Vimentin tunes cell migration on collagen by controlling ß1 integrin activation and clustering.

Vimentin is a structural protein that is required for mesenchymal cell migration and directly interacts with actin, ß1 integrin and paxillin. We examined how these interactions enable vimentin to regulate cell migration on collagen. In fibroblasts, depletion of vimentin increased talin-dependent activation of ß1 integrin by more than 2-fold. Loss of vimentin was associated with reduction of ß1 integrin clustering by 50% and inhibition of paxillin recruitment to focal adhesions by more than 60%, which was restored by vimentin expression. This reduction of paxillin was associated with 65% lower Cdc42 activation, a 60% reduction of cell extension formation and a greater than 35% decrease in cell migration on collagen. The activation of PAK1, a downstream effector of Cdc42, was required for vimentin phosphorylation and filament maturation. We propose that vimentin tunes cell migration through collagen by acting as an adaptor protein for focal adhesion proteins, thereby regulating ß1 integrin activation, resulting in well-organized, mature integrin clusters.This article has an associated First Person interview with the first author of the paper.

Diet quality trajectories and cardiovascular phenotypes/metabolic syndrome risk by 11-12 years.

OBJECTIVE: To investigate associations between early-life diet trajectories and preclinical cardiovascular phenotypes and metabolic risk by age 12 years. METHODS: Participants were 1861 children (51% male) from the Longitudinal Study of Australian Children. At five biennial waves from 2-3 to 10-11 years: Every 2 years from 2006 to 2014, diet quality scores were collected from brief 24-h parent/self-reported dietary recalls and then classified using group-based trajectory modeling as 'never healthy' (7%), 'becoming less healthy' (17%), 'moderately healthy' (21%), and 'always healthy' (56%). At 11-12 years: During children's physical health Child Health CheckPoint (2015-2016), we measured cardiovascular functional (resting heart rate, blood pressure, pulse wave velocity, carotid elasticity/distensibility) and structural (carotid intima-media thickness, retinal microvasculature) phenotypes, and metabolic risk score (composite of body mass index z-score, systolic blood pressure, high-density lipoproteins cholesterol, triglycerides, and glucose). Associations were estimated using linear regression models (n = 1100-1800) adjusted for age, sex, and socioeconomic position. RESULTS: Compared to 'always healthy', the 'never healthy' trajectory had higher resting heart rate (2.6 bpm, 95% CI 0.4, 4.7) and metabolic risk score (0.23, 95% CI 0.01, 0.45), and lower arterial elasticity (-0.3% per 10 mmHg, 95% CI -0.6, -0.1) and distensibility (-1.2%, 95% CI -1.9, -0.5) (all effect sizes 0.3-0.4). Heart rate, distensibility, and diastolic blood pressure were progressively poorer for less healthy diet trajectories (linear trends p ≤ 0.02). Effects for systolic blood pressure, pulse wave velocity, and structural phenotypes were less evident. CONCLUSIONS: Children following the least healthy diet trajectory had poorer functional cardiovascular phenotypes and metabolic syndrome risk, including higher resting heart rate, one of the strongest precursors of all-cause mortality. Structural phenotypes were not associated with diet trajectories, suggesting the window to prevent permanent changes remains open to at least late childhood.

How body composition influences hearing status by mid-childhood and mid-life: The Longitudinal Study of Australian Children.

BACKGROUND: Hearing loss is a disabling condition whose prevalence rises with age. Obesity-a risk factor common to many non-communicable diseases-now appears to be implicated. We aimed to determine: (1) cross-sectional associations of body composition measures with hearing in mid-childhood and mid-life and (2) its longitudinal associations with 10-year body mass index (BMI) trajectories. METHODS: Design & Participants: There were 1481 11-12-year-old children and 1266 mothers in the population-based cross-sectional CheckPoint study nested within the Longitudinal Study of Australian Children (LSAC). Anthropometry (CheckPoint): BMI, fat/fat-free mass indices, waist-to-height ratio; LSAC wave 2-6-biennial measured BMI. Audiometry (CheckPoint): Mean hearing threshold across 1, 2 and 4 kHz; hearing loss (threshold > 15 dB HL, better ear). ANALYSIS: Latent class models identifying BMI trajectories; linear/logistic regression quantifying associations of body composition/trajectories with hearing threshold/loss. RESULTS: Measures of adiposity, but not fat-free mass, were cross-sectionally associated with hearing. Fat mass index predicted the hearing threshold and loss in children (ß 0.6, 95% confidence interval (CI) 0.3-0.8, P < 0.001;, odds ratio (OR) 1.2, 95% CI 1.0-1.4, P = 0.05) and mothers (ß 0.8, 95% CI 0.5-1.2, P < 0.001; OR 1.2, 95% CI 1.1-1.4, P = 0.003). Concurrent obesity (OR 1.5, 95% CI 1.1-2.1, P = 0.02) and waist-to-height ratio (WHtR) ≥ 0.6 (OR 1.6, 95% CI 1.2-2.3, P = 0.01) predicted maternal hearing, with similar but attenuated patterns in children. In longitudinal analyses, mothers', but not children's, BMI trajectories predicted hearing (OR for severely obese 3.0, 95% CI 1.4-6.6, P = 0.01). CONCLUSIONS: Concurrent adiposity and decade-long BMI trajectories showed small, but clear, associations with poor hearing in mid-life women, with emergent patterns by mid-childhood. This suggests that obesity may play a role in the rising global burden of hearing loss. Replication and mechanistic and body compositional studies could elucidate possible causal relationships.

Assessment of Serum microRNA Biomarkers to Predict Reclassification of Prostate Cancer in Patients on Active Surveillance.

PURPOSE: Conventional clinical variables cannot accurately differentiate indolent from aggressive prostate cancer in patients on active surveillance. We investigated promising circulating miRNA biomarkers to predict the reclassification of active surveillance cases. MATERIALS AND METHODS: We collected serum samples from 2 independent active surveillance cohorts of 196 and 133 patients for the training and validation, respectively, of candidate miRNAs. All patients were treatment naïve and diagnosed with Gleason score 6 prostate cancer. Samples were collected prior to potential reclassification. We analyzed 9 circulating miRNAs previously shown to be associated with prostate cancer progression. Logistic regression and ROC analyses were performed to assess the predictive ability of miRNAs and clinical variables. RESULTS: A 3-miR (miRNA-223, miRNA-24 and miRNA-375) score was significant to predict patient reclassification (training OR 2.72, 95% CI 1.50-4.94 and validation OR 3.70, 95% CI 1.29-10.6). It was independent of clinical characteristics in multivariable models. The ROC AUC was maximized when combining the 3-miR score and prostate specific antigen, indicating additive predictive value. The 3-miR score plus the prostate specific antigen panel cutoff achieved 89% to 90% negative predictive value and 66% to 81% specificity. CONCLUSIONS: The 3-miR score combined with prostate specific antigen represents a noninvasive biomarker panel with high negative predictive value. It may be used to identify patients on active surveillance who have truly indolent prostate cancer.

Takeaway food, sugar-sweetened beverages and preclinical cardiometabolic phenotypes in children and adults.

AIMS: To investigate relationships between takeaway food and sugar-sweetened beverage (SSB) consumption with cardiometabolic phenotypes during childhood and mid-adulthood. METHOD: Design: Cross-sectional Child Health CheckPoint within the national population-representative Longitudinal Study of Australian Children. Participants: 1838 children (mean age 11.5 years; 49.1% female) and 1846 adults (mean age 43.7 years; 87.6% female). Exposures: Self-reported takeaway food and SSB consumption ('frequent': ≥ weekly). Outcomes: Functional (pulse wave velocity (PWV), blood pressure (BP)) and structural (carotid intima-media thickness, retinal microvascular calibre) preclinical cardiovascular phenotypes; lipids (total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides). Analysis: Linear regression (exposure: takeaway or SSB consumption, individually or together) adjusted for age, sex and socio-economic position; and mediation analysis for body mass index (BMI). RESULTS: Associations were small among children (standardized mean difference (SMD) ≤0.15). In adults, associations were stronger with functional, but not structural, cardiovascular phenotypes and lipids, particularly for frequent takeaway food consumption (e.g. PWV (0.20 m/s; 95% confidence interval (CI) 0.03 to 0.37); systolic (3.3 mmHg; 95% CI 1.3 to 5.3) and diastolic BP (1.4 mmHg; 95% CI 0.2 to 2.6); LDL (0.10 mmol/L; 95% CI 0.02 to 0.18); HDL (-0.14 mmol/L; 95% CI -0.19 to -0.10) and triglycerides (0.30 mmol/L; 95% CI 0.12 to 0.48)]. BMI mediated associations between takeaway food consumption and PWV, BP, HDL and TG (proportion of mediation 34% to 75%), while mediation effects were smaller for SSB consumption. CONCLUSIONS: Frequent takeaway food consumption in adults was associated with adverse blood lipids and vascular function (mainly via BMI). Lack of strong associations in children highlights opportunities for prevention.

Cooperative roles of PAK1 and filamin A in regulation of vimentin assembly and cell extension formation.

The formation of extensions in cell migration requires tightly coordinated reorganization of all three cytoskeletal polymers but the mechanisms by which intermediate filament networks interact with actin to generate extensions are not well-defined. We examined interactions of the actin binding protein filamin A (FLNA) with vimentin in extension formation by fibroblasts. Knockdown (KD) of vimentin in fibroblasts reduced the lengths of cell extensions by 50% (p < 0.001). After cell binding to fibronectin, there was a time-dependent increase of phosphorylation of serine 39, 56 and 72 in vimentin, which was associated with vimentin filament assembly. Of the FLNA-interacting kinases that could phosphorylate vimentin, we focused on PAK1, which we found by reciprocal immunoprecipitation associated with FLNA. Enzyme inhibitor studies and siRNA KD demonstrated that PAK1 was required for vimentin phosphorylation and formation of cell extensions. In sedimentation assays, vimentin was exclusively detected in the insoluble pellet fraction of cells expressing FLNA while in FLNA KD cells there was increased vimentin in the supernatants of FLN KD cells. Compared with wild type, FLNA KD cells showed loss of phosphorylation of serine 56 and 72 in vimentin and reduced numbers and lengths of cell extensions by >4-fold. We suggest that the association of PAK1 with FLNA enables vimentin phosphorylation and filament assembly, which are important in the development and stabilization of cell extensions during cell migration.

Association of brachial-cuff excess pressure with carotid intima-media thickness in Australian adults: a cross-sectional study.

OBJECTIVE: Reservoir pressure parameters [e.g. reservoir pressure (RP) and excess pressure (XSP)] measured using tonometry predict cardiovascular events beyond conventional risk factors. However, the operator dependency of tonometry impedes widespread use. An operator-independent cuff-based device can reasonably estimate the intra-aortic RP and XSP from brachial volumetric waveforms, but whether these estimates are clinically relevant to preclinical phenotypes of cardiovascular risk has not been investigated. METHODS: The RP and XSP were derived from brachial volumetric waveforms measured using cuff oscillometry (SphygmoCor XCEL) in 1691 mid-life adults from the CheckPoint study (a population-based cross-sectional study nested in the Longitudinal Study of Australian Children). Carotid intima--media thickness (carotid IMT, n = 1447) and carotid--femoral pulse wave velocity (PWV, n = 1632) were measured as preclinical phenotypes of cardiovascular risk. Confounders were conventional risk factors that were correlated with both exposures and outcomes or considered as physiologically important. RESULTS: There was a modest association between XSP and carotid IMT (ß = 0.76 µm, 95% CI, 0.25-1.26 partial R = 0.8%) after adjusting for age, sex, BMI, heart rate, smoking, diabetes, high-density lipoprotein cholesterol and mean arterial pressure. Neither RP nor XSP were associated with PWV in the similarly adjusted models (ß = -0.47 cm/s, 95% CI, -1.15 to 0.20, partial R = 0.2% for RP, and ß = 0.04 cm/s, 95% CI, -0.59 to 0.67, partial R = 0.01% for XSP). CONCLUSION: Cuff-based XSP associates with carotid IMT independent of conventional risk factors, including traditional BP, but the association was weak, indicating that further investigation is warranted to understand the clinical significance of reservoir pressure parameters.

Inflammation and hearing status in mid-childhood and mid-life: a population-based cross-sectional study.

BACKGROUND: Lifelong inflammation - known to be associated with many non-communicable diseases - has not been thoroughly investigated in hearing. We aimed to determine if glycoprotein A (GlycA), a novel biomarker of chronic inflammation, is associated with hearing acuity in mid-childhood and mid-life. METHODS: Population-based cross-sectional study within the Longitudinal Study of Australian Children with plasma GlycA and audiometry data (1169 children and 1316 parents). We calculated high Fletcher Index (mean threshold across 1, 2 and 4 kHz), defining hearing loss as threshold >15 decibel hearing level (dB HL) (better ear). Linear/logistic regression quantified associations of GlycA with hearing threshold/loss. RESULTS: Mean [standard deviation (SD)] high Fletcher Indices (dB HL) were 8.0 (5.7) for children and 13.1 (6.9) for adults, with 8.7% and 26.1% respectively showing hearing loss. 1-SD rise in GlycA (children 0.13 mmol/L, adults 0.17 mmol/L) predicted higher hearing thresholds for the lower individual frequencies [1 kHz: children ß 0.8, 95% confidence interval (CI) 0.3-1.3; adults ß 0.8, 95% CI 0.2-1.4]. This same pattern was evident for the high Fletcher Index (children ß 0.7, 95% CI 0.3-1.1; adults ß 0.8, 95% CI 0.3-1.4). This translated into 1-SD rise in GlycA predicting adult hearing loss [odds ratio (OR) 1.2, 95% CI 1.0-1.5] with similar but attenuated patterns in children. CONCLUSIONS: GlycA is associated with poorer hearing by mid-childhood. This potentially reframes hearing loss as a life-course condition with inflammatory antecedents common to other non-communicable diseases. Replication and mechanistic studies could inform causal inference and early prevention efforts.

Combining urinary DNA methylation and cell-free microRNA biomarkers for improved monitoring of prostate cancer patients on active surveillance.

PURPOSE: Prostate cancer (CaP) patients with low-grade tumors are enrolled in active surveillance (AS) programs and monitored with digital rectal exams (DREs), prostate-specific antigen (PSA) tests, and periodic invasive biopsies. Patients are "reclassified" with higher-risk disease if they show signs of disease progression. However, AS patients who will reclassify cannot be easily identified upfront and suffer morbidities associated with biopsy. Biomarkers derived from noninvasively obtained specimens such as serum or urine samples are promising alternatives to monitor patients with clinically insignificant cancer. Previously, we have characterized and validated a urinary DNA methylation panel and a serum miRNA panel for the prediction of patient reclassification in 2 independent AS cohorts. In this exploratory study, we have investigated cell-free miRNAs in the urinary supernatant combined with urinary DNA methylation markers to form an integrative panel for prediction of AS patient reclassification. METHODS: Post-DRE urine was collected from 103 CaP patients on active surveillance. Urinary sediment DNA methylation levels of selected genes were previously analyzed using qPCR-based MethyLight assay. Using qRT-PCR, we analyzed the urinary supernatants for relative quantities of 10 miRNAs previously shown to be associated with AS reclassification. Logistic regression and Receiver Operating Characteristics curve analyses were performed to assess the predictive ability of miRNAs and DNA methylation biomarkers. RESULTS: We identified a 3-marker panel, consisting of miR-24, miR-30c and CRIP3 methylation, that was significant for prediction of patient reclassification (Odds ratio = 2.166, 95% confidence interval = 1.22-3.847) with a negative predictive value of 90.9%. Our 3-marker panel also demonstrated additive value to PSA for prediction of patient reclassification (c-statistic = 0.717, ROC bootstrapped 1000 iteration P = 0.041). CONCLUSION: A urinary integrated panel of methylation and miRNA markers is a promising approach to identify AS patients at risk for reclassification. Our 3-marker panel, with its high negative predictive value, would be beneficial to identify and preclude AS patients with truly indolent cancer and to personalize monitoring strategies for AS patients.

GBX2 Methylation Is a Novel Prognostic Biomarker and Improves Prediction of Biochemical Recurrence Among Patients with Prostate Cancer Negative for Intraductal Carcinoma and Cribriform Architecture.

BACKGROUND: Tumor intraductal carcinoma/cribriform architecture (IDC/C) is associated with an unfavorable prognosis and biochemical recurrence (BCR) in prostate cancer (PCa). Up to 70% of PCa patients are IDC/C-negative, but it is estimated that 20% of these cases still experience BCR. Thus, biomarkers for better detection of aggressive disease in IDC/C-negative patients are required. OBJECTIVE: To investigate tumor-specific methylation of the transcription factor GBX2 as a novel prognosticator and predictor of BCR in PCa patients stratified by histopathologic features including IDC/C. DESIGN, SETTING, AND PARTICIPANTS: Using genome-wide methylome profiling, we identified higher GBX2 methylation in grade group (GG) 4 tumors compared to GG1 (discovery cohort). The prognostic nature of GBX2 methylation was validated in silico using The Cancer Genome Atlas data (n=478) and a quantitative methylation assay for radical prostatectomy samples (n=254). Regulation of GBX2 methylation was investigated in prostate cells using methyl-CpG-binding domain sequencing and methylation analysis in functional knockouts of TET2, a key epigenetic player in prostate carcinogenesis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of GBX2 methylation with Gleason score (GS), pathologic stage (pT), IDC/C, and BCR was analyzed using Kruskal-Wallis and Mann-Whitney tests. Univariate and multivariate Cox regression analyses were used to predict BCR. RESULTS: GBX2 methylation was associated with GS (p<0.05), pT (p<0.01), and BCR (p<0.05). GBX2 methylation (p=0.004), GS (p<0.001), pT (p=0.012), and prostate-specific antigen (p=0.005) were independent predictors of BCR. Among IDC/C-negative patients, GBX2 methylation improved prediction of BCR (p=0.002). Loss of TET2 in prostate cells resulted in greater GBX2 methylation. CONCLUSIONS: We identified GBX2 methylation as a novel prognostic factor in PCa and an independent predictor of BCR. We demonstrated the additive value of GBX2 methylation in predicting BCR among IDC/C-negative patients and elucidated a novel TET2-mediated upstream epigenetic regulatory mechanism of GBX2. PATIENT SUMMARY: We identified GBX2 methylation as a promising prognostic biomarker that could improve the identification of prostate cancer patients at higher risk of biochemical recurrence.

Cross-sectional associations between Ideal Cardiovascular Health scores and vascular phenotypes in 11- to 12-year-olds and their parents: The Longitudinal Study of Australian Children.

BACKGROUND: Understanding early-life relationships between the Ideal Cardiovascular Health (ICVH) score and vascular phenotypes could inform likely effectiveness and timing of cardiovascular disease prevention strategies. We aimed to describe associations between ICVH scores and vascular phenotypes in 11- to 12-year-old children and their parents. METHODS AND RESULTS: Cross-sectional ICVH scores (range 0-7, higher indicating better health), derived by summing dichotomized metrics for cholesterol, glucose, blood pressure (BP), body mass index (BMI), diet, physical activity and smoking, were constructed for 1235 adults (89% female, mean age 43 years) and 1028 children (48% female, 12 years). The median scores were 4 and 5 for adults and children respectively. Child ICVH scores were associated with parent scores (0.18 higher child score per additional point in parent's score, 95% CI 0.12 to 0.22, P < 0.001). Each additional point in the adult ICVH score was associated with slower carotid-femoral pulse wave velocity (PWV, -0.32 m/s, 95% CI -0.37 to -0.27), greater carotid elasticity (0.017%/mm Hg, 95% CI 0.014 to 0.020) and reduced carotid intima-media thickness (IMT, -7.3 µm, 95% CI -12.0 to -2.5). An additional point in the child score was associated with functional phenotypes (PWV -0.07 m/s, 95% CI -0.11 to -0.03; carotid elasticity 0.009%/mm Hg, 95% CI 0.004 to 0.015) but not structural phenotypes (IMT -1.8 µm, 95% CI -5.2 to 1.5). CONCLUSION: Few Australian children and even fewer parents have ideal cardiovascular health. Lower ICVH scores were associated with adverse adult vascular phenotypes and adverse child vascular function. Family-based interventions optimizing ICVH metrics may delay onset and progression of subclinical atherosclerosis and later cardiovascular disease.

Carotid artery intima-media thickness, distensibility and elasticity: population epidemiology and concordance in Australian children aged 11-12 years old and their parents.

OBJECTIVES: To describe a well-established marker of cardiovascular risk, carotid intima-media thickness (IMT) and related measures (artery distensibility and elasticity) in children aged 11-12 years old and mid-life adults, and examine associations within parent-child dyads. DESIGN: Cross-sectional study (Child Health CheckPoint), nested within a prospective cohort study, the Longitudinal Study of Australian Children (LSAC). SETTING: Assessment centres in seven Australian major cities and eight selected regional towns, February 2015 to March 2016. PARTICIPANTS: Of all participating CheckPoint families (n=1874), 1489 children (50.0% girls) and 1476 parents (86.8% mothers) with carotid IMT data were included. Survey weights and methods were applied to account for LSAC's complex sample design and clustering within postcodes and strata. OUTCOME MEASURES: Ultrasound of the right carotid artery was performed using standardised protocols. Primary outcomes were mean and maximum far-wall carotid IMT, quantified using semiautomated edge detection software. Secondary outcomes were carotid artery distensibility and elasticity. Pearson's correlation coefficients and multivariable linear regression models were used to assess parent-child concordance. Random effects modelling on a subset of ultrasounds (with repeated measurements) was used to assess reliability of the child carotid IMT measure. RESULTS: The average mean and maximum child carotid IMT were 0.50 mm (SD 0.06) and 0.58 mm (SD 0.05), respectively. In adults, average mean and maximum carotid IMT were 0.57 mm (SD 0.07) and 0.66 mm (SD 0.10), respectively. Mother-child correlations for mean and maximum carotid IMT were 0.12 (95% CI 0.05 to 0.23) and 0.10 (95% CI 0.03 to 0.21), respectively. For carotid artery distensibility and elasticity, mother-child correlations were 0.19 (95% CI 0.10 to 0.25) and 0.11 (95% CI 0.02 to 0.18), respectively. There was no strong evidence of father-child correlation in any measure. CONCLUSIONS: We provide Australian values for carotid vascular measures and report a modest mother-child concordance. Both genetic and environmental exposures are likely to contribute to carotid IMT.

Cross-sectional epidemiology of hearing loss in Australian children aged 11-12 years old and 25-year secular trends.

OBJECTIVE: In a national study of Australian children aged 11-12 years old, we examined the (1) prevalence and characteristics of hearing loss, (2) its demographic risk factors and (3) evidence for secular increases since 1990. METHODS: This is a cross-sectional CheckPoint wave within the Longitudinal Study of Australian Children. 1485 children (49.8% retention; 49.7% boys) underwent air-conduction audiometry. Aim 1: hearing loss (≥16 decibels hearing level (dB HL)) was defined in four ways to enable prior/future comparisons: high Fletcher Index (mean of 1, 2 and 4 kHz; primary outcome relevant to speech perception), four-frequency (1, 2, 4 and 8 kHz), lower frequency (1 and 2 kHz) and higher frequency (4 and 8 kHz); aim 2: logistic regression of hearing loss by age, gender and disadvantage index; and aim 3: P for trend examining CheckPoint and reported prevalence in studies arranged by date since 1990. RESULTS: For high Fletcher Index, the prevalence of bilateral and unilateral hearing loss ≥16 dB HL was 9.3% and 13.3%, respectively. Slight losses (16-25 dB HL) were more prevalent than mild or greater (≥26 dB HL) losses (bilateral 8.5% vs 0.8%; unilateral 12.5% vs 0.9%), and lower frequency more prevalent than higher frequency losses (bilateral 11.0% vs 6.9%; unilateral 15.4% vs 11.5%). Demographic characteristics did not convincingly predict hearing loss. Prevalence of bilateral/unilateral lower and higher frequency losses ≥16 dB HL has risen since 1990 (all P for trend <0.001). CONCLUSIONS AND RELEVANCE: Childhood hearing loss is prevalent and has risen since 1990. Future research should investigate the causes, course and impact of these changes.

Socioeconomic status in childhood and C reactive protein in adulthood: a systematic review and meta-analysis.

BACKGROUND: Inflammation plays a central role in cardiometabolic disease and may represent a mechanism linking low socioeconomic status (SES) in early life and adverse cardiometabolic health outcomes in later life. Accumulating evidence suggests an association between childhood SES and adult inflammation, but findings have been inconsistent. METHODS: We conducted a systematic review and meta-analysis of observational studies to quantify the association between childhood (age <18 years) SES and the inflammatory marker C reactive protein (CRP) in adulthood. Studies were identified in Medline and Embase databases, and by reviewing the bibliographies of articles published from 1946 to December 2015. Study-specific estimates were combined into meta-analyses using random-effects models. RESULTS: 15 of 21 eligible studies (n=43 629) were ultimately included in two separate meta-analyses. Compared with those from the most advantaged families, participants from the least advantaged families had 25% higher CRP levels (ratio change in geometric mean CRP: 1.25; 95% CI 1.19 to 1.32) in minimally adjusted analyses. This finding was attenuated by the inclusion of adult body mass index (BMI) in adjusted models, suggesting BMI has a strong mediating role in CRP levels. CONCLUSIONS: We observed an inverse association between childhood SES and adulthood CRP, potentially mediated through BMI. Investigating how childhood SES is associated with childhood BMI and CRP would provide insight into the effective timing of social and clinical interventions to prevent cardiometabolic disease.

Socioeconomic Position Is Associated With Carotid Intima-Media Thickness in Mid-Childhood: The Longitudinal Study of Australian Children.

BACKGROUND: Lower socioeconomic position (SEP) predicts higher cardiovascular risk in adults. Few studies differentiate between neighborhood and family SEP or have repeated measures through childhood, which would inform understanding of potential mechanisms and the timing of interventions. We investigated whether neighborhood and family SEP, measured biennially from ages 0 to 1 year onward, was associated with carotid intima-media thickness (IMT) at ages 11 to 12 years. METHODS AND RESULTS: Data were obtained from 1477 families participating in the Child Health CheckPoint study, nested within the Longitudinal Study of Australian Children. Disadvantaged family and neighborhood SEP was cross-sectionally associated with thicker maximum carotid IMT in separate univariable linear regression models. Associations with family SEP were not attenuated in multivariable analyses, and associations with neighborhood SEP were attenuated only in models adjusted for family SEP. The difference in maximum carotid IMT between the highest and lowest family SEP quartile measured at ages 10 to 11 years was 10.7 µm (95% CI, 3.4-18.0; P=0.004), adjusted for age, sex, pubertal status, passive smoking exposure, body mass index, blood pressure, and arterial lumen diameter. In longitudinal analyses, family SEP measured as early as age 2 to 3 years was associated with maximum carotid IMT at ages 11 to 12 years (difference between highest and lowest quartile: 8.5 µm; 95% CI, 1.3-15.8; P=0.02). No associations were observed between SEP and mean carotid IMT. CONCLUSIONS: We report a robust association between lower SEP in early childhood and carotid IMT in mid-childhood. Further investigation of mechanisms may inform pediatric cardiovascular risk assessment and prevention strategies.

Childhood Infections, Socioeconomic Status, and Adult Cardiometabolic Risk.

BACKGROUND AND OBJECTIVES: Socioeconomic disadvantage throughout the life course is associated with increased risk of cardiometabolic diseases, but traditional risk factors do not fully account for the social gradient. We investigated the interactions between low socioeconomic status (SES) and infection in childhood and adverse cardiometabolic parameters in adulthood. METHODS: Participants from the Cardiovascular Risk in Young Finns Study, a cohort well phenotyped for childhood and adulthood cardiometabolic risk factors and socioeconomic parameters, were linked to lifetime hospitalization data from birth onward available from the Finnish National Hospital Registry. In those with complete data, we investigated relationships between infection-related hospitalization in childhood, SES, and childhood and adult cardiometabolic parameters. RESULTS: The study cohort consisted of 1015 participants (age range 3-18 years at baseline and 30-45 years at follow-up). In adults who were raised in below-median income families, childhood infection-related hospitalizations (at age 0-5 years) were significantly associated with higher adult BMI (ß ± SE comparing those with 0 vs ≥1 hospitalizations 2.4 ± 0.8 kg/m(2), P = .008), waist circumference (7.4 ± 2.3 cm, P = .004), and reduced brachial flow-mediated dilatation (-2.7 ± 0.9%, P = .002). No equivalent associations were observed in participants from higher-SES families. CONCLUSIONS: Infection was associated with worse cardiovascular risk factor profiles only in those from lower-SES families. Childhood infection may contribute to social gradients observed in adult cardiometabolic disease risk factors. These findings suggest reducing childhood infections, especially in socioeconomic disadvantaged children, may reduce the cardiometabolic disease burden in adults.

Whole-genome sequencing of quartet families with autism spectrum disorder.

Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics.