Targeting histone deacetylases for the treatment of immune, endocrine and metabolic disorders

The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as histone acetyltransferases or HATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The proinflammatory environment is increasingly being recognised as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential & current development of histone deacetylases for the treatment of diseases for which a proinflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the proinflammatory environment. © 2009 Bentham Science Publishers Ltd.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Urinary biomarkers of physical activity : candidates and clinical utility

Chronic physical inactivity is a major risk factor for a number of important lifestyle diseases, while inappropriate exposure to high physical demands is a risk factor for musculoskeletal injury and fatigue. Proteomic and metabolomic investigations of the physical activity continuum - extreme sedentariness to extremes in physical performance - offer increasing insight into the biological impacts of physical activity. Moreover, biomarkers, revealed in such studies, may have utility in the monitoring of metabolic and musculoskeletal health or recovery following injury. As a diagnostic matrix, urine is non-invasive to collect and it contains many biomolecules, which reflect both positive and negative adaptations to physical activity exposure. This review examines the utility and landscape of biomarkers of physical activity with particular reference to those found in urine.

Physical activity patterns and correlates among adults from a developing country : the Sri Lanka Diabetes and Cardiovascular Study

OBJECTIVE: To evaluate patterns of physical activity (PA), the prevalence of physical inactivity and the relationships between PA and sociodemographic, clinical and biochemical parameters among Sri Lankan adults. DESIGN: Descriptive cross-sectional study. SETTING: Nationally representative population-based survey conducted in Sri Lanka. SUBJECTS: Data on PA and associated details were obtained from 5000 adults. PA was assessed using the International Physical Activity Questionnaire (short-form). A binary logistic regression analysis was performed using the dichotomous variable ‘health-enhancing PA’ (05‘active’, 15‘inactive’). RESULTS: Sample size was 4485. Mean age was 46.1 (SD 15.1) years, 39.5% were males. The mean weekly total MET (metabolic equivalents of task) minutes of PA among the study population was 4703 (SD 4369). Males (5464 (SD 5452)) had a significantly higher weekly total MET minutes than females (4205 (SD 3394); P,0.001). Rural adults (5175 (SD 4583)) were significantly more active than urban adults (2956 (SD 2847); P<0.001). Tamils had the highest mean weekly total MET minutes among ethnicities. Those with tertiary education had lowest mean weekly total MET minutes. In all adults 60.0% were in the ‘highly active’ category, while only 11.0% were ‘inactive’ (males 14.6%, females 8.7%; P<0.001). Of the ‘highly active’ adults, 85.8% were residing in rural areas. Results of the binary logistic regression analysis indicated that female gender (OR52?1), age .70 years (OR53.8), urban living (OR52.5), Muslim ethnicity (OR52.7), tertiary education (OR53.6), obesity (OR51.8), diabetes (OR51.6), hypertension (OR51.2) and metabolic syndrome (OR51.3) were all associated with significantly increased odds of being physically ‘inactive’. CONCLUSIONS: The majority of Sri Lankan adults were ‘highly active’ physically. Female gender, older age, urban living, Muslim ethnicity and tertiary education were all significant predictors of physical inactivity. Physical inactivity was associated with obesity, diabetes, hypertension and metabolic syndrome.

Genomic organisation, activity and distribution analysis of the microbial putrescine oxidase degradation pathway

The catalytic action of putrescine specific amine oxidases acting in tandem with 4-aminobutyraldehyde dehydrogenase is explored as a degradative pathway in Rhodococcus opacus. By limiting the nitrogen source, increased catalytic activity was induced leading to a coordinated response in the oxidative deamination of putrescine to 4-aminobutyraldehyde and subsequent dehydrogenation to 4-aminobutyrate. Isolating the dehydrogenase by ion exchange chromatography and gel filtration revealed that the enzyme acts principally on linear aliphatic aldehydes possessing an amino moiety. Michaelis-Menten kinetic analysis delivered a Michaelis constant (KM=0.014mM) and maximum rate (Vmax=11.2μmol/min/mg) for the conversion of 4-aminobutyraldehyde to 4-aminobutyrate. The dehydrogenase identified by MALDI-TOF mass spectrometric analysis (E value=0.031, 23% coverage) belongs to a functionally related genomic cluster that includes the amine oxidase, suggesting their association in a directed cell response. Key regulatory, stress and transport encoding genes have been identified, along with candidate dehydrogenases and transaminases for the further conversion of 4-aminobutyrate to succinate. Genomic analysis has revealed highly similar metabolic gene clustering among members of Actinobacteria, providing insight into putrescine degradation notably among Micrococcaceae, Rhodococci and Corynebacterium by a pathway that was previously uncharacterised in bacteria.

Comparison of accelerometer cut points for predicting activity intensity in youth

The absence of comparative validity studies has prevented researchers from reaching consensus regarding the application of intensity-related accelerometer cut points for children and adolescents. PURPOSE This study aimed to evaluate the classification accuracy of five sets of independently developed ActiGraph cut points using energy expenditure, measured by indirect calorimetry, as a criterion reference standard. METHODS A total of 206 participants between the ages of 5 and 15 yr completed 12 standardized activity trials. Trials consisted of sedentary activities (lying down, writing, computer game), lifestyle activities (sweeping, laundry, throw and catch, aerobics, basketball), and ambulatory activities (comfortable walk, brisk walk, brisk treadmill walk, running). During each trial, participants wore an ActiGraph GT1M, and VO 2 was measured breath-by-breath using the Oxycon Mobile portable metabolic system. Physical activity intensity was estimated using five independently developed cut points: Freedson/Trost (FT), Puyau (PU), Treuth (TR), Mattocks (MT), and Evenson (EV). Classification accuracy was evaluated via weighted κ statistics and area under the receiver operating characteristic curve (ROC-AUC). RESULTS Across all four intensity levels, the EV (κ = 0.68) and FT (κ = 0.66) cut points exhibited significantly better agreement than TR (κ = 0.62), MT (κ = 0.54), and PU (κ = 0.36). The EV and FT cut points exhibited significantly better classification accuracy for moderate-to vigorous-intensity physical activity (ROC-AUC = 0.90) than TR, PU, or MT cut points (ROC-AUC = 0.77-0.85). Only the EV cut points provided acceptable classification accuracy for all four levels of physical activity intensity and performed well among children of all ages. The widely applied sedentary cut point of 100 counts per minute exhibited excellent classification accuracy (ROC-AUC = 0.90). CONCLUSIONS On the basis of these findings, we recommend that researchers use the EV ActiGraph cut points to estimate time spent in sedentary, light-, moderate-, and vigorous-intensity activity in children and adolescents. Copyright © 2011 by the American College of Sports Medicine.

Artificial neural networks to predict activity type and energy expenditure in youth

Previous studies have demonstrated that pattern recognition approaches to accelerometer data reduction are feasible and moderately accurate in classifying activity type in children. Whether pattern recognition techniques can be used to provide valid estimates of physical activity (PA) energy expenditure in youth remains unexplored in the research literature. Purpose: The objective of this study is to develop and test artificial neural networks (ANNs) to predict PA type and energy expenditure (PAEE) from processed accelerometer data collected in children and adolescents. Methods: One hundred participants between the ages of 5 and 15 yr completed 12 activity trials that were categorized into five PA types: sedentary, walking, running, light-intensity household activities or games, and moderate-to-vigorous intensity games or sports. During each trial, participants wore an ActiGraph GTIM on the right hip, and (V) Over dotO(2) was measured using the Oxycon Mobile (Viasys Healthcare, Yorba Linda, CA) portable metabolic system. ANNs to predict PA type and PAEE (METs) were developed using the following features: 10th, 25th, 50th, 75th, and 90th percentiles and the lag one autocorrelation. To determine the highest time resolution achievable, we extracted features from 10-, 15-, 20-, 30-, and 60-s windows. Accuracy was assessed by calculating the percentage of windows correctly classified and root mean square en-or (RMSE). Results: As window size increased from 10 to 60 s, accuracy for the PA-type ANN increased from 81.3% to 88.4%. RMSE for the MET prediction ANN decreased from 1.1 METs to 0.9 METs. At any given window size, RMSE values for the MET prediction ANN were 30-40% lower than the conventional regression-based approaches. Conclusions: ANNs can be used to predict both PA type and PAEE in children and adolescents using count data from a single waist mounted accelerometer.

Correlates of physical activity behavior in rural youth

The purpose of this study was to identify correlates of physical activity behavior in a sample of rural, predominantly African American youth. Three hundred sixty-one fifth-grade students from two rural counties in South Carolina (69% African American, median age = II years) completed a questionnaire designed to measure beliefs and social influences regarding physical activity, physical activity self-efficacy, perceived physical activity habits of family members and friends, and access to exercise and fitness equipment at home. After school physical activity and television watching were assessed using the Previous Day Physical Activity Recall (PDPAR). Students were classified as physically active according to a moderate physical activity standard: two or more 30-min blocks at an intensity of 3 METs (metabolic equivalents) or greater, and a vigorous physical activity standard: one or more 30-min blocks at an intensity of 6 METs or greater According to the moderate physical activity standard, 34.9% of students were classified as low-active. Multivariate analysis revealed age, gender television watching, and exercise equipment at home to be significant correlates of low activity status. According to the vigorous physical activity standard, 32.1 % of the students were classified as low-active. Multivariate analysis revealed age, gender television watching, and self-efficacy with respect to seeking support for physical activity to be significant correlates of low activity status. In summary, gender and the amount of television watching were found to be the most important correlates of physical activity in rural, predominantly African American youth.

Community wide interventions for increasing physical activity

Background Multi-strategic community wide interventions for physical activity are increasingly popular but their ability to achieve population level improvements is unknown. Objectives To evaluate the effects of community wide, multi-strategic interventions upon population levels of physical activity. Search methods We searched the Cochrane Public Health Group Segment of the Cochrane Register of Studies,The Cochrane Library, MEDLINE, MEDLINE in Process, EMBASE, CINAHL, LILACS, PsycINFO, ASSIA, the British Nursing Index, Chinese CNKI databases, EPPI Centre (DoPHER, TRoPHI), ERIC, HMIC, Sociological Abstracts, SPORTDiscus, Transport Database and Web of Science (Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index). We also scanned websites of the EU Platform on Diet, Physical Activity and Health; Health-Evidence.org; the International Union for Health Promotion and Education; the NIHR Coordinating Centre for Health Technology (NCCHTA); the US Centre for Disease Control and Prevention (CDC) and NICE and SIGN guidelines. Reference lists of all relevant systematic reviews, guidelines and primary studies were searched and we contacted experts in the field. The searches were updated to 16 January 2014, unrestricted by language or publication status. Selection criteria Cluster randomised controlled trials, randomised controlled trials, quasi-experimental designs which used a control population for comparison, interrupted time-series studies, and prospective controlled cohort studies were included. Only studies with a minimum six-month follow up from the start of the intervention to measurement of outcomes were included. Community wide interventions had to comprise at least two broad strategies aimed at physical activity for the whole population. Studies which randomised individuals from the same community were excluded. Data collection and analysis At least two review authors independently extracted the data and assessed the risk of bias. Each study was assessed for the setting, the number of included components and their intensity. The primary outcome measures were grouped according to whether they were dichotomous (per cent physically active, per cent physically active during leisure time, and per cent physically inactive) or continuous (leisure time physical activity time (time spent)), walking (time spent), energy expenditure (as metabolic equivalents or METS)). For dichotomous measures we calculated the unadjusted and adjusted risk difference, and the unadjusted and adjusted relative risk. For continuous measures we calculated percentage change from baseline, unadjusted and adjusted. Main results After the selection process had been completed, 33 studies were included. A total of 267 communities were included in the review (populations between 500 and 1.9 million). Of the included studies, 25 were set in high income countries and eight were in low income countries. The interventions varied by the number of strategies included and their intensity. Almost all of the interventions included a component of building partnerships with local governments or non-governmental organisations (NGOs) (29 studies). None of the studies provided results by socio-economic disadvantage or other markers of equity. However, of those included studies undertaken in high income countries, 14 studies were described as being provided to deprived, disadvantaged or low socio-economic communities. Nineteen studies were identified as having a high risk of bias, 10 studies were unclear, and four studies had a low risk of bias. Selection bias was a major concern with these studies, with only five studies using randomisation to allocate communities. Four studies were judged as being at low risk of selection bias although 19 studies were considered to have an unclear risk of bias. Twelve studies had a high risk of detection bias, 13 an unclear risk and four a low risk of bias. Generally, the better designed studies showed no improvement in the primary outcome measure of physical activity at a population level. All four of the newly included, and judged to be at low risk of bias, studies (conducted in Japan, United Kingdom and USA) used randomisation to allocate the intervention to the communities. Three studies used a cluster randomised design and one study used a stepped wedge design. The approach to measuring the primary outcome of physical activity was better in these four studies than in many of the earlier studies. One study obtained objective population representative measurements of physical activity by accelerometers, while the remaining three low-risk studies used validated self-reported measures. The study using accelerometry, conducted in low income, high crime communities of USA, emphasised social marketing, partnership with police and environmental improvements. No change in the seven-day average daily minutes of moderate to vigorous physical activity was observed during the two years of operation. Some program level effect was observed with more people walking in the intervention community, however this result was not evident in the whole community. Similarly, the two studies conducted in the United Kingdom (one in rural villages and the other in urban London; both using communication, partnership and environmental strategies) found no improvement in the mean levels of energy expenditure per person per week, measured from one to four years from baseline. None of the three low risk studies reporting a dichotomous outcome of physical activity found improvements associated with the intervention. Overall, there was a noticeable absence of reporting of benefit in physical activity for community wide interventions in the included studies. However, as a group, the interventions undertaken in China appeared to have the greatest possibility of success with high participation rates reported. Reporting bias was evident with two studies failing to report physical activity measured at follow up. No adverse events were reported.The data pertaining to cost and sustainability of the interventions were limited and varied. Authors' conclusions Although numerous studies have been undertaken, there is a noticeable inconsistency of the findings in the available studies and this is confounded by serious methodological issues within the included studies. The body of evidence in this review does not support the hypothesis that the multi-component community wide interventions studied effectively increased physical activity for the population, although some studies with environmental components observed more people walking. Plain language summary Community wide interventions for increasing physical activity Not having enough physical activity leads to poorer health. Regular physical activity can reduce the risk of chronic disease and improve one's health and wellbeing. The lack of physical activity is a common and in some cases a growing health problem. To address this, 33 studies have used improvement activities directed at communities, using more than one approach in a single program. When we first looked at the available research in 2011 we observed that there was a lack of good studies which could show whether this approach was beneficial or not. Some studies claimed that community wide programs improved physical activities and other studies did not. In this update we found four new studies that were of good quality; however none of these four studies increased physical activity levels for the population. Some studies reported program level effects such as observing more people walking, however the population level of physical activity had not increased. This review found that community wide interventions are very difficult to undertake, and it appears that they usually fail to provide a measurable benefit in physical activity for a population. It is apparent that many of the interventions failed to reach a substantial portion of the community, and we speculate that some single strategies included in the combination may lack individual effectiveness. Laički sažetak Intervencije u zajednici za povećanje tjelesne aktivnosti Nedostatna tjelesna aktivnost povezana je s lošijim zdravljem.Redovita tjelesna aktivnost može umanjiti rizik od kroničnih bolesti te poboljšati zdravlje i kvalitetu života pojedinca.Manjak tjelesne aktivnosti čest je problem, a učestalost tog problema se povećava.Cochrane sustavni pregled je analizirao 33 studije koje su istražile programe za povećanje tjelesne aktivnosti u zajednici, u kojima se koristilo više od jednog pristupa.Kad su prvi put pregledani dokazi iz istraživanja koja su bila dostupna 2011. godine, utvrđeno je da nema dovoljno dobrih studija koje bi mogle pokazati je li takav pristup koristan ili ne.Primjerice, neke studije tvrde da programi za povećanje tjelesne aktivnosti u zajednici poboljšavaju tjelesnu aktivnost pojedinaca u zajednici, a druge studije tvrde suprotno.U ovom obnovljenom sustavnom pregledu pronađene su 4 nove studije koje su bile visoke kvalitete, ail nijedna od tih studija nije pokazala da je istraživana intervencija dovela do povećanja tjelesne aktivnosti u zajednici.Neke su studije opisale učinak na način da je opisano da je uočeno da više ljudi u zajednici hoda, međutim, ukupna razina tjelesne aktivnosti u promatranoj populaciji nije se povećala.Ovaj sustavni pregled je utvrdio da je intervencije za povećanje tjelesne aktivnosti u zajednici teško provesti i čini se da one obično ne uspijevaju u svojoj namjeri da na mjerljiv način povećaju tjelesnu aktivnost u populaciji.Čini se da mnoge intervencije nisu uspjele doseći veći broj stanovnika u zajednici pa se može smatrati da neke od strategija uključene u analizirane kombinacije nisu zasebno učinkovite.

The influence of family history of hypertension on disease prevalence and associated metabolic risk factors among Sri Lankan adults

Background Hypertension is a major contributor to the global non-communicable disease burden. Family history is an important non-modifiable risk factor for hypertension. The present study aims to describe the influence of family history (FH) on hypertension prevalence and associated metabolic risk factors in a large cohort of South Asian adults, from a nationally representative sample from Sri Lanka. Methods A cross-sectional survey among 5,000 Sri Lankan adults, evaluating FH at the levels of parents, grandparents, siblings and children. A binary logistic regression analysis was performed in all patients with ‘presence of hypertension’ as dichotomous dependent variable and using family history in parents, grandparents, siblings and children as binary independent variables. The adjusted odds ratio controlling for confounders (age, gender, body mass index, diabetes, hyperlipidemia and physical activity) are presented below. Results In all adults the prevalence of hypertension was significantly higher in patients with a FH (29.3 %, n = 572/1951) than those without (24.4 %, n = 616/2530) (p < 0.001). Presence of a FH significantly increased the risk of hypertension (OR:1.29; 95 % CI:1.13-1.47), obesity (OR:1.36; 95 % CI: 1.27–1.45), central obesity (OR:1.30; 95 % CI 1.22–1.40) and metabolic syndrome (OR:1.19; 95 % CI: 1.08–1.30). In all adults presence of family history in parents (OR:1.28; 95 % CI: 1.12–1.48), grandparents (OR:1.34; 95 % CI: 1.20–1.50) and siblings (OR:1.27; 95 % CI: 1.21–1.33) all were associated with significantly increased risk of developing hypertension. Conclusions Our results show that the prevalence of hypertension was significantly higher in those with a FH of hypertension. FH of hypertension was also associated with the prevalence of obesity, central obesity and metabolic syndrome. Individuals with a FH of hypertension form an easily identifiable group who may benefit from targeted interventions.

Influence of habitual physical activity on gastric emptying in healthy males and relationships with body composition and energy expenditure

Although a number of studies have examined the role of gastric emptying (GE) in obesity, the influences of habitual physical activity level, body composition and energy expenditure (EE) on GE have received very little consideration. In this study, we have compared GE in active and inactive males, and we have characterised relationships with body composition (fat and fat free mass) and EE. Forty-four males (Active: n=22, Inactive: n=22; range BMI 21-36kg/m2; range percent fat mass 9-42%) were studied, with GE of a standardised (1676 kJ) pancake meal being assessed by 13C-octanoic acid breath test, body composition by air displacement plethysmography, resting metabolic rate (RMR) by indirect calorimetry and activity EE (AEE) by accelerometry. Results showed that GE was faster in active compared to inactive males (mean ±SD half time (t1/2): Active: 157±18 and Inactive: 179±21 min, p<0.001). When data from both groups were pooled, GE t1/2 was associated with percent fat mass (r=0.39, p<0.01) and AEE (r =-0.46, p<0.01). After controlling for habitual physical activity status, the association between AEE and GE remained, but not that for percent fat mass and GE. BMI and RMR were not associated with GE. In summary, faster GE is considered to be a marker of a habitually active lifestyle in males, and is associated with a higher AEE and lower percent fat mass. The possibility that GE contributes to a gross physiological regulation (or dysregulation) of food intake with physical activity level deserves further investigation.

Living well with diabetes: 24-month outcomes from a randomized trial of telephone-delivered weight loss and physical activity intervention to improve glycemic control

OBJECTIVE: To evaluate the effectiveness of a telephone-delivered behavioral weight loss and physical activity intervention targeting Australian primary care patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Pragmatic randomized controlled trial of telephone counseling (n = 151) versus usual care (n = 151). Reported here are 18-month (end-of-intervention) and 24-month (maintenance) primary outcomes of weight, moderate-to-vigorous-intensity physical activity (MVPA; via accelerometer), and HbA1c level. Secondary outcomes include dietary energy intake and diet quality, waist circumference, lipid levels, and blood pressure. Data were analyzed via adjusted linear mixed models with multiple imputation of missing data. RESULTS: Relative to usual-care participants, telephone counseling participants achieved modest, but significant, improvements in weight loss (relative rate [RR] -1.42% of baseline body weight [95% CI -2.54 to -0.30% of baseline body weight]), MVPA (RR 1.42 [95% CI 1.06-1.90]), diet quality (2.72 [95% CI 0.55-4.89]), and waist circumference (-1.84 cm [95% CI -3.16 to -0.51 cm]), but not in HbA1c level (RR 0.99 [95% CI 0.96-1.02]), or other cardio-metabolic markers. None of the outcomes showed a significant change/deterioration over the maintenance period. However, only the intervention effect for MVPA remained statistically significant at 24 months. CONCLUSIONS: The modest improvements in weight loss and behavior change, but the lack of changes in cardio-metabolic markers, may limit the utility, scalability, and sustainability of such an approach.

Exploring metrics to express energy expenditure of physical activity in youth

Background Several approaches have been used to express energy expenditure in youth, but no consensus exists as to which best normalizes data for the wide range of ages and body sizes across a range of physical activities. This study examined several common metrics for expressing energy expenditure to determine whether one metric can be used for all healthy children. Such a metric could improve our ability to further advance the Compendium of Physical Activities for Youth. Methods A secondary analysis of oxygen uptake (VO2) data obtained from five sites was completed, that included 947 children ages 5 to 18 years, who engaged in 14 different activities. Resting metabolic rate (RMR) was computed based on Schofield Equations [Hum Nutr Clin Nut. 39(Suppl 1), 1985]. Absolute oxygen uptake (ml.min-1), oxygen uptake per kilogram body mass (VO2 in ml.kg-1.min-1), net oxygen uptake (VO2 – resting metabolic rate), allometric scaled oxygen uptake (VO2 in ml.kg-0.75.min-1) and YOUTH-MET (VO2.[resting VO2] -1) were calculated. These metrics were regressed with age, sex, height, and body mass. Results Net and allometric-scaled VO2, and YOUTH-MET were least associated with age, sex and physical characteristics. For moderate-to-vigorous intensity activities, allometric scaling was least related to age and sex. For sedentary and low-intensity activities, YOUTH-MET was least related to age and sex. Conclusions No energy expenditure metric completely eliminated the influence of age, physical characteristics, and sex. The Adult MET consistently overestimated EE. YOUTH-MET was better for expressing energy expenditure for sedentary and light activities, whereas allometric scaling was better for moderate and vigorous intensity activities. From a practical perspective, The YOUTH-MET may be the more feasible metric for improving of the Compendium of Physical Activities for Youth.