Abstract
Background
Governments internationally have invested hugely in the implementation and scale-up of school-based physical activity interventions, but have little evidence of how to best ...sustain these interventions once active implementation support ceases. This study will assess the effectiveness of a multi-strategy sustainability intervention on classroom teachers’ sustainment of energisers (short 3–5 min physical activity breaks during class-time) scheduled across the school day from baseline to 12 and 24-month follow-up.
Methods
A cluster randomised controlled trial will be conducted in 50 primary schools within the Hunter New England, Illawarra Shoalhaven, Murrumbidgee and Northern New South Wales (NSW) Local Health Districts of NSW Australia. Schools will be randomly allocated to receive either usual support or the multi-strategy sustainability intervention that includes: centralised technical assistance from a trained project officer; formal commitment and mandated change obtained from school principals; training in-school champions; reminders for teachers; educational materials provided to teachers; capturing and sharing local knowledge; and engagement of parents, carers and the wider school community. The primary trial outcome will be measured via a teacher logbook to determine the between-group difference in the change in mean minutes of energisers scheduled across the school day at 12 and 24-month follow-up compared to baseline. Analyses will be performed using an intention to treat framework. Linear mixed models will be used to assess intervention effects on the primary outcome at both follow-up periods.
Discussion
This study will be one of the first randomised controlled trials to examine the impact of a multi-strategy sustainability intervention to support schools’ sustainment of a physical activity intervention. The proposed research will generate new evidence needed for the partnering organisations to protect their considerable investments to date in physical activity promotion in this setting and will provide seminal evidence for the field globally.
Trial registration
ACTRN12620000372987 version 1 registered 17
th
March 2020. Version 3 (current version) updated 4
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August 2023.
This study aimed to quantify, and examine grade level (Grade Kindergarten-2 vs. 3–6) and sex differences in the daily minutes of moderate-to-vigorous physical activity (MVPA) of primary school ...children, and the proportion of children meeting MVPA recommendations, across the school day and in break times. Consenting children in Kindergarten to Grade 6 from 12 Catholic primary schools within the Hunter region of New South Wales, Australia (February-April 2017) wore accelerometers during school hours (approx. 9am-3 pm) for five school days. Differences in student physical activity by Grade (Kindergarten-2; Grade 3–6) and sex were analysed using regression mixed modelling for the whole school day, during class time and break time. Valid data was available for 1862 students. Mean (SD) minutes of MVPA were consistently higher for Grade K-2 compared to Grade 3–6 students respectively, 37.02 (12.4) and 32.6 (12.2) across the school day; 20.4 (8.4) and 15.3 (7.6) minutes within breaks. Over the whole school day 69.7% of Grade K-2 and 54.1% of Grade 3–6 met the recommended 30 min of MVPA. Boys had higher MVPA than girls and a higher proportion of boys met MVPA recommendations than girls with 68.9% and 52.4% over whole school day and 6.43% and 0.98% respectively during break times. A large percentage of Australian children are not meeting physical activity guidelines whilst at school, with declining levels of physical activity from Grade K-2 to Grade 3–6 especially evident in girls.
Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by ...small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.
Vascular endothelial growth factor (VEGF) is a potent molecule that mediates tumor angiogenesis primarily through VEGF receptor 2 (VEGFR2). Bevacizumab, a recombinant humanized monoclonal antibody to ...VEGF, was administered to previously untreated patients to evaluate parameters of angiogenesis.
Twenty-one patients with inflammatory and locally advanced breast cancer were treated with bevacizumab for cycle 1 (15 mg/kg on day 1) followed by six cycles of bevacizumab with doxorubicin (50 mg/m(2)) and docetaxel (75 mg/m(2)) every 3 weeks. After locoregional therapy, patients received eight cycles of bevacizumab alone, and hormonal therapy when indicated. Tumor biopsies and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were obtained at baseline, and after cycles 1, 4, and 7.
A median decrease of 66.7% in phosphorylated VEGFR2 (Y951) in tumor cells (P = .004) and median increase of 128.9% in tumor apoptosis (P = .0008) were seen after bevacizumab alone. These changes persisted with the addition of chemotherapy. There were no significant changes in microvessel density or VEGF-A expression. On DCE-MRI, parameters reflecting reduced angiogenesis, a median decrease of 34.4% in the inflow transfer rate constant (P = .003), 15.0% in the backflow extravascular- extracellular rate constant (P = .0007) and 14.3% in extravascular-extracellular volume fraction (P = .002) were seen after bevacizumab alone.
Bevacizumab has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells.
Background
Patients with hormone receptor-positive, HER2-negative breast cancer who have residual invasive disease after neoadjuvant chemotherapy (NACT) are at a high risk of relapse. PENELOPE-B was ...a double-blind, placebo-controlled, phase III trial that investigated adding palbociclib (PAL) for thirteen 28-day cycles to adjuvant endocrine therapy (ET) in these patients. Clinical results showed no significant improvement in invasive disease-free survival with PAL.
Methods
We performed a pre-planned cost-effectiveness analysis of PAL within PENELOPE-B from the perspective of the German statutory health insurance. Health-related quality of life scores, collected in the trial using the EQ-5D-3L instrument, were converted to utilities based on the German valuation algorithm. Resource use was valued using German price weights. Outcomes were discounted at 3% and modeled with mixed-level linear models to adjust for attrition, repeated measurements, and residual baseline imbalances. Subgroup analyses were performed for key prognostic risk factors. Scenario analyses addressed data limitations and evaluated the robustness of the estimated cost-effectiveness of PAL to methodological choices.
Results
The effects of PAL on quality-adjusted life years (QALYs) were marginal during the active treatment phase, increasing thereafter to 0.088 (95% confidence interval: −0.001; 0.177) QALYs gained over the 4 years of follow-up. The incremental costs were dominated by PAL averaging EUR 33,000 per patient; costs were higher in the PAL arm but not significantly different after the second year. At an incremental cost-effectiveness ratio of EUR 380,000 per QALY gained, PAL was not cost-effective compared to the standard-of-care ET. Analyses restricted to Germany and other subgroups were consistent with the main results. Findings were robust in the scenarios evaluated.
Conclusions
One year of PAL added to ET is not cost-effective in women with residual invasive disease after NACT in Germany.
Background: To determine if a school-based physical activity (PA) intervention that supported primary school teachers to schedule PA during school hours impacted their own PA.
Methods: A 2x2 ...factorial group cluster-randomised controlled trial was undertaken in 12 Australian primary schools. The nine-month intervention supported classroom teachers to increase scheduled weekly PA for their class via physical education, sport, Energisers and integrated lessons. Teachers' PA (n = 76) was m easured a t follow- up only using accelerometers (Actigraph GT3X or GT9X). Linear mixed models were used to estimate between-group differences in teachers' mean minutes of sedentary, light, moderate-to- vigorous- intensity physical activity (MVPA) across the school day and during class-time.
Results: At follow-up, there were non-significant between-group differences favouring intervention teachers, compared to controls, for light PA (4.9 minutes, 95% CI: -6.3, 16.0; P =.33) and MVPA (0.4 minutes, 95% CI: -10.9, 11.6; P =.94) across the school day; although not favouring the intervention for sedentary behaviour (5.1 minutes, 95% CI: -11.4, 21.7; P =.48). Similar patterns were seen during class-time for light PA and sedentary time, but not for MVPA.
Conclusions: Supporting teachers with the scheduling of PA for their class may impact on their own PA. Fully powered studies are needed to better understand the impact of the intervention on teachers' PA.
The aim of the current study was to examine the association between Australian primary school children’s objectively measured in-school-hours weekly physical activity (PA) and their health-related ...quality of life (HRQoL). A cross-sectional study of 1128 Grade 2 and 3 children, aged 7–9 years, from 62 primary schools was conducted in New South Wales, Australia between October 2017 and April 2018. Children’s PA was assessed via an accelerometer worn for five days during school hours. Their parents completed a telephone interview, answering demographic, child HRQoL and out-of-school-hours PA questions. Children’s in-school-hours PA was classified as total PA and moderate-to-vigorous PA (MVPA). HRQoL scores were aggregated and reported at the high construct level domains (Total Quality of Life (Total HRQoL), Physical and Psychosocial Health Summary Scores). Multiple linear mixed regression analyses accounting for clustering were conducted to evaluate the association between children’s in-school-hours weekly PA and their HRQoL. After adjusting for potential confounders, significant positive associations were found between children’s in-school-hours weekly total PA and Total HRQoL (0.62 units, 95% CI: 0.29; 0.94, p < 0.001), Physical (0.71 units, 95% CI: 0.38; 1.04, p ≤ 0.001) and Psychosocial (0.58 units, 95% CI: 0.19; 0.97, p = 0.004) scores, with a stronger association observed between average weekly MVPA than average weekly total PA. There were also positive associations between PA and HRQoL for each sex when analysed separately. Our findings demonstrate a positive association between children’s objectively-measured in-school-hours PA and parent-reported child HRQoL, strengthening evidence supporting the continued implementation of school-based PA programs for broader health outcomes.
Research consistently indicates that schools fail to implement mandatory physical activity policies. This review aimed to describe factors (barriers and facilitators) that may influence the ...implementation of school physical activity policies which specify the time or intensity that physical activity should be implemented and to map these factors to a theoretical framework.
A systematic search was undertaken in six databases for quantitative or qualitative studies published between 1995-March 2016 that examined teachers', principals' or school administrators' reported barriers and/or facilitators to implementing mandated school physical activity policies. Two independent reviewers screened texts, extracted and coded data from identified articles using the Theoretical Domains Framework (TDF).
Of the 10,346 articles identified, 17 studies met the inclusion criteria (8 quantitative, 9 qualitative). Barriers and facilitators identified in qualitative studies covered 9 and 10 TDF domains respectively. Barriers and facilitators reported in quantitative studies covered 8 TDF domains each. The most common domains identified were: ‘environmental context and resources’ (e.g., availability of equipment, time or staff), ‘goals’ (e.g., the perceived priority of the policy in the school), ‘social influences’ (e.g., support from school boards), and ‘skills’ (e.g., teachers' ability to implement the policy).
Implementation support strategies that target these factors may represent promising means to improve implementation of physical activity policies and increase physical activity among school-aged children. Future studies assessing factors that influence school implementation of physical activity policies would benefit from using a comprehensive framework to help identify if any domains have been overlooked in the current literature.
This review was prospectively registered with PROSPERO (CRD42016051649) on the 8th December 2016.
•A review of factors impacting schools' physical activity policy implementation•The most frequently reported barriers/facilitators pertain to 4 domains of the TDF.•These are environmental context and resources, social influences, goals, and skills.•Gives a theoretical basis for policy-makers to design implementation interventions•Strategies such as modelling, encouragement, or hierarchical support may be helpful.
The purpose is to define intratumoral microvessel density (MVD) and potential biological markers that correlate with inflammatory breast cancer (IBC), we examined MVD, estrogen receptor a (ER) ...status, MIB-1 proliferation index, p53, and c-erbB-2 by immunohistochemistry in archival specimens from 67 women diagnosed with breast cancer with or without the inflammatory phenotype at the Institut Salah Azaiz (Tunis, Tunisia).
The moderate (25-50/x400 field) to high microvessel count (>50/x400 field) was observed in 23 (51%) of 45 IBC tumors compared with 3 (14%) of 22 non-IBC tumors (P = 0.0031; chi(2) test). The presence of ER was found in 6 (14%) of 44 cases versus 7 (32%) of 22 cases in IBC and non-IBC, respectively (P = 0.10). In this series of 67 patient tumors, the median MVD count in ER-negative breast tumors was 21, whereas the median count was 4 in ER-positive breast tumors (P = 0.08; Wilcoxon rank-sum test). However, MIB-1, p53, and c-erbB-2 were not significantly different between IBC and non-IBC tumors. The intratumoral MVD between IBC and non-IBC was still statistically significant after adjustment for multiple comparisons (P = 0.02; Bonferroni test).
These data suggest that there is an increased MVD in breast cancer with the inflammatory phenotype as compared with breast cancer without the inflammatory phenotype.
The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately ...one‐third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling‐centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.
The current article reviews the most up‐to‐date literature on Endoplasmic Reticulum (ER) biology and articulates this information from a signalling perspective. Not only do we cover the basic cell biology aspects of adaptive ER signalling but also provide information about the latest discoveries on ER stress targeting drugs and their potential use in the clinic.
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