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ImportanceThe clinical utility of polygenic risk scores (PRS) for coronary artery disease (CAD) has not yet been established.ObjectiveTo investigate the ability of a CAD PRS to potentially guide statin initiation in primary prevention after accounting for age and clinical risk.Design, Setting, and ParticipantsThis was a longitudinal cohort study with enrollment starting on January 1, 2006, and ending on December 31, 2010, with data updated to mid-2021, using data from the UK Biobank, a long-term population study of UK citizens. A replication analysis was performed in Biobank Japan. The analysis included all patients without a history of CAD and who were not taking lipid-lowering therapy. Data were analyzed from January 1 to June 30, 2022.ExposuresPolygenic risk for CAD was defined as low (bottom 20%), intermediate, and high (top 20%) using a CAD PRS including 241 genome-wide significant single-nucleotide variations (SNVs). The pooled cohort equations were used to estimate 10-year atherosclerotic cardiovascular disease (ASCVD) risk and classify individuals as low (Main Outcomes and MeasuresMyocardial infarction (MI) and ASCVD events (defined as incident clinical CAD [including MI], stroke, or CV death).ResultsA total of 330 201 patients (median [IQR] age, 57 [40-74] years; 189 107 female individuals [57%]) were included from the UK Biobank. Over the 10-year follow-up, 4454 individuals had an MI. The CAD PRS was significantly associated with the risk of MI in all age groups but had significantly stronger risk prediction at younger ages (age 60 years: HR, 1.42; 95% CI, 1.37-1.48; P for interaction Conclusions and RelevanceResults of this cohort study suggest that the predictive ability of a CAD PRS was greater in younger individuals and can be used to better identify patients with borderline and intermediate clinical risk who should initiate statin therapy.

This chapter explores register in the outer movements of the ‘Eroica’ Symphony. Engaging closely with Schenker’s 1930 analysis, in which the two-line register is understood as the obligate Lage while the three-line octave is treated as essentially decorative or reinforcing, it argues to the contrary, asserting the structural significance of the latter. By paying particular attention to Beethoven’s scoring for the flute, it develops a narrative of registral ‘failure’ in the finale that is in stark contrast to the standard ‘heroic’ readings of this work.

Funder: K.G.A. has received support from the American Heart Association Institute for Precision Cardiovascular Medicine (17IFUNP3384001), a KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from the Harvard Catalyst (KL2 TR002542), and the NIH (1K08HL153937)., Funder: B.N.W is supported by the National Science Foundation Graduate Research Program (DGE 1256260)., Funder: I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School., Funder: I.K., S.Ko., and K.It. are funded by the Japan Agency for Medical Research and Development, AMED, under Grant Numbers JP16ek0109070h0003, JP18kk0205008h0003, JP18kk0205001s0703, JP20km0405209, and JP20ek0109487. The BioBank Japan is supported by AMED under Grant Number JP20km0605001., Funder: J.L.M.B. acknowledges research support from NIH R01HL125863, American Heart Association (A14SFRN20840000), the Swedish Research Council (2018-02529) and Heart Lung Foundation (20170265) and the Foundation Leducq (PlaqueOmics: Novel Roles of Smooth Muscle and Other Matrix Producing Cells in Atherosclerotic Plaque Stability and Rupture, 18CVD02., Funder: P.S.dV was supported by American Heart Association grant number 18CDA34110116 and National Heart, Lung, and Blood Institute grant R01HL146860. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research., Funder: O.G. has received funding from the British Heart Foundation (BHF) (FS/14/66/3129)., Funder: T.K. is supported by the Corona-Foundation (Junior Research Group Translational Cardiovascular Genomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02)., Funder: D.S.A. has received support from a training grant from the NIH (T32HL007604)., Funder: N.P.B., M.C.C., J.F., and D.-K.J. have been funded by the National Institute of Diabetes and Digestive and Kidney Diseases (2UM1DK105554)., Funder: A.V.K. has been funded by 1K08HG010155 from the National Human Genome Research Institute., Funder: C.P.N. and T.R.W received funding from the British Heart Foundation (SP/16/4/32697)., Funder: The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology; and Central Norway Regional Health Authority. Whole genome sequencing for the HUNT study was funded by HL109946., Funder: O.M. was funded by the Swedish Heart- and Lung Foundation, the Swedish Research Council, the European Research Council ERC-AdG-2019-885003 and Lund University Infrastructure grant ”Malmö population-based cohorts” (STYR 2019/2046)., Funder: This work was supported by the European Commission (HEALTH-F2–2013-601456) and the TriPartite Immunometabolism Consortium [TrIC]- NovoNordisk Foundation (NNF15CC0018486), VIAgenomics (SP/19/2/344612), the British Heart Foundation, a Wellcome Trust core award (M.F., H.W., 203141/Z/16/Z) and support from the NIHR Oxford Biomedical Research Centre. M.F. and H.W. are members of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health., Funder: J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator., Funder: J.C.H. acknowledges personal funding from the British Heart Foundation (FS/14/55/30806) and is a member of the Oxford BHF Centre of Research Excellence (RE/13/1/30181)., Funder: R.C. has received funding from the British Heart Foundation and British Heart Foundation Centre of Research Excellence., Funder: This research was supported by BHF (SP/13/2/30111) and conducted using the UK Biobank Resource (application number 9922)., Funder: The GerMIFs gratefully acknowledge the support of the Bavarian State Ministry of Health and Care, furthermore founded this work within its framework of DigiMed Bayern (grant No: DMB-1805-0001), the German Federal Ministry of Education and Research (BMBF) within the framework of ERA-NET on Cardiovascular Disease (Druggable-MI-genes: 01KL1802), within the scheme of target validation (BlockCAD: 16GW0198K), within the framework of the e:Med research and funding concept (AbCD-Net: 01ZX1706C), the British Heart Foundation (BHF)/German Centre of Cardiovascular Research (DZHK)-collaboration (VIAgenomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02) and the Sonderforschungsbereich SFB TRR 267 (B05)., Funder: C.J.W. is funded by NIH grant R35-HL135824., Funder: This work was supported by the British Heart Foundation (BHF) grant RG/14/5/30893 (P.D.) and forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR)., The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

For more than thirty years, Schenker scholarship has been challenged by Schenker’s apparent repudiation, in ‘Der Geist der musikalischen Technik’ (1895), of the possibility of organicism in music. The present article seeks to reconsider the issue—and particularly the shift from Geist’ to the much more organically-charged thinking of Harmonielehre (1906)—by introducing an unpublished and unexamined essay by Schenker: ‘Der Weg zum Gleichniss’ (‘The Path to Likeness’). It is argued that this undated essay, which draws heavily upon examples from Beethoven’s piano sonatas, was written between ‘Geist’ and Harmonielehre, and is intimately related to the latter text while it yet explicitly repeats the earlier essay’s position on organicism. Despite this, ‘Der Weg zum Gleichniss’ asserts that in music ‘a new art was established artificially, as it were a distinct, second, artificial and higher nature’, and that nature herself was ‘elevated’ through music’s ability to be created in its own likeness rather than in a likeness to nature, as is the case for the other arts. Likenesses are primarily purely musical (essentially, they are motivic imitations), though these, once established, can be supplemented by the ‘second, secondary likeness of the poetic’, namely programmatic likeness. An investigation of possible sources for Schenker’s unusual use of the word Gleichnis leads forward to his 1933 newspaper article ‘Was wird aus der Musik?’ and back as far as the Old Testament.

It is testament to the current security of music theory and analysis within the academy that recent years have witnessed a trio of substantial publications that, while augmenting the music-analytical literature on the ‘Bach to Brahms (and beyond)’ repertoire, more particularly celebrate – and, in two cases, capture – the pedagogical legacy of three scholars (my title honours a fourth ), two now deceased, another two centrally concerned with Schenkerian theory. Explorations in Schenkerian Analysis is a Gedenkschrift for Edward Laufer, who died in 2014. Its fifteen chapters reach from Bach (the C major Prelude noch einmal) to Debussy; Laufer, whose reluctance to publish restricted his principal influence to those he directly taught, is present only in the form of an interview from 2003. That same year saw the death of David Lewin, described by Richard Cohn as ‘the most original and far-ranging theorist of his generation’. And Cohn provides the introduction to David Lewin’s Morgengruß, the first publication of the text of a 1974 Yale graduate lecture that had been circulating informally ever since. Although Lewin’s approach is by no means exclusively Schenkerian, he straightforwardly acknowledges the role of Schenkerian theory in aspects of that approach; meanwhile, the Preface to Explorations records that ‘a projected volume on the teaching of Schenkerian analysis’ was a large-scale casualty of Laufer’s death.