Effects of Compliance to a Training Intervention for High School Students with ADHD.

OBJECTIVE: We evaluated the effects of treatment compliance with the Challenging Horizons Program (CHP) for high school aged adolescents with attention-deficit hyperactivity disorder (ADHD). METHOD: Participants were 185 high school aged adolescents (65% non-Hispanic White; 79% male) with a diagnosis of ADHD who were randomly assigned to either CHP or community control. Outcomes included parent-rated academic functioning, parent- and self-rated social-emotional functioning, and GPA. The complier average causal effect (CACE) was estimated using propensity-weighted models for youth engaging in ≥ 30 CHP individual sessions (15-20 min) across the academic year. RESULTS: Most (78%) CHP participants engaged in≥30 CHP sessions. CACE analyses using latent growth curve modeling revealed significant treatment effects among treatment compliers across ratings of academic and social outcomes relative to similar control participants. For most outcomes, CACE estimates were larger than those found in intent-to-treat analyses, especially at 6-months follow-up. CONCLUSIONS: Compliance with 30 or more individual CHP sessions appeared to be an attainable threshold associated with incremental gains across several academic and social outcomes. Effects of compliance were amplified at 6-months follow-up, supporting the hypothesized theory of change of training interventions. Future work should focus on facilitators of treatment engagement and feasibility of the CHP as delivered by high school personnel.

Social Functioning Outcomes of a High School-Based Treatment Program for Adolescents with ADHD.

OBJECTIVE: We evaluated the extent to which receiving the multi-component treatment of the Challenging Horizons Program (CHP) would lead to significant improvements in social functioning, as well as in inattention, internalizing symptoms, parent stress, and emotion dysregulation for high-school-aged adolescents with attention-deficit hyperactivity disorder (ADHD). METHOD: Participants were 186 high-school-aged adolescents (74% White) with a diagnosis of ADHD who were randomly assigned to either CHP (n = 92; 80% boys; M age = 15.0; SD = 0.8) or Community Care (CC; n = 94; 78% boys; M age = 15.1; SD = 0.9) within each of 12 participating schools. Parent and adolescent reports of social functioning were the primary outcome measures. Secondary outcomes included ratings of symptoms of ADHD and related disorders, parent stress, and emotion regulation. RESULTS: Intent-to-treat analyses using hierarchical linear modeling revealed significant group-by-time interactions of medium magnitude (d range = .40 to .52) on parent-rated social skills. Significant group-by-time benefits were also identified for adolescent self-rated social skills as well as the secondary outcomes of parent-rated inattention symptoms, emotion regulation, and parenting stress. DISCUSSION: CHP appears to benefit social skills along with related characteristics for adolescents with ADHD. Understanding these unique findings for this population informs additional research related to treatment mechanisms and effectiveness trials.

Associations between cross-racial friendships and children's social and academic adjustment in racially diverse classrooms.

This study examined bidirectional associations between cross-racial friendships and children's social and academic adjustment. Participants were 583 elementary school-age children in western Canada, or the midwestern United States (4-10 years; 279 girls; 143 Asian, 88 Black, 65 Hispanic or Latinx, 171 White, 116 mixed). Children's adjustment (social preference, academic enablers, academic performance) and friendship nominations (reciprocated, received, given) were measured in fall and spring over one school year from 2017 to 2018, or from 2018 to 2019. Regarding reciprocated nominations, fall adjustment positively predicted spring reciprocated cross-racial friendships, but not vice-versa. For received nominations, academic enablers and received cross-racial friendship nominations were positively and bidirectionally related to one another. Fall same-racial friendship nominations positively predicted spring academic performance and social preference. Effect sizes were small.

Promoting Classroom Social and Academic Functioning among Children at Risk for ADHD: The MOSAIC Program.

OBJECTIVE: Social and academic functioning are linked in elementary school, and both are frequently impaired in children with elevated symptoms of attention-deficit/hyperactivity disorder (ADHD). This study evaluated the Making Socially Accepting Inclusive Classrooms (MOSAIC) program, a classroom intervention to support children's social and academic functioning, especially for children at risk for ADHD. Teachers delivered MOSAIC practices to the whole class and applied some strategies more frequently to target children selected for elevated ADHD symptoms and peer impairment. METHOD: Participants were 34 general education teachers (grades K-5) and 558 children in their classrooms, randomized to MOSAIC or to a typical practice control group for one academic year. In the fall and spring, we assessed (a) peers' sociometric judgments of children, (b) children's self-report of supportive relationships with teachers and peers, and (c) teachers' report of children's social and academic competencies and impairments. RESULTS: Regarding whole class effects, relative to control group children, children in MOSAIC classrooms (target and non-target children) were rated by teachers in spring as having better competencies and lower impairment, after controlling for fall functioning. There were no main effects of MOSAIC on peer sociometrics or child perceptions of supportive relationships. Target status moderated some effects such that, in spring, target children in MOSAIC perceived greater support from their teachers but received poorer sociometrics than did target children in control classrooms. CONCLUSIONS: We discuss the difficulty in changing peers' perceptions of children with ADHD symptoms, even in the presence of improvements in other aspects of social and academic functioning.

Mechanisms of Motivational Interviewing: a Conceptual Framework to Guide Practice and Research.

Reviews of the motivational interviewing (MI) training literature demonstrate MI is a nuanced skill set that takes carefully planned didactic training, application of skills in context-specific practice settings, and ongoing support to promote reflective practice and sustained proficiency. Despite the robust knowledge base related to training and how MI works to achieve favorable outcomes, these two literature bases are not well integrated. In an effort to inform and guide future research, we propose the mechanisms of motivational interviewing (MMI) conceptual framework, which expands upon previous work. Specifically, the framework adds training as an ongoing process consistent with Bennett-Levy's (Behav Cogn Psychother 34:57-78, 2006) model of skill development and acquisition to the existing two-path framework that helps us to understand how MI works to achieve its desired effects (Magill et al., J Consult Clin Psychol 82:973-983, 2014). Herein, we describe measures used to evaluate the mechanisms within the four MMI framework links: initial training to competency, competency to proficiency, proficiency to talk about change, and talk about change to behavior change. Next, we synthesize the literature associated with each of the mechanisms of the MMI. We conclude by discussing implications for practice and research. This framework offers a more complete path structure to understand the mechanisms of change associated with MI that could improve our understanding of inconsistent effect sizes observed across prior trials evaluating MI effectiveness.

Community-Based Prevalence of Externalizing and Internalizing Disorders among School-Aged Children and Adolescents in Four Geographically Dispersed School Districts in the United States.

The Project to Learn About Youth-Mental Health (PLAY-MH; 2014-2018) is a school-based, two-stage study designed to estimate the prevalence of selected mental disorders among K-12 students in four U.S.-based sites (Colorado, Florida, Ohio, and South Carolina). In Stage 1, teachers completed validated screeners to determine student risk status for externalizing or internalizing problems or tics; the percentage of students identified as being at high risk ranged from 17.8% to 34.4%. In Stage 2, parents completed a structured diagnostic interview to determine whether their child met criteria for fourteen externalizing or internalizing disorders; weighted prevalence estimates of meeting criteria for any disorder were similar in three sites (14.8%-17.8%) and higher in Ohio (33.3%). PLAY-MH produced point-in-time estimates of mental disorders in K-12 students, which may be used to supplement estimates from other modes of mental disorder surveillance and inform mental health screening and healthcare and educational services.

Prioritizing teacher emotions: shifting teacher training to a digital environment.

This paper is in response to the manuscript entitled, "Success, failure and emotions: Examining the relationship between performance feedback and emotions in diagnostic reasoning," (Jarrell, Harley, Lajoie, & Naismith, Educational Technology & Research Development, 65, 1263-1284: 2017) from a K-12 teacher and administrator educational perspective. Jarrell et al.'s (Educational Technology & Research Development, 65, 1263-1284: 2017) findings indicate a strong relationship between outcome emotions and performance tasks: highest performing medical students had the most positive emotions. The authors suggested that medical students who fail and experience negative emotions could experience a loss of confidence and lead to dropping out of medical school. These results can be applied to teachers and administrators in K-12 settings as they make the shift to digital learning by including emotional assessments into the new digital learning platforms in order to address areas of emotional stress and teacher burnout before leading to attrition. This perspective makes suggestions of ways Jarrell et al.'s (Educational Technology & Research Development, 65, 1263-1284: 2017) findings could be a starting place for educational stakeholders to prioritize teachers' emotional well-being and offer an opportunity to provide intervention support in order to increase teacher self-efficacy in the shift to digital and possibly reduce teacher burnout.

Future Directions for Psychosocial Interventions for Children and Adolescents with ADHD.

Multiple psychosocial interventions are efficacious for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) including behavioral parent training, behavioral classroom management, behavioral peer interventions, and organization training programs. Unfortunately, there is a significant gap between research and practice such that evidence-based treatments often are not implemented in community and school settings. Using a life course model for ADHD treatment implementation, we discuss future research directions that support movement from the current, fragmented system of care to a more comprehensive, integrated, and multisystemic approach. Specifically, we offer six recommendations for future research. Within the realm of treatment development and evaluation, we recommend (1) identifying and leveraging mechanisms of change, (2) examining impact of youth development on treatment mechanisms and outcomes, and (3) designing intervention research in the context of a life course model. Within the realm of implementation and dissemination, we recommend investigating strategies to (4) enhance access to evidence-based treatment, (5) optimize implementation fidelity, and (6) examine and optimize costs and cost-effectiveness of psychosocial interventions. Our field needs to go beyond short-term, efficacy trials to reduce symptomatic behaviors conducted under ideal controlled conditions and successfully address the research-to-practice gap by advancing development, evaluation, implementation, and dissemination of evidence-based treatment strategies to ameliorate ADHD-related impairment that can be used with fidelity by parents, teachers, and community health providers.

Sex-specific programming of adult insulin resistance in guinea pigs by variable perinatal growth induced by spontaneous variation in litter size.

Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in programming of insulin resistance later in life. Spontaneous IUGR in the guinea pig, due to natural variation in litter size, produces offspring with asymmetric IUGR and neonatal catch-up growth. We hypothesized that spontaneous IUGR and/or accelerated neonatal growth would impair insulin sensitivity in adult guinea pigs. Insulin sensitivity of glucose metabolism was determined by hyperinsulinemic-euglycemic clamp (HEC) in 38 (21 male, 17 female) young adult guinea pigs from litters of two-to-four pups. A subset (10 male, 8 female) were infused with d-[3-3H]glucose before and during the HEC to determine rates of basal and insulin-stimulated glucose utilization, storage, glycolysis, and endogenous glucose production. n males, the insulin sensitivity of whole body glucose uptake ( r = 0.657, P = 0.002) and glucose utilization ( r = 0.884, P = 0.004) correlated positively and independently with birth weight, but not with neonatal fractional growth rate (FGR10-28). In females, the insulin sensitivity of whole body and partitioned glucose metabolism was not related to birth weight, but that of endogenous glucose production correlated negatively and independently with FGR10-28 ( r = -0.815, P = 0.025). Thus, perinatal growth programs insulin sensitivity of glucose metabolism in the young adult guinea pig and in a sex-specific manner; impaired insulin sensitivity, including glucose utilization, occurs after IUGR in males and impaired hepatic insulin sensitivity after rapid neonatal growth in females.

Gestational weight gain outside the Institute of Medicine recommendations and adverse pregnancy outcomes: analysis using individual participant data from randomised trials.

BACKGROUND: High Body Mass Index (BMI) and gestational weight gain (GWG) affect an increasing number of pregnancies. The Institute of Medicine (IOM) has issued recommendations on the optimal GWG for women according to their pre-pregnancy BMI (healthy, overweight or obese). It has been shown that pregnant women rarely met the recommendations; however, it is unclear by how much. Previous studies also adjusted the analyses for various women's characteristics making their comparison challenging. METHODS: We analysed individual participant data (IPD) of healthy women with a singleton pregnancy and a BMI of 18.5 kg/m2 or more from the control arms of 36 randomised trials (16 countries). Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were used to describe the association between GWG outside (above or below) the IOM recommendations (2009) and risks of caesarean section, preterm birth, and large or small for gestational age (LGA or SGA) infants. The association was examined overall, within the BMI categories and by quartile of GWG departure from the IOM recommendations. We obtained aOR using mixed-effects logistic regression, accounting for the within-study clustering and a priori identified characteristics. RESULTS: Out of 4429 women (from 33 trials) meeting the inclusion criteria, two thirds gained weight outside the IOM recommendations (1646 above; 1291 below). The median GWG outside the IOM recommendations was 3.1 kg above and 2.7 kg below. In comparison to GWG within the IOM recommendations, GWG above was associated with increased odds of caesarean section (aOR 1.50; 95%CI 1.25, 1.80), LGA (2.00; 1.58, 2.54), and reduced odds of SGA (0.66; 0.50, 0.87); no significant effect on preterm birth was detected. The relationship between GWG below the IOM recommendation and caesarean section or LGA was inconclusive; however, the odds of preterm birth (1.94; 1.31, 2.28) and SGA (1.52; 1.18, 1.96) were increased. CONCLUSIONS: Consistently with previous findings, adherence to the IOM recommendations seem to help achieve better pregnancy outcomes. Nevertheless, even in the context of clinical trials, women find it difficult to adhere to them. Further research should focus on identifying ways of achieving a healthier GWG as defined by the IOM recommendations.

Effects of an antenatal dietary intervention in overweight and obese women on 6 month infant outcomes: follow-up from the LIMIT randomised trial.

BACKGROUND: The immediate impact of providing an antenatal dietary intervention during pregnancy has been extensively studied, but little is known of the effects beyond the neonatal period. Our objective was to evaluate the effect of an antenatal dietary intervention in overweight or obese women on infant outcomes 6 months after birth. METHODS: We conducted a follow up study of infants born to women who participated in the LIMIT trial during pregnancy. Live-born infants at 6-months of age, and whose mother provided consent to ongoing follow-up were eligible. The primary follow-up study endpoint was the incidence of infant BMI z-score ≥90th centile for infant sex and age. Secondary study outcomes included a range of infant anthropometric measures, neurodevelopment, general health, and infant feeding. Analyses used intention to treat principles according to the treatment group allocated in pregnancy. Missing data were imputed and analyses adjusted for maternal early pregnancy BMI, parity, study centre, socioeconomic status, age, and smoking status. Outcome assessors were blinded to the allocated treatment group. RESULTS: A total of 1754 infants were assessed at age 6 months (Lifestyle Advice n = 869; Standard Care n = 885), representing 82.1% of the eligible sample (n = 2136). There were no statistically significant differences in the incidence of infant BMI z-score ≥90th centile for infants born to women in the Lifestyle Advice group, compared with the Standard Care group (Lifestyle Advice 233 (21.71%) vs. Standard Care 233 (21.90%); adjusted relative risk (aRR) 0.99; 95% confidence interval 0.82 to 1.18; p = 0.88). There were no other effects on infant growth, adiposity, or neurodevelopment. CONCLUSION: Providing pregnant women who were overweight or obese with an antenatal dietary and lifestyle intervention did not alter 6-month infant growth and adiposity. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).

Late-gestation maternal dietary methyl donor and cofactor supplementation in sheep partially reverses protection against allergic sensitization by IUGR.

Perinatal exposures are associated with altered risks of childhood allergy. Human studies and our previous work suggest that restricted growth in utero (IUGR) is protective against allergic disease. The mechanisms are not clearly defined, but reduced fetal abundance and altered metabolism of methyl donors are hypothesized as possible underlying mechanisms. Therefore, we examined whether late-gestation maternal dietary methyl donor and cofactor supplementation of the placentally restricted (PR) sheep pregnancy would reverse allergic protection in progeny. Allergic outcomes were compared between progeny from control pregnancies (CON; n = 49), from PR pregnancies without intervention (PR; n = 28), and from PR pregnancies where the dam was fed a methyl donor plus cofactor supplement from day 120 of pregnancy until delivery (PR + Methyl; n = 25). Both PR and PR + Methyl progeny were smaller than CON; supplementation did not alter birth size. PR was protective against cutaneous hypersensitivity responses to ovalbumin (OVA; P < 0.01 in singletons). Cutaneous hypersensitivity responses to OVA in PR + Methyl progeny were intermediate to and not different from the responses of CON and PR sheep. Cutaneous hypersensitivity responses to house dust mites did not differ between treatments. In singleton progeny, upper dermal mast cell density was greater in PR + Methyl than in PR or CON (each P < 0.05). The differences in the cutaneous allergic response were not explained by treatment effects on circulating immune cells or antibodies. Our results suggest that mechanisms underlying in utero programming of allergic susceptibility by IUGR and methyl donor availability may differ and imply that late-gestation methyl donor supplementation may increase allergy risk.

Forming first impressions of children: the role of attention-deficit/hyperactivity disorder symptoms and emotion dysregulation.

BACKGROUND: Previous research on peer status of children with attention-deficit/hyperactivity disorder (ADHD) has focused on already-established peer groups, rendering the specific social behaviors that influence peers' initial impressions largely unknown. Recently, theorists have argued that emotion dysregulation is a key aspect of ADHD, with empirical work finding relations between emotion dysregulation and social outcomes. Therefore, the current study focuses on the initial interactions among children varying in ADHD symptoms duringh a novel playgroup, proposing that emotion dysregulation displayed during the playgroup may serve as a possible pathway between ADHD symptoms and peers' initial negative impressions. METHODS: Participants were 233 elementary-age children ranging from 8 to 10 years old (M = 8.83, 70% male). Parents and teachers rated children's ADHD symptoms and related impairment; 51% of the children met criteria for an ADHD diagnosis. Then, children participated with unfamiliar peers in a three-hour playgroup that included three structured and two unstructured tasks. After the tasks, children and staff rated each child on social outcomes. Coders unaware of child's diagnostic status watched videos of the groups and rated each child's global emotion dysregulation during each task. RESULTS: Using multiple raters and methods, ADHD severity was associated with more negative peer ratings, through observed emotion dysregulation. Results were consistent for both parent and teacher ratings of ADHD severity as well as for both peer ratings of likeability and staff ratings of perceived peer likeability. CONCLUSIONS: When focusing on improving peers' initial impressions of children with ADHD symptoms, emotion dysregulation may be a valuable target for intervention.

Evidence-Based Psychosocial Treatments for Children and Adolescents With Attention Deficit/Hyperactivity Disorder.

The purpose of this research was to update the series of articles on evidence-based treatment for children and adolescents with attention deficit/hyperactivity disorder that have appeared in this journal (Evans, Owens & Bunford, 2014; Pelham & Fabiano, 2008; Pelham, Wheeler, & Chronis, 1998). We completed a systematic review of the literature published between 2012 and 2016 to establish levels of evidence for psychosocial treatments for these youth. We identified articles using criteria established by the Society of Clinical Child and Adolescent Psychology using keyword searches of abstracts and titles. Articles were classified according to a modified version of the Division 12 task force guidelines that was used in other reviews in this series. The results revealed that findings are becoming increasingly nuanced with variations in levels of evidence related to ages of the children and characteristics of the specific treatment. In addition, we focused our critique on generalization of treatment effects across settings and time and on sample diversity (with regard to ethnicity and levels of parent education) in relation to the population. Children of parents with higher levels of education than average appear to be overrepresented in the literature. Implications for future treatment development and evaluation and for dissemination research are discussed.

Maternal methyl donor and cofactor supplementation in late pregnancy increases ß-cell numbers at 16 days of life in growth-restricted twin lambs.

Restricted growth before birth (IUGR) increases adult risk of Type 2 diabetes by impairing insulin sensitivity and secretion. Altered fetal one-carbon metabolism is implicated in developmental programming of adult health and disease by IUGR. Therefore, we evaluated effects of maternal dietary supplementation with methyl donors and cofactors (MMDS), designed to increase fetal supply, on insulin action in the spontaneously IUGR twin lamb. In vivo glucose-stimulated insulin secretion and insulin sensitivity were measured at days 12-14 in singleton controls (CON, n = 7 lambs from 7 ewes), twins (IUGR, n = 8 lambs from 8 ewes), and twins from ewes that received MMDS (2 g rumen-protected methionine, 300 mg folic acid, 1.2 g sulfur, 0.7 mg cobalt) daily from 120 days after mating (~0.8 of term) until delivery (IUGR+MMDS, n = 8 lambs from 4 ewes). Body composition and pancreas morphometry were assessed in lambs at day 16 IUGR reduced size at birth and increased neonatal fractional growth rate. MMDS normalized long bone lengths but not other body dimensions of IUGR lambs at birth. IUGR did not impair glucose control or insulin action at days 12-14, compared with controls. MMDS increased metabolic clearance rate of insulin and increased ß-cell numerical density and tended to improve insulin sensitivity, compared with untreated IUGR lambs. This demonstrates that effects of late-pregnancy methyl donor supplementation persist until at least the third week of life. Whether these effects of MMDS persist beyond early postnatal life and improve metabolic outcomes after IUGR in adults and the underlying mechanisms remain to be determined.

The effect of an antenatal lifestyle intervention in overweight and obese women on circulating cardiometabolic and inflammatory biomarkers: secondary analyses from the LIMIT randomised trial.

BACKGROUND: Maternal overweight and obesity during pregnancy is associated with insulin resistance, hyperglycaemia, hyperlipidaemia and a low-grade state of chronic inflammation. The aim of this pre-specified analysis of secondary outcome measures was to evaluate the effect of providing antenatal dietary and lifestyle advice on cardiometabolic and inflammatory biomarkers. METHODS: We conducted a multicentre trial in which pregnant women who were overweight or obese were randomised to receive either Lifestyle Advice or Standard Care. We report a range of pre-specified secondary maternal and newborn cardiometabolic and inflammatory biomarker outcomes. Maternal whole venous blood was collected at trial entry (mean 14 weeks gestation; non-fasting), at 28 weeks gestation (fasting), and at 36 weeks gestation (non-fasting). Cord blood was collected after birth and prior to the delivery of the placenta. A range of cardiometabolic and inflammatory markers were analysed (total cholesterol, triglycerides, non-esterified fatty acids, high-density lipoprotein cholesterol, insulin, glucose, leptin, adiponectin, C-reactive protein, granulocyte macrophage-colony stimulating factor, interferon gamma, TNF-α, and interleukins 1ß, 2, 4, 5, 6, 8, and 10). Participants were analysed in the groups to which they were randomised, and were included in the analyses if they had a measure at any time point. RESULTS: One or more biological specimens were available from 1951 women (989 Lifestyle Advice and 962 Standard Care), with cord blood from 1174 infants (596 Lifestyle Advice and 578 Standard Care). There were no statistically significant differences in mean cardiometabolic and inflammatory marker concentrations across pregnancy and in infant cord blood between treatment groups. Estimated treatment group differences were close to zero, with 95% confidence intervals spanning a range of differences that were short of clinical relevance. There was no evidence to suggest that the intervention effect was modified by maternal BMI category. CONCLUSIONS: Despite our findings, it will be worth considering potential relationships between cardiometabolic and inflammatory markers and clinical outcomes, including longer-term infant health and adiposity. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426 ; Date Registered 09/03/2007).

Use of the hyperinsulinemic euglycemic clamp to assess insulin sensitivity in guinea pigs: dose response, partitioned glucose metabolism, and species comparisons.

The guinea pig is an alternate small animal model for the study of metabolism, including insulin sensitivity. However, only one study to date has reported the use of the hyperinsulinemic euglycemic clamp in anesthetized animals in this species, and the dose response has not been reported. We therefore characterized the dose-response curve for whole body glucose uptake using recombinant human insulin in the adult guinea pig. Interspecies comparisons with published data showed species differences in maximal whole body responses (guinea pig ≈ human < rat < mouse) and the insulin concentrations at which half-maximal insulin responses occurred (guinea pig > human ≈ rat > mouse). In subsequent studies, we used concomitant d-[3-3H]glucose infusion to characterize insulin sensitivities of whole body glucose uptake, utilization, production, storage, and glycolysis in young adult guinea pigs at human insulin doses that produced approximately half-maximal (7.5 mU·min-1·kg-1) and near-maximal whole body responses (30 mU·min-1·kg-1). Although human insulin infusion increased rates of glucose utilization (up to 68%) and storage and, at high concentrations, increased rates of glycolysis in females, glucose production was only partially suppressed (~23%), even at high insulin doses. Fasting glucose, metabolic clearance of insulin, and rates of glucose utilization, storage, and production during insulin stimulation were higher in female than in male guinea pigs (P < 0.05), but insulin sensitivity of these and whole body glucose uptake did not differ between sexes. This study establishes a method for measuring partitioned glucose metabolism in chronically catheterized conscious guinea pigs, allowing studies of regulation of insulin sensitivity in this species.

Infant birth outcomes are associated with DNA damage biomarkers as measured by the cytokinesis block micronucleus cytome assay: the DADHI study.

Accumulation of DNA damage in the first 1000 days may increase risk of accelerated ageing and degenerative diseases in adult life such as cancers. The extent of DNA damage in infants and the correlation of maternal factors during pregnancy with neonate birth outcomes and DNA damage is not known in infants born in Australia. Therefore, we performed a prospective cohort study to collect data on DNA damage in lymphocytes of Australian infants (aged 0, 3 and 6 months), using the cytokinesis block micronucleus cytome (CBMN-Cyt) assay. The study also explored correlation of CBMN-Cyt biomarkers with infant birth outcomes and maternal anthropometric and lifestyle variables. Peripheral blood lymphocytes were isolated from the infants at birth (cord blood) (n = 82), 3 months (n = 64) and 6 months (n = 53) after birth. DNA damage biomarkers measured ex vivo in binucleated lymphocytes (BNC) included: micronuclei (MN), nucleoplasmic bridges (NPB) and nuclear buds (NBUD). Apoptotic and necrotic lymphocytes were also scored and nuclear division index (NDI) was measured using the frequency of mono-, bi- and multinucleated lymphocyte. MN and NBUD were also scored in mononucleated lymphocytes (MNC). The mean (± SD) frequency of MN, NPB and NBUD in BNCs at birth was 2.0 (± 1.2), 5.8 (± 3.7) and 11.1 (± 5.7) per 1000 BNC, respectively, and tended to decrease significantly at 3 months (P < 0.01, P < 0.0001, P < 0.001, respectively) and 6 months (P < 0.05, P < 0.0001, P < 0.0001, respectively) after birth relative to cord blood when compared with the same cohort of infants (n = 48 at birth, 48 at 3 months and 39 at 6 months). None of the CBMN cytome biomarkers measured at birth was associated with maternal smoking status, alcohol and folic acid intake during pregnancy. The mean gestation age correlated positively with MN (r = 0.38, P = 0.006), NPB (r = 0.30, P = 0.03) and negatively with NDI (r = -0.29, P = 0.03). Infant birth weight associated positively with MN, NPB and NBUD in cord blood (r = 0.24, P = 0.08; r = 0.32, P = 0.02; r = 0.28, P = 0.04, respectively), birth length associated positively with NPB (r = 0.32, P = 0.02) and NBUD (r = 0.27, P = 0.04) while head circumference associated negatively with apoptotic cells (r = -0.27, P = 0.06). APGAR score at 1 and 5 min after birth associated positively with NDI at birth (r = 0.3, P = 0.05, r = 0.28, P = 0.06, respectively). Mother's weight and body mass index (BMI) recorded at the time of recruitment associated positively with NPB (r = 0.38, P = 0.006, r = 0.32, P = 0.02, respectively) and negatively with APGAR score at 5 min (r = -0.25, P = 0.07). The significant positive associations of infant birth weight and length and maternal BMI with CBMN-Cyt biomarkers suggest the possibility of a genotoxic effect of metabolic processes that promote excessive growth and high BMI.

Effects of induced placental and fetal growth restriction, size at birth and early neonatal growth on behavioural and brain structural lateralization in sheep.

Poor perinatal growth in humans results in asymmetrical grey matter loss in fetuses and infants and increased functional and behavioural asymmetry, but specific contributions of pre- and postnatal growth are unclear. We therefore compared strength and direction of lateralization in obstacle avoidance and maze exit preference tasks in offspring of placentally restricted (PR: 10M, 13F) and control (CON: 23M, 17F) sheep pregnancies at 18 and 40 weeks of age, and examined gross brain structure of the prefrontal cortex at 52 weeks of age (PR: 14M, 18F; CON: 23M, 25F). PR did not affect lateralization direction, but 40-week-old PR females had greater lateralization strength than CON (P = .021). Behavioural lateralization measures were not correlated with perinatal growth. PR did not alter brain morphology. In males, cross-sectional areas of the prefrontal cortex and left hemisphere correlated positively with skull width at birth, and white matter area correlated positively with neonatal growth rate of the skull (all P < .05). These studies reinforce the need to include progeny of both sexes in future studies of neurodevelopmental programming, and suggest that restricting in utero growth has relatively mild effects on gross brain structural or behavioural lateralization in sheep.

Chronic high-fat diet in fathers programs ß-cell dysfunction in female rat offspring.

The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood obesity. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established, the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs ß-cell 'dysfunction' in rat F(1) female offspring. Chronic HFD consumption in Sprague-Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P < 0.01); genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed (P < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring.