Extracellular Loop 2 of the Free Fatty Acid Receptor 2 Mediates Allosterism of a Phenylacetamide Ago-Allosteric Modulator

Allosteric agonists are powerful tools for exploring the pharmacology of closely related G protein-coupled receptors that have nonselective endogenous ligands, such as the short chain fatty acids at free fatty acid receptors 2 and 3 (FFA2/GPR43 and FFA3/GPR41, respectively). We explored the molecular mechanisms mediating the activity of 4-chloro-alpha-(1-methylethyl)-N-2-thiazolylbenzeneacetamide (4-CMTB), a recently described phenylacetamide allosteric agonist and allosteric modulator of endogenous ligand function at human FFA2, by combining our previous knowledge of the orthosteric binding site with targeted examination of 4-CMTB structure-activity relationships and mutagenesis and chimeric receptor generation. Here we show that 4-CMTB is a selective agonist for FFA2 that binds to a site distinct from the orthosteric site of the receptor. Ligand structure-activity relationship studies indicated that the N-thiazolyl amide is likely to provide hydrogen bond donor/acceptor interactions with the receptor. Substitution at Leu(173) or the exchange of the entire extracellular loop 2 of FFA2 with that of FFA3 was sufficient to reduce or ablate, respectively, allosteric communication between the endogenous and allosteric agonists. Thus, we conclude that extracellular loop 2 of human FFA2 is required for transduction of cooperative signaling between the orthosteric and an as-yet-undefined allosteric binding site of the FFA2 receptor that is occupied by 4-CMTB.

Relative biological effectiveness (RBE) and out-of-field cell survival responses to passive scattering and pencil beam scanning proton beam deliveries

The relative biological effectiveness (RBE) of passive scattered (PS) and pencil beam scanned (PBS) proton beam delivery techniques for uniform beam configurations was determined by clonogenic survival. The radiobiological impact of modulated beam configurations on cell survival occurring in- or out-of-field for both delivery techniques was determined with intercellular communication intact or physically inhibited. Cell survival responses were compared to those observed using a 6 MV photon beam produced with a linear accelerator. DU-145 cells showed no significant difference in survival response to proton beams delivered by PS and PBS or 6 MV photons taking into account a RBE of 1.1 for protons at the centre of the spread out Bragg peak. Significant out-of-field effects similar to those observed for 6 MV photons were observed for both PS and PBS proton deliveries with cell survival decreasing to 50-60% survival for scattered doses of 0.05 and 0.03 Gy for passive scattered and pencil beam scanned beams respectively. The observed out-of-field responses were shown to be dependent on intercellular communication between the in-and out-of-field cell populations. These data demonstrate, for the first time, a similar RBE between passive and actively scanned proton beams and confirm that out-of-field effects may be important determinants of cell survival following exposure to modulated photon and proton fields

In-vitro investigation of out-of-field cell survival following the delivery of conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans

The aim of this work is to determine the out-of-field survival of cells irradiated with either the primary field or scattered radiation in the presence and absence of intercellular communication following delivery of conformal, IMRT and VMAT treatment plans. Single beam, conformal, IMRT and VMAT plans were created to deliver 3 Gy to half the area of a T80 flask containing either DU-145 or AGO-1522 cells allowing intercellular communication between the in-and out-of-field cell populations. The same plans were delivered to a similar custom made phantom used to hold two T25 culture flasks, one flask in-field and one out-of-field to allow comparison of cell survival responses when intercellular communication is physically inhibited. Plans were created for the delivery of 8 Gy to the more radio-resistant DU-145 cells only in the presence and absence of intercellular communication. Cell survival was determined by clonogenic assay. In both cell lines, the out-of-field survival was not statistically different between delivery techniques for either cell line or dose. There was however, a statistically significant difference between survival out-of-field when intercellular communication was intact (single T80 culture flask) or inhibited (multiple T25 culture flasks) to in-field for all plans. No statistically significant difference was observed in-field with or without cellular communication to out-of-field for all plans. These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields when cellular communication between differentially irradiated cell populations is present. This data is further evidence that refinement of existing radiobiological models to include indirect cell killing effects is required.

“Boundary-setting as a core activity in complex public systems”

Title: Boundary-setting as a core activity in complex public systems
Authors: Joanne Murphy & Mary Lee Rhodes

The definition of the boundary of a system is at the core of any systems approach (Midgley 2000; 2003). By defining boundaries we enable – and delimit – the range of outcomes sought and the actions and resources that can be brought to bear. In complex adaptive systems (CAS) analysis, the conceptualisaion and definition of boundaries is particularly challenging as they are constantly undergoing redefinition through agent action, interaction and entry/exit. (Rhodes et al 2011). The concept of ‘boundaries’ appears regularly in a wide range of literature around public management, administration, geopolitics, regeneration and organisational development. Discussions around boundaries focus on many things from concrete physical manifestations and barriers, to virtual interfaces between one organisational unit and another, or even entirely theoretical demarcations between different schools of thought (Kaboolian, 1998, Levi-Faur, 2004, Agranoff & McGuire, 2004).

However, managing ‘beyond’ such boundaries is a routinely recurring aspiration that transcends sectors and local concerns. Unsurprisingly then, there is an increasing understanding of the need to acknowledge and manage such boundaries (whether they be physical, social or organisational) within public management as a discipline (Currie et al 2007, Fitzsimmons and White, 1997, Murtagh, 2002). This paper explores the impact of boundaries on public management strategic decision-making in the sectors of urban regeneration and healthcare. In particular, it focuses on demarcations to physical space, communal identity and within professional relationships in these sectors.

The first section describes the research that gave rise to the paper and the cases examined. Next we briefly define what we mean by boundaries. We explore issues that have emerged from our analysis of urban regeneration and health care singularly, before looking at how the concept of boundaries is a recurrent concern across the sectors. The main contribution of the paper is an exploration of how a CAS lens can bring a new insight into the concept of boundaries and decision-making in the two sets of case studies. This discussion will concentrate on initial conditions, bifurcation and adaptation as key CAS factors in relation to boundaries. We conclude with a brief discussion on the benefits of a CAS lens to an analysis of boundaries in public management decision-making.
References:

Agranoff, R. and McGuire, M. (2003) Collaborative Public Management: Strategies for Local Government. Washington, DC: Georgetown Univ. Press.

Currie, G., Lockett, A. (2007) “A critique of transformational leadership: moral, professional & contingent dimensions of leadership within public services organizations”. Human Relations 60: 341-370.

Fitzsimmons and White, (1997) "Crossing boundaries: communication between professional groups", Journal of Management in Medicine, Vol. 11 Iss: 2, pp.96 – 101

Kaboolian, L. (1998) “The New Public Management: Challenging the Boundaries of the Management vs. Administration Debate” Public Administration Review Vol. 58, No. 3 pp.189-193

Levi-Faur D. and Vigoda-Gadot Eran (eds) (2004) International Public Policy and Management: Policy Learning Beyond Regional, Cultural and Political Boundaries, Marcel Dekker,
Midgley, G. (ed) (2003) Systems Thinking. London: Sage Publications

Midgley, G. (2000) Systemic Intervention: Philosophy, Methodology and Practice. New York, NY: Kluwer.

Murtagh, B. (2002). The Politics of Territory: Policy and Segregation in Northern Ireland. Basingstoke, Palgrave.

Rhodes, ML, Joanne Murphy, Jenny Muir, John Murray (2011) Public Management & Complexity Theory: Richer Decision Making in Irish Public Services, UK: Routledge

Compliance with recommendations in a geriatric outreach assessment service

Objectives: to measure the extent to which the recommendations of a geriatric outreach assessment service were being followed, and to determine what patient-related factors were associated with compliance with assessment recommendations. Methods: eighty-one eligible patients or caregivers who had an assessment in a geriatric outreach service participated in a telephone interview. The interview focused on the use of health services and compliance with assessment recomendations. Patient-related variables obtained from charts included demographics, caregiver support and stability, health status and assessment recommendations. Results: overall compliance with recommendations from the geriatric outreach assessment service was 65%. Patients were less likely comply fully with recommendations if they had a high number of recommendations [odds ratio (OR) = 0.23; 95% confidence interval (CI) = 0.12-0.46; P = 0.0001], inadequate caregiver support (OR) = 0.212; 95% CI = 0.04 to 1.02; P = 0.0523), or the ability to transfer themselves independently (OR = 0.12; 95% CI = 0.02-0.63; P = 0.0124). They were more likely to have full compliance if they had normal vision (OR = 6.67; 95% CI = 1.22- 36.46; P = 0.0284). Conclusion: it is important to focus on key issues when developing service recommendations and on the role of the informal caregiver in facilitating compliance with them. Good communication between the patient or caregiver and the family physician and geriatric services can help to identify strategies which might improve acceptance of recommendations.

Enhancing family physician capacity to deliver quality palliative home care:An end-of-life, shared-care model

PROBLEM BEING ADDRESSED: Family physicians face innumerable challenges to delivering quality palliative home care to meet the complex needs of end-of-life patients and their families. OBJECTIVE OF PROGRAM: To implement a model of shared care to enhance family physicians' ability to deliver quality palliative home care, particularly in a community-based setting. PROGRAM DESCRIPTION: Family physicians in 3 group practices (N = 21) in Ontario's Niagara West region collaborated with an interprofessional palliative care team (including a palliative care advanced practice nurse, a palliative medicine physician, a bereavement counselor, a psychosocial-spiritual advisor, and a case manager) in a shared-care partnership to provide comprehensive palliative home care. Key features of the program included systematic and timely identification of end-of-life patients, needs assessments, symptom and psychosocial support interventions, regular communication between team members, and coordinated care guided by outcome-based assessment in the home. In addition, educational initiatives were provided to enhance family physicians' knowledge and skills. CONCLUSION: Because of the program, participants reported improved communication, effective interprofessional collaboration, and the capacity to deliver palliative home care, 24 hours a day, 7 days a week, to end-of-life patients in the community.

Performance of Nonlocal Optics When Applied to Plasmonic Nanostructures

Semiclassical nonlocal optics based on the hydrodynamic description of conduction electrons might be an adequate tool to study complex phenomena in the emerging field of nanoplasmonics. With the aim of confirming this idea, we obtain the local and nonlocal optical absorption spectra in a model nanoplasmonic device in which there are spatial gaps between the components at nanometric and subnanometric scales. After a comparison against time-dependent density functional calculations, we conclude that hydrodynamic nonlocal optics provides absorption spectra exhibiting qualitative agreement but not quantitative accuracy. This lack of accuracy, which is manifest even in the limit where induced electric currents are not established between the constituents of the device, is mainly due to the poor description of induced electron densities.

Complementary Therapy: perceptions of older people with lung or colorectal cancer

Aim: To explore how older people with lung and colorectal cancer
view registered complementary therapy (CT) services in Northern
Ireland. Background: A literature review highlighted gaps around
information, access, and communication between patients and health
professionals regarding CT services. Methods: Using structured
interviews, a survey of 68 patients in one hospital and one hospice was
conducted in Belfast, Northern Ireland. Results: All respondents felt
that CT services should be better promoted and more easily
accessible to older people with cancer. Some patients were concerned
about the lack of written information provided regarding CT services,
which they believed led to poorer uptake and uncertainty regarding
the potential benefits. Others were concerned that engaging in or
disclosing CT usage might negatively affect existing relationships with
medical professionals. Conclusion: Patients should be offered high
quality written information on CT services to enable choice, improve
knowledge, and promote wider access. Increased physician education
may facilitate provision of such information.

Evaluation of a substructured soft Real-time Hybrid Test for performing Seismic analysis of complex structural systems

The hybrid test method is a relatively recently developed dynamic testing technique that uses numerical modelling combined with simultaneous physical testing. The concept of substructuring allows the critical or highly nonlinear part of the structure that is difficult to numerically model with accuracy to be physically tested whilst the remainder of the structure, that has a more predictable response, is numerically modelled. In this paper, a substructured soft-real time hybrid test is evaluated as an accurate means of performing seismic tests of complex structures. The structure analysed is a three-storey, two-by-one bay concentrically braced frame (CBF) steel structure subjected to seismic excitation. A ground storey braced frame substructure whose response is critical to the overall response of the structure is tested, whilst the remainder of the structure is numerically modelled. OpenSees is used for numerical modelling and OpenFresco is used for the communication between the test equipment and numerical model. A novel approach using OpenFresco to define the complex numerical substructure of an X-braced frame within a hybrid test is also presented. The results of the hybrid tests are compared to purely numerical models using OpenSees and a simulated test using a combination of OpenSees and OpenFresco. The comparative results indicate that the test method provides an accurate and cost effective procedure for performing
full scale seismic tests of complex structural systems.

Categorizations of physical gesture in piano teaching: A preliminary enquiry

The significance of the “physicality” involved in learning to play a musical instrument and the essential role of teachers are areas in need of research. This article explores the role of gesture within teacher–student communicative interaction in one-to-one piano lessons. Three teachers were required to teach a pre-selected repertoire of two contrasting pieces to three students studying piano grade 1. The data was collected by video recordings of piano lessons and analysis based on the type and frequency of gestures employed by teachers in association to teaching behaviours specifying where gestures fit under (or evade) predefined classifications. Spontaneous co-musical gestures were observed in the process of piano tuition emerging with similar general communicative purposes as spontaneous co-verbal gestures and were essential for the process of musical communication between teachers and students. Observed frequencies of categorized gestures varied significantly between different teaching behaviours and between the three teachers. Parallels established between co-verbal and co-musical spontaneous gestures lead to an argument for extension of McNeill’s (2005) ideas of imagery–language–dialectic to imagery–music–dialectic with relevant implications for piano pedagogy and fields of study invested in musical communication.

An audit of drug shortages in a community pharmacy practice

Background: There are no firm data on drug shortages in Irish community pharmacy. This prospective observational study aimed to characterise the drug shortage problem in an Irish community pharmacy.
Aims: The primary aim was to determine numbers and durations of drug shortages. Secondary aims included comparing these shortages with Irish Pharmacy Union (IPU) drug shortage lists and determining the frequency with which notifications were received prior to shortages. Further secondary aims were to examine relationships between causes of drug shortages and drug costs and between causes of drug shortages and shortage durations.
Methods: The study took place in a community pharmacy in a Limerick City suburb between October 2012 and February 2013. Data were collected daily regarding drugs that were dispensed, but unavailable to purchase. Suppliers/manufacturers provided data on the reasons for shortages.
Results: 65/1,232 dispensed drugs (5.3 %) were in short supply over the study period. Median shortage duration was 13 days (interquartile range 4–32 days) and median cost was €8.10. Numbers of unavailable drugs by month varied from 13 to 38. Monthly IPU drug shortage lists identified between six and eight of these shortages depending on the month. Two notifications were received from suppliers/manufacturers regarding shortages. Parallel exports had the highest mean costs (mean €38.05) and manufacturing problems were associated with the longest durations (mean 57.44 days).
Conclusions: This study highlights the drug shortage problem in an Irish community pharmacy. We propose that enhanced communication between all stakeholders is the most worthwhile solution. Further studies are needed.

Defining the Impact of Non-Native Species

Non-native species cause changes in the ecosystems to which they are introduced. These changes, or some of them, are usually termed impacts; they can be manifold and potentially damaging to ecosystems and biodiversity. However, the impacts of most non-native species are poorly understood, and a synthesis of available information is being hindered because authors often do not clearly define impact. We argue that explicitly defining the impact of non-native species will promote progress toward a better understanding of the implications of changes to biodiversity and ecosystems caused by non-native species; help disentangle which aspects of scientific debates about non-native species are due to disparate definitions and which represent true scientific discord; and improve communication between scientists from different research disciplines and between scientists, managers, and policy makers. For these reasons and based on examples from the literature, we devised seven key questions that fall into 4 categories: directionality, classification and measurement, ecological or socio-economic changes, and scale. These questions should help in formulating clear and practical definitions of impact to suit specific scientific, stakeholder, or legislative contexts.

Managing grid computations: An ORC-based approach

In this paper a model of grid computation that supports both heterogeneity and dynamicity is presented. The model presupposes that user sites contain software components awaiting execution on the grid. User sites and grid sites interact by means of managers which control dynamic behaviour. The orchestration language ORC [9,10] offers an abstract means of specifying operations for resource acquisition and execution monitoring while allowing for the possibility of non-responsive hardware. It is demonstrated that ORC is sufficiently expressive to model typical kinds of grid interactions.

The metastability of human UDP-galactose 4'-epimerase (GALE) is increased by variants associated with type III galactosemia but decreased by substrate and cofactor binding

Type III galactosemia is an inherited disease caused by mutations which affect the activity of UDP-galactose 4'-epimerase (GALE). We evaluated the impact of four disease-associated variants (p.N34S, p.G90E, p.V94M and p.K161N) on the conformational stability and dynamics of GALE. Thermal denaturation studies showed that wild-type GALE denatures at temperatures close to physiological, and disease-associated mutations often reduce GALE's thermal stability. This denaturation is under kinetic control and results partly from dimer dissociation. The natural ligands, NAD(+) and UDP-glucose, stabilize GALE. Proteolysis studies showed that the natural ligands and disease-associated variations affect local dynamics in the N-terminal region of GALE. Proteolysis kinetics followed a two-step irreversible model in which the intact protein is cleaved at Ala38 forming a long-lived intermediate in the first step. NAD(+) reduces the rate of the first step, increasing the amount of undigested protein whereas UDP-glucose reduces the rate of the second step, increasing accumulation of the intermediate. Disease-associated variants affect these rates and the amounts of protein in each state. Our results also suggest communication between domains in GALE. We hypothesize that, in vivo, concentrations of natural ligands modulate GALE stability and that it should be possible to discover compounds which mimic the stabilising effects of the natural ligands overcoming mutation-induced destabilization.

An Appraisal of End-of-Life Care in Persons with Chronic Kidney Disease Dying in Hospital Wards

AIM: To review end-of-life care provided by renal healthcare professionals to hospital in-patients with chronic kidney disease, and their carers, over a 12-month period in Northern Ireland.

METHODS: Retrospective review of 100 patients.

RESULTS: Mean age at death was 72 years (19-95) and 56% were male. Eighty three percent of patients had a 'Not For Attempted Resuscitation' order during their last admission and this was implemented in 42%. Less than 20% of all patients died in a hospital ward. No patients had an advanced care plan, although 42% had commenced the Liverpool Care Pathway for the Dying Patient. Patients suffered excessive end-of-life symptoms. In addition, there was limited documentation of carer involvement and carer needs were not formally assessed.

CONCLUSION: End-of-life care for patients with advanced chronic renal disease can be enhanced. There is significant variation in the recording of discussions regarding impending death and little preparation. There is poor recording of the patients' wishes regarding death. Those with declining functional status, including those frequently admitted to hospital require holistic assessment regarding end-of-life needs. More effective communication between the patient, family and multi-professional team is required for patients who are dying and those caring for them.