84; P .001). Soluble CD163, a marker of macrophage polarization to a proinflammatory profile, was elevated in the obese compared to nonobese children (135 vs 105 ng/mL; P .03). Invariant natural killer T cells were reduced in the obese children (CD3 T cells, 0.31 vs 0.53%; P .001). Cytokine profiling revealed significantly elevated TNF- (6.7 vs 5.1 pg/mL; P .01) and leptin (1186 vs 432 pg/mL; P .001) and reduced adiponectin (884 vs 1321 pg/mL; P .001) in obese compared to nonobese children. Stimulation of peripheral blood mononuclear cells from obese children resulted in higher levels of IL-1 (2100 vs 1500 pg/mL; P .018). There was a 4-fold increase in expression of microRNA33a (P .001) and a 3-fold increase in microRNA33b (P .017) in obese children. Conclusion: Childhood obesity is associated with changes in immune cell frequency, inflammatory environment, and regulation of metabolic gene expression. These changes have been causally linked to the onset of metabolic disease in adulthood and suggest the future trajectory of obese children to the development of type 2 diabetes mellitus and premature cardiovascular diseas

NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient

Childhood obesity is a major global concern, with over 50 million children now classified as obese. Obesity has been linked to the development of numerous chronic inflammatory diseases, including type 2 diabetes and multiple cancers. NK cells are a subset of innate effector cells, which play an important role in the regulation of adipose tissue and antitumor immunity. NK cells can spontaneously kill transformed cells and coordinate subsequent immune responses through their production of cytokines. We investigated the effect of obesity on NK cells in a cohort of obese children, compared to children with a healthy weight. We demonstrated a reduction in peripheral NK cell frequencies in childhood obesity and inverse correlations with body mass index and insulin resistance. Compared with NK cells from children with normal weight, we show increased NK cell activation and metabolism in obese children (PD-1, mTOR activation, ECAR, and mitochondrial ROS), along with a reduced capacity to respond to stimulus, ultimately leading to loss of function (proliferation and tumor lysis). Collectively we show that NK cells from obese children are activated, metabolically stressed, and losing the ability to perform their basic duties. Paired with the reduction in NK cell frequencies in childhood obesity, this suggests that the negative effect on antitumor immunity is present early in the life course of obesity and certainly many years before the development of overt malignancies

NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient

Childhood obesity is a major global concern, with over 50 million children now classified as obese. Obesity has been linked to the development of numerous chronic inflammatory diseases, including type 2 diabetes and multiple cancers. NK cells are a subset of innate effector cells, which play an important role in the regulation of adipose tissue and antitumor immunity. NK cells can spontaneously kill transformed cells and coordinate subsequent immune responses through their production of cytokines. We investigated the effect of obesity on NK cells in a cohort of obese children, compared to children with a healthy weight. We demonstrated a reduction in peripheral NK cell frequencies in childhood obesity and inverse correlations with body mass index and insulin resistance. Compared with NK cells from children with normal weight, we show increased NK cell activation and metabolism in obese children (PD-1, mTOR activation, ECAR, and mitochondrial ROS), along with a reduced capacity to respond to stimulus, ultimately leading to loss of function (proliferation and tumor lysis). Collectively we show that NK cells from obese children are activated, metabolically stressed, and losing the ability to perform their basic duties. Paired with the reduction in NK cell frequencies in childhood obesity, this suggests that the negative effect on antitumor immunity is present early in the life course of obesity and certainly many years before the development of overt malignancies