Influence of Participant Perceptions of Adherence-Related Interactions with Study/Study Team on Drug Levels: HPTN069 Analysis of Self-Reported Adherence Experiences While on Study.

Adherence to HIV pre-exposure prophylaxis (PrEP) study drug is critical for safety, tolerability, and efficacy trials, and may be affected by how adherence is communicated by the study staff to trial participants. Increasingly, clinical trials investigating PrEP are creating and implementing 'participant-centered' approaches that discuss potential non-adherence neutrally (without negative judgement) and support efforts to adhere versus insisting on perfect adherence. In the HPTN069/ACTG A5305 study, we evaluated participant experiences of potentially negative adherence-related interactions with study teams using ten items to characterize the frequency of such experiences. We related these individual items and a combined set of seven negative experience items (total negative experience score) to drug concentrations (detectable or consistent with daily-dosing). The exploratory analyses used logistic regression for each experience item on the full sample and disaggregated by sex. Several experiences were related to drug detection and to daily-dosing, although more so for participants identifying as men than women. Total negative experience scores associated with not having detection drug concentrations for the full sample, and remained significant even when controlling for sex, age, and race. Daily dosing was associated with total negative experience score for men in the sample. Additional investigations into adherence-related interactions with study teams that are most problematic or helpful in general and uniquely for men and women are warranted.

Evidence for energy conservation during pubertal growth. A 10-year longitudinal study (EarlyBird 71).

BACKGROUND: Diabetes is closely linked to obesity, and obesity rates climb during adolescence for reasons that are not clear. Energy efficiency is important to obesity, and we describe a temporary but substantial fall in absolute energy expenditure, compatible with improved energy efficiency, during the rapid growth phase of puberty. METHODS: In a longitudinal cohort study lasting 10 years, we measured voluntary energy expenditure as physical activity (PA) by accelerometry, involuntary energy expenditure as resting energy expenditure (REE) by oxygen consumption, body mass index (BMI) and body composition by dual energy X-ray absorptiometry annually on 10 occasions from 7 to 16 years in the 347 children of the EarlyBird study. We used mixed effects modelling to analyse the trends in REE and their relationship to BMI, lean mass (LM), fat mass (FM), age, PA and pubertal stage. RESULTS: Relative REE and total PA fell during puberty, as previously described, but the longitudinal data and narrow age-range of the cohort (s.d.±4m) revealed for the first time a substantial fall in absolute REE during the period of maximum growth. The fall became clearer still when adjusted for FM and LM. The fall could not be explained by fasting insulin, adiponectin, leptin, luteinising hormone or follicle stimulating hormone. CONCLUSIONS: There appears to be a temporary but substantial reduction in energy expenditure during puberty, which is unrelated to changes in body composition. If it means higher energy efficiency, the fall in REE could be advantageous in an evolutionary context to delivering the extra energy needed for pubertal growth, but unfavourable to weight gain in a contemporary environment.

Childhood obesity: evidence for distinct early and late environmental determinants a 12-year longitudinal cohort study (EarlyBird 62).

BACKGROUND/OBJECTIVE: The prevalence of childhood obesity continues to rise in most countries, but the exposures responsible remain unclear. The shape of the body mass index (BMI) distribution curve defines how a population responds, and can be described by its three parameters-skew (L), median (M) and variance (S). We used LMS analysis to explore differences in the BMI trajectories of contemporary UK children with those of 25 years ago, and to draw inferences on the exposures responsible. SUBJECTS/METHODS: We applied Cole's LMS method to compare the BMI trajectories of 307 UK children (EarlyBird cohort) measured annually from 5-16 years (2000-2012) with those of the BMI data set used to construct the UK 1990 growth centiles, and used group-based trajectory modelling (GBTM) to establish whether categorical trajectories emerged. RESULTS: Gender-specific birth weights were normally distributed and similar between both data sets. The skew and variance established by 5 years in the 1990 children remained stable during the remainder of their childhood, but the pattern was different for children 25 years on. The skew at 5 years among the EarlyBird children was greatly exaggerated, and involved selectively the offspring of obese parents, but returned to 1990 levels by puberty. As the skew diminished, so the variance in BMI rose sharply. The median BMI of the EarlyBird children differed little from that of 1990 before puberty, but diverged from it as the variance rose. GBTM uncovered four groups with distinct trajectories, which were related to parental obesity. CONCLUSIONS: There appear to be two distinct environmental interactions with body mass among contemporary children, the one operating selectively according to parental BMI during early childhood, the second more generally in puberty.

Awareness of body weight by mothers and their children: repeated measures in a single cohort (EarlyBird 64).

BACKGROUND: Mothers often do not realize when their child is overweight. We aimed to compare mothers' perceptions of children's weight before and during puberty, and to explore factors at 7 years predicting recognition of overweight at 16 years. METHODS: Mothers of 237 children (136 boys) from the EarlyBird study estimated their own weight category and that of their child aged 7 years and 16 years. The children estimated their own weight category at 16 years. Annual measures: body mass index standard deviation score (BMIsds), per cent fat, physical activity. Pubertal development assessed by age at peak height velocity (APHV). MATERNAL MEASURES: BMI, education, socio-economic status. RESULTS: At 7 years 21% of girls and 16% of boys were overweight or obese, rising to 27% and 22% respectively at 16 years. The accuracy of the mother's perception of her child's weight category improved from 44% at 7 years to 74% at 16 years, but they were less able to judge overweight in sons than daughters. The mothers' level of concern about overweight was greater for girls than boys, and increased for girls (52% mothers of overweight/obese girls were worried at 7 years, 62% at 16 years), but remained static in the boys (42% vs. 39%). Over 80% of the youngsters realized when they were overweight, but 25% normal-weight girls also classed themselves as overweight. Only BMI predicted a mother's ability to correctly perceive her child's weight. Neither her awareness, nor concern, about the child's weight at 7 years had any impact on the trajectory of the child's BMI from 7 years to 16 years. CONCLUSIONS: Parents are central to any successful weight reduction programme in their children, but will not engage while they remain ignorant of the problem. Crucially, any concern mothers may have about their child's excess weight at 7 years appears to have no impact on subsequent weight change.

The convergence of type 1 and type 2 diabetes in childhood: the accelerator hypothesis.

It seems likely that type 1 and type 2 diabetes lie at different points of the same spectrum, separated by the misunderstanding that one belongs to childhood and the other to adulthood. The spectrum is that of tempo--the rate at which beta cell function is lost over time. A combination of beta cell up-regulation (insulin demand, largely determined by obesity) and the genetically-determined immune response to it ('autoimmunity') determines tempo, ranging from slow to fast with every variant in between. There is good evidence that people who go on to develop type 1 (fast) diabetes are, like those who develop type 2 (slow diabetes), insulin resistant, and overwhelming evidence that body mass plays a key role. The prevention of type 1 diabetes may lie in weight restriction from an early age.

Can we modulate physical activity in children? No.

Intuition tells us that physical activity is central to weight reduction in obese children. Evidence, on the other hand, suggests that increases in physical activity are difficult to achieve in the short term, and may not be possible in the long term. One explanation could be an 'activitystat', a feedback loop in the child's brain that controls physical activity according to a set point. This brief article, which argues that it may not be possible to modulate the activity of children, reviews the principles of feedback control as they apply to physical activity, discusses evidence for its central control, and demonstrates how a physical activity control loop might operate to defend the set point. Studies restricted to objective measurement suggest that the physical activity of children varies in a systematic, rather than random manner. It varies little from environment to environment, from year to year or from place to place. Where children undertake more activity at one time of day, they appear to compensate at another. Systematic variation of this kind implies control, and the control of physical activity appears to lie with the child, not with his environment. Perturbation (temporary change in response to disturbance) during short-term physical activity interventions may be mistaken for modulation (permanent change in set point), a fundamentally different response. Perturbation lasts no longer than the disturbance that causes it, and there is little evidence that interventions raise activity long term, if at all.

BMI was right all along: taller children really are fatter (implications of making childhood BMI independent of height) EarlyBird 48.

OBJECTIVE: Several studies suggest that taller children may be wrongly labelled as 'overweight' because body mass index (BMI) is not independent of height (Ht) in childhood, and recommend adjustment to render the index Ht independent. We used objective measures of %body fat and hormonal/metabolic markers of fatness to investigate whether BMI and the corresponding fat mass index (FMI) mislead in childhood, or whether taller children really are fatter. DESIGN: Longitudinal observational study measuring children annually from age 7 to 12 years. SUBJECTS: Two hundred and eighty healthy children (56% boys) from the EarlyBird study. MEASUREMENTS: BMI (body mass (BM)/Ht(2)), FMI (fat mass (FM)/Ht(2)), %body fat ((FM/BM) × 100, where FM was measured by dual-energy X-ray absorptiometry), fasting leptin (a hormonal measure of body fatness) and insulin resistance (a metabolic marker derived from the validated homeostasis model assessment program for insulin resistance--HOMA2-IR) were all analysed in relation to Ht. Alternative Ht-independent indices of BM and FM were compared with BMI and FMI as indicators of true fatness and related health risk. RESULTS: BMI and FMI correlated with Ht at each annual time point (r~0.47 and 0.46, respectively), yet these correlations were similar in strength to those between Ht and %fat (r~0.47), leptin (r~0.41) and insulin resistance (r~0.40). Also, children who grew the most between 7 and 12 years showed greater increases in BMI, FMI, leptin and insulin resistance (tertile 1 vs 3, all p<0.05). BMI and FMI explained ~20% more of the variation in %fat, ~15% more in leptin and ~10% more in insulin resistance than the respective Ht-independent reformulations (BM/Ht(3.5) and FM/Ht(7), both p<0.001). CONCLUSION: Taller children really are fatter than their shorter peers, have higher leptin levels and are more insulin resistant. Attempts to render indices of BM or FM independent of Ht in children seem inappropriate if the object of the index is to convey health risk.

The impact of school-time activity on total physical activity: the activitystat hypothesis (EarlyBird 46).

OBJECTIVES: To explore the activitystat hypothesis in primary school children by asking whether more physical activity (PA) in school time is compensated for by less PA at other times. STUDY DESIGN: Observational, repeated measures (four consecutive occasions over a 12-month period). SETTING: South-west England. PARTICIPANTS: A total of 206 children (115 boys, aged 8-10 years) from 3 primary schools (S1, S2 and S3), which recorded large differences in PA during school time. MEASUREMENTS: Total PA (TPA) and its moderate-and-vigorous component were recorded weekly by accelerometry, in school and out of school, and adjusted for local daily rainfall and daylight hours. Habitual PA was assessed by linear mixed-effects modelling on repeated measures. RESULTS: S1 children recorded 64% more in-school PA, but S2 and S3 children compensated with correspondingly more out-of-school PA, so that TPA between the three schools was no different: 35.6 (34.3-36.9), 37.3 (36.0-38.6) and 36.2 (34.9-37.5) Units, respectively (P=0.38). CONCLUSIONS: The PA of children seems to compensate in such a way that more activity at one time is met with less activity at another. The failure of PA programmes to reduce childhood obesity could be attributable to this compensation.

Fecundity selection on ornamental plumage colour differs between ages and sexes and varies over small spatial scales.

Avian plumage colours are some of the most conspicuous sexual ornaments, and yet standardized selection gradients for plumage colour have rarely been quantified. We examined patterns of fecundity selection on plumage colour in blue tits (Cyanistes caeruleus L.). When not accounting for environmental heterogeneity, we detected relatively few cases of selection. We found significant disruptive selection on adult male crown colour and yearling female chest colour and marginally nonsignificant positive linear selection on adult female crown colour. We discovered no new significant selection gradients with canonical rotation of the matrix of nonlinear selection. Next, using a long-term data set, we identified territory-level environmental variables that predicted fecundity to determine whether these variables influenced patterns of plumage selection. The first of these variables, the density of oaks within 50 m of the nest, influenced selection gradients only for yearling males. The second variable, an inverse function of nesting density, interacted with a subset of plumage selection gradients for yearling males and adult females, although the strength and direction of selection did not vary predictably with population density across these analyses. Overall, fecundity selection on plumage colour in blue tits appeared rare and inconsistent among sexes and age classes.

Reliability of energy expenditure prediction equations in the weight management clinic.

BACKGROUND: Few weight management clinics have access to indirect calorimetry with which to measure energy expenditure. Instead, they use energy expenditure prediction equations, which were not designed for use in obesity. We aimed to establish the extent to which such equations overestimate and underestimate resting energy expenditure (REE) in overweight and obese individuals. METHODS: We compared the Schofield, Harris & Benedict, James & Lean and World Health Organisation (WHO) REE prediction equations with the clinical gold standard of indirect calorimetry in 28 males and 168 females, with a mean (SD) age of 28.9 (6.4) years and body mass index (BMI) of 19-67 kg m(-2). RESULTS: The mean REE estimated by indirect calorimetry, and the Schofield, Harris & Benedict, James & Lean and WHO equations were 8.09, 8.30, 8.09, 8.37 and 8.23 MJ day(-1) (1934, 1983, 1933, 2001 and 1966 kcal day(-1)), respectively. Although rising BMI exerted only a small effect on the mean differences between indirect calorimetry and the predicted REE [Schofield: +272 kJ (+65 kcal)/10 units BMI, P = 0.02; Harris & Benedict: +42 kJ (+10 kcal)/10 units BMI, P = 0.69; James & Lean: +217 kJ (+52 kcal) 10 units BMI, P = 0.06 and WHO: +42 kJ (+10 kcal) BMI, P = 0.11], the variance among overweight and obese patients of BMI >25 was substantially higher compared to that among normal weight subjects of BMI <25, on whom the equations were based. The estimated REE by Schofield for an individual of BMI 35 kg m(-2), for example, could lie anywhere from 2.78 MJ (661 kcal) above the indirect calorimetry value to 2.59 MJ (618) kcal below it. CONCLUSIONS: Prediction equations offer a quick assessment of energy needs for hypocaloric diets although, in reality, they run the random risk of excessive restriction or further weight gain.

The accelerator hypothesis: a review of the evidence for insulin resistance as the basis for type I as well as type II diabetes.

Although some 40 years have passed since type I diabetes was first defined, its cause remains unknown. The autoimmunity paradigm of immune dysregulation has not offered an explanation for its rising incidence, nor means of preventing it, and there is arguably good reason to consider alternatives. The accelerator hypothesis is a singular, unifying concept that argues that type I and type II diabetes are the same disorder of insulin resistance, set against different genetic backgrounds. The hypothesis does not deny the role of autoimmuniy, only its primacy in the process. It distinguishes type I and type II diabetes only by tempo, the faster tempo reflecting the more susceptible genotype and (inevitably) earlier presentation. Insulin resistance is closely related to the rise in overweight and obesity, a trend that the hypothesis deems central to the rising incidence of all diabetes in the developed and developing world. Rather than overlap between the two types of diabetes, the accelerator hypothesis envisages overlay-each a subset of the general population differing from each other only by genotype. Indeed, it views type I and type II diabetes as a continuum, where the infinitely variable interaction between insulin resistance and genetic response determines the age at which beta-cell loss becomes critical. Adult diabetes is not viewed as an entity, but rather as diabetes presenting in adulthood. Childhood diabetes, similarly, is diabetes presenting in childhood. The increasing incidence of both is primarily the result of lifestyle change and the rise in body weight that has resulted.

Assortative weight gain in mother-daughter and father-son pairs: an emerging source of childhood obesity. Longitudinal study of trios (EarlyBird 43).

OBJECTIVE: To look for same-sex (gender assortative) association of body mass index (BMI) in healthy trios (mother, father and child) from a contemporary birth cohort, which might imply shared environment rather than shared genes because selective mother-daughter and father-son gene transmission is not a common Mendelian trait. DESIGN: Prospective (longitudinal) cohort study with four annual time points, from 5 to 8 years. SUBJECTS: 226 healthy trios from a 1995 to 1996 birth cohort randomly selected in the city of Plymouth, UK. MEASUREMENTS: Average BMI of the two parents and maternal/paternal BMI separately related to the BMI-SDS (standard deviation score) of all offspring and to the BMI-SDS of the sons and the daughters separately. RESULTS: There were big differences in BMI-SDS among the daughters grouped according to mothers' category of BMI (effect size 1.37 SDS), but not their sons (effect size 0.16 SDS, gender interaction P<0.004), and among the sons grouped according to their fathers' BMI (effect size 1.28 SDS), but not their daughters (effect size 0.17, gender interaction P=0.02). Children whose same-sex parents were of normal weight, weighed either close to (girls+0.20 BMI-SDS) or less than (boys,-0.34 BMI-SDS) children of 20 years ago, and did not change from 5 to 8 years. In contrast, the risks of obesity at 8 years were 10-fold greater (girls 41%, P<0.001) or sixfold greater (boys 18%, P<0.05) if the same-sex parent was obese. Longitudinal linear mixed effects (multilevel) modelling showed a marked influence of maternal and paternal BMI on the rate of weight gain, which was unaffected by birth weight of the child. We report perhaps the largest effect sizes so far recorded in childhood obesity. CONCLUSIONS: Childhood obesity today seems to be largely confined to those whose same-sex parents are obese, and the link does not seem to be genetic. Parental obesity, like smoking, might be targeted in the interests of the child.

Children from low-income families have less access to sports facilities, but are no less physically active: cross-sectional study (EarlyBird 35).

BACKGROUND: Rising levels of childhood obesity have led to an increasing number of Government sponsored initiatives attempting to stem the problem. Much of the focus to date has been on physical activity and out-of-school activity in particular. There is an assumption that children from low-income families suffer most where there is a lack of structured physical education in school. Accordingly, provision of additional facilities for sport and other forms of active recreation tend to target areas of socio-economic deprivation. AIM: We have assessed the relationship between parental income, the use of out-of-school sports facilities and the overall physical activity of young children across a wide socio-economic range. METHODS: Total weekly physical activity was measured, objectively, over 7 days both at 7 years and 8 years in a healthy cohort of 121 boys and 93 girls using actigraph accelerometers. Questionnaires were used to establish parental income and parents reported the child's weekly use of out-of-school facilities for structured physical activity. RESULTS: Children from low-income families attended significantly fewer sessions of structured out-of-school activities than those from wealthier families (r = 0.39), with a clear dose-response relationship across income groups. Nevertheless, total physical activity, measured objectively over seven continuous days, showed no relationship between parental income and the mean activity level of the children (r = -0.08). Nor did we find a relationship between parental income and time spent in higher intensity activity (r = -0.04). CONCLUSION: Social inequality appears to have little impact on physical activity in young children. Those from poorer families make less use of facilities for structured activity out-of-school but they nevertheless record the same overall level of activity as others. What they lack in opportunity they appear to make up in the form of unstructured exercise. Improving provision for sport may not lead to the expected rise in activity levels in young children.

Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes.

The transcription factor insulin promoter factor-1 (IPF-1) plays a central role in both the development of the pancreas and the regulation of insulin gene expression in the mature pancreatic beta cell. A dominant-negative frameshift mutation in the IPF-l gene was identified in a single family and shown to cause pancreatic agenesis when homozygous and maturity-onset diabetes of the young (MODY) when heterozygous. We studied the role of IPF-1 in Caucasian diabetic and nondiabetic subjects from the United Kingdom. Three novel IPF-1 missense mutations (C18R, D76N, and R197H) were identified in patients with type 2 diabetes. Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human beta-cell line Nes2y. These mutations are present in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25-53 years of age. We conclude that mutations in the IPF-1 gene may predispose to type 2 diabetes and are a rare cause of MODY and pancreatic agenesis, with the phenotype depending upon the severity of the mutation.

Increased urinary dopamine excretion in association with bilateral carotid body tumours-- clinical, biochemical and genetic findings.

This report describes a rare case of a patient with increased urinary dopamine excretion in association with bilateral carotid body tumours. Excretion of adrenaline, noradrenaline, metadrenaline, normetadrenaline and 4-hydroxy-3-methoxymandelic acid (HMMA) were within the reference ranges, and an (123)I-meta-iodobenzylguanidine (MIBG) scan showed uptake in the neck masses, with no other abnormal uptake anywhere else in the body. The patient is being managed conservatively as the tumours are not amenable to resection on account of their size and vascularity. There are only four previous case reports of dopamine-secreting tumours of the carotid body described in the literature, all of whom were women. The tumours were unilateral in three cases and bilateral in the fourth case. Familial cases of carotid body tumours have a higher prevalence of bilateral tumours than non-familial cases. Recent reports in the literature have suggested that a significant number of patients with extra-adrenal catecholamine-secreting paragangliomas have a genetic mutation in one of the identified susceptibility genes for catecholamine-secreting tumours, despite having no other affected family members, and a mutation has been found in the succinate dehydrogenase gene for this patient.

Differences in epitope restriction of autoantibodies to native human insulin (IAA) and antibodies to heterologous insulin (IA).

The binding profiles of insulin autoantibodies (IAA) and insulin antibodies (IA) to highly purified species variants and fragments of insulin were studied in direct immunospecific enzyme-linked immunosorbent assay (ELISA) and indirect absorption experiments with insulins covalently coupled to Sepharose beads. Five of 10 IAA-containing sera from insulin-naive nondiabetics that bound whole human (H) insulin did not bind whole porcine (P) or whole bovine (B) insulins. These sera bound H insulin B-chain but not P B-chain or desalanated P insulin, suggesting they were dependent on the presence of threonine B30. The other 5 IAA-containing sera bound H, P, B, and desalanated porcine insulins, but only 1 bound isolated B-chains. All 10 IA-containing sera from insulin-treated diabetics bound H, P, B, and desalanated P insulins, but only 1 bound to human (and porcine) B-chain. Further binding studies with ovine, rabbit, rat, and guinea pig insulins confirmed the H (threonine B30) specificity of the 5 IAA-containing sera. B30 residues do not appear to be dominant, however, when insulin is administered exogenously. Instead, IA bind predominantly to A-chain or conformational determinants involving both chains. Scatchard analysis of a representative H insulin-specific IAA serum suggested that it contained a single binding affinity, whereas analysis of a representative IA-diabetic serum suggested it contained several different affinities.

Increased preproinsulin mRNA in pancreatic islets incubated with islet cell-stimulating antibodies from serums of type I diabetic patients.

We recently described autoantibodies that stimulate the release of insulin from pancreatic beta-cells both in vitro and in vivo. The aim of this study was to establish whether islet cell-stimulating antibodies (ICSTAs) also increase islet cell preproinsulin mRNA content. Wistar rat islets, isolated by collagenase digestion, were exposed to 2.7 and 11.1 mM glucose. Insulin release increased 10-fold in response to the higher glucose concentration, and dot-blot analysis of islet mRNA with a rat preproinsulin cDNA probe showed a concomitant increase in mRNA levels. The globulin fractions of four test serums, three from patients with type I (insulin-dependent) diabetes and one from a patient with the insulin autoimmune syndrome, showed clear (5- to 8-fold) stimulation of insulin release. The nonglobulin fractions of these serums and both fractions of three control serums failed to stimulate secretion of insulin. The insulin mRNA content of islets incubated with the ICSTA globulin fractions was greatly increased compared with levels observed in islets treated with control serum globulin fractions. We conclude that ICSTAs not only can stimulate the release of insulin but also increase the preproinsulin mRNA content of islet cells.