This is a repository copy of Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH) : a stepped-wedge cluster-randomised trial. Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH) : a stepped-wedge cluster-randomised trial. The Lancet. ISSN 0140-6736 https://doi.org/10.1016/S0140-6736(18)32521-2 eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ ReuseThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can't change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Implications of all the available evidenceDespite the success of some smaller projects, there was no survival benefit from a national quality improvement programme to implement a care pathway for patients undergoing emergency abdominal surgery. To succeed, large national quality improvement programmes need to allow for differences between hospitals and ensure teams have both the time and resources needed to improve patient care.

The aim of this study was to compare in-school and out-of-school physical activity within a representative sample. Socio-demographic, physical activity, and anthropometric data were collected from a random sample of children (250 boys, 253 girls) aged 3-16 years attending nine primary and two secondary schools. Actigraph GT1M accelerometers, worn for seven days, were used to estimate physical activity levels for in-school (typically 09.00-15.00 h), out-of-school (weekday), and weekend periods. Physical activity as accelerometer counts per minute were lower in school versus out of school overall (in school: 437.2 +/- 172.9; out of school: 575.5 +/- 202.8; P < 0.001), especially in secondary school pupils (secondary: 321.6 +/- 127.5; primary: 579.2 +/- 216.3; P < 0.001). Minutes of moderate-to-vigorous physical activity accumulated in school accounted for 29.4 +/- 9.8% of total weekly moderate-to-vigorous physical activity overall but varied by sector (preschool: 37.4 +/- 6.2%; primary: 33.6 +/- 8.1%; secondary: 23.0 +/- 9.3%; F = 114.3, P < 0.001). Approximately half of the children with the lowest in-school activity compensated out of school during the week (47.4%) and about one-third at the weekend (30.0%). Overall, physical activity during the school day appears to be lower than that out of school, especially in secondary school children, who accumulate a lower proportion of their total weekly moderate-to-vigorous physical activity at school than younger children. As low in-school activity was compensated for beyond the school setting by less than half of children, promoting physical activity within the school day is important, especially in secondary schools.

Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming.Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy.Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID).Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.

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BackgroundPrevious data suggests that anti-OX40 mAb can elicit anti-tumor effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. Human trials with anti-OX40 antibodies have shown that these entities are well tolerated but to date have delivered disappointing clinical responses, indicating that the rules for the optimal use of anti-human OX40 (hOX40) antibodies is not yet fully understood. Changes to timing and dosages may lead to improved outcomes; however, here we focus on addressing the role of agonism versus depleting activity in determining therapeutic outcomes. We investigated a novel panel of anti-hOX40 mAb to understand how these reagents and mechanisms may be optimized for therapeutic benefit.MethodsThis study examines the binding activity and in vitro activity of a panel of anti-hOX40 antibodies. They were further evaluated in several in vivo models to address how isotype and epitope determine mechanism of action and efficacy of anti-hOX40 mAb.ResultsBinding analysis revealed the antibodies to be high affinity, with epitopes spanning all four cysteine-rich domains of the OX40 extracellular domain. In vivo analysis showed that their activities relate directly to two key properties: (1) isotype—with mIgG1 mAb evoking receptor agonism and CD8+ T-cell expansion and mIgG2a mAb evoking deletion of Treg and (2) epitope—with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumor models by engaging these different mechanisms.ConclusionThese findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T-cell expansion or Treg depletion might be preferred according to the composition of different tumors. As many of the current clinical trials using OX40 antibodies are now using combination therapies, this understanding of how to manipulate therapeutic activity will be vital in directing new combinations that are more likely to improve efficacy and clinical outcomes.

Treatment for osteosarcoma (OS) has been largely unchanged for several decades, with typical therapies being a mixture of chemotherapy and surgery. Although therapeutic targets and products against cancer are being continually developed, only a limited number have proved therapeutically active in OS. Thus, the understanding of the OS microenvironment and its interactions are becoming more important in developing new therapies. Three-dimensional (3D) models are important tools in increasing our understanding of complex mechanisms and interactions, such as in OS. In this review, in vivo animal models, in vitro 3D models and in ovo chorioallantoic membrane (CAM) models, are evaluated and discussed as to their contribution in understanding the progressive nature of OS, and cancer research. We aim to provide insight and prospective future directions into the potential translation of 3D models in OS.

Introduction:Standardized patient (SP) methodology has been used in health professional education to help students develop communication, deeper diagnostic reasoning, and critical thinking skills. Few examples demonstrate the use of SPs to practice difficult conversations with pediatric caregivers in the pediatric dentistry literature. The objective of this educational activity was to describe the implementation of three SPs in a pediatric dentistry course for second-year dental students. Methods: We developed three SP encounters covering interactions with caregivers of an infant with severe early childhood caries, an adolescent on the path to gender affirmation, and a child with autism and dental caries whose caregiver was resistant to fluoride-and silver-containing dental materials. We describe the case design process, rubric construction and calibration, student debriefing, and pandemic modifications. We evaluated the effectiveness of the implementation by thematic analysis of student reflections following each encounter using a qualitative descriptive framework. Results: Eighty-three students completed each encounter. Qualitative analysis showed that students preferred a more realistic encounter by having a child or other distraction present. Students relied on different elements of motivational interviewing depending on the objective of each encounter and the age of the patient. Overall, the SP encounters were well received by students and faculty as an alternative or supplement to traditional student evaluation methods. Discussion: We noted a number of lessons learned about implementing SP methodology in pediatric dental education. With these experiences now in place, future evaluations should measure student performance in the SP encounters against student performance during clinical care.

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