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- Hageman, Steven H. J., et al.
(författare)
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Estimation of recurrent atherosclerotic cardiovascular event risk in patients with established cardiovascular disease : the updated SMART2 algorithm
- 2022
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 43:18, s. 1715-1727
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Tidskriftsartikel (refereegranskat)abstract
- Aims The 10-year risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events in patients with established ASCVD can be estimated with the Secondary Manifestations of ARTerial disease (SMART) risk score, and may help refine clinical management. To broaden generalizability across regions, we updated the existing tool (SMART2 risk score) and recalibrated it with regional incidence rates and assessed its performance in external populations.Methods and results Individuals with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms were included from the Utrecht Cardiovascular Cohort-SMART cohort [n = 8355; 1706 ASCVD events during a median follow-up of 8.2 years (interquartile range 4.2-12.5)] to derive a 10-year risk prediction model for recurrent ASCVD events (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular mortality) using a Fine and Gray competing risk-adjusted model. The model was recalibrated to four regions across Europe, and to Asia (excluding Japan), Japan, Australia, North America, and Latin America using contemporary cohort data from each target region. External validation used data from seven cohorts [Clinical Practice Research Datalink, SWEDEHEART, the international REduction of Atherothrombosis for Continued Health (REACH) Registry, Estonian Biobank, Spanish Biomarkers in Acute Coronary Syndrome and Biomarkers in Acute Myocardial Infarction (BACS/BAMI), the Norwegian COgnitive Impairment After STroke, and Bialystok PLUS/Polaspire] and included 369 044 individuals with established ASCVD of whom 62 807 experienced an ASCVD event. C-statistics ranged from 0.605 [95% confidence interval (CI) 0.547-0.664] in BACS/BAMI to 0.772 (95% CI 0.659-0.886) in REACH Europe high-risk region. The clinical utility of the model was demonstrated across a range of clinically relevant treatment thresholds for intensified treatment options.Conclusion The SMART2 risk score provides an updated, validated tool for the prediction of recurrent ASCVD events in patients with established ASCVD across European and non-European populations. The use of this tool could allow for a more personalized approach to secondary prevention based upon quantitative rather than qualitative estimates of residual risk.
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- Gennemark, Peter, et al.
(författare)
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An oral antisense oligonucleotide for PCSK9 inhibition
- 2021
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:593
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
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- Jonsson, C. E., et al.
(författare)
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High-resolution diatom d18O records from two sub-Arctic high-altitude lakes in the Swedish Scandes
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Ingår i: Journal of Quaternary Science. - 0267-8179 .- 1099-1417.
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Tidskriftsartikel (refereegranskat)abstract
- Waters from high altitude alpine lakes are mainly recharged by meteoric water. Because of seasonal variations in precipitation and temperature, and relatively short hydraulic residence times, most high altitude lakes have lake water isotopic compositions (δ18Olake) that fluctuate due to seasonality in water balance processes. Input from snowmelt, in particular, has a significant role in determining lake water d18O. Here we compare two high resolution δ18Odiatom records from lake sediments in the Swedish Scandes with instrumental data from the last century obtained from nearby meteorological stations. The time period AD 1900 to AD 1990 is characterized by an increase in winter precipitation and high winter/summer precipitation ratios and this is recorded in δ18Odiatom as decreasing trends. Lowest δ18Odiatom values and highest amount of winter precipitation are found around AD 1990 when the winter North Atlantic Oscillation index was above +2. We conclude that for the last 150 years the main factor affecting the δ18Odiatom signal in these sub-Arctic high altitude lakes with short residence times has been changes in amount of winter precipitation and that δ18Odiatom derived from high altitude lakes in the Swedish Scandes can be used as a winter precipitation proxy.
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- Jonsson, Christina E., et al.
(författare)
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High-resolution diatom delta O-18 records, from the last 150 years, reflecting changes in amount of winter precipitation in two sub-Arctic high-altitude lakes in the Swedish Scandes
- 2010
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Ingår i: Journal of Quaternary Science. - : Wiley. - 0267-8179 .- 1099-1417. ; 25:6, s. 918-930
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Tidskriftsartikel (refereegranskat)abstract
- Waters from high-altitude alpine lakes are mainly recharged by meteoric water. Because of seasonal variations in precipitation and temperature and relatively short hydraulic residence times, most high-altitude lakes have lake water isotopic compositions (delta O-18(lake)) that fluctuate due to seasonality in water balance processes. Input from snowmelt, in particular, has a significant role in determining lake water delta O-18. Here we compare two high-resolution delta O-18(diatom) records from lake sediments in the Swedish Scandes with instrumental data from the last century obtained from nearby meteorological stations. The time period AD 1900-1990 is characterised by an increase in winter precipitation and high winter/summer precipitation ratios and this is recorded in delta O-18(diatom) as decreasing trends. Lowest delta O-18(diatom) values and highest amount of winter precipitation are found around AD 1990 when the winter North Atlantic Oscillation index was above +2. We conclude that for the last 150 a the main factor affecting the delta O-18(diatom) signal in these sub-Arctic high-altitude lakes with short residence times has been changes in amount of winter precipitation and that delta O-18(diatom) derived from high-altitude lakes in the Swedish Scandes can be used as a winter precipitation proxy.
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