Adam J. Streeter

Age Before Stage: Insulin Resistance Rises Before the Onset of Puberty: A 9-year longitudinal study (EarlyBird 26)

OBJECTIVE Insulin resistance (IR) is associated with diabetes. IR is higher during puberty in both sexes, with some studies showing the increase to be independent of changes in adiposity. Few longitudinal studies have reported on children, and it remains unclear when the rise in IR that is often attributed to puberty really begins. We sought to establish from longitudinal data its relationship to pubertal onset, and interactions with age, sex, adiposity, and IGF-1. RESEARCH DESIGN AND METHODS The EarlyBird Diabetes study is a longitudinal prospective cohort study of healthy children aged 5–14 years. Homeostasis model assessment (HOMA-IR), skinfolds (SSF), adiposity (percent fat, measured by dual-energy X-ray absorptiometry), serum leptin, and IGF-1 were measured annually in 235 children (134 boys). Pubertal onset was adduced from Tanner stage (TS) and from the age at which luteinizing hormone (LH) first became serially detectable (≥0.2 international units/L). RESULTS IR rose progressively from age 7 years, 3–4 years before TS2 was reached or LH became detectable. Rising adiposity and IGF-1 together explained 34% of the variance in IR in boys and 35% in girls (both P < 0.001) over the 3 years preceding pubertal onset. The contribution of IGF-1 to IR was greater in boys, despite their comparatively lower IGF-1 levels. CONCLUSIONS IR starts to rise in mid-childhood, some years before puberty. Its emergence relates more to the age of the child than to pubertal onset. More than 60% of the variation in IR prior to puberty was unexplained. The demography of childhood diabetes is changing, and prepubertal IR may be important.

Adiposity, Chronic Inflammation, and the Prepubertal Decline of Sex Hormone Binding Globulin in Children: Evidence for Associations With the Timing of Puberty (Earlybird 58)

BACKGROUND The regulation and role of SHBG in children are poorly defined. Here we investigated whether adiposity-related mechanisms regulate SHBG and whether SHBG levels are associated with the age of puberty. METHODS Longitudinal modelling of annual physiological and endocrine measurements from age 5 to 15 years in a cohort of 347 Plymouth schoolchildren. RESULTS SHBG levels were highest at age 5 years and then declined. Mean (SE) SHBG levels were higher in boys than girls at age 5 years [mean (SE) difference 7.68 (3.80) nmol/L; P = .045] but lower in boys by age 15 years [difference 12.19 (3.4) nmol/L; P < .001]. SHBG correlated inversely with adiposity [body mass index SD score (BMI SDS)], insulin, IGF-I, C-reactive protein (CRP), and leptin and positively with adiponectin but not with dehydroepiandrosterone sulphate, androstenedione, or T. In linear mixed models, five adiposity-related covariates (insulin, leptin, adiponectin, IGF-I, and CRP) all exerted significant main effects on SHBG (boys P = .04 to < .001; girls P = .007 to < .001). However, the further addition of BMI SDS rendered the effects of leptin, insulin, and adiponectin nonsignificant, whereas CRP and IGF-I remained significant. In separate models, the individual effects on SHBG of insulin, leptin, IGF-I, and adiponectin, but not CRP, were displaced by BMI SDS. Finally, in linear regression, BMI SDS little affected R(2) resulting from the five adiposity-related signals. Girls with lower SHBG levels at age 5 years reached Tanner stage 2 earlier, tended to have earlier LH secretion, and earlier age at peak height velocity and menarche. In contrast, boys with lower SHBG levels at age 5 years reached Tanner stage 2 earlier, but there were no relationships between SHBG and earlier onset of LH secretion or age at peak height velocity. CONCLUSIONS Adiposity-related endocrine mechanisms and chronic inflammation were associated with the prepubertal decline of SHBG, and lower SHBG levels anticipated earlier puberty. These findings may be relevant to the occurrence of earlier puberty in recent decades.

Body fat in children does not adversely influence bone development: a 7-year longitudinal study (EarlyBird 18).

Both negative and positive associations have been reported between body fat and bone density. Extra mechanical loading from excess fat may lead to greater bone mass. Excess ectopic fat may lead to bone demineralisation through inflammatory pathways.

Adjusting for unmeasured confounding in non-randomised longitudinal studies: a methodological review

Objectives Motivated by recent calls to use electronic health records for research, we reviewed the application and development of methods for addressing the bias from unmeasured confounding in longitudinal data. Study Design and Setting Methodological review of existing literature. We searched MEDLINE and EMBASE for articles addressing the threat to causal inference from unmeasured confounding in nonrandomized longitudinal health data through quasi-experimental analysis. Results Among the 121 studies included for review, 84 used instrumental variable analysis (IVA), of which 36 used lagged or historical instruments. Difference-in-differences (DiD) and fixed effects (FE) models were found in 29 studies. Five of these combined IVA with DiD or FE to try to mitigate for time-dependent confounding. Other less frequently used methods included prior event rate ratio adjustment, regression discontinuity nested within pre-post studies, propensity score calibration, perturbation analysis, and negative control outcomes. Conclusion Well-established econometric methods such as DiD and IVA are commonly used to address unmeasured confounding in nonrandomized longitudinal studies, but researchers often fail to take full advantage of available longitudinal information. A range of promising new methods have been developed, but further studies are needed to understand their relative performance in different contexts before they can be recommended for widespread use.

Anti-Müllerian hormone in children: a ten-year prospective longitudinal study (EarlyBird 39)

Abstract Background: Anti-Müllerian hormone (AMH) is produced by Sertoli cells of the testes and granulosa cells of the ovary. There are limited prospective longitudinal data assessing AMH concentrations throughout childhood in both sexes. Objective: This study aimed to examine AMH throughout childhood with particular reference to the relationship of AMH to pubertal development in both sexes. Design: This is a prospective longitudinal non-intervention cohort study with annual sampling for participants aged 5–14 years. Setting: Community cohort study. Participants: A total of 307 healthy children (170 boys) recruited at 5 years from randomly selected schools in Plymouth, UK, participated in this study. Data sets are complete in 76% of the children at 14 years of age. Main outcome measure(s): Annual measures of serum AMH, follicle stimulating hormone (FSH) and luteinising hormone (LH), Tanner stage (TS). Results: Boys: AMH was stable from 5 to 7 years, increased slightly from 8 to 10 years, then declined at TS2. This decline was preceded by rising FSH and the appearance of LH. AMH correlated inversely with gonadotrophic hormones during puberty. Girls: AMH increased slightly between 6 and 10 years, peaking during the final prepubertal year before returning to near baseline levels at TS3. Inverse correlations between AMH and FSH were apparent during the prepubertal years. Conclusions: Our longitudinal data clarified the development of individual AMH levels over a 10-year period. We described modest late prepubertal peaks in both boys and girls, and confirmed the pubertal decline in boys. The inverse association of AMH with gonadotrophins in young females supports its role as a marker of ovarian function, while the precise role for AMH in relation to testicular function in young males remains unclear.

Divergence between HbA1c and fasting glucose through childhood: implications for diagnosis of impaired fasting glucose (EarlyBird 52)

An HbA1c threshold of ≥6.5% has recently been adopted for the diagnosis of diabetes in adults, and of ≥5.7% to identify adults at risk. Little, however, is known of HbA1cs behaviour or diagnostic value in youth. Our aim was to describe the course of HbA1c during childhood, and its association with fasting glucose.

Effectiveness of the Healthy Lifestyles Programme (HeLP) to prevent obesity in UK primary-school children: a cluster randomised controlled trial

Summary Background Although childhood overweight and obesity prevalence has increased substantially worldwide in the past three decades, scarce evidence exists for effective preventive strategies. We aimed to establish whether a school-based intervention for children aged 9–10 years would prevent excessive weight gain after 24 months. Methods This pragmatic cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP), a school-based obesity prevention intervention, was done in 32 schools in southwest England. All state-run primary and junior schools in Devon and Plymouth (UK) with enough pupils for at least one year-5 class were eligible. Schools were assigned (1:1) using a computer-generated sequence to either intervention or control, stratified by the number of year-5 classes (one vs more than one) and the proportion of children eligible for free school meals (<19% [the national average] vs ≥19%). HeLP was delivered to year-5 children (ages 9–10 years) over 1 year, and included dynamic and interactive activities such as physical activity workshops, education sessions delivered by teachers with short homework tasks, drama sessions, and setting goals to modify behaviour (with parental support and one-to-one discussions with HeLP coordinators). The primary outcome was change in body-mass index (BMI) standard deviation score (SDS) between baseline and 24 months, analysed in children with BMI data available for both timepoints. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN15811706, and the trial status is complete. Findings Between March 21, 2012, and Sept 30, 2013, 32 eligible schools with 1324 children were recruited, of which 16 schools (676 children) were randomly assigned to the HeLP intervention and 16 schools (648 children) to control. All schools that began the trial completed the intervention, and 1244 children (628 in intervention group and 616 in control group) had BMI data at both baseline and 24 months for the primary outcome analysis. Mean BMI SDS was 0·32 (SD 1·16) at baseline and 0·35 (1·25) at 24 months in the intervention group, and 0·18 (1·14) at baseline and 0·22 (1·22) at 24 months in the control group. With adjustment for school-level clustering, baseline BMI scores, sex, cohort, and number of year-5 classes and socioeconomic status of each school, the mean difference in BMI SDS score (intervention–control) at 24 months was −0·02 (95% CI −0·09 to 0·05), p=0·57. One parent reported an adverse event related to their childs eating and activity behaviours, but agreed for the child to continue trial participation after discussion with the chief investigator. Interpretation Despite a theoretically informed and extensively piloted intervention that achieved high levels of engagement, follow-up, and fidelity of delivery, we found no effect of the intervention on preventing overweight or obesity. Although schools are an ideal setting in which to deliver population-based interventions, school-based interventions might not be sufficiently intense to affect both the school and the family environment, and hence the weight status of children. Future research should focus on more upstream determinants of obesity and use whole-systems approaches. Funding UK National Institute for Health Research, Public Health Research Programme.

Evidence of early beta-cell deficiency among children who show impaired fasting glucose: 10-yr cohort study (EarlyBird 56).

Impaired fasting glucose (IFG) is a predictor of future diabetes and is increasingly common in children, but the extent to which it results from excess insulin demand or failure of supply is unclear. Our aim was to compare the behaviour of insulin sensitivity and beta‐cell function in children who developed IFG with those whose glucose levels remained within the normal range.

Assessment of the transmural unipolar electrogram morphology change radius during contact force-guided pulmonary vein isolation using the VISITAG™ Module and CARTOREPLAY™

Aims To investigate the radius of transmural (TM) ablation effect at the left atrial posterior wall (LAPW) during contact force (CF)-guided pulmonary vein isolation (PVI), using pure R unipolar electrogram (UE) morphology change – a histologically validated marker of radiofrequency (RF)-induced TM atrial ablation. Methods Following PVI in 24 consecutive patients (30W, continuous RF), VISITAG™ Module and CARTOREPLAY™ (Biosense Webster Inc.) RF and UE data at left and right-sided LAPW annotated sites 1 and 2 were analysed. Results Acutely durable PVI without spontaneous / dormant recovery was achieved following 15s and 10-11s RF, at sites 1 and 2, respectively (p<0.0001). At site 1, RS UE morphology was noted pre-ablation, with RF-induced pure R UE morphology change in 47/48 (98%). Left and right-sided second RF site annotation was at 5.8mm and 5.2mm from site 1 respectively (p=0.64), yet immediate pure R UE morphology was noted in 35/48 (73%). For second-annotated sites, 30 demonstrated inter-ablation site transition time ≤17ms; pure R UE morphology was noted at annotation onset in 22/30 (73%), with overall median time to pure R morphology change significantly shorter than at site 1 – 0.0s, versus 4.1s and 5.3s, for left and right-sided first-annotated LAPW sites, respectively (p<0.0001). Conclusion When the first and second-annotated LAPW RF sites were within 7mm, 73% second-annotated sites demonstrated immediate pure R UE morphology change. These analyses support a paradigm of shorter RF duration at immediately adjacent sites during continuous RF application, and may usefully inform the further development of “tailored” approaches towards CF-guided PVI. What’s known? The VISITAG™ Module and CARTOREPLAY™ permit investigations into the tissue effects of RF energy delivery in vivo, via objective annotation methodology and retrospective evaluation of histologically validated unipolar electrogram (UE) criteria for transmural (TM) atrial ablation. Greater RF energy effect is seen at left compared to right-sided first-annotated left atrial posterior wall (LAPW) sites during pulmonary vein isolation (PVI). What’s new? Following ∼15s RF delivery at first-annotated LAPW sites and aiming for ≤6mm inter-ablation site distance during continuous RF delivery, 73% second-annotated sites demonstrated immediate TM UE morphology change. At second-annotated sites, ∼10s RF resulted in acutely durable PVI in all. Greater left-sided RF energy effect was observed, not explained by differences in RF duration, mean CF or catheter position stability. The radius of TM RF effect may be determined at the LAPW following CF and VISITAG™ Module-guided PVI.

Transmural unipolar electrogram morphology is achieved within 7s at the posterior left atrial wall during pulmonary vein isolation: VISITAG™ Module-based lesion assessment during radiofrequency ablation

Aims To assess the occurrence of a histologically validated measure of transmural (TM) atrial ablation – pure R unipolar electrogram (UE) morphology change – at first-ablated left atrial posterior wall (LAPW) sites during contact force (CF)-guided pulmonary vein isolation (PVI). Methods and results Exported VISITAG™ Module and CARTOREPLAY™ (Biosense Webster Inc.) UE morphology data was retrospectively analysed in 23 consecutive patients undergoing PVI under general anaesthesia. PVI without spontaneous / dormant recovery was achieved in all, employing 16.3[3.2] minutes (mean [SD]) of temperature-controlled RF at 30W. All first-ablated LAPW sites demonstrated RS UE morphology pre-ablation, with RF-induced pure R UE morphology change in 98%. Time to pure R UE morphology was significantly shorter at left-sided LAPW sites (4.9[2.1] s versus 6.7[2.5] s; p=0.02), with significantly greater impedance drop (median 13.5Ω versus 9.9Ω; p=0.003). Importantly, neither the first-site RF duration (14.9 versus 15.0s) nor the maximum ablation catheter tip distance moved (during RF) were significantly different, yet the mean CF was significantly higher at right-sided sites (16.5g versus 11.2g; p=0.002). Concurrent impedance and objectively annotated bipolar electrogram (BE) data demonstrated ~6-8Ω impedance drop and ~30% BE decrease at the time of first pure R UE morphology change. Conclusion Using objective ablation site annotation, TM UE morphology change was typically achieved within 7s at the LAPW, with significantly greater ablative effect evident at left-sided sites. The methodology described in this report represents a novel and scientifically more rigorous foundation towards future research into the biological effects of RF ablation in vivo. Condensed abstract Through appropriate use of the VISITAG™ Module and CARTOREPLAY™, unipolar electrogram morphology change indicative of histologically confirmed transmural atrial ablation in animal models, was proven to occur typically within 7s, during first-site contact force-guided ablation at the left atrial posterior wall during pulmonary vein isolation.