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OBJECTIVES: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components. DESIGN: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup (n = 46), recorded d-dimer (n = 967), comparing males with females. SETTING: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces. PATIENTS: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation (p = 0.006) and vasopressors (p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females. CONCLUSIONS: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19.

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose-bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.

Background:Patients with peripheral arterial disease (PAD) are at increased risk of cardiovascular morbidity and mortality. Medical prevention with antithrombotic and statin therapies is a mainstay of treatment to prevent adverse outcomes; nevertheless, patients with PAD are often undertreated. This study describes the temporal changes in medical prevention and adverse outcomes in a national cohort of patients with symptomatic PAD after revascularization.Methods:We identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark, from 2000 to 2016. We examined temporal changes in the use of aspirin, clopidogrel, and statins and 1-year cause-specific hazard ratios for adverse clinical outcomes, after adjusting for procedure type, treatment indication, age, sex, and cardiovascular risk factors. The analyses were performed overall and within strata of index procedure (endovascular versus surgical), treatment indication, age, sex, and high-risk comorbidities.Results:Between 2000 and 2016, we identified 32 911 patients who underwent revascularization for symptomatic PAD. The mean age was 69 years and increased over time, as did the burden of comorbidity. The cumulative incidence of medication use increased between 2000 to 2004 and 2013 to 2016, respectively, from 57.3% to 64.3% for aspirin, 3.6% to 24.8% for clopidogrel, and 36.2% to 77.1% for statins. Concurrently, the 1-year outcome rates declined. Compared with 2000 to 2004, the adjusted hazard ratios in 2013 to 2016 were 0.73 (95% CI, 0.62-0.84) for major adverse cardiovascular events, 0.92 (95% CI, 0.85-1.00) for major adverse limb events, 0.60 (95% CI, 0.48-0.74) for myocardial infarction, 0.94 (95% CI, 0.75-1.18) for ischemic stroke, 0.92 (95% CI, 0.75-1.12) for major bleeding, 0.54 (95% CI, 0.39-0.76) for cardiovascular death, and 0.80 (95% CI, 0.72-0.88) for all-cause death. These improvements in prognosis were most prominent from 2000 to 2004 to 2005 to 2008 and occurred in all strata of index procedure, treatment indication, sex, age, and comorbidity. In contrast, the adjusted hazard ratio for major amputations was 1.00 (95% CI, 0.90-1.11) when comparing 2013 to 2016 to 2000 to 2004.Conclusions:Medical prevention of adverse events has increased considerably over time in patients who underwent revascularization for symptomatic PAD. This increase was accompanied by reductions in all adverse outcomes, except major amputations.

Venice, where all that is cheerful and bright, free and light, has only served as a face for a life that is dark, violent and unrelentingly functional, the city's decline has left behind a merely lifeless stage-set, the mendacious beauty of the mask. --Georg Simmel, "Venice" What place better sums up the paradox of "a matter of lifedeath" than the city of Venice, depicted in Andreas Pichler's 2012 documentary, The Venice Syndrome, as already well on its way to becoming a veritable ghost town in the next fifteen years? "Venice" is a fluid construct, its identity determined by the medium in question. Whether in painting, literature, photography, or film, however, Venice figures consistently as one of Europe's strangest cities. For centuries a major Mediterranean power, the centre of a vast maritime empire, Venice is now a simulacrum of its former self, slowly sinking beneath the combined burden of mass tourism and global warming. The city tends to be represented in literature and film especially as a mercurial, enigmatic, paradoxical, and infinitely mutable urban space. It is at once a labyrinth of narrow stone streets, canals, and bridges; a network of picturesque piazze; one of Italy's most famous beachfronts (the Lido); a grouping of small islands in a large lagoon; a romantic vacation destination; a living theatre; a sinister necropolis; a place to live and a place in which to die--or rather, in which to witness life and death at one remove, intermingled and, at times, even indistinguishable. In what follows I will discuss Visconti's Death in Venice in relation to Sebald's first prose work, Vertigo. Both book and film, in radically different ways, exemplify the productive impurity of intermedial adaptation at the root of which is a certain idea of "Venice." I hope to show how in each of these works Venice is not only setting or backdrop to the action, but emerges as a location uniquely suited to bring the protagonist, the specific (masculine) subject, into a life-changing confrontation with death. The cinematic norms that came to dominance in the Classical Hollywood period guaranteed the triumph of individual bodies and faces on screens around the world, leaving to the novel the exploration of more discursively variegated, dialogized modalities of subjectivity. To refer to the nineteenth century as the age of the novel and the twentieth as that of cinema is to overlook the rich mutual interpenetration from which each modality has benefited since the invention of the cinematograph in the 1890s. It is a critical commonplace that the nineteenth-century realist novel concerns itself with the verbal representation of psychological interiority as much as an objective, documentarist representation of bourgeois society. As Stephen Prince argues, the poststructuralist deconstruction of novelistic mimesis need not necessarily be extended to the reproduction of "profilmic reality" in cinema (87). Film, like photography, emphasizes exteriority: the visible externality of things as they exist in space and through time. The temptation to invoke psychoanalytic tropes in this context is countered by the recognition of their failure to address the radical exteriorization of subjective interiority constitutive of film as a medium. Even the postwar art cinema that arose out of Italian neorealism and the French New Wave, in reacting against the conventions of mid-century American narrative film, had to negotiate the challenges of suggesting the protagonist's interiority through the audio-visual capturing and arranging of the images of a set of pro-filmic objects. At this point the literary and filmic representation or mediation of "reality" are absolutely distinct. It is nevertheless possible today to identify many points of intersection and intermedial influence between narrative film and the novel. Among these, the most significant and contentious, historically, is the subject, which, like the nebulous concept of "story," is arguably one of the few things that carries over in the process of translation or adaptation from one medium to another. …

Sepsis is a major growing global burden and a major challenge to intensive care clinicians, researchers, guideline committee members and policy makers, because of its high and increasing incidence and great pathophysiological, molecular, genetic and clinical complexity. In spite of recent progress, short-term mortality remains high and there is growing evidence of long-term morbidity and increased long-term mortality in survivors of sepsis both in developed and developing countries. Further improvement in the care of patients with sepsis will impact upon global health. In this narrative review, invited experts describe the expected challenges and progress to be made in the near future. We focus on diagnosis, resuscitation (fluids, vasopressors, inotropes, blood transfusion and hemodynamic targets) and infection (antibiotics and infection biomarkers), as these areas are key, if initial management and subsequent outcomes are to be improved in patients with sepsis. © 2016, Springer-Verlag Berlin Heidelberg and ESICM.

Le film The Matrix n’est pas une allégorie Baudrillardienne, comme certains critiques l’ont suggéré, mais plutôt une oeuvre qui repose sur des prémisses ontologiques et épistémologiques tout à fait non postmodernes. L’auteur offre une interprétation du film qui révèle la thématique de la lecture ou du déchiffrement des codes du réel en tant que processus de ré-écriture des règles qui organisent une fausse «réalité». Cette tâche de déchiffrage, entreprise par le protagoniste, traduit une recherche de soi; un soi qui a toujours été là, quelque part.

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p

The role of AT1 and AT2 receptors in mediating the drinking response induced by angiotensin II in the rat was examined. Angiotensin II (0.1-1.0 mg/kg s.c.) caused a dose-dependent increase in drinking in water-replete rats. The angiotensin Il-induced drinking response was dose dependently blocked by the selective AT1 receptor antagonist DuP 753 (1-30 mg/kg s.c.). In contrast, the selective AT2 receptor antagonist WL 19 failed to block angiotensin II-induced drinking up to doses of 100 mg/kg s.c. and significantly enhanced the response at 3 and 100 mg/kg. These data suggest that drinking induced by angiotensin II is mediated by AT1 receptors and that AT2 receptor activation may inhibit the drinking response.

Background:\ud \ud Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear.\ud Objective\ud \ud This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF.\ud Methods:\ud \ud Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique.\ud Results:\ud \ud The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 ± 8 ms; 52 cells, 18 patients vs 233 ± 7 ms; 134 cells, 49 patients; P 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P Conclusion:\ud \ud LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF.