A National Review of Neonatal Jaundice Identification.

Background Physiological neonatal hyperbilirubinemia is a normal transitional phenomenon, however bilirubin encephalopathy can develop due to exposure to very high bilirubin levels. A systematic approach to early detection of high levels can prevent this outcome. Methods We designed a questionnaire to assess local jaundice management practices in Irish maternity units. Results All 19 units responded to our clinical questionnaire. Early discharge (<48 hours) occurs in 12 units (63%). Six units universally screen all babies with a transcutaneous bilirubinometer (TCB) (32%) while 12 units only do so if clinically jaundiced (83%). 12 units follow up <5% of their babies for jaundice monitoring after discharge (67%), which is lower than expected for optimal jaundice management. Conclusion Our survey responses show a high degree of variability in jaundice identification and follow up practices around the country. As maternity units trend towards earlier discharge of mothers due to resource constraints, we need to develop national systems to stratify risk before discharge and monitor jaundice in the out-patient setting. Introduction

Genetics of osteoarthritis.

Osteoarthritis genetics has been transformed in the past decade through the application of large-scale genome-wide association scans. So far, over 100 polymorphic DNA variants have been associated with this common and complex disease. These genetic risk variants account for over 20% of osteoarthritis heritability and the vast majority map to non-protein coding regions of the genome where they are presumed to act by regulating the expression of target genes. Statistical fine mapping, in silico analyses of genomics data, and laboratory-based functional studies have enabled the identification of some of these targets, which encode proteins with diverse roles, including extracellular signaling molecules, intracellular enzymes, transcription factors, and cytoskeletal proteins. A large number of the risk variants correlate with epigenetic factors, in particular cartilage DNA methylation changes in cis, implying that epigenetics may be a conduit through which genetic effects on gene expression are mediated. Some of the variants also appear to have been selected as humans adapted to bipedalism, suggesting that a proportion of osteoarthritis genetic susceptibility results from antagonistic pleiotropy, with risk variants having a positive role in joint formation but a negative role in the long-term health of the joint. Although data from an osteoarthritis genetic study has not yet directly led to a novel treatment, some of the osteoarthritis associated genes code for proteins that have available therapeutics. Genetic investigations are therefore revealing fascinating fundamental insights into osteoarthritis and can expose options for translational intervention.

Mediating role of body-related shame and guilt in the relationship between weight perceptions and lifestyle behaviours.

INTRODUCTION: A substantial proportion of individuals with overweight or obesity perceive themselves as 'too heavy' relative to 'about right'. Perceiving one's weight as 'too heavy' is associated with lower levels of physical activity and higher levels of sedentary behaviour. However, the mechanisms underpinning the associations between weight perception and lifestyle behaviours have not been identified. Based on theoretical tenets and empirical evidence, the self-conscious emotions of shame and guilt may mediate these associations. METHODS: Participants were young adults (n = 618, Mage = 24.0 ± .6 years) who provided data on weight, weight perception, body-related shame and guilt, physical activity and screen time. RESULTS: Mediation analyses using the PROCESS macro indicated that shame and guilt significantly mediated the relationships between weight perception and physical activity and shame significantly mediated the relationship between weight perception and screen time. CONCLUSIONS: These findings provide preliminary evidence that self-conscious emotions may be mechanisms by which weight perception influences physical activity and sedentary behaviour in young adults. However, longitudinal investigations of this mechanism are needed.

Multi-tissue epigenetic analysis of the osteoarthritis susceptibility locus mapping to the plectin gene PLEC.

OBJECTIVE: In cartilage, the osteoarthritis (OA) associated single nucleotide polymorphism (SNP) rs11780978 correlates with differential expression of PLEC, and with differential methylation of PLEC CpG dinucleotides, forming eQTLs and mQTLs respectively. This implies that methylation links chondrocyte genotype and phenotype, thus driving the functional effect of this genetic risk signal. PLEC encodes plectin, a cytoskeletal protein that enables tissues to respond to mechanical forces. We sought to assess whether these PLEC functional effects were cartilage specific. METHOD: Cartilage, fat pad, synovium and peripheral blood were collected from patients undergoing arthroplasty. PLEC CpGs were analysed for mQTLs and allelic expression imbalance (AEI) was performed to test for eQTLs. Plectin was knocked down in a mesenchymal stem cell (MSC) line using CRISPR/Cas9 and cells phenotyped by RNA-sequencing. RESULTS: mQTLs were discovered in fat pad, synovium and blood. Their effects were however stronger in the joint tissues and of comparable effect between these tissues. We observed AEI in synovium in the same direction as for cartilage and correlations between methylation and PLEC expression. Knocking-down plectin impacted on pathways reported to have a role in OA, including Wnt signalling, glycosaminoglycan biosynthesis and immune regulation. CONCLUSIONS: Synovium is also a target of the rs11780978 OA association functionally operating on PLEC. In fat pad, mQTLs were identified but these did not correlate with PLEC expression, suggesting the functional effect is not joint-wide. Our study highlights interplay between genetic risk, DNA methylation and gene expression in OA, and reveals clear differences between tissues from the same diseased joint.

Discovery and analysis of methylation quantitative trait loci (mQTLs) mapping to novel osteoarthritis genetic risk signals.

OBJECTIVE: Osteoarthritis (OA) is polygenic with over 90 independent genome-wide association loci so far reported. A key next step is the identification of target genes and the molecular mechanisms through which this genetic risk operates. The majority of OA risk-conferring alleles are predicted to act by modulating gene expression. DNA methylation at CpG dinucleotides may be a functional conduit through which this occurs and is detectable by mapping methylation quantitative trait loci, or mQTLs. This approach can therefore provide functional insight into OA risk and will prioritize genes for subsequent investigation. That was our goal, with a focus on the largest set of OA loci yet to be reported. METHOD: We investigated DNA methylation, genotype and RNA sequencing data derived from the cartilage of patients who had undergone arthroplasty and combined this with in silico analyses of expression quantitative trait loci, epigenomes and chromatin interactions. RESULTS: We investigated 42 OA risk loci and in ten of these we identified 24 CpGs in which methylation correlated with genotype (false discovery rate (FDR) P-values ranging from 0.049 to 1.73x10-25). In silico analyses of these mQTLs prioritised genes and regulatory elements at the majority of the ten loci, with COLGALT2 (encoding a collagen galactosyltransferase), COL11A2 (encoding a polypeptide chain of type XI collagen) and WWP2 (encoding a ubiquitin ligase active during chondrogenesis) emerging as particularly compelling target genes. CONCLUSION: We have highlighted the pivotal role of DNA methylation as a link between genetic risk and OA and prioritized genes for further investigation.

Nicotine dependence and sleep quality in young adults.

INTRODUCTION: More cigarette smokers report poor sleep quality than non-smokers, but the association between nicotine dependence (ND) and sleep quality has not been well-characterized. The objective of this study was to describe the associations among frequency and intensity of cigarette smoking, ND symptoms, and sleep quality in young adults. METHODS: Data on past-year smoking frequency, number of cigarettes smoked in the past month, five ND indicators (i.e., withdrawal, craving, self-medication symptoms, mFTQ, ICD-10 criteria for tobacco dependence), and sleep quality (measured with the Pittsburgh Sleep Quality Index (PSQI)) were collected in 2011-12 in self-report questionnaires completed by 405 young adult smokers (mean age 24 (0.6) years; 45% male; 45% daily smokers) participating in a longitudinal investigation of the natural course of ND. Associations between indicators of cigarette smoking, ND symptoms, and sleep quality were examined in multivariable logistic regression analyses controlling for age, sex, mother's education, and alcohol use. RESULTS: Thirty-six percent of participants reported poor sleep quality (PSQI>5). Higher cigarette consumption (OR(95% CI), 1.03(1.001-1.05)) but not frequency of past-year smoking, more frequent withdrawal symptoms (1.05(1.004-1.10)), more frequent cravings (1.05(1.004-1.10)), higher mFTQ scores (1.14(1.02-1.27)), and endorsing more ICD-10 criteria for tobacco dependence (1.19(1.04-1.36)) were also associated with poor sleep quality. CONCLUSION: Cigarette smoking and ND symptoms are associated with poor sleep quality in young adult smokers. Advice from practitioners to cut back on number of cigarettes smoked per day and treatment of ND symptoms may improve sleep quality in young adult smokers.

Age-related changes in mesenchymal stem cells identified using a multi-omics approach.

Mesenchymal stem cells (MSC) are capable of multipotent differentiation into connective tissues and as such are an attractive source for autologous cell-based treatments for many clinical diseases and injuries. Ageing is associated with various altered cellular phenotypes coupled with a variety of transcriptional, epigenetic and translational changes. Furthermore, the regeneration potential of MSCs is reduced with increasing age and is correlated with changes in cellular functions. This study used a systems biology approach to investigate the transcriptomic (RNASeq), epigenetic (miRNASeq and DNA methylation) and protein alterations in ageing MSCs in order to understand the age-related functional and biological variations, which may affect their applications to regenerative medicine. We identified no change in expression of the cellular senescence markers. Alterations were evident at both the transcriptional and post-transcriptional level in a number of transcription factors. There was enrichment in genes involved in developmental disorders at mRNA and differential methylated loci (DML) level. Alterations in energy metabolism were apparent at the DML and protein level. The microRNA miR-199b-5p, whose expression was reduced in old MSCs, had predicted gene targets involved in energy metabolism and cell survival. Additionally, enrichment of DML and proteins in cell survival was evident. Enrichment in metabolic processes was revealed at the protein level and in genes identified as undergoing alternate splicing. Overall, an altered phenotype in MSC ageing at a number of levels implicated roles for inflamm-ageing and mitochondrial ageing. Identified changes represent novel insights into the ageing process, with implications for stem cell therapies in older patients.

The role of inflammation-related genes in osteoarthritis.

In this review article we examine the role of inflammation-related genes in osteoarthritis (OA) from the perspective of genetics, epigenetics and gene expression. There have been great strides in such genomic analyses of OA in recent years thanks to the study of adequately powered patient cohorts, the detailed analysis of candidate genes, and the application of genome-wide approaches. These have led to some unexpected and therefore exciting discoveries, implicating pathways that would not necessarily have been predicted to have a role in this common arthritis. Inflammatory-related genes sit firmly in the candidate camp based on prior observations that the OA disease process can have an inflammatory component. What is clear from the genetic studies published to date is that there is no compelling evidence that DNA variation in inflammatory genes is an OA risk factor. This conclusion may of course change as ever more powerful association studies are conducted. There is, however, compelling evidence that epigenetic effects involving inflammatory genes are a component of OA and that alteration in the expression of these genes is also highly relevant to the disease process. We may in fact be close to demonstrating, at the genomic level, a clear separation of OA patients into those in whom inflammation is a key driver of the disease and those in whom it is not. This has obvious implications for the design of trials of novel OA interventions and may also guide the intelligent re-purposing of anti-inflammatory therapies.

Night-eating symptoms and 2-year weight change in parents enrolled in the QUALITY cohort.

BACKGROUND/OBJECTIVE: The timing of food intake may be implicated in weight gain. This study tested the hypothesis that symptoms commonly associated with night-eating syndrome are related to measures of weight gain in adults. SUBJECTS/METHODS: Parents participating in QUALITY (Québec Adipose and Lifestyle InvesTigation in Youth) completed the night eating questionnaire (NEQ) at baseline (2005-2008) and at follow-up (2008-2010). Height and weight were measured and self-report questionnaire data were available for 388 parents (59% female, mean (s.d.) age: 41.8±5.7, mean (s.d.) body mass index (BMI): 29.6±5.7). Linear regression models were used to test the associations between baseline night-eating symptoms (NEQ scores, night-eating behaviours) and percent change in each of BMI and waist circumference (WC). RESULTS: A high NEQ score predicted a small increase in percent change in BMI in nonobese parents but a decrease among those who were severely obese. Nocturnal ingestions of food predicted an increase in percent change in BMI; however, the effect size was small. Morning anorexia predicted an increase in percent change in WC. CONCLUSION: Certain night-eating symptoms may predict measures of weight gain in adults but the effects seem small and the findings need to be confirmed in more symptomatic samples.

Chronicling changes to the chronic disease prevention landscape in Canada's public health system 2004-2010.

The collective impact of major shifts in public health infrastructure and numerous new chronic disease prevention (CDP) capacity-building initiatives that have taken place in Canada over the last decade is unknown. The objective of this study was to determine if CDP capacity (i.e., skills and resources) and involvement in CDP programming improved in public health organizations in Canada from 2004 to 2010. Data for this repeated cross-sectional study were drawn from two waves of a national census of organizations mandated to carry out primary prevention of chronic disease and/or promotion of healthy eating, physical activity and tobacco control. Medians for continuous variables and frequencies for categorical variables were compared across time. Neither resources nor level of priority for CDP increased over time. There was little difference in the proportion of organizations with high levels of skills and involvement in core CDP practices (i.e., needs assessment, identification of relevant practices, planning, evaluation). Skills and involvement in CDP risk factor programming showed some gains, some steady states and some losses. Specifically, skill and involvement in tobacco control programming declined markedly while the proportion of organizations involved in healthy eating and physical activity programming increased. Skills to address and involvement in programming related to social determinants of health remained low over time as did involvement in programming addressing multiple risk factors concurrently. The lack of marked improvement in CDP capacity between 2004 and 2010 against a backdrop of initiatives favourable to strengthening the preventive health system in Canada suggests that efforts may have fallen short.

Identification and analysis of a SMAD3 cis-acting eQTL operating in primary osteoarthritis and in the aneurysms and osteoarthritis syndrome.

OBJECTIVE: The TGF-ß pathway plays a central role in joint development with polymorphism in TGF-ß pathway genes implicated in osteoarthritis susceptibility. One association is to rs12901499, within intron 1 of SMAD3. Since rs12901499 is not in linkage disequilibrium with a non-synonymous polymorphism, it is likely the association is operating by influencing expression of SMAD3. DESIGN: Using tissues from the joints of primary osteoarthritis patients who had undergone joint replacement we measured the overall expression of SMAD3 by quantitative real-time PCR. We also measured allelic expression of SMAD3 using these tissues and vascular smooth muscle cells from patients with aneurysms and osteoarthritis syndrome, a rare condition featuring early-onset osteoarthritis. We tested the functional effect of SNPs in vitro using luciferase assays and assessed association with osteoarthritis using a large osteoarthritis case-control dataset. RESULTS: We observed that genotype at rs12901499 did not correlate with overall SMAD3 expression or allelic expression. However, genotype at a 3'UTR SNP, rs8031440, did correlate with SMAD3 expression in cartilage (P = 0.005) which was supported by allelic expression data showing that the G allele correlated with decreased SMAD3 expression in joint tissues and vascular smooth muscle cells. This G allele was underrepresented in osteoarthritis cases vs controls (P = 0.027, odds ratio = 0.921). rs8031440 is in perfect linkage disequilibrium with five other SMAD3 3'UTR SNPs and our luciferase analysis identified rs3743342 and rs12595334 as being functional. CONCLUSION: SMAD3 is subject to cis-acting regulatory polymorphism in the tissues of relevance to both primary osteoarthritis and the aneurysms-osteoarthritis syndrome.

Adiposity and glucose intolerance exacerbate components of metabolic syndrome in children consuming sugar-sweetened beverages: QUALITY cohort study.

BACKGROUND: Sugar-sweetened beverage (SSB) consumption is linked to weight gain and metabolic syndrome (MetS) components in children, but whether these associations are modified by excess weight and glucose tolerance status in children is not known. OBJECTIVE: The objective of this study was to examine the cross-sectional associations between SSB intake and MetS components among children above and below the 85th body mass index (BMI) percentile and those with and without impaired glucose tolerance (IGT). METHODS: Data were from the QUébec Adiposity and Lifestyle InvesTigation in Youth study (2005-2008). Caucasian children aged 8-10 years (n = 632) were recruited from 1040 primary schools in Québec, Canada. SSB consumption was assessed by three 24-h dietary recalls, body fat mass by dual-energy absorptiometry, physical activity by 7-d accelerometer. Multivariate linear regressions were used, with age, sex, fat mass index and physical activity as covariates, including waist circumference (WC), systolic blood pressure (SBP), concentrations of triglyceride and high-density lipoprotein cholesterol and homeostasis model assessment of insulin resistance (HOMA-IR) as outcome variables. RESULTS: Among overweight children, a 100-mL higher SSB consumption was associated with a 0.1-unit higher HOMA-IR (P = 0.009) and a 1.1-mm Hg higher SBP (P = 0.001). In children with IGT, a 100-mL higher SSB consumption was associated with a 1.4-mm Hg higher SBP and a 4.0-cm higher WC (P < 0.001). These associations were not observed among children <85th BMI percentile. CONCLUSIONS: Our results suggest that the association between higher SSB consumption and MetS components is more evident in overweight/obese and glucose-intolerant children.

Identification of the pathogenic pathways in osteoarthritic hip cartilage: commonality and discord between hip and knee OA.

OBJECTIVE: To define for the first time the transcriptomes of normal and end-stage osteoarthritis (OA) hip cartilage. MATERIALS AND METHODS: RNA was isolated from cartilage within 2h of joint replacement surgery. Gene expression was analyzed using Agilent GeneSpring GX 11 following hybridization to Illumina Human HT-12 V3 microarrays. Real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to validate the expression of six genes identified by microarray as differentially expressed. Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) were used to investigate enriched functions or canonical pathways amongst differentially expressed genes respectively. RESULTS: In total we identified 998 differentially expressed genes (fold change ≥ ±1.5, P-value ≤ 0.01) between neck of femur fracture (NOF) (n = 10) and OA hip (n = 9) patient cartilage. These differentially expressed genes were enriched within 71 canonical pathways. A comparison between a comparable knee dataset(20) only identified 229 genes similarly differentially expressed although remarkably 34 canonical pathways overlapped between experiments. CONCLUSIONS: This study is the first to report a comprehensive gene expression analysis of human hip OA cartilage compared to control (NOF) cartilage at the whole-genome level. Our differential gene expression dataset shows excellent correlation with similar defined studies using comparable tissue but reveals discord between hip and knee OA at the individual gene status but with commonality with regards the molecular pathways involved.

Gene expression analysis reveals HBP1 as a key target for the osteoarthritis susceptibility locus that maps to chromosome 7q22.

OBJECTIVES: An osteoarthritis (OA) susceptibility locus has been mapped to chromosome 7q22, to a region of high-linkage disequilibrium encompassing six genes: PRKAR2B, HBP1, COG5, GPR22, DUS4L and BCAP29. The authors assessed whether these genes were subject to cis-acting regulatory polymorphisms that are active in joint tissues and which could contribute to the association signal. METHODS: Using joint tissues from 156 patients with OA, and control cartilage from 25 patients who had neck of the femur fractures, the authors measured the overall gene expression by quantitative PCR and the allelic expression of the genes, using an assay that can distinguish mRNA output from each allele of a transcript single nucleotide polymorphism. RESULTS: Five of the genes were expressed in joint tissues, the exception being GPR22, which the authors could not detect. In OA cartilage compared with control cartilage, significantly reduced expression levels were observed for these five genes. Carriers of the OA-associated alleles showed a significant reduction in expression of HBP1 in cartilage (p=0.0002) and synovium (p=0.02), and of DUS4L in fat pad (p=0.04). HBP1 and DUS4L also demonstrated allelic expression imbalance across a range of different joint tissues, with carriers of the associated allele showing an HBP1 allelic expression imbalance profile that was significantly different from non-carriers (p=0.008). CONCLUSION: Cis-acting regulatory polymorphisms acting on HBP1 contribute to the OA association signal at chromosome 7q22. HBP1 codes for a transcription factor and studies by the authors have enabled them to prioritise this gene for further investigation.

Physical activity fluctuations and body fat during adolescence.

OBJECTIVE: The objective of the study was to test the hypothesis that greater fluctuations in physical activity lead to greater increases in body fat during adolescence. METHODS: Seven hundred fifty-six adolescents in Montreal, Canada, aged 12-13 years at baseline, completed a 7-d physical activity recall questionnaire every 3 months over 5 years. Body mass index (BMI), waist circumference, and triceps and subscapular skinfold thickness were measured at baseline and at the end of follow-up. Subject-specific linear regressions, expressing physical activity as a function of time, were fitted and physical activity fluctuation scores were obtained by averaging the absolute values of regression residuals. The association between body fat after 5 years and the physical activity fluctuation score was assessed in linear regressions adjusting for baseline body fat, average number of physical activity sessions per week, diet and sociodemographic variables. RESULTS: Among boys, there were statistically significant positive associations between physical activity fluctuation and BMI (ß, 95% confidence interval: 0.12, 0.02-0.21) and triceps skinfold (0.40, 0.17-0.63). The associations with waist circumference or subscapular skinfold were not statistically significant (0.22, -0.04-0.49; 0.13, -0.05-0.32, respectively). In girls, there were statistically significant negative associations between physical activity fluctuation and BMI (-0.12, -0.20 to -0.03), waist circumference (-0.54, -0.91 to -0.17), subscapular skinfold (-0.41, -0.56 to -0.26) and triceps skinfold (-0.22, -0.38 to -0.05). CONCLUSION: Physical activity fluctuations appear to affect body fat during adolescence. Sex-specific interventions may be needed given that greater physical activity fluctuations seem unfavourable for boys and beneficial for girls.

Physical activity vs. sedentary time: independent associations with adiposity in children.

OBJECTIVE: To investigate the independent associations between objectively measured levels of movement intensity (i.e., time spent sedentary and at light, moderate and vigorous intensities) and indicators of adiposity in a cohort of Canadian children. METHODS: A cross-sectional study was conducted in 550 Caucasian children aged 8-10 years with at least one obese biological parent. Physical activity and sedentary time (accelerometer over 7 d) and indicators of adiposity (% body fat measured by dual-energy X-ray absorptiometry and waist-to-height ratio) were objectively measured. We examined the associations between levels of movement intensity and adiposity in multi-level linear regression models adjusted for age, sex, sleep duration, energy intake, sexual maturation, parental socioeconomic status and parental body mass index. RESULTS: Objectively measured sedentary time was not associated with adiposity indicators in this cohort (unadjusted and adjusted models). However, moderate-to-vigorous physical activity (MVPA) was inversely associated with % body fat (adj. ß = -0.047; P = 0.02) and waist-to-height ratio (adj. ß = -0.071; P < 0.001), independent of sedentary time and other covariates. Additionally, we observed that children who did not accumulate ≥60 min d(-1) of MVPA were more likely to be overweight or obese compared to those who met the recommendation (odds ratio [OR] 2.22, 95% confidence interval [CI] 1.45-3.38). In contrast, there was no difference in the likelihood of being categorized as overweight or obese between those who met the recommendation of ≤2 h d(-1) of screen time and those who did not meet this recommendation (OR 1.27, 95% CI 0.75-2.01). CONCLUSION: The present study suggests that MVPA is independently associated with adiposity indices in this sample of children while sedentary time is not. Future studies should examine the best approach to increase MVPA in children and youth.

The effect of smoking cessation counselling in pregnant women: a meta-analysis of randomised controlled trials.

BACKGROUND: Pregnant smokers are often prescribed counselling as part of multicomponent cessation interventions. However, the isolated effect of counselling in this population remains unclear, and individual randomised controlled trials (RCTs) are inconclusive. OBJECTIVE: To conduct a meta-analysis of RCTs examining counselling in pregnant smokers. SEARCH STRATEGY: We searched the CDC Tobacco Information and Prevention, Cochrane Library, EMBASE, Medline and PsycINFO databases for RCTs evaluating smoking cessation counselling. SELECTION CRITERIA: We included RCTs conducted in pregnant women in which the effect of counselling could be isolated and those that reported biochemically validated abstinence at 6 or 12 months after the target quit date. DATA COLLECTION AND ANALYSIS: Overall estimates were derived using random effects meta-analysis models. MAIN RESULTS: Our search identified eight RCTs (n = 3290 women), all of which examined abstinence at 6 months. The proportion of women that remained abstinent at the end of follow up was modest, ranging from 4 to 24% among those randomised to counselling and from 2 to 21% among control women. The absolute difference in abstinence reached a maximum of only 4%. Summary estimates are inconclusive because of wide confidence intervals, albeit with little evidence to suggest that counselling is efficacious at promoting abstinence (odds ratio 1.08, 95% confidence interval 0.84-1.40). There was no evidence to suggest that efficacy differed by counselling type. CONCLUSIONS: Available data from RCTs examining the isolated effect of smoking cessation counselling in pregnant women are limited but sufficient to rule out large treatment effects. Future RCTs should examine pharmacological therapies in this population.