Average acceleration and intensity gradient of primary school children and associations with indicators of health and wellbeing

Average acceleration (AvAcc) and intensity gradient (IG) have been proposed as standardised metrics describing physical activity (PA) volume and intensity, respectively. We examined hypothesised between-group PA differences in AvAcc and IG, and their associations with health and wellbeing indicators in children. ActiGraph GT9X wrist accelerometers were worn for 24-h·d−1 over seven days by 145 children aged 9-10. Raw accelerations were averaged per 5-s epoch to represent AvAcc over 24-h. IG represented the relationship between log values for intensity and time. Moderate-to-vigorous PA (MVPA) was estimated using youth cutpoints. BMI z-scores, waist-to-height ratio (WHtR), peak oxygen uptake (VO2peak), Metabolic Syndrome risk (MetS score), and wellbeing were assessed cross-sectionally, and 8-weeks later. Hypothesised between-group differences were consistently observed for IG only (p<.001). AvAcc was strongly correlated with MVPA (r=0.96), while moderate correlations were observed between IG and MVPA (r=0.50) and AvAcc (r=0.54). IG was significantly associated with health indicators, independent of AvAcc (p<.001). AvAcc was associated with wellbeing, independent of IG (p<.05). IG was significantly associated with WHtR (p<.01) and MetS score (p<.05) at 8-weeks follow-up. IG is sensitive as a gauge of PA intensity that is independent of total PA volume, and which relates to important health indicators in children

The backwards comparability of wrist worn GENEActiv and waist worn ActiGraph accelerometer estimates of sedentary time in children

Objectives: To examine the backward comparability of a range of wrist-worn accelerometer estimates of sedentary time (ST) with ActiGraph 100 count∙min-1 waist ST estimates. Design: Cross-sectional, secondary data analysis Method: One hundred and eight 10-11-year-old children (65 girls) wore an ActiGraph GT3X+ accelerometer (AG) on their waist and a GENEActiv accelerometer (GA) on their non-dominant wrist for seven days. GA ST data were classified using a range of thresholds from 23-56 mg. ST estimates were compared to AG ST 100 count∙min-1 data. Agreement between the AG and GA thresholds was examined using Cronbach’s alpha, intraclass correlation coefficients (ICC), limits of agreement (LOA), Kappa values, percent agreement, mean absolute percent error (MAPE) and equivalency analysis. Results: Mean AG total ST was 492.4 minutes over the measurement period. Kappa values ranged from 0.31-0.39. Percent agreement ranged from 68-69.9%. Cronbach’s alpha values ranged from 0.88-0.93. ICCs ranged from 0.59-0.86. LOA were wide for all comparisons. Only the 34 mg threshold produced estimates that were equivalent at the group level to the AG ST 100 count∙min-1 data though sensitivity and specificity values of ~64% and ~74% respectively were observed. Conclusions: Wrist-based estimates of ST generated using the 34 mg threshold are comparable with those derived from the AG waist mounted 100 count∙min-1 threshold at the group level. The 34 mg threshold could be applied to allow group-level comparisons of ST with evidence generated using the ActiGraph 100 count∙min-1 method though it is important to consider the observed sensitivity and specificity results when interpreting findings

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

The degree of damage to DNA following ifosfamide (IFO) treatment may be linked to the therapeutic efficacy. The pharmacokinetics and metabolism of IFO were studied in 19 paediatric patients, mostly with rhabdomyosarcoma or Ewings sarcoma. Ifosfamide was dosed either as a continuous infusion or as fractionated doses over 2 or 3 days. Samples of peripheral blood lymphocytes were obtained during and up to 96 h after treatment, and again prior to the next cycle of chemotherapy. DNA damage was measured using the alkaline COMET assay, and quantified as the percentage of highly damaged cells per sample. Samples were also taken for the determination of IFO and metabolites. Pharmacokinetics and metabolism of IFO were comparable with previous studies. Elevations in DNA damage could be determined in all patients after IFO administration. The degree of damage increased to a peak at 72 h, but had returned to pretreatment values prior to the next dose of chemotherapy. There was a good correlation between area under the curve of IFO and the cumulative percentage of cells with DNA damage (r2 = 0.554, P = 0.004), but only in those patients receiving fractionated dosing. The latter patients had more DNA damage (mean ± s.d., 2736 ± 597) than those patients in whom IFO was administered by continuous infusion (1453 ± 730). The COMET assay can be used to quantify DNA damage following IFO therapy. Fractionated dosing causes a greater degree of DNA damage, which may suggest a greater degree of efficacy, with a good correlation between pharmacokinetic and pharmacodynamic data

Cut-point-free accelerometer metrics to assess children's physical activity: an example using the school day

The aims were to (i) investigate associations between a novel accelerometer metric: the minimum acceleration value above which the most active 30-minutes were accumulated during the school day (M30ACC), and health indicators, and (ii) demonstrate that applying an equivalent cut-point to the M30ACC metric gives comparable prevalence results as a moderate-to-vigorous physical activity (MVPA) cut-point approach. Two-hundred-and-ninety-six children (age 9-10-years) wore wrist-mounted accelerometers for 7-days. School day MVPA and M30ACC were calculated. Body mass index (BMI), waist-to-height ratio (WHtR), and cardiorespiratory fitness (CRF) were also measured. Mixed linear models investigated associations between M30ACC and health indicators. Agreement between ranked MVPA and M30ACC values was assessed using percent agreement, kappa, sensitivity, and specificity statistics. M30ACC thresholds associated with health indicators were 213 mg (BMI), 206 mg (WHtR), and 269 mg (CRF) for girls. The equivalent values for boys were 234mg (BMI), 230 mg (WHtR), and 327 mg (CRF). Less than half of girls and 75% of boys accumulated 30 minutes of school day MVPA. Just less than 50% of girls and >80% of boys had M30ACC values ≥200 mg, which is equivalent to brisk walking. Agreement between MVPA and M30ACC tertiles was high, reflected by the sensitivity and specificity values of > 90%. Results demonstrate the utility of M30ACC as a PA metric that is not heavily influenced by researcher decisions. M30ACC has potential as an accelerometer-specific metric for generating PA guidelines related to health indicators, and easily understood forms of activity such as brisk walking

Validating the Sedentary Sphere method in children: does wrist or accelerometer brand matter?

This study aimed to validate the Sedentary Sphere posture classification method from wrist-worn accelerometers in children. Twenty-seven 9-10-year-old children wore ActiGraph GT9X (AG) and GENEActiv (GA) accelerometers on both wrists, and activPAL on the thigh while completing prescribed activities: five sedentary activities, standing with phone, walking (criterion for all 7: observation) and ten minutes free-living play (criterion: activPAL). In an independent sample, 21 children wore AG and GA accelerometers on the non-dominant wrist and activPAL for two days of free-living. Percent accuracy, pairwise 95% equivalence tests (±10% equivalence zone) and intra-class correlation coefficients (ICC) analyses were completed. Accuracy was similar, for prescribed activities irrespective of brand (non-dominant wrist: 77%-78%; dominant wrist: 79%). Posture estimates were equivalent between wrists within brand (±6%, ICC>0.81, lower 95% CI>0.75), between brands worn on the same wrist (±5%, ICC>0.84, lower 95% CI>0.80) and between brands worn on opposing wrists (±6%, ICC>0.78, lower 95% CI>0.72). Agreement with activPAL during free-living was 77%, but sedentary time was underestimated by 7% (GA) and 10% (AG). The Sedentary Sphere can be used to classify posture from wrist-worn AG and GA accelerometers for group-level estimates in children, but future work is needed to improve the algorithm for better individual-level results

A population pharmacokinetic model of AT9283 in adults and children to predict the maximum tolerated dose in children with leukaemia

Aims AT9283 is used to treat patients with solid tumours and patients with leukaemia. However, the maximum tolerated dose (MTD) for children with leukaemia remains unknown due to early termination of the Phase I trial. The aim of this study was to develop a population model of AT9283 to describe the pharmacokinetics in adults and children and to estimate the MTD in children with leukaemia. Methods Data from Phase I dose‐escalation studies in adults and children were used to build a population pharmacokinetic model (NONMEM v7.3). Potential covariates investigated included body weight, body surface area (BSA), glomerular filtration rate (GFR), age and sex. Model‐derived area under the concentration–time curve was used to investigate the relationship between dose and exposure in adults and children. Results The plasma concentrations of AT9283 (n = 1770) from 92 patients (53 adults, 39 children) were used to build a two‐compartment model with all pharmacokinetic parameters scaled using body weight. Renal function (GFR), but not BSA, was a significant covariate for the clearance of AT9283. In children with leukaemia (median weight 16 kg), a flat dose of 500 mg 72 h–1 provided similar drug exposures at the MTD as the adult population. The estimated MTD for children with leukaemia, therefore, is 30 mg kg−1 72 h–1. Conclusion For adults, GFR was a significant predictor of clearance, whilst body‐weight based dosing was more useful than BSA in determining the drug exposure in children. The MTD was estimated to be 30 mg kg−1 72 h–1 children with leukaemia

Choice of activity-intensity classification thresholds impacts upon accelerometer-assessed physical activity-health relationships in children

It is unknown whether using different published thresholds (PTs) for classifying physical activity (PA) impacts upon activity-health relationships. This study explored whether relationships between PA (sedentary [SED], light PA [LPA], moderate PA [MPA], moderate-to-vigorous PA, vigorous PA [VPA]) and health markers differed in children when classified using three different PTs

Associations between cardiorespiratory fitness, physical activity and clustered cardiometabolic risk in children and adolescents: the HAPPY study

Clustering of cardiometabolic risk factors can occur during childhood and predisposes individuals to cardiometabolic disease. This study calculated clustered cardiometabolic risk in 100 children and adolescents aged 10-14 years (59 girls) and explored differences according to cardiorespiratory fitness (CRF) levels and time spent at different physical activity (PA) intensities. CRF was determined using a maximal cycle ergometer test, and PA was assessed using accelerometry. A cardiometabolic risk score was computed as the sum of the standardised scores for waist circumference, blood pressure, total cholesterol/high-density lipoprotein ratio, triglycerides and glucose. Differences in clustered cardiometabolic risk between fit and unfit participants, according to previously proposed health-related threshold values, and between tertiles for PA subcomponents were assessed using ANCOVA. Clustered risk was significantly lower (p < 0.001) in the fit group (mean 1.21 ± 3.42) compared to the unfit group (mean -0.74 ± 2.22), while no differences existed between tertiles for any subcomponent of PA. Conclusion These findings suggest that CRF may have an important cardioprotective role in children and adolescents and highlights the importance of promoting CRF in youth

Converting between estimates of moderate-to-vigorous physical activity derived from raw accelerations measured at the wrist and from ActiGraph counts measured at the hip: The Rosetta Stone

The ability to compare published group-level estimates of objectively measured moderate-to-vigorous physical activity (MVPA) across studies continues to increase in difficulty. The objective of this study was to develop conversion equations and demonstrate their utility to compare estimates of MVPA derived from the wrist and hip. Data from three studies of youth (N = 232, 9-12yrs, 50% boys) who concurrently wore a hip-worn ActiGraph and a wrist-worn GENEActiv for 7-days. ActiGraph hip count data were reduced using four established cutpoints: Evenson, Pate, Puyau, and Freedson 3MET. Wrist accelerations were reduced using the Hildebrand MVPA 200 mg threshold. Conversion equations were developed on a randomly selected subsample of 132 youth. Equations were cross-validated and absolute error, absolute percent error, and modified Bland-Altman plots were evaluated for conversion accuracy. Across equations R2adj was 0.51-0.56 with individual-level absolute error in minutes ranging from 7 (wrist-to-hip Puyau) to 14.5 minutes (wrist-to-hip Freedson 3MET) and absolute percent differences ranging from 13.9%-24.5%. Group-level cross-validation to convert hip-to-wrist MVPA resulted in average absolute percent errors ranging from 3.1%-4.9%. Conversion of wrist- to-hip MVPA resulted in average absolute percent errors ranging from 3.0%-10.0%. We recommend the use of these equations to compare published estimates of MVPA between the wear-site cut-point combinations presented

A phase I and pharmacokinetic study of NK105, a paclitaxel-incorporating micellar nanoparticle formulation

This phase I study was designed to examine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), the recommended dose (RD) for phase II, and the pharmacokinetics of NK105, a new polymeric micelle carrier system for paclitaxel (PTX). NK105 was administered as a 1-h intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg m−2, and the dose was escalated according to the accelerated titration method. Nineteen patients were recruited. The tumour types treated included pancreatic (n=11), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common haematological toxicity. A grade 3 fever developed in one patient given 180 mg m−2. No other grades 3 or 4 nonhaematological toxicities, including neuropathy, was observed during the entire study period. DLTs occurred in two patients given 180 mg m−2 (grade 4 neutropenia lasting for more than 5 days). Thus, this dose was designated as the MTD. Grade 2 hypersensitivity reactions developed in only one patient given 180 mg m−2. A partial response was observed in one patient with pancreatic cancer. The maximum concentration (Cmax) and area under the concentration (AUC) of NK105 were dose dependent. The plasma AUC of NK105 at 150 mg m−2 was approximately 15-fold higher than that of the conventional PTX formulation. NK105 was well tolerated, and the RD for the phase II study was determined to be 150 mg m−2 every 3 weeks. The results of this phase I study warrant further clinical evaluation