New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Why Don’t Teachers Understand Our Questions? Reconceptualizing Teachers’ “Misinterpretation” of Survey Items

This study examined sources of inconsistency between teachers’ and researchers’ interpretations of survey items. We analyzed cognitive interview data from 12 middle school mathematics teachers to understand their interpretations of survey items focused on one aspect of their practice: the content of their advice-seeking interactions. Through this analysis we found that previously documented conceptualizations of sources of misinterpretation within teacher surveys (e.g., structural complexity, use of reform language) did not adequately account for all of the inconsistencies between the survey items and teachers’ interpretations. We found it useful to reconceptualize the broader source of many of the misinterpretations as an issue of fit between the researchers’ intended interpretation and teachers’ professional practice

Symbolizing lines and planes as linear combinations in a dynamic geometry environment

In this paper, we focus on students’ symbolizing activity and mathematization relating to linear combination and span in the context of a task sequence designed with digital tools. Considering tools and functions of a digital environment (specifically of GeoGebra) with design heuristics of Realistic Mathematics Education, we introduce four tasks (in R2 and R3) and results of pilot studies. Data sources come from six individual task-based interviews with two linear algebra students. We analyzed these with a lens of mathematization, with a particular focus on tool use. We found students’ use of sliders supported their reasoning about individual linear combinations; the trace function and slider animation supported their intuition for all possible linear combinations of vectors. After shifting from two to three dimensions, students symbolized all possible linear combinations with a parametric vector equation and reasoned about how this could represent particular points on the corresponding lines or planes

A progression of student symbolizing: soultions to systems of linear equations

Systems of linear equations (SLE) comprise a fundamental concept in linear algebra, but there is relatively little research regarding the teaching and learning of SLE, especially students’ conceptions of solutions. It has been shown that solving systems with no or infinitely many solutions tends to be less intuitive for students, pointing to the need for more research on the teaching and learning of the topic. We interviewed two mathematics majors who were also preservice teachers in a paired teaching experiment to see how they reasoned about solutions to SLE in ℝ3. We present findings focused on the progression of students’ reasoning about solutions to SLE through the lens of symbolizing. We document their progression of reasoning as an accumulation of coordinated numeric, algebraic, and graphical meanings and symbolizations for solution sets

Avances de investigación en educación matemática

Resumen basado en el de la publicaciónResumen en españolMonográfico con el título: "El aprendizaje y la enseñanza de las matemáticas en la Universidad"Los sistemas de ecuaciones lineales (SEL) corresponden a un concepto fundamental del álgebra lineal, pero hay relativamente poca investigación acerca de la enseñanza y el aprendizaje de los SEL, particularmente de las concepciones de los estudiantes acerca de sus soluciones. Se ha encontrado que la resolución de sistemas con un número infinito de soluciones o sin solución tiende a ser menos intuitivo para los estudiantes, lo cual indica la necesidad de más investigación en la enseñanza y aprendizaje de este tema. Se entrevistó a dos estudiantes de matemáticas que eran también maestros en formación a través de un experimento de enseñanza por parejas para mirar cómo razonaban acerca de las soluciones de SEL en ℝ3. Se presentan los resultados enfocando en la progresión del razonamiento de los estudiantes sobre las soluciones de los SEL a través del lento de simbolización. Se documenta la progresión de su razonamiento como una acumulación de significados numéricos, algebraicos y gráficos coordinados y las simbolizaciones de sus conjuntos soluciónES