Expert Statements on the Standard of Care in Critically Ill Adult Patients With Atypical Hemolytic Uremic Syndrome.

A typical hemolytic uremic syndrome (aHUS) presents similarly to thrombotic thrombocytopenic purpura (TTP) and other causes or conditions with thrombotic microangiopathy (TMA), such as disseminated intravascular coagulation or sepsis. Similarity in clinical presentation may hinder diagnosis and optimal treatment selection in the urgent setting in the ICU. However, there is currently no consensus on the diagnosis or treatment of aHUS for ICU specialists. This review aims to summarize available data on the diagnosis and treatment strategies of aHUS in the ICU to enhance the understanding of aHUS diagnosis and outcomes in patients managed in the ICU. To this end, a review of the recent literature (January 2009-March 2016) was performed to select the most relevant articles for ICU physicians. Based on the paucity of adult aHUS cases overall and within the ICU, no specific recommendations could be formally graded for the critical care setting. However, we recognize a core set of skills required by intensivists for diagnosing and managing patients with aHUS: recognizing thrombotic microangiopathies, differentiating aHUS from related conditions, recognizing involvement of other organ systems, understanding the pathophysiology of aHUS, knowing the diagnostic workup and relevant outcomes in critically ill patients with aHUS, and knowing the standard of care for patients with aHUS based on available data and guidelines. In conclusion, managing critically ill patients with aHUS requires basic skills that, in the absence of sufficient data from patients treated within the ICU, can be gleaned from an increasingly relevant literature outside the ICU. More data on critically ill patients with aHUS are needed to validate these conclusions within the ICU setting

Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial

BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia. OBJECTIVES: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B. METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg(-1) ) or s.c. (50-3000 μg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24). RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL(-1) and a maximum mean concentration of 247 μg mL(-1) was measured at the highest dose. CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment

Grounds for engagement: Dissonances and overlaps at the intersection of contemporary civilizations analysis and postcolonial sociology

This article elucidates grounds for engagement between two fields of the social sciences engaged in critique of Eurocentrism: contemporary civilizations analysis and postcolonial sociology. Between the two fields there are both evident dissonances and points of potential dialogue and engagement. The article identifies three areas of high contention: divergent perceptions of essentialism, commitments to transformative politics and evaluations of the paradigm of multiple modernities. Despite extensive theoretical and normative differences, a notional intersection of the two fields is outlined in the form of three conceptual and methodological shifts. The first is a displacement of ideal typology. The second move is the most original. ‘Intercivilizational encounters’ and ‘intracivilizational encounters’ are re-cast as ‘intercivilizational engagement’. The goal is the demarcation of a discrete position based on a strong version of interaction that goes further than the notion of intercivilizational encounters recently re-developed in civilizational analysis. To illustrate potential grounds for engagement on this point, the article reviews the historiography of ‘connected histories’ and the insights of relational historians. Finally, the article urges for a nuanced definition of ‘region’ and deeper appreciation of the multiplicity of regionalisms as a meeting point for both fields of critique of Eurocentrism

Altered gene expression in the brain and liver of female fathead minnows \u3ci\u3ePimephales promelas\u3c/i\u3e Rafinesque exposed to fadrozole

The fathead minnow Pimephales promelas is a small fish species widely used for ecotoxicology research and regulatory testing in North America. This study used a 2000 gene oligonucleotide microarray to evaluate the effects of the aromatase inhibitor, fadrozole, on gene expressionin the liver and brain tissue of exposed females. Reproductive measures, plasma vitellogenin and gene expression data for the brain isoform of aromatase (cytP19B), vitellogenin precursors and transferrin provided evidence supporting the efficacy of the fadrozole exposure. Unsupervised analysis of the microarray results identified 20 genes in brain and 41 in liver as significantly up-regulated and seven genes in brain and around 45 in liver as significantly down-regulated.Differentially expressed geneswere associated with a broad spectrum of biological functions, many with no obvious relationship to aromatase inhibition. However, in brain, fadrozole exposure elicited significant up-regulation of several genes involved in the cholesterol synthesis, suggesting it as a potentially affected pathway.Gene ontologybased analysis of expression changes in liver suggested overall down-regulation of protein biosynthesis. While real-time polymerase chain reaction analyses supported some of the microarray responses, others could not be verified. Overall, results of this study provide a foundation for developing novel hypotheses regarding the system-wide effects of fadrozole, and other chemical stressors with similar modes of action, on fish biology

Concizumab exposure-response modeling in hemophilia A patients

WOS: 000423774100142Baxalta; Biotest; CSL Behring; PfizerPfizer; Sobi; Biogen IdecBiogen; Baxter Healthcare; BayerBayer AG; Novo NordiskNovo Nordisk; Octapharma; RocheRoche Holding; SanofiSanofi-Aventis; Novo Nordisk, A/SNovo NordiskH. Eichler Grant/Research support from: Baxalta, Biotest, CSL Behring, Pfizer, Sobi, P. Angchaisuksiri: None declared, K. Kavakli Speaker Bureau of: Novo Nordisk, A/S, P. Knoebl Consultant for: Novo Nordisk, A/S, J. Windyga Grant/Research support from: Baxalta, Biogen Idec, Baxter Healthcare, Bayer, CSL Behring, Novo Nordisk, Octapharma, Roche, Sanofi, V. Jimenez-Yuste Grant/Research support from: Novo Nordisk, A/S, Consultant for: Novo Nordisk, A/S, U. Friedrich Employee of: Novo Nordisk, A/S, P. Anderson Employee of: Novo Nordisk, A/S, P. Chowdary Grant/Research support from: Baxalta, CSL Behring, Bayer, Sobi, Pfizer, Novo Nordisk, Consultant for: Novo Nordisk, Pfizer, Sobi, Bayer, Shire, CSL Behring, Roche, Baxalta, Biogen, Speaker Bureau of: Novo Nordisk, Pfizer, Sobi, Shire, CSL Behring, Roche, Baxalta