Reduced fetal vitamin D status by maternal undernutrition during discrete gestational windows in sheep

Placental transport of vitamin D and other nutrients (e.g. amino acids, fats and glucose) to the fetus is sensitive to maternal and fetal nutritional cues. We studied the effect of maternal calorific restriction on fetal vitamin D status and the placental expression of genes for nutrient transport (aromatic T-type amino acid transporter-1 [TAT-1]; triglyceride hydrolase / lipoprotein uptake facilitator lipoprotein lipase [LPL]) and vitamin D homeostasis (CYP27B1; vitamin D receptor [VDR]), and their association with markers of fetal cardiovascular function and skeletal muscle growth. Pregnant sheep received 100% total metabolizable energy (ME) requirements (control), 40% total ME requirements peri-implantation (PI40, 1–31 days of gestation [dGA]) or 50% total ME requirements in late gestation (L, 104–127 dGA). Fetal, but not maternal, plasma 25-hydroxy-vitamin D (25OHD) concentration was lower in PI40 and L maternal undernutrition groups (p<0.01) compared with the control group at 0.86 gestation. PI40 group placental CYP27B1 mRNA levels were increased (p<0.05) compared with the control group. Across all groups, higher fetal plasma 25OHD concentration was associated with higher skeletal muscle myofibre and capillary density (p<0.05). In the placenta, higher VDR mRNA levels were associated with higher TAT-1 (p<0.05) and LPL (p<0.01) mRNA levels. In the PI40 maternal undernutrition group only, reduced fetal plasma 25OHD concentration may be mediated in part by altered placental CYP27B1. The association between placental mRNA levels of VDR and nutrient transport genes suggests a way in which the placenta may integrate nutritional cues in the face of maternal dietary challenges and alter fetal physiology

Transformational school leadership as a key factor for teachers’ job attitudes during their first year in the profession

Teacher attrition is a global concern that is particularly prevalent among beginning teachers. Teachers' intrinsic motivation to teach, affective organisational commitment and job satisfaction are considered job attitudes that stop them from dropping out of the profession. This study explores the interplay between factors at the school level (i.e. transformational leadership of the principal, professional collegial support) and the teacher level (i.e. self-efficacy) influencing these job attitudes. A sample of 292 first-year primary-school teachers participated. The results of the path analysis demonstrated that transformational leadership of the principal is directly related to teachers' job attitudes in a positive way. Moreover, transformational leadership of the principal is also indirectly related to these attitudes, via both professional collegial support and teachers' self-efficacy. Implications for the supportive role of the principal in the teachers' first year in the profession are discussed

Belongingness in early secondary school: Key factors that primary and secondary schools need to consider

© 2015 Vaz et al. It is unknown if, and how, students redefine their sense of school belongingness after negotiating the transition to secondary school. The current study used longitudinal data from 266 students with, and without, disabilities who negotiated the transition from 52 primary schools to 152 secondary schools. The study presents the 13 most significant personal student and contextual factors associated with belongingness in the first year of secondary school. Student perception of school belongingness was found to be stable across the transition. No variability in school belongingness due to gender, disability or household-socio-economic status (SES) was noted. Primary school belongingness accounted for 22% of the variability in secondary school belongingness. Several personal student factors (competence, coping skills) and school factors (low-level classroom task-goal orientation), which influenced belongingness in primary school, continued to influence belongingness in secondary school. In secondary school, effort-goal orientation of the student and perception of their school's tolerance to disability were each associated with perception of school belongingness. Family factors did not influence belongingness in secondary school. Findings of the current study highlight the need for primary schools to foster belongingness among their students at an early age, and transfer students' belongingness profiles as part of the handover documentation. Most of the factors that influenced school belongingness before and after the transition to secondary are amenable to change

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

Effect and cost-effectiveness of human-centred design-based approaches to increase adolescent uptake of modern contraceptives in Nigeria, Ethiopia and Tanzania: Population-based, quasi-experimental studies.

Around half of adolescent pregnancies in low- and middle-income countries are unintended, contributing to millions of unsafe abortions per year. Adolescents 360 (A360), a girl-centred initiative, aimed to increase voluntary uptake of modern contraceptives among adolescents in Nigeria, Ethiopia and Tanzania. We evaluated the effectiveness and cost-effectiveness of A360 in increasing modern contraceptive use in selected geographies. We used before-and-after cross-sectional studies of adolescent girls in four settings. Two Nigerian settings had purposefully selected comparison areas. Baseline and endline household surveys were conducted. The primary study outcome was modern contraceptive prevalence rate (mCPR). Secondary outcomes mapped onto the A360 Theory of Change. Interpretation was aided by a process evaluation along with secular mCPR trends and self-reported A360 exposure data. Incremental design and implementation costs were calculated from implementer systems, site visits, surveys, and interviews. mCPR change was modelled into maternal disability-adjusted life years (DALY) averted to calculate incremental cost-effectiveness ratios. In Oromia, Ethiopia, mCPR increased by 5% points (95% CI 1-10; n = 1,697). In Nigeria, there was no evidence of an effect of A360 on mCPR in Nasarawa (risk ratio: 0·96, 95% CI: 0·76-1·21; n = 5,414) or in Ogun (risk ratio: 1·08, 95% CI: 0·92-1·26; n = 3,230). In Mwanza, Tanzania, mCPR decreased by 9% points (-17 to -0.3; n = 1,973). Incremental cost per DALY averted were $30,855 in Oromia,$111,416 in Nasarawa, $30,114 in Ogun, and$25,579 in Mwanza. Costs per DALY averted were 14-53 times gross domestic product per capita. A360 did not lead to increased adolescent use of modern contraceptives at a population level, except in Oromia, and was not cost-effective. This novel adolescent-centred design approach showed some promise in addressing the reproductive health needs of adolescents, but must be accompanied by efforts to address the contextual drivers of low modern contraceptive use

Climate evolution through the onset and intensification of Northern Hemisphere glaciation

The Pliocene Epoch (∼5.3–2.6 million years ago, Ma) was characterized by a warmer than present climate with smaller Northern Hemisphere ice sheets, and offers an example of a climate system in long-term equilibrium with current or predicted near-future atmospheric CO2 concentrations (pCO2). A long-term trend of ice-sheet expansion led to more pronounced glacial (cold) stages by the end of the Pliocene (∼2.6 Ma), known as the “intensification of Northern Hemisphere Glaciation” (iNHG). We assessed the spatial and temporal variability of ocean temperatures and ice-volume indicators through the late Pliocene and early Pleistocene (from 3.3 to 2.4 Ma) to determine the character of this climate transition. We identified asynchronous shifts in long-term means and the pacing and amplitude of shorter-term climate variability, between regions and between climate proxies. Early changes in Antarctic glaciation and Southern Hemisphere ocean properties occurred even during the mid-Piacenzian warm period (∼3.264–3.025 Ma) which has been used as an analog for future warming. Increased climate variability subsequently developed alongside signatures of larger Northern Hemisphere ice sheets (iNHG). Yet, some regions of the ocean felt no impact of iNHG, particularly in lower latitudes. Our analysis has demonstrated the complex, non-uniform and globally asynchronous nature of climate changes associated with the iNHG. Shifting ocean gateways and ocean circulation changes may have pre-conditioned the later evolution of ice sheets with falling atmospheric pCO2. Further development of high-resolution, multi-proxy reconstructions of climate is required so that the full potential of the rich and detailed geological records can be realized