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Microsegregation in the single crystal superalloy CMSX-4 has been studied using electron probe microanalysis, both in the as-cast condition and after solution heat treatment. In order to establish the solidification path, a statistical treatment of the data is proposed, which is based upon the local value of the quantity Cra -CR=. Using differential scanning calorimetry and by appealing to a database of thermodynamic parameters, it is shown that the solidification path cannot be explained without acknowledging that backdiffusion occurs. Analysis of the microsegregation remaining after progressive heat treatment reveals that the dendritic and interdendritic regions homogenise at different rates, owing to the presence of the eutectic mixture; there is evidence of up-hill diffusion of solutes in the eutectic region during homogenisation. Simple expressions based upon a sinusoidal variation of composition are inadequate for the estimation of homogenisation times. A coupled thermodynamic/kinetic theory is able to explain most of the effects which occur, i.e. incipient melting, enrichment of residual y' by Ta, MO and subsequent 7' dissolution. Although more work needs to be carried out to better establish the thermodynamic and kinetic parameters required by the model, it is at this stage already useful for the assessment of new superalloy compositions and for the design of optimal heat treatments.

Word count: 3313 excluding references ABSTRACT Aims. To systematically investigate causal relationships between circulating lipids and cardiovascular outcomes, using a Mendelian randomization approach.Methods and Results. In the primary analysis, we performed two-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188,577 participants, and genetic associations with cardiovascular outcomes from 367,703 participants in UK Biobank.For LDL-cholesterol, in addition to the expected positive associations with coronary artery disease (CAD) risk (odds ratio per 1 standard deviation increase [OR], 1.45; 95% confidence interval [95%CI] 1.35-1.57) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically-predicted LDLcholesterol with abdominal aortic aneurysm (OR 1.75; 95%CI 1.40-2.17), and aortic valve stenosis (OR 1.46; 95%CI 1.25-1.70). Genetically-predicted triglyceride levels were positively associated with CAD (OR 1.25; 95%CI 1.12-1.40), aortic valve stenosis (OR 1.29; 95%CI 1.04-1.61), and hypertension (OR 1.17; 95%CI 1.07-1.27), but inversely associated with venous thromboembolism (OR 0.79; 95%CI 0.67-0.93). The positive associations of genetically-predicted LDL-cholesterol and triglycerides with heart failure and aortic stenosis appeared to be mediated by CAD. Conclusion.Lowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis, but may increase risk of thromboembolism. KEYWORDSLipids, Cardiovascular disease, Aetiology, Epidemiology, Mendelian randomization 0 2 5 Supplementary Table S3: Estimates (odds ratio per 1 standard deviation increase in lipid fraction and 95% confidence interval) from polygenic multivariable Mendelian randomization analyses for all lipid-related variants. Estimates with p < 0.05 are reported in bold. 0.91 (0.83-1.00) 1.45 (1.35-1.57) 1.25 (1.12-1.40) Ischaemic Cerebrovascular Disease (all) 0.95 (0.86-1.05) 1.14 (1.04-1.24) 0.98 (0.87-1.10) Ischaemic Stroke 0.98 (0.86-1.12) 1.10 (0.98-1.23) 1.03 (0.87-1.20) Transient Ischaemic Attack 0.91 (0.80-1.03) 1.16 (1.04-1.29) 0.94 (0.81-1.10) Haemorrhagic Stroke (all) 0.76 (0.63-0.92) 0.90 (0.76-1.05) 0.78 (0.62-0.98) Intracerebral Haemorrhage 0.65 (0.51-0.82) 0.86 (0.70-1.05) 0.65 (0.49-0.86) Subarachnoid Haemorrhage 0.82 (0.63-1.06) 0.90 (0.72-1.12) 0.85 (0.62-1.17) Aortic Aneurysm (all) 0.79 (0.65-0.96) 1.43 (1.21-1.68) 1.06 (0.84-1.33) Abdominal Aortic Aneurysm 0.65 (0.51-0.85) 1.75 (1.40-2.17) 0.94 (0.68-1.28) Thoracic Aortic An...

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