The International Mass Loading Service

The International Mass Loading Service computes four loadings: a) atmospheric pressure loading; b) land water storage loading; c) oceanic tidal loading; and d) non-tidal oceanic loading. The service provides to users the mass loading time series in three forms: 1) pre-computed time series for a list of 849 space geodesy stations; 2) pre-computed time series on the global 1deg x 1deg grid; and 3) on-demand Internet service for a list of stations and a time range specified by the user. The loading displacements are provided for the time period from 1979.01.01 through present, updated on an hourly basis, and have latencies 8-20 hours.Comment: 8 pages, 3 figures, to appear in the Proceedings of the Reference Frames for Applications in Geosciences Simposium, held in Luxemboug in October 201

Cardiac rehabilitation versus standard care after aortic aneurysm repair (Aneurysm CaRe): study protocol for a randomised controlled trial.

BACKGROUND: Abdominal and thoracic aortic aneurysms (A/TAA) are an important cause of mortality amongst the older population. Although A/TAA repair can be performed with low peri-operative risk, overall life expectancy remains poor in the years that follow surgery. The majority of deaths are caused by heart attack or stroke, which can both be prevented by cardiac rehabilitation (CR) in patients with clinically-manifest coronary artery disease. A Cochrane review has urged researchers to widen the use of CR to other populations with severe cardiovascular risk, and patients surviving A/TAA repair appear ideal candidates. However, it is unknown whether CR is feasible or acceptable to A/TAA patients, who are a decade older than those currently enrolling in CR. Aneurysm-CaRe is a feasibility randomised controlled trial (RCT) that will address these issues. METHODS AND DESIGN: Aneurysm-CaRe is a pilot RCT of CR versus standard care after A/TAA repair, with the primary objectives of estimating enrolment to a trial of CR after A/TAA repair and estimating compliance with CR amongst patients with A/TAA. Aneurysm-CaRe will randomise 84 patients at two sites. Patients discharged from hospital after elective A/TAA repair will be randomised to standard care or enrolment in their local CR programme with a protocolised approach to medical cardiovascular risk reduction. The primary outcome measures are enrolment in the RCT and compliance with CR. Secondary outcomes will include phenotypic markers of cardiovascular risk and smoking cessation, alongside disease-specific and generic quality-of-life measures. TRIAL REGISTRATION: ISRCTN 65746249 5 June 2014

The transcriptional repressor protein NsrR senses nitric oxide directly via a [2Fe-2S] cluster

The regulatory protein NsrR, a member of the Rrf2 family of transcription repressors, is specifically dedicated to sensing nitric oxide (NO) in a variety of pathogenic and non-pathogenic bacteria. It has been proposed that NO directly modulates NsrR activity by interacting with a predicted [Fe-S] cluster in the NsrR protein, but no experimental evidence has been published to support this hypothesis. Here we report the purification of NsrR from the obligate aerobe Streptomyces coelicolor. We demonstrate using UV-visible, near UV CD and EPR spectroscopy that the protein contains an NO-sensitive [2Fe-2S] cluster when purified from E. coli. Upon exposure of NsrR to NO, the cluster is nitrosylated, which results in the loss of DNA binding activity as detected by bandshift assays. Removal of the [2Fe-2S] cluster to generate apo-NsrR also resulted in loss of DNA binding activity. This is the first demonstration that NsrR contains an NO-sensitive [2Fe-2S] cluster that is required for DNA binding activity

Lateral Gene Expression in Drosophila Early Embryos Is Supported by Grainyhead-Mediated Activation and Tiers of Dorsally-Localized Repression

The general consensus in the field is that limiting amounts of the transcription factor Dorsal establish dorsal boundaries of genes expressed along the dorsal-ventral (DV) axis of early Drosophila embryos, while repressors establish ventral boundaries. Yet recent studies have provided evidence that repressors act to specify the dorsal boundary of intermediate neuroblasts defective (ind), a gene expressed in a stripe along the DV axis in lateral regions of the embryo. Here we show that a short 12 base pair sequence (“the A-box”) present twice within the ind CRM is both necessary and sufficient to support transcriptional repression in dorsal regions of embryos. To identify binding factors, we conducted affinity chromatography using the A-box element and found a number of DNA-binding proteins and chromatin-associated factors using mass spectroscopy. Only Grainyhead (Grh), a CP2 transcription factor with a unique DNA-binding domain, was found to bind the A-box sequence. Our results suggest that Grh acts as an activator to support expression of ind, which was surprising as we identified this factor using an element that mediates dorsally-localized repression. Grh and Dorsal both contribute to ind transcriptional activation. However, another recent study found that the repressor Capicua (Cic) also binds to the A-box sequence. While Cic was not identified through our A-box affinity chromatography, utilization of the same site, the A-box, by both factors Grh (activator) and Cic (repressor) may also support a “switch-like” response that helps to sharpen the ind dorsal boundary. Furthermore, our results also demonstrate that TGF-β signaling acts to refine ind CRM expression in an A-box independent manner in dorsal-most regions, suggesting that tiers of repression act in dorsal regions of the embryo

An approach for computationally expensive multi-objective optimization problems with independently evaluable objectives

Multi-objective optimization problems involve simultaneous optimization of two or more objectives in conflict. For example, in automotive design, one might be interested in simultaneously minimizing the aerodynamic drag and maximizing the torsional rigidity/collision strength of the vehicle. For a number of problems encountered in engineering design, the objectives can be independently evaluated and such evaluations are often computationally expensive. While surrogate-assisted optimization (SAO) methods are typically used to deal with such problems, they evaluate all objectives for the chosen infill solution(s). If however the objectives can be independently evaluated, there is an opportunity to improve the computational efficiency by evaluating the selected objective(s) only. In this study, we introduce a SAO approach capable of selectively evaluating the objective(s) of the infill solution(s). The approach exploits principles of non-dominance and sparse subset selection to facilitate decomposition and identifies the infill solutions through maximization of probabilistic dominance measure. Thereafter, for each of these infill solutions, one or more objectives are evaluated, taking into account the evaluation status of its closest neighbor and the probability of improvement along each objective. The performance of the approach is benchmarked against state-of-the-art methods on a range of mathematical problems to highlight the efficacy of the approach. Thereafter, we present the performance on two engineering design problems namely a vehicle crashworthiness design problem and an airfoil design problem. We hope that this study would motivate further algorithmic developments to cater to such classes of problems

A Multifidelity Approach for Bilevel Optimization with Limited Computing Budget

Bilevel optimization refers to a specialized class of problems where the optimum of an upper level (UL) problem is sought subject to the optimality of a nested lower level (LL) problem as a constraint. This nested structure necessitates a large number of function evaluations for the solution methods, especially population-based metaheuristics such as evolutionary algorithms (EAs). Reducing this effort remains critical for practical uptake of bilevel EAs, particularly for computationally expensive problems where each solution evaluation may involve a significant cost. This letter aims to contribute toward this field by a novel and previously unexplored proposition that bilevel optimization problems can be posed as multifidelity optimization problems. The underpinning idea is that an informed judgment of how accurate the LL optimum estimate should be to confidently determine its ranking can significantly cut down redundant evaluations during the search. Toward this end, we propose an algorithm which learns the appropriate fidelity to evaluate a solution during the search based on the seen data, instead of resorting to an exhaustive LL optimization. Numerical experiments are conducted on a range of standard as well as more complex variants of the SMD test problems to demonstrate the advantages of the proposed approach when compared to state-of-the-art surrogate-assisted algorithms

Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer

background: SCALOP, a randomised, phase II trial, tested the activity and safety of gemcitabine (GEM)-based and capecitabine (CAP)-based chemoradiation (CRT) for locally advanced pancreatic cancer (LAPC). Here we present the long-term outcomes. methods: Eligibility: histologically proven LAPC less than or equal to7 cm. Following 12 weeks of induction GEMCAP chemotherapy (three cycles: GEM 1000 mg m−2 days 1, 8, 15; CAP 830 mg m−2 days 1–21 q28 days) patients with stable/responding disease, tumour less than or equal to6 cm, and WHO Performance Status 0–1 were randomised to receive one cycle GEMCAP followed by CAP (830 mg m−2 b.d. on weekdays only) or GEM (300 mg m−2 weekly) with radiation (50.4 Gy per 28 fractions). results: One-hundred fourteen patients (28 UK centres) were registered between 24 December 2009 and 25 October 2011, and 74 were randomised (CAP-RT=36; GEM-RT=38). At the time of this analysis, 105 of the 114 patients had died and the surviving 9 patients had been followed up for a median of 10.9 months (IQR: 2.9–18.7). Updated median OS was 17.6 months (95% CI: 14.6–22.7) in the CAP-CRT arm and 14.6 months (95% CI: 11.1–16.0) in the GEM-CRT arm (intention-to-treat adjusted hazard ratio (HR): 0.68 (95% CI: 0.38–1.21, P=0.185)); median progression-free survival (PFS) was 12.0 months (95% CI: 10.0–15.2) in the CAP-CRT arm and 10.4 months (95% CI: 8.8–12.7) in the GEM-CRT arm (intention-to-treat adjusted HR: 0.60 (95% CI: 0.32–1.14, P=0.120)). In baseline multivariable model, age greater than or equal to65 years, better performance status, CA19.9<613 IU l−1, and shorter tumour diameter predicted improved OS. CAP-CRT, age greater than or equal to65 years, better performance status, CA19.9 <46 IU ml−1 predicted improved OS and PFS in the pre-radiotherapy model. Nine-month PFS was highly predictive of OS. conclusions: CAP-CRT remains the superior regimen. SCALOP showed that patients with CA19.9 <46 IU ml−1 after induction chemotherapy are more likely to benefit from CRT

A cluster randomized controlled trial of the effectiveness and cost-effectiveness of Intermediate Care Clinics for Diabetes (ICCD) : study protocol for a randomized controlled trial

Background World-wide healthcare systems are faced with an epidemic of type 2 diabetes. In the United Kingdom, clinical care is primarily provided by general practitioners (GPs) rather than hospital specialists. Intermediate care clinics for diabetes (ICCD) potentially provide a model for supporting GPs in their care of people with poorly controlled type 2 diabetes and in their management of cardiovascular risk factors. This study aims to (1) compare patients with type 2 diabetes registered with practices that have access to an ICCD service with those that have access only to usual hospital care; (2) assess the cost-effectiveness of the intervention; and (3) explore the views and experiences of patients, health professionals and other stakeholders. Methods/Design This two-arm cluster randomized controlled trial (with integral economic evaluation and qualitative study) is set in general practices in three UK Primary Care Trusts. Practices are randomized to one of two groups with patients referred to either an ICCD (intervention) or to hospital care (control). Intervention group: GP practices in the intervention arm have the opportunity to refer patients to an ICCD - a multidisciplinary team led by a specialist nurse and a diabetologist. Patients are reviewed and managed in the ICCD for a short period with a goal of improving diabetes and cardiovascular risk factor control and are then referred back to practice. or Control group: Standard GP care, with referral to secondary care as required, but no access to ICCD. Participants are adults aged 18 years or older who have type 2 diabetes that is difficult for their GPs to control. The primary outcome is the proportion of participants reaching three risk factor targets: HbA1c (≤7.0%); blood pressure (<140/80); and cholesterol (<4 mmol/l), at the end of the 18-month intervention period. The main secondary outcomes are the proportion of participants reaching individual risk factor targets and the overall 10-year risks for coronary heart disease(CHD) and stroke assessed by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. Other secondary outcomes include body mass index and waist circumference, use of medication, reported smoking, emotional adjustment, patient satisfaction and views on continuity, costs and health related quality of life. We aimed to randomize 50 practices and recruit 2,555 patients

Nested evolutionary algorithms for computationally expensive bilevel optimization problems: Variants and their systematic analysis

© 2019 Elsevier B.V. Bilevel optimization problems involve a hierarchical model where an upper level optimization problem is solved with a constraint on the optimality of a nested lower level problem. The use of evolutionary algorithms (EAs) and other metaheuristics has been gaining attention to solve bilevel problems, especially when they contain non-linear/black-box objective(s) and/or constraint(s). However, EAs typically operate in a nested mode wherein a lower level optimization is executed for each upper level solution. Evidently, this process requires excessive number of function evaluations, which might become untenable if the underlying functions are computationally expensive. In order to reduce this expense, the use of approximations (also referred to as surrogates or meta-models) has been suggested previously. However, the previous works have focused only on the use of surrogates for the lower level problem, whereas the computational expense of the upper level problem has not been considered. In this paper, we aim to make two contributions to address this research gap. The first is to introduce an improved nested EA which uses surrogate-assisted search at both levels in order to solve bilevel problems using limited number of function evaluations. The second is the revelation and a systematic investigation of a previously overlooked aspect of bilevel search – that the objective/constraints at the upper and lower levels may involve different computational expense. Consideration of this aspect can help in deciding a suitable strategy, i.e., in which level is the use of surrogates most appropriate for the given problem. Towards this end, four different nested strategies – with surrogate at either level, none or at both levels, are compared under various experimental settings. Numerical experiments are presented on a wide range of problems to demonstrate the efficacy and utility of the proposed contributions

Binary and Millisecond Pulsars at the New Millennium

We review the properties and applications of binary and millisecond pulsars. Our knowledge of these exciting objects has greatly increased in recent years, mainly due to successful surveys which have brought the known pulsar population to over 1300. There are now 56 binary and millisecond pulsars in the Galactic disk and a further 47 in globular clusters. This review is concerned primarily with the results and spin-offs from these surveys which are of particular interest to the relativity community.Comment: 59 pages, 26 figures, 5 tables. Accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org