MILO: Models of innovation in learning online at Key Stage 3 and 14-19: Final report executive summary

This summary report presents and analyses the key findings from eight case studies, which reflect a wide range of models of online learning, each of which has been developed for specific reasons, largely in relation to visions of how technology can transform learning, but also to solve practical problems such as re-engaging disaffected learners and coping with rising pupil numbers

MILO: Models of innovation in learning online at Key Stage 3 and 14-19: Final report appendices

This document contains the appendices to the main report, which presents case studies, which reflect a wide range of models of online learning, each of which has been developed for specific reasons, largely in relation to visions of how technology can transform learning, but also to solve practical problems such as re-engaging disaffected learners and coping with rising pupil numbers

MILO: Models of innovation in learning online at Key Stage 3 and 14-19: Final report

The report presents and analyses eight case studies, which reflect a wide range of models of online learning, each of which has been developed for specific reasons, largely in relation to visions of how technology can transform learning, but also to solve practical problems such as re-engaging disaffected learners and coping with rising pupil numbers

Solar Flare Intermittency and the Earth's Temperature Anomalies

We argue that earth's short-term temperature anomalies and the solar flare intermittency are linked. The analysis is based upon the study of the scaling of both the spreading and the entropy of the diffusion generated by the fluctuations of the temperature time series. The joint use of these two methods evidences the presence of a L\'{e}vy component in the temporal persistence of the temperature data sets that corresponds to the one that would be induced by the solar flare intermittency. The mean monthly temperature datasets cover the period from 1856 to 2002.Comment: 4 pages, 5 figure

Empirical analysis of the solar contribution to global mean air surface temperature change

The solar contribution to global mean air surface temperature change is analyzed by using an empirical bi-scale climate model characterized by both fast and slow characteristic time responses to solar forcing: $\tau_1 =0.4 \pm 0.1$ yr, and $\tau_2= 8 \pm 2$ yr or $\tau_2=12 \pm 3$ yr. Since 1980 the solar contribution to climate change is uncertain because of the severe uncertainty of the total solar irradiance satellite composites. The sun may have caused from a slight cooling, if PMOD TSI composite is used, to a significant warming (up to 65% of the total observed warming) if ACRIM, or other TSI composites are used. The model is calibrated only on the empirical 11-year solar cycle signature on the instrumental global surface temperature since 1980. The model reconstructs the major temperature patterns covering 400 years of solar induced temperature changes, as shown in recent paleoclimate global temperature records.Comment: 9 pages, 6 figure

A multifactorial intervention for frail older people is more than twice as effective among those who are compliant: complier average causal effect analysis of a randomised trial

AbstractQuestion: What is the effect of a multifactorial intervention on frailty and mobility in frail older people who comply with their allocated treatment? Design: Secondary analysis of a randomised, controlled trial to derive an estimate of complier average causal effect (CACE) of treatment. Participants: A total of 241 frail community-dwelling people aged ≥ 70 years. Intervention: Intervention participants received a 12-month multidisciplinary intervention targeting frailty, with home exercise as an important component. Control participants received usual care. Outcome measures: Primary outcomes were frailty, assessed using the Cardiovascular Health Study criteria (range 0 to 5 criteria), and mobility measured using the 12-point Short Physical Performance Battery. Outcomes were assessed 12 months after randomisation. The treating physiotherapist evaluated the amount of treatment received on a 5-point scale. Results: 216 participants (90%) completed the study. The median amount of treatment received was 25 to 50% (range 0 to 100). The CACE (ie, the effect of treatment in participants compliant with allocation) was to reduce frailty by 1.0 frailty criterion (95% CI 0.4 to 1.5) and increase mobility by 3.2 points (95% CI 1.8 to 4.6) at 12 months. The mean CACE was substantially larger than the intention-to-treat effect, which was to reduce frailty by 0.4 frailty criteria (95% CI 0.1 to 0.7) and increase mobility by 1.4 points (95% CI 0.8 to 2.1) at 12 months. Conclusion: Overall, compliance was low in this group of frail people. The effect of the treatment on participants who comply with allocated treatment was substantially greater than the effect of allocation on all trial participants. Trial registration: Australian and New Zealand Trial Registry ANZCTRN12608000250336. [Fairhall N, Sherrington C, Cameron ID, Kurrle SE, Lord SR, Lockwood K, Herbert RD (2016) A multifactorial intervention for frail older people is more than twice as effective among those who are compliant: complier average causal effect analysis of a randomised trial. Journal of Physiotherapy 63: 40–44

A distinctive requirement for p53 in the genome protective Topoisomerase 2a-dependent G2 arrest in hTERT positive cancer cells

Topoisomerase 2a (Topo2a)-dependent G2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G2 arrest by determining that p53-p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G2 arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G2 arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G2 arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention.SignificanceThe identification of a requirement for p53 in stringent Topo2a-dependent G2 arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality

A genome-wide RNAi screen identifies the SMC5/6 complex as a non-redundant regulator of a Topo2a-dependent G2 arrest

The Topo2a-dependent arrest is associated with faithful segregation of sister chromatids and has been identified as dysfunctional in numerous tumour cell lines. This genome-protecting pathway is poorly understood and its characterization is of significant interest, potentially offering interventional opportunities in relation to synthetic lethal behaviours in arrest-defective tumours. Using the catalytic Topo2a inhibitor ICRF193, we have performed a genome-wide siRNA screen in arrest-competent, non-transformed cells, to identify genes essential for this arrest mechanism. In addition, we have counter-screened several DNA-damaging agents and demonstrate that the Topo2a-dependent arrest is genetically distinct from DNA damage checkpoints. We identify the components of the SMC5/6 complex, including the activity of the E3 SUMO ligase NSE2, as non-redundant players that control the timing of the Topo2a-dependent arrest in G2. We have independently verified the NSE2 requirement in fibroblasts from patients with germline mutations that cause severely reduced levels of NSE2. Through imaging Topo2a-dependent G2 arrested cells, an increased interaction between Topo2a and NSE2 is observed at PML bodies, which are known SUMOylation hotspots. We demonstrate that Topo2a is SUMOylated in an ICRF193-dependent manner by NSE2 at a novel non-canonical site (K1520) and that K1520 sumoylation is required for chromosome segregation but not the G2 arrest

Trends and patterns in antibiotic prescribing among out-of-hours primary care providers in England, 2010–14

Objectives: Antimicrobial resistance is a global threat, increasing morbidity and mortality. In England, publicly funded clinical commissioning groups (CCGs) commission out-of-hours (OOH) primary care services outside daytime hours. OOH consultations represent 1% of in-hours general practice (GP) consultations. Antibiotic prescriptions increased 32% in non-GP community services between 2010 and 2013. We describe OOH antibiotic prescribing patterns and trends between 2010 and 2014. Methods: We: estimated the proportion of CCGs with OOH data available; described and compared antibiotic prescribing by volume of prescribed items, seasonality and trends in GP and OOH, using linear regression; and compared the proportion of broad-spectrum to total antibiotic prescriptions in OOHs with their respective CCGs in terms of seasonality and trends, using binomial regression. Results: Data were available for 143 of 211 (68%) CCGs. OOH antibiotic prescription volume represented 4.5%-5.4% of GP prescription volume and was stable over time ( P  =   0.37). The proportion of broad-spectrum antibiotic prescriptions increased in OOH when it increased in the CCG they operated in (regression coefficient 0.98; 95% CI 0.96-0.99). Compared with GP, the proportion of broad-spectrum antibiotic prescriptions in OOH was higher but decreased both in GP and OOH (-0.57%, 95% CI - 0.54% to - 0.6% and -0.76%, 95% CI - 0.59% to - 0.93% per year, respectively). Conclusions: OOH proportionally prescribed more antibiotics than GPs although we could not comment on prescribing appropriateness. OOH prescribing volume was stable over time, and followed GP seasonal patterns. OOH antibiotic prescribing reflected the CCGs they operated in but with relatively more broad-spectrum antibiotics than in-hours GP. Understanding factors influencing prescribing in OOH will enable the development of tailored interventions promoting optimal prescribing in this setting