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Sökning: WFRF:(Kröger R.)

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1.
  • Kanis, J A, et al. (författare)
  • Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.
  • 2023
  • Ingår i: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. - : Springer Nature. - 1433-2965 .- 0937-941X. ; 34:12, s. 2027-2045
  • Tidskriftsartikel (refereegranskat)abstract
    • A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX.The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD).We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted β-coefficients.A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination.A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.
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  • Vandenput, Liesbeth, 1974, et al. (författare)
  • Update of the fracture risk prediction tool FRAX : a systematic review of potential cohorts and analysis plan
  • 2022
  • Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 33:10, s. 2103-2136
  • Forskningsöversikt (refereegranskat)abstract
    • Summary: We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures.Introduction: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors.Methods: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible.Results: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed.Conclusions: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).
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  • Barosi, G, et al. (författare)
  • Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms : consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
  • 2015
  • Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 29:1, s. 20-26
  • Tidskriftsartikel (refereegranskat)abstract
    • The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.
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  • Moldanova, Jana, et al. (författare)
  • Resonance-Enhanced Detection of Metals in Aerosols using Single Particle Mass Spectrometry
  • 2020
  • Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 20:12, s. 7139-7152
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe resonance effects in laser desorption–ionization (LDI) of particles that substantially increase the sensitivity and selectivity to metals in single-particle mass spectrometry (SPMS). Within the proposed scenario, resonant light absorption by ablated metal atoms increases their ionization rate within a single laser pulse. By choosing the appropriate laser wavelength, the key micronutrients Fe, Zn and Mn can be detected on individual aerosol particles with considerably improved efficiency. These ionization enhancements for metals apply to natural dust and anthropogenic aerosols, both important sources of bioavailable metals to marine environments. Transferring the results into applications, we show that the spectrum of our KrF-excimer laser is in resonance with a major absorption line of iron atoms. To estimate the impact of resonant LDI on the metal detection efficiency in SPMS applications, we performed a field experiment on ambient air with two alternately firing excimer lasers of different wavelengths. Herein, resonant LDI with the KrF-excimer laser (248.3 nm) revealed iron signatures for many more particles of the same aerosol ensemble compared to the more common ArF-excimer laser line of 193.3 nm (nonresonant LDI of iron). Many of the particles that showed iron contents upon resonant LDI were mixtures of sea salt and organic carbon. For nonresonant ionization, iron was exclusively detected in particles with a soot contribution. This suggests that resonant LDI allows a more universal and secure metal detection in SPMS. Moreover, our field study indicates relevant atmospheric iron transport by mixed organic particles, a pathway that might be underestimated in SPMS measurements based on nonresonant LDI. Our findings show a way to improve the detection and source attribution capabilities of SPMS for particle-bound metals, a health-relevant aerosol component and an important source of micronutrients to the surface oceans affecting marine primary productivity.
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  • Paskova, Tanja, et al. (författare)
  • Polar and nonpolar HVPE GaN substrates: impact of doping on the structural, electrical and optical characteristics
  • 2009
  • Ingår i: Physica Status Solidi. C, Current topics in solid state physics. - : Wiley. - 1610-1634 .- 1610-1642. ; 6:2, s. 344-347
  • Tidskriftsartikel (refereegranskat)abstract
    • Polar and nonpolar bulk GaN substrates with low defect density and high structural and optical quality are demonstrated. The effect of doping by silicon, oxygen and iron within moderate doping levels on the properties of the polar GaN substrates was found uncompromised, as confirmed by high resolution X-ray diffraction and low temperature photoluminescence spectroscopy. In contrast, the lattice parameters were affected significantly, which has to be considered in the subsequent homoepitaxial device growth. The boule growth and respectively the nonpolar substrate homogeneity were found to be hampered by the doping, due to surface microcracking and higher impurity incorporation, while n-type undoped nonpolar substrates were demonstrated of superior quality.
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  • Vandenput, Liesbeth, et al. (författare)
  • A meta-analysis of previous falls and subsequent fracture risk in cohort studies
  • 2024
  • Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 35:3, s. 469-494
  • Tidskriftsartikel (refereegranskat)abstract
    • SummaryThe relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm.IntroductionPrevious falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD).MethodsThe resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients.ResultsFalls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33–1.51) and men (HR 1.53, 95% CI 1.41–1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27–1.84) in men vs. HR 1.32 (95% CI 1.20–1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men.ConclusionsA previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.
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  • Zhu, B., et al. (författare)
  • X-ray emission associated with radiative recombination for Pb82+ ions at threshold energies
  • 2022
  • Ingår i: Physical Review A: covering atomic, molecular, and optical physics and quantum information. - 2469-9926 .- 2469-9934. ; 105:5
  • Tidskriftsartikel (refereegranskat)abstract
    • For decelerated bare lead ions at a low beam energy of 10 MeV/u, the x-ray emission associated with radiative recombination (RR) at threshold energies has been studied at the electron cooler of CRYRING@ESR at GSI, Darmstadt. In our experiment, we observed the full x-ray emission pattern by utilizing dedicated x-ray detection chambers installed at 0∘ and 180∘ observation geometry. Most remarkably, no line distortion effects due to delayed emission are present in the well-defined x-ray spectra, spanning a wide range of x-ray energies (from about 5 to 100 keV), which enables us to identify fine-structure resolved Lyman, Balmer, and Paschen x-ray lines along with the RR transitions into the K, L, and M shells of the ions. For comparison with theory, an elaborate theoretical model is established taking into account the initial population distribution via RR for all atomic levels up to Rydberg states with principal quantum number n=165 in combination with time-dependent feeding transitions. Within the statistical accuracy, the experimental data are in very good agreement with the results of rigorous relativistic predictions. Most notably, this comparison sheds light on the contribution of prompt and delayed x-ray emission (up to 70 ns) to the observed x-ray spectra, originating in particular from yrast transitions into inner shells.
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  • Ebbestad, Jan Ove R., 1967-, et al. (författare)
  • Late Ordovician molluscs of the central and eastern Anti-Atlas, Morocco
  • 2019
  • Ingår i: Geological Society Special Publication. - 0305-8719 .- 2041-4927. ; 485
  • Tidskriftsartikel (refereegranskat)abstract
    • More than 30 species of tergomyan, gastropod, bivalve and cephalopod molluscs are described fromthe Late Ordovician of central and eastern Anti-Atlas, Morocco. For the cephalopods this represents the firstsystematically known taxa of the region. Tergomyans and gastropods are most common in the more shalypart of the Lower Ktaoua Formation, while bivalves are more frequent in the sandy part of the Lower Second Bani Formation. A southern Gondwana aspect is evident for the tergomyan, gastropod and bivalve assemblages,sharing many taxa with Bohemia, while no clear signal is present for the cephalopods. The latter reflects insufficientknowledge of the fauna of large parts of these areas. The widely recognized Holopea? antiquata is transferredto the genus Radvanospira gen. nov.; other new gastropod taxa include Allossospira gen. nov.,Tritonophon grandis sp. nov., Radvanospira baniensis sp. nov. and Lophospira latilabra sp. nov. Most ofthe diverse bivalve fauna and the few cephalopods are left in open nomenclature but new taxa include thebivalve Praenucula pojetai sp. nov. and the cephalopods Wadema tattai sp. nov. and Tafadnatoceras tiouririnensegen. et. sp. nov. The Late Ordovician bivalves from Morocco are dominated by pteriomorphs andprotobranchs, inhabiting infaunal, semi-infaunal and epifaunal niches.
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  • Johansson, Helena, 1981, et al. (författare)
  • A meta-analysis of the association of fracture risk and body mass index in women.
  • 2014
  • Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 1523-4681. ; 29:1, s. 223-33
  • Tidskriftsartikel (refereegranskat)abstract
    • Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20-105) years and follow up of 2.2 million person-years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30kg/m(2) ) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non-obese women. Compared to a BMI of 25kg/m(2) , the hazard ratio (HR) for osteoporotic fracture at a BMI of 35kg/m(2) was 0.87 (95% confidence interval [CI], 0.85-0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09-1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored. © 2014 American Society for Bone and Mineral Research.
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  • Kröger, Björn, et al. (författare)
  • Mass concentration of Hirnantian cephalopods from the Siljan District, Sweden; taxonomy, palaeoecology and palaeobiogeographic relationships
  • 2011
  • Ingår i: Fossil Record. - : Pensoft Publishers. - 1435-1943. ; 14:1, s. 35-53
  • Tidskriftsartikel (refereegranskat)abstract
    • The Hirnantian Glisstjarn Formation (Normalograptus persculptus graptolite Biozone) is a succession of limestones and shales onlapping the Katian Boda Limestone in the Siljan District, Sweden. It contains a conspicuous, up to several decimeter thick bed densely packed with bipolarly oriented, orthoconic cephalopod conchs that can reach lengths of more than 120 cm. Conch fragmentation, bioereosion and the generally poor preservation of the conchs indicate time averaging and the conchs are tentatively interpreted as beached, and a result of winnowing. Ten nautiloid species were collected from the Glisstjarn Formation of which five are new: Dawsonoceras gregarium n. sp., Discoceras siljanense n. sp., Isorthoceras dalecarlense n. sp., Retizitteloceras rarum gen. et sp. n., and Transorthoceras osmundsbergense gen. et sp. n. The non-endemic taxa in most cases are known from elsewhere in Baltoscandia, except one species which is known from Siberia, and North America respectively. Proteocerid orthoceridans dominate the association, of which T. osmundsbergense is the predominant species. Oncocerids are diverse but together with tarphycerids very rare. Notable is the lack of many higher taxa, that are typical for other Late Ordovician shallow water depositional settings. Based on the taxonomical composition of the cephalopod mass occurrence it is interpreted as an indicator of eutrophication of the water masses in the area.
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19.
  • Kröger, Björn, et al. (författare)
  • Palaeoecology and palaeogeography of Late Ordovician (Katian–Hirnantian) cephalopods of the Boda Limestone, Siljan district, Sweden
  • 2014
  • Ingår i: Lethaia. - : John Wiley & Sons. - 0024-1164 .- 1502-3931. ; 47:1, s. 15-30
  • Tidskriftsartikel (refereegranskat)abstract
    • The carbonates associated with the Late Ordovician (Katian–Hirnantian) Boda mounds of the Siljan district, Sweden, contain a rich cephalopod fauna. Cephalopodsare rare in the micritic stromatactis facies of the Katian Boda Core Member, but are concentrated together with other molluscs and trilobites in synsedimentary fillings of caves and crevices of the lithified mound limestone. More than 60 cephalopod species are known from these fillings. The assemblage is dominated in richness and abundance by small orthoconic proteoceratids of the genus Isorthoceras and by curved barrandeocerids, and is considerably less endemic than the benthic fauna of the Boda mounds. Similarities are remarkable at the species level with assemblages from elsewhere in Baltica, with Avalonia and south-western Kazakhstan. A genus-level comparison reveals affinities with Laurentia. However, the genus-level similarities are interpreted as reflecting mainly similarities of the depositional environment and of physicochemical conditions. The presence of calcareous algae in the Boda Limestone and maximum hydrostatic septal strength of cephalopods indicate a depositional depth of <100 m, well within the euphotic zone. The dominance and diversity of cephalopods with vertical migrant lifestyle and the absence of actinocerids indicate a cool, nutrient-rich deeper neritic environment. The post-Katian sediments contain a drastically reduced diversity, dominated by orthocerids. The maximum hydrostatic septal strength of the Hirnantian cephalopods and sedimentological features indicate a shallowing during the Hirnantian, but a continuation of high food availability for cephalopods in the water column.
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  • Thurber, Andrew R., et al. (författare)
  • Stable isotope signatures and methane use by New Zealand cold seep benthos
  • 2010
  • Ingår i: MARINE GEOLOGY. - 0025-3227. ; 272:1-4, s. 260-269
  • Tidskriftsartikel (refereegranskat)abstract
    • The carbon isotopic composition of seep faunal tissue represents a time-integrated view of the interaction between biology and the biogeochemical gradients within the environment. Here we provide an initial description of carbon and nitrogen stable isotope signatures of dominant symbiont-bearing megafauna and heterotrophic mega- and macrofauna from 10 methane-seep sites on the continental margin of the North Island of New Zealand (662–1201 m water depth). Isotopic signatures suggest that sulfide oxidation supports symbiont-bearing taxa including solemyid and vesicomyid bivalves, and methanotrophic symbionts are present in the seep mussel Bathymodiolus sp. Multiple species of Frenulata (Siboglinidae) are present and have a range of isotopic values that are indicative of both thiotroph- and methanotroph-based nutrition. Isotopic composition of the tubeworm Lamellibrachia sp. varied by 23.3‰ among individuals although there was no consistent difference among sites. Variation in methane use by heterotrophic fauna appears to reflect the availability of hard vs. soft substrate; macrofauna on hard substrates had high δ13C signatures, reflecting consumption of photosynthetic-derived organic matter. Two unique, biotic assemblages were discovered to be fueled largely by methane: a hard-substrate, multi-phyla sponge-associated community (inhabiting the sponge Pseudosuberites sp.) and a soft-sediment assemblage dominated by ampharetid polychaetes. Isotope signatures yield estimates of 38–100% and 6–100% methane-derived carbon in sponge associates and ampharetid-bed macrofauna, respectively. These estimates are comparable to those made for deeper methane seeps at the Florida Escarpment (3290 m) and Kodiak, Alaska seeps (4445 m). The overall high use of methane as a carbon source by both symbiont-bearing and heterotrophic fauna suggests that New Zealand methane seeps are an ideal model system to study the interaction among metazoans, bacteria, archaea, and their resulting effect on methane cycles.
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  • Virtanen, Jyrki K., et al. (författare)
  • Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish Vitamin D Trial : a randomized controlled trial
  • 2022
  • Ingår i: American Journal of Clinical Nutrition. - : Oxford University Press. - 0002-9165 .- 1938-3207. ; 115:5, s. 1300-1310
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Vitamin D insufficiency is associated with risk of cardiovascular diseases (CVD) and cancer in observational studies, but evidence for benefits with vitamin D supplementation is limited.OBJECTIVES: To investigate the effects of vitamin D3 supplementation on CVD and cancer incidence.DESIGN: The study was a 5-year randomized placebo-controlled trial among 2495 male participants ≥ 60 years and post-menopausal female participants ≥ 65 years from a general Finnish population who were free of prior CVD or cancer. The study had three arms: placebo, 1600 IU/day or 3200 IU/day vitamin D3. Follow-up was by annual study questionnaires and national registry data. A representative sub-cohort of 551 participants had more detailed in-person investigations. The primary endpoints were incident major CVD and invasive cancer. Secondary endpoints included the individual components of the primary CVD endpoint (myocardial infarction, stroke, and CVD mortality), site-specific cancers and cancer death.RESULTS: During the follow-up, there were 41 (4.9%), 42 (5.0%) and 36 (4.3%) major CVD events in the placebo, 1600 IU/d (vs. placebo: hazard ratio (HR), 0.97;95% CI, 0.63,1.49; P = 0.89), and 3200 IU/d (HR, 0.84;95% CI, 0.54,1.31; P = 0.44) arms, respectively. Invasive cancer was diagnosed in 41 (4.9%), 48 (5.8%) and 40 (4.8%) participants in the placebo, 1600 IU/d (HR, 1.14;95% CI, 0.75,1.72; P = 0.55), and 3200 IU/d (HR, 0.95;95% CI, 0.61,1.47; P = 0.81) arms, respectively. There were no significant differences in the secondary endpoints or total mortality. In the sub-cohort, the mean (standard deviation) baseline serum 25-hydroxyvitamin D concentration was 75 (18) nmol/L. After 12 months, the concentrations were 73 (18) nmol/L, 100 (21) nmol/L and 120 (22) nmol/L in the placebo, 1600 IU/d and 3200 IU/d arms, respectively.CONCLUSIONS: Vitamin D3 supplementation did not lower the incidence of major CVD events or invasive cancer among older adults, possibly due to sufficient vitamin D status in most participants at baseline. Clinical Trial Registry number: ClinicalTrials.gov: NCT01463813, https://clinicaltrials.gov/ct2/show/NCT01463813.
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