Brain templates for Chinese babies from newborn to three months of age.

The infant brain develops rapidly and this area of research has great clinical implications. Neurodevelopmental disorders such as autism and developmental delay have their origins, potentially, in abnormal early brain maturation. Searching for potential early neural markers requires a priori knowledge about infant brain development and anatomy. One of the most common methods of characterizing brain features requires normalization of individual images into a standard stereotactic space and conduct of group-based analyses in this space. A population representative brain template is critical for these population-based studies. Little research is available on constructing brain templates for typical developing Chinese infants. In the present work, a total of 120 babies from 5 to 89 days of age were included with high resolution structural magnetic resonance imaging scans. T1-weighted and T2-weighted templates were constructed using an unbiased registration approach for babies from newborn to 3 months of age. Age-specific templates were also estimated for babies aged at 0, 1, 2 and 3 months old. Then we conducted a series of evaluations and statistical analyses over whole tissue segmentations and brain parcellations. Compared to the use of population mismatched templates, using our established templates resulted in lower deformation energy to transform individual images into the template space and produced a smaller registration error, i.e., smaller standard deviation of the registered images. Significant volumetric growth was observed across total brain tissues and most of the brain regions within the first three months of age. The total brain tissues exhibited larger volumes in baby boys compared to baby girls. To the best of our knowledge, this is the first study focusing on the construction of Chinese infant brain templates. These templates can be used for investigating birth related conditions such as preterm birth, detecting neural biomarkers for neurological and neurodevelopmental disorders in Chinese populations, and exploring genetic and cultural effects on the brain.

Assessing the safety of lipid-modifying medications among Chinese adolescents: a drug-target Mendelian randomization study.

BACKGROUND: With increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear. This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics. METHODS: A drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong's "Children of 1997" birth cohort (n = 3443, aged ~ 17.6 years). Safety outcomes (n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. Positive control outcomes were cholesterol markers from the "Children of 1997" birth cohort and coronary artery disease from Biobank Japan. RESULTS: Genetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta [95% CI], - 1.06 [- 1.52 to - 0.60]; PCSK9: - 0.93 [- 1.56 to - 0.31]) and had the expected effect on the positive control outcomes. After correcting for multiple comparisons (p-value < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid - 0.79 [- 1.25 to - 0.35]. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed. CONCLUSIONS: Statins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Larger studies were warranted to verify these findings. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics.

Neonatal outcome of infants with umbilical cord arterial pH less than 7.

INTRODUCTION: Umbilical arterial pH of less than 7 is often used as the threshold below which the risks of neonatal death and adverse long-term neurological outcomes are considered to be higher. Yet within the group with pH <7, the risks have not been further stratified. Here, we aimed to investigate the predictors of adverse long-term outcomes of this group of infants. MATERIAL AND METHODS: This was a retrospective study of 248 infants born after 34 weeks of gestation in a tertiary obstetric unit, between 2003 and 2017, with cord arterial pH <7 or base excess ≤-12 mmol/L at birth. The infants were categorized into two groups: (1) intact survivors, or (2) neonatal/infant deaths or cerebral palsy or developmental delay. The umbilical arterial pH and base excess levels, Apgar scores, mode of delivery, gestational age, small for gestational age, birth in the era before the implementation of neonatal hypothermic therapy, and the presence of a known sentinel event, were compared between the groups using univariate analysis followed by multivariate analysis. RESULTS: Among the 248 infants, there were 222 intact survivors (89.5%) and 26 infants with poor outcomes (10.5%), including eight deaths (3.2%) and 18 (7.3%) with cerebral palsy and/or developmental delay. Univariate analysis showed that infants with adverse outcomes had significantly lower cord arterial pH (6.85 vs 6.95, with p < 0.001), lower cord arterial base excess (-19.95 vs -15.90 mmol/L, p < 0.001), a higher proportion of having AS at 5 min <7 (65.4% vs 13.1%, p < 0.001), and a higher proportion of having a sentinel event (34.6% vs 16.7%, p = 0.034). Multivariate analysis confirmed cord arterial pH of <6.9 and an Apgar score at 5 min <7 as independent prognostic factors (the adjusted odds ratios were 4.64 and 6.62, respectively). The risk of adverse outcome increased from 4.3% when the arterial pH was between 6.9 and <7, to 30% when the pH was <6.9. CONCLUSIONS: Infants born with umbilical artery pH <7 still have a high chance of 89.5% to become intact survivors. A cord arterial pH of <6.9 and an Apgar score at 5 min <7 are independent prognostic factors for neonatal/infant death or adverse long-term neurological outcomes.

Prenatal methylmercury exposure is associated with decrease heart rate variability in children.

BACKGROUND: Although several epidemiological studies have suggested mercury (Hg) might be associated with cardiotoxicity, the impact of Hg exposure on cardiac autonomic activity and blood pressure in children has not been investigated at Hg exposure levels equivalent to the Environmental Protection Agency (EPA) reference dose. OBJECTIVE: To investigate the association between low dose prenatal and recent methylmercury (MeHg) exposures and cardiac autonomic function and blood pressure with adjustment for factors such as fish consumption among children from a high fish consumption coastal city. METHODS: Children aged 7-8 years were recruited from the birth cohort of our previous study. Heart rate variability (HRV), resting heart rate (RHR) and blood pressure were measured as surrogate markers of cardiac autonomic function. Cord blood and current whole blood Hg concentration were used as biomarkers of prenatal and recent MeHg exposure, respectively. Recent fish consumption information was estimated with a food frequency questionnaire. RESULTS: Among 604 children, median cord blood and whole blood Hg concentrations were 45.9 nmol/L (IQR: 32.8-65.03 nmol/L) and 13.57 nmol/L (IQR: 9.29-19.72 nmol/L), respectively. Our results demonstrated that prenatal MeHg exposure was associated with decreased HRV (i.e. low CVRR, SDRR, and RMSSD), reflecting reduced parasympathetic activity (i.e. low CCVHF and HF), and a sympathovagal balance shift toward sympathetic predominance (i.e. high %LF and LF/HF ratio). Adjustment of recent fish consumption further increased the significance and magnitude of the adverse associations of MeHg. CONCLUSION: The results of this study suggest that prenatal MeHg exposure is associated with decreased parasympathetic modulation of cardiac autonomic function in children.

The Use of Somatex Shunt for Fetal Pleural Effusion: A Cohort of 8 Procedures.

INTRODUCTION: Fetal pleural effusion may require in utero shunting which is associated with procedure-related complications. OBJECTIVE: To evaluate the efficacy and complications of the newly designed Somatex shunt in treating fetal pleural effusion. METHODS: Consecutive cases with primary fetal pleural effusion who were treated with the Somatex shunt between 2018 and 2019 were evaluated. Perinatal outcomes and complications were retrospectively analyzed. RESULTS: There were 6 cases of unilateral and 1 case of bilateral pleural effusion, and hence a total of 8 pleuroamniotic shunting procedures were performed. The median gestational age at diagnosis and shunting was 20.7 and 22.6 weeks, respectively. All 8 procedures were successful, achieving complete in utero drainage. All but one were live births (85.7%) with a median gestational age of 38 weeks. The single case of in utero death occurred 4.7 weeks after successful shunting, and no cause could be identified after autopsy. The rates of preterm birth and premature rupture of membranes were 33.3% (2/6) and 16.7% (1/6), respectively. Four of the 8 procedures (50%) had minor shunt-related complications such as dislodgement and entrapment, occurring at a median of 7.7 weeks after shunting. None of the shunts became blocked. CONCLUSIONS: The Somatex shunt is effective in relieving fetal pleural effusions with good survival rate. Overall, it was a safe instrument, though minor shunt complications occurred.

Dysregulation of miR-431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis.

The level of microRNA (miR)-431 was found to be markedly up-regulated in intestinal tissue of necrotizing enterocolitis (NEC). The objective of this study was to identify the target gene of miR-431 and to investigate the role of the miR-431-FOXA1 axis in the pathophysiology of NEC. The target gene of miR-431 was identified by in silico target prediction bioinformatics, luciferase assay, and Western blotting. Effects of miR-431 on downstream expression signals, cell proliferation, and apoptosis were investigated by overexpression in Caco-2 cells upon stimulation by LPS or lipoteichoic acid (LTA). FOXA1 was identified as the target gene of miR-431. Overexpression of miR-431 in Caco-2 cells significantly inhibited FOXA1, ESRRG, and HNF4A and activated IL-6, LGR5, NFKB2, PLA2G2A, PRKCZ, and TNF. IL-8 and - 10 were enhanced when costimulated with LPS or LTA. These potential downstream genes were also significantly dysregulated in primary NEC tissues compared with surgical-control tissues. Overexpression of miR-431 significantly decreased proliferation and increased apoptosis of Caco-2 cells. A proposed network of miR-431-FOXA1 interaction with LPS and LTA receptors demonstrates dysregulation of transcription factors, inflammatory mediators, epithelium tight junction regulators, and cell proliferation and apoptosis signals. The miR-431-FOXA1 axis could in part be responsible for the intensification of the inflammatory response in NEC tissues and contribute to the proinflammatory pathophysiology.-Wu, Y. Z., Chan, K. Y. Y., Leung, K. T., Lam, H. S., Tam, Y. H., Lee, K. H., Li, K., Ng, P. C. Dysregulation of miR-431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis.

Association between genetic variations in GSH-related and MT genes and low-dose methylmercury exposure in children and women of childbearing age: a pilot study.

BACKGROUND: Genetic variations in glutathione (GSH)-related and metallothionein (MT) genes, which are involved in producing enzymes in the methylmercury (MeHg) metabolism pathway, have been proposed as one of the reasons for the individual variability in MeHg toxicokinetics. OBJECTIVE: To investigate the impact of genetic variations in MT and GSH-related genes on the association of fish consumption with body burden of MeHg, as measured by hair Hg concentrations among young children and women of childbearing age. METHODS: A total of 179 unrelated children and 165 mothers with either high or low fish consumption were recruited from the community. Their hair total Hg (tHg) and MeHg levels and genotypes for SNPs located on the GCLC, GCLM, GPX1, GSTA1, GSTP1, MT1A, MT2A, and MT4 genes were determined. Based on their 14-day food records, the amounts of fish consumed and their MeHg intakes were estimated. The impact of genetic variations on hair Hg concentrations was examined by using Mann-Whitney tests and multivariable linear regression analyses. RESULTS: The presence of minor alleles of GCLC-129 (rs17883901), GPX1-198 (rs1050450) and MT1M (rs9936741) were associated with significantly lower hair tHg levels in mothers whereas mothers with minor alleles of GSTP1-105(rs1695) and MT1M (rs2270836) have significantly higher hair tHg levels. After adjustment for fish consumption and other confounding factors, apart from MT1M (rs2270836), all of the above SNPs remain significant in the multivariable linear regression models. CONCLUSIONS: Our results in a group of children and women show that genetic variants of GSH-related and MT genes are associated with hair Hg concentrations. These genetic variations are likely to significantly affect MeHg metabolism and thus influence the accumulation of Hg in the human body.

Plasma miR-1290 Is a Novel and Specific Biomarker for Early Diagnosis of Necrotizing Enterocolitis-Biomarker Discovery with Prospective Cohort Evaluation.

OBJECTIVE: To discover specific circulating microRNA (miRNA) biomarkers for the early differentiation of necrotizing enterocolitis (NEC) from neonatal sepsis and inflammatory conditions. STUDY DESIGN: The study comprised 3 distinct phases: differential microarray analysis to compare plasma miRNA expression profiles of NEC vs sepsis and non-NEC/nonsepsis cases, a case-control study to quantify dysregulated miRNAs as potential specific biomarkers of NEC, and a prospective cohort study to assess the diagnostic usefulness of the best miRNA biomarker(s). RESULTS: A distinct miRNA expression profile was observed in the NEC compared with the sepsis and non-NEC/nonsepsis groups. miR-1290, miR-1246, and miR-375 were discovered to be specific biomarkers of NEC in the case-control study. In the cohort study (n = 301), plasma miR-1290 (day 0; >220 copies/µL) provided the greatest diagnostic usefulness for identifying both mild medical and severe surgical NEC cases. Of 20 infants with miR-1290 >650 copies/µL, 15 were diagnosed with NEC. Incorporating C-reactive protein (day 1; >15.8 mg/L) for cases with intermediate levels (220-650 copies/µL) in a 2-stage algorithm further optimized the diagnostic profile with a sensitivity of 0.83, a specificity of 0.96, a positive predictive value of 0.75, and a negative predictive value of 0.98. Importantly, 7 of 36 infants with NEC (19.4%) could be diagnosed 7.8-32.2 hours earlier (median, 13.3 hours) using miR-1290. CONCLUSIONS: Plasma miR-1290 is a novel and specific biomarker that can effectively differentiate NEC cases from neonatal sepsis. miR-1290 facilitates neonatologists to confidently and timely reach a decision for early transfer of sick infants with NEC from community-based hospitals to tertiary surgical centers.

Sleep duration and risk of diabetes: Observational and Mendelian randomization studies.

Inadequate sleep could contribute to type 2 diabetes, but observational studies are inconsistent and open to biases, particularly from confounding. We used Mendelian randomization (MR) to obtain an unconfounded estimate of the effect of sleep duration on diabetes, fasting glucose (FG) and hemoglobin A1c (HbA1c), and an observation study to assess differences by sex. Using MR, we assessed the effects of genetically instrumented sleep on diabetes, based on 68 single nucleotide polymorphisms (SNPs), applied to the DIAbetes Genetics Replication and meta-analysis case (n = 26,676)-control (n = 132,532) study and on FG and HbA1c, based on 55 SNPs, applied to the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) study of FG (n = 122,743) and HbA1c (n = 123,665). In the population-representative Hong Kong Chinese "Children of 1997" birth cohort we assessed whether associations of sleep duration at ~17.5 years with FG and HbA1c differed by sex. Using inverse variance weighting with multiplicative random effects, sleep duration was not associated with diabetes (odds ratio (OR) 0.85 per hour of sleep, 95% confidence interval (CI) 0.64 to 1.13), FG (-0.032 mmol/l per hour of sleep, 95% CI -0.126 to 0.063) or HbA1c (-0.022% per hour of sleep, 95% CI -0.069 to 0.024). In "Children of 1997", the associations of sleep duration with FG differed by sex (p for interaction 0.05) but not with HbA1c. Overall sleep duration does not appear to be related to diabetes, FG or HbA1c, but the possibility of sex differences merits investigation.

Methylmercury levels in commonly consumed fish and methylmercury exposure of children and women of childbearing age in Hong Kong, a high fish consumption community.

BACKGROUND: Despite high fish consumption levels of Hong Kong residents, little is known about the MeHg exposure levels of Hong Kong high-risk populations (i.e. young children and women of childbearing age). OBJECTIVES: To investigate the MeHg levels in fish commonly consumed in Hong Kong and assess the exposure levels of local kindergarten children and women of childbearing age. METHODS: A community-based survey was conducted in randomly recruited local kindergartens. The MeHg concentrations of the most commonly consumed fish items were measured. Based on their fish consumption data, subjects' MeHg exposure levels were estimated and compared with the reference dose (RfD) set by U.S. Environmental Protection Agency. RESULTS: A total of 2917 mother-child pairs were recruited. The MeHg levels of the fish samples ranged from < 2-1498.7 ng/g. Six frozen cod fish samples contained MeHg levels exceeding the local legal limit of 500 ng/g. The median estimated MeHg intake for children and mothers were 0.29 and 0.22 µg/kg bw/wk, respectively. Approximately 16% children and 9% mothers exceeded the RfD. CONCLUSIONS: Apart from frozen cod fish, most fish species commonly consumed in Hong Kong had low MeHg content. Although the majority of our subjects were exposed to low MeHg levels, high fish consumers could still exceed the RfD and are potentially at risk of MeHg toxicity. To avoid excessive MeHg exposure, we suggest that young children and their mothers may consume a variety of locally available fish, but avoid consumption of frozen cod fish.

Attitudes of Parents and Health Care Workers to Major Surgery for High-Risk Preterm Infants.

OBJECTIVES: To assess preferences of health care workers (HCWs) and parents of term and preterm infants to adverse health outcomes, and how perceived surgical mortality influences decision-making. STUDY DESIGN: A total of 536 participants (157 HCWs, 201 parents of term infants, and 178 parents of preterm infants) were recruited to take part in a structured interview. Preferences related to treatment of a critically ill preterm infant with necrotizing enterocolitis were measured by health state rank permutation analysis and pivotal risk analysis. Between-group and subgroup comparisons were performed. RESULTS: HCWs rank adverse health states less favorably than parents of preterm infants, consistently ranking 2 of the most adverse health states worse than death. Pivotal risk values of HCWs for all health states were consistently the lowest of the 3 groups. High operative mortality was associated uniformly with reduction in pivotal risks for all groups both in favorable and adverse health states. Subgroup analyses revealed significant discrepancies in preferences between fathers and mothers as well as doctors and nurses. Regular religious practice was significantly associated with increased pivotal risks in parental subgroups. CONCLUSIONS: As discrepancies in health state preferences existed between subgroups (ie, doctors vs nurses, mothers vs fathers) and perceived operative mortality consistently biased parental and HCW health state preferences, we recommend that HCWs should first identify differences regarding patient management before interviewing the parents together. HCWs should be aware of inadvertently biasing parents when discussing the risks and outcomes of surgery in conjunction with the overall long-term prognosis of the underlying condition.

Prenatal dioxin exposure and neurocognitive development in Hong Kong 11-year-old children.

BACKGROUND AND OBJECTIVES: In utero exposure to dioxins and related compounds have been associated with adverse neurocognitive development in infants. It is unclear whether neurodevelopmental deficits persist to childhood. We assessed the association of prenatal dioxin exposure with neurocognitive function in 11-year-old children, and to test whether the association is modified by duration of breastfeeding. METHODS: In this prospective study of 161 children born in Hong Kong in 2002, prenatal dioxin exposure was proxied by the dioxin toxicity equivalence (TEQ) in breast milk collected during the early postnatal period as determined by the Chemical-Activated LUciferase gene eXpression (CALUX) bioassay. We used multivariate linear regression analyses to assess the association of prenatal dioxin exposure with the performance on the Wechsler Intelligence Scale for Children-IV, Hong Kong, the Hong Kong List Learning Test, the Tests for Everyday Attention for Children and the Grooved Pegboard Test, adjusting for child's sex, mother's place of birth, mother's habitual seafood consumption, mother's age at delivery and socioeconomic position. RESULTS: Measures of neurocognitive and intellectual function, including full-scale IQ, fine motor coordination, verbal and non-verbal reasoning, learning ability and attention at 11 years old did not show significant variations with prenatal dioxin exposures (proxied by CALUX-TEQ total dioxin load in early breast milk). None of these associations varied by breastfeeding duration or sex. CONCLUSIONS: Neurocongitive function, as measured with psychological tests, in 11-year-old children was not associated with prenatal dioxin exposure to background levels of dioxins in the 2000s in Hong Kong.

Impact of fetal and childhood mercury exposure on immune status in children.

BACKGROUND: Mercury exposure have been shown to affect immune status in animals as reflected by cytokine expression. It is unclear whether low levels of exposure during fetal and/or childhood periods could impact on immune status in humans. OBJECTIVES: To test the hypothesis that fetal and childhood mercury exposure is associated with childhood cytokine profiles and to investigate whether childhood selenium levels interact with any of the associations found. METHODS: Children were recruited from a previously established birth cohort between the ages of 6-9 years for assessment and measurement of blood mercury, selenium and cytokine profile (interleukin (IL)-4, IL-6, IL-8, IL-10, IL-13 and TNF-alpha). Multivariable linear regression models were used to assess the adjusted association of cord blood mercury concentration and current mercury concentrations with levels of the cytokine levels. We tested whether the association with current mercury level varied by current selenium level and cord blood mercury level. RESULTS: IL-10 was negatively associated with current blood mercury concentration. The effect was greatest in cases with low cord blood mercury and low current selenium concentrations. None of the other cytokine levels were associated with either cord blood or current blood mercury concentrations, except that cord blood mercury was negatively associated with IL-6. CONCLUSIONS: Childhood mercury exposure was negatively associated with childhood IL-10 levels. It is postulated that while selenium is protective, low levels of fetal mercury exposure may increase the degree of this negative association during childhood. Further studies into the clinical significance of these findings are required.

Genome-wide expression profiles of necrotizing enterocolitis versus spontaneous intestinal perforation in human intestinal tissues: dysregulation of functional pathways.

OBJECTIVE: To provide a comprehensive database of gene regulation and compare differentially regulated molecular networks in human tissues of necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP). BACKGROUND: Both NEC and SIP are devastating surgical emergencies associated with high morbidity and mortality in preterm infants. Their pathophysiology and molecular mechanisms remain unclear. METHODS: Differential whole genome microarray analysis was performed on intestinal tissues collected from NEC (n = 15) and SIP (n = 12) infants and compared with tissues collected from surgical-control patients with noninflammatory intestinal conditions (n = 14). Validation of 52 target gene expressions was performed by quantitative polymerase chain reaction. Regulatory networks of significantly affected genes were constructed according to functional pathways. RESULTS: Extensive and significant changes of gene expression were observed in NEC tissues, which comprised multiple pathways of angiogenesis, arginine metabolism, cell adhesion and chemotaxis, extracellular matrix remodeling, hypoxia and oxidative stress, inflammation, and muscle contraction. These dysregulated genes could be networked downstream of key receptors, TLR2, TLR4, and TREM1, and mediated via NF-κB, AP-1, and HIF1A transcription factor pathways, indicating predominant microbial and inflammatory involvement. In contrast, SIP tissues exhibited much milder and less diversified expressional changes, with target genes significantly associated with G-protein-mediated muscle contraction and extracellular matrix remodeling. CONCLUSIONS: The molecular evidence suggests that NEC and SIP are likely 2 different diseases caused by distinct etiology and pathophysiology. This first comprehensive database on differential gene expression profiles of human NEC and SIP tissues could lead to development of disease-specific diagnostic and prognostic biomarkers and new therapeutic strategies for improving outcomes.

Enhanced Category-Based Risk Assessment for Neonatal Early-Onset Sepsis: A Prospective Observational Study.

INTRODUCTION: Compared with multivariate risk assessment, traditional category-based risk assessment (CRA) approaches for neonatal early-onset sepsis (EOS) screening are usually straightforward to use, do not require electronic devices, but are associated with higher rates of antibiotic use. This study aims to evaluate the performance of a novel enhanced CRA (eCRA) framework on EOS admissions and antibiotic use and to investigate whether a modified version with adjustments in risk factor weighting can allow its performance to match the EOS calculator while remaining easy to implement. METHOD: This is a prospective, single-center, two-phase observational study. Infants of all gestations delivered in a tertiary hospital in Hong Kong with risk factors or clinical features of EOS were recruited. PHASE I: A novel eCRA framework (period 2) was compared with the CDC 2010-based protocol (period 1). PHASE II: A modified eCRA framework was compared theoretically with the EOS calculator. EOS-specific admissions and antibiotic use were measured. RESULTS: Phase I: 1,025 at-risk infants were recruited during period 2 and compared with 757 infants of period 1. Admissions and antibiotic use decreased from 45.8% to 29.4% and 41.1% to 28.2%, respectively. Antibiotics among those at-risk but well-appearing infants decreased from 25.3% to 16.3% (p < 0.001 for all). PHASE II: antibiotic use was similar (7.3 vs. 6.4%, p = 0.42) between the modified eCRA framework and the EOS calculator. CONCLUSIONS: An eCRA framework can effectively and safely provide individualized guidance for EOS screening without the need for tools such as the EOS calculator.

Iron status and non-alcoholic fatty liver disease: A Mendelian randomization study.

OBJECTIVES: The aim of this study was to assess the association of genetically determined iron status with the risk for non-alcoholic fatty liver disease (NAFLD) using two-sample Mendelian randomization (MR) analysis. METHODS: We applied single nucleotide polymorphisms (SNPs) associated at genome-wide significance with iron status proxied by serum iron, ferritin, transferrin, and transferrin saturation from the Genetics of Iron status Consortium (N = 48 793), in a genome-wide association study of 1664 NAFLD cases and 400 055 controls from the United Kingdom Biobank. A SNP associated with multiple markers of iron status was only applied to one marker with the strongest association in the main analysis. Their effects on NAFLD were calculated using inverse variance weighting after excluding SNPs associated with alkaline phosphatase and lipid metabolism. RESULTS: The risk for NAFLD is negatively associated with genetically predicted serum transferrin level with a 20% reduction in NAFLD risk per SD (0.65g/L) increase in transferrin (95% confidence interval [CI], 0.66-0.97), and trending positive association with transferrin saturation (odds ratio [OR], 1.50; 95% CI, 0.96-2.35) but it was not associated with serum iron (OR, 0.90; 95% CI, 0.63-1.29) and ferritin (OR, 1.33; 95% CI, 0.54-3.30). CONCLUSIONS: MR analysis provided evidence that genetically predicted higher serum transferrin, indicating lower iron status, may be protective against NAFLD, whereas higher transferrin saturation, indicating higher iron status, might increase the risk for NAFLD and its pathogenesis.

Association of childhood food consumption and dietary pattern with cardiometabolic risk factors and metabolomics in late adolescence: prospective evidence from 'Children of 1997' birth cohort.

BACKGROUND: Healthy diet might protect against cardiometabolic diseases, but uncertainty exists about its definition and role in adolescence. METHOD: In a subset of Hong Kong's 'Children of 1997' birth cohort (n=2844 out of 8327), we prospectively examined sex-specific associations of food consumption and dietary pattern, proxied by the Global Diet Quality Score (GDQS) at~12.0 years, with cardiometabolic risk factors and metabolomics at~17.6 years. RESULT: Higher vegetable (-0.04 SD, 95% CIs: -0.09 to 0.00) and soy consumption (-0.05 SD, 95% CI: -0.09 to -0.01) were associated with lower waist-to-hip ratio. Higher fruit and vegetable consumption were associated with lower fasting glucose (p<0.05). Higher fish consumption was associated with 0.06 SD (95% CI: 0.01 to 0.10) high-density lipoprotein cholesterol and -0.07 SD (95% CI: -0.11 to -0.02) triglycerides. After correcting for multiple comparisons (p<0.001), higher fish, fruit and vegetable consumption were associated with higher fatty acid unsaturation, higher concentration and percentage of omega-3 and a lower ratio of omega-6/omega-3. At nominal significance (p<0.05), higher fish consumption was associated with lower very-low-density lipoprotein and triglycerides relevant metabolomics. Higher vegetable and fruit consumption were associated with lower glycolysis-related metabolomics. Lower sugar-sweetened beverages (SSBs) consumption was associated with lower branched-chain amino acids. Similar associations with adiposity and metabolomics biomarkers were observed for GDQS. CONCLUSIONS: Higher consumption of fruit, vegetables and fish and lower ice cream and SSBs consumption were associated with lower cardiometabolic risk in adolescents.

Neutrophil CD64 for daily surveillance of systemic infection and necrotizing enterocolitis in preterm infants.

BACKGROUND: Early detection and treatment of infected preterm infants could decrease morbidity and mortality. Neutrophil CD64 has been shown to be an excellent early diagnostic biomarker of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC). We aimed to study whether using CD64 as a daily surveillance biomarker could predict LOS/NEC before clinical manifestation. METHODS: We collected 0.1 mL whole blood from very low birth weight (VLBW) infants from day 7 postnatal age until routine daily blood tests were no longer required. Four categories of responses were defined: proven sepsis, clinical sepsis, nonsepsis/non-NEC, and asymptomatic CD64 activation. RESULTS: A total of 146 infants were consecutively recruited and 155 episodes of sepsis evaluation were performed. The biomarker screening utility, sensitivity, specificity, positive predictive value, and negative predictive value for surveillance of LOS/NEC using a cutoff of 5655 antibody-PE (phycoerythrin) molecules bound/cell were 89%, 98%, 41%, and 99.8%, respectively. LOS/NEC was detected a mean of 1.5 days before clinical presentation. However, 63 episodes of CD64 activation occurred in asymptomatic infants who would not otherwise have required sepsis evaluations. CONCLUSIONS: As a surveillance biomarker, neutrophil CD64 detected LOS/NEC 1.5 days before clinical presentation, but at the expense of performing 41% additional sepsis evaluations. This was mainly attributed to an unexpected group of asymptomatic infants with CD64 activation, who recovered spontaneously and did not require antimicrobial treatment. The latter group has not been previously recognized in VLBW infants and could represent subclinical infection secondary to transient bacterial translocation or mild viral infection.

IL-15 and macrophage secretory factors facilitate immune activation of neonatal natural killer cells by lipoteichoic acid.

Neonates possess a relatively "naive", yet inducible immune system. Our hypothesis is that upon strategic antigen exposure, cytokine priming and sensitization by accessory cells, natural killer (NK) cells could be activated to become a functional phenotype. We investigated the in vitro stimulation of cord blood (CB) and adult NK cells upon challenge with lipoteichoic acid (LTA), interleukin (IL)-15 and LTA-primed autologous macrophage-conditioned medium, using CD107a and CD69 phenotypes as indicators of activation. We also examined response of CB macrophages to LTA, in terms of P44/42 extracellular signal-regulated kinases (ERK1/2) activation and cytokine secretion. LTA significantly induced secretion of inflammatory cytokines tumor necrotic factor (TNF)-α, IL-6, IL-12 and activated the upstream signal of ERK1/2 phosphorylation in neonatal macrophages. The magnitude of responses to stimulation differed between neonatal and adult NK cells. Co-stimulation with IL-15 was critical for expansion of the CD69 and CD107a NK subpopulations in both neonatal and adult cells, upon a LTA challenge. NK cell activation could be enhanced by LTA-primed autologous macrophages through secretory factors. Our results indicated that neonatal macrophages and NK cells can evoke immunologic responses to a Gram-positive bacterial antigen. The combinatory priming strategy is relevant for development of novel protocols, such as IL-15 treatment, to compensate for the immaturity of the innate immune system in newborns against bacterial infections.