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Objective Methods Results Conclusion The impact of a transversus abdominis plane (TAP) block in patients undergoing cesarean section requires further evaluation. The aim of this study was to compare postoperative pain scores and opioid use in cesarean surgery patients undergoing either a TAP block and scheduled multimodal pain management (SMPM) or SMPM alone.In this retrospective, dual cohort study, cesarean surgery patients underwent neuraxial anesthesia and a TAP block (SMPM/TAP) or SMPM; the TAP block incorporated ropivacaine (20–30 mL) administered bilaterally. The group analyses involved a comparison of postoperative pain scores using the visual analog scale and opioid consumption at 24 and 24–48 h.There were 94 (52.8%) patients in the SMPM/TAP group and 84 (47.2%) subjects in the SMPM alone group. At 24 h postoperatively, the SMPM/TAP group exhibited significantly lower pain scores (4.07 vs 4.54) than the SMPM group (P < 0.001) and reduced opioid consumption (2.29 vs 3.28 mg; P < 0.001). However, at 24–48 h, the SMPM group demonstrated lower pain scores (5.46 vs 5.98) compared to the SMPM/TAP group (P < 0.001) and reduced opioid consumption (8.75 vs 10.21 mg; P < 0.001); overall opioid consumption was higher (12.50 vs 12.02 mg) in the SMPM/TAP group (P < 0.001).The TAP block improved cesarean surgery patients' pain scores and reduced opioid consumption at 24 h postoperatively but the effect of the TAP block was ephemeral as the SMPM/TAP group exhibited inferior pain scores and greater opioid consumption compared to the SMPM group at 24–48 h postoperatively. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the impact of usual care plus a fundamental nursing care guideline compared to usual care only for patients in hospital with COVID‐19 on patient experience, care quality, functional ability, treatment outcomes, nurses' moral distress, patient health‐related quality of life and cost‐effectiveness. Design: Parallel two‐arm, cluster‐level randomized controlled trial. Methods: Between 18th January and 20th December 2021, we recruited (i) adults aged 18 years and over with COVID‐19, excluding those invasively ventilated, admitted for at least three days or nights in UK Hospital Trusts; (ii) nurses caring for them. We randomly assigned hospitals to use a fundamental nursing care guideline and usual care or usual care only. Our patient‐reported co‐primary outcomes were the Relational Aspects of Care Questionnaire and four scales from the Quality from the Patient Perspective Questionnaire. We undertook intention‐to‐treat analyses. Results: We randomized 15 clusters and recruited 581 patient and 418 nurse participants. Primary outcome data were available for 570–572 (98.1%–98.5%) patient participants in 14 clusters. We found no evidence of between‐group differences on any patient, nurse or economic outcomes. We found between‐group differences over time, in favour of the intervention, for three of our five co‐primary outcomes, and a significant interaction on one primary patient outcome for ethnicity (white British vs. other) and allocated group in favour of the intervention for the 'other' ethnicity subgroup. Conclusion: We did not detect an overall difference in patient experience for a fundamental nursing care guideline compared to usual care. We have indications the guideline may have aided sustaining good practice over time and had a more positive impact on non‐white British patients' experience of care. Implications for the Profession and/or Patient Care: We cannot recommend the wholescale implementation of our guideline into routine nursing practice. Further intervention development, feasibility, pilot and evaluation studies are required. Impact: Fundamental nursing care drives patient experience but is severely impacted in pandemics. Our guideline was not superior to usual care, albeit it may sustain good practice and have a positive impact on non‐white British patients' experience of care. Reporting Method: CONSORT and CONSERVE. Patient or Public Contribution: Patients with experience of hospitalization with COVID‐19 were involved in guideline development and writing, trial management and interpretation of findings. [ABSTRACT FROM AUTHOR]

The article is a personal account written by David Richards, a survivor of severe acute respiratory distress syndrome (ARDS) during the swine flu pandemic in 2009-2010. Richards spent six weeks in the intensive care unit (ICU) and received mechanical ventilation and ECMO treatment. His former partner, Rose, kept a diary during his time in the ICU, documenting his medical updates, conversations, and the emotional impact on their family. Richards reflects on the importance of the diary in helping him understand his prognosis, extract true memories from delusions, and appreciate the care he received. The diary also helped him cope with anxiety and depression and serves as a reminder of his recovery journey. Richards emphasizes the value of ICU diaries in providing a timeline of events, filtering out false memories, and supporting mental health. [Extracted from the article]

This article considers the levelling‐up agenda in the UK, examining the Johnson government's original proposals to tackle regional and local inequality and its continuation under new Prime Minister Rishi Sunak following the short‐lived premiership of Liz Truss. The 2022 Levelling Up in the United Kingdom White Paper is notable for the frank and wholesale critique it provides of previous governments'—both Tory and Labour—efforts to address the pressing issue of geographic inequality. The assessment was that a pattern of ad hoc and incoherent reforms needed to be replaced by a stable, long term and system‐wide approach to change. Yet, under Johnson, Truss and now Sunak, policy churn is continuing, with an approach that falls short in following the lessons set out in the White Paper. We provide a detailed analysis of the government's critique of past reforms, the lessons it has set out and why its reform programme is likely to repeat past failings. Crucially, the approach leaves the structure of central government almost untouched, with substantive reforms instead focussed at the local governance level. We argue the government's programme perpetuates the 'power‐hoarding' tendencies of the Westminster model, a key bulwark against meaningfully addressing the UK's spatial inequality problem. We conclude that the levelling‐up agenda, missions and targets are unlikely to be met under Rishi Sunak, reflecting the endemic nature of short‐termism and centralisation of power in the UK's public policy approach. We then consider the approach of Starmer's Labour Party to levelling up and the issues it needs to confront if it forms the next government. [ABSTRACT FROM AUTHOR]

Simple Summary: Within cells, there are numerous compartments called 'organelles' that perform a range of specialised functions required to support life. Organelles are constantly adapting to their environment, changing shape and cooperating with each other depending on the cellular needs, which is essential for cell health as defects in these processes lead to human diseases. One example of organelle dynamic behaviour is the formation of thin tubules that extend and retract from the membranes that delimit the organelles. With a focus on two organelles (peroxisomes and mitochondria) that have roles in cell metabolism and protection, we examine how and why these membrane extensions form, and what their function is within the cell. This includes forming new organelles or organelle networks; increasing the organelle surface area to maximise uptake of molecules; mediating communication between different organelles. We propose that these membrane extensions allow organelles to 'reach out' and explore their surroundings more efficiently. Together, this review highlights the importance of organelle dynamics, and specifically membrane extension, in maintaining healthy cell function, as well as exploring the questions remaining to be answered to further our understanding of this essential aspect of cell biology. Organelles within eukaryotic cells are not isolated static compartments, instead being morphologically diverse and highly dynamic in order to respond to cellular needs and carry out their diverse and cooperative functions. One phenomenon exemplifying this plasticity, and increasingly gaining attention, is the extension and retraction of thin tubules from organelle membranes. While these protrusions have been observed in morphological studies for decades, their formation, properties and functions are only beginning to be understood. In this review, we provide an overview of what is known and still to be discovered about organelle membrane protrusions in mammalian cells, focusing on the best-characterised examples of these membrane extensions arising from peroxisomes (ubiquitous organelles involved in lipid metabolism and reactive oxygen species homeostasis) and mitochondria. We summarise the current knowledge on the diversity of peroxisomal/mitochondrial membrane extensions, as well as the molecular mechanisms by which they extend and retract, necessitating dynamic membrane remodelling, pulling forces and lipid flow. We also propose broad cellular functions for these membrane extensions in inter-organelle communication, organelle biogenesis, metabolism and protection, and finally present a mathematical model that suggests that extending protrusions is the most efficient way for an organelle to explore its surroundings. [ABSTRACT FROM AUTHOR]

Aims: To identify strategies used by registered nurses and non‐registered nursing care staff in overcoming barriers when providing fundamental nursing care for non‐invasively ventilated inpatients with COVID‐19. Design: Online survey with open‐ended questions to collect qualitative data. Methods: In August 2020, we asked UK‐based nursing staff to describe any strategies they employed to overcome barriers to delivering care in 15 fundamental nursing care categories when providing care to non‐invasively ventilated patients with COVID‐19. We analysed data using Framework Analysis. Results: A total of 1062 nurses consented to participate in our survey. We derived four themes. 1) Communication behaviours included adapting verbal and non‐verbal communication with patients, using information technology to enable patients' significant others to communicate with staff and patients, and establishing clear information‐sharing methods with other staff. 2) Organizing care required clustering interventions, carefully managing supplies, encouraging patient self‐care and using 'runners' and interdisciplinary input. 3) Addressing patients' well‐being and values required spending time with patients, acting in loco familiae, providing access to psychological and spiritual support, obtaining information about patients' wishes early on and providing privacy and comforting/meaningful items. 4) Management and leadership behaviours included training, timely provision of pandemic information, psychological support, team huddles and facilitating regular breaks. Conclusions: Our respondents identified multiple strategies in four main areas of clinical practice. Management and leadership are crucial to both fundamental care delivery and the well‐being of nurses during pandemics. Grouping strategies into these areas of action may assist nurses and leaders to prepare for pandemic nursing. Impact As these strategies are unlikely to be exclusive to the COVID‐19 pandemic, their global dissemination may improve patient experience and help nurses deliver fundamental care when planning pandemic nursing. However, their effectiveness is unknown. Therefore, we are currently evaluating these strategies in a cluster randomized controlled trial. [ABSTRACT FROM AUTHOR]

Pile foundations for masts supporting overhead line equipment (OLE) on railways in Western Europe have traditionally been designed using empirical formulae derived from tests carried out in the 1950s under the auspices of the Union Internationale des Chemins de fer (UIC). Recent application in the UK of ostensibly more analytical approaches led to significantly increased pile lengths, which contributed to the high-profile cost over-run on the Great Western electrification programme. Further, the loads associated with some newer designs of mast are greater than those covered by the original field tests, and hence are outside the evidence base for the empirical approach. To address this, full-scale field tests were carried out on three, 610 mm dia. circular hollow-section steel piles installed in a railway embankment at the High Marnham test track (Nottinghamshire, UK). Each pile was designed according to the empirical OLE master index (OLEMI) method for a different form of modern OLE mast, and instrumented using Shape accelerometer arrays (SAAs) to determine pile deformations. The results provide valuable insights into the mechanisms of deformation of piles of different lengths, both at and beyond the expected in-service loads. p–y curves derived from the SAA measurements compare reasonably well with curves constructed using the American Petroleum Institute method for undrained clay soils. The tests also demonstrate the suitability of the OLEMI approach for large structures and loads; and that the Eurocode 7 partial factors on load and undrained shear strength applied to an undrained (total stress) limit equilibrium calculation are likely to be sufficient to meet serviceability requirements for standard single-and twin-track cantilever structures. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7–10% of non-Ashkenazi PD individuals carrying a GBA1 mutation (PD-GBA1). Although similar to idiopathic PD, the clinical presentation of PD-GBA1 includes a slightly younger age of onset, a higher incidence of neuropsychiatric symptoms, and a tendency to earlier, more prevalent and more significant cognitive impairment. The pathophysiological mechanisms underlying PD-GBA1 are incompletely understood, but, as in idiopathic PD, α-synuclein accumulation is thought to play a key role. It has been hypothesized that this overexpression of α-synuclein is caused by epigenetic modifications. In this paper, we analyze DNA methylation levels at 17 CpG sites located within intron 1 and the promoter of the α-synuclein (SNCA) gene in three different brain regions (frontal cortex, putamen and substantia nigra) in idiopathic PD, PD-GBA1 and elderly non-PD controls. In all three brain regions we find a tendency towards a decrease in DNA methylation within an eight CpG region of intron 1 in both idiopathic PD and PD-GBA1. The trend towards a reduction in DNA methylation was more pronounced in PD-GBA1, with a significant decrease in the frontal cortex. This suggests that PD-GBA1 and idiopathic PD have distinct epigenetic profiles, and highlights the importance of separating idiopathic PD and PD-GBA1 cases. This work also provides initial evidence that different genetic subtypes might exist within PD, each characterized by its own pathological mechanism. This may have important implications for how PD is diagnosed and treated. [ABSTRACT FROM AUTHOR]

Cell function can be directly influenced by the mechanical and structural properties of the extracellular environment. In particular, cell morphology and phenotype can be regulated via the modulation of both the stiffness and surface topography of cell culture substrates. Previous studies have highlighted the ability to design cell culture substrates to optimise cell function. Many such examples, however, employ photo-crosslinkable polymers with a terminal stiffness or surface profile. This study presents a system of polyacrylamide hydrogels, where the surface topography can be tailored and the matrix stiffness can be altered in situ with photoirradiation. The process allows for the temporal regulation of the extracellular environment. Specifically, the surface topography can be tailored via reticulation parameters to include creased features with control over the periodicity, length and branching. The matrix stiffness can also be dynamically tuned via exposure to an appropriate dosage and wavelength of light, thus, allowing for the temporal regulation of the extracellular environment. When cultured on the surface of the hydrogels, the morphology and alignment of immortalised human mesenchymal stem cells can be directly influenced through the tailoring of surface creases, while cell size can be altered via changes in matrix stiffness. This system offers a new platform to study cellular mechanosensing and the influence of extracellular cues on cell phenotype and function. [ABSTRACT FROM AUTHOR]

Ladybird beetles (Coleoptera: Coccinellidae) possess strong chemical defences that are secreted in response to stress and are also found on the coating of eggs, which are rich in alkaloids that are responsible for their toxicity to other species. Recent studies have shown that alkaloids from several species of ladybird beetle can target nicotinic acetylcholine receptors (nAChRs) acting as receptor antagonists. Here, we have explored the actions of (−)-adaline, found in the 2-spot (Adalia bipunctata) and 10-spot (Adalia decempunctata) ladybirds, on both mammalian (α1β1γδ, α7, α4β2, α3β4) and insect nAChRs using patch-clamp of TE671 cells and locust brain neurons natively expressing nAChRs, as well as two-electrode voltage clamp of Xenopus laevis oocytes recombinantly expressing nAChRs. All nAChR subtypes were antagonised by (−)-adaline in a time-dependent, voltage-dependent and non-competitive manner with the lowest IC50s at rat α3β4 (0.10 μM) and locust neuron (1.28 μM) nAChRs, at a holding potential of −75 mV. The data imply that (−)-adaline acts as an open channel blocker of nAChRs. [ABSTRACT FROM AUTHOR]

Highway authorities make efforts to relate visual ratings with directly measured pavement condition data to reduce or remove the necessity of manual pavement condition surveys that involve subjectivity and potential safety risk of assessors. This research develops a set of relationships between pavement surface condition rating and objective pavement condition parameters to assist road asset managers in triggering periodic bituminous resurfacing programs at the network level. These condition parameters include cracking (% area affected), rutting (mm), texture loss (% of left wheel path texture), and roughness (m/km). In the literature, deterministic and probabilistic modelling approaches are used to predict visual surface inspection rating (SIR) from directly measured pavement distresses. The Factorial ANOVA results that are typically used have inferred that cracking and rutting interact with each other significantly for the asphalt surfaced road network. However, the percentages of variation explained by the linear regression models that predict SIR from cracking/rutting are low (24–31%). Alternatively, developed ordinal logistic models for predicting the probability of a road section being in any particular surface condition, with any quantified cracking/rutting data, prove to be statistically better with overall success rates of 46% and 51% for sprayed sealed and asphalt surfaced network, respectively. [ABSTRACT FROM AUTHOR]

This article explores the question of devolution in the light of the Covid‐19 pandemic's impact on English local government. Criticism of the government's handling of the crisis is widespread and tends to focus on the highly centralised nature of the British state. Here, we attribute the challenges faced by regional and local government in responding to the pandemic primarily to the asymmetric nature of power relations that characterise financial planning and control mechanisms, devised and overseen by the Treasury. We argue that the ongoing crisis underlines the need for a democratic form of devolution—including further fiscal powers for regional and local government—to support the economic recovery. In a context of increasing fiscal uncertainty, the Treasury should seek to unlock the existing powers of local leaders by reforming centralised budgetary constraints and taking accountability and monitoring mechanisms closer to citizens. [ABSTRACT FROM AUTHOR]

The article discusses the study of the ion-molecule interactions enable unexpected phase transitions in organic-inorganic aerosol. Topics discussed include atmospheric aerosol particles are commonly complex, aqueous organic-inorganic mixtures, and accurately predicting the properties of these particles is essential for air quality and climate projections; and the prevailing assumption is that aqueous organic-inorganic aerosols exist predominately with liquid properties.

Railway electrification offers significant benefits in terms of decarbonisation at the point of use and reduced traction costs. However, to realise these benefits, the fixed infrastructure must be provided at an affordable cost. Recent schemes in the UK have seen the cost of railway electrification soar: one of a number of reasons for this has been the substantial increase in mast foundation pile lengths compared with historic practice. The paper explores this through a comparative review of traditional and modern pile design methods. In addressing the ultimate limit state, the various approaches are shown to give broadly consistent results in terms of pile length. However, increased pile lengths will be calculated if three-dimensional effects are not allowed for in limit equilibrium (ultimate limit state) calculations, or if a serviceability limit state calculation is carried out using unrealistically low soil stiffness. The results of the comparative analyses should give designers the confidence to use the traditional empirical approach, or a limit equilibrium calculation without the need for an explicit serviceability limit state check (as permitted by Eurocode 7) using potentially inappropriate soil stiffness parameters. [ABSTRACT FROM AUTHOR]

Endocrine cells in the pituitary gland typically display either spiking or bursting electrical activity, which is related to the level of hormone secretion. Recent work, which combines mathematical modelling with dynamic clamp experiments, suggests the difference is due to the presence or absence of a few large-conductance potassium channels. Since endocrine cells only contain a handful of these channels, it is likely that stochastic effects play an important role in the pattern of electrical activity. Here, for the first time, we explicitly determine the effect of such noise by studying a mathematical model that includes the realistic noisy opening and closing of ion channels. This allows us to investigate how noise affects the electrical activity, examine the origin of spiking and bursting, and determine which channel types are responsible for the greatest noise. Further, for the first time, we address the role of cell size in endocrine cell electrical activity, finding that larger cells typically display more bursting, while the smallest cells almost always only exhibit spiking behaviour. Author summary: The pituitary gland, situated just below the brain, is the body's master hormone gland. Hormones produced by the pituitary control many essential functions, including growth, reproduction, and our response to emotional and physical stress. The cells that produce these hormones generate electrical activity, exactly like neurons, and this electrical activity controls the amount of hormone that is released. Here, we use mathematics and computing to help understand the electrical activity of these cells. This allows us to perform manipulations that we cannot do experimentally. In particular, we analyse a type of mathematical model that, for the first time, takes into account the role that is played by random processes within pituitary cells. These random processes are particularly important for these types of cell. Using this approach, we determine what causes the different types of electrical activity seen in pituitary cells. A particularly exciting aspect of this work is that it allows us, for the first time, to find out how the electrical activity of big cells is different to that for small cells. Long term, the aim of this work is to understand better how drugs affect hormone production and so suggest ways to reduce their side effects. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoid-induced TNFR-related protein (TNFRSF18, GITR, CD357), expressed by T cells, and its ligand (TNFSF18, GITRL), expressed by myeloid populations, provide co-stimulatory signals that boost T cell activity. Due to the important role that GITR plays in regulating immune functions, agonistic stimulation of GITR is a promising therapeutic concept. Multiple strategies to induce GITR signaling have been investigated. The limited clinical efficacy of antibody-based GITR agonists results from structural and functional characteristics of antibodies that are unsuitable for stimulating the well-defined trimeric members of the TNFRSF. Methods: To overcome limitations of antibody-based TNFRSF agonists, we have developed HERA-GITRL, a fully human hexavalent TNF receptor agonist (HERA) targeting GITR and mimicking the natural signaling concept. HERAGITRL is composed of a trivalent but single-chain GITRL-receptor-binding-domain (scGITRL-RBD) unit fused to an IgG1 derived silenced Fc-domain serving as dimerization scaffold. A specific mouse surrogate, mmHERA-GITRL, was also generated to examine in vivo activity in respective mouse tumor models. Results: For functional characterization of HERA-GITRL in vitro, human immune cells were isolated from healthydonor blood and stimulated with anti-CD3 antibody in the presence of HERA-GITRL. Consistently, HERA-GITRL increased the activity of T cells, including proliferation and differentiation, even in the presence of regulatory T cells. In line with these findings, mmHERA-GITRL enhanced antigen-specific clonal expansion of both CD4+ (OT-II) and CD8+ (OT-I) T cells in vivo while having no effect on non-specific T cells. In addition, mmHERA-GITRL showed single-agent anti-tumor activity in two subcutaneous syngeneic colon cancer models (CT26wt and MC38-CEA). Importantly, this activity is independent of its FcγR-binding functionality, as both mmHERA-GITRL with a functional Fc- and a silenced Fc-domain showed similar tumor growth inhibition. Finally, in a direct in vitro comparison to a bivalent clinical benchmark anti-GITR antibody and a trivalent GITRL, only the hexavalent HERA-GITRL showed full biological activity independent of additional crosslinking. Conclusion: In this manuscript, we describe the development of HERA-GITRL, a true GITR agonist with a clearly defined mechanism of action. By clustering six receptor chains in a spatially well-defined manner, HERA-GITRL induces potent agonistic activity without being dependent on additional FcγR-mediated crosslinking. [ABSTRACT FROM AUTHOR]

This document is one of a series of white papers from the USQCD Collaboration. Here, we discuss opportunities for Lattice QCD in neutrino-oscillation physics, which inevitably entails nucleon and nuclear structure. In addition to discussing pertinent Lattice QCD calculations of nucleon and nuclear matrix elements, the interplay with models of nuclei is discussed. This program of Lattice QCD calculations is relevant to current and upcoming neutrino experiments, becoming increasingly important on the timescale of LBNF/DUNE and HyperK. [ABSTRACT FROM AUTHOR]

Background and Purpose: The P2X3 receptor is an ATP-gated ion channel expressed by sensory afferent neurons and is used as a target to treat chronic sensitisation conditions. The first-in-class, selective P2X3 and P2X2/3 receptor antagonist, the diaminopyrimidine MK-7264 (gefapixant), has progressed to Phase III trials for refractory or unexplained chronic cough. We used patch clamp to elucidate the pharmacology and kinetics of MK-7264 and rat models of hypersensitivity and hyperalgesia to test its efficacy on these conditions.Experimental Approach: Whole-cell patch clamp of 1321N1 cells expressing human P2X3 and P2X2/3 receptors was used to determine mode of MK-7264 action, potency, and kinetics. The analgesic efficacy was assessed using paw withdrawal threshold and limb weight distribution in rat models of inflammatory, osteoarthritic, and neuropathic sensitisation.Key Results: MK-7264 is a reversible allosteric antagonist at human P2X3 and P2X2/3 receptors. Experiments with the slowly desensitising P2X2/3 heteromer revealed concentration- and state-dependency to wash-on, with faster rates and greater inhibition when applied before agonist compared to during agonist application. The wash-on rate (τ value) for MK-7264 at maximal concentrations was much lower when applied before compared to during agonist application. In vivo, MK-7264 displayed efficacy comparable to naproxen in inflammatory and osteoarthritic sensitisation models and gabapentin in neuropathic sensitisation models, increasing paw withdrawal threshold and decreasing weight-bearing discomfort.Conclusions and Implications: MK-7264 is a reversible and selective P2X3 and P2X2/3 antagonist, exerting allosteric antagonism via preferential activity at closed channels. Its efficacy in rat models supports its clinical investigation for chronic sensitisation conditions. [ABSTRACT FROM AUTHOR]

Native mussels likely occurred in Mill Creek and the Jordan River, Utah, in the past. However, humaninduced impacts have virtually eliminated the possibility of their continued existence in these waters. We conducted an intensive native mussel survey upstream and downstream of a water reclamation facility discharge into Mill Creek and the Jordan River to determine its effects on mussel populations. The survey was conducted from September to October 2017 and resulted in approximately 7.6 m3 of >4 mm-sized substrate particles being thoroughly examined at near 100% efficiency. We then used statistical models to estimate population densities as a function of probability of detection and search efficiencies based on this and other surveys. Regrettably, no live or recently dead native mussels were found. Given that our survey methods provided near perfect search efficiency, native mussel densities were estimated to be <<0.03 per m2, which is much lower than what we consider to be a viable population density. Combined with multiple lines of evidence from other surveys, this low density strongly points toward the conclusion that native mussels are extinct in the survey area. Reasons for the demise of native mussels in Mill Creek and the Jordan River are numerous, and these factors need to be aggressively addressed if native mussels are to survive in the drainage. [ABSTRACT FROM AUTHOR]

Abstract In this article we ask our profession to consider whether something is rotten at the core of modern nursing. We will use our own experiences as patients, together with published literature, to ask questions of our profession in perpetrating what one of our colleagues recently, and with great embarrassment, referred to as ' shitty nursing'. Our intention is most certainly not to offend any readers, for this term has been used in literature for more than one hundred years to describe bad situations, including those where events or people's behaviour are of a low standard. Our intention instead, is to challenge ourselves, the profession and you the reader by raising a measured debate which seems at present to be missing within the profession. We examine the potential idea that poor nursing care may not be the exception, but horrifyingly, may be the new normal. We are particularly concerned that patients' fundamental care needs may be falling into an ever widening gap between assistant and registered nurses. Whilst we acknowledge the potential causes of poor nursing care, causes that are often cited by nurses themselves, we come to the conclusion that a mature profession including clinicians, educators, administrators, researchers and regulators cannot continually blame contextual factors for its failings. A mature profession with an intact contract between itself and society must shoulder some of the responsibility for its own problems. We do suggest a way forward, including a mix of reconciliation, refocus and research, underpinned by what we argue is a much needed dose of professional humility. Readers may take us to task for potentially overstating the problem, ignoring non-nursing drivers, and downplaying other significant factors. You may think that there is much in nursing to glory in. However, we make no apology for presenting our views. Our lived experiences tell us something different. As professional nurses our main aim is to ensure that our adverse experiences as patients are statistical anomalies, and our future encounters with nursing care represent all that we know to be excellent in our profession. We leave you to judge and comment. [ABSTRACT FROM AUTHOR]

Abstract Critical Race Theory contends that institutions codify and sustain racial inequalities even absent explicitly racist motives or actions. College ranking systems perpetuate such institutional racism by socially constructing minority-serving institutions (MSIs) as less valuable and prestigious. By assigning greater worth to criteria favoring more selective institutions, ranking systems assign lower scores to institutions enrolling higher percentages of underrepresented students. The authors compared three higher education institution ranking systems' appraisals of MSIs. These systems employ varying methodological approaches to classifying college status, with apparent impacts on MSIs' performances. Implications of these rankings on the standings and fortunes of MSIs are considered. [ABSTRACT FROM AUTHOR]

This article offers responses to the book Clinical Encounters in Sexuality: Psychoanalytic Practice & Queer theory. The author proposes that the book's dialogic structure itself encourages a particular kind of lively engagement with the ideas, and observes his own experience of reading it and how this has contributed valuably to his stance in clinical work. Each of the book's three sections is referenced, briefly reflecting on the themes of Queer Theories, Psychoanalytic Responses, and Responses to Psychoanalytic Practices Encountering Queer Theories. This includes various writers' thoughts on how unknowable sexuality remains and perhaps beyond interpretation; psychoanalysis and its history of homophobia post Freud; and the significant connections and tensions between the apparent "queerness" of psychoanalysis and the separate discipline of Queer Theory itself. In essence, central issues prompted by the book are related to what can be known with regard to sexuality internally and interpersonally, and the language we have (or not) to voice it. [ABSTRACT FROM AUTHOR]

The Washington Accord is one of seven mutual recognition agreements managed by the International Engineering Alliance. Its signatories recognize the substantial equivalency of programs accredited by the signatory bodies, and they agree to make every reasonable effort to ensure that licensing boards in their respective countries recognize this. Despite 25 years of the Washington Accord, however, only a minority of U.S. state licensing boards acknowledge it in their statutes. This paper compares Engineering Council (EC) guidelines for accreditation with those of the Accreditation Board for Engineering and Technology (ABET). It concludes that there are substantial similarities in the EC and ABET accreditation criteria. This should encourage U.S. state licensing boards to acknowledge EC-accredited programs in their statutes explicitly if not through the Washington Accord. A number of key differences in EC and ABET accreditation criteria are also highlighted. Both the ABET and the EC accredit programs at various levels. This paper recommends that the International Engineering Alliance clarify the correspondence between the various levels of accredited programs of the Washington Accord signatories. [ABSTRACT FROM AUTHOR]

The question of what constitutes torture has perhaps never held as prominent a place in US political discourse as it has since the attacks on 9/11. This has fueled a national conversation that causes us to consider to what extent do our actions as a nation reflect our values as a nation? In a post 9/11 world in which the country will confront terrorism at home and abroad and our values will be tested we should strive for a better understanding of citizens' attitudes towards the practices that are (and have been) used to counter terrorism. To the extent that democratic theory is correct in necessitating public policy and public opinions to be reasonably congruent, understanding the distribution and formation of citizen attitudes towards torture is an important endeavor. [ABSTRACT FROM AUTHOR]

Aims and objectives: To investigate the components of the Amalgamation of Marginal Gains (AMG) performance system to identify a set of principles that can be built into an innovative fundamental nursing care protocol. Background: Nursing is urged to refocus on its fundamental care activities, but little evidence exists to guide practising nurses. Fundamental care is a combination of many small behaviours aimed at meeting a person's care needs. AMG is a successful system of performance management that focusses on small (or marginal) gains, and might provide a new delivery framework for fundamental nursing care. Design: Qualitative interview study. Methods: We undertook in‐depth interviews with healthcare and sports professionals experienced in AMG. We analysed data using open coding in a framework analysis, and then interrogated the data using Normalisation Process Theory (NPT). We triangulated findings with AMG literature to develop an intervention logic model. Results: We interviewed 20 AMG practitioners. AMG processes were as follows: focusing on many details to optimise performance, identification of marginal gains using different sources, understanding current versus optimum performance, monitoring at micro and macro level and strong leadership. Elements of normalisation were as follows: whole team belief in AMG to improve performance, a collective desire for excellence using evidence‐based actions, whole team engagement to identify choose and implement changes, and individual and group responsibility for monitoring performance. Conclusions: We have elicited the processes described by AMG innovators in health care and sport and have mapped the normalisation potential and work required to embed such a system into nursing practice. Relevance to clinical practice: The development of our logic model based on AMG and NPT may provide a practical framework for improving fundamental nursing care and is ripe for further development and testing in clinical trials. [ABSTRACT FROM AUTHOR]

Aims and objectives: To determine the effects of nursing interventions for people's nutrition, elimination, mobility and hygiene needs. Background: Patient experience of health care is sensitive to nursing quality. A refocus on fundamental nursing care is undermined by lack of evidence of effectiveness for interventions in core areas such as elimination, nutrition, mobility and hygiene. Design: Systematic review. Methods: We searched for and included experimental studies on interventions by professionally qualified and unregistered nurses that addressed participants' nutrition, elimination, mobility and hygiene needs. We extracted data on scope, quality and results of studies followed by descriptive narrative synthesis of included study outcomes using a novel form of harvest plots. Results: We included 149 studies, 35 nutrition, 56 elimination, 16 mobility, 39 hygiene and three addressing two or more areas simultaneously (67 randomised controlled trials, 32 non‐randomised controlled trials and 50 uncontrolled trials). Studies into interventions on participant self‐management of nutrition (n = 25), oral health (n = 26), catheter care (n = 23) and self‐management of elimination (n = 21) were the most prevalent. Most studies focussed their outcomes on observational or physiological measures, with very few collecting patient‐reported outcomes, such as quality of life, experience or self‐reported symptoms. All but 13 studies were of low quality and at significant risk of bias. The majority of studies did not define primary outcomes, included multiple measures of identical concepts, used inappropriate analyses and did not conform to standard reporting quality criteria. Conclusions: The current evidence for fundamental nursing care interventions is sparse, of poor quality and unfit to provide evidence‐based guidance to practising nurses. Relevance to clinical practice: Researchers in nursing internationally should now undertake a programme of work to produce evidence for clinical practice in the fundamentals of care that is reliable, replicable and robust. [ABSTRACT FROM AUTHOR]

Peroxisomes are dynamic organelles which fulfil essential roles in lipid and ROS metabolism. Peroxisome movement and positioning allows interaction with other organelles and is crucial for their cellular function. In mammalian cells, such movement is microtubule‐dependent and mediated by kinesin and dynein motors. The mechanisms of motor recruitment to peroxisomes are largely unknown, as well as the role this plays in peroxisome membrane dynamics and proliferation. Here, using a combination of microscopy, live‐cell imaging analysis and mathematical modelling, we identify a role for Mitochondrial Rho GTPase 1 (MIRO1) as an adaptor for microtubule‐dependent peroxisome motility in mammalian cells. We show that MIRO1 is targeted to peroxisomes and alters their distribution and motility. Using a peroxisome‐targeted MIRO1 fusion protein, we demonstrate that MIRO1‐mediated pulling forces contribute to peroxisome membrane elongation and proliferation in cellular models of peroxisome disease. Our findings reveal a molecular mechanism for establishing peroxisome‐motor protein associations in mammalian cells and provide new insights into peroxisome membrane dynamics in health and disease. [ABSTRACT FROM AUTHOR]

Background: Interventions aiming to coordinate services for the community-based dementia population vary in components, organisation and implementation. In this review we aimed to investigate the views of stakeholders on the key components of community-based interventions coordinating care in dementia.Methods: We searched four databases from inception to June 2015; Medline, The Cochrane Library, EMBASE and PsycINFO, this was aided by a search of four grey literature databases, and backward and forward citation tracking of included papers. Title and abstract screening was followed by a full text screen by two independent reviewers, and quality was assessed using the CASP appraisal tool. We then conducted thematic synthesis on extracted data.Results: A total of seven papers from five independent studies were included in the review, and encompassed the views of over 100 participants from three countries. Through thematic synthesis we identified 32 initial codes that were grouped into 5 second-order themes: (1) case manager had four associated codes and described preferences for the case manager personal and professional attributes, including a sound knowledge in dementia and availability of local services; (2) communication had five associated codes and emphasized the importance stakeholders placed on multichannel communication with service users, as well as between multidisciplinary teams and across organisations; (3) intervention had 11 associated codes which focused primarily on the practicalities of implementation such as the contact type and frequency between case managers and service users, and the importance of case manager training and service evaluation; (4) resources had five associated codes which outlined stakeholder views on the required resources for coordinating interventions and potential overlap with existing resources, as well as arising issues when available resources do not meet those required for successful implementation; and (5) support had seven associated codes that reflect the importance that was placed on the support network around the case manager and the investment of professionals involved directly in care as well as the wider professional network.Conclusion: The synthesis of relevant qualitative studies has shown how various stakeholder groups considered dementia care coordination interventions to be acceptable, useful and appropriate for dementia care, and have clear preferences for components, implementation methods and settings of these interventions. By incorporating stakeholders' perspectives and preferences when planning and developing coordinating interventions we may increase the likelihood of successful implementation and patient benefits. [ABSTRACT FROM AUTHOR]

Determination of 135 Cs/ 137 Cs atom ratios has the potential to be a powerful tool for nuclear forensics and monitoring environmental processes. We present optimized chemical separation techniques and thermal ionization mass spectrometry (TIMS) protocols to obtain precise 135 Cs/ 137 Cs atom ratios for a range of environmental sample types. We use a combination of double AMP-PAN separation and Sr-spec resin column purification to yield excellent separation from the alkali metals (Rb separation factor > 600), which normally suppress ionization of Cs. A range of emission activators for the ionization of Cs were evaluated and glucose solution yielded the optimal combination of a stable Cs + beam, minimal low-temperature polyatomic interferences and improved ionization efficiency. Mass-spectrometric determination of low abundance 135 Cs and 137 Cs is compromised by the presence of a very large 133 Cs + beam, which may be scattered and cause significant spectral interferences. These are explored using multi-static Faraday cup – ion counter methods and a range of energy filter settings. The method is evaluated using environmental samples and standards from regions affected by fallout from Chernobyl (IAEA-330) and Fukushima nuclear disasters. Where the intensity of 133 Cs + is large relative to 135 Cs + and 137 Cs + (< 30 cps), minor polyatomic interferences need to be considered. In the absence of a standard with 135, 137 Cs/ 133 Cs < 1 × 10 −8 , we explored the reproducibility of 135 Cs/ 137 Cs atom ratios at these high dynamic ranges and extremely low abundance ( 137 Cs ≈ 12 fg g −1 ) for sediments from an estuarine setting in SW England, UK. [ABSTRACT FROM AUTHOR]

The actin cytoskeleton is essential in eukaryotes, not least in the plant kingdom where it plays key roles in cell expansion, cell division, environmental responses and pathogen defence. Yet, the precise structure-function relationships of properties of the actin network in plants are still to be unravelled, including details of how the network configuration depends upon cell type, tissue type and developmental stage. Part of the problem lies in the difficulty of extracting high-quality, quantitative measures of actin network features from microscopy data. To address this problem, we have developed DRAGoN, a novel image analysis algorithm that can automatically extract the actin network across a range of cell types, providing seventeen different quantitative measures that describe the network at a local level. Using this algorithm, we then studied a number of cases in Arabidopsis thaliana, including several different tissues, a variety of actin-affected mutants, and cells responding to powdery mildew. In many cases we found statistically-significant differences in actin network properties. In addition to these results, our algorithm is designed to be easily adaptable to other tissues, mutants and plants, and so will be a valuable asset for the study and future biological engineering of the actin cytoskeleton in globally-important crops. Author summary: Most biological cells contain an internal network of protein filaments called the cytoskeleton. This helps provide shape and structure to the cell, and is used for transporting cargo within the cell. One example is actin, the thinnest part of the cytoskeleton, which is present as both individual filaments and thicker bundles. Actin forms complex branched networks that continually change as required. Studying the actin network is difficult since it has hard to accurately find the shape of the network and follow how this changes over time. Here, by focusing on plants, we develop a novel computational algorithm called DRAGoN that can automatically extract the shape of the actin network, giving seventeen precise numerical measurements that describe the network. We then use our algorithm to examine actin in the model plant Arabidopsis thaliana, finding significant differences in the actin network between tissue types, key actin mutants and when the cells are attacked by powdery mildew. This work has important potential applications to global food security and is likely to be easily adaptable to organisms other than plants. [ABSTRACT FROM AUTHOR]

Background: According to the World Health Organization, drowning is the 3rd leading cause of unintentional injury-related deaths worldwide, accounting for 370,000 annual deaths and 7% of all injury-related deaths. Low- and middle-income countries are the most affected, accounting for 91% of unintentional drowning deaths.Methods: The authors performed a systematic review of literature indexed in EMBASE, PubMed, Web of Science, Cochrane Library, and Traumatology journals formerly indexed in PubMed in January 2014 and again in September 2016. Abstracts were limited to human studies in English, conducted in low- and middle-income countries, and containing quantitative data on drowning epidemiology.Results: A total of 62 articles met inclusion criteria. The majority of articles originate from Asia (56%) and Africa (26%). Risk factors for drowning included young age (<17-20 years old), male gender (75% vs. 25% female), rural environment (84% vs. 16% urban), occurring in the daytime (95% vs. 5% night time), lack of adult supervision (76% vs. 18% supervised), and limited swimming ability (86% vs. 10% with swimming ability). There was almost equal risk of drowning in a small body of water versus a large body of water (42% ponds, ditches, streams, wells; 46% lakes, rivers, sea, ocean).Conclusion: Drowning is a significant cause of injury-related deaths, especially in LMICs. Young males who are unsupervised in rural areas and have limited formal swimming instruction are at greatest risk of drowning in small bodies of water around their homes. Preventative strategies include covering wells and cisterns, fencing off ditches and small ponds, establishing community daycares, providing formal swimming lessons, and increasing awareness of the risks of drowning. [ABSTRACT FROM AUTHOR]

The article argues that Nathaniel Hawthorne's portrayal inThe Scarlet Letterof how patriarchy harms its two male protagonists (Dimmesdale and Chillingworth) was the inspiration for Herman Melville's further investigation into these harms inMoby DickandBilly Budd. It argues that it was Melville's love for Hawthorne, never sexually consummated, that explains how Melville was able to investigate the harms patriarchy inflicts on men in deeper ways than Hawthorne, including both the personally and self-destructively political irrational violence of Ahab inMoby Dickand the homophobic violence of Claggart and Vere against Billy inBilly Budd, a boy they both desired and, in Vere's case, loved. [ABSTRACT FROM PUBLISHER]

I present a survey of calculations of the excited $$N^*$$ spectrum in lattice QCD. I then describe recent advances aimed at extracting the momentum-dependent phase shifts from lattice calculations, notably in the meson sector, and the potential for their application to baryons. I conclude with a discussion of calculations of the electromagnetic transition form factors to excited nucleons, including calculations at high $$Q^2$$ . [ABSTRACT FROM AUTHOR]

This article argues that the principle of indivisibility in the relationship between political and administrative elites acted as a central convention of the Westminster system for much of the twentieth century. It explores how in more recent decades this principle has been challenged by the shift to a principal-agent approach. It considers the extent to which this shift diminishes the traditional Westminster model's understanding of the minister-civil servant relationship as one based on a symbiotic interdependent partnership. In its place has emerged a more universal command and control relationship that is seen as necessary to meet the demands of modern accountability and transparency. Such a change has fundamentally altered a long-established power-bargain between ministers and civil servants and undermined a core tenet of the Westminster model. [ABSTRACT FROM AUTHOR]

The user-level failure mitigation (ULFM) interface has been proposed to provide fault-tolerant semantics in the Message Passing Interface (MPI). Previous work presented performance evaluations of ULFM; yet questions related to its programability and applicability, especially to non-trivial, bulk synchronous applications, remain unanswered. In this article, we present our experiences on using ULFM in a case study with a large, highly scalable, bulk synchronous molecular dynamics application to shed light on the advantages and difficulties of this interface to program fault-tolerant MPI applications. We found that, although ULFM is suitable for master–worker applications, it provides few benefits for more common bulk synchronous MPI applications. To address these limitations, we introduce a new, simpler fault-tolerant interface for complex, bulk synchronous MPI programs with better applicability and support than ULFM for application-level recovery mechanisms, such as global rollback. [ABSTRACT FROM AUTHOR]

Background Depression is a common, debilitating, and costly disorder. Many patients request psychological therapy, but the best-evidenced therapy—cognitive behavioural therapy (CBT)—is complex and costly. A simpler therapy—behavioural activation (BA)—might be as effective and cheaper than is CBT. We aimed to establish the clinical efficacy and cost-effectiveness of BA compared with CBT for adults with depression. Methods In this randomised, controlled, non-inferiority trial, we recruited adults aged 18 years or older meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for major depressive disorder from primary care and psychological therapy services in Devon, Durham, and Leeds (UK). We excluded people who were receiving psychological therapy, were alcohol or drug dependent, were acutely suicidal or had attempted suicide in the previous 2 months, or were cognitively impaired, or who had bipolar disorder or psychosis or psychotic symptoms. We randomly assigned participants (1:1) remotely using computer-generated allocation (minimisation used; stratified by depression severity [Patient Health Questionnaire 9 (PHQ-9) score of <19 vs ≥19], antidepressant use, and recruitment site) to BA from junior mental health workers or CBT from psychological therapists. Randomisation done at the Peninsula Clinical Trials Unit was concealed from investigators. Treatment was given open label, but outcome assessors were masked. The primary outcome was depression symptoms according to the PHQ-9 at 12 months. We analysed all those who were randomly allocated and had complete data (modified intention to treat [mITT]) and also all those who were randomly allocated, had complete data, and received at least eight treatment sessions (per protocol [PP]). We analysed safety in the mITT population. The non-inferiority margin was 1·9 PHQ-9 points. This trial is registered with the ISCRTN registry, number ISRCTN27473954. Findings Between Sept 26, 2012, and April 3, 2014, we randomly allocated 221 (50%) participants to BA and 219 (50%) to CBT. 175 (79%) participants were assessable for the primary outcome in the mITT population in the BA group compared with 189 (86%) in the CBT group, whereas 135 (61%) were assessable in the PP population in the BA group compared with 151 (69%) in the CBT group. BA was non-inferior to CBT (mITT: CBT 8·4 PHQ-9 points [SD 7·5], BA 8·4 PHQ-9 points [7·0], mean difference 0·1 PHQ-9 points [95% CI −1·3 to 1·5], p=0·89; PP: CBT 7·9 PHQ-9 points [7·3]; BA 7·8 [6·5], mean difference 0·0 PHQ-9 points [–1·5 to 1·6], p=0·99). Two (1%) non-trial-related deaths (one [1%] multidrug toxicity in the BA group and one [1%] cancer in the CBT group) and 15 depression-related, but not treatment-related, serious adverse events (three in the BA group and 12 in the CBT group) occurred in three [2%] participants in the BA group (two [1%] patients who overdosed and one [1%] who self-harmed) and eight (4%) participants in the CBT group (seven [4%] who overdosed and one [1%] who self-harmed). Interpretation We found that BA, a simpler psychological treatment than CBT, can be delivered by junior mental health workers with less intensive and costly training, with no lesser effect than CBT. Effective psychological therapy for depression can be delivered without the need for costly and highly trained professionals. [ABSTRACT FROM AUTHOR]

Presents a study which used the characteristics of the Henkel plot and the delta-M plot in the interpretation of interaction field effects in barium ferrite coatings. Characteristics of remanence studies; Theoretical framework of magnetic interactions in particulate and quasiparticulate coatings; Description of the measured delta-H plots for in-house fabricated oriented coatings of barium ferrite.

Phagocytosis and receptor-mediated endocytosis are vitally important particle uptake mechanisms in many cell types, ranging fromsingle-cell organisms to immune cells. In both processes, engulfment by the cell depends critically on both particle shape and orientation. However, most previous theoretical work has focused only on spherical particles and hence disregards the wide-ranging particle shapes occurring in nature, such as those of bacteria. Here, by implementing a simple model in one and two dimensions, we compare and contrast receptormediated endocytosis and phagocytosis for a range of biologically relevant shapes, including spheres, ellipsoids, capped cylinders, and hourglasses. We find awhole range of different engulfment behaviors with some ellipsoids engulfing faster than spheres, and that phagocytosis is able to engulf a greater range of target shapes than other types of endocytosis. Further, the 2D model can explain why some nonspherical particles engulf fastest (not at all) when presented to the membrane tip-first (lying flat). Our work reveals how some bacteria may avoid being internalized simply because of their shape, and suggests shapes for optimal drug delivery. [ABSTRACT FROM AUTHOR]

The article discusses issues tackled in an article by Ann Marie Clark and Kathryn Sikkink relating to indicators of government respect for physical integrity rights from the Cingranelli-Richards Human Rights Data Project and the Political Terror Scale index of physical integrity conditions. Topics covered include the role of information in the U.S. State Department Country Reports on Human Rights Practices in a decline in bias in scores on government respect for human rights.

Background: Morita Therapy, a psychological therapy for common mental health problems, is in sharp contrast to established western psychotherapeutic approaches in teaching that undesired symptoms are natural features of human emotion rather than something to control or eliminate. The approach is widely practiced in Japan, but untested and little known in the UK. A clinical trial of Morita Therapy is required to establish the effectiveness of Morita Therapy for a UK population. However, a number of methodological, procedural and clinical uncertainties associated with such a trial first require addressing.Methods/design: The Morita Trial is a mixed methods study addressing the uncertainties associated with an evaluation of Morita Therapy compared with treatment as usual for depression and anxiety. We will undertake a pilot randomised controlled trial with embedded qualitative study. Sixty participants with major depressive disorder, with or without anxiety disorders, will be recruited predominantly from General Practice record searches and randomised to receive Morita Therapy plus treatment as usual or treatment as usual alone. Morita Therapy will be delivered by accredited psychological therapists. We will collect quantitative data on depressive symptoms, general anxiety, attitudes and quality of life at baseline and four month follow-up to inform future sample size calculations; and rates of recruitment, retention and treatment adherence to assess feasibility. We will undertake qualitative interviews in parallel with the trial, to explore people's views of Morita Therapy. We will conduct separate and integrated analyses on the quantitative and qualitative data.Discussion: The outcomes of this study will prepare the ground for the design and conduct of a fully-powered evaluation of Morita Therapy plus treatment as usual versus treatment as usual alone, or inform a conclusion that such a trial is not feasible and/or appropriate. We will obtain a more comprehensive understanding of these issues than would be possible from either a quantitative or qualitative approach alone.Trial Registration: Current Controlled Trials ISRCTN17544090 registered on 23 July 2015. [ABSTRACT FROM AUTHOR]

Recent studies have leveraged MHC tetramer and TCR sequencing approaches towards a more precise characterization of the peripheral T cell repertoire, providing important insight into both the contribution of self-reactive T cells to the overall repertoire and their function. The peripheral T cell repertoire of healthy individuals contains a high frequency of diverse, self-reactive T cells. Furthermore, self-reactive T cells can perform essential beneficial physiological functions. We review these recent findings here, and discuss their implications to the current understanding of peripheral tolerance and the role of self-reactive T cells in autoimmune disease. We outline gaps in understanding, and argue that an important step forward is to revise the definition of self-reactive T cells to incorporate new concepts regarding the nature and physiological functions of different populations of T cells capable of recognizing self-antigens. [ABSTRACT FROM AUTHOR]

Proteins are important targets of chemical disinfectants. To improve the understanding of disinfectant-protein reactions, this study characterized the disinfectant:protein molar ratios at which 50% degradation of oxidizable amino acids (i.e., Met, Tyr, Trp, His, Lys) and structure were observed during HOCl, HOBr, and O3 treatment of three well-characterized model proteins and bacteriophage MS2. A critical question is the extent to which the targeting of amino acids is driven by their disinfectant rate constants rather than their geometrical arrangement. Across the model proteins and bacteriophage MS2 (coat protein), differing widely in structure, methionine was preferentially targeted, forming predominantly methionine sulfoxide. This targeting concurs with its high disinfectant rate constants and supports its hypothesized role as a sacrificial antioxidant. Despite higher HOCl and HOBr rate constants with histidine and lysine than for tyrosine, tyrosine generally was degraded in preference to histidine, and to a lesser extent, lysine. These results concur with the prevalence of geometrical motifs featuring histidines or lysines near tyrosines, facilitating histidine and lysine regeneration upon Cl[+1] transfer from their chloramines to tyrosines. Lysine nitrile formation occurred at or above oxidant doses where 3,5-dihalotyrosine products began to degrade. For O3, which lacks a similar oxidant transfer pathway, histidine, tyrosine, and lysine degradation followed their relative O3 rate constants. Except for its low reactivity with lysine, the O3 doses required to degrade amino acids were as low as or lower than for HOCl or HOBr, indicating its oxidative efficiency. Loss of structure did not correlate with loss of particular amino acids, suggesting the need to characterize the oxidation of specific geometric motifs to understand structural degradation. [ABSTRACT FROM AUTHOR]

This article explores the nature of devolution unfolding in England following on from the September 2014 Scottish Referendum. It argues that the process of devolution can best be understood as one of elite co-option. Limited attention is being paid to the interest of citizens and the nature of the process to date reveals little evidence to suggest that the existing structures of power in the British political system are being challenged. These dynamics are explained through the conceptual lens offered by the British political tradition (BPT), which stresses the importance the Westminster class places on maintaining central power and control in the context of current devolutionary pressures. This is revealed by the absence from the devolutionary agenda of any meaningful, subsidiarity-informed democratic settlement. The article concludes by suggesting that what is unfolding is a process of economic and administrative rather than democratically informed devolution which will do little to arrest the rise of ‘anti-politics’. [ABSTRACT FROM PUBLISHER]

The Washington Accord known as a mutual recognition agreement between national engineering regulatory bodies was signed in 1989 by six founding signatories. Through this mutual recognition agreement the signatories recognize that the formal educational programs accredited by the respective signatories are substantially equivalent. The stated objective of the Washington Accord is to ease the path of engineering graduates to professional registration or licensing in different jurisdictions. Since 1989, the signatories to theWashington Accord has increased threefold with an additional five countries as currently provisional signatories. This rapid expansion is a reflection of the need for international recognition of educational qualifications and competency across borders in an increasingly globalized world. Engineering accreditation bodies, particularly in developing countries, are proactively seeking recognition and mobility of their graduates. Within this context, theWashington Accord celebrates 25 years and charts a course for the next 25 years. This paper examines in detail the position of the U.S. licensing boards on the Washington Accord. It is concluded that with respect to the U.S. licensing boards, the Washington Accord has made only modest inroads in its first 25 years and needs to set a much more ambitious path for the next 25 to achieve truly reciprocal mobility. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) differentiate in the thymus, but the mechanisms that control this process are not fully understood. We generated a comprehensive quantitative and differential proteome of murine Tregs and conventional T cells. We identified 5225 proteins, 164 of which were differentially expressed in Tregs. Together with the comparative analysis of proteome and gene expression data, we identified TCF7 as a promising candidate. Genetic elimination of transcription factor 7 (TCF7) led to increased fractions of Tregs in the thymus. Reduced levels of TCF7, found in the heterozygote, resulted in a greater potential for Treg precursors to differentiate into the Treg lineage. In contrast, activation of TCF7 through β-catenin had the opposite effect. TCF7 levels influenced the required TCR signaling strength of Treg precursors, and TCF7 deficiency broadened the repertoire and allowed lower TCR affinities to be recruited into the Treg lineage. FOXP3 was able to repress TCF7 protein expression. In summary, we propose a regulatory role for TCF7 in limiting access to the Treg lineage. [ABSTRACT FROM AUTHOR]

Geomorphological and biological archives of relative sea-level change in the western North Atlantic-Caribbean region following the Last Glacial Maximum have traditionally supported the hypothesis of a punctuated rise towards the present sea level. Such records, however, are often at insufficient resolution to discern centennial-scale changes. In caves where the water table is closely controlled by sea level, active periods of speleothem growth constraining maximum sea level, used in combination with marine overgrowths constraining minimum sea level, are a promising alternative archive recording sea-level variability at higher resolution. Here, we present a U-Th-dated early–middle Holocene speleothem record from a submerged cave on the tectonically stable Yucatán Peninsula, Mexico. Our record shows that polychaetes (Annelida, Polychaeta) colonised a sub-aerially deposited stalagmite during four individual submergence events. Submergence events occurred at approximately 8.9, 8.6, 8.4 and 6.0 ka, which we attribute to previously unrecognised minor sea-level oscillation events (OE1–OE4) above and below −6.12 ± 0.1 m relative to present sea level (r.s.l.). Combining these results with mangrove-derived relative sea-level constraints from another submerged cave on the Yucatán Peninsula, we are able to suggest that OE1 and OE2 did not reach as high as −5.26 m r.s.l., but that OE3 and OE4 exceeded −5.22 m r.s.l. We conclude that subsidence of the North American ice-load bulge was the main cause of relative sea-level rise. Superimposed on the glacio-isostatic adjustment were periods of widespread northern hemisphere cooling and ice margin re-advance, resulting in a relative sea-level fall on four occasions during the early–middle Holocene. [ABSTRACT FROM AUTHOR]

Individual self-reactive T cells have been discovered in both humans and mice. It is difficult to assess the entire contained selfreactive peripheral T cell repertoire in healthy individuals because regulatory T cells (Tregs) can render these cells anergic and, therefore, functionally indistinguishable. We addressed this issue by removing regulatory T cells, thereby allowing us to characterize the exposed self-reactive T cells. This resulted in activation of approximately 4% of both CD4+ and CD8+ T cells. Activation and division of these cells was not a bystander product of Ag-independent signals but required TCR stimulation. Analysis of TCR sequences showed that these responding cells were polyclonal and encompassed a broad range of structural TCR diversity. Adoptive transfer of naive and effector/memory T cell populations showed that even the naive T cell pool contained selfreactive T cell precursors. In addition, transfer of mature thymocytes showed that this response was an intrinsic T cell property rather than a peripheral adaptation. Finally, we found that the unexpectedly strong contribution of the naive CD5low T cell pool showed that the overall self-reactive response has not only a diverse polyclonal TCR repertoire, but also comprises a broad range of affinities for self. [ABSTRACT FROM AUTHOR]