Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-expansion stage of a multicentre, open-label, phase I trial.

BACKGROUND: The aim of this study was to investigate the antitumour activity, safety, and tolerability of pamiparib plus tislelizumab in patients with previously treated advanced solid tumours. METHODS: In this study, patients were enrolled into eight arms by tumour type. All received pamiparib 40 mg orally twice daily plus tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR), assessed by the investigator per Response Evaluation Criteria in Solid Tumours v1.1. Secondary endpoints included duration of response (DoR), safety, and tolerability. RESULTS: Overall, 180 patients were enrolled. In the overall population, the ORR was 20.0% (range: 0-47.4 across study arms), with median DoR of 17.1 months (95% confidence interval [CI]: 6.2, not estimable [NE]). The highest ORR was observed in the triple-negative breast cancer (TNBC) arm (patients with BRCA1/2 mutations and/or homologous recombination deficiency) (ORR: 47.4%; median DoR: 17.1 months [95% CI: 3.0, NE]). Treatment-emergent adverse events (TEAEs) of ≥Grade 3 occurred in 61.7% of patients. Serious TEAEs occurred in 50.0% of patients. CONCLUSIONS: Pamiparib plus tislelizumab showed a variable level of antitumour activity in patients with advanced solid tumours, with the highest ORR in TNBC and was associated with a manageable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT02660034.

Evaluating the scaling up of an effective implementation intervention (PACE) to increase the delivery of a mandatory physical activity policy in primary schools.

BACKGROUND: Physically Active Children in Education (PACE) is an effective implementation intervention for increasing the number of minutes classroom teachers schedule physical activity each week. To date, evaluations of PACE have included a smaller number of schools from only one region in New South Wales Australia. If PACE is to have population-wide benefits we must be able to deliver this support to a larger number of schools across multiple regions. This study aimed to evaluate the scale-up of PACE. METHODS: An uncontrolled before and after study, with 100 schools from three regions was conducted. Participating schools received PACE for approximately 12 months. We assessed the following outcomes: delivery of the evidence-based intervention (EBI) (i.e. minutes of physical activity scheduled by classroom teachers per week); delivery of the implementation strategies (i.e. reach, dose delivered, adherence and indicators of sustainability); and key determinants of implementation (i.e. acceptability of strategies and cost). Data were collected via project officer records, and principal and teacher surveys. Linear mixed models were used to assess EBI delivery by evaluating the difference in the mean minutes teachers scheduled physical activity per week from baseline to follow-up. Descriptive data were used to assess delivery of the implementation strategies and their perceived acceptability (i.e. PACE). A prospective, trial-based economic evaluation was used to assess cost. RESULTS: Delivery of the EBI was successful: teachers increas their average minutes of total physical activity scheduled across the school week by 26.8 min (95% CI: 21.2, 32.4, p < 0.001) after receiving PACE. Indicators for delivery of implementation strategies were high: 90% of consenting schools received all strategies and components (reach); 100% of strategies were delivered by the provider (dose); >50% of schools adhered to the majority of strategies (11 of the 14 components); and acceptability was > 50% agreement for all strategies. The incremental cost per additional minute of physical activity scheduled per week was $27 per school (Uncertainty Interval $24, $31). CONCLUSIONS: PACE can be successfully delivered across multiple regions and to a large number of schools. Given the ongoing and scalable benefits of PACE, it is important that we continue to extend and improve this program while considering ways to reduce the associated cost.

A cluster randomised controlled trial to assess the effectiveness of a multi-strategy sustainability intervention on teachers' sustained implementation of classroom physical activity breaks (energisers): study protocol.

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 17th March 2020. Version 3 (current version) updated 4th August 2023.

Optimising a multi-strategy implementation intervention to improve the delivery of a school physical activity policy at scale: findings from a randomised noninferiority trial.

BACKGROUND: To maximise their potential health benefits, school-based physical activity policies need to be implemented at scale. This paper describes the third in a sequence of trials that sought to optimise an effective strategy (PACE) to assist schools' implementation of a physical activity policy. Specifically, it aimed to determine the probability that a multi-strategy intervention adapted to reduce in-person contact (Adapted PACE) was "as good as" the original intervention (PACE) in increasing the weekly minutes of structured physical activity implemented by classroom teachers. METHODS: A noninferiority cluster randomised controlled trial was undertaken with 48 primary schools in New South Wales, Australia. Schools were randomised to receive PACE or a model with adaptations made to the delivery modes (Adapted PACE). Teachers' scheduled minutes of weekly physical activity was assessed at baseline (Oct 2018-Feb 2019) and 12-month follow-up (Oct-Dec 2019). The noninferiority margin was set at - 16.4 minutes based on previous data and decision panel consensus. A linear mixed model analysed within a Bayesian framework was used to explore noninferiority between the two PACE models. A cost minimisation analysis was conducted from the health service provider perspective, using the Australian dollar (AUD). RESULTS: The posterior estimate for the between group difference at follow-up was - 2.3 minutes (95% credible interval = - 18.02, 14.45 minutes). There was an estimated 96% probability of Adapted PACE being considered noninferior (only 4% of the posterior samples crossed the noninferiority margin of - 16.4 minutes). That is, the minutes of physical activity implemented by teachers at Adapted PACE schools was not meaningfully less than the minutes of physical activity implemented by teachers at PACE schools. The mean total cost was AUD$25,375 (95% uncertainty interval = $21,499, $29,106) for PACE and AUD$16,421 (95% uncertainty interval = $13,974, $19,656) for Adapted PACE; an estimated reduction of AUD$373 (95% uncertainty interval = $173, $560) per school. CONCLUSIONS: It is highly probable that Adapted PACE is noninferior to the original model. It is a cost-efficient alternative also likely to be a more suitable approach to supporting large scale implementation of school physical activity policies. TRIAL REGISTRATION: Retrospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619001229167).

School-level factors associated with the sustainment of weekly physical activity scheduled in Australian elementary schools: an observational study.

BACKGROUND: We aimed to: (1) identify school-level factors associated with the sustainment of weekly physical activity (PA) scheduled in elementary schools following withdrawal of effective implementation support; and (2) determine teacher's perceived usefulness of suggested strategies for sustaining the scheduling of weekly PA. METHODS: A secondary exploratory analysis was employed of data from the intervention arm (n = 31 schools) of a randomised controlled trial. Self-report survey data from 134 classroom teachers in New South Wales, Australia, collected following withdrawal of initial implementation support (follow-up T1) and six-months following completion of support (follow-up T2) were used. The outcomes of sustainment of weekly overall PA and energisers (short classroom PA breaks) scheduled were measured via teachers' completion of a daily activity logbook, with results presented as the difference in mean minutes of PA and energisers scheduled at T1 and T2. An adapted version of the Program Sustainability Assessment Tool (PSAT) was used to measure capacity for program sustainability across seven key domains at follow-up T2. Linear mixed regressions were conducted to evaluate associations between school-level sociodemographic characteristics (e.g., school size, remoteness, and type), teacher-reported school factors (i.e., seven adapted PSAT domains) and the sustainment of PA and energisers scheduled across the school week. Perceived usefulness of 14 proposed sustainability strategies was measured via the teacher survey at follow-up T2 and reported descriptively. RESULTS: No school-level factor was statistically associated with the sustainment of overall weekly PA or energisers scheduled. Teacher-reported factors in two PSAT domains - 'strategic planning' and 'program evaluation' were statistically negatively associated with the sustainment of weekly energisers scheduled (- 6.74, 95% CI: - 13.02; - 0.47, p = 0.036 and - 6.65, 95% CI: - 12.17; - 1.12, p = 0.019 respectively). The proposed support sustainability strategy - 'provision of PA equipment packs that enable energisers or integrated lessons' was perceived useful by the most teachers (85%). CONCLUSIONS: Further research is required to explore additional contextual-specific, and end-user appropriate factors associated with schools' sustainment of weekly PA scheduled. This will help accurately inform the development of strategies to address these determinants and support the sustainment and long-term benefits of school-based health interventions more broadly.

Multi-strategy intervention increases school implementation and maintenance of a mandatory physical activity policy: outcomes of a cluster randomised controlled trial.

OBJECTIVES: To assess if a multi-strategy intervention effectively increased weekly minutes of structured physical activity (PA) implemented by classroom teachers at 12 months and 18 months. METHODS: A cluster randomised controlled trial with 61 primary schools in New South Wales Australia. The 12-month multi-strategy intervention included; centralised technical assistance, ongoing consultation, principal's mandated change, identifying and preparing school champions, development of implementation plans, educational outreach visits and provision of educational materials. Control schools received usual support (guidelines for policy development via education department website and telephone support). Weekly minutes of structured PA implemented by classroom teachers (primary outcome) was measured via teacher completion of a daily log-book at baseline (October-December 2017), 12-month (October-December 2018) and 18-month (April-June 2019). Data were analysed using linear mixed effects regression models. RESULTS: Overall, 400 class teachers at baseline, 403 at 12 months follow-up and 391 at 18 months follow-up provided valid primary outcome data. From baseline to 12-month follow-up, teachers at intervention schools recorded a greater increase in weekly minutes of PA implemented than teachers assigned to the control schools by approximately 44.2 min (95% CI 32.8 to 55.7; p<0.001) which remained at 18 months, however, the effect size was smaller at 27.1 min (95% CI 15.5 to 38.6; p≤0.001). CONCLUSION: A multi-strategy intervention increased mandatory PA policy implementation. Some, but not all of this improvement was maintained after implementation support concluded. Further research should assess the impact of scale-up strategies on the sustainability of PA policy implementation over longer time periods. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12617001265369).

Exploring the effect of a school-based cluster-randomised controlled trial to increase the scheduling of physical activity for primary school students on teachers' physical activity.

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 measured at 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. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12616001228471 (http://www.anzctr.org.au/).

The impact of school uniforms on primary school student's physical activity at school: outcomes of a cluster randomized controlled trial.

BACKGROUND: Many school-based physical activity (PA) interventions are complex and have modest effects when delivered in real world contexts. A commonly reported barrier to students' PA, particularly among girls, are uniforms that are impractical (e.g. tunic/dress and black leather shoes). Modifying student uniforms may represent a simple intervention to enhance student PA. The primary aim of this trial was to assess the impact of a PA enabling uniform intervention (shorts, polo shirt and sports shoes) on girls' moderate-to-vigorous physical activity (MVPA) and total PA i.e. counts per minute (cpm). METHODS: A cluster randomized controlled trial was undertaken in 42 primary schools in New South Wales, Australia. Schools were randomized on one school day to the intervention group, where students wore a PA enabling uniform (their sports uniform) or a control group, where students wore their usual traditional uniform. Student PA was measured using wrist-worn Actigraph GT3X and GT9X accelerometers. Linear mixed models controlling for student characteristics were used to examine the effects of the intervention.. RESULTS: Of the 3351 eligible students, 2315 (69.1%) had parental consent and 2180 of these consenting students participated (94.2%) of which 1847 (84.7%) were included in the analysis. For the primary aim the study found no significant differences between girls at schools allocated to the intervention relative to the control on change in MVPA (0.76 min, 95% CI - 0.47 to 1.99, p = 0.22) or cpm (36.99, 95% CI - 13.88 to 87.86, p = 0.15). Exploratory analysis revealed small effects for a number of findings, including significant reduction in sedentary activity (- 1.77, 95% CI - 3.40 to - 0.14, p = 0.035) among all students at schools allocated to the intervention, and non-significant improvements in girls' light intensity PA (1.47 min, 95% CI - 0.06 to 3.00, p = 0.059) and sedentary activity (- 2.23 min; 95% CI - 4.49 to 0.02, p = 0.052). CONCLUSION: The findings suggests that the intervention may yield small improvements in some measure of PA and require substantiation in a larger RCT with longer-term follow-up. The inclusion of additional intervention components may be required to achieve more meaningful effects. TRIAL REGISTRATION: The trial was prospectively registered with Australian New Zealand Clinical Trials Register ACTRN12617001266358 1st September 2017.

Efficacy of a school-based physical activity and nutrition intervention on child weight status: Findings from a cluster randomized controlled trial.

Despite the benefits of factorial designs in quantifying the relative benefits of different school-based approaches to prevent unhealthy weight gain among students, few have been undertaken. The aims of this 2 × 2 cluster randomized factorial trial was to evaluate the impact of a physical activity and nutrition intervention on child weight status and quality of life. Twelve primary schools in New South Wales, Australia randomly allocated to one of four groups: (i.) physical activity (150 min of planned in-school physical activity); (ii.) nutrition (a healthy school lunch-box); (iii.) combined physical activity and nutrition; or (iv.) control. Outcome data assessing child weight and quality of life were collected at baseline and 9-months post-baseline. Within Grades 4-6 in participating schools, 742 students participated in anthropometric measurements, including child body mass index (BMI) and waist circumference, at baseline and follow-up. Findings indicated that students that received the nutrition intervention had higher odds of being classified in the BMI category of underweight/healthy weight (OR 1.64 95%CI 1.07, 2.50; p = 0.0220), while those who received the physical activity intervention reported a lower waist circumference (mean difference - 1.86 95%CI -3.55, -0.18; p = 0.030). There were no significant effects of the nutrition or physical activity intervention on child BMI scores or child quality of life, and no significant synergistic effects of the two interventions combined. Future research assessing the longer-term impact of both intervention strategies, alone and combined, is warranted to better understand their potential impact on child health. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN: ACTRN12616001228471.

NF-κB contributes to Smac mimetic-conferred protection from tunicamycin-induced apoptosis.

Smac mimetics that deplete cellular inhibitor of apoptosis (cIAP) proteins have been shown to activate Nuclear Factor-kappa B (NF-κB). Here, we report that Smac mimetic-mediated activation of NF-κB contributes to the rescue of cancer cells from tunicamycin (TM)-triggered apoptosis. The prototypic Smac mimetic BV6 activates non-canonical and canonical NF-κB pathways, while TM has little effect on NF-κB signaling. Importantly, ectopic expression of dominant-negative IκBα superrepressor (IκBα-SR), which inhibits canonical and non-canonical NF-κB activation, significantly reversed this BV6-imposed protection against TM. Similarly, transient or stable knockdown of NF-κB-inducing kinase, which accumulated upon exposure to BV6 alone and in combination with TM, significantly counteracted BV6-mediated inhibition of TM-induced apoptosis. Interestingly, while cIAP2 was initially degraded upon BV6 treatment, it was subsequently upregulated in an NF-κB-dependent manner, as this restoration of cIAP2 expression was abolished in IκBα-SR-overexpressing cells. Interestingly, upon exposure to TM/BV6 apoptosis was significantly increased in cIAP2 knockdown cells. Furthermore, NF-κB inhibition partially prevented BV6-stimulated expression of Mcl-1 upon TM treatment. Consistently, Mcl-1 silencing significantly inhibited BV6-mediated protection from TM-induced apoptosis. Thus, NF-κB activation by Smac mimetic contributes to Smac mimetic-mediated protection against TM-induced apoptosis.

A cluster randomised controlled trial of an intervention to increase the implementation of school physical activity policies and guidelines: study protocol for the physically active children in education (PACE) study.

BACKGROUND: In an attempt to improve children's physical activity levels governments have introduced policies specifying the minimum time schools are to schedule physical activity each week. Despite this, the majority of schools in many jurisdictions fail to implement these policies. This study will assess the effectiveness of a multi-component implementation strategy on increasing the minutes of planned physical activity scheduled by primary school teachers each week. METHODS: A cluster randomised controlled trial will be conducted in 62 primary schools in the Hunter New England region of New South Wales, Australia. Schools will be randomly allocated to receive either a multi-component implementation strategy that includes; obtaining executive support, training in-school champions, provision of tools and resources, implementation prompts, reminders and feedback; or usual practice. The study will employ an effectiveness-implementation hybrid design, assessing both policy implementation and individual (student) behavioural outcomes. The primary trial outcome of mean minutes of physical activity scheduled by classroom teachers across the school week will be measured via teacher log-book at baseline and approximately 12 and 18 months post baseline. A nested evaluation of the impact of policy implementation on child physical activity will be undertaken of students in Grades 2 and 3. Analyses will be performed using an intention to treat framework. Linear mixed effects regression models will be used to assess intervention effects on the primary outcome at both follow-up periods. DISCUSSION: This study will be the one of the first well powered randomised trials internationally to examine the impact of an implementation strategy for a physical activity policy in primary schools and will address a fundamental research translation gap. Given the dearth of research, the findings will be important in informing future implementation efforts in this setting. TRIAL REGISTRATION: ANZCTR ACTRN12617001265369 version 1 registered 1st September 2017.

Barriers and facilitators to the implementation of physical activity policies in schools: A systematic review.

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. REGISTRATION: This review was prospectively registered with PROSPERO (CRD42016051649) on the 8th December 2016.

Living well after breast cancer randomized controlled trial protocol: evaluating a telephone-delivered weight loss intervention versus usual care in women following treatment for breast cancer.

BACKGROUND: Obesity, physical inactivity and poor diet quality have been associated with increased risk of breast cancer-specific and all-cause mortality as well as treatment-related side-effects in breast cancer survivors. Weight loss intervention trials in breast cancer survivors have shown that weight loss is safe and achievable; however, few studies have examined the benefits of such interventions on a broad range of outcomes and few have examined factors important to translation (e.g. feasible delivery method for scaling up, assessment of sustained changes, cost-effectiveness). The Living Well after Breast Cancer randomized controlled trial aims to evaluate a 12-month telephone-delivered weight loss intervention (versus usual care) on weight change and a range of secondary outcomes including cost-effectiveness. METHODS/DESIGN: Women (18-75 years; body mass index 25-45 kg/m2) diagnosed with stage I-III breast cancer in the previous 2 years are recruited from public and private hospitals and through the state-based cancer registry (target n = 156). Following baseline assessment, participants are randomized 1:1 to either a 12-month telephone-delivered weight loss intervention (targeting diet and physical activity) or usual care. Data are collected at baseline, 6-months (mid-intervention), 12-months (end-of-intervention) and 18-months (maintenance). The primary outcome is change in weight at 12-months. Secondary outcomes are changes in body composition, bone mineral density, cardio-metabolic and cancer-related biomarkers, metabolic health and chronic disease risk, physical function, patient-reported outcomes (quality of life, fatigue, menopausal symptoms, body image, fear of cancer recurrence) and behaviors (dietary intake, physical activity, sitting time). Data collected at 18-months will be used to assess whether outcomes achieved at end-of-intervention are sustained six months after intervention completion. Cost-effectiveness will be assessed, as will mediators and moderators of intervention effects. DISCUSSION: This trial will provide evidence needed to inform the wide-scale provision of weight loss, physical activity and dietary interventions as part of routine survivorship care for breast cancer survivors. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry (ANZCTR) - ACTRN12612000997853 (Registered 18 September 2012).

Integrated Measure of PRogram Element SuStainability in Childcare Settings (IMPRESS-C): development and psychometric evaluation of a measure of sustainability determinants in the early childhood education and care setting.

BACKGROUND: There is a need for valid and reliable measures of determinants of sustainability of public health interventions in early childhood education and care (ECEC) settings. This study aimed to develop and evaluate the psychometric and pragmatic properties of such a measure - the Integrated Measure of PRogram Element SuStainability in Childcare Settings (IMPRESS-C). METHODS: We undertook a two-phase process guided by the COnsensus-based Standards for the selection of health status Measurement INstruments checklist (COSMIN) and Psychometric and Pragmatic Evidence Rating Scale (PAPERS). Phase 1 involved measure development; i.e., determining items and scales through an iterative process and assessment of face and content validity. Phase 2 involved the evaluation of psychometric and pragmatic properties. The 29-item measure completed by service executives (directors and nominated supervisors) was embedded in a larger survey from a national sample of Australian ECEC services assessing their implementation of nutrition and physical activity programs. Structural validity, concurrent validity, known groups validity, internal consistency, floor and ceiling effects, norms, and pragmatic qualities of the measure were assessed according to the PAPERS criteria. RESULTS: The final measure contained 26 items, with respondents reporting how strongly they agreed or disagreed on a five-point Likert scale. Phase 1 assessments confirmed the relevance, and face and content validity of the scale. In Phase 2, we obtained 482 completed surveys, of which 84% (n = 405) completed the entire measure across 405 ECEC settings (one executive per service). Three of the four fit indices for the confirmatory factor analysis met the pre-specified criteria (SRMR = 0.056, CFI = 0.993, RMSEA = 0.067) indicating 'good' structural validity. The IMPRESS-C illustrated: 'good' internal consistency, with Cronbach's alpha values from 0.53 to 0.92; 'emerging' concurrent validity; 'poor' known groups validity; 'good' norms; and 'good' overall pragmatic qualities (cost, readability, length, and assessor burden). CONCLUSIONS: The IMPRESS-C possesses strong psychometric and pragmatic qualities for assessing service executive-level perceptions of determinants influencing sustainment of public health interventions within ECEC settings. To achieve a full range of perspectives in this setting, future work should be directed to also develop and test measures of sustainability determinants at the implementer level (e.g., among individual educators and staff).

Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer.

INTRODUCTION: This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADPribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). METHODS: Eligible patients who had received ≤1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade ≥2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). RESULTS: Nineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade ≥3) and four in cohort 2 (two grade ≥3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. CONCLUSIONS: The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707).

The impact of an implementation intervention that increased school's delivery of a mandatory physical activity policy on student outcomes: A cluster-randomised controlled trial.

OBJECTIVES: Assess the impact of an implementation intervention on student's physical activity, health-related quality of life (HRQoL) and on-task behaviour. DESIGN: A cluster-randomised controlled trial. METHODS: Following baseline 61 eligible schools were randomised to a 12-month, implementation intervention to increase teacher scheduling of physical activity, or a waitlist control. Whole school-day and class-time physical activity of students from grades 2 and 3 (~ages 7 to 9) were measured via wrist-worn accelerometers and included: moderate-to-vigorous physical activity, light physical activity, sedentary behaviour and activity counts per minute. Children's health related quality of life (HRQoL) and out-of-school-hours physical activity was measured via parent-proxy surveys. Class level on-task behaviour was measured via teacher self-report surveys. Student and teacher obtained outcomes were measured at baseline and 12-month follow-up. Parent reported outcomes were measured at 12-month follow-up. Linear mixed models compared between group differences in outcomes. Differential effects by sex were explored for student and parent reported outcomes. RESULTS: Data from 2485 students, 1220 parents and >500 teachers were analysed. There was no statistically significant between group differences in any of the outcomes, including accelerometer measured physical activity, out-of-school-hours physical activity, HRQoL, and on-task behaviour. A statistically significant differential effect by sex was found for sedentary behaviour across the whole school day (3.16 min, 95% CI: 0.19, 6.13; p = 0.028), with females illustrating a greater difference between groups than males. CONCLUSIONS: Only negligible effects on student physical activity were found. Additional strategies including improving the quality of teacher's delivery of physical activity may be required to enhance effects.

Palbociclib plus letrozole as treatment for postmenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer for whom letrozole therapy is deemed appropriate: An expanded access study in Australia and India.

AIM: Palbociclib was approved in the United States in 2015 to treat estrogen receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This study evaluated outcomes and safety in patients treated with palbociclib in Australia and India with hormone receptor-positive (HR+)/HER2- ABC before palbociclib became commercially available. METHODS: Postmenopausal women (≥18 years) with HR+/HER2- ABC who were appropriate candidates for letrozole therapy received palbociclib 125 mg once daily for 21 days followed by 7 days off, and letrozole 2.5 mg once daily (continuous). Safety, tumor response, and patient-reported outcomes (Australian cohort) were evaluated. RESULTS: In total, 252 patients received palbociclib plus letrozole (Australia, n = 152; India, n = 100). More patients in the Australian versus Indian cohort had received prior chemotherapy (advanced/metastatic setting: 45.9% vs. 32.0%), endocrine therapy (advanced/metastatic setting: 63.2% vs. 54.3%), and advanced/metastatic therapies (61.8% vs. 31.0%). The most frequently reported all-grade palbociclib-related treatment-emergent adverse events were neutropenia (66.7%), fatigue (35.3%), and stomatitis (26.6%); grade 3/4 neutropenia was reported as palbociclib-related in 62.7% of patients. Febrile neutropenia was reported in six patients (2.4%). Eight patients (3.2%) discontinued because of an adverse event. The objective response rate was 19.4% (95% CI, 14.7%-24.9%) overall and 2.3% in Australian patients with ≥2 lines of prior therapy for metastatic disease. Patient-reported quality of life scores were maintained throughout the study. CONCLUSIONS: In an expanded access setting in Australia and India, palbociclib plus letrozole was well tolerated in patients with HR+/HER2- ABC, with a safety profile consistent with previous reports.

Cluster randomised controlled trial to determine the impact of an activity enabling uniform on primary school student's fitness and physical activity: study protocol for the Active WeAR Everyday (AWARE) study.

IntroductionMulticomponent school-based physical activity (PA) interventions can improve students' cardiorespiratory fitness (CRF) and PA. Due to the complex nature of such interventions when delivered at scale their effect sizes markedly reduce. Modifying student school uniforms, so that they are more PA enabling, may be a simple intervention that could enhance student health. The primary aim of this trial is to assess the effectiveness of an activity enabling uniform intervention (shorts, polo shirt and sports shoes) in improving children's CRF. METHODS AND ANALYSIS: A cluster randomised controlled trial will be conducted in 24 primary schools in New South Wales (NSW), Australia. Schools will be randomly allocated to either intervention or usual practice following baseline data collection. Active WeAR Everyday intervention schools will allow students in grades 4-6 (aged approx. 9-12 years) to wear their existing sports uniform (shorts, polo shirt and sports shoes) every day. To avoid any financial cost to students they will be provided with two additional sports shirts and one pair of shorts. Study outcomes will be assessed at baseline and 9 months postbaseline. The primary outcome is students' CRF measured using the 20 m multistage fitness test. Secondary outcomes include students': mean daily steps and steps/minute measured via accelerometer, quality of life, mental well-being and perceived PA self-efficacy. The acceptability, feasibility and cost of the intervention will be assessed. Analyses will be performed using an intention-to-treat framework. Linear mixed effects regression models will be used to assess intervention effects on the primary outcome at follow-up. Planned exploratory analyses will examine effects by subgroups (eg, gender). ETHICS AND DISSEMINATION: This study has received approval from Hunter New England Local Health District Human Ethics Committee (2020/ETHO2602) the University of Newcastle, Human Research Ethics Committee (H-2021-0013), NSW Department of Education (SERAP: 2020387) and Catholic School Offices. TRIAL REGISTRATION NUMBER: ACTRN12621000201875.

Cost-effectiveness of palbociclib in early breast cancer patients with a high risk of relapse: Results from the PENELOPE-B trial.

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.

Australian children are not meeting recommended physical activity levels at school: Analysis of objectively measured physical activity data from a cross sectional study.

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.