Realising transition pathways for a more electric, low-carbon energy system in the United Kingdom: challenges, insights and opportunities

The United Kingdom has placed itself on a transition towards a low-carbon economy and society, through the imposition of a legally-binding goal aimed at reducing its ‘greenhouse gas’ emissions by 80% by 2050 against a 1990 baseline. A set of three low-carbon, socio-technical transition pathways were developed and analysed via an innovative collaboration between engineers, social scientists and policy analysts. The pathways focus on the power sector, including the potential for increasing use of low-carbon electricity for heating and transport, within the context of critical European Union developments and policies. Their development started from narrative storylines regarding different governance framings, drawing on interviews and workshops with stakeholders and analysis of historical analogies. The quantified UK pathways were named Market Rules, Central Co-ordination and Thousand Flowers; each reflecting a dominant logic of governance arrangements. The aim of the present contribution was to use these pathways to explore what is needed to realise a transition that successfully addresses the so-called energy policy ‘trilemma,’ i.e. the simultaneous delivery of low carbon, secure and affordable energy services. Analytical tools were developed and applied to assess the technical feasibility,social acceptability, and environmental and economic impacts of the pathways. Technological and behavioural developments were examined, alongside appropriate governance structures and regulations for these low-carbon transition pathways, as well as the roles of key energy system ‘actors’ (both large and small). An assessment of the part that could possibly be played by future demand side response was also undertaken in order to understand the factors that drive energy demand and energy-using behaviour, and reflecting growing interest in demand side response for balancing a system with high proportions of renewable generation. A set of interacting and complementary engineering and technoeconomic models or tools were then employed to analyse electricity network infrastructure investment and operational decisions to assist market design and option evaluation. This provided a basis for integrating the analysis within a whole systems framework of electricity system development, together with the evaluation of future economic benefits, costs and uncertainties. Finally, the energy and environmental performance of the different energy mixes were appraised on a‘life-cycle’ basis to determine the greenhouse gas emissions and other ecological or health burdens associated with each of the three transition pathways. Here, the challenges, insights and opportunities that have been identified over the transition towards a low-carbon future in the United Kingdom are described with the purpose of providing a valuable evidence base for developers, policy makers and other stakeholders

The efficacy and mechanism evaluation of treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole (EME-TIPAC): study protocol for a randomised controlled trial

Background: We hypothesise, based upon the findings from our previous trial, that the addition of co-trimoxazole to standard therapy is beneficial to patients with moderate to severe idiopathic pulmonary fibrosis (IPF). We aim to investigate this by assessing unplanned hospitalisation-free survival (defined as time from randomisation to first non-elective hospitalisation, lung transplant or death) and to determine whether any effect relates to changes in infection and/or markers of disease control and neutrophil activity. Methods/design: The EME-TIPAC trial is a double-blind, placebo-controlled, randomised, multicentre clinical trial. A total of 330 symptomatic patients, aged 40 years old or older, with IPF diagnosed by a multidisciplinary team (MDT) according to international guidelines and a FVC ≤ 75% predicted will be enrolled. Patients are randomised equally to receive either two tablets of co-trimoxazole 480 mg or two placebo tablets twice daily over a median treatment period of 27 (range 12–42) months. All patients receive folic acid 5 mg daily whilst on the trial IMP to reduce the risk of bone marrow depression. The primary outcome for the trial is a composite endpoint consisting of the time to death, transplant or first nonelective hospital admission and will be determined from adverse event reporting, hospital databases and the Office of National Statistics with active tracing of patients missing appointments. Secondary outcomes include the individual components of the primary outcome, (1) King’s Brief Interstitial Lung Disease Questionnaire, (2) MRC Dyspnoea Score, (3) EQ5D, (4) spirometry, (5) total lung-diffusing capacity and (6) routine sputum microbiology. Blood will be taken for cell count, biochemistry and analysis of biomarkers including C-reactive protein and markers of disease. The trial will last for 4 years. Recruitment will take place in a network of approximately 40 sites throughout the UK (see Table 1 for a full list of participating sites). We expect recruitment for 30 months, follow-up for 12 months and trial analysis and reporting to take 4 months. Discussion: The trial is designed to test the hypothesis that treating IPF patients with co-trimoxazole will increase the time to death (all causes), lung transplant or first non-elective hospital admission compared to standard care (https://www.nice.org.uk/guidance/cg163), in patients with moderate to severe disease. The mechanistic aims are to investigate the effect on lung microbiota and other measures of infection, markers of epithelial injury and markers of neutrophil activity. Trial registration: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 17464641. Registered on 29 January 2015. Keywords: Idiopathic pulmonary fibrosis, Co-trimoxazole, Forced vital capacity, Mortalit

Counseling versus antidepressant therapy for the treatment of mild to moderate depression in primary care: economic analysis.

OBJECTIVE: To compare the cost-effectiveness of generic psychological therapy (counseling) with routinely prescribed antidepressant drugs in a naturalistic general practice setting for a follow-up period of 12 months. METHODS: Economic analysis alongside a randomized clinical trial with patient preference arm. Comparison of depression-related health service costs at 12 months. Cost-effectiveness analysis of bootstrapped trial data using net monetary benefits and acceptability curves. RESULTS: No significant difference between the mean observed costs of patients randomized to antidepressants or to counseling (342 pounds sterling vs 302 pounds sterling , p = .56 [t test]). If decision makers are not willing to pay more for additional benefits (value placed on extra patient with good outcome, denoted by K, is zero), then we find little difference between the treatment modalities in terms of cost-effectiveness. If decision makers do place value on additional benefit (K > 0 pounds sterling), then the antidepressant group becomes more likely to be cost-effective. This likelihood is in excess of 90% where decision makers are prepared to pay an additional 2,000 pounds sterling or more per additional patient with a good global outcome. The mean values for incremental net monetary benefits (INMB) from antidepressants are substantial for higher values of K (INMB = 406 pounds sterling when K = 2,500 pounds sterling). CONCLUSION: For a small proportion of patients, the counseling intervention (as specified in this trial) is a dominant cost-effective strategy. For a larger proportion of patients, the antidepressant intervention (as specified in this trial) is the dominant cost-effective strategy. For the remaining group of patients, cost-effectiveness depends on the value of K. Since we cannot observe K, acceptability curves are a useful way to inform decision makers

Sheep Updates 2016

This session covers eleven papers from different authors: 1. Forward, Dr Bruce Mullan, Director Sheep Industry Development, Department of Agriculture and Food Western Australia 2. The Australian sheep industry in 2025, Mick Keogh, Australian Farm Institute 3. Decision making in a risky environment, David Cornish, Cornish Consulting 4. Business Transitioning, Michael Chilvers, Nile Tasmania 5. Advisory Boards in WA Agriculture - making life \u27easier\u27 for everyone, Gerry Hinkley, Producer, Tincurrin and Danielle England, Aginnovate 6. Principles of Successful Family Business Succession Strategies, Rosemary Bartle, Succession Planning Facilitator, Rabobank 7. Diversifying the Feedbase...is the grass really greener? Brad Wooldrige, Producer West Arthur, Dr Norm Stantich, Landgate 8. Seasonality of Lamb Supply - Have We Interpreted the price signals? John Young, Farming Systems Analysis Service 9. A comparative analysis ising Gross Margin for grain and sheep enterprises, Ashley Herbert, Farm Management Consultant, Agrarian Management 10. Tri Lamb Focus Program, Jamie Heinrich 11. The Dorper Lamb Story, Graeme Howi

Effect of the CXCR4 antagonist plerixafor on endogenous neutrophil dynamics in the bone marrow, lung and spleen

Treatment with the CXCR4 antagonist, plerixafor (AMD3100), has been proposed for clinical use in patients with WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) syndrome and in pulmonary fibrosis. However, there is controversy with respect to the impact of plerixafor on neutrophil dynamics in the lung, which may affect its safety profile. In this study we investigated the kinetics of endogenous neutrophils by direct imaging, using confocal intravital microscopy in mouse bone marrow, spleen and lungs. Neutrophils are observed increasing their velocity and exiting the bone marrow following plerixafor administration, with a concomitant increase in neutrophil numbers in the blood and spleen, while the marginated pool of neutrophils in the lung microvasculature remained unchanged in terms of numbers and cell velocity. Use of autologous radiolabeled neutrophils and SPECT/CT imaging in healthy volunteers showed that plerixafor did not affect GM-CSF-primed neutrophil entrapment or release in the lungs. Taken together these data suggest that plerixafor causes neutrophil mobilization from the bone marrow but does not impact on lung marginated neutrophil dynamics and thus is unlikely to compromise respiratory host defense both in humans and mice.This work was funded by a grant provided to JP by the Lung Foundation Netherlands (5.2.14.058JO), the NIHR Cambridge Biomedical Research Centre and NIHR Imperial Biomedical Research Centre. ERC and CS’ laboratories receive grant support from the Medical Research Council, Wellcome Trust, NIHR, GlaxoSmithKline, MedImmune Ltd., and Bristol-Myers Squibb. CLC is supported by Bloodwise (12033), CRUK (C36195/A1183) and European Research Council (ERC) (337066). CP is supported by Bloodwise (12033). The Facility for Imaging by Light Microscopy (FILM) at Imperial College London is part-supported by funding from the Wellcome Trust (grant 104931/Z/14/Z) and BBSRC (grant BB/L015129/1). KDF is supported by funding from the Wellcome Trust (201356/Z/16/Z). LMC is supported by core funding from Cancer Research UK (A23983 and A17196)

Cardiovascular adaptation to hypoxia and the role of peripheral resistance.

Systemic vascular pressure in vertebrates is regulated by a range of factors: one key element of control is peripheral resistance in tissue capillary beds. Many aspects of the relationship between central control of vascular flow and peripheral resistance are unclear. An important example of this is the relationship between hypoxic response in individual tissues, and the effect that response has on systemic cardiovascular adaptation to oxygen deprivation. We show here how hypoxic response via the HIF transcription factors in one large vascular bed, that underlying the skin, influences cardiovascular response to hypoxia in mice. We show that the response of the skin to hypoxia feeds back on a wide range of cardiovascular parameters, including heart rate, arterial pressures, and body temperature. These data represent the first demonstration of a dynamic role for oxygen sensing in a peripheral tissue directly modifying cardiovascular response to the challenge of hypoxia

Pulmonary endothelial HIF2α\alpha-arginase axis plays an essential role in the development of hypoxia pulmonary hypertension

This is the author accepted manuscript. The final version is available from the Proceedings of the National Academy of Sciences (PNAS) via https://doi.org/10.1073/pnas.1602978113Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodelling. The hypoxia-inducible transcription factors (HIFs), HIF-1$\alpha$ and HIF-2$\alpha$ are known to contribute to the process of hypoxic pulmonary vascular remodelling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2$\alpha$ is a critical regulator of hypoxia-induced pulmonary arterial hypertension (PAH). The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2$\alpha$ deletion. The RVSP of mice lacking HIF-2$\alpha$ in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic wild type (WT) mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1$\alpha$ exposed to hypoxia. Endothelial HIF-2$\alpha$ deletion also protected mice from hypoxia remodelling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2$\alpha$, likewise attenuated many of the pathophysiological symptoms associated with HPH. We propose a mechanism whereby chronic hypoxia enhances HIF-2$\alpha$ stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2$\alpha$ in regulating the pulmonary vascular response to hypoxia.This study was funded by The Wellcome Trust, Papworth Hospital NIHR Cambridge Biomedical Research Centre

LC-ICP-MS analysis of inositol phosphate isomers in soil offers improved sensitivity and fine‐scale mapping of inositol phosphate distribution

1. Organic forms of phosphorus (P) prevail in soils and their quantification is vital to better understand global biogeochemical cycles. P speciation in soil is commonly assessed by 31P NMR spectroscopy of sodium hydroxide-EDTA (NaOH-EDTA) extracts. 3. A liquid chromatography-inductively coupled plasma-mass spectrometry (LC-ICP-MS) method that employs NaOH-EDTA is described. 3. Comparison with 31P NMR shows that LC-ICP-MS is up to three orders of magnitude more sensitive. It allows measurement in samples as small as 1 mg. We reveal variation of inositol phosphate distribution in Swedish boreal forest soil and identify myo- and scyllo-inositol hexakisphosphates and other isomers including scyllo-inositol pentakisphosphate. 4. Speciation of the major inositol phosphates was not altered by long-term nitrogen fertilization

C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling.

Critical illness is accompanied by the release of large amounts of the anaphylotoxin, C5a. C5a suppresses antimicrobial functions of neutrophils which is associated with adverse outcomes. The signaling pathways that mediate C5a-induced neutrophil dysfunction are incompletely understood. Healthy donor neutrophils exposed to purified C5a demonstrated a prolonged defect (7 hours) in phagocytosis of Staphylococcus aureus. Phosphoproteomic profiling of 2712 phosphoproteins identified persistent C5a signaling and selective impairment of phagosomal protein phosphorylation on exposure to S. aureus. Notable proteins included early endosomal marker ZFYVE16 and V-ATPase proton channel component ATPV1G1. An assay of phagosomal acidification demonstrated C5a-induced impairment of phagosomal acidification, which was recapitulated in neutrophils from critically ill patients. Examination of the C5a-impaired protein phosphorylation indicated a role for the PI3K VPS34 in phagosomal maturation. Inhibition of VPS34 impaired neutrophil phagosomal acidification and killing of S. aureus. This study provides a phosphoproteomic assessment of human neutrophil signaling in response to S. aureus and its disruption by C5a, identifying a defect in phagosomal maturation and mechanisms of immune failure in critical illness.AJTW was a Gates Cambridge Scholar supported by the Gates Cambridge Trust from 2015-2018. ACM is supported by a Clinical Research Career Development Fellowship from the Wellcome Trust (WT 2055214/Z/16/Z). Grants to ACM from the Academy of Medical Sciences and European Society for Intensive Care Medicine supported this work. The study was also supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre (IS-BRC-1215-20001) and the Medical Research Council SHIELD antimicrobial resistance consortium (MR/ N02995X/1