It's PRIMETIME. Postoperative Avoidance of Radiotherapy: Biomarker Selection of Women at Very Low Risk of Local Recurrence.

PRIMETIME is funded by Cancer Research UK (Grant number: C17918/A20015). C.E. Coles is supported by the Cambridge National Institute of Health Research Biomedical Research Centre. C.C. Kirwan is supported by a National Institute of Health Research Clinician Scientist Award (​NIHR-CS-011014).PRIMETIME is funded by Cancer Research UK (Grant number: C17918/A20015). C.E. Coles is supported by the Cambridge National Institute of Health Research Biomedical Research Centre. C.C. Kirwan is supported by a National Institute of Health Research Clinician Scientist Award (​NIHR-CS-011014)

A new approach to generating research-quality phenology data: The USA National Phenology Monitoring System

The USA National Phenology Network (www.usanpn.org) has recently initiated a national effort to encourage people at different levels of expertise—from backyard naturalists to professional scientists—to observe phenology and contribute to a national database that will be used to greatly improve our understanding of spatio-temporal variation in phenology and associated phenological responses to climate change. Many phenological observation protocols identify specific single dates at which individual phenological events are observed, but the scientific usefulness of long-term phenological observations can be improved with a more carefully structured protocol. At the USA-NPN we have developed a new approach that directs observers to record each day that they observe an individual plant, and to assess and report the state of specific life stages (or phenophases) as occurring or not occurring on that plant for each observation date. Observations of animal phenophases are similarly recorded, although for a species as a whole rather than for a specific individual. Evaluation is phrased in terms of simple, easy-to-understand, questions (e.g. “Do you see open flowers?”) which makes it appropriate for a broad audience. From this method, a rich dataset of phenological metrics can be extracted, including the duration of a phenophase (e.g. open flowers), the beginning and end points of a phenophase (e.g. traditional phenological events such as first flower and end flowering), multiple distinct occurrences of phenophases within a single growing season (e.g multiple flowering events, common in drought-prone regions), as well as quantification of sampling frequency and observational uncertainties. The system also includes a mechanism for translation of phenophase start and end points into standard traditional phenological events to facilitate comparison of contemporary data collected with this new “phenophase status” monitoring approach to historical datasets collected with the “phenological event” monitoring approach. These features greatly enhance the utility of the resulting data for statistical analyses addressing questions such as how phenological events vary in time and space, and in response to global change

Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE

Introduction: The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS. Aims: The primary aim is to demonstrate, in patients with APS and previous VTE, with or without systemic lupus erythematosus (SLE), that the intensity of anticoagulation achieved with rivaroxaban is not inferior to that of warfarin. Secondary aims are to compare rates of recurrent thrombosis, bleeding and the quality of life in patients on rivaroxaban with those on warfarin. Methods: Rivaroxaban in antiphospholipid syndrome (RAPS) is a phase II/III prospective non-inferiority RCT in which eligible patients with APS, with or without SLE, who are on warfarin, target international normalized ratio (INR) 2.5 for previous VTE, will be randomized either to continue warfarin (standard of care) or to switch to rivaroxaban. Intensity of anticoagulation will be assessed using thrombin generation (TG) testing, with the primary outcome the percentage change in endogenous thrombin potential (ETP) from randomization to day 42. Other TG parameters, markers of in vivo coagulation activation, prothrombin fragment 1.2, thrombin antithrombin complex and D-dimer, will also be assessed. Discussion: If RAPS demonstrates i) that the anticoagulant effect of rivaroxaban is not inferior to that of warfarin and ii) the absence of any adverse effects that cause concern with regard to the use of rivaroxaban, this would provide sufficient supporting evidence to make rivaroxaban a standard of care for the treatment of APS patients with previous VTE, requiring a target INR of 2.5

An application of hybrid life cycle assessment as a decision support framework for green supply chains

In an effort to achieve sustainable operations, green supply chain management has become an important area for firms to concentrate on due to its inherent involvement with all the processes that provide foundations to successful business. Modelling methodologies of product supply chain environmental assessment are usually guided by the principles of life cycle assessment (LCA). However, a review of the extant literature suggests that LCA techniques suffer from a wide range of limitations that prevent a wider application in real-world contexts; hence, they need to be incorporated within decision support frameworks to aid environmental sustainability strategies. Thus, this paper contributes in understanding and overcoming the dichotomy between LCA model development and the emerging practical implementation to inform carbon emissions mitigation strategies within supply chains. Therefore, the paper provides both theoretical insights and a practical application to inform the process of adopting a decision support framework based on a LCA methodology in a real-world scenario. The supply chain of a product from the steel industry is considered to evaluate its environmental impact and carbon ‘hotspots’. The study helps understanding how operational strategies geared towards environmental sustainability can be informed using knowledge and information generated from supply chain environmental assessments, and for highlighting inherent challenges in this process

Improving contemporary approaches to the master planning process.

Master-planning has had a strong revival in recent years. However, significant demographic and social changes are on-going amidst the constraints of the current economic stagnation, the policy of reduced public spending and the drive to respond to environmental imperatives. These conditions challenge the feasibility of the application of past master-planning practice. The way we conceive of master-planning now requires re-visiting. The traditional perspective of master-planning as a design-led activity concerned with the architectural form of buildings, spaces and infrastructures is out-dated and inadequate to coordinating the plural processes of negotiating sustainable place development which, in addition to realising a visually pleasing townscape, critically satisfies social, functional, economic and environmental requirements. Masterplanning requires both a business planning component, without which there is no delivery, and a governance component, without which the physical strategy has no legitimacy. A more adaptive master-planning approach is required. The paper proposes how a flexible master-planning process can provide a basis of a suitable approach for the development of sustainable settlements. Published in Proceedings of the ICE - Urban Design and Planning, Vol 167, Issue 1, October 2013. Permission is granted by ICE Publishing to print one copy for personal use. Any other use of this PDF file is subject to reprint fees.</p

Amprenavir and efavirenz pharmacokinetics before and after the addition of nelfinavir, indinavir, ritonavir, or saquinavir in seronegative individuals

Adult AIDS Clinical Trials Group 5043 examined pharmacokinetic (PK) interactions between amprenavir (APV) and efavirenz (EFV) both by themselves and when nelfinavir (NFV), indinavir (IDV), ritonavir (RTV), or saquinavir (SQV) is added. A PK study was conducted after the administration of single doses of APV (day 0). Subjects (n = 56) received 600 mg of EFV every 24 h (q24h) for 10 days and restarted APV with EFV for days 11 to 13 with a PK study on day 14. A second protease inhibitor (PI) (NFV, 1,250 mg, q12h; IDV, 1,200 mg, q12h; RTV, 100 mg, q12h; or SQV, 1,600 mg, q12h) was added to APV and EFV on day 15, and a PK study was conducted on day 21. Controls continued APV and EFV without a second PI. Among subjects, the APV areas under the curve (AUCs) on days 0, 14, and 21 were compared using the Wilcoxon signed-rank test. Ninety-percent confidence intervals around the geometric mean ratios (GMR) were calculated. APV AUCs were 46% to 61% lower (median percentage of AUC) with EFV (day 14 versus day 0; P values of <0.05). In the NFV, IDV, and RTV groups, day 21 APV AUCs with EFV were higher than AUCs for EFV alone. Ninety-percent confidence intervals around the GMR were 3.5 to 5.3 for NFV (P < 0.001), 2.8 to 4.5 for IDV (P < 0.001), and 7.8 to 11.5 for RTV (P = 0.004). Saquinavir modestly increased the APV AUCs (GMR, 1.0 to 1.4; P = 0.106). Control group AUCs were lower on day 21 compared to those on day 14 (GMR, 0.7 to 1.0; P = 0.042). African-American non-Hispanics had higher day 14 efavirenz AUCs than white non-Hispanics. We conclude that EFV lowered APV AUCs, but nelfinavir, indinavir, or ritonavir compensated for EFV induction

Change in Brain Magnetic Resonance Spectroscopy after Treatment during Acute HIV Infection

Objective: Single voxel proton magnetic resonance spectroscopy (MRS) can be used to monitor changes in brain inflammation and neuronal integrity associated with HIV infection and its treatments. We used MRS to measure brain changes during the first weeks following HIV infection and in response to antiretroviral therapy (ART). Methods: Brain metabolite levels of N-acetyl aspartate (NAA), choline (tCHO), creatine (CR), myoinositol (MI), and glutamate and glutamine (GLX) were measured in acute HIV subjects (n = 31) and compared to chronic HIV+individuals (n = 26) and HIV negative control subjects (n = 10) from Bangkok, Thailand. Metabolites were measured in frontal gray matter (FGM), frontal white matter (FWM), occipital gray matter (OGM), and basal ganglia (BG). Repeat measures were obtained in 17 acute subjects 1, 3 and 6 months following initiation of ART. Results: After adjustment for age we identified elevated BG tCHO/CR in acute HIV cases at baseline (median 14 days after HIV infection) compared to control (p = 0.0014), as well as chronic subjects (p = 0.0023). A similar tCHO/CR elevation was noted in OGM; no other metabolite abnormalities were seen between acute and control subjects. Mixed longitudinal models revealed resolution of BG tCHO/CR elevation after ART (p = 0.022) with tCHO/CR similar to control subjects at 6 months. Interpretation We detected cellular inflammation in the absence of measurable neuronal injury within the first month of HIV infection, and normalization of this inflammation following acutely administered ART. Our findings suggest that early ART may be neuroprotective in HIV infection by mitigating processes leading to CNS injury

Compartmental pharmacokinetic analysis of oral amprenavir with secondary peaks

Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring