The use and effectiveness of the eLib subject gateways: a preliminary investigation

Internet subject gateways were set up under the Electronic Libraries Programme (eLib) in order to address some of the problems of searching the Internet which have been identified by information professionals, i.e. locating relevant, good quality information. This preliminary study examines the extent to which academics in two universities use three eLib subject gateways (EEVL, OMNI and SOSIG). The results are generally encouraging for the eLib programme, but it is necessary for the gateways to be more effectively promoted. The study also found that academics do not have the same misgivings about the general search engines as the information professionals and seem to use them more readily than the gateways

Evaluation of dental therapists undertaking dental examinations in a school setting in Scotland

Objective: To measure agreement between dental therapists and the Scottish gold-standard dentist undertaking National Dental Inspection Programme (NDIP) examinations. Methods: A study of interexaminer agreement between 19 dental therapists and the national gold-standard dentist was carried out. Pre-calibration training used the caries diagnostic criteria and examination techniques agreed by the British Association for the Study of Community Dentistry (BASCD). Twenty-three 5-year-old children (Primary 1) and 17 11-year-old children (Primary 7) children were examined. Agreement was assessed using kappa statistics on d 3 mft and D 3 MFT for P1 and P7 children, sensitivity and specificity values, and kappa statistics on d 3 t/D 3 T and ft/FT. Calibration data on P1 and P7 children from 2009–2012 involving dentists as examiners were used for comparison. Economic evaluation was undertaken using a cost minimization analysis approach. Results: The mean kappa score was 0.84 (SD 0.07) ranging from 0.69 to 0.94. All dental therapists scored good or very good agreement with the gold-standard dentist. This compares with historic NDIP calibration data with dentists, against the same gold-standard dentist, where the mean kappa value was 0.68 (SD 0.22) with a range of 0.35-1.00. The mean sensitivity score was 0.98 (SD 0.04) (range 0.88-1.0) and mean specificity score was 0.90 (SD 0.06) (range 0.78-0.96). Health economic analysis estimated that salary costs would be 33.6% lower if dental therapists were substituted for dentists in the year 2013, with an estimated saving of approximately £103 646 per annum on the national budget. Conclusion: We conclude that dental therapists show a high level of interexaminer agreement, and with the appropriate annual training and calibration, they could undertake dental examinations as part of the NDIP programme

eIF4A inhibitors suppress cell-cycle feedback response and acquired resistance to CDK4/6 inhibition in cancer

CDK4/6 inhibitors are FDA-approved drugs for estrogen receptor-positive (ER+) breast cancer and are being evaluated to treat other tumor types, including KRAS-mutant non-small cell lung cancer (NSCLC). However, their clinical utility is often limited by drug resistance. Here, we sought to better understand the resistant mechanisms and help devise potential strategies to overcome this challenge. We show that treatment with CDK4/6 inhibitors in both ER+ breast cancer and KRAS-mutant NSCLC cells induces feedback upregulation of cyclin D1, CDK4, and cyclin E1, mediating drug resistance. We demonstrate that rocaglates, which preferentially target translation of key cell-cycle regulators, effectively suppress this feedback upregulation induced by CDK4/6 inhibition. Consequently, combination treatment of CDK4/6 inhibitor palbociclib with the eukaryotic initiation factor (eIF) 4A inhibitor, CR-1-31-B, is synergistic in suppressing the growth of these cancer cells in vitro and in vivo Furthermore, ER+ breast cancer and KRAS-mutant NSCLC cells that acquired resistance to palbociclib after chronic drug exposure are also highly sensitive to this combination treatment strategy. Our findings reveal a novel strategy using eIF4A inhibitors to suppress cell-cycle feedback response and to overcome resistance to CDK4/6 inhibition in cancer.Accepted manuscrip

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide, yet ASCVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure- and cholesterol-lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of ASCVD. OBJECTIVES: To determine the effect of fixed-dose combination therapy on all-cause mortality, fatal and non-fatal ASCVD events, and adverse events. We also sought to determine the effect of fixed-dose combination therapy on blood pressure, lipids, adherence, discontinuation rates, health-related quality of life, and costs. SEARCH METHODS: We updated our previous searches in September 2016 of CENTRAL, MEDLINE, Embase, ISI Web of Science, and DARE, HTA, and HEED. We also searched two clinical trials registers in September 2016. We used no language restrictions. SELECTION CRITERIA: We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure-lowering and one lipid-lowering component versus usual care, placebo, or an active drug comparator for any treatment duration in adults 18 years old or older, with no restrictions on presence or absence of pre-existing ASCVD. DATA COLLECTION AND ANALYSIS: Three review authors independently selected studies for inclusion and extracted the data for this update. We evaluated risk of bias using the Cochrane 'Risk of bias' assessment tool. We calculated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I2 < 50%) and random-effects models when heterogeneity was high (I2 ≥ 50%). We used the GRADE approach to evaluate the quality of evidence. MAIN RESULTS: In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed-dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow-up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow-up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed-dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89,  I2 = 0%, 5 studies, N = 5300) and fatal and non-fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low-quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed-dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed-dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate-quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was -6.34 mmHg (95% CI -9.03 to -3.64, 13 trials, 7638 participants, moderate-quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.61 mmol/L (95% CI -0.88 to -0.35, 11 trials, 6565 participants, low-quality evidence) and -0.70 mmol/L (95% CI -0.98 to -0.41, 12 trials, 7153 participants, moderate-quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate-quality evidence). AUTHORS' CONCLUSIONS: The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes

Molecular Dynamics Simulations of Weak Detonations

Detonation of a three-dimensional reactive non-isotropic molecular crystal is modeled using molecular dynamics simulations. The detonation process is initiated by an impulse, followed by the creation of a stable fast reactive shock wave. The terminal shock velocity is independent of the initiation conditions. Further analysis shows supersonic propagation decoupled from the dynamics of the decomposed material left behind the shock front. The dependence of the shock velocity on crystal nonlinear compressibility resembles solitary behavior. These properties categorize the phenomena as a weak detonation. The dependence of the detonation wave on microscopic potential parameters was investigated. An increase in detonation velocity with the reaction exothermicity reaching a saturation value is observed. In all other respects the model crystal exhibits typical properties of a molecular crystal.Comment: 38 pages, 20 figures. Submitted to Physical Review

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

The effects of social service contact on teenagers in England

Objective: This study investigated outcomes of social service contact during teenage years. Method: Secondary analysis was conducted of the Longitudinal Survey of Young People in England (N = 15,770), using data on reported contact with social services resulting from teenagers’ behavior. Outcomes considered were educational achievement and aspiration, mental health, and locus of control. Inverse-probability-weighted regression adjustment was used to estimate the effect of social service contact. Results: There was no significant difference between those who received social service contact and those who did not for mental health outcome or aspiration to apply to university. Those with contact had lower odds of achieving good exam results or of being confident in university acceptance if sought. Results for locus of control were mixed. Conclusions: Attention is needed to the role of social services in supporting the education of young people in difficulty. Further research is needed on the outcomes of social services contact

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit

The WiggleZ Dark Energy Survey: the transition to large-scale cosmic homogeneity

We have made the largest-volume measurement to date of the transition to large-scale homogeneity in the distribution of galaxies. We use the WiggleZ survey, a spectroscopic survey of over 200,000 blue galaxies in a cosmic volume of ~1 (Gpc/h)^3. A new method of defining the 'homogeneity scale' is presented, which is more robust than methods previously used in the literature, and which can be easily compared between different surveys. Due to the large cosmic depth of WiggleZ (up to z=1) we are able to make the first measurement of the transition to homogeneity over a range of cosmic epochs. The mean number of galaxies N(<r) in spheres of comoving radius r is proportional to r^3 within 1%, or equivalently the fractal dimension of the sample is within 1% of D_2=3, at radii larger than 71 \pm 8 Mpc/h at z~0.2, 70 \pm 5 Mpc/h at z~0.4, 81 \pm 5 Mpc/h at z~0.6, and 75 \pm 4 Mpc/h at z~0.8. We demonstrate the robustness of our results against selection function effects, using a LCDM N-body simulation and a suite of inhomogeneous fractal distributions. The results are in excellent agreement with both the LCDM N-body simulation and an analytical LCDM prediction. We can exclude a fractal distribution with fractal dimension below D_2=2.97 on scales from ~80 Mpc/h up to the largest scales probed by our measurement, ~300 Mpc/h, at 99.99% confidence.Comment: 21 pages, 16 figures, accepted for publication in MNRA