| 1. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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| 2. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Deschasaux, M., et al.
(författare)
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Nutritional quality of food as represented by the FSAm-NPS nutrient profiling system underlying the Nutri-Score label and cancer risk in Europe: Results from the EPIC prospective cohort study
- 2018
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Ingår i: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 15:9
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Tidskriftsartikel (refereegranskat)abstract
- Background Helping consumers make healthier food choices is a key issue for the prevention of cancer and other diseases. In many countries, political authorities are considering the implementation of a simplified labelling system to reflect the nutritional quality of food products. The Nutri-Score, a five-colour nutrition label, is derived from the Nutrient Profiling System of the British Food Standards Agency (modified version) (FSAm-NPS). How the consumption of foods with high/low FSAm-NPS relates to cancer risk has been studied in national/regional cohorts but has not been characterized in diverse European populations. This prospective analysis included 471,495 adults from the European Prospective Investigation into Cancer and Nutrition (EPIC, 1992-2014, median follow-up: 15.3 y), among whom there were 49,794 incident cancer cases (main locations: breast, n = 12,063; prostate, n = 6,745; colon-rectum, n = 5,806). Usual food intakes were assessed with standardized country-specific diet assessment methods. The FSAm-NPS was calculated for each food/beverage using their 100-g content in energy, sugar, saturated fatty acid, sodium, fibres, proteins, and fruits/vegetables/legumes/nuts. The FSAm-NPS scores of all food items usually consumed by a participant were averaged to obtain the individual FSAm-NPS Dietary Index (DI) scores. Multi-adjusted Cox proportional hazards models were computed. A higher FSAm-NPS DI score, reflecting a lower nutritional quality of the food consumed, was associated with a higher risk of total cancer (HRQ5 versus (Q1) = 1.07; 95% CI 1.03-1.10, P-trend < 0.001). Absolute cancer rates in those with high and low (quintiles 5 and 1) FSAm-NPS DI scores were 81.4 and 69.5 cases/10,000 person-years, respectively. Higher FSAm-NPS DI scores were specifically associated with higher risks of cancers of the colon-rectum, upper aerodigestive tract and stomach, lung for men, and liver and postmenopausal breast for women (all P < 0.05). The main study limitation is that it was based on an observational cohort using self-reported dietary data obtained through a single baseline food frequency questionnaire; thus, exposure misclassification and residual confounding cannot be ruled out. In this large multinational European cohort, the consumption of food products with a higher FSAm-NPS score (lower nutritional quality) was associated with a higher risk of cancer. This supports the relevance of the FSAm-NPS as underlying nutrient profiling system for front-of-pack nutrition labels, as well as for other public health nutritional measures.
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| 4. |
- Aoude, Lauren G, et al.
(författare)
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Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma.
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:2, s. 408-408
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Tidskriftsartikel (refereegranskat)abstract
- The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.
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| 5. |
- EL Andaloussi, Samir, et al.
(författare)
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Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo
- 2011
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 39:9, s. 3972-3987
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Tidskriftsartikel (refereegranskat)abstract
- While small interfering RNAs (siRNAs) have been rapidly appreciated to silence genes, efficient and non-toxic vectors for primary cells and for systemic in vivo delivery are lacking. Several siRNA-delivery vehicles, including cell-penetrating peptides (CPPs), have been developed but their utility is often restricted by entrapment following endocytosis. Hence, developing CPPs that promote endosomal escape is a prerequisite for successful siRNA implementation. We here present a novel CPP, PepFect 6 (PF6), comprising the previously reported stearyl-TP10 peptide, having pH titratable trifluoromethylquinoline moieties covalently incorporated to facilitate endosomal release. Stable PF6/siRNA nanoparticles enter entire cell populations and rapidly promote endosomal escape, resulting in robust RNAi responses in various cell types (including primary cells), with minimal associated transcriptomic or proteomic changes. Furthermore, PF6-mediated delivery is independent of cell confluence and, in most cases, not significantly hampered by serum proteins. Finally, these nanoparticles promote strong RNAi responses in different organs following systemic delivery in mice without any associated toxicity. Strikingly, similar knockdown in liver is achieved by PF6/siRNA nanoparticles and siRNA injected by hydrodynamic infusion, a golden standard technique for liver transfection. These results imply that the peptide, in addition to having utility for RNAi screens in vitro, displays therapeutic potential.
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| 6. |
- Flannick, Jason, et al.
(författare)
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
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Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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| 7. |
- Ward, Heather A., et al.
(författare)
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Haem iron intake and risk of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
- 2019
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Ingår i: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 0954-3007 .- 1476-5640. ; 8:73, s. 1122-1132
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding. Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n = 3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available. Results: Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00–1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02–1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case–control subset. Conclusions: Greater haem iron intake may be modestly associated with lung cancer risk.
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| 8. |
- Arguello, Gabriela, 1983, et al.
(författare)
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Ice Management Research and the Arctic Marine Environment
- 2023
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Ingår i: in Basu Bal Abhinayan, Rajput Trisha, Argüello Gabriela, and Langlet David Regulation of Risk: Transport, Trade and Environment in Perspective. - Leiden : Brill. - 9789004518681 ; , s. 63-97
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Bokkapitel (refereegranskat)abstract
- The Arctic Ocean plays a fundamental role in climate regulation. However, the ice is rapidly disappearing, threatening the Arctic Ocean’s capacity to regulate the global climate. Even if State parties to the 2015 Paris Agreement fully implement the Convention, these efforts will most likely not prevent, at least not until mid-century, the ongoing warming of the Arctic Ocean. Novel scientific research advances the possibility of deploying geoengineering techniques to restore Arctic sea ice to its historical levels. Ice management techniques are claimed to be different from traditional solar radiation management (SRM) techniques since the former are regionally constrained and potentially reversible. However, serious concerns have already been raised about these apparently innocuous techniques. Geoengineering elicits a high degree of risk and for this reason, an open public discussion of geoengineering research can no longer wait. This chapter analyses geoengineering research governance with particular emphasis on the Arctic Ocean and novel ice management techniques. There is no comprehensive legal regulation on geoengineering research. The common international policy standpoint appears to be ‘governance before deployment.’ However, we argue that ‘governance before research’ is just as crucial.
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| 9. |
- Argüello Moncayo, Gabriela, 1983, et al.
(författare)
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Deadly bouquets: environmental (in)justice and the cut flower industry
- 2022
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Ingår i: Rachel Carson Center: Silent Springs - Global Histories of Pesticides and Our Toxic World(s).
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Konferensbidrag (refereegranskat)abstract
- The cut flower industry is rapidly expanding in the Global South. Such floriculture industry is not locally consumed but exported to the United States of America, the European Union, the United Kingdom, Russia, and Japan. Taking as an illustrative example the cut flower industry in Ethiopia and Kenya, we analyze the land-grabbing practices of the Global North in the Global South. For this, we map the values of the EU plant health regulatory system and problematize how pest control regulation may exacerbate the health and working conditions of cut flower workers and increase pollution of soil and water sources in producer States. We argue that EU plant health regulation should internalize its detrimental effects on third countries. The first step in this direction is the establishment of maximum residue limits (MRL) for pesticides in plants not destined for consumption. Such a limit should be included in relevant EU legislation.
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| 10. |
- Argüello Moncayo, Gabriela, 1983, et al.
(författare)
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Governing Technological Climate Revolution: Geoengineering Research and the Arctic Marine Environment : Session 4: Regulating Risk in the Marine Environment
- 2021
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Ingår i: Revisiting Trade, Transport, and Marine Law: Risk and Technology in Perspective.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The Arctic Ocean plays a fundamental role in climate regulation. However, Arctic Ocean’ ice is rapidly disappearing, which threatens its capacity to regulate the global climate. Even if State parties to the 2015 Paris Agreement fully implement the convention, these efforts will most likely not prevent, at least until mid-century, the ongoing warming of the Arctic Ocean. Novel scientific research advances the possibility to deploy geoengineering techniques to restore Arctic sea ice to its historical levels. Ice management techniques claim to be different from traditional solar radiation management (SRM) techniques since these are regionally constrained and potentially reversible. However, serious concerns have been raised about these apparently innocuous techniques. Geoengineering elicits high degree of risk and for this reason, an open public discussion of geoengineering research can no longer wait. This chapter analyzes geoengineering research governance with particular emphasis on the Arctic Ocean and novel ice management techniques. There is no comprehensive legal regulation on geoengineering research. The common international policy standpoint appears to be ‘governance before deployment.’ However, we argue that ‘governance before research’ is also required, something that is currently missing.
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| 11. |
- Flannick, Jason, et al.
(författare)
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Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1380-1380
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Tidskriftsartikel (refereegranskat)abstract
- Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1-7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates8-12. We sequenced seven genes for maturity-onset diabetes of the young (MODY) 13 in well-phenotyped population samples14,15 (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.
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| 12. |
- Johansson, Julia M., et al.
(författare)
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The European heat wave of 2018 and its promotion of the ozone climate penalty in southwest Sweden
- 2020
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Ingår i: Boreal Environment Research. - 1239-6095 .- 1797-2469. ; 25, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- The ozone concentration ([O-3]), temperature (T) and vapour pressure deficit (VPD) during the 2018 heat wave (HW) was compared with conditions from 2013-2017. The study included one coastal and two inland sites in southwest Sweden. The positive relationship between [O-3] and T was stronger in 2018. The average daytime T from April-September was higher by 2.0-2.4 degrees C in 2018. The VPD was strongly and positively affected by the 2018 HW. The daytime mean [O-3] was enhanced by 7-12% in 2018. The relationship between hourly daytime [O-3] and T, as well as that between the daily maximum [O-3] and daily maximum T, was steeper in 2018. The stronger promotion of [O-3] by T in 2018 was possibly partly a result of dry conditions causing stomatal closure of vegetation and thus a weaker O-3 sink. If HWs like that in 2018 become more common, they can be expected to promote higher [O-3] and risk larger health and ecosystem effects.
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| 13. |
- Maliqueo, Manuel, et al.
(författare)
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Continuous Administration of a P450 Aromatase Inhibitor Induces Polycystic Ovary Syndrome with a Metabolic and Endocrine Phenotype in Female Rats at Adult Age
- 2013
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 154:1, s. 434-445
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Tidskriftsartikel (refereegranskat)abstract
- Studying the mechanisms for the complex pathogenesis of polycystic ovary syndrome (PCOS) requires animal models with endocrine, reproductive, and metabolic features of the syndrome. Hyperandrogenism seems to be a central factor in PCOS, leading to anovulation and insulin resistance. In female rats, continuous administration of letrozole, a nonsteroidal inhibitor of P450 aromatase, at 400 mu g/d starting before puberty induces hyperandrogenemia and reproductive abnormalities similar to those in women with PCOS. However, despite high circulating testosterone levels, these rats do not develop metabolic abnormalities, perhaps because of their supraphysiological testosterone concentrations or because estrogen synthesis is completely blocked in insulin-sensitive tissues. To test the hypothesis that continuous administration of lower doses of letrozole starting before puberty would result in both metabolic and reproductive phenotypes of PCOS, we performed a 12-wk dose-response study. At 21 d of age, 46 female Wistar rats were divided into two letrozole groups (100 or 200 mu g/d) and a control group (placebo). Both letrozole doses resulted in increased body weight, inguinal fat accumulation, anovulation, larger ovaries with follicular atresia and multiples cysts, endogenous hyperandrogemia, and lower estrogen levels. Moreover, rats that received 200 mu g/d had insulin resistance and enlarged adipocytes in inguinal and mesenteric fat depots, increased circulating levels of LH, decreased levels of FSH, and increased ovarian expression of Cyp17a1 mRNA. Thus, continuous administration of letrozole, 200 mu g/d, to female rats for 90 d starting before puberty results in a PCOS model with reproductive and metabolic features of the syndrome. (Endocrinology 154: 434-445, 2013)
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| 14. |
- Osika, Walter, 1966, et al.
(författare)
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Increasing peripheral artery intima thickness from childhood to seniority
- 2007
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Ingår i: Arteriosclerosis Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 27:3, s. 671-676
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Tidskriftsartikel (refereegranskat)abstract
- Background - Using new, very high-resolution ultrasound biomicroscopy, we examined the thickness of artificial layers of silicone and intima thickness (IT) of radial and anterior tibial arteries in healthy subjects and in patients with vascular disease. Methods and Results - Silicone layers of varying thicknesses and mesenteric artery specimens obtained from 18 patients undergoing colectomy were measured by both ultrasound biomicroscopy (55 MHz) and morphometry. There was high correlation (r > 0.9; P < 0.0001) between IT and intima area versus ultrasound biomicroscopy. In 90 healthy subjects (aged between 10 and 90 years), radial and anterior tibial arterial IT and intima-media thickness were measured, as was carotid intima-media thickness in 56 of these subjects. Age was strongly related with both media thickness and IT of both peripheral arteries. Correlations were found between carotid intima-media thickness and both radial and anterior tibial IT/intima-media thickness (r=0.44 to 0.53; P < 0.0001). The IT-to-lumen diameter ratio increased with age and was larger at all ages in the anterior tibial artery (0.067 +/- 0.034) versus the radial artery (0.036 +/- 0.012; P < 0.0001). A thicker radial intimal layer was found in patients with peripheral artery disease. Conclusion - This study is the first to our knowledge in humans to show the feasibility of measuring IT of the radial and anterior tibial arteries using very high-resolution ultrasound. IT progresses with age, and the IT-to-lumen diameter ratio is largest in the arteries of the foot. Assessment of IT by ultrasound biomicroscopy may aid in detecting early peripheral vascular abnormalities.
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| 15. |
- Trey, Stacy M., et al.
(författare)
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Electron-Beam-Initiated Polymerization of Poly(ethylene glycol)-Based Wood Impregnants
- 2010
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Ingår i: ACS APPL MATER INTERFACES. - : American Chemical Society (ACS). - 1944-8244. ; 2:11, s. 3352-3362
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Tidskriftsartikel (refereegranskat)abstract
- The current study demonstrates that methacrylate and acrylate poly(ethylene glycol) (PEG) functional oligomers can be effectively impregnated into wood blocks and cured efficiently to high conversions without catalyst by e-beam radiation, allowing for less susceptibility to leaching, and favorable properties including higher Brinell hardness values. PEG based monomers were chosen because there is a long history of this water-soluble monomer being able to penetrate the cell wall, thus bulking it and decreasing the uptake of water which further protects the wood from fungal attack. Diacrylate dimethacrylate and dihydroxyl functional PEG of M-v, 550-575 of concentration 0-30, 60 and 100 wt % in water, were vacuum pressure impregnated into Scots Pine blocks of 15 x 25 x 50 mm in an effort to bulk the cell wall. The samples were then irradiated and compared with nonirradiated samples it was shown by IR, DSC that the acrylate polymers were fully cured to much higher conversions than can be reached with conventional methods Leaching studies indicated a much lower amount of oligomer loss from the cured to much higher conversions than can be reached with conventional methods functional PEG indication a high degree of fastening of the polymer in the wood. The Brinell hardness indicated a significant increase in hardness to hardwood levels in the modified samples compared to the samples of hydroxyl functional PEG and uncured vinyl PEC samples, which actually became softer than the untreated Scots Pine. By monitoring the dimensions of the sample it was found by weight percent gain calculations WPC %) that water helps to swell the wood structure and allow better access of the oligomers into the cell wall as this was not observed for methyl methacrylate which is well-cocumented to remain in the lumen. However dimensional stability of the viny ploymer modified blocks when placed in water was not observed to the same extent as PEG.
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| 16. |
- Westerlund, Julia, et al.
(författare)
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Suppression of T-Cell Proliferation by Normal Density Granulocytes Led to CD183 Downregulation and Cytokine Inhibition in T-Cells
- 2022
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Ingår i: Journal of Immunology Research. - : Hindawi Limited. - 2314-7156 .- 2314-8861. ; 2022
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Tidskriftsartikel (refereegranskat)abstract
- Normal density granulocytes (NDGs) can suppress T-cell responses in a similar way as myeloid-derived suppressor cells (MDSCs). In this study, we tested the hypothesis that NDGs from healthy donors preferentially inhibit T helper 1 (Th1) cells and investigated the myeloid-derived suppressive effect in different T-cell populations. We found that NDG-induced suppression of T-cell proliferation was contact dependent, mediated by integrin CD11b, and dependent on NDG-production of reactive oxygen species (ROS). The suppression was rapid and occurred within the first few hours of coculture. The suppression did not influence the CD8 +/CD4 + ratio indicating an equal sensitivity in these populations. We further analyzed the CD4 + T helper subsets and found that NDGs induced a loss of Th1 surface marker, CD183, that was unrelated to ligand-binding to CD183. In addition, we analyzed the Th1, Th2, and Th17 cytokine production and found that all cytokine groups were suppressed when T-cells were incubated with NDGs. We therefore concluded that NDGs do not preferentially suppress Th1-cells. Instead, NDGs generally suppress Th cells and cytotoxic T-cells but specifically downregulate the Th1 marker CD183.
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| 17. |
- Wiviott, Stephen D, et al.
(författare)
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Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.
- 2019
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Ingår i: The New England journal of medicine. - 1533-4406. ; 380:4, s. 347-357
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Tidskriftsartikel (refereegranskat)abstract
- The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).
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