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Background:\ud Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1.\ud \ud Objectives:\ud To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP.\ud \ud Methods:\ud This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks.\ud \ud Results:\ud A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator’s global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [–1·65, 95% confidence interval (CI) –4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI –26·44 to 32·33; favouring anakinra), total pustule count (–30·08, 95% CI –83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was –3·80 (95% CI –10·76 to 3·16; P = 0·285). No serious adverse events occurred.\ud \ud Conclusions:\ud No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Aim To describe the methods and feasibility of the nutritional intervention carried out within the SPRINTT Randomized cotrolled trial. We also illustrate how nutrition interventionists identified participants at risk of malnutrition and the lessons learnt from the nutrition intervention. Findings SPRINTT nutrition intervention was well-received by the majority of the participants. It was mainly carried out using tailored nutrition counselling, but also other means of delivering the intervention were successfully used. Compared with a standard nutrition prescription, an individualized protocol to diagnose malnutrition and follow-up by tailored nutrition counselling helped achieve nutritional targets more effectively in spite of diversity of population in nutritional habits and in some cases reluctance to accept changes. Message The SPRINTT nutrition intervention was feasible and allowed flexibility to the varying needs and cultural differences of this heterogeneous population of frail, older Europeans. It may serve as a model to educate and improve nutrition among community-dwelling older people at risk of mobility limitations. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-020-00438-4., Background The “Sarcopenia and Physical Frailty in Older People: Multicomponent Treatment Strategies” (SPRINTT) project sponsored a multi-center randomized controlled trial (RCT) with the objective to determine the effect of physical activity and nutrition intervention for prevention of mobility disability in community-dwelling frail older Europeans. We describe here the design and feasibility of the SPRINTT nutrition intervention, including techniques used by nutrition interventionists to identify those at risk of malnutrition and to carry out the nutrition intervention. Methods SPRINTT RCT recruited older adults (≥ 70 years) from 11 European countries. Eligible participants (n = 1517) had functional limitations measured with Short Physical Performance Battery (SPPB score 3–9) and low muscle mass as determined by DXA scans, but were able to walk 400 m without assistance within 15 min. Participants were followed up for up to 3 years. The nutrition intervention was carried out mainly by individual nutrition counseling. Nutrition goals included achieving a daily protein intake of 1.0–1.2 g/kg body weight, energy intake of 25–30 kcal/kg of body weight/day, and serum vitamin D concentration ≥ 75 mmol/L. Survey on the method strategies and feasibility of the nutrition intervention was sent to all nutrition interventionists of the 16 SPRINTT study sites. Results Nutrition interventionists from all study sites responded to the survey. All responders found that the SPRINTT nutrition intervention was feasible for the target population, and it was well received by the majority. The identification of participants at nutritional risk was accomplished by combining information from interviews, questionnaires, clinical and laboratory data. Although the nutrition intervention was mainly carried out using individual nutritional counselling, other assisting methods were used as appropriate. Conclusion The SPRINTT nutrition intervention was feasible and able to adapt flexibly to varying needs of this heterogeneous population. The procedures adopted to identify older adults at risk of malnutrition and to design the appropriate intervention may serve as a model to deliver nutrition intervention for community-dwelling older people with mobility limitations. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-020-00438-4.

BACKGROUND Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVES To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. METHODS This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator's global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [-1·65, 95% confidence interval (CI) -4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI -26·44 to 32·33; favouring anakinra), total pustule count (-30·08, 95% CI -83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was -3·80 (95% CI -10·76 to 3·16; P = 0·285). No serious adverse events occurred. CONCLUSIONS No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Microorganisms produce secondary metabolites with a remarkable range of bioactive properties. The constantly increasing amount of published genomic data provides the opportunity for efficient identification of biosynthetic gene clusters by genome mining. On the other hand, for many natural products with resolved structures, the encoding biosynthetic gene clusters have not been identified yet. Of those secondary metabolites, the scaffolds of nonribosomal peptides and polyketides (type I modular) can be predicted due to their building block-like assembly. SeMPI v2 provides a comprehensive prediction pipeline, which includes the screening of the scaffold in publicly available natural compound databases. The screening algorithm was designed to detect homologous structures even for partial, incomplete clusters. The pipeline allows linking of gene clusters to known natural products and therefore also provides a metric to estimate the novelty of the cluster if a matching scaffold cannot be found. Whereas currently available tools attempt to provide comprehensive information about a wide range of gene clusters, SeMPI v2 aims to focus on precise predictions. Therefore, the cluster detection algorithm, including building block generation and domain substrate prediction, was thoroughly refined and benchmarked, to provide high-quality scaffold predictions. In a benchmark based on 559 gene clusters, SeMPI v2 achieved comparable or better results than antiSMASH v5. Additionally, the SeMPI v2 web server provides features that can help to further investigate a submitted gene cluster, such as the incorporation of a genome browser, and the possibility to modify a predicted scaffold in a workbench before the database screening.

BACKGROUND AND OBJECTIVES:Human research ethics statements support equitable inclusion of diverse groups. Yet older people are under-represented in clinical research, especially those with impaired decision-making capacity. The aim of this study was to identify perspectives and experiences of older persons and their caregivers of research participation with impaired decision-making capacity. RESEARCH DESIGN AND METHODS:Scoping review of literature and online sources in January-February 2019 (updated June 2020) according to Joanna Briggs Institute methodology and PRISMA Extension for Scoping Reviews. English-language peer-reviewed research articles and Australian online narratives were included. Data were tabulated and narratively synthesized. RESULTS:From 4171 database records and 93 online resources, 22 articles (2000-2019, 82% United States, 16 first authors) and one YouTube webinar (2018) were initially included; updated searches yielded an additional article (2020) and YouTube webinar (2020). Studies were heterogeneous in terminology, methods and foci, with hypothetical scenarios, quantitative analyses and examination of proxy consent predominating. Participants (n=7331) were older persons (71%), caregivers of older persons with dementia/cognitive impairment (23%) and older persons with dementia/cognitive impairment (6%). Synthesis identified two themes: willingness to participate and decision-making approaches. DISCUSSION AND IMPLICATIONS:Research participation by older persons with dementia may be optimized through reducing risks and burdens and increasing benefits for participants, greater consumer input into study development, and shared and supported decision-making. Older persons' and caregivers' perspectives and experiences of research participation with impaired decision-making capacity require investigation in a greater range of countries and conditions other than dementia, and dissemination through more varied media.

The softening and strengthening contributions in pre-deformed and aged Al-Mg-Cu alloys containing 3wt.%Mg and 0.5wt.%Cu are evaluated by a combination of microscopy, mechanical testing and modelling. A refined phenomenological model for the work hardening response, accounting for the separate effects of recovery and precipitation, is shown to be suitable for an unambiguous determination of the precipitation hardening contribution in these alloys. Significantly, it is found that the mechanical response of these alloys is not strongly impacted by Cu content (in the low Cu content regime), pre-deformation level or aging temperature meaning that the alloys are robust with respect to variations in composition. This is interesting from the perspective of alloy design concepts based on `recycling friendly' compositions in applications that include paint-baking., Comment: 33 pages, 10 figures

Advance care planning (ACP) is a process of discussion about a person’s goals and values for future care, which is aimed at extending personal autonomy into a time when they cannot make decisions. We know the loss of decision-making capacity is more certain for those with dementia, hence the importance of ensuring people with dementia and their carers participate in ACP, with the opportunity to discuss support and the ‘type’ of care they would prefer, thus extending their autonomy as far as possible. This chapter is based on broad consultation with health professionals and consumer organisations across Australia, to identify how to increase uptake of ACP among people with dementia and their carers. Respondents indicated that the traditional approach focussing on medical end-of-life interventions was less appropriate for people with dementia, while approaches oriented to a psychosocial philosophy of care were considered more suitable. These might include, for example, family- and person-centred approaches, incorporating values and spiritual, cultural and lifestyle issues. Respondents across all settings emphasised the relational aspects of ACP: what matters most are conversations that value and inform ‘rest-of-life’ not just end-of-life, as well as the appointment of trusted substitute decision-makers. Rather than focusing on medical decision-making, ACP models need to incorporate broader social, personal and community contexts to ensure that outcomes reflect those identified as important by people with dementia.

An archaeological watching brief was conducted on the site of All Saints Church, High Street, Banstead, Surrey SM7 2NG. All Saints Church is under the jurisdiction of the Diocese of Guildford and the Archdeaconry of Dorking. The church is within Reigate and Banstead Borough Council and is listed Grade II*. Two areas inside the church were excavated under the constant supervision of an archaeologist over two separate days in July and August 2019. The two interventions did not fully penetrate the concrete slab and therefore natural and archaeological deposits were not encountered. The concrete slab continued below the lower limit of excavation.

Paul Verrills,1 Chantelle Sinclair,2 Adele Barnard2 1Metro Pain Group, 2Monash Clinical Research, Monash House, Clayton, Victoria, Australia Abstract: Spinal cord stimulation (SCS) applications and technologies are fast advancing. New SCS technologies are being used increasingly in the clinical environment, but often there is a lag period between the clinical application and the publishing of high-quality evidence on safety and efficacy. Recent developments will undoubtedly expand the applicability of SCS, allowing more effective and individualized treatment for patients, and may have the potential to salvage patients who have previously failed neuromodulation. Already, high-level evidence exists for the safety, efficacy, and cost-effectiveness (Level I–II) of traditional SCS therapies in the treatment of chronic refractory low back with predominant limb pain (regardless of surgical history). More than half of all patients with chronic painful conditions experience sustained and significant levels of pain reduction following SCS treatment. Although only limited evidence exists for burst stimulation, there is now Level I evidence for both dorsal root ganglion SCS and high-frequency SCS that demonstrates compelling results compared with traditional therapies. The body of evidence built on traditional SCS research may be redundant, with newer iterations of SCS therapies such as dorsal root ganglion SCS, high-frequency SCS, and burst SCS. A number of variables have been identified that can affect SCS efficacy: implanter experience, appropriate patient selection, etiologies of patient pain, existence of comorbidities, including psychiatric illness, smoking status, and delay to SCS implant following pain onset. Overall, scientific literature demonstrates SCS to be a safe, effective, and drug-free treatment option for many chronic pain etiologies. Keywords: spinal cord stimulator, neuromodulation, chronic pain, low back pain

An archaeological watching brief conducted on the site of Creata House, 9 Stratford Place, London, W1C 1AZ. Twelve pits were dug by hand under the constant supervision of an archaeologist. A post-medieval brick well was uncovered; no other archaeological remains were observed.

International audience

A robust understanding of the deformation behaviour of magnesium alloys under complex loading paths is a prerequisite to the successful fabrication of parts and understanding of their in- service performance. To facilitate this, multi-axial testing has been conducted on thin walled cylindrical samples of cast AZ80 alloy possessing weak initial texture. Internal pressurization, controlled by closed-loop feedback system permits hoop stresses to be created within the sample wall. When generated in conjunction with axial loading this allows a range of biaxial tensile loadings to be induced within the tension-tension quadrant of stress space. In order to facilitate an understanding of the textural evolution of weakly textured AZ80 subjected to these loadings, texture measurements have been conducted on as tested samples via neutron diffraction. This work builds off of prior work which has characterized the behaviour of AZ80 in uniaxial tension and compression and integrates these results. These mechanical testing results have been compared to those predicted by crystal plasticity simulations in order to help understand the deformation behaviour well as texture evolution., Mg2012: 9th International Conference on Magnesium Alloys and their Applications, 8-12 July 2012, Vancouver, Canada

CD4+CD8+ double positive (DP) precursors undergo positive selection in the thymus, and subsequently commit to either the CD4 or CD8 single positive (SP) lineage. Mice lacking Zap70, a crucial kinase involved in T-cell receptor (TCR) signal transduction are developmentally arrested at the DP stage, showing that this process depends on TCR signalling. Furthermore, the resultant SP populations are major histocompatibility (MHC) matched, as CD4 lineage cells recognise MHC-II whereas CD8 lineage T cells recognise MHC-I. There are currently two favoured models describing how the MHC restriction of the TCR correlates with lineage choice. These suggest that differences in either the TCR signalling strength or signalling length underlie the CD4/CD8 lineage decision during the DP stage. Both models posit that differences in signalling strength/length are properties that are conferred by the different signalling capacities of the CD4/CD8 coreceptors. However, questions remain over the mechanisms behind this process, including how the selecting cell interprets the proximal differences in TCR activation and whether the quality of this signal impacts on its future homeostatic survival potential. A major obstacle in addressing these questions is the lack of tools to facilitate understanding of the kinetic regulation of positive selection. We therefore sought to examine the kinetics of T-cell development using a tetracycline inducible Zap70 mouse model (TetZap70 hereon). In the absence of the tetracycline derivative doxycycline (dox), T-cells were arrested at the DP stage, prior to positive selection. However, the administration of dox induced positive selection of a synchronized wave of positively selecting thymocytes, enabling the resolution of intermediate populations of positively selecting DPs. We found that CD4 and CD8 lineage development occurred with temporal distinction, from phenotypically disparate populations of DP thymocytes. Furthermore, we found that endogenous Zap70 was developmentally regulated in different DP populations of WT mice, and loss of this regulation in TetZap70 mice corresponded to an impairment in CD8 lineage generation. Thus we suggest that temporal regulation of T-cell signalling sensitivity during thymic development facilitates the resolution of strong/consistent signals versus weak/intermittent signals. Finally we find evidence that the quality of the positive selection signal not only controls the CD4/CD8 lineage decision, but also impacts on the future homeostatic survival potential of T-cells by influencing levels of the prosurvival interleukin-7 receptor alpha chain (IL7rα).

International audience; A recently developed Fe-C interatomic potential has been used to investigate carbon in highly supersaturated

Purpose - This paper aims to complement a more conventional positive accounting theory (PAT)-based study of accounting method choice in Egyptian firms by examining three alternative computational reasons for depreciation method choice: simplicity; compatibility with industry norm; and suitability for class of asset. Design/methodology/approach - The paper draws on a questionnaire survey, sent to Egyptian companies, in which managers were asked to indicate their reasons for choosing depreciation methods as well as the actual depreciation methods used. Findings - The paper finds that technical reasons were frequently given in survey responses from managers. However, the available evidence on the actual depreciation methods used by their firms and industries is in fact more consistent with PAT-based theories of accounting choice than with such alternatives. This suggests that the responses to the survey reflected managers' rationalisations of decisions made for self-interested purposes. Originality/value - Most recent work on managerial decisions concerning accounting choices utilises data gathered from databases of published financial information and is undertaken within a PAT context. This study extends that approach by utilising the results of a questionnaire distributed in Egypt to test some additional hypotheses that reflect possible technical accounting reasons for justifying depreciation methods.

M-Report (2001).

Bunch lengths as short as 84 fs (rms) have been measured at Jefferson Lab using a zero-phasing RF technique. To the best of our knowledge, this is the first accurate bunch length measurement in this regime. In this letter, an analytical approach for computing the longitudinal distribution function and bunch length is described for arbitrary longitudinal and transverse distributions. The measurement results are presented, which are in excellent agreement with numerical simulations.

Background Laparoscopic surgery has become the preferred approach for many procedures because of reduced post-operative pain, better recovery, shorter hospital stay and improved cosmesis. Single incision laparoscopic surgery is one of the many recent variants where either standard ports or a specially designed single multi-channel port is introduced through a single skin incision. While the cosmetic advantage of this is obvious, the evidence base for claims of reduced morbidity and better post-operative recovery is weak. This study aims to compare the effectiveness of single port/incision laparoscopic appendicectomy with standard three-port laparoscopic appendicectomy in adult patients at six weeks post-surgery. We also wish to assess the feasibility of a multicentre randomised controlled trial comparing single port/incision laparoscopic surgery with standard three-port laparoscopic surgery for other surgical techniques. Methods and design Patients diagnosed with suspected appendicitis and requiring surgical treatment will be randomised to receive either standard three-port or single incision laparoscopic surgery. Data will be collected from clinical notes, operation notes and patient reported questionnaires. The following outcomes will be considered: 1. Effectiveness of the surgical procedure in terms of: •patient reported outcomes •clinical outcomes •resource use 2. Feasibility of conducting a randomised controlled trial (RCT) in the emergency surgical setting by quantifying: •patient eligibility •randomisation acceptability •feasibility of blinding participants to the intervention received •completion rates of case report forms and patient reported questionnaires Trial registration ISRCTN66443895 (assigned 10 March 2011, first patient randomised 09 January 2011)

ILO pub-WEP pub. Working paper on the impact of international migration on employment in Saudi Arabia and Libyan Arab Jamahiriya - examines the reliance on migrant worker labour supply to meet labour demand resulting from petroleum industry expansion, and considers internal development of human capital to fulfill further requirements. Bibliography pp. 83 to 86, graphs and statistical tables.

ILO pub-WEP pub. Working paper on a case study of the impact of international migration movements on the labour market in Egypt and Sudan - includes general information on economic conditions, human capital, population, employment and labour demand, examines the effects of emigration and immigration on economic development in relation to each country, and discusses the present number of egyptian migrants in Arab country, and constitutes part of a WEP research project. Bibliography pp. 84 to 87 and statistical tables.

ILO pub-WEP pub. Working paper on a case study of the impact of international migration movements on the labour market in Oman - covers labour supply, labour demand, migrant worker characteristics by age, sex, occupation and educational level (incl. Expatriate workers), considers the effects of labour force emigration on economic development, and constitutes part of a WEP research project on migration for employment. One-page bibliography, diagrams, references and statistical tables.

ILO pub-WEP pub. Working paper on the role and economic implications of migrant worker labour supply for the labour market and economic and social development in the Gulf States - covers population trends, human resources, educational level, industrialization policy, labour demand, etc., characterizes the size, social structure and occupational structure of expatriate worker communitys, and constitutes part of a WEP research project on migration for employment. Bibliography pp. 83 and 84, diagrams and statistical tables.

This paper is concerned with aspects of organization and procedure in nuclear accident management. Because all accidents can be argued to have common characteristics, a comparative approach is taken here for the discussion of emergency planning for nuclear accidents. This approach reveals several deficiencies in selected European emergency plans, the most important concerning formal and informal communication channels. The most important principle which emerges from this discussion, and which was reinforced by the recent U.S. nuclear accident at Three Mile Island, is that planning efforts should be directed toward reducing the information Load carried by each person involved in managing an accident

ILO pub-WEP pub. Working paper on labour shortage problems and dependency on immigration in capital-rich Arab country, analysing patterns and processes of labour mobility in the Middle East - assesses the implications for importing and for supplying countries, speculates on future trends in migration policy, and contributes to a WEP research project on migration and employment. References and statistical tables.

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Physical review letters 25(17), 1223 - 1226 (1970). doi:10.1103/PhysRevLett.25.1223, Published by APS, College Park, Md.

Pendant une mission d’etude de l’Universite d’Amsterdam sur le comportement des chimpanzes a l’etat sauvage (Republique de Guinee, province de Kindia) les auteurs se sont interesses egalement aux relations entre ces anthropoides et les etres humains. La population humaine se montre tres tolerante et plutot indifferente envers les chimpanzes malgre que ces derniers peuvent faire des degats a leurs produits agricoles. De ce point de vue l’avenir des chimpanzes est assure dans cette province de la Republique de Guinee a la condition que les autres facteurs qui peuvent nuire a la presence de chimpanzes ne changeraient pas.

Background: Perfectionism has been linked to suicide. According to the Narrative-Crisis Model of suicide, individuals with trait vulnerabilities are prone to develop a certain mindset, known as a Suicidal Narrative, which may precipitate the Suicide Crisis Syndrome (SCS), culminating in suicide. The purpose of this study was to investigate the association between perfectionism (trait vulnerability), fear of humiliation (component of the Suicidal Narrative), SCS, and prospective near-term suicidal thoughts and behaviors (STB). Methods: Adult psychiatric outpatient participants (N = 336) were assessed at baseline with the Suicidal Narrative Inventory for perfectionism and fear of humiliation. The questions used to assess perfectionism were adapted from the Multidimensional Perfectionism Scale. The severity of the SCS was calculated using the Suicide Crisis Inventory. STB were assessed at baseline and after one month using the Columbia Suicide Severity Rating Scale. Serial mediation analyses were conducted using PROCESS version 3.3 in SPSS. Results: While the direct effect of perfectionism on prospective STB was not significant (b = 0.01, p = 0.19), the indirect effect of perfectionism on STB, through serial mediation by fear of humiliation and the SCS, was significant (indirect effect p = 0.007, 95% CI [0.003, 0.013]). The indirect effect was not significant for models that did not include both mediators. Limitations: Variables were assessed at one time only. Conclusion: Perfectionism did not directly modulate STB. Perfectionism may be related to suicidal behavior through fear of humiliation, leading to the SCS. These results support the Narrative-Crisis Model of suicide and clarify the role of perfectionism in the etiology of suicide.

The synthesis and pharmacological characterisation of (S)-CPW 399 as a novel, potent and subtype-selective agonist of the AMPA receptor was recently reported. Studies have been extended to investigate its excitotoxic action in primary cultures of mouse cerebellar granule cells. (S)-CPW 399 induced neuronal cell death in a time- and concentration-dependent manner (EC(50) approximately 70 microM) at 24-h exposure. (S)-CPW-induced neuronal death could be prevented by co-administration with either of the AMPA/kainate selective receptor antagonists 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX) or by the 2,3-benzodiazepine, GYKI 53655 (a selective AMPA receptor antagonist); while no protection was afforded by either the NMDA receptor antagonist D,L(+/-)-2-amino-5-phosphonopentanoate (APV) or by nifedipine (an L-type calcium channel antagonist) when used alone or in combination. Cyclothiazide, which blocks AMPA receptor desensitisation, caused minimal potentiation of (S)-CPW 399-induced neuronal death, supporting accumulating evidence that (S)-CPW 399 is a full AMPA receptor agonist that markedly prevents a receptor desensitised conformation. (S)-AMPA, (S)-willardiine (a naturally-occurring heterocyclic excitatory amino acid) and its halogenated derivative, (S)-5-fluorowillardiine, had no deleterious effect on neuronal viability when used alone but each, in the presence of cyclothiazide, induced a concentration-dependent excitotoxic cell death with a rank order of potency (fluorowillardiineAMPA=willardiine). (S)-CPW 399 stimulated an increase in intracellular free-calcium levels ([Ca(2+)](i)) in a concentration-dependent fashion (EC(50) approximately 5 microM) attaining a value of six-fold that of 'resting' cells at maximum stimulation; achieved at approximately 100 microM (S)-CPW 399. The (S)-CPW 399-stimulated increase in [Ca(2+)](i) was virtually abolished by GYKI 53655, NBQX, CNQX and by cobalt ions; markedly inhibited by nifedipine and marginally affected by D-APV. These results suggest that (S)-CPW 399 may be used as a pharmacological tool to aid in the investigation of the role of AMPA receptors in excitotoxicity and their molecular mechanisms of desensitisation.

Networked Learning, e-Learning and Technology Enhanced Learning have each been defined in different ways, as people's understanding about technology in education has developed. Yet each could also be considered as a terminology competing for a contested conceptual space. Theoretically this can be a ‘fertile trans-disciplinary ground for represented disciplines to affect and potentially be re-orientated by others’ (Parchoma and Keefer, 2012), as differing perspectives on terminology and subject disciplines yield new understandings. Yet when used in government policy texts to describe connections between humans, learning and technology, terms tend to become fixed in less fertile positions linguistically. A deceptively spacious policy discourse that suggests people are free to make choices conceals an economically-based assumption that implementing new technologies, in themselves, determines learning. Yet it actually narrows choices open to people as one route is repeatedly in the foreground and humans are not visibly involved in it. An impression that the effective use of technology for endless improvement is inevitable cuts off critical social interactions and new knowledge for multiple understandings of technology in people's lives. This paper explores some findings from a corpus-based Critical Discourse Analysis of UK policy for educational technology during the last 15 years, to help to illuminate the choices made. This is important when through political economy, hierarchical or dominant neoliberal logic promotes a single ‘universal model’ of technology in education, without reference to a wider social context (Rustin, 2013). Discourse matters, because it can ‘mould identities’ (Massey, 2013) in narrow, objective economically-based terms which 'colonise discourses of democracy and student-centredness' (Greener and Perriton, 2005:67). This undermines subjective social, political, material and relational (Jones, 2012: 3) contexts for those learning when humans are omitted. Critically confronting these structures is not considered a negative activity. Whilst deterministic discourse for educational technology may leave people unconsciously restricted, I argue that, through a close analysis, it offers a deceptively spacious theoretical tool for debate about the wider social and economic context of educational technology. Methodologically it provides insights about ways technology, language and learning intersect across disciplinary borders (Giroux, 1992), as powerful, mutually constitutive elements, ever-present in networked learning situations. In sharing a replicable approach for linguistic analysis of policy discourse I hope to contribute to visions others have for a broader theoretical underpinning for educational technology, as a developing field of networked knowledge and research (Conole and Oliver, 2002; Andrews, 2011).

This paper describes development of networked learning using Fraser's powerful analogy between human migration and scientific research. It recognises that most contributions to the field are developed in diverse and often mutually incommensurable research traditions from education to engineering, and identifies dialogue across different conceptual frameworks as the main challenge in their interpretation. It explores the rise of disciplinarity, and exposes its dialectical relationships with education and class. Based on wide body of research developed by members of Frankfurt School of Social Science and their successors, it analyses the relationships between technologies, society and human beings and asserts that the rise of technoscience is dialectically intertwined with the rise of disciplinarity. Moving on to the present, the paper shows that exponential rise in complexity of our tools, characteristic for the network society, has transformed disciplinarity into the new normality. During the process, it has reinforced the existing power relationships and supported further social stratification. In the network society, disciplinarity bears exactly the same consequences as in earlier historic periods. However, the stakes are much higher. Contemporary disciplinarity has significantly reduced blue-skies research to applied research, caused rapid commodification of education, and actively contributed to various environmental crises. On such basis, the paper proposes that networked learning should be analysed beyond traditional disciplinarity. It acknowledges epistemological consequences of such fundamental changes in scientific understanding of the world, and evokes a new postdisciplinary intellectual universe based on the ruins of traditional disciplinary structures. Finally, the paper briefly outlines the main postdisciplinary approaches: multidisciplinarity, interdisciplinarity, transdisciplinarity and antidisciplinarity. It warns that the outlined approaches are currently still in flux, briefly analyses their mutual relationships, and links them to issues pertaining to networked learning. On such basis, the paper proposes that postdisciplinary approaches might transcend methodological restrictions inherent to disciplinary research methodologies and provide the field of networked learning with a unified explanatory framework. Recognising that validity and verifiability of our research methods are still grounded in various disciplinary frameworks, it concludes that there is a long way from this modest proposal to its full realisation and calls for further investigation of postdisciplinary research methods for networked learning.

This paper calls for a debate concerning the dominant tropes, which we have assigned the power to define learning processes in higher education today. The argument of the paper takes a critical stand towards the tropes of taxonomy-based and Bildung-oriented understandings of learning processes and student voice in higher education. We argue that learning processes are more than mere phenomena of linear progression capable of being measured based on pre-set criteria for learning outcomes. On the other hand, we do not argue, that it is productive to take the easy way out using an abstract and shadowy vocabulary of Bildung, authenticity and personal growth. Instead we call for a new vocabulary in educational theory, which is capable of addressing the half-formed, premature and idiosyncratic dimensions of learning processes present in the everyday life of higher education. Inspired by the jelly as a metaphor, and drawing on thinkers such as Richard Sennett, Graham Harman and Friedrich Nietzsche, we call for a gelatinous pedagogy, which, in thought and language, match the motley-coloured, mongrel and queer developmental processes and strategies applied by students and teachers in higher education practice. By developing and applying the jelly as a new metaphor for learning processes and student voice in higher education we are able to address critical issues otherwise overlooked. Out of this application three findings and one suggestion for further research emerge: Firstly, vocabularies for understanding learning processes must have the ambition of making visible those queer processes. This must be done in a language and using a vocabulary, which has gelatinous qualities enabling the capability to grasp specific learning experiences in situ. Secondly, such a language should embrace the tentative, uncertain and troublesome character of learning processes – hereby acknowledging that such processes might never reach an end point and therefore not necessarily lead anywhere. Thirdly, an understanding of learning processes, therefore, cannot be adequately understood as a fixed structure or linear layout, but must rather be approached as jelly-like structures of entanglement and swarm. Fourthly, and finally, the challenge for understanding networked learning within higher education in a more nuanced way can be met by developing a gelatinous pedagogy; a pedagogy linguistically and conceptually sensitive to the multifarious dimensions of learning and being whether these be skills, forms of identity, or sheer ambivalence and obscurity in thought.

This study explores the role of Massive Open Online Courses (MOOCs) in supporting and enabling professional learning, or learning for work. The research examines how professionals self-regulate their learning in MOOCs. The study is informed by contemporary theories of professional learning, that argue that conventional forms of learning are no longer effective in knowledge intensive domains. As work roles evolve and learning for work becomes continual and personalised, self-regulation is becoming a critical element of professional learning. Yet, established forms of professional learning generally have not taken advantage of the affordances of social, semantic technologies to support self-regulated learning. MOOCs present a potentially useful approach to professional learning that may be designed to encourage self-regulated learning. The study is contextualised within ‘Fundamentals of clinical trials', a MOOC for health professionals designed and run by the Harvard Medical School, Harvard School of Public Health, and Harvard Catalyst, the Harvard Clinical and Translational Science Center, and offered by edX. The research design builds on the authors' previous studies in the areas of Technology Enhanced Learning and Professional Learning and in particular, research which explored the learning behaviours of education professionals in the Change 11 MOOC. The previous studies demonstrated a link between individual learners SRL profile and their goal setting behaviour in the Change 11 MOOC as well as uncovering other factors which influenced their engagement with the MOOC environment. The present study extends the original study by further focusing on specific aspects of self-regulation identified by the Change11 studies and our parallel studies of self-regulated learning in knowledge workers. The analysis of learner behaviour in the Fundamentals of Clinical Trials is complemented by additional exploration of the design considerations of the MOOC, to determine the extent to which course design can support or inhibit self-regulation of learning. The study poses three research questions: How are Massive Open Online Courses currently designed to support self-regulated learning? What self-regulated learning strategies and behaviours do professionals adopt? and How can MOOCs be designed to encourage professionals to self-regulate their learning? Validated methods and instruments from the original study will be adapted and employed. The research is unique in providing evidence around two critical aspects of MOOCs that are not well understood: the skills and dispositions necessary for self-regulated learning in MOOC environments, and how MOOCs can be designed to encourage the development and emergence of SRL behaviours.

(S)-CPW399 (2b) is a novel, potent, and subtype-selective AMPA receptor full agonist that, unlike (S)-willardiine and related compounds, in mouse cerebellar granule cells, stimulated an increase in [Ca(2+)](i), and induced neuronal cell death in a time- and concentration-dependent manner. Compound 2b appears to be a weakly desensitizing, full agonist at AMPA receptors and therefore represents a new pharmacological tool to investigate the role of AMPA receptors in excitotoxicity and their molecular mechanisms of desensitization.

This thesis is concerned principally with the problem of estimating the parameters of the Weibull and Beta distributions using several different techniques. These distributions are used in the area of reliability testing and it is important to achieve the best estimates possible of the parameters involved. After considering several accepted methods of estimating the relevant parameters, it is considered that the best method depends on the aim of the analysis, and on the value of the shape parameter 𝛽. For estimating the two-parameter Weibull distribution, it is recommended that Generalized Least Squares (GLS) is the best method to use for values of 𝛽 between 0.5 and 30. However, Maximum Likelihood Estimator (MLE) is a good method for estimating quantiles. On this basis, the three-parameter Weibull distribution is investigated. The traditional parametrization is compared with a new parametrization developed in this work. By considering parameter effects and intrinsic curvature it is shown that the new parametrization results in a linear effect of the shape parameter. Also it has advantages in quantile estimation because of its ability to provide estimates for a wider range of data sets. A less frequently used distribution in the field of reliability is the Beta distribution. The lack of frequency of its use is partly due to the difficulty in estimating its parameters. A simple, applicable method is developed here of estimating these parameters. This 'group method' involves estimating the two ends of the distribution. It is shown that this procedure can be used, together with other methods of estimating the two- parameter Beta distribution successfully to estimate the four-parameter Beta distribution.

Estimation of the probability of occurrence of future flood events at one or more locations across a river system is frequently required for the design of bridges, culverts, spillways, dams and other engineering works. This study investigates some of the statistical aspects for estimating the flood frequency distribution at a single site and on regional basis. It is demonstrated that generalized logistic (GL) distribution has many properties well suited for the modelling of flood frequency data. The GL distribution performs better than the other commonly recommended flood frequency distributions in terms of several key properties. Specifically, it is capable of reproducing almost the same degree of skewness typically present in observed flood data. It appears to be more robust to the presence of extreme outliers in the upper tail of the distribution. It has a relatively simpler mathematical form. Thus all the well known methods of parameter estimation can be easily implemented. It is shown that the method of probability weighted moments (PWM) using the conventionally recommended plotting position substantially effects the estimation of the shape parameter of the generalized extreme value (GEV) distribution by relocating the annual maximum flood series. A location invariant plotting position is introduced to use in estimating, by the method of PWM, the parameters of the GEV and the GL distributions. Tests based on empirical distribution function (EDF) statistics are proposed to assess the goodness of fit of the flood frequency distributions. A modified EDF test is derived that gives greater emphasis to the upper tail of a distribution which is more important for flood frequency prediction. Significance points are derived for the GEV and GL distributions when the parameters are to be estimated from the sample data by the method of PWMs. The critical points are considerably smaller than for the case where the parameters of a distribution are assumed to be specified. Approximate formulae over the whole range of the distribution for these tests are also developed which can be used for regional assessment of GEV and GL models based on all the annual maximum series simultaneously in a hydrological region. In order to pool at-site flood data across a region into a single series for regional analysis, the effect of standardization by at-site mean on the estimation of the regional shape parameter of the GEV distribution is examined. Our simulation study based on various synthetic regions reveals that the standardization by the at-site mean underestimates the shape parameter of the GEV by about 30% of its true value and also contributes to the separation of skewness of observed and simulated floods. A two parameter standardization by the at-site estimates of location and scale parameters is proposed. It does not distort the shape of the flood frequency data in the pooling process. Therefore, it offers significantly improved estimate of the shape parameter, allows pooling data with heterogeneous coefficients of variation and helps to explain the separation of skewness effect. Regions on the basis of flood statistics L-CV and USKEW are derived for Scotland and North England. Only about 50% of the basins could be correctly identified as belonging to these regions by a set of seven catchment characteristics. The alternative approach of grouping basins solely on the basis of physical properties is preferable. Six physically homogeneous groups of basins are identified by WARD's multivariate clustering algorithm using the same seven characteristics. These regions have hydrological homogeneity in addition to their physical homogeneity. Dimensionless regional flood frequency curves are produced by fitting GEV and GL distributions for each region. The GEV regional growth curves imply a larger return period for a given magnitude flood. When floods are described by GL model the respective return periods are considerably smaller.