Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Differential autophosphorylation of CaM kinase II from phasic and tonic smooth muscle tissues

Ca²⁺/calmodulin-dependent protein kinase II (CaM kinase II) is regulated by calcium oscillations, autophosphorylation, and its subunit composition. All four subunit isoforms were detected in gastric fundus and proximal colon smooth muscles by RT-PCR, but only the and isoforms are expressed in myocytes. Relative and message levels were quantitated by real time PCR. CaM kinase II protein and Ca2+/calmodulin-stimulated (total) activity levels are higher in proximal colon smooth muscle lysates than in fundus lysates, but Ca²⁺/calmodulin-independent (autonomous) activity is higher in fundus lysates. CaM kinase II in fundus lysates is relatively unresponsive to Ca²⁺/calmodulin. Alkaline phosphatase decreased CaM kinase II autonomous activity in fundus lysates and restored its responsiveness to Ca²⁺/calmodulin. Acetylcholine (ACh) increased autonomous CaM kinase II activity in fundus and proximal colon smooth muscles in a time- and dose-dependent manner. KN-93 enhanced ACh-induced fundus contractions but inhibited proximal colon contractions. The different properties of CaM kinase II from fundus and proximal colon smooth muscles suggest differential regulation of its autophosphorylation and activity in tonic and phasic gastrointestinal smooth muscles.Jillinda M Lorenz, Marilyn H Riddervold, Elizabeth A Beckett, Salah A Baker and Brian A Perrin

European Union Agencies

This chapter investigates the difficulties which eu agencies face within a union in crisis. The institutional position of autonomous eu regulators has been challenged both in european law and within the coordination demands of a broader european crisis regime. At a deeper level, however, crisis has heightened underlying concerns about the appropriate place of autonomous governance institutions within the broader scheme of democratic politics and government. Similarly, mandate overload finds its counterpart in renewed calls for the enhanced legitimation of agency operation, a phenomenon which itself is claimed to undermine agency functionality. Autonomous agencies find themselves subjects of problems of accountability overload and of reputational risk. Finally, eu agencies are also implicated within a modern epistemological crisis which pitches a technocratic arm of administration against a rising tide of politics

A humanitarian mission in line with human rights? Assessing Sophia, the EU’s naval response to the migration crisis

This article adds to our understanding of the role of norms in the European Union’s (EU) response to the migration crisis by conducting a critical assessment of the EU’s anti-smuggling naval mission “Sophia”. Is Sophia in line with the normative standards the EU has set for itself in its foreign policies? Conducting the analysis in two steps in line with the main criteria of a humanitarian foreign policy model – first exploring Sophia’s launch and then assessing Sophia’s in theatre behaviour – findings suggest that although concerns for migrants at sea mobilised the initial launch of the mission, the mission is not conducted in line with key human rights principles. As the operation mandate is amended and updated with new tasks, and as the EU-NATO in theatre cooperation increases, the EU is moving further away from what one would expect of a humanitarian foreign policy actor