The centre cannot (always) hold:Examining pathways towards energy system de-centralisation

This is the final version. Available on open access from Elsevier via the DOI in this record'Energy decentralisation' means many things to many people. Among the confusion of definitions and practices that may be characterised as decentralisation, three broad causal narratives are commonly (implicitly or explicitly) invoked. These narratives imply that the process of decentralisation: i) will result in appropriate changes to rules and institutions, ii) will be more democratic and iii) is directly and causally linked to energy system decarbonisation. The principal aim of this paper is to critically examine these narratives. By conceptualising energy decentralisation as a distinct class of sociotechnical transition pathway, we present a comparative analysis of energy decentralisation in Cornwall, South West UK, the French island of Ushant and the National Electricity Market in Australia. We show that, while energy decentralisation is often strongly correlated with institutional change, increasing citizen agency in the energy system, and enhanced environmental performance, these trends cannot be assumed as given. Indeed, some decentralisation pathways may entrench incumbent actors' interests or block rapid decarbonisation. In particular, we show how institutional context is a key determinant of the link between energy decentralisation and normative goals such as democratisation and decarbonisation. While institutional theory suggests that changes in rules and institutions are often incremental and path-dependent, the dense legal and regulatory arrangements that develop around the electricity sector seem particularly resistant to adaptive change. Consequently, policymakers seeking to pursue normative goals such as democratisation or decarbonisation through energy decentralisation need to look beyond technology towards the rules, norms and laws that constitute the energy governance system.Engineering and Physical Sciences Research Council (EPSRC)European Structural and Investment FundINTERREG V FC

Rivaroxaban Compared with Standard Anticoagulants for the Treatment of Acute Venous Thromboembolism in Children: a Randomised, Controlled, Phase 3 Trial

Background: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. Methods: In a multicentre, parallel-group, open-label, randomised study, children (aged 0–17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. Findings: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87–95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29–35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11–1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51–6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. Interpretation: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. Funding: Bayer AG and Janssen Research & Development. © 2020 Elsevier Ltd

Sex Differences in the Behavioral and Neuromolecular Effects of the Rapid-Acting Antidepressant Drug Ketamine in Mice

Over 350 million people currently suffer from Major Depressive Disorder (MDD). This debilitating neuropsychiatric disease is the greatest cause of disability worldwide, and available pharmacotherapeutic treatment options are largely ineffective in many depressed patients. Currently, conventional antidepressants (e.g., selective serotonin reuptake inhibitors; SSRIs and tricyclic antidepressants; TCAs) are only partially effective in managing depressive symptoms in MDD patients. Additionally, currently marketed antidepressant drugs require weeks to alleviate symptomology in depressed patients. Notably, women are twice as likely to be diagnosed with MDD as compared to men, yet until recently most clinical and preclinical studies in this field were conducted in the male sex. Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist is the first rapid-acting antidepressant agent discovered that has the unique ability to relieve depressive symptoms within hours in both MDD patients and in animal models of depression. While earlier studies have determined that this drug has great promise for treating refractory depression, little is still known as to ketamine\u27s putative sex differentiated effects and about its long-term safety. In the context of the current dissertation we explored the sex-differentiated behavioral and neuromolecular effects of antidepressant-relevant doses of ketamine following acute and repeated drug treatment in male and female mice. Specifically, we showed that behavioral responsiveness to ketamine in female mice is not accompanied by the neurochemical and synaptogenic effects that are typically observed in the male brain, and we further exposed a brain region that may be implicated in the sex-differentiated response to this drug. Moreover, we provided the first evidence that repeated ketamine dosing induced beneficial antidepressant-like effects in male mice but was associated with adverse anxiety-like and depressive-like effects in females. Taken together, the research findings pertaining to the current dissertation provide novel insights into the sex-dependent effects of the rapid-acting antidepressant drug ketamine and also suggests that the heightened sensitivity of females to this drug may put them at risk for sex-specific adverse effects following chronic treatment

Sex Differences in the Behavioral and Neuromolecular Effects of the Rapid-Acting Antidepressant Drug Ketamine in Mice

Over 350 million people currently suffer from Major Depressive Disorder (MDD). This debilitating neuropsychiatric disease is the greatest cause of disability worldwide, and available pharmacotherapeutic treatment options are largely ineffective in many depressed patients. Currently, conventional antidepressants (e.g., selective serotonin reuptake inhibitors; SSRIs and tricyclic antidepressants; TCAs) are only partially effective in managing depressive symptoms in MDD patients. Additionally, currently marketed antidepressant drugs require weeks to alleviate symptomology in depressed patients. Notably, women are twice as likely to be diagnosed with MDD as compared to men, yet until recently most clinical and preclinical studies in this field were conducted in the male sex. Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist is the first rapid-acting antidepressant agent discovered that has the unique ability to relieve depressive symptoms within hours in both MDD patients and in animal models of depression. While earlier studies have determined that this drug has great promise for treating refractory depression, little is still known as to ketamine\u27s putative sex differentiated effects and about its long-term safety. In the context of the current dissertation we explored the sex-differentiated behavioral and neuromolecular effects of antidepressant-relevant doses of ketamine following acute and repeated drug treatment in male and female mice. Specifically, we showed that behavioral responsiveness to ketamine in female mice is not accompanied by the neurochemical and synaptogenic effects that are typically observed in the male brain, and we further exposed a brain region that may be implicated in the sex-differentiated response to this drug. Moreover, we provided the first evidence that repeated ketamine dosing induced beneficial antidepressant-like effects in male mice but was associated with adverse anxiety-like and depressive-like effects in females. Taken together, the research findings pertaining to the current dissertation provide novel insights into the sex-dependent effects of the rapid-acting antidepressant drug ketamine and also suggests that the heightened sensitivity of females to this drug may put them at risk for sex-specific adverse effects following chronic treatment

Operative Benefits of Residential Battery Storage for Decarbonizing Energy Systems: A German Case Study

The reduction in PV prices and interest in energy independence accelerate the adoption of residential battery storage. This storage can support various functions of an energy system undergoing decarbonization. In this work, operative benefits of storage from the system perspective, namely, generation cost reduction and congestion mitigation, are investigated. Germany is chosen as a case study due to its strong reliance on variable renewable energy. For the analysis, an economic dispatch model with a high spatial resolution is coupled with a pan-European transmission grid model. It is shown that the system’s generation costs are highest when the assets are used only to maximize PV self-consumption, and the costs are lowest when the storage also reacts to the market dynamics. This amounts to a 6% cost reduction. Both operation strategies result in an equal level of grid congestion and infrastructure loading. This is improved with a strategy that accounts for regional peak reduction as a secondary objective. The high congestion level emphasizes that grid expansion needs to keep pace with the generation and electrification expansion necessary to decarbonize other sectors. Lastly, policymakers should enable multipurpose utilization, e.g., via the introduction of market-oriented retail electricity prices with intervention options for grid operators

A novel role for phospholamban in the thalamic reticular nucleus

Abstract The thalamic reticular nucleus (TRN) is a brain region that influences vital neurobehavioral processes, including executive functioning and the generation of sleep rhythms. TRN dysfunction underlies hyperactivity, attention deficits, and sleep disturbances observed across various neurodevelopmental disorders. A specialized sarco-endoplasmic reticulum calcium (Ca2+) ATPase 2 (SERCA2)-dependent Ca2+ signaling network operates in the dendrites of TRN neurons to regulate their bursting activity. Phospholamban (PLN) is a prominent regulator of SERCA2 with an established role in myocardial Ca2 +-cycling. Our findings suggest that the role of PLN extends beyond the cardiovascular system to impact brain function. Specifically, we found PLN to be expressed in TRN neurons of the adult mouse brain, and utilized global constitutive and innovative conditional genetic knockout mouse models in concert with electroencephalography (EEG)-based somnography and the 5-choice serial reaction time task (5-CSRTT) to investigate the role of PLN in sleep and executive functioning, two complex behaviors that map onto thalamic reticular circuits. The results of the present study indicate that perturbed PLN function in the TRN results in aberrant TRN-dependent phenotypes in mice (i.e., hyperactivity, impulsivity and sleep deficits) and support a novel role for PLN as a critical regulator of SERCA2 in the TRN neurocircuitry