Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial

BACKGROUND: In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223.

METHODS: We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16.

FINDINGS: Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5-11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13-not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months-NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11-15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14-NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8-14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months-NA) than for patients with an ECOG PS of 1 (median 13 months, 11-NA) or an ECOG PS of 2 or more (median 7 months, 5-11); and for patients with no reported baseline pain (median NA, 16 months-NA) than for those with mild pain (median 14 months, 13-NA) or moderate-severe pain (median 11 months, 9-13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months-NA) than in those who did not receive these agents (median 13 months, 12-16), and in patients who received radium-223 plus denosumab (median NA, 15 months-NA) than in patients who received radium-223 without denosumab (median 13 months, 12-NA).

INTERPRETATION: Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials.

FUNDING: Pharmaceutical Division of Bayer.

The international evidence on the prevention of drug and alcohol use Summary and examples of implementation in England

The United Nations Office of Drug Control (UNODC) published ‘International Standards on Drug Use Prevention’ in 2013. The Standards were developed through a systematic assessment of the international evidence on prevention and they provide a summary of the available scientific evidence. The briefing provides a summary of the UNODC prevention standards and gives corresponding examples of relevant UK guidelines,programmes and interventions currently available in England. Its aim is to help people who commission, develop and implement prevention strategies and interventions to translate the standards into the English operating landscape. It also aims to support local authority commissioners to develop their prevention strategies and implement them in line with evidence.  

Designing and Developing Digital and Blended Learning Solutions

The continuous advancement in computing, together with the decline in its cost, has resulted in technology becoming ubiquitous (Arbaugh, 2008, Gros, 2007). Technology is growing and is part of our lives in almost every respect, including the way we learn. Technology helps to collapse time and space in learning. For example, technology allows learners to engage with their instructors synchronously, in real time and also asynchronously, by enabling sessions to be recorded. Space and distance is no longer an issue provided there is adequate bandwidth, which determines the most appropriate format such text, audio or video. Technology has revolutionised the way learners learn; courses are designed; and ‘lessons’ are delivered, and continues to do so. The learning process can be made vastly more efficient as learners have knowledge at their fingertips, and unfamiliar concepts can be easily searched and an explanation found in seconds. Technology has also enabled learning to be more flexible, as learners can learn anywhere; at any time; and using different formats, e.g. text or audio. From the perspective of the instructors and L&D providers, technology offers these same advantages, plus easy scalability. Administratively, preparatory work can be undertaken more quickly even whilst student numbers grow. Learners from far and new locations can be easily accommodated. In addition, many technologies can be easily scaled to accommodate new functionality and/ or other new technologies. ‘Designing and Developing Digital and Blended Learning Solutions’ (5DBS), has been developed to recognise the growing importance of technology in L&D. This unit contains four learning outcomes and two assessment criteria, which is the same for all other units, besides Learning Outcome 3 which has three assessment criteria. The four learning outcomes in this unit are: • Learning Outcome 1: Understand current digital technologies and their contribution to learning and development solutions; • Learning Outcome 2: Be able to design blended learning solutions that make appropriate use of new technologies alongside more traditional approaches; • Learning Outcome 3: Know about the processes involved in designing and developing digital learning content efficiently and what makes for engaging and effective digital learning content; • Learning Outcome 4: Understand the issues involved in the successful implementation of digital and blended learning solutions. Each learning outcome is an individual chapter and each assessment unit is allocated its own sections within the respective chapters. This first chapter addresses the first learning outcome, which has two assessment criteria: summarise the range of currently available learning technologies; critically assess a learning requirement to determine the contribution that could be made through the use of learning technologies. The introduction to chapter one is in Section 1.0. Chapter 2 discusses the design of blended learning solutions in consideration of how digital learning technologies may support face-to-face and online delivery. Three learning theory sets: behaviourism; cognitivism; constructivism, are introduced, and the implication of each set of theory on instructional design for blended learning discussed. Chapter 3 centres on how relevant digital learning content may be created. This chapter includes a review of the key roles, tools and processes that are involved in developing digital learning content. Finally, Chapter 4 concerns delivery and implementation of digital and blended learning solutions. This chapter surveys the key formats and models used to inform the configuration of virtual learning environment software platforms. In addition, various software technologies which may be important in creating a VLE ecosystem that helps to enhance the learning experience, are outlined. We introduce the notion of personal learning environment (PLE), which has emerged from the democratisation of learning. We also review the roles, tools, standards and processes that L&D practitioners need to consider within a delivery and implementation of digital and blended learning solution.

Review of Geometric Design Criteria and Lighting Design Criteria, 1968

The investigations for this report were initiated in October, 1967, to perform the following: l. Review the current Iowa State Highway Commission roadway geometric design standards and criteria for conformance with national policies and recent research findings with special attention to high way safety. 2. Review the current Iowa State Highway Commission roadway lighting design standards and criteria for conformance with national policies and recent research findings with special attention to high way safety

St. Louis to St. Paul Corridor Feasibility and Necessity Study: Consultant's Report to the States, 1990

The study analyzes the need for a four-lane highway between St. Louis and St. Paul, and finds it to be needed; it analyzes the highway's feasibility, and finds it to be feasible; it analyzes alternative design standards and suggests that it be built to expressway standards; and, the study evaluates alternative routes and presents four "finalist" routes for your consideration.

St. Louis to St. Paul Corridor Feasibility and Necessity Study: Consultant's Summary Report, 1990

The study analyzes the need for a four-lane highway between St. Louis and St. Paul, and finds it to be needed; it analyzes the highway's feasibility, and finds it to be feasible; it analyzes alternative design standards and suggests that it be built to expressway standards; and, the study evaluates alternative routes and presents four "finalist" routes for your consideration.

In Service to Iowa : Public Library Standards, 6th edition, August 8, 2016

The Standards and Accreditation Program exists to encourage the ongoing development of high quality public library services in Iowa. In Service to Iowa: Public Library Standards is the manual for the State Library of Iowa’s standards program. It was first published in 1985 and was updated in 1989, 1997, 2004, 2010, and now in 2016. Iowa’s voluntary public library standards program was established to give public libraries a tool to identify strengths and areas for improvement. It is also used to document the condition of public library service in Iowa, to distribute Direct State Aid funding, and to meet statutory requirements. In 2015, the Iowa Commission of Libraries appointed the Public Library Standards Advisory Task Force to revise In Service to Iowa. The Task Force in turn solicited feedback from the State Library Advisory Panel to ensure that proposed standards meet the changing needs of Iowa’s public libraries. All task force members support and stress the importance of the accreditation process and thank the Iowa public library community for its assistance.

Evaluation of Community-led Complementary Feeding and Learning Sessions

Thesis (Master's)--University of Washington, 2016-08

Standard Essential Patent in Telecommunication Standard: United States and China Comparison

Thesis (Ph.D.)--University of Washington, 2016-08

In Service to Iowa : Public Library Standards, 4th edition, 2004

The State Library of Iowa’s Standards and Accreditation Program exists to encourage the ongoing development of high quality public library services in Iowa. The Public Library Standards Advisory Task Force will work with State Library staff to review current standards in light of known best practices and current trends, and to develop the 4th edition of In Service to Iowa: Public Library Measures of Quality.

Value and proportions of intangible assets : A comparison between the private- and the public sector

Organizations within the public- and the private sector have different aims with their accounting. Privately held organizations often have the intention to make profit, while authorities within the public sector aim to provide citizens with different services. The difference between these two sectors is also visible in the legislation, where International Accounting Standards Board set the standards for privately held organizations and Ekonomistyrningsverket do the same for the public sector. Because of the larger demand by the society for knowledge and technology, included in the category intangible assets, these are more emphasized in the accounting for organizations. Intangible assets are although linked with complexity which is associated with the measurement. The purpose of this study is therefore to see whether there are any existing differences in how to measure and value intangible assets and internally generated ones between listed companies in the private sector and authorities operating in the public sector. This study is conducted with both a qualitative and quantitative perspective. The data collected for this study is secondary, and is gathered through samples of annual reports from different companies in order to be representative for the whole population. The main results of this study is that there are differences in the measurement and valuation of intangible assets dependent on which sector an organization operates within and this is not due to the standards and regulations. The differences are visible in the percentage change in value of intangible assets since they fluctuate more heavily in the private sector than in the public sector. Simultaneously, the proportions of internally generated intangible assets compared to intangible assets in general differ between the two sectors.

Business Signage Control in Seattle's Chinatown International District, Pursuing Healthy Balance of Preservation and Commercial Vitalization in a Historic Commercial Districts

Thesis (Master's)--University of Washington, 2016-06

Theory development in humanitarian logistics : A framework and three cases

Purpose: There is a need for theory development within the field of humanitarian logistics to understand logistics needs in different stages of a crisis and how to meet these. This paper aims to discuss three dimensions identified in logistics and organization theories and how they relate to three different cases of humanitarian logistics operations - the regional concept of the International Federation of Red Cross Red Crescent Societies, the development and working of the United Nations Joint Logistics Centre and coordination challenges of military logistics in UN mandated peacekeeping operations. The purpose is to build a framework to be used in further studies. Design/methodology/approach: A framework for the study of humanitarian logistics along three dimensions is developed, followed by a discussion of the chosen cases in relation to these dimensions. The framework will be used as basis for the case studies to be undertaken for the purpose of understanding and identification of new questions and needs for other or revised concepts from theory. Findings: The paper shows the relevance of a wide literature to the issues pertinent to humanitarian logistics. There is considerable promise in extant literature on logistics, SCM and coordination, but this needs to be confronted with the particular issues seen in the humanitarian logistics setting to achieve further theory development. Originality/value: The major contribution of the paper lies in its breadth of theoretical perspectives presented and combined in a preliminary theoretical framework. This is applied more specifically in the three case studies described in the paper.

Seasonal variation of acetylcholinesterase, catalase, glutathione s transferase in different size of Pinctada radiata and metal pollution (Pb, Cd, Ni) in Persian Gulf

There are various tools for monitoring the concentration of pollutants on aquatic ecosystems. Today these studies are based on biological monitoring and biomarkers. The aim of this study was to measure the concentration of the acetylcholinesterase (AChE), glutathione S-transferase and catalase as biomarkers of heavy metal contamination in pearl oyster Pinctada radiata and their mechanism in aquatic ecosystems. Heavy metals lead, cadmium and nickel were measured in soft tissue and studied stations in four seasons. Samples were collected seasonally in Lavan stations, Hendurabi and Nakhilo (in the northern Persian Gulf) from spring 2013 to winter of that year by scuba diving. Pearl oysters are divided according to their shells size; shells separated from soft tissues and were transferred to the laboratory for analysis of heavy metals and enzymes. Moopam standard method for were used for measuring the concentration of heavy metals and for analyzing tissue concentrations of glutathione S-transferase in Clam the method recommended by Habig et al in 1974 were used. For measuring acetylcholinesterase Ellman method were used. Catalase contamination in pearl oyster in the supernatant obtained from the study based on the method homogeate soft tissue of mussels (Abei, 1974) was evaluated. The results showed that the concentration of lead has significant difference in sediments station, the concentration of lead in Lavan is significantly higher than the other two stations, This could be due to the movement of tanker, boats and floating refueling and with a considerable amount of wastewater containing oil and Petroleum into the water, and also due to precipitation and industrial discharges the lead in the region is increasing, land-disposed sewage sludge, has large concentrations of lead. Compare the results of this study with standards related and other similar studies at the regional and international level showed that pollutant concentration of heavy metals in all cases significantly less than all the standards and guide values associated. And also compared to other world research results have been far less than others, Being Less of the conclusion given in this research according that nickel is one of the indicators of oil pollution in the study area and emissions have been relatively low of oil. The concentration of acetylcholinesterase at several stations, in large and small sizes and in the seasons had no significant difference. Variations of catalase, and glutathione S-transferase were almost similar to each other and parameters, station and seasons were significantly different in the concentrations of these enzymes. The effects and interaction between various parameters indicate that following parameters has impact on the concentration of catalase and glutathione S-transferase. Stations; Seasonal changes in antioxidant enzymes related to (assuming a constant in salinity and oxygen) to age, reproductive cycle, availability of food and water temperature. With increasing temperature at warm season, antioxidant enzymes were increase, with increasing temperature and abundance of food in the environment the amount of antioxidant enzymes may increase. The presence of the enzyme concentration may indicate that the higher levels of the enzyme to eliminate ROS activities to be any healthier situation. At the time of gonads maturation and spawning season catalase activity increases. This study also indicates that catalase was significantly higher in the warm season. Due to low pollutants of heavy metals in the study area, a lower level of contaminants were observed in shellfish tissue incidents of international standards and strong correlation between the amount of heavy metal contamination in pearl oyster tissue and enzymes was not observed. Therefore, we can say that the pearl oyster remains in a healthy condition and the amount of enzyme is normal.

A Belief rule-based environmental responsibility assessment system for small and medium-sized enterprises

Various environmental management systems, standards and tools are being created to assist companies to become more environmental friendly. However, not all the enterprises have adopted environmental policies in the same scale and range. Additionally, there is no existing guide to help them determine their level of environmental responsibility and subsequently, provide support to enable them to move forward towards environmental responsibility excellence. This research proposes the use of a Belief Rule-Based approach to assess an enterprise’s level commitment to environmental issues. The Environmental Responsibility BRB assessment system has been developed for this research. Participating companies will have to complete a structured questionnaire. An automated analysis of their responses (using the Belief Rule-Based approach) will determine their environmental responsibility level. This is followed by a recommendation on how to progress to the next level. The recommended best practices will help promote understanding, increase awareness, and make the organization greener. BRB systems consist of two parts: Knowledge Base and Inference Engine. The knowledge base in this research is constructed after an in-depth literature review, critical analyses of existing environmental performance assessment models and primarily guided by the EU Draft Background Report on "Best Environmental Management Practice in the Telecommunications and ICT Services Sector". The reasoning algorithm of a selected Drools JBoss BRB inference engine is forward chaining, where an inference starts iteratively searching for a pattern-match of the input and if-then clause. However, the forward chaining mechanism is not equipped with uncertainty handling. Therefore, a decision is made to deploy an evidential reasoning and forward chaining with a hybrid knowledge representation inference scheme to accommodate imprecision, ambiguity and fuzzy types of uncertainties. It is believed that such a system generates well balanced, sensible and Green ICT readiness adapted results, to help enterprises focus on making improvements on more sustainable business operations.