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BACKGROUND: The Childrens Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. METHODS: In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. RESULTS: One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. CONCLUSIONS: The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Predictions of the distribution of groundfish species are needed to support ongoing marine spatial planning initiatives in Canadian Pacific waters. Data to inform species distribution models are available from several fishery-independent surveys. However, no single survey covers the entire region and different gear types are required to survey the range of relevant habitat. Here, we demonstrated a method for integrating presence-absence data across surveys and gear types that allows us to predict the coastwide distributions of 65 groundfish species in British Columbia. Our model leverages data from multiple surveys to estimate how species respond to environmental gradients while accounting for differences in survey catchability. We find that this method has two main benefits: (1) it increases the accuracy of predictions in data-limited surveys and regions while having negligible impacts on accuracy when data are already sufficient, and (2) it reduces uncertainty, resulting in tighter confidence intervals on predicted occurrences. These benefits are particularly relevant in areas of our coast where our understanding of habitat suitability is limited due to a lack of spatially comprehensive long-term groundfish surveys. Key words: demersal fish, species distribution modelling, integrated model, spatiotemporal random field, species richness, Introduction Coastwide predictions of the distribution of groundfish species are needed to support ongoing marine spatial planning (e.g., PNCIMA 2017) and oil spill response planning in Canada's Pacific Region. Data [...]

Researchers have been interested in students' transition to calculus since the early 1900s. One line of inquiry highlights students' understandings of high school mathematics as impeding or supporting their successful transition to university mathematics. This paper addresses an underlying question in this line of inquiry: does school mathematics provide opportunities for students to develop productive meanings for calculus? This article reports on U.S. calculus students' responses to items that assessed students' variational reasoning, meanings for average rate of change, and representational use of notation--ideas ostensibly addressed in school mathematics. To make sense of students' difficulty on these items we sought to understand the opportunities students had to reason with these ideas prior to calculus. We use two data sources to understand the likelihood that students have opportunities to construct productive meanings for function notation, variation, and average rate of change in their secondary mathematics education: meanings for these ideas supported by precalculus textbooks and meanings secondary teachers demonstrated. Our analysis revealed a disconnect between meanings productive for learning calculus and the meanings conveyed by textbooks and held by U.S. high school teachers. We include a comparison of meanings held by U.S. and Korean teachers to highlight that these meanings are culturally embedded in the U.S. educational system.

Existing literature reviews of calculus learning made an important contribution to our understanding of the development of mathematics education research in this area, particularly their documentation of how research transitioned from studying students' misconceptions to investigating students' understanding and ways of thinking per se. This paper has three main goals relative to this contribution. The first goal is to offer a conceptual analysis of how students' difficulties surveyed in three major literature review publications originate in the mathematical meanings and ways of thinking students develop in elementary, middle and early high school. The second goal is to highlight a contribution to an important aspect that the articles in this issue make but was overshadowed by other aspects addressed in existing literature reviews: the nature of the mathematics students experience under the name "calculus" in various nations or regions around the world, and the relation of this mathematics to ways ideas foundational to it are developed over the grades. The third goal is to outline research questions entailed from these articles for future research regarding each of them.

Background: 6‐mercaptopurine is a cornerstone of maintenance therapy for pediatric ALL. Response to 6MP is typically determined by the ANC. Therapeutic ANC range while receiving 6MP is between 500 and 1500/μL. In addition to desired myelosuppression, 6MP is associated with multiple adverse drug effects. Increased doses of 6MP can lead to therapeutic ANC values; however, patients may experience adverse effects before obtaining therapeutic myelosuppression, often deemed "skewed metabolism." Allopurinol may potentially correct skewed 6MP metabolism. Procedure: Pediatric patients with ALL with 6MMP and 6TGN metabolites drawn during maintenance therapy were analyzed for allopurinol use. The primary outcome evaluated the percentage of time spent in therapeutic ANC range before and after allopurinol initiation. In addition, the difference in 6MMP:6TGN ratios before and after allopurinol initiation, incidence of hepatotoxicity, and rates of relapse, were analyzed. Results: Ninety‐five patients were included for analysis. Thirty‐two (34%) patients received allopurinol. There were no significant differences in baseline demographics between the patients who received allopurinol and those who did not. When comparing ANC values pre‐ and post‐allopurinol initiation, a statistically significant increase in the percentage of time spent in therapeutic range was observed (27% vs. 43%; p =.03). In addition, when comparing metabolite ratios pre‐ and post‐allopurinol initiation, a statistically significant decrease in 6MMP:6TGN metabolite ratio values was observed (86.7 vs. 3.6; p <.0001). Conclusions: Allopurinol significantly increased the percent time in therapeutic ANC range and can be safely utilized to significantly lower the ratio of 6MMP:6TGN metabolites, alleviating the undesirable side effects of 6MMP, and optimizing the anti‐leukemic effects associated with 6TGN. [ABSTRACT FROM AUTHOR]

In the UK uplands, prescribed burning of unenclosed heath, grass and blanket bog ('moorland') is used to support game shooting and grazing. Burning on moorland is contentious due to its impact on peat soils, hydrology and habitat condition. There is little information on spatial and temporal patterns of burning, the overlap with soil carbon and sensitive habitats and, importantly, whether these patterns are changing. This information is required to assess the sustainability of burning and the effectiveness of new legislation. We developed a method for semi‐automated detection of burning using satellite imagery – our best performing model has a balanced accuracy of 84.9%. We identified annual burn areas in Great Britain in five burning seasons from 2017/18 to 2021/22 of 8333 to 20 974 ha (average 15 250 ha year−1). Annual extent in England in 2021/22 was 73% lower than the average of the four previous seasons. Burning was identified over carbon‐rich soils (mean 5150 ha or 34% by area of all burning annually) and on steep slopes – 915 ha across the five seasons (1.3%), contravening guidance. Burning (>1 ha) was recorded in 14% of UK protected areas (PAs) and, within these, the percentage area of moorland burned varied from 2 to 31%. In England in some years, the percentage area of moorland burned inside PAs was higher than outside, while this was not the case in Scotland. Burning in sensitive alpine habitats totalled 158 ha across the five seasons. The reduction in burned area in England in 2021/22 could relate to England‐specific legislation, introduced in May 2021, to prohibit burning on deep peat in PAs. This suggests that regulation can be effective. However, the continued overlap with sensitive features suggests that burning falls short of sustainable practices. Our method will enable repeatable re‐assessment of burning extents and overlap with ecosystem services. [ABSTRACT FROM AUTHOR]