Licogliflozin versus placebo in women with polycystic ovary syndrome (PCOS): a randomised, double-blind, phase 2 trial.Background: PCOS is the most common endocrinopathy in women of childbearing age. Currently, there is no approved therapy available. The dual sodium-glucose transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. Its effect on androgens is unknown.Methods: In a multi-center, randomised, placebo-controlled, double-blind trial, patients with PCOS type A or B and insulin resistance were randomised to either licogliflozin 50 mg or placebo TID in a 1:1 ratio for two weeks. Change from baseline free testosterone (FT) serum concentrations served as primary outcome. Serum levels of various androgens and parameters of insulin resistance were secondary outcomes and exploratory objectives.Findings: Between October 4, 2017, and June 4, 2018, 29 patients were allocated to licogliflozin or placebo (n: 15 vs. 14). After exclusion per protocol of 5 and 4 patients in the licogliflozin and placebo groups, 10 patients were eligible for analysis in each group. The treatment effect of licogliflozin on FT (primary outcome) did not reach statistical significance (TRLIK066 :TRPCB(FT): 0·88; 90%CI: 0·70-1·11; p=0·353). Licogliflozin improved hyperandrogenaemia with reductions of androstendione (A4) by 19% (TRLIK066:TRPCB(A4): 0·81; 90%CI: 0·68-0·99; p=0·089) and dehydroepiandrosteronsulfate (DHEAS) by 24% (TRLIK066:TRPCB(DHEAS): 0·76; 90%CI: 0·65-0·89; p=0·008). Moreover, hyperinsulinaemia was reduced by 70% in the licogliflozin treatment group (highest insulin concentration (MAXI); TRLIK066:TRPCB(MAXI): 0·26; 90%CI: 0·20-0·34; p<0·001 and area under the curve insulin (AUCI); TRLIK066:TRPCB(AUCI): 0·32; 90%CI: 0·25-0·41; p<0·001). The most common adverse events were diarrhea and nausea without occurrence of serious adverse events.Interpretation: Dual inhibition of SGLT1/2 for two weeks reduced hyperinsulinaemia and as a trend hyperandrogenism in women with PCOS in a phase 2 trial. Licogliflozin may represent a promising novel treatment option for PCOS.Trial Registration: This trial is registered at ClinicalTrials.gov (NCT0315259) and EudraCT (2017-001373-16).Funding Statement: The study is funded by Novartis.Declaration of Interests: PM and MH are employees of Novartis. MZ, NH were employees of Novartis when the study was conducted. SI, DZ, and FW declare no competing interests. AD received honoraria for consultancy from Ablacare, Abbvie, Bayer, and Medtronics and received grant funding from the National Institutes of Health. DF received honoria and/or expenses for invited speeches from Eisai, Ipsen, and Sanofi Genzyme, is member of the advisory board of Eisai, Ipsen, and Sanofi Genzyme, and participated in funded research of Astra Zeneca, Bayer Pharma, Bristol-Myers Squibb, Eiger BioPharmaceuticals, Eli Lilly, Horizon Pharma, Hoffmann-La Roche Ltd, HRA Pharma, Immunovant Sciences GmbH, Incyte Biosciences International Sàrl, Ipsen, Janssen-Cilag GmbH, Lexicon Pharmaceuticals, Madrigal Pharmaceuticals, Novartis and Otsuka Pharmaceutical. JS received honoraria for talks and/or consultancy and/or research funding from Abbott, Astra Zeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb (BMS), GI- Dynamics, Glaxo Smith Kline (GSK), Intarcia, Ipsen, Janssen, LifeScan, Lilly, Merck Sharp Dohme (MSD), MedScape, Mundipharma, Novartis, NovoNordisk, Omniamed, Pfizer, Roche, Sanofi Aventis, Servier, Takeda and Ypsomed. KD participated in funded research of Astra Zeneca, Bayer Pharma, Bristol-Myers Squibb, Eiger BioPharmaceuticals, Eli Lilly, Exelixis, Horizon Pharma, Hoffmann-La Roche Ltd, HRA Pharma, Immunovant Sciences GmbH, Incyte Biosciences International Sàrl, Ipsen, Janssen-Cilag GmbH, Lexicon Pharmaceuticals, Madrigal Pharmaceuticals, Novartis and Otsuka Pharmaceutical. ST received honoria and/or expenses for invited speeches and/or consultancy from Abbott, Boehringer Ingelheim, BSN Medical, Chugai, Eli Lilly, Janssen-Cilag, KWHC, Merck, Nationale Gesundheitsakademie, Nova Biomedical, NovoNordisk, and Sanofi-Aventis, and participated in funded research of Astra Zeneca, Bristol-Myers Squibb, Eiger BioPharmaceuticals, Eli Lilly, Exelixis, Horizon Pharma, Lexicon Pharmaceuticals, Madrigal Pharmaceuticals, Novartis, NovoNordisk, and Incyte Biosciences International Sàrl.Ethics Approval Statement: Ethics approval Germany (University of Duisburg-Essen, University of Freiburg and Charité Research Organisation GmbH): 17-7599-AF; USA: University of Pennsylvania: 827907.
Objectives: Mitral valve regurgitation (MR) of any degree is a common finding in failing hearts and is caused by left ventricular dilatation. However, the impact of MR at time of ventricular assist implantation on outcome is a matter of debate. The aim of this study is to evaluate the influence of pre-implant MR on long-term outcome and to assess changes in MR severity and left ventricular geometry during follow-up.
DeutschDer Umfang der Hegellekture Brechts ist beachtlich: Philosophie der Kunst, der Geschichte, des Rechts, dann auch die Wissenschaft der Logik, in Ausschnitten zwar, doch immer gezielt. Die Hervorhebungen und Randglossen sind in Brechts Nachlass-Bibliothek gut dokumentiert, bisher aber kaum ausgewertet. Hier wird Brechts Lekture der Logik Hegels vorgestellt, dem Umfang nach prasentiert und unter Einbezug von Hinweisen aus Brechts literarischem Werk und seinen theoretischen Grundlagen erlautert. Speziell Hegels Fassung des Widerspruchs fand Brechts Interesse. Die poetische Ikonografie des Philosophen Hegel ist dabei fur Brecht so wichtig wie im Jahrhundert davor fur Heine. Brecht schreibt so auf seine Art eine vielzitierte Tradition in die Moderne fort. EnglishBrecht read a remarkable amount of Hegel: the philosophy of art, history, law, then the science of logic, only in parts, but always targeted. The headings and marginal notes are well documented in the Brecht estate library, but they have rarely been evaluated. This article outlines the extent of Brecht's reading of Hegel's logic and analyses it with the help of references from Brecht's literary work and its theoretical foundations. Specifically, Brecht was interested in Hegel's version of contradiction. The poetic iconography of the philosopher Hegel is as important for Brecht as it was in the previous century for Heine. Writing was Brecht's way of continuing a much-quoted tradition into modernity.
Inhaled nitric oxide (iNO) therapy is an effective treatment of pulmonary hypertension following left ventricular assist device (LVAD) implantation. As iNO may also modulate circulating endothelin-1 (ET-1) and big endothelin following LVAD implantation, we investigated the effects of iNO on ET-1 and big endothelin plasma concentration gradients. In order to assist weaning from cardiopulmonary bypass, iNO was administered to 15 consecutive patients with secondary pulmonary hypertension following implantation of a LVAD. Central venous, pulmonary arterial and arterial ET-1 and big endothelin plasma levels were measured preoperatively, on cardiopulmonary bypass prior to iNO administration, 12, 24 and 48 hours postoperatively, and 72 hours after weaning from iNO. The ET-1 gradients between central venous and pulmonary arterial plasma levels decreased significantly with time, and there was a trend for lower arterial-pulmonary arterial plasma concentration gradients. Big endothelin plasma concentration gradients were not altered significantly. The decrease in ET-1 plasma concentration gradients during and after iNO administration may reflect a restoration of the physiologic balance between the different vascular beds. This provides further evidence that intermittent iNO therapy may modulate ET-1 after LVAD implantation.
Volume of the United States Reports containing the final decisions and opinions of the Supreme Court justices regarding cases between October 5, 1992, and February 19, 1993. Also includes notes regarding the members of the Supreme Court, orders, and other relevant materials. Index starts on page 1303.
To date, donor-specific markers to predict outcome after heart transplantation (HTx) are unknown. Increased procalcitonin (PCT) levels have been found in infectious inflammation with systemic reactions and/or poor organ perfusion but have not been studied in heart donors. We evaluated PCT as a predictor of early graft failure-related mortality after HTx.PCT and C-reactive protein (CRP) serum concentrations were measured in samples collected immediately before pericardium opening from 81 consecutive brain-dead multiple-organ donors. Donors for high-urgency-status recipients (n=2) were excluded from analysis. The remaining donors were retrospectively divided into 2 groups: donors for recipients who died within 30 days after HTx, after an early graft failure (group II, n=8), and all other donors (group I, n=71). No differences in donor and recipient demographic characteristics were found between groups. Areas under the receiver operating characteristic curves for graft failure-related mortality were 0.71 for PCT and 0.64 for CRP. A PCT value >2 ng/mL as a predictor of graft failure-related mortality had a specificity of 95.8% and sensitivity of 50.0%. The odds ratio for graft failure-related mortality for recipients of hearts from donors with PCT levels >2 ng/mL was 22.7 (unadjusted, 95% CI 3.7 to 137.8, P=0.0007) and 43.8 (after adjustment for prespecified potential confounders, 95% CI 1.4 to 1361.0, P=0.031).A PCT level >2 ng/mL in a cardiac donor at the time of explantation appears to predict early graft failure-related mortality.
