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

Thinking About Power and Schooling Through Educational Theorists

Multiethnic practitioner researchers explore issues of power and schooling in relation to curriculum studies in the South. We discuss how the articulation and examination of issues of power and schooling are illuminated in the eleven key texts of prominent educational thinkers (e.g., Bell, 1992; Foucault, 1977; Freire, 1970/1992; Kozol, 1992; Nussbaum, 2010; Palmer, 1998; Saïd, 1994; Schubert, 2009; Takaki, 1993; Watkins, 2011; Zinn, 1980/2003). We particularly explore how the eleven educational thinkers cultivate critical consciousness through counternarratives to explore issues of power and schooling such as race, gender, class, power, and place to contest the official or metanarrative that often portrays disenfranchised individuals and groups as deficient and inferior. The counternarratives in the eleven key texts help tell silenced and neglected stories of repressions, suppressions, and subjugations that challenge stereotypes of Southern women, Blacks, and other disenfranchised individuals and groups and encourage examination of the forces of slavery, racism, sexism, classism, religious repression, and other forms of oppression on the life curriculum in schools, neighborhoods, and communities in the South.There are six specific purposes to the session. One purpose is to understand multiple theories of power. A second purpose is to engage in power analyses and critiques of pedagogical practices. The third purpose is to engage in power analyses and critiques of institutions in contemporary schooling. The fourth purpose is to engage in power analyses and critiques of policies and contexts in contemporary schooling. The fifth purpose is to explore the contradictions and complexities of competing theories of power

Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by <i>N</i>-retinylidene-<i>N</i>-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (<b>3</b>), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of <i>Abca4</i>^{<i>–/–</i>} mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, <b>43</b>, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%

Bicyclic [3.3.0]-Octahydrocyclopenta[<i>c</i>]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-<i>trans</i> retinol (<b>1</b>) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss associated with geographic atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydro­cyclopenta­[<i>c</i>]­pyrrolo analogue <b>4</b>. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of <b>4</b>, which led to the discovery of standout antagonist <b>33</b>. Analogue <b>33</b> possesses exquisite <i>in vitro</i> RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels <i>in vivo</i> in a robust manner (>90%)

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London