Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease.

The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability. Here we present the genetic interaction profiles of APE2, APE1, and TDP1 deficiency coupled to biochemical and structural dissection of APE2. We conclude that the main role of APE2 is to reverse blocked 3' DNA ends, problematic lesions that preclude DNA synthesis. Our work also suggests that TOP1 processing of genomic ribonucleotides is the main source of 3'-blocking lesions relevant to APEX2-BRCA1/2 synthetic lethality. The exquisite sensitivity of BRCA-deficient cells to 3' blocks indicates that they represent a tractable vulnerability in homologous recombination-deficient tumor cells.

Role of Physical Activity and Sedentary Behaviors on Vascular and Myocardial Structure and Function in Type 1 Diabetes.

OBJECTIVE: To estimate associations between physical activity and sedentary behaviors and early markers of cardiovascular diseases in adolescents with and without type 1 diabetes. STUDY DESIGN: Cross-sectional data stem from the CARdiovascular Disease risk in pEdiatric type 1 diAbetes (CARDEA) study, a study investigating early cardiovascular disease development in 100 adolescents with type 1 diabetes recruited at Sainte-Justine University Hospital Diabetes Clinic and 97 healthy adolescents without diabetes (14-18 years), in Montreal, Canada. Outcomes included arterial stiffness by pulse-wave velocity, endothelial function (velocity time integral) by flow-mediated dilation test, and cardiac magnetic resonance imaging markers. Moderate-to-vigorous physical activity (MVPA) and sedentary time were estimated by accelerometry and leisure screen time by questionnaire. We estimated multivariable linear regression models stratified by group. RESULTS: In adolescents with type 1 diabetes, 10-minutes daily increase in MVPA was associated with 3.69 g/m (95% CI: -1.16; 8.54) higher left ventricular (LV) mass/height and 1-hour increase in device-measured sedentary time with 0.68 mm (0.20; 1.16) higher wall thickness but only in those with glycated hemoglobin ≤7.5%. In healthy adolescents, a 10-minute increase in MVPA was associated with 1.32 g/m (-0.03; 2.66) higher LV mass/height. Every 1-hour increase in sedentary time was associated with -1.82 cm (-3.25; -0.39) lower velocity time integral, -2.99 g/m (-5.03; -0.95) lower LV mass/height, and -0.47 mm (-0.82; -0.12) lower wall thickness. CONCLUSIONS: Being active and limiting sedentary time appears beneficial for cardiac structure and endothelial function in healthy adolescents; however, adequate glycemic control combined with higher levels of MVPA may be required for adolescents with type 1 diabetes to overcome the impact of diabetes.

Adiposity and cardiac autonomic function in children with a family history of obesity.

PURPOSE: Data on associations between adiposity and heart rate variability (HRV) in prepubertal children are limited. We examined the associations between adiposity indices and HRV, independent of lifestyle behaviors, comparing multiple indicators of adiposity, and explored differences between boys and girls. METHODS: Data stem from 469 participants of the QUALITY cohort (630 children aged 8-10 years with a parental history of obesity). Adiposity indices included waist-to-height ratio, body mass index (BMI) percentiles and categories (overweight, obesity), dual-energy x-ray absorptiometry (DEXA) defined fat mass percentage and android/gynoid ratio. HRV indices in the frequency and the spectral domain were derived from a daytime 3-h Holter recording. Multivariable linear regression models were adjusted for age, sex, Tanner stage, physical activity, screen time, and fitness. Interactions between sex and adiposity were tested. RESULTS: Greater adiposity was associated with decreased parasympathetic modulation and increased sympathetic dominance. Waist-to-height ratio was associated with lower parasympathetic activity: root mean square of the successive differences (RMSSD) [B = -23.32, 95% confidence interval (CI) -42.42, -4.22], pNN50 (B = -16.93, 95% CI - 28.58, - 5.27), LF/HF ratio (B = 1.83, 95% CI 0.97-2.70). Patterns of association were similar for android/gynoid ratio. Overweight was not associated with altered HRV. Obesity was negatively associated with RMSSD and pNN50 and positively with LF/HF ratio. Greater fat mass percentage was associated with lower RMSSD, pNN50, and HF, and increased LF/HF ratio. There were no differences between boys and girls. CONCLUSIONS: Specific markers of adiposity relate to altered HRV in childhood, with waist-to-height ratio being potentially a more relevant marker of HRV than BMI and more pragmatic than percent body fat. TRIAL REGISTRATION: NCT03356262, 11 November 2017.

Intensity and Appreciation of Sweet Taste Solutions Are Modulated by High-Intensity Aerobic Exercise in Adolescent Athletic Males.

PURPOSE: Exercise seems to influence taste, but the effect of exercise on specific tastes is still to be elucidated among youths. METHODS: Athlete boys aged 14-16 years were recruited. Participants (n = 19) ages ranged 14.7 (0.7) years, weight 59.6 (7.8) kg, and height of 173.4 (7.9) cm. Distinct taste tests were administered using low and high concentrations of sweet, salty, and bitter solutions before and after a 30-minute aerobic exercise session (70%-90% of estimated maximal heart rate). McNemmar tests, standard paired t tests, Wilcoxon signed-rank tests, and Cohen d effect size tests were used to analyze taste identification, intensity, and appreciation. RESULTS: There were no significant differences in taste identification capacities after exercise. Participants perceived more intense (P = .037) and appreciated better (P = .004) the low-concentration sweet solution after exercise. Taste appreciation was increased for the high-concentration sweet solution (P = .009) after exercise. Effect sizes were moderate (0.516-0.776). Possible effects were noted for the intensity of salty solutions (P = .0501 and .0543). CONCLUSION: Following an exercise session, participants had increased perceived intensity and appreciation of sweet solutions. This adds new insights into how exercise influences taste in youths, a topic less documented compared with adults, suggesting further research into its impact on dietary choices is needed.

Use of MFM-20 to monitor SMA types 1 and 2 patients treated with nusinersen.

OBJECTIVE: To evaluate sensitivity to change and discriminant validity of the 20-item Motor Function Measure (MFM-20) in 2-7-year-old patients with spinal muscular atrophy types 1 (SMA1) or 2 (SMA2) treated with nusinersen. METHODS: Children aged 2 to 7 years old with SMA1 or SMA2 treated with nusinersen were assessed at least three times using the MFM-20 over an average follow-up time of 17 months. Evolution of 4-month-standardized MFM-20 scores was calculated for each MFM-20 domain (D1 standing and transfers, D2 axial and proximal, D3 distal) and for the total score (TS). RESULTS: Included in the study were 22 SMA1 subjects and 19 SMA2 subjects. Baseline MFM scores were significantly lower in patients with SMA1 than SMA2 (TS 29.5% vs. 48.3%, D1 4.5% vs. 10.6%, D2 43.6% vs. 72.6%, D3 51.2% vs. 75.0%). When considering the mean change during nusinersen treatment, standardized over a 4-month period, TS was improved for both SMA1 (+ 4.1%, SRM 1.5) and SMA2 (+ 2.8%, SRM 0.89) patients. For SMA1 patients, considerable changes were observed in D2 (+ 6.2%, SRM 0.89) and D3 (+ 6.0%, SRM 0.72), whereas the change in D1 was small (+ 0.5%, SRM 0.44). In SMA2 2 subjects, D3 was improved to a larger extent (+ 4.2%, SRM 0.53) than D1 (+ 1.8% SRM 0.63) or D2 (+ 3.2%, SRM 0.69). CONCLUSION: Our results validate use of MFM-20 to monitor function of young SMA1 and SMA2 subjects treated with nusinersen. Significant motor function improvements following treatment were observed in both SMA1 and SMA2 patients.

Multidimensional school features associated with physical activity among youth at risk of obesity: an exploratory principal component and generalized estimating equation analysis.

BACKGROUND: Schools may be high-leverage points for the promotion of physical activity (PA), yet little is known about school built and social environments among youth at high risk of obesity. PURPOSE: To characterise school built and social environments that may be salient for PA and to examine associations between school PA environments and PA in youth at risk of obesity. METHODS: Data from youth attending 206 schools (314 youth in 2005-2008, and 129 youth in 2008-2010) within the QUALITY cohort study, a longitudinal investigation of youth at high risk of obesity were used. Features of schools, based on built, policy/programming and social environments were identified using principal components (PC) analysis. Gender-stratified generalized estimating equation (GEE) models were used to explore associations between school features and accelerometer measured mean counts per minute (MCPM), mean daily moderate-to-vigorous physical activity (MVPA) and the odds of meeting MVPA guidelines cross-sectionally and prospectively using 90% confidence intervals. RESULTS: Nine PCs were identified. Associations were observed between PA and 7 of the 9 PCs. The social environment seemed to be particularly important. Social Norms to Promote PA was associated with an increase in girls' baseline MCPM and MVPA. High Willingness to Promote PA was associated with boys' MCPM, MVPA, and odds of meeting MVPA guidelines, at both baseline and follow-up. CONCLUSION: School built and social contexts may be associated with PA cross-sectionally and over time. Further studies are necessary to confirm the direction and magnitude of effects and to establish their relevance to school-based health promotion efforts.

Activate Your Health: impact of a real-life programme promoting healthy lifestyle habits in Canadian workers.

The workplace has been suggested as a good setting for the promotion of healthy lifestyles. This article examines the impact of Activate Your Health programme, provided over an average of 1.35 years, on employee health and lifestyle habits (actual and intention to improve). Companies selected one of the programme's four options (number of interventions in parentheses): Control (2), Light (8), Moderate (13) and High (14). Employees (n = 524) completed an online questionnaire at baseline and post-intervention. Mixed-effect models and generalized estimating equations models were used, where appropriate. There was an interaction effect of time by option for the number of employees intending to improve sleep habits (p = 0.030): +11.0% in Light (p = 0.013). No significant interaction effect of time by option was observed for body weight, body mass index, number of health problems or lifestyle habits (actual and intention to improve). When stratified by sex, there was an interaction effect of time by option for the number of women intending to improve sleep habits (p = 0.023): -26.1% in Moderate (p = 0.014). There was an interaction effect of time by option for body weight in men (p = 0.001): -0.58 kg in High (p = 0.031) and +2.58 kg in Control (p = 0.005). Other outcomes of interest were stable or improved post-intervention, regardless of option. The Activate Your Health programme allowed employees to maintain or improve outcomes related to health and lifestyle habits. A package like High may be beneficial for body weight regulation in men.

Trajectories of cardiorespiratory fitness from childhood to adolescence: Findings from the QUALITY cohort.

Estimate the shape and number of cardiorespiratory fitness (CRF) trajectories from childhood to adolescence; and verify whether CRF trajectory membership can be predicted by sex, biological maturation, body weight, body composition and physical activity (PA) in childhood. Data from QUALITY were used. Participants attended baseline (8-10 y old, n = 630) and follow-ups 2 years (n = 564) and 7 years (n = 359) after baseline. Group-based trajectory analysis for relative peak oxygen consumption (VO2peak, ml·kg-1·min-1) was performed. A multinomial logistic regression model was used to estimate the associations between baseline predictors and trajectory membership. Mean age of the 454 participants was 9.7 ± 0.9 years at baseline. Three distinct VO2peak trajectories were identified and all tended to decrease. They were labelled according to the starting point and slope. High-Decreasers were mostly boys, had lower body weight and fat-free mass index and higher PA levels at baseline (p < 0.05). Female sex and higher weight were associated with higher odds of being classified in the Low-Decreaser trajectory (OR = 74.03, 95%CI = 27.06-202.54; OR = 1.48, 95%CI = 1.36-1.60). Those with higher PA were less likely to be Low-Decreasers (OR = 0.96, 95%CI = 0.94-0.97). Sex, body weight and PA in childhood are important influencing factors of VO2peak (ml·kg-1·min-1) trajectories across adolescence.

Complete characterisation of two new large Xq28 duplications involving F8 using whole genome sequencing in patients without haemophilia A.

INTRODUCTION: Depending on the location of insertion of the gained region, F8 duplications can have variable clinical impacts from benign impact to severe haemophilia A phenotype. AIM: To characterize two large Xq28 duplications involving F8 incidentally detected by chromosome microarray analysis (CMA) in two patients presenting severe intellectual disability but no history of bleeding disorder. METHODS: Whole genome sequencing (WGS) was performed in order to characterize the two large Xq28 duplications at nucleotide level. RESULTS: In patient 1, a 60-73 kb gained region encompassing the exons 23-26 of F8 and SMIM9 was inserted at the int22h-2 locus following a non-homologous recombination between int22h-1 and int22h-2. We hypothesized that two independent events, micro-homology-mediated break-induced replication (MMBIR) and break-induced replication (BIR), could be involved in this rearrangement. In patient 2, the CMA found duplication from 101 to 116-kb long encompassing the exons 16-26 of F8 and SMIM9. The WGS analysis identified a more complex rearrangement with the presence of three genomic junctions. Due to the multiple micro-homologies observed at breakpoints, a replication-based mechanism such as fork stalling and template switching (FoSTeS) was greatly suspected. In both cases, these complex rearrangements preserved an intact copy of the F8. CONCLUSION: This study highlights the value of WGS to characterize the genomic junction at the nucleotide level and ultimately better describe the molecular mechanisms involved in Xq28 structural variations. It also emphasizes the importance of specifying the structure of the genomic gain in order to improve genotype-phenotype correlation and genetic counselling.

Associations of neighborhood walkability with moderate to vigorous physical activity: an application of compositional data analysis comparing compositional and non-compositional approaches.

BACKGROUND: We compared the relation between neighborhood features and moderate to vigorous physical activity (MVPA) using linear regression analysis and the more novel compositional data analysis (CoDA). Compositional data analysis allows us to take the time children allocate to different movement behaviours during a 24-hour time period into account. METHODOLOGY: Data from youth participants (n = 409) in the QUALITY (QUebec Adipose and Lifestyle InvesTigation in Youth) cohort were included. Time spent in MVPA, light physical activity, sedentary behavior, and sleep ("24-hour movement behaviours") was measured using accelerometers. Neighborhood data were collected using a geographic information system and through direct observation. In CoDA models, we used orthogonal logratio coordinates, which allows for the association of neighbourhood walkability with MVPA to be estimated with respect to the average composition of all other behaviours within a 24-hour time frame. In baseline linear regression models, MVPA was regressed cross-sectionally on neighborhood walkability. All models were stratified by sex, and controlled for BMI z-scores, pubertal development, seasonal variation, parental education, and neighbourhood safety. RESULTS: Based on CoDA, girls who lived in more walkable neighborhoods had 10% higher daily MVPA (95% CI: 2%, 19%), taking into account all other movement behaviours. Based on linear regression, girls who resided in more walkable neighborhoods engaged in 4.2 (95% confidence interval [CI]: 1.2, 6.6) more minutes of MVPA per day on average than girls residing in less walkable neighborhoods. CONCLUSIONS: Unlike with traditional linear models, all movement behaviours were included in a single model using CoDA, allowing for a more complete picture of the strength and direction of the association between neighbourhood Walkability and MVPA. Application of CoDA to investigate determinants of physical activity provides additional insight into potential mechanisms and the ways in which people allocate their time.

Natural history and determinants of dysglycemia in Canadian children with parental obesity from ages 8-10 to 15-17 years: The QUALITY cohort.

In children, the mechanisms implicated in deterioration of glucose homeostasis versus reversion to normal glucose tolerance (NGT) remain uncertain. We aimed to describe the natural history of dysglycemia from childhood to late adolescence and to identify its early determinants. We used baseline (8-10 years, n = 630), 1st follow-up (10-12 years, n = 564) and 2nd follow-up (15-17 years, n = 377) data from the QUALITY cohort of White Canadian children with parental obesity. Children underwent a 2-h oral glucose tolerance test at each cycle with plasma glucose and insulin measured at 0/30/60/90/120 min. American Diabetes Association criteria defined dysglycemia (impaired fasting glucose, impaired glucose tolerance or type 2 diabetes). Longitudinal patterns of insulin sensitivity and beta-cell function were estimated using generalized additive mixed models. Model averaging identified biological, sociodemographic and lifestyle-related determinants of dysglycemia. Of the children NGT at baseline, 66 (21%) developed dysglycemia without reverting to NGT. Among children with dysglycemia at baseline, 24 (73%) reverted to NGT. In children with dysglycemia at 1st follow-up, 18 (53%) later reverted to NGT. Among biological, sociodemographic and lifestyle determinants at 8-10 years, only fasting and 2-h glucose were associated with developing dysglycemia (odds ratio [95% CI] per 1 mmol/L increase: 4.50 [1.06; 19.02] and 1.74 [1.11; 2.73], respectively). Beta-cell function decreased by 40% in children with overweight or obesity. In conclusion, up to 75% of children with dysglycemia reverted to NGT during puberty. Children with higher fasting and 2-h glucose were at higher risk for progression to dysglycemia, while no demographic/lifestyle determinants were identified.

Body image and health-related behaviors among fitspirit participants.

BACKGROUND: Body image variables such as body size perception (BSP) and body size dissatisfaction (BSD) can influence health-related behaviors. However, few studies have investigated these body image variables in adolescent girls participating in a physical activity intervention. Therefore, the study objectives were to examine the 1) associations between health-related behaviors (physical activity, screen-time, eating habits and sleep duration) and BSP and BSD among girls participating in FitSpirit, a physical activity intervention for girls; and 2) influence of weight control practices on the association between health-related behaviors and BSP and BSD. METHODS: This cross-sectional study assessed a sample of 545 adolescent girls (mean age: 15.0±1.5 years) from 240 schools. Body mass index, health-related behaviors, perceived actual body size and desired body size variables were self-reported and collected via an online questionnaire at the end of the FitSpirit intervention. A negative BSP score [perceived actual body size - calculated BMI z-score] indicates an underestimation of body size. A positive BSD score [perceived actual body size - desired body size] indicates a desire to reduce body size. A multiple linear regression analysis examined the effects of age, zBMI and health behaviors on BSP and BSD. A second multiple linear regression analysis examined the independent associations between BSP and BSD by weight control practice. The linear relationships between BSP and BSD were evaluated with Pearson's correlations. RESULTS: Underestimation and dissatisfaction of body size are more prevalent in participants living with overweight/obesity. Screen-time and sleep duration were independently associated with BSP score (Beta=0.02; P<0.05 and Beta=-0.07; P<0.05, respectively), whereas only screen-time was associated with the BSD score (Beta=0.07; P<0.001). Physical activity was independently associated with the BSP score only in participants trying to control (maintain) their weight (Beta=-0.18; P<0.05). CONCLUSIONS: Body size overestimation and dissatisfaction are associated with health-related behaviors, specifically with more screen-time and less optimal sleeping habits. Physical activity level does not appear to be associated with body image in girls engaged in a physical activity intervention and who want to lose or gain weight. Health promotion interventions could include screen-time and sleep components as they may influence body image.

Which healthy lifestyle habits mitigate the risk of obesity and cardiometabolic risk factors in Caucasian children exposed to in utero adverse gestational factors?

BACKGROUND AND AIMS: This study explored if lifestyle habits [physical activity (PA), sleep duration, intake of fruits and vegetables, grains, and dairy products] can moderate the positive associations between prenatal exposure to suboptimal gestational factors (SGF: i.e. gestational diabetes mellitus, hypertensive disorders during pregnancy, maternal smoking during pregnancy) and obesity and cardiometabolic risk factors in children. METHODS AND RESULTS: Data from the "Quebec Adiposity and Lifestyle Investigation in Youth" (QUALITY) study collected between 2005 - 2008 in Montreal and Quebec City, were used. Analyses included a sample of 619 children aged 8-10 years. Children's PA and sleep duration were obtained using an accelerometer and daily servings of food were assessed using three 24 h diet recalls. Moderation analyses were performed to investigate if each lifestyle habit, in all children, and in boys and girls, could reduce the positive associations between SGF, and obesity and cardiometabolic risk factors. High LPA duration was protective against low levels of HDL cholesterol in boys who were exposed to more than one SGF (p = 0.005). Sleep duration did not have a protective effect respectively against high waist circumference and obesity in children and girls who were prenatally exposed to maternal smoking during pregnancy. Diet and MVPA did not moderate the positive associations between SGF, obesity and cardiometabolic risk factors in children. CONCLUSION: Among the three lifestyle habits, only LPA had a protective effect against low levels of HDL-cholesterol in boys. More studies are needed to confirm these results to inform future lifestyle intervention in this population.

The FitSpirit approach for increasing physical activity in canadian teenage girls: protocol of a longitudinal, quasi-experimental study.

BACKGROUND: Worldwide, most adolescent girls do not meet physical activity (PA) recommendations and very few PA programs are tailored specifically towards them. Even fewer information exists about the long-term effects of such programs. Some Canadian schools have implemented the FitSpirit PA intervention designed specifically for girls aged 12 to 17 years old. This paper describes the protocol of a quasi-experimental study evaluating long-term changes in health behaviours and outcomes following FitSpirit participation. METHODS: The study is conducted among schools that partner with FitSpirit every year. It started in 2018 and will be completed in 2022. The intervention comprises motivational talks, a turnkey running program, PA sessions and special events. Study participants fill out an online questionnaire twice a year. Follow-up questionnaires are sent at the end of each school year to the study participants who dropout from FitSpirit. The main outcome, changes in PA levels, is evaluated using questions validated for adolescents. Secondary outcomes are health (perceived health); lifestyle habits (sedentary activities, eating and sleeping habits); psychosocial outcomes (physical self-efficacy and body satisfaction); and FitSpirit appreciation (activity participation and satisfaction). Most questions originate from questionnaires validated for the adolescent population. Cross-sectional and longitudinal analyses will be performed. DISCUSSION: This study will provide one of the first longitudinal reports on the impact of a large extra-curricular PA intervention designed specifically for adolescent girls. The current study will uniquely contribute to PA research by assessing outcomes additional to PA levels, including markers of health, lifestyle habits and psychosocial determinants. TRIAL REGISTRATION: NCT, NCT03804151 , Registered on January 22, 2019; retrospectively registered.

Better health indicators of FitSpirit participants meeting 24-h movement guidelines for Canadian children and youth.

This study aims to determine the proportion of girls who meet the recommendations for moderate-to-vigorous physical activity (MVPA), screen time and sleep duration among FitSpirit participants and evaluate the associations of these recommendations with perceived health-related quality of life (QOL), perceived health, physical activity (PA), self-efficacy and body mass index. Cross-sectional analyses of FitSpirit data were performed. All variables were collected through an online questionnaire. The proportion of girls meeting all recommendations was 2.2%, while 72.5% met either one or two and 25.4% met none. A greater percentage of girls with ≥3 years in FitSpirit met MVPA and sleep recommendations combined when compared with fewer years (12.9% vs. 1.7% with 1 year; vs. 10.1% with 2 years; p < 0.05). Meeting the combinations of MVPA and screen time (ß = 0.19, 95% CI = 0.40, 1.68), MVPA and sleep (ß = 0.20, 95% CI = 0.27, 1.04) and all three combined (ß = 0.17, 95% CI = 0.33, 1.71) was the most significant predictors of better perceived QOL. Respecting MVPA recommendations predicted a better perceived health (ß = 0.18, 95% CI = 0.18, 0.87) while girls who slept as recommended had a better PA-related self-efficacy (ß = 0.23, 95% CI = 0.51, 2.11). Not meeting any recommendation was associated with inferior PA-related self-efficacy (ß = -0.32, 95% CI = -3.03, -1.21). Lastly, meeting MVPA and sleep recommendations was significantly associated with lower body mass index z-scores (ß = -0.14, 95% CI = -1.16, -0.11). There was a small percentage of girls following all of the recommendations. Furthermore, meeting individual and combined recommendations was associated with better perceived QOL and health, PA self-efficacy as well as healthier body mass index z-score.

Substrate Oxidation Is Altered by Obesity During Submaximal Cycling in Prepubertal and Early Pubertal Children: A Quality Study.

BACKGROUND: To examine substrate oxidation in prepubertal and early pubertal children as a function of body weight, body composition, and sex during an exhaustive cycling test. METHODS: This study included 320 children in prepubertal and early puberty (Tanner stage 1 or 2; n = 188 males) who completed a minimum of 4 stages (2-5 min/stage) of an adapted version of the McMaster exhaustive exercise protocol on an upright cycle ergometer. Substrate utilization, relative to individual VO2peak, was determined using VO2 and VCO2 data, obtained with breath-by-breath gas analysis during exercise. RESULTS: Both peak (mg/kg lean body mass·min) and submaximal lipid oxidation (mg/kg lean body mass·min) were highest (P < .01) in children with healthy weight (HW), then overweight, and lowest in obese (OB). Both females with HW (compared with males with HW) and females with OB (compared with males with OB) had higher (P < .01) peak and submaximal lipid oxidation. In children with OB, fat-free mass correlated positively (P < .01) with submaximal lipid oxidation (r = .50). In contrast, in children with HW and overweight, fat-free mass correlated positively (P < .01) with carbohydrate oxidation (r = .52 and r = .47, respectively). CONCLUSION: Obesity during childhood may alter substrate oxidation during exercise. These results may have implications in the implementation of exercise programs in prepubertal or early puberty to control adiposity.

[2021 update of the GEFPICS' recommendations for HER2 status assessment in invasive breast cancer in France]. / Mise à jour 2021 des recommandations du GEFPICS pour l'évaluation du statut HER2 dans les cancers infiltrants du sein en France.

The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.

Reduction in ambulatory distance from childhood through adolescence: The impact of the number and length of steps.

BACKGROUND: The aim of this study was to explore the relationship between ambulatory distance with steps/day and increased step length as children age. METHODS: This is a prospective cohort study. Forty-five children from the QUALITY cohort were assessed at childhood (baseline) and seven years later during adolescence (follow-up). Daily step count was evaluated by accelerometry, step length by a standardized test, and daily ambulatory distance was calculated based on step count and length. RESULTS: Children grew by an average of 0.33 m from childhood to adolescence (p < 0.001). The daily ambulatory distance decreased by an average 3008 m from childhood to adolescence (p < 0.001). Step length increased an average of 0.10 m (p < 0.001) from childhood to adolescence, while the number of steps taken decreased by an average of 5549 steps (childhood to adolescence) (p < 0.001). The change in the number of steps between childhood and adolescence represents 84.6% of the change in the ambulatory distance while the change in step length explained an additional 13.0. CONCLUSIONS: The decrease in the ambulatory distance from childhood to adolescence was strongly explained by the decrease in step count; however the increase in step length should not to be neglected.

Promoting healthy lifestyle behaviours in youth: Findings from a novel intervention for children at risk of cardiovascular disease.

OBJECTIVES: Obesity is the most prevalent risk factor for cardiovascular disease (CVD) in children. We developed a 2-year lifestyle intervention for youth at risk of CVD. We assessed changes in body mass index z-scores (zBMI) and key cardiometabolic risk factors, physical fitness, and capacity among those who completed the program. METHODS: The CIRCUIT program is a multidisciplinary lifestyle intervention for children aged 4 to 18 years at risk of CVD, based on a personalized plan to improve cardiometabolic outcomes by increasing physical activity and reducing sedentary behaviours. Both at baseline and 2-year follow-up, we measured zBMI, blood pressure z-scores (zBP), adiposity (%body and %trunk fat), fasting blood glucose and lipid profile, aerobic (VO2max) and anaerobic (5×5 m shuttle run test) fitness, and physical capacity indicators. Differences between baseline and follow-up were examined using paired t-tests (for age-sex standardized outcomes) and multivariable mixed effect models, adjusted for age and sex (for other outcomes). RESULTS: Among the 106 participants (53 males) who completed the 2-year program, mean age at baseline was 10.9 years (SD=3.2). After 2 years, zBMI and diastolic zBP decreased by 0.30SD (95% CI: -0.44; -0.16) and 0.43SD (95% CI: -0.65; -0.23), respectively. Participants improved %body and %trunk fat, lipid profile, aerobic and anaerobic fitness levels, and physical capacity (p<0.02). No changes in systolic zBP nor in fasting plasma glucose were observed. CONCLUSION: Our findings showed improved zBMI, cardiometabolic outcomes, physical fitness, and capacity among children at risk of CVD, suggesting that CIRCUIT is a promising intervention.

Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy.

Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.