Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P = 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

Midwifery research by midwifery researchers: challenges and considerations

This paper will discuss some of the challenges which may be encountered by midwifery researchers when conducting research where the research setting is familiar or study participants are known to the researchers. The paper identifies some of the key challenges which should be considered such as researching in a familiar culture, perception of participants, sample selection, finding space in the setting and interview dynamics. Examples are provided from three previous qualitative research projects conducted by the authors in educational and clinical settings with both pre registration and post registration midwives (pre and post registration). Each of the key issues will be discussed highlighting specific issues relevant to each with further consideration of how these issues may impact on progress of the project, data collected and subsequent findings. Finally, these will be drawn together with recommendations for future research conducted by midwives or where the setting or participants are known to the researchers. Although the paper is focused on midwifery research the issues raised may bear relevance in other areas where the setting or participants are known to researchers.

Extreme events and the morphodynamics of gravel-dominated coastal barriers: Strengthening uncertain ground

The long-term morphodynamic ordering of gravel-dominated coastal systems (GDCS), many of which serve as coastal defences in northwest Europe, is dominated by extreme events that generate barrier crest overflow. An understanding of this morphodynamic ordering is fraught with several unresolved difficulties. These are related to the twin problems of the inadequacy of pertinent morphodynamic parameterisation and of obtaining data from modern shores enabling such parameterisation. Major uncertainties concern the timing of over-crest flow in terms of return period of extreme elevation; the intensity and structure of the overflow field; antecedent beachface characteristics in response to storms; the rate of relative sea-level change; tidal stage control; and barrier resistance to forcing, itself determined by a number of unknowns including barrier form and size, sediment size and mosaics, and barrier resilience. While generalised extreme value modelling may provide a means of characterising overwashing return-period and its variability, exceptional tsunami events are outside the scope of such modelling. The characterisation of GDCS morphodynamics in terms of the forcing extreme events will necessitate integrating some or all of these parameters into a single model.

Quotients, exactness, and nuclearity in the operator system category

We continue our study of tensor products in the operator system category. We define operator system quotients and exactness in this setting and refine the notion of nuclearity by studying operator systems that preserve various pairs of tensor products. One of our main goals is to relate these refinements of nuclearity to the Kirchberg conjecture. In particular, we prove that the Kirchberg conjecture is equivalent to the statement that every operator system that is (min,er)-nuclear is also (el,c)-nuclear. We show that operator system quotients are not always equal to the corresponding operator space quotients and then study exactness of various operator system tensor products for the operator system quotient. We prove that an operator system is exact for the min tensor product if and only if it is (min,el)-nuclear. We give many characterizations of operator systems that are (min,er)-nuclear, (el,c)-nuclear, (min,el)-nuclear and (el,max)-nuclear. These characterizations involve operator system analogues of various properties from the theory of C*-algebras and operator spaces, including the WEP and LLP.

An Impact Of Various Shroud Bleed Slot Configurations And Cavity Vanes On Compressor Map Width And The Inducer Flow Field

This paper describes an investigation of map width enhancement and a detailed analysis of the inducer flow field due to various bleed slot configurations and vanes in the annular cavity of a turbocharger centrifugal compressor. The compressor under investigation is used in a turbocharger application for a heavy duty diesel engine of approximately 400 hp. This investigation has been undertaken using a computational fluid dynamics (CFD) model of the full compressor stage, which includes a manual multiblock-structured grid generation method. The influence of the bleed slot flow on the inducer flow field at a range of operating conditions has been analyzed, highlighting the improvement in surge and choked flow capability. The impact of the bleed slot geometry variations and the inclusion of cavity vanes on the inlet incidence angle have been studied in detail by considering the swirl component introduced at the leading edge by the recirculating flow through the slot. Further, the overall stage efficiency and the nonuniform flow field at the inducer inlet have been also analyzed. The analysis revealed that increasing the slot width has increased the map width by about 17%. However, it has a small impact on the efficiency, due to the frictional and mixing losses. Moreover, adding vanes in the cavity improved the pressure ratio and compressor performance noticeably. A detail analysis of the compressor with cavity vanes has also been presented.

A Randomized, Double-Blind, Dose-Finding, Multicenter, Phase 2 Study of Radium Chloride (Ra 223) in Patients with Bone Metastases and Castration-Resistant Prostate Cancer

BACKGROUND: Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile. OBJECTIVE: To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases. DESIGN, SETTING, AND PARTICIPANTS: In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n=41), 50 kBq/kg (n=39), or 80 kBq/kg (n=42). The study compared the proportion of patients in each dose group who had a confirmed decrease of =50% in baseline prostate-specific antigen (PSA) levels. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups. RESULTS AND LIMITATIONS: The study met its primary end point with a statistically significant dose-response relationship in confirmed =50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p=0.0297). A =50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p

Identifying educational needs in end-of-life care for staff and families of residents in care facilities.

AIM: the purpose of this article is to describe educational needs in end-of-life (EoL) care for staff and families of residents in long-term care (LTC) facilities in the province of Ontario, Canada. Barriers to providing end-of-life care education in LTC facilities are also identified. DESIGN, SETTING AND PARTICIPANTS: cross-sectional survey of directors of care in all licensed LTC facilities in the province of Ontario, Canada. RESULTS: directors of care from 426 (76.9% response rate) licensed LTC facilities completed a postal-survey questionnaire. Topics identified as very important for staff education included pain and symptom management and communication with family members about EoL care. Priorities for family education included respecting the residents' expressed wishes for care and communication about EoL care. Having sufficient institutional resources was identified as a major barrier to providing continuing education to both staff and families. CONCLUSION: through examining educational needs in EoL care this study identified an environment of inadequate staffing and over-burdened care providers. The importance of increased staffing concomitant with education is a priority for LTC facilities.

Characterization of physio-chemical processes and hydration kinetics in concretes containing supplementary cementitious materials using electrical property measurements

The current study monitors both the short- and long-term hydration characteristics of concrete using discretized conductivity measurements from initial gauging, through setting and hardening, the latter comprising both the curing and post-curing periods. In particular, attention is directed to the near-surface concrete as it is this zone which protects the steel from the external environment and has a major influence on durability, performance and service-life. A wide range of concrete mixes is studied comprising both plain Portland cement concretes and concretes containing fly-ash and ground granulated blast furnace slag. The parameter normalised conductivity was used to identify four distinct stages in the hydration process and highlight the influence of supplementary cementitious materials (SCM) on hydration and hydration kinetics. A relationship has been presented to account for the temporal decrease in conductivity, post 10-days hydration. The testing procedure and methodology presented lend itself to in-situ monitoring of reinforced concrete structures. (c) 2013 Elsevier Ltd. All rights reserved.

History taking and clinical examination skills from a stoma nurse’s perspective

Comprehensive history-taking and clinical examination skills are examples of role development for a stoma care nurse specialist. Comprehensive history-taking is a thorough exploration of a patient's presenting complaint and the gathering of subjective information, while clinical examination is the gathering of objective information from a head-to-toe assessment or a focused assessment of a particular body system. This paper demonstrates the application of comprehensive history-taking and gastrointestinal clinical examination skills by the stoma care nurse in a clinical community setting, and explores their advantages and disadvantages in stoma care practice.

Banking compliance and dependence corruption: towards an attachment perspective

Why did banking compliance fail so badly in the recent financial crisis and why, according to many, does it continue to do so? Rather than point to the lack of oversight of individuals in bank compliance roles, as many commentators do, in this paper I examine in depth the organizational context that surrounded people in such roles. I focus on those compliance personnel who did speak out about risky practices in their banks, who were forced to escalate the problem and 'whistle-blow' to external parties, and who were punished for doing so. Drawing on recent empirical data from a wider study, I argue that the concept of dependence corruption is useful in this setting, and that it can be extended to encompass interpersonal attachments. This, in turn, problematises the concept of dependence corruption because interpersonal attachments in organisational settings are inevitable. The paper engages with recent debates on whether institutional corruption is an appropriate lens for studying private-sector organisations by arguing for a focus on roles, rather than remaining at the level of institutional fields or individual organisations. Finally, the paper contributes to studies on banking compliance in the context of the recent crisis; without a deeper understanding of those who were forced to extremes to simply do their jobs, reform of the banking sector will prove difficult.

Spectres of Shakespeare:Ong Keng Sen’s Search: Hamlet and the Intercultural Myth

Arguably, the myth of Shakespeare is a myth of universality. Much has been written about the dramatic, thematic and ‘humanistic’ transference of Shakespeare’s works: their permeability, transcendence of cultures and histories, geographies and temporalities. Located within this debate is a belief that this universality, among other dominating factors, is founded upon the power and poeticism of Shakespeare’s language. Subsequently, if we acknowledge Frank Kermode’s assertion that “the life of the plays is the language” and “the secret (of Shakespeare’s works) is in the detail,” what then becomes of this myth of universality, and how is Shakespeare’s language ‘transferred’ across cultures? In Asian intercultural adaptations, language becomes the primary site of confrontation as issues of semantic accuracy and poetic affiliation abound. Often, the language of the text is replaced with a cultural equivalent or reconceived with other languages of the stage – song and dance, movement and music; metaphor and imagery consequently find new voices. Yet if myth is, as Roland Barthes propounds, a second-order semiotic system that is predicated upon the already constituted sign, here being language, and myth is parasitical on language, what happens to the myth of Shakespeare in these cultural re-articulations? Wherein lies the ‘universality’? Or is ‘universality’ all that it is – an insubstantial (mythical) pageant? Using Ong Keng Sen’s Search Hamlet (2002), this paper would examine the transference of myth and / as language in intercultural Shakespeares. If, as Barthes argues, myths are to be understood as metalanguages that adumbrate social hegemonies, intercultural imaginings of Shakespeare can be said to expose the hollow myth of universality yet in a paradoxical double-bind reify and reinstate this self-same myth.

Barriers to Goals of Care Discussions With Seriously Ill Hospitalized Patients and Their Families: A Multicenter Survey of Clinicians

Importance: Seriously ill hospitalized patients have identified communication and decision making about goals of care as high priorities for quality improvement in end-of-life care. Interventions to improve care are more likely to succeed if tailored to existing barriers.

Objective: To determine, from the perspective of hospital-based clinicians, (1) barriers impeding communication and decision making about goals of care with seriously ill hospitalized patients and their families and (2) their own willingness and the acceptability for other clinicians to engage in this process.

Design, Setting, and Participants: Multicenter survey of medical teaching units of nurses, internal medicine residents, and staff physicians from participating units at 13 university-based hospitals from 5 Canadian provinces.

Main Outcomes and Measures: Importance of 21 barriers to goals of care discussions rated on a 7-point scale (1 = extremely unimportant; 7 = extremely important).

Results: Between September 2012 and March 2013, questionnaires were returned by 1256 of 1617 eligible clinicians, for an overall response rate of 77.7% (512 of 646 nurses [79.3%], 484 of 634 residents [76.3%], 260 of 337 staff physicians [77.2%]). The following family member-related and patient-related factors were consistently identified by all 3 clinician groups as the most important barriers to goals of care discussions: family members' or patients' difficulty accepting a poor prognosis (mean [SD] score, 5.8 [1.2] and 5.6 [1.3], respectively), family members' or patients' difficulty understanding the limitations and complications of life-sustaining treatments (5.8 [1.2] for both groups), disagreement among family members about goals of care (5.8 [1.2]), and patients' incapacity to make goals of care decisions (5.6 [1.2]). Clinicians perceived their own skills and system factors as less important barriers. Participants viewed it as acceptable for all clinician groups to engage in goals of care discussions-including a role for advance practice nurses, nurses, and social workers to initiate goals of care discussions and be a decision coach.

Conclusions and Relevance: Hospital-based clinicians perceive family member-related and patient-related factors as the most important barriers to goals of care discussions. All health care professionals were viewed as playing important roles in addressing goals of care. These findings can inform the design of future interventions to improve communication and decision making about goals of care.

Enabling and constraining features of donor accountability and its relationship to beneficiary accountability

Purpose: The purpose of this paper is to theorise and empirically examine the views of various NGO stakeholders on the role of donors in facilitating beneficiary accountability.

Method: The paper adopts a case study design and draws primarily on semi-structured interviews with the officials of a large development NGO, donor representatives and regulators.

Findings: We find that donor accountability contains both enabling and constraining features in relation to beneficiary accountability. Our evidence shows that while legitimising their own actions, donors’ accountability requirements embed some enabling provisions of beneficiary accountability, such as participation, monitoring, evaluation and lessons learning, which facilitate beneficiary accountability (Ebrahim, 2003b). We argue that exerting the attributes of power, legitimacy and urgency donors are in a position to realise their accountability claims (Mitchell, Agle, & Wood, 1997) and can hold funded NGOs to account. In the absence of beneficiaries’ power and the unwillingness of regulators to hold NGOs to account, donors’ accountability can play a complementary role in making an NGO accountable to its beneficiaries. Finally, we capture and illustrate some constraining features of donor accountability which limits the promotion of beneficiary accountability.

Research limitations/implications: The findings have significant implications for the policy makers and donors in the context of the current phenomenon of NGOs drive for self-sustainability via commercial activities which are actively encouraged by the donors.

Originality: This paper provides an alternative theorisation of donor accountability in a development NGO context. It draws on rare qualitative empirical data which incorporate the views of multiple groups (including donors which is hitherto rare in the NGO accountability literature) who are directly and/or indirectly involved in setting and negotiating NGO-donors accountability relationship. It enhances our understanding in terms providing a more nuanced portrayal of donor accountability.

Developing management capability within a horizontal supply chain in performance measurement deployment and evolution: A Dynamic Capabilities and Goal Theory perspective

Complex collaboration in rapidly changing business environments create challenges for management capability in Utility Horizontal Supply Chains (UHSCs) involving the deploying and evolving of performance measures. The aim of the study is twofold. First, there is a need to explore how management capability can be developed and used to deploy and evolve Performance Measurement (PM), both across a UHSC and within its constituent organisations, drawing upon a theoretical nexus of Dynamic Capability (DC) theory and complementary Goal Theory. Second, to make a contribution to knowledge by empirically building theory using these constructs to show the management motivations and behaviours within PM-based DCs. The methodology uses an interpretive theory building, multiple case based approach (n=3) as part of a USHC. The data collection methods include, interviews (n=54), focus groups (n=10), document analysis and participant observation (reflective learning logs) over a five-year period giving longitudinal data. The empirical findings lead to the development of a conceptual framework showing that management capabilities in driving PM deployment and evolution can be represented as multilevel renewal and incremental Dynamic Capabilities, which can be further understood in terms of motivation and behaviour by Goal-Theoretic constructs. In addition three interrelated cross cutting themes of management capabilities in consensus building, goal setting and resource change were identified. These management capabilities require carefully planned development and nurturing within the UHSC. 

Fludarabine, Cyclophosphamide and Rituximab:an effective chemoimmunotherapy combination with high remission rates for chronic lymphocytic leukaemia

BACKGROUND: Combined Fludarabine and Cyclophosphamide is now standard first-line therapy in chronic lymphocytic leukaemia (CLL) and the addition of Rituximab improves outcome.

METHODS: We adopted a modified Fludarabine, Cyclophosphamide and Rituximab (FCR) protocol in treating 39 patients (median age 57 years) with progressive or advanced CLL. Depending on CR, treatment was given for four or six cycles.

RESULT: Twenty-six patients were treatment naïve and 13 were pre-treated. Twelve patients had progressive Binet stage A, 16 stage B and 11 stage C disease. The overall response rate (ORR) was 100%, with 75% achieving CR. Neutropenia was the major toxicity in 71/187 (38%) of the cycles. There were five deaths, two from infection and three from progressive disease. Twenty-six of 31 patients have maintained their post-treatment disease status for a median of 17 months (2-41).

CONCLUSION: We conclude that FCR is a feasible, well-tolerated and effective treatment for patients with CLL.