Objective: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at nearnormal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.Methods: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.Results: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conven-tional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; PϽ.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (PϽ.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. Conclusion:The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning.

Background: Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath's four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results: Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18-20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions: Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10−8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10−11) and 8q12 (minimum p value 1.82×10−11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. “Replication-level” association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

the first physician since Galen to envisage a concept of the unity of tuberculosis and the first physician ever to state that tubercles are always present in its pulmonary form, was born in the county of Suffolk and baptised on 30 July 1637 in the parish of Ribbesford, Worcestershire, where his father, Robert Morton, was minister of Bewdley Chapel from 1635 to 1646. Richard Morton matriculated from Magdalen Hall, Oxford, but moved to New College when Magdalen Hall was absorbed by Magdalen College. He graduated Bachelor of Arts on 30 January 1656, and Master of Arts on 8 July 1659. During the interval he was Chaplain to New College and must have had the opportunity of meeting Sydenham, who held his Fellowship of All Souls until some time around 1661. Shortly afterwards he became Chaplain to the family of Philip Foley of Prestwood, and vicar of the parish of Kinver in Worcestershire. Philip Foley was his cousin, the fourth son of Thomas Foley, ironmaster at Stourbridge, and at various times between 1673 and 1701 Member of Parliament for Bewdley, Stafford and Droitwich. The founder of the family, which Munk describes as 'old and highly respectable', was Richard Foley, a seller of nails, and later a forgemaster, who had settled in Stourbridge in 1627, when he bought the manor of Bedcote from John Sparry. According to Scrivenor's History of the Iron Trade (1841) he had built his splitting mills on drawings of the ironfoundries in Sweden, to which he had gained entrance on the pretence that he was entertaining the workers on his fiddle. The Foley family had such influence in Whig Parliamentary circles during the reign of William and Mary that Sir Edward Harley welcomed the engagement of his son Robert, later first Earl of Oxford, to Philip's niece, Elizabeth. The parish registers of Kinver of between 1659 and 1662 show a distinct handwriting which is certainly Morton's. We know he had left the parish before 1662, evicted as a non-conformist unable to give his 'unfeigned consent and assent' to everything in Laud's Prayer Book, for in the Visitation Book of that month (B/V/1/67) his name is crossed out and 'vacat' is written against the living. In the parish he left a group of dissenters; in the Visitation Book of May, 1663 (B/V/1/71), we read that the churchwarden, Richard Bird, was presented 'for not presenting the names of those as sitt with their hatts on in tyme ofdivine service and sermon, and such as keepe conventicles in Vicaridge House, which is out of repaire, but no minister'. Morton did not forget his parisb; in his will he left £50 to its industrious poor. On 20 December 1670, he was created doctor of medicine at Oxford on the nomination of William, Prince of Orange, and according to Munk settled in practice in Grey-Friars Court, Newgate Street, in the City of London. He was admitted a candidate of the College of Physicians on 20 March 1676, and elected a Fellow on * The Gideon Delaune Lecture, delivered at Apothecaries' Hall on

delivered before the Faculty of the History of Medicine of the Worshipful Society of Apothecaries on I8 November I964.