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See detailThe effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.
Cleland, John G. F.; Teerlink, John R.; Senior, Roxy et al

in Lancet (2011), 378(9792), 676-83

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are ... [more ▼]

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. FINDINGS: 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9.7 mL) were recorded, associated with a small reduction in heart rate (up to 2.7 beats per min; p<0.0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0.0026) and end-diastolic volumes (16 mL, p=0.0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. FUNDING: Cytokinetics Inc. [less ▲]

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See detailIncidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study Lancet
Patterson, C.C.; Dahlquist, G.G.; Gyürüs, E. et al

in Lancet (2009), 373(9680), 2027-2033

Background The incidence of type 1 diabetes in children younger than 15 years is increasing. Prediction of future incidence of this disease will enable adequate fund allocation for delivery of care to be ... [more ▼]

Background The incidence of type 1 diabetes in children younger than 15 years is increasing. Prediction of future incidence of this disease will enable adequate fund allocation for delivery of care to be planned. We aimed to establish 15-year incidence trends for childhood type 1 diabetes in European centres, and thereby predict the future burden of childhood diabetes in Europe. Methods 20 population-based EURODIAB registers in 17 countries registered 29 311 new cases of type 1 diabetes, diagnosed in children before their 15th birthday during a 15-year period, 1989–2003. Age-specific log linear rates of increase were estimated in five geographical regions, and used in conjunction with published incidence rates and population projections to predict numbers of new cases throughout Europe in 2005, 2010, 2015, and 2020. Findings Ascertainment was better than 90% in most registers. All but two registers showed significant yearly increases in incidence, ranging from 0·6% to 9·3%. The overall annual increase was 3·9% (95% CI 3·6–4·2), and the increases in the age groups 0–4 years, 5–9 years, and 10–14 years were 5·4% (4·8–6·1), 4·3% (3·8–4·8), and 2·9% (2·5–3·3), respectively. The number of new cases in Europe in 2005 is estimated as 15 000, divided between the 0–4 year, 5–9 year, and 10–14 year age-groups in the ratio 24%, 35%, and 41%, respectively. In 2020, the predicted number of new cases is 24 400, with a doubling in numbers in children younger than 5 years and a more even distribution across age-groups than at present (29%, 37%, and 34%, respectively). Prevalence under age 15 years is predicted to rise from 94 000 in 2005, to 160 000 in 2020. Interpretation If present trends continue, doubling of new cases of type 1 diabetes in European children younger than 5 years is predicted between 2005 and 2020, and prevalent cases younger than 15 years will rise by 70%. Adequate health-care resources to meet these children's needs should be made available. Funding European Community Concerted Action Program. [less ▲]

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See detailVariation and trends in incidence of childhood diabetes in Europe
De Beaufort, Carine UL

in Lancet (2000), 355

BACKGROUND: To study the epidemiology of childhood-onset type 1 insulin-dependent diabetes in Europe, the EURODIAB collaborative group established in 1988 prospective geographically-defined registers of ... [more ▼]

BACKGROUND: To study the epidemiology of childhood-onset type 1 insulin-dependent diabetes in Europe, the EURODIAB collaborative group established in 1988 prospective geographically-defined registers of new cases diagnosed under 15 years of age. This report is based on 16 362 cases registered during the period 1989-94 by 44 centres representing most European countries and Israel and covering a population of about 28 million children. METHODS: Multiple sources of ascertainment were used in most centres to validate the completeness of registration by the capture-recapture method. Trends in incidence during the period were analysed by Poisson regression, the data from centres within each country being pooled. FINDINGS: The standardised average annual incidence rate during the period 1989-94 ranged from 3.2 cases per 100000 per year in the Former Yugoslav Republic of Macedonia to 40.2 cases per 100000 per year in two regions of Finland. By pooling over all centres, the annual rate of increase in incidence was 3.4% (95% CI 2.5-4.4%), but in some central European countries it was more rapid than this. Pooled over centres and sexes, the rates of increase were 6.3% (4.1-8.5%) for children aged 0-4 years, 3.1% (1.5-4.8%) for 5-9 years, and 2.4% (1.0-3.8%) for 10-14 years. INTERPRETATION: The results confirm a very wide range of incidence rates within Europe and show that the increase in incidence during the period varied from country to country. The rapid rate of increase in children aged under 5 years is of particular concern. PMID: 10752702 [PubMed - indexed for MEDLI [less ▲]

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See detailIncidence of childhood-onset insulin-dependent diabetes mellitus: the EURODIAB ACE Study
Green, A.; Patterson, C.C.; Gale, E.A. et al

in Lancet (1992), 339(8798), 905-909

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See detailAcceptability in food of NaCl/KCl mixture.
Neyses, Ludwig UL; Groth, H.; Vetter, W.

in Lancet (1983), 2(8364), 1427-8

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