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).
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).
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.
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).
Abstract 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).
Abstract
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.
Although comprehensive school-based physical activity interventions are efficacious when tested under research conditions, they often require adaptation in order for implementation at scale. This ...paper reports the effectiveness of an adapted efficacious school-based intervention in improving children’s moderate to vigorous physical activity. The impact of strategies to support program implementation was also assessed.
A cluster RCT of low socioeconomic elementary schools in New South Wales, Australia.
Consenting schools were randomized (25 intervention, 21 control) using a computerized random number function. Follow-up measures were taken at 6 months post-randomization (May–August 2015) by blinded research assistants. The multicomponent school-based intervention, based on an efficacious school-based physical activity program (Supporting Children’s Outcomes using Rewards, Exercise and Skills), consisted of four physical activity strategies and seven implementation support strategies. The intervention was adapted for scalability and delivery by a local health service over 6 months. The primary outcome was accelerometer assessed, student mean daily minutes spent in moderate to vigorous physical activity. Physical education lesson quality and other school physical activity practices were also assessed.
Participants (n=1,139, 49% male) were third- through sixth-grade students at follow-up (May–August 2015). Valid wear time and analysis of data were provided for 989 (86%) participants (571 intervention, 568 control). At 6-month follow-up, there were no significant effects in overall daily minutes of moderate to vigorous physical activity between groups (1.96 minutes, 95% CI= –3.49, 7.41, p=0.48). However, adjusted difference in mean minutes of overall vigorous physical activity (2.19, 95% CI=0.06, 4.32, p=0.04); mean minutes of school day moderate to vigorous physical activity (2.90, 95% CI=0.06, 5.85, p=0.05); and mean minutes of school day vigorous physical activity (1.81, 95% CI=0.78, 2.83, p≤0.01) were significantly different in favor of the intervention group. Physical education lesson quality and school physical activity practices were significantly different favoring the intervention group (analyzed October 2015–January 2016).
The modified intervention was not effective in increasing children’s overall daily minutes of moderate to vigorous physical activity, when adapted for implementation at scale. However, the intervention did improve daily minutes of vigorous physical activity and school day moderate to vigorous physical activity, lesson quality, and school physical activity practices.
Australian New Zealand Clinical Trials Registry: ACTRN12615000437561.
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. 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). 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. 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.
Abstract
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.
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.
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.
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.
ANZCTR ACTRN12617001265369 version 1 registered 1st September 2017.
Limited evidence exists on the effects of weight loss on chronic disease risk and patient-reported outcomes in breast cancer survivors. Breast cancer survivors (stage I–III; body mass index 25–45 ...kg/m2) were randomized to a 12-month, remotely delivered (22 telephone calls, mailed material, optional text messages) weight loss (diet and physical activity) intervention (n = 79) or usual care (n = 80). Weight loss (primary outcome), body composition, metabolic syndrome risk score and components, quality of life, fatigue, musculoskeletal pain, menopausal symptoms, fear of recurrence, and body image were assessed at baseline, 6 months, 12 months (primary endpoint), and 18 months. Participants were 55 ± 9 years and 10.7 ± 5.0 months post-diagnosis; retention was 81.8% (12 months) and 80.5% (18 months). At 12-months, intervention participants had significantly greater improvements in weight (−4.5% 95%CI: −6.5, −2.5; p < 0.001), fat mass (−3.3 kg −4.8, −1.9; p < 0.001), metabolic syndrome risk score (−0.19 −0.32, −0.05; p = 0.006), waist circumference (−3.2 cm −5.5, −0.9; p = 0.007), fasting plasma glucose (−0.23 mmol/L −0.44, −0.02; p = 0.032), physical quality of life (2.7 0.7, 4.6; p = 0.007; Cohen’s effect size (d) = 0.40), musculoskeletal pain (−0.5 −0.8, −0.2; p = 0.003; d = 0.49), and body image (−0.2 −0.4, −0.0; p = 0.030; d = 0.31) than usual care. At 18 months, effects on weight, adiposity, and metabolic syndrome risk scores were sustained; however, significant reductions in lean mass were observed (−1.1 kg −1.7, −0.4; p < 0.001). This intervention led to sustained improvements in adiposity and metabolic syndrome risk.
The aim of the study was to determine whether infliximab use and other potential predictors are associated with decreased prevalence and severity of depression in pediatric patients with Crohn ...disease (CD).
A total of 550 (n = 550) youth ages 9 to 17 years with biopsy-confirmed CD were consecutively recruited as part of a multicenter randomized controlled trial. Out of the 550, 499 patients met study criteria and were included in the analysis. At recruitment, each subject and a parent completed the Children's Depression Inventory (CDI). A child or parent CDI score ≥ 12 was used to denote clinically significant depressive symptoms (CSDS). Child and parent CDI scores were summed to form total CDI (CDIT). Infliximab use, demographic information, steroid use, laboratory values, and Pediatric Crohn's Disease Activity Index (PCDAI) were collected as the potential predictors of depression. Univariate regression models were constructed to determine the relations among predictors, CSDS, and CDIT. Stepwise multivariate regression models were constructed to predict the relation between infliximab use and depression while controlling for other predictors of depression.
Infliximab use was not associated with a decreased proportion of CSDS and CDIT after adjusting for multiple comparisons. CSDS and CDIT were positively associated with PCDAI, erythrocyte sedimentation rate, and steroid dose (P < 0.01) and negatively associated with socioeconomic status (SES) (P < 0.001). In multivariate models, PCDAI and SES were the strongest predictors of depression.
Disease activity and SES are significant predictors of depression in youth with Crohn disease.
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