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Abstract: With the increasing number of patients with diabetes, and with the increasing complexity of care, managing the care of patients in a co-ordinated effective and efficient way is an increasing challenge. Data linkage of health-care databases using a single patient identifier has enabled us to establish a comprehensive patient management system. Originally developed as a research programme (DARTS) looking at epidemiology and patient outcomes, it is now a patient management system acting as a common repository of clinical information for all health-care professionals involved ion the care of patients with diabetes. This has aided the sharing of clinical information, improving communication and enhancing the efficiency of patient care. This system is now being rolled out across Scotland as a National diabetes clinical system. [Copyright &y& Elsevier]

Tayside is a region in the East of Scotland and forms one of nine local government regions in the country. It is home to approximately 416,000 individuals who fall under the National Health Service (NHS) Tayside health board, which provides health care services to the population. In Tayside, Scotland, a comprehensive informatics network for diabetes care and research has been established for over 25 years. This has expanded more recently to a comprehensive Scotland-wide clinical care system, Scottish Care Information - Diabetes (SCI-Diabetes). This has enabled improved diabetes screening and integrated management of diabetic retinopathy, neuropathy, nephropathy, cardiovascular health, and other comorbidities. The regional health informatics network links all of these specialized services with comprehensive laboratory testing, prescribing records, general practitioner records, and hospitalization records. Not only do patients benefit from the seamless interconnectedness of these data, but also the Tayside bioresource has enabled considerable research opportunities and the creation of biobanks. In this article we describe how health informatics has been used to improve care of people with diabetes in Tayside and Scotland and, through anonymized data linkage, our understanding of the phenotypic and genotypic etiology of diabetes and associated complications and comorbidities. [ABSTRACT FROM AUTHOR]

Objective: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post‐RI and compare effectiveness of common management strategies. Design: Retrospective, multicentre and observational study. Patients: Adult patients with Graves' disease treated with RI with 12 months' follow‐up. Measurements: Euthyroidism was defined as both serum thyrotropin (thyroid‐stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo‐ and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4. Results: Of 812 patients studied post‐RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post‐RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%–28.7%). No negative outcomes (new‐onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres. Conclusions: Dysthyroidism in the 12 months post‐RI was common. Differences between post‐RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to determine the extent of drug interactions affecting levothyroxine, using study drugs often co-administered to patients on long-term levothyroxine therapy. Design A retrospective population analysis linking biochemistry and prescription data between 1 January 1993 and 31 December 2012 was used. Patients The study population was Tayside residents prescribed levothyroxine on at least three occasions, within a six-month period, prior to the start of a study drug. Individuals acted as their own controls pre- and postinitiation of study drug. Overall, 10 999 patients (mean age 58 years, 82% female) being treated with thyroxine were included in the study. Measurements Changes in TSH following initiation of study drug. Results Iron, calcium, proton pump inhibitors and oestrogen all increased serum TSH concentration: an increase of 0·22 mU/l ( P < 0.001), 0·27 mU/l ( P < 0·001), 0·12 mU/l ( P < 0·01), and 0·08 mU/l ( P < 0·007), respectively. For these four study drugs, there was a clinically significant increase of over 5 mU/l in serum TSH, in 7·5%, 4·4%, 5·6% and 4·3% patients, respectively. There was a decrease of 0·17 mU/l ( P-value 0.01) in the TSH concentration for those patients on statins. The TSH decreased by 5 mU/l in 3·7% of patients. There was no effect with H2 receptor antagonists or glucocorticoids. Conclusion This large population-based study demonstrates significant interaction between levothyroxine and iron, calcium, proton pump inhibitors, statins and oestrogens. These drugs may reduce the effectiveness of levothyroxine, and patients' TSH concentrations should be carefully monitored. [ABSTRACT FROM AUTHOR]

Aims. To compare different packages of care across care providers in Scotland on foot-related outcomes. Methods. A retrospective cohort study with primary and secondary care electronic health records from the Scottish Diabetes Registry, including 6,845 people with type 2 diabetes and a first foot ulcer occurring between 2013 and 2017. We assessed the association between exposure to care processes and major lower extremity amputation and death. Proportional hazards were used for time-to-event univariate and multivariate analyses, adjusting for case-mix characteristics and care processes. Results were expressed in terms of hazard ratios with 95% confidence intervals. Results. 2,243 (32.7%) subjects had a major amputation or death. Exposure to all nine care processes at all ages (HR = 0.63 ; 95% CI: 0.58-0.69; p <.001) and higher foot care attendance in people aged >70 years (HR = 0.88 ; 0.78-0.99; p =.03) were associated with longer major amputation-free survival. Waiting time ≥ 12 weeks between ulceration and clinic attendance was associated with worse outcomes (HR = 1.59 ; 1.37-1.84; p <.001). In people > 70 years, minor amputations were associated with improved major amputation-free survival (HR = 0.69 ; 0.52-0.92; p =.01). Conclusions. Strict adherence to a standardised package of general diabetes care before foot ulceration, timely foot care after ulceration, and specific treatment pathways were associated with longer major amputation-free survival among a large cohort of people with type 2 diabetes in Scotland, with a larger impact on older age groups. [ABSTRACT FROM AUTHOR]

An 18-year-old man who underwent bilateral pinning of his hip joints after a left unstable Slipped Capital Femoral Epiphysis (right pinned prophylactically) was noted to have delayed secondary sexual characteristics and post-operative diabetes insipidus. The patient also described a history of fatigue, headache and polydipsia for the past 4 years. Endocrine investigations revealed reduced androgen levels, hypocortisolism, a borderline normal Serum ACE and secondary hypothyroidism. Magnetic Resonance Imaging of the pituitary gland identified an enhancing mass and a thickened stalk which trans-nasal endoscopic biopsy found to be necrotic with pus. Histology confirmed a diagnosis of Xanthomatous Hypophysitis, an inflammatory condition likely related to a partial rupture of a Rathke cleft cyst. The patient was subsequently commenced on Androgen, Thyroxine, Desmopressin and Hydrocortisone therapy with on-going endocrine follow-up. Although endocrine dysfunction & hypogonadism has been recognised to be a risk factor for SCFE at an atypically older age, due to reduced androgen levels leading to a weakened physeal plate, this is the first known case of a Xanthomatous Hypophysitis resulting in pituitary dysfunction and eventual SCFE. This case highlights that an increased range of pituitary disorders should be considered in late presentations of SCFE; and vice versa the risk of SCFE should be considered in patients with prolonged hypogonadotropic hypogonadism. [ABSTRACT FROM AUTHOR]

Objective: To describe incidence of foot ulceration and amputation-free survival associated with foot ulceration status in a national population-based cohort study of people with diabetes.Research Design and Methods: The study population included 233,459 people with diabetes who were alive in Scotland on 1 January 2012 identified from the national population-based register (national prevalence 4.9%). Characteristics of patients identified from linked hospital and mortality records during follow-up to the end of November 2017 were compared by outcome. Cox regression was used to assess the association between history of foot ulcer and amputation-free survival.Results: The population included 23,395 people with type 1 diabetes and 210,064 people with type 2 diabetes. In total there were 13,093 (5.6%) people who had a previous foot ulceration, 9,023 people who developed a first ulcer, 48,995 who died, and 2,866 who underwent minor or major amputation during follow-up. Overall incidence of first-time foot ulcers was 7.8 per 1,000 person-years (95% CI7.6-7.9) and 11.2 (11.0-11.4) for any ulcer. Risk factors for reduced amputation-free survival included social deprivation, mental illness, and being underweight in addition to conventional cardiovascular risk factors. Adjusted hazard ratios (95% CI) were 2.09 (1.89-2.31) for type 1 diabetes and 1.65 (1.60-1.70) for type 2 diabetes.Conclusions: The overall incidence of foot ulceration in a population-based study of people with diabetes was 11.2 per 1,000 person-years. Foot ulceration is associated with lower amputation-free survival rate, a potential measure of effectiveness of care among people with diabetes. Mental illness and social deprivation are also highlighted as risk factors. [ABSTRACT FROM AUTHOR]

Background: National guidelines in most countries set screening intervals for diabetic retinopathy (DR) that are insufficiently informed by contemporary incidence rates. This has unspecified implications for interval disease risks (IDs) of referable DR, disparities in ID between groups or individuals, time spent in referable state before screening (sojourn time), and workload. We explored the effect of various screening schedules on these outcomes and developed an open-access interactive policy tool informed by contemporary DR incidence rates.Methods and Findings: Scottish Diabetic Retinopathy Screening Programme data from 1 January 2007 to 31 December 2016 were linked to diabetes registry data. This yielded 128,606 screening examinations in people with type 1 diabetes (T1D) and 1,384,360 examinations in people with type 2 diabetes (T2D). Among those with T1D, 47% of those without and 44% of those with referable DR were female, mean diabetes duration was 21 and 23 years, respectively, and mean age was 26 and 24 years, respectively. Among those with T2D, 44% of those without and 42% of those with referable DR were female, mean diabetes duration was 9 and 14 years, respectively, and mean age was 58 and 52 years, respectively. Individual probability of developing referable DR was estimated using a generalised linear model and was used to calculate the intervals needed to achieve various IDs across prior grade strata, or at the individual level, and the resultant workload and sojourn time. The current policy in Scotland-screening people with no or mild disease annually and moderate disease every 6 months-yielded large differences in ID by prior grade (13.2%, 3.6%, and 0.6% annually for moderate, mild, and no prior DR strata, respectively, in T1D) and diabetes type (2.4% in T1D and 0.6% in T2D overall). Maintaining these overall risks but equalising risk across prior grade strata would require extremely short intervals in those with moderate DR (1-2 months) and very long intervals in those with no prior DR (35-47 months), with little change in workload or average sojourn time. Changing to intervals of 12, 9, and 3 months in T1D and to 24, 9, and 3 months in T2D for no, mild, and moderate DR strata, respectively, would substantially reduce disparity in ID across strata and between diabetes types whilst reducing workload by 26% and increasing sojourn time by 2.3 months. Including clinical risk factor data gave a small but significant increment in prediction of referable DR beyond grade (increase in C-statistic of 0.013 in T1D and 0.016 in T2D, both p < 0.001). However, using this model to derive personalised intervals did not have substantial workload or sojourn time benefits over stratum-specific intervals. The main limitation is that the results are pertinent only to countries that share broadly similar rates of retinal disease and risk factor distributions to Scotland.Conclusions: Changing current policies could reduce disparities in ID and achieve substantial reductions in workload within the range of IDs likely to be deemed acceptable. Our tool should facilitate more rational policy setting for screening. [ABSTRACT FROM AUTHOR]

Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea ( SU)-induced hypoglycaemia ( SH) are inconsistent. Recent studies showed that variants in the P450 oxidoreductase ( POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1770 patients were included in the analysis of SU efficacy, assessed as the combined outcome of the HbA1c reduction and the prescribed SU daily dose. Sixty-nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia ( OR, 2.81; 95% CI, 1.30-6.09; P = .009) and better response to SU treatment (β, −0.218; SE, 0.074; P = .003) only in patients carrying the POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment. [ABSTRACT FROM AUTHOR]

Objective To estimate the prevalence and incidence of hyperprolactinaemia. Hyperprolactinaemia is a common problem in endocrine practice, but its epidemiology has not been accurately established. Study design A population-based retrospective follow-up study in Tayside, Scotland (population 400,000), from 1993 to 2013. Patients Record linkage technology (biochemistry, prescribing, hospital admissions, radiology, mortality and maternity data) was used to identify all patients with a serum prolactin measurement. From these, cases were defined as those with a prolactin greater than 1000 mU/L (47·2 ng/ml) or at least three prescriptions for a dopamine agonist. Measurements Number of prevalent and incident cases of hyperprolactinaemia per calendar year by age, sex and cause of hyperprolactinaemia. Results A total of 32289 patients had a serum prolactin assay undertaken, of which 1301 had hyperprolactinaemia not related to pregnancy: 25·6% patients had pituitary disorder, 45·9% were drug-induced, 7·5% had macroprolactin and 6·1% had hypothyroidism, leaving 15·0% idiopathic. Over the 20 years, there was a fourfold increase in the number of prolactin assays performed, and prevalence of hyperprolactinaemia was initially 0·02%, but rose to 0·23% by 2013. Overall incidence was 13·8 cases per 100000 person-years (20·6 in 2008-13) and was 3·5 times higher in women than in men. The highest rates were found in women aged 25-44 years. Drug-induced causes tripled during the 20 years. Conclusions Rising prevalence of hyperprolactinaemia is probably due to an increased ascertainment and increased incidence of psychoactive drug-related causes. Rates are higher in women than in men but only before the age of 65 years. [ABSTRACT FROM AUTHOR]

The management of primary hypothyroidism with levothyroxine (L-T4) is simple, effective and safe, and most patients report improved well-being on initiation of treatment. However, a proportion of individuals continue to suffer with symptoms despite achieving adequate biochemical correction. The management of such individuals has been the subject of controversy and of considerable public interest. The American Thyroid Association ( ATA) and the European Thyroid Association ( ETA) have recently published guidelines on the diagnosis and management of hypothyroidism. These guidelines have been based on extensive reviews of the medical literature and include sections on the role of combination therapy with L-T4 and liothyronine (L-T3) in individuals who are persistently dissatisfied with L-T4 therapy. This position statement by the British Thyroid Association ( BTA) summarises the key points in these guidelines and makes recommendations on the management of primary hypothyroidism based on the current literature, review of the published positions of the ETA and ATA, and in line with best principles of good medical practice. The statement is endorsed by the Association of Clinical Biochemistry, ( ACB), British Thyroid Foundation, ( BTF), Royal College of Physicians ( RCP) and Society for Endocrinology ( SFE). [ABSTRACT FROM AUTHOR]

IMPORTANCE Type 1 diabetes has historically been associated with a significant reduction in life expectancy. Major advances in treatment of type 1 diabetes have occurred in the past 3 decades. Contemporary estimates of the effect of type 1 diabetes on life expectancy are needed. OBJECTIVE To examine current life expectancy in people with and without type 1 diabetes in Scotland. We also examined whether any loss of life expectancy in patients with type 1 diabetes is confined to those who develop kidney disease. DESIGN. SETTING. AND PARTICIPANTS Prospective cohort of all individuals alive in Scotland with type 1 diabetes who were aged 20 years or older from 2008 through 2010 and were in a nationwide register (n=24 691 contributing 67 712 person-years and 1043 deaths). MAIN OUTCOMES AND MEASURES Differences in life expectancy between those with and those without type 1 diabetes and the percentage of the difference due to various causes. RESULTS Life expectancy at an attained age of 20 years was an additional 46.2 years among men with type 1 diabetes and 57.3 years among men without it, an estimated loss in life expectancy with diabetes of 11.1 years (95% Cl, 10.1-12.1). Life expectancy from age 20 years was an additional 48.1 years among women with type 1 diabetes and 61.0 years among women without it, an estimated loss with diabetes of 12.9 years (95% Cl, 11.7-14.1). Even among those with type 1 diabetes with an estimated glomerular filtration rate of 90 mL/min/1.73 m² or higher, life expectancy was reduced (49.0 years in men, 53.1 years in women) giving an estimated loss from age 20 years of 8.3 years (95% Cl, 6.5-10.1) for men and 7.9 years (95% Cl, 5.5-10.3) for women. Overall, the largest percentage of the estimated loss in life expectancy was related to ischemic heart disease (36% in men, 31% in women) but death from diabetic coma or ketoacidosis was associated with the largest percentage of the estimated loss occurring before age 50 years (29.4% in men, 21.7% in women). CONCLUSIONS AND RELEVANCE Estimated life expectancy for patients with type 1 diabetes in Scotland based on data from 2008 through 2010 indicated an estimated loss of life expectancy at age 20 years of approximately 11 years for men and 13 years for women compared with the general population without type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background/aims Retinal screening programmes in England and Scotland have similar photographic grading schemes for background (non-proliferative) and proliferative diabetic retinopathy, but diverge over maculopathy. We looked for the most cost-effective method of identifying diabetic macular oedema from retinal photographs including the role of automated grading and optical coherence tomography, a technology that directly visualises oedema. Methods Patients from seven UK centres were recruited. The following features in at least one eye were required for enrolment: microaneurysms/dot haemorrhages or blot haemorrhages within one disc diameter, or exudates within one or two disc diameters of the centre of the macula. Subjects had optical coherence tomography and digital photography. Manual and automated grading schemes were evaluated. Costs and QALYs were modelled using microsimulation techniques. Results 3540 patients were recruited, 3170 were analysed. For diabetic macular oedema, England's scheme had a sensitivity of 72.6% and specificity of 66.8%; Scotland's had a sensitivity of 59.5% and specificity of 79.0%. When applying a ceiling ratio of £30 000 per quality adjusted life years (QALY) gained, Scotland's scheme was preferred. Assuming automated grading could be implemented without increasing grading costs, automation produced a greater number of QALYS for a lower cost than England's scheme, but was not cost effective, at the study's operating point, compared with Scotland's. The addition of optical coherence tomography, to each scheme, resulted in cost savings without reducing health benefits. Conclusions Retinal screening programmes in the UK should reconsider the screening pathway to make best use of existing and new technologies. [ABSTRACT FROM AUTHOR]

Background: Findings from cardiovascular outcome trials suggest that fenofibrate therapy may reduce the progression of diabetic retinopathy., Methods: We recruited and followed adults with nonreferable diabetic retinopathy or maculopathy using the national Diabetic Eye Screening (DES) program in Scotland. We randomly assigned participants to receive 145-mg fenofibrate tablets or placebo (taken daily or, in those with impaired renal function, on alternate days). The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy (based on Scotland's DES grading scheme) or treatment (intravitreal injection, retinal laser, vitrectomy) for retinopathy or maculopathy., Results: A total of 1151 participants were randomly assigned to treatment. During a median of 4.0 years, progression to referable diabetic retinopathy or maculopathy, or treatment thereof, occurred in 131 (22.7%) of 576 participants in the fenofibrate group and 168 (29.2%) of 575 in the placebo group (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.91; P=0.006). In the fenofibrate group compared with the placebo group, the frequencies for any progression of retinopathy or maculopathy were 185 (32.1%) vs. 231 (40.2%); hazard ratio, 0.74; 95% CI, 0.61 to 0.90 and for the development of macular edema were 22 (3.8%) vs. 43 (7.5%); hazard ratio, 0.50; 95% CI, 0.30 to 0.84. Seventeen (3.0%) participants assigned fenofibrate and 28 (4.9%) assigned placebo were given treatment for retinopathy (hazard ratio, 0.58; 95% CI, 0.31 to 1.06). There was no effect on visual function, quality of life, or visual acuity. Trial-averaged estimated glomerular filtration rate was 7.9 (95% CI, 6.8 to 9.1) ml/min/1.73 m 2 lower in participants in the fenofibrate group compared with the placebo group. Serious adverse events occurred in 208 (36.1%) participants allocated fenofibrate and 204 (35.5%) participants allocated placebo., Conclusions: Fenofibrate reduced progression of diabetic retinopathy compared with placebo among participants with early retinal changes. (Funded by the National Institute for Health and Care Research; ClinicalTrials.gov number, NCT03439345; ISRCTN number, ISRCTN15073006.).

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases., (© 2024. The Author(s).)

Context: Previous studies, including our own, have demonstrated a highly variable incidence of primary hyperparathyroidism (PHPT) from year to year., Objective: We planned to provide a current estimate of the incidence and prevalence of PHPT in a community-based study., Methods: A population-based retrospective follow-up study was conducted in Tayside (Scotland) from 2007 to 2018. Record-linkage technology (demography, biochemistry, prescribing, hospital admissions, radiology, and mortality data) was used to identify all patients. Cases of PHPT were defined as those with at least 2 raised serum corrected calcium concentration CCA (> 2.55 mmol/L) and/or hospital admissions with PHPT diagnoses and/or surgery records with parathyroidectomy during the follow-up period. The number of prevalent and incident cases of PHPT per calendar year by age and sex were estimated., Results: A total of 2118 people (72.3% female, mean age 65 years) were identified with an incident case of PHPT. The overall prevalence of PHPT over the 12 years of the study was 0.84% (95% CI, 0.68%-1.02%), steadily increasing from 0.71% in 2007 to 1.02% in 2018. From 2008, the incidence of PHPT was relatively stable from 4 to 6 cases per 10 000 person-years, declining from 11.5 per 10 000 person-years in 2007. The incidence varied from 0.59 per 10 000 person-years (95% CI, 0.40%-0.77%) for those aged 20 to 29 years, to 12.4 per 10 000 person-years (95% CI, 11.2%-13.3%) in those aged 70 to 79 years. Incidence of PHPT was 2.5 times higher in women than in men., Conclusion: This study is the first showing a relatively steady annual incidence of PHPT at 4 to 6 per 10 000 person-years. This population-based study reports a PHPT prevalence of 0.84%., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Primary hyperparathyroidism (PHPT) is associated with increased risk of morbidity and death, and vitamin D levels are a potentially confounding variable., Objective: The aim of this study was to assess morbidity and mortality associated with primary hyperparathyroidism (PHPT)., Methods: In this population-based retrospective matched cohort study, data linkage of biochemistry, hospital admissions, prescribing, imaging, pathology, and deaths was used to identify patients across the region of Tayside, Scotland, who had PHPT from 1997 to 2019. Cox proportional hazards models and hazards ratios (HR) were used to explore the relationship between exposure to PHPT and several clinical outcomes. Comparisons were made with an age- and gender-matched cohort., Results: In 11 616 people with PHPT (66.8% female), with a mean follow-up period of 8.8 years, there was an adjusted HR of death of 2.05 (95% CI, 1.97-2.13) for those exposed to PHPT. There was also an increased risk of cardiovascular disease (HR = 1.34; 95% CI, 1.24-1.45), cerebrovascular disease (HR = 1.29; 95% CI, 1.15-1.45), diabetes (HR = 1.39; 95% CI, 1.26-1.54), renal stones (HR = 3.02; 95% CI, 2.19-4.17) and osteoporosis (HR = 1.31; 95% CI, 1.16-1.49). Following adjustment for serum vitamin D concentrations (n = 2748), increased risks for death, diabetes, renal stones, and osteoporosis persisted, but not for cardiovascular or cerebrovascular disease., Conclusion: In a large population-based study, PHPT was associated with death, diabetes, renal stones, and osteoporosis, independent of serum vitamin D concentration., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: A hypothesis-free genetic association analysis has not been reported for patients with primary hyperparathyroidism (PHPT)., Objective: We aimed to investigate genetic associations with PHPT using both genome-wide association study (GWAS) and candidate gene approaches., Methods: A cross-sectional study was conducted among patients of European White ethnicity recruited in Tayside (Scotland, UK). Electronic medical records were used to identify PHPT cases and controls, and linked to genetic biobank data. Genetic associations were performed by logistic regression models and odds ratios (ORs). The combined effect of the genotypes was researched by genetic risk score (GRS) analysis., Results: We identified 15 622 individuals for the GWAS that yielded 34 top single-nucleotide variations (formerly single-nucleotide polymorphisms), and LPAR3-rs147672681 reached genome-wide statistical significance (P = 1.2e-08). Using a more restricted PHPT definition, 8722 individuals with data on the GWAS-identified loci were found. Age- and sex-adjusted ORs for the effect alleles of SOX9-rs11656269, SLITRK5-rs185436526, and BCDIN3D-AS1-rs2045094 showed statistically significant increased risks (P < 1.5e-03). GRS analysis of 5482 individuals showed an OR of 2.51 (P = 1.6e-04), 3.78 (P = 4.0e-08), and 7.71 (P = 5.3e-17) for the second, third, and fourth quartiles, respectively, compared to the first, and there was a statistically significant linear trend across quartiles (P < 1.0e-04). Results were similar when stratifying by sex., Conclusion: Using genetic loci discovered in a GWAS of PHPT carried out in a Scottish population, this study suggests new evidence for the involvement of genetic variants at SOX9, SLITRK5, LPAR3, and BCDIN3D-AS1. It also suggests that male and female carriers of greater numbers of PHPT-risk alleles both have a statistically significant increased risk of PHPT., Competing Interests: Conflict of Interest: The authors declare that there are no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: The Scottish Diabetes Research Network (SDRN)-diabetes research platform was established to combine disparate electronic health record data into research-ready linked datasets for diabetes research in Scotland. The resultant cohort, 'The SDRN-National Diabetes Dataset (SDRN-NDS)', has many uses, for example, understanding healthcare burden and socioeconomic trends in disease incidence and prevalence, observational pharmacoepidemiology studies and building prediction tools to support clinical decision making., Participants: We estimate that >99% of those diagnosed with diabetes nationwide are captured into the research platform. Between 2006 and mid-2020, the cohort comprised 472 648 people alive with diabetes at any point in whom there were 4 million person-years of follow-up. Of the cohort, 88.1% had type 2 diabetes, 8.8% type 1 diabetes and 3.1% had other types (eg, secondary diabetes). Data are captured from all key clinical encounters for diabetes-related care, including diabetes clinic, primary care and podiatry and comprise clinical history and measurements with linkage to blood results, microbiology, prescribed and dispensed drug and devices, retinopathy screening, outpatient, day case and inpatient episodes, birth outcomes, cancer registry, renal registry and causes of death., Findings to Date: There have been >50 publications using the SDRN-NDS. Examples of recent key findings include analysis of the incidence and relative risks for COVID-19 infection, drug safety of insulin glargine and SGLT2 inhibitors, life expectancy estimates, evaluation of the impact of flash monitors on glycaemic control and diabetic ketoacidosis and time trend analysis showing that diabetic ketoacidosis (DKA) remains a major cause of death under age 50 years. The findings have been used to guide national diabetes strategy and influence national and international guidelines., Future Plans: The comprehensive SDRN-NDS will continue to be used in future studies of diabetes epidemiology in the Scottish population. It will continue to be updated at least annually, with new data sources linked as they become available., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Patients with diabetes have an increased risk of dementia. Improved prediction of dementia is an important goal in developing future prevention strategies. Diabetic retinopathy screening (DRS) photographs may be a convenient source of imaging biomarkers of brain health. We therefore investigated the association of retinal vascular measures (RVMs) from DRS photographs in patients with type 2 diabetes with dementia risk., Research Design and Methods: RVMs were obtained from 6,111 patients in the GoDARTS bioresource (635 incident cases) using VAMPIRE software. Their association, independent of Apo E4 genotype and clinical parameters, was determined for incident all cause dementia (ACD) and separately Alzheimer's disease (AD) and vascular dementia (VD). We used Cox's proportional hazards with competing risk of death without dementia. The potential value of RVMs to increase the accuracy of risk prediction was evaluated., Results: Increased retinal arteriolar fractal dimension associated with increased risk of ACD (csHR 1.17; 1.08-1.26) and AD (HR 1.33; 1.16-1.52), whereas increased venular fractal dimension (FDV) was associated with reduced risk of AD (csHR 0.85; 0.74-0.96). Conversely, FDV was associated with increased risk of VD (csHR 1.22; 1.07-1.40). Wider arteriolar calibre was associated with a reduced risk of ACD (csHR 0.9; 0.83-0.98) and wider venular calibre was associated with a reduced risk of AD (csHR 0.87; 0.78-0.97). Accounting for competing risk did not substantially alter these findings. RVMs significantly increased the accuracy of prediction., Conclusions: Conventional DRS photographs could enhance stratifying patients with diabetes at increased risk of dementia facilitating the development of future prevention strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Doney, Nar, Huang, Trucco, MacGillivray, Connelly, Leese and McKay.)

Aims/hypothesis: We assessed the real-world effect of flash monitor (FM) usage on HbA 1c levels and diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH) rates among people with type 1 diabetes in Scotland and across sociodemographic strata within this population., Methods: This study was retrospective, observational and registry based. Using the national diabetes registry, 14,682 individuals using an FM at any point between 2014 and mid-2020 were identified. Within-person change from baseline in HbA 1c following FM initiation was modelled using linear mixed models accounting for within-person pre-exposure trajectory. DKA and SHH events were captured through linkage to hospital admission and mortality data. The difference in DKA and SHH rates between FM-exposed and -unexposed person-time was assessed among users, using generalised linear mixed models with a Poisson likelihood. In a sensitivity analysis, we tested whether changes in these outcomes were seen in an age-, sex- and baseline HbA 1c -matched sample of non-users over the same time period., Results: Prevalence of ever-FM use was 45.9% by mid-2020, with large variations by age and socioeconomic status: 64.3% among children aged <13 years vs 32.7% among those aged ≥65 years; and 54.4% vs 36.2% in the least-deprived vs most-deprived quintile. Overall, the median (IQR) within-person change in HbA 1c in the year following FM initiation was -2.5 (-9.0, 2.5) mmol/mol (-0.2 [-0.8, 0.2]%). The change varied widely by pre-usage HbA 1c : -15.5 (-31.0, -4.0) mmol/mol (-1.4 [-2.8, -0.4]%) in those with HbA 1c  > 84 mmol/mol [9.8%] and 1.0 (-2.0, 5.5) mmol/mol (0.1 [-0.2, 0.5]%) in those with HbA 1c  < 54 mmol/mol (7.1%); the corresponding estimated fold change (95% CI) was 0.77 (0.76, 0.78) and 1.08 (1.07, 1.09). Significant reductions in HbA 1c were found in all age bands, sexes and socioeconomic strata, and regardless of prior/current pump use, completion of a diabetes education programme or early FM adoption. Variation between the strata of these factors beyond that driven by differing HbA 1c at baseline was slight. No change in HbA 1c in matched non-users was observed in the same time period (median [IQR] within-person change = 0.5 [-5.0, 5.5] mmol/mol [0.0 (-0.5, 0.5)%]). DKA rates decreased after FM initiation overall and in all strata apart from the adolescents. Estimated overall reduction in DKA event rates (rate ratio) was 0.59 [95% credible interval (CrI) 0.53, 0.64]) after FM vs before FM initiation, accounting for pre-exposure trend. Finally, among those at higher risk for SHH, estimated reduction in event rates was rate ratio 0.25 (95%CrI 0.20, 0.32) after FM vs before FM initiation., Conclusions/interpretation: FM initiation is associated with clinically important reductions in HbA 1c and striking reduction in DKA rate. Increasing uptake among the socioeconomically disadvantaged offers considerable potential for tightening the current socioeconomic disparities in glycaemia-related outcomes., (© 2021. The Author(s).)

Objective: We aimed to validate the association of genome-wide association study (GWAS)-identified loci and polygenic risk score with serum thyroid-stimulating hormone (TSH) concentrations and the diagnosis of hypothyroidism. Then, the causal relationship between serum TSH and osteoporotic bone fracture risk was tested., Methods: A cross-sectional study was done among patients of European Caucasian ethnicity recruited in Tayside (Scotland, UK). Electronic medical records (EMRs) were used to identify patients and average serum TSH concentration and linked to genetic biobank data. Genetic associations were performed by linear and logistic regression models. One-sample Mendelian randomization (MR) was used to test causality of serum TSH on bone fracture risk., Results: Replication in 9,452 euthyroid individuals confirmed known loci previously reported. The 58 polymorphisms accounted for 11.08% of the TSH variation ( p < 1e-04). TSH-GRS was directly associated with the risk of hypothyroidism with an odds ratio (OR) of 1.98 for the highest quartile compared to the first quartile ( p = 2.2e-12). MR analysis of 5,599 individuals showed that compared with those in the lowest tertile of the TSH-GRS, men in the highest tertile had a decreased risk of osteoporotic bone fracture (OR = 0.59, p = 2.4e-03), while no difference in a similar comparison was observed in women (OR = 0.93, p = 0.61). Sensitivity analysis yielded similar results., Conclusions: EMRs linked to genomic data in large populations allow replication of GWAS discoveries without additional genotyping costs. This study suggests that genetically raised serum TSH concentrations are causally associated with decreased bone fracture risk in men., (Copyright © 2021 by S. Karger AG, Basel.)

Aims: Atrial fibrillation (AF) is a risk for patients receiving thyroid hormone replacement therapy. No published work has focused on pharmacogenetics relevant to thyroid dysfunction and AF risk. We aimed to assess the effect of L-thyroxine on AF risk stratified by a variation in a candidate gene., Methods and Results: A retrospective follow-up study was done among European Caucasian patients from the Genetics of Diabetes Audit and Research in Tayside Scotland cohort (Scotland, United Kingdom). Linked data on biochemistry, prescribing, hospital admissions, demographics, and genetic biobank were used to ascertain patients on L-thyroxine and diagnosis of AF. A GWAS-identified insulin receptor- INSR locus (rs4804416) was the candidate gene. Cox survival models and sensitivity analyses by taking competing risk of death into account were used. Replication was performed in additional sample (The Genetics of Scottish Health Research register, GoSHARE), and meta-analyses across the results of the study and replication cohorts were done. We analyzed 962 exposed to L-thyroxine and 5,840 unexposed patients who were rs4804416 genotyped. The rarer G/G genotype was present in 18% of the study population. The total follow-up was up to 20 years, and there was a significant increased AF risk for patients homozygous carriers of the G allele exposed to L-thyroxine (RHR = 2.35, P = 1.6e-02). The adjusted increased risk was highest within the first 3 years of exposure (RHR = 9.10, P = 8.5e-04). Sensitivity analysis yielded similar results. Effects were replicated in GoSHARE ( n = 3,190)., Conclusion: Homozygous G/G genotype at the INSR locus (rs4804416) is associated with an increased risk of AF in patients on L-thyroxine, independent of serum of free thyroxine and thyroid-stimulating hormone serum concentrations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Soto-Pedre, Siddiqui, Maroteau, Dawed, Doney, Palmer, Pearson and Leese.)

Introduction: The aim of the study was to develop and validate a clinical prediction rule (CPR) for foot ulceration in people with diabetes., Research Design and Methods: Development of a CPR using individual participant data from four international cohort studies identified by systematic review, with validation in a fifth study. Development cohorts were from primary and secondary care foot clinics in Europe and the USA (n=8255, adults over 18 years old, with diabetes, ulcer free at recruitment). Using data from monofilament testing, presence/absence of pulses, and participant history of previous ulcer and/or amputation, we developed a simple CPR to predict who will develop a foot ulcer within 2 years of initial assessment and validated it in a fifth study (n=3324). The CPR's performance was assessed with C-statistics, calibration slopes, calibration-in-the-large, and a net benefit analysis., Results: CPR scores of 0, 1, 2, 3, and 4 had a risk of ulcer within 2 years of 2.4% (95% CI 1.5% to 3.9%), 6.0% (95% CI 3.5% to 9.5%), 14.0% (95% CI 8.5% to 21.3%), 29.2% (95% CI 19.2% to 41.0%), and 51.1% (95% CI 37.9% to 64.1%), respectively. In the validation dataset, calibration-in-the-large was -0.374 (95% CI -0.561 to -0.187) and calibration slope 1.139 (95% CI 0.994 to 1.283). The C-statistic was 0.829 (95% CI 0.790 to 0.868). The net benefit analysis suggested that people with a CPR score of 1 or more (risk of ulceration 6.0% or more) should be referred for treatment., Conclusion: The clinical prediction rule is simple, using routinely obtained data, and could help prevent foot ulcers by redirecting care to patients with scores of 1 or above. It has been validated in a community setting, and requires further validation in secondary care settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Diabetes-related foot ulcers give rise to considerable morbidity, generate a high monetary cost for health and social care services and precede the majority of diabetes-related lower extremity amputations. There are many clinical prediction rules in existence to assess risk of foot ulceration but few have been subject to validation., Objectives: Our objectives were to produce an evidence-based clinical pathway for risk assessment and management of the foot in people with diabetes mellitus to estimate cost-effective monitoring intervals and to perform cost-effectiveness analyses and a value-of-information analysis., Design: We developed and validated a prognostic model using predictive modelling, calibration and discrimination techniques. An overview of systematic reviews already completed was followed by a review of randomised controlled trials of interventions to prevent foot ulceration in diabetes mellitus. A review of the health economic literature was followed by the construction of an economic model, an analysis of the transitional probability of moving from one foot risk state to another, an assessment of cost-effectiveness and a value-of-information analysis., Interventions: The effects of simple and complex interventions and different monitoring intervals for the clinical prediction rules were evaluated., Main Outcome Measure: The main outcome was the incidence of foot ulceration. We compared the new clinical prediction rules in conjunction with the most effective preventative interventions at different monitoring intervals with a 'treat-all' strategy., Data Sources: Data from an electronic health record for 26,154 people with diabetes mellitus in one Scottish health board were used to estimate the monitoring interval. The Prediction Of Diabetic foot UlcerationS (PODUS) data set was used to develop and validate the clinical prediction rule., Review Methods: We searched for eligible randomised controlled trials of interventions using search strategies created for Ovid ® (Wolters Kluwer, Alphen aan den Rijn, the Netherlands), MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. Randomised controlled trials in progress were identified via the International Standard Randomised Controlled Trial Number Registry and systematic reviews were identified via PROSPERO. Databases were searched from inception to February 2019., Results: The clinical prediction rule was found to accurately assess the risk of foot ulceration. Digital infrared thermometry, complex interventions and therapeutic footwear with offloading devices were found to be effective in preventing foot ulcers. The risk of developing a foot ulcer did not change over time for most people. We found that interventions to prevent foot ulceration may be cost-effective but there is uncertainty about this. Digital infrared thermometry and therapeutic footwear with offloading devices may be cost-effective when used to treat all people with diabetes mellitus regardless of their ulcer risk., Limitations: The threats to the validity of the results in some randomised controlled trials in the review and the large number of missing data in the electronic health record mean that there is uncertainty in our estimates., Conclusions: There is evidence that interventions to prevent foot ulceration are effective but it is not clear who would benefit most from receiving the interventions. The ulceration risk does not change over an 8-year period for most people with diabetes mellitus. A change in the monitoring interval from annually to every 2 years for those at low risk would be acceptable., Future Work Recommendations: Improving the completeness of electronic health records and sharing data would help improve our knowledge about the most clinically effective and cost-effective approaches to prevent foot ulceration in diabetes mellitus., Study Registration: This study is registered as PROSPERO CRD42016052324., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 62. See the NIHR Journals Library website for further project information.

The new NICE guidelines on thyroid disease and its management do not recommend the routine use of liothyronine, but do not completely rule it out either. Guidelines from the British and European Thyroid Associations are open to a "trial of liothyronine" on an individual basis. Some patients do not feel well on L-thyroxine despite a serum TSH in the reference range. Key issues to consider in such patients include establishing whether the patient had established hypothyroidism initially, and whether the L-thyroxine has been titrated carefully enough, possibly using small increments, to achieve a careful balance between symptoms and serum TSH concentrations. Patients should also be considered for other causes of the symptoms which may be wide-ranging. Meta-analyses of several, but small, randomised control trials show no advantage, or disadvantage of liothyronine over L-thyroxine. However, detailed sub-analysis identifies some tantalising results eg on preferential weight loss, patient preference, and possibly genetic markers. Although linked with plausible theoretical explanations, these results may be over-interpreted. The key questions are whether a short-term trial treatment is worthwhile and safe, and whether in the future sub-groups of patients can be identified who may benefit from liothyronine. These questions remain divisive but require additional focussed research. It could be argued that inflated costs of liothyronine in some countries have either distracted from or helped focus on the science. Costs need to be addressed. However better biomarkers of tissue level thyroid action, and a better understanding of the impact of genetic polymorphisms will help to make progress when choosing if there is a place for liothyronine in the future. (words: 262)., Competing Interests: Competing interestsThere are no competing interests., (© The Author(s) 2020.)

Aims/hypothesis: Foot ulceration is a serious complication for people with diabetes that results in high levels of morbidity for individuals and significant costs for health and social care systems. Nineteen systematic reviews of preventative interventions have been published, but none provides a reliable numerical summary of treatment effects. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to make the best possible use of the currently available data., Methods: We conducted a systematic review and meta-analysis of RCTs of preventative interventions for foot ulceration. OVID MEDLINE and EMBASE were searched to February 2019 and the Cochrane Central Register of Controlled Trials to October 2018. RCTs of interventions to prevent foot ulcers in people with diabetes who were free from foot ulceration at trial entry were included. Two independent reviewers read the full-text articles and extracted data. The quality of trial reporting was assessed using the Cochrane Risk of Bias tool. The primary outcome of foot ulceration was summarised using pooled relative risks in meta-analyses., Results: Twenty-two RCTs of eight interventions were eligible for analysis. One trial of digital silicone devices (RR 0.07 [95% CI 0.01, 0.55]) and meta-analyses of dermal infrared thermometry (RR 0.41 [95% CI 0.19, 0.86]), complex interventions (RR 0.59 [95% CI 0.38, 0.90], and custom-made footwear and offloading insoles (RR 0.53 [95% CI 0.33, 0.85]) showed beneficial effects for these interventions., Conclusions/interpretation: Four interventions were identified as being effective in preventing foot ulcers in people with diabetes, but uncertainty remains about what works and who is most likely to benefit.

Aims/hypothesis: The aim of this work was to examine whether glycaemic control has improved in those with type 1 diabetes in Scotland between 2004 and 2016, and whether any trends differed by sociodemographic factors., Methods: We analysed records from 30,717 people with type 1 diabetes, registered anytime between 2004 and 2016 in the national diabetes database, which contained repeated measures of HbA 1c . An additive mixed regression model was used to estimate calendar time and other effects on HbA 1c ., Results: Overall, median (IQR) HbA 1c decreased from 72 (21) mmol/mol [8.7 (4.1)%] in 2004 to 68 (21) mmol/mol (8.4 [4.1]%) in 2016. However, all of the improvement across the period occurred in the latter 4 years: the regression model showed that the only period of significant change in HbA 1c was 2012-2016 where there was a fall of 3 (95% CI 1.82, 3.43) mmol/mol. The largest reductions in HbA 1c in this period were seen in children, from 69 (16) mmol/mol (8.5 [3.6]%) to 63 (14) mmol/mol (7.9 [3.4]%), and adolescents, from 75 (25) mmol/mol (9.0 [4.4]%) to 70 (23) mmol/mol (8.6 [4.3]%). Socioeconomic status (according to Scottish Index of Multiple Deprivation) affected the HbA 1c values: from the regression model, the 20% of people living in the most-deprived areas had HbA 1c levels on average 8.0 (95% CI 7.4, 8.9) mmol/mol higher than those of the 20% of people living in the least-deprived areas. However this difference did not change significantly over time. From the regression model HbA 1c was on average 1.7 (95% CI 1.6, 1.8) mmol/mol higher in women than in men. This sex difference did not narrow over time., Conclusions/interpretation: In this high-income country, we identified a modest but important improvement in HbA 1c since 2012 that was most marked in children and adolescents. These changes coincided with national initiatives to reduce HbA 1c including an expansion of pump therapy. However, in most people, overall glycaemic control remains far from target levels and further improvement is badly needed, particularly in those from more-deprived areas.

Aims/hypothesis: Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is indicated for improving glycaemic control in type 2 diabetes mellitus. Whether its effects on HbA 1c and other variables, including safety outcomes, in clinical trials are obtained in real-world practice needs to be established., Methods: We used data from the comprehensive national diabetes register, the Scottish Care Information-Diabetes (SCI-Diabetes) collaboration database, available from 2004 to mid-2016. Data within this database were linked to mortality data from the General Registrar, available from the Information Services Division (ISD) of the National Health Service in Scotland. We calculated crude within-person differences between pre- and post-drug-initiation values of HbA 1c , BMI, body weight, systolic blood pressure (SBP) and eGFR. We used mixed-effects regression models to adjust for within-person time trajectories in these measures. For completeness, we evaluated safety outcomes, cardiovascular disease events, lower-limb amputation and diabetic ketoacidosis, focusing on cumulative exposure effects, using Cox proportional hazard models, though power to detect such effects was limited., Results: Among 8566 people exposed to dapagliflozin over a median of 210 days the crude within-person change in HbA 1c was -10.41 mmol/mol (-0.95%) after 3 months' exposure. The crude change after 12 months was -12.99 mmol/mol (-1.19%) but considering the expected rise over time in HbA 1c gave a dapagliflozin-exposure-effect estimate of -15.14 mmol/mol (95% CI -15.87, -14.41) (-1.39% [95% CI -1.45, -1.32]) at 12 months that was maintained thereafter. A drop in SBP of -4.32 mmHg (95% CI -4.84, -3.79) on exposure within the first 3 months was also maintained thereafter. Reductions in BMI and body weight stabilised by 6 months at -0.82 kg/m 2 (95% CI -0.87, -0.77) and -2.20 kg (95% CI -2.34, -2.06) and were maintained thereafter. eGFR declined initially by -1.81 ml min -1 [1.73 m] -2 (95% CI -2.10, -1.52) at 3 months but varied thereafter. There were no significant effects of cumulative drug exposure on safety outcomes., Conclusions/interpretation: Dapagliflozin exposure was associated with reductions in HbA 1c , SBP, body weight and BMI that were at least as large as in clinical trials. Dapagliflozin also prevented the expected rise in HbA 1c and SBP over the period of study.

Aims/hypothesis: Our aim was to investigate amputation-free survival in people at high risk for foot ulceration in diabetes ('high-risk foot'), and to compare different subcategories of high-risk foot., Methods: Overall, 17,353 people with diabetes and high-risk foot from January 2008 to December 2011 were identified from the Scotland-wide diabetes register (Scottish Care Information-Diabetes: N = 247,278). Participants were followed-up for up to 2 years from baseline and were categorised into three groups: (1) those with no previous ulcer, (2) those with an active ulcer or (3) those with a healed previous ulcer. Participants with prior minor or major amputation were excluded. Accelerated failure time models were used to compare amputation-free survival up to 2 years between the three exposure groups., Results: The 2 year amputation-free survival rate in all people with diabetes with high-risk foot was 84.5%. In this study group, 270 people (10.0%) had an amputation and 2424 (90.0%) died during the 2 year follow-up period. People who had active and healed previous ulcers at baseline had significantly lower 2 year amputation-free survival compared with those who had no previous ulcer (both p < 0.0001). The percentage of people who died within 2 years for those with healed ulcer, active ulcer or no baseline ulcer was 22.8%, 16% and 12.1%, respectively., Conclusions/interpretation: In people judged to be at high risk of foot ulceration, the risk of death was up to nine times the risk of amputation. Death rates were higher for people with diabetes who had healed ulcers than for those with active ulcers. However, people with active ulcers had the highest risk of amputation.

Aims/hypothesis: We aimed to examine time trends in national perinatal outcomes in pregnancies complicated by pre-existing type 1 or type 2 diabetes., Methods: We analysed episode-level data on all obstetric inpatient delivery events (live or stillbirth) between 1 April 1998 and 31 March 2013 (n = 813,921) using the Scottish Morbidity Record (SMR02). Pregnancies to mothers with type 1 (n = 3229) and type 2 (n = 1452) diabetes were identified from the national diabetes database (Scottish Care Information-Diabetes), and perinatal outcomes were compared among women with type 1 diabetes, type 2 diabetes and those without diabetes., Results: The number of pregnancies complicated by diabetes increased significantly, by 44% in type 1 diabetes and 90% in type 2 diabetes, across the 15 years examined, to rates of 1 in 210 and 1 in 504 deliveries, respectively. Compared with women without diabetes, delivery occurred 2.6 weeks earlier (type 1 diabetes 36.7 ± 2.3 weeks) and 2 weeks earlier (type 2 diabetes 37.3 ± 2.4 weeks), respectively, showing significant reductions for both type 1 (from 36.7 weeks to 36.4 weeks, p = 0.03) and type 2 (from 38.0 weeks to 37.2 weeks, p < 0.001) diabetes across the time period. The proportions of preterm delivery were markedly increased in women with diabetes (35.3% type 1 diabetes, 21.8% type 2 diabetes, 6.1% without diabetes; p < 0.0001), and these proportions increased with time for both groups (p < 0.005). Proportions of elective Caesarean sections (29.4% type 1 diabetes, 30.5% type 2 diabetes, 9.6% without diabetes) and emergency Caesarean sections (38.3% type 1 diabetes, 29.1% type 2 diabetes, 14.6% without diabetes) were greatly increased in women with diabetes and increased over time except for stable rates of emergency Caesarean section in type 1 diabetes. Gestational age-, sex- and parity-adjusted z score for birthweight (1.33 ± 1.34; p < 0.001) were higher in type 1 diabetes and increased over time from 1.22 to 1.47 (p < 0.001). Birthweight was also increased in type 2 diabetes (0.94 ± 1.34; p < 0.001) but did not alter with time. There were 65 perinatal deaths in offspring of mothers with type 1 diabetes and 39 to mothers with type 2 diabetes, representing perinatal mortality rates of 20.1 (95% CI 14.7, 24.3) and 26.9 (16.7, 32.9) per 1000 births, respectively, and rates 3.1 and 4.2 times, respectively, those observed in the non-diabetic population (p < 0.001). Stillbirth rates in type 1 and type 2 diabetes were 4.0-fold and 5.1-fold that in the non-diabetic population (p < 0.001). Perinatal mortality and stillbirth rates showed no significant fall over time despite small falls in the rates for the non-diabetic population., Conclusions/interpretation: Women with diabetes are receiving increased intervention in pregnancy (earlier delivery, increased Caesarean section rates), but despite this, higher birthweights are being recorded. Improvements in rates of stillbirth seen in the general population are not being reflected in changes in stillbirth or perinatal mortality in our population with diabetes.

Objective: Replication of associations in genome-wide association studies is desirable to ensure that such signals are potentially clinically meaningful. This study aimed to replicate associations of selected single-nucleotide polymorphisms (SNPs) with hypothyroidism and serum thyroid-stimulating hormone (TSH) using electronic medical records (EMRs)., Patients and Methods: A cross-sectional study was carried out among patients of European Caucasian ethnicity from the Genetics of Diabetes Audit and Research Tayside recruited in Tayside (Scotland, UK). EMRs (biochemistry, prescribing, hospital admissions and demographics) were used to ascertain patients with hypothyroidism and their controls as well as average serum TSH concentration, and linked to genetic biobank data. Genetic tests of association were performed using logistic and linear regression models., Results: We analysed 1703 cases of hypothyroidism and 9457 controls. All four SNPs located on chromosome 9 at FOXE1 were associated with hypothyroidism with similar effect estimates (odds ratio=0.75-0.76, P<5e-08). Also, loci on chromosomes 1 (PTPN22), six (HLA-E/HLA-C) and 12 (SH2B3) were replicated. For serum TSH, we confirmed 12 SNPs previously reported at PDE8B, CAPZB, PDE10A, LOC105371356, NR3C2, VEGFA, IGFBP5, INSR, PRDM11, NFIA, ITPK1 and ABO. Overall, these SNPs accounted for 6.8% of the serum TSH variation (P<1e-04)., Conclusion: EMRs linked to genomic data in large populations enable validation of genome-wide association studies discoveries without additional genotyping costs. Our replication confirmed at genome-wide significance the association of loci at FOXE1 with hypothyroidism, and PDE8B, CAPZB and PDE10A with serum TSH. A total of 12 SNPs seemed to explain nearly 7% of the serum TSH variation.

Background: Healthcare events related to diabetic foot disease carry a burden of morbidity, mortality and economic cost. Prompt identification of clinical infection with appropriate tissue sampling limits use of broad spectrum empirical antibiotics and improves antibiotic stewardship. Staphylococcus aureus remains the commonest infecting organism and high-dose flucloxacillin remains the empirical antibiotic of choice for antibiotic naïve patients. Barriers to microbe-specific treatment include: adequate tissue sampling, delays in culture results, drug allergies and the emergence of multidrug-resistant organisms which can complicate the choice of targeted antibiotics. Even appropriate antibiotic treatment carries a risk of adverse events including the selection of resistant organisms., Aims: Multidisciplinary clinical assessment of a diabetic foot infection is supported by the use of appropriate imaging modalities and deep tissue sampling, both of which are encouraged to enhance sampling accuracy. Narrow-spectrum, high dose, short duration antimicrobial therapy is ideal. Further clarity in these areas would be of benefit to clinicians involved in management of diabetic foot infections., Methods: A combination of literature review with expert discussion was used to generate consensus on management of diabetic foot infection, with a specific focus on empirical antimicrobial therapy., Results: Gram positive organisms represent the commonest pathogens in diabetic foot infection. However there are developing challenges in antimicrobial resistance and antibiotic availability., Discussion: Recommendations for empirical therapy, including the choice of alternative oral agents and use of outpatient antibiotics would be of benefit to those involved in diabetic foot care., Conclusion: This paper provides advice on empirical antibiotic therapy that may be used as a framework for local guideline development to support clinicians in the management of diabetic foot infection., (© 2017 John Wiley & Sons Ltd.)

Quality improvement depends on data collection and audit of clinical services to inform clinical improvements. Various steps in the care of the diabetic foot can be used to audit a service but need defined audit standards. A diabetes foot service should have risk stratification system in place that should compare to the population-based figures of 76% having low-risk feet, 17% moderate risk and 7% being at high risk of ulceration. Resources can then be directed towards those with high-risk feet. Prevalence of foot ulceration needs to be audited. Community-based studies give an audit standard of around 2%, with 2 to 9% having had an ulcer at some stage in the past. Amputation rates should be easier to measure, and the best results are reported to be around 1.5-3 per 1000 people with diabetes. This is a useful benchmark figure, and the rate has been shown to decrease by approximately a third over the last 15 years in some centres. Ulceration rates and ulcer healing rates are the ultimate outcome audit measure as they are always undesirable, whilst occasionally for defined individuals, an amputation can be a good outcome. In addition to clinical outcomes, processes of care can be audited such as provision of clinical services, time from new ulcer to be seen by health care professional, inpatient foot care or use of antibiotics. Measurement of clinical services can be a challenge in the diabetic foot, but it is essential if clinical services and patient outcomes are to be improved., (Copyright © 2016 John Wiley & Sons, Ltd.)

Aims/hypothesis: Potential differences in cardiovascular risk by ethnicity remain uncertain. We evaluated the association of ethnicity with cardiovascular disease (CVD) incidence in a large cohort of people with type 2 diabetes living in Scotland., Methods: Data from Scottish Care Information-Diabetes (SCI-Diabetes) were linked to Scottish Morbidity Records (SMR01) and National Records of Scotland data for mortality for dates between 2005 and 2011. Of 156,991 people with type 2 diabetes with coded ethnicity, 121,535 (77.4%) had no CVD at baseline (White: 114,461; Multiple Ethnic: 2,554; Indian: 797; Other Asian: 319; Pakistani: 2,250; Chinese: 387; African-Caribbean: 301 and Other: 466) and were followed up (mean ± SD: 4.8 ± 2.3 years) for the development of fatal and non-fatal CVD., Results: During follow-up, 16,265 (13.4%) patients developed CVD (ischaemic heart or cerebrovascular diseases). At baseline, Pakistanis were younger and had developed diabetes earlier, had higher HbA1c and longer duration of diabetes, but had lower BP, BMI, creatinine, proportion of smokers and proportion on antihypertensive therapy than whites. The age and sex adjusted HRs for CVD were HR 1.31 (CI 1.17, 1.47), p < 0.001 in Pakistanis and HR 0.66 (CI 0.47, 0.92), p = 0.014 in Chinese compared with whites. Adjusting additionally for an area measure of deprivation, duration of diabetes, conventional CVD and other risk factors, the HR for Pakistanis (HR 1.45 [CI 1.14, 1.85], p = 0.002) was significantly higher, and that for Chinese (HR = 0.58 [CI 0.24, 1.40], p = 0.228) lower, compared with whites., Conclusions/interpretation: Compared with whites with type 2 diabetes, those of Pakistani ethnicity in Scotland were at increased risk of CVD, whereas Chinese were at lower risk, with these differences unexplained by known risk factors.

Objective: This study aimed to follow the natural progression of retinal changes in patients with diabetes. Such information should inform decisions with regard to the screening intervals for such patients., Research Design and Methods: An observational study was undertaken linking the data from seven diabetes retinal screening programs across the U.K. for retinal grading results between 2005 and 2012. Patients with absent or background retinopathy were followed up for progression to the end points referable retinopathy and treatable retinopathy (proliferative retinopathy)., Results: In total, 354,549 patients were observed for up to 4 years during which 16,196 patients progressed to referable retinopathy. Of patients with no retinopathy in either eye for two successive screening episodes at least 12 months apart, the conditions of between 0.3% (95% CI 0.3-0.8%) and 1.3% (1.0-1.6%) of patients progressed to referable retinopathy, and rates of treatable eye disease were <0.3% at 2 years. The corresponding progression rates for patients with bilateral background retinopathy in successive screening episodes were 13-29% and up to 4%, respectively, in the different programs., Conclusions: It may be possible to stratify patients for risk, according to baseline retinal criteria, into groups with low and high risk of their conditions progressing to proliferative retinopathy. Screening intervals for such diverse groups of patients could safely be modified according to their risk., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: The aim of this study was to determine the extent of drug interactions affecting levothyroxine, using study drugs often co-administered to patients on long-term levothyroxine therapy., Design: A retrospective population analysis linking biochemistry and prescription data between 1 January 1993 and 31 December 2012 was used., Patients: The study population was Tayside residents prescribed levothyroxine on at least three occasions, within a six-month period, prior to the start of a study drug. Individuals acted as their own controls pre- and postinitiation of study drug. Overall, 10 999 patients (mean age 58 years, 82% female) being treated with thyroxine were included in the study., Measurements: Changes in TSH following initiation of study drug., Results: Iron, calcium, proton pump inhibitors and oestrogen all increased serum TSH concentration: an increase of 0·22 mU/l (P < 0.001), 0·27 mU/l (P < 0·001), 0·12 mU/l (P < 0·01), and 0·08 mU/l (P < 0·007), respectively. For these four study drugs, there was a clinically significant increase of over 5 mU/l in serum TSH, in 7·5%, 4·4%, 5·6% and 4·3% patients, respectively. There was a decrease of 0·17 mU/l (P-value 0.01) in the TSH concentration for those patients on statins. The TSH decreased by 5 mU/l in 3·7% of patients. There was no effect with H2 receptor antagonists or glucocorticoids., Conclusion: This large population-based study demonstrates significant interaction between levothyroxine and iron, calcium, proton pump inhibitors, statins and oestrogens. These drugs may reduce the effectiveness of levothyroxine, and patients' TSH concentrations should be carefully monitored., (© 2014 John Wiley & Sons Ltd.)

Objective: The aim of the study was to examine the association of tested TSH with age, gender, and diabetes in a large population-based cohort without evidence of thyroid disease., Design: Record-linkage technology was used retrospectively to identify people without evidence of thyroid disease in the general population of Tayside, Scotland, from July 1, 2003, to December 31, 2009., Cohort: All Tayside residents who had thyroid function tests performed were identified. Using a unique patient identifier, data linkage enabled a cohort without thyroid disease to be identified by excluding anyone with thyroid or antithyroid prescription, thyroid-related admission or surgery, treatment with radioactive iodine and/or positive thyroid antibodies. Cases below 18 years of age were also excluded., Outcome Measures: We measured TSH distribution among different age groups and by gender., Results: We identified the latest TSH measurements in 153127 people from the reference population after applying the exclusion criteria. There was a significant increase in median TSH (1.58 mU/L at 31-40 y to 1.86 mU/L at >90 y; P < .001) and 97.5th centile TSH (3.98 to 5.94 mU/L, respectively) with increasing age. The 2.5th centile decreased with age (0.51 to 0.31 mU/L). Patients with diabetes had marginally higher TSH concentration (1.80 vs 1.70 mU/L; P < .001)., Conclusion: The use of these age-specific reference intervals for TSH, especially in those over 70 years old, would result in the reclassification of many TSH results from "abnormal" to "normal" (within the 95th centile reference interval) and avoid unnecessary treatment.

Objective: Our objective was to investigate the long-term outcomes for patients with endogenous subclinical hyperthyroidism (SH)., Design: Population record-linkage technology was used retrospectively to identify patients with SH and hospital admissions from January 1, 1993, to December 31, 2009., Patients: All Tayside residents over 18 yr old with at least two serum TSH measurements below the reference range for at least 4 months apart and normal free T(4)/total T(4) and normal total T(3) concentrations at baseline were included as potential cases. Using a unique patient identifier, data linkage enabled a cohort of SH cases to be identified from biochemistry, prescription, admission, and radioactive iodine treatment records matched to five comparators from the general population., Outcome Measures: The association between endogenous SH and cardiovascular disease, fracture, dysrhythmia, dementia, and cancer was assessed., Results: Compared with the reference population, SH was associated with an increased risk of nonfatal cardiovascular morbidity, osteoporotic fracture, dysrhythmia, and dementia, with adjusted hazard ratios (HR) of 1.39 (1.22-1.58), 1.25 (1.04-1.50), 1.65 (1.26-2.17), and 1.64 (1.20-2.25), respectively. When SH patients who developed overt hyperthyroidism during follow-up were excluded, SH patients were associated with an increased risk of cardiovascular morbidity [HR = 1.36 (1.19-1.57)], dysrhythmia [HR = 1.39 (1.02-1.90)], and dementia [HR = 1.79 (1.28-2.51)] but not fracture and cancer., Conclusion: Patients with endogenous SH have an increased risk of cardiovascular disease and dysrhythmia. There is an association with fracture and dementia that is not related to TSH concentration and therefore is less likely to be causally related. No association was found between SH and cancer.

Objective: For patients with subclinical hyperthyroidism (SH), the objective of the study was to define the rates of progression to frank hyperthyroidism and normal thyroid function., Design: Record-linkage technology was used retrospectively to identify patients with SH in the general population of Tayside, Scotland, from January 1, 1993, to December 31, 2009., Patients: All Tayside residents with at least two measurements of TSH below the reference range for at least 4 months from baseline and normal free T(4)/total T(4) and total T(3) concentrations at baseline were included as potential cases. Using a unique patient identifier, data linkage enabled a cohort of SH cases to be identified from prescription, admission, and radioactive iodine treatment records. Cases younger than 18 yr of age were also excluded from the study., Outcome Measures: The status of patients was investigated at 2, 5, and 7 yr after diagnosis., Results: We identified 2024 cases with SH, a prevalence of 0.63% and an incidence of 29 per 100,000 in 2008. Most SH cases without thyroid treatment remained as SH at 2 (81.8%), 5 (67.5%), and 7 yr (63.0%) after diagnosis. Few patients (0.5-0.7%) developed hyperthyroidism at 2, 5, and 7 yr. The percentage of SH cases reverting to normal increased with time: 17.2% (2 yr), 31.5% (5 yr), and 35.6% (7 yr), and this was more common in SH patients with baseline TSH between 0.1 and 0.4 mU/liter., Conclusion: Very few SH patients develop frank hyperthyroidism, whereas a much larger proportion revert to normal, and many remain with SH.

The two-compound ointment (Taclonex/Daivobet/Dovobet ointment) combining calcipotriene 50 microg/g and betamethasone 0.5 mg/g (as dipropionate) is very effective in the treatment of psoriasis vulgaris. There is a possibility that hypothalamo-pituitary-axis (HPA) suppression may occur if the potent corticosteroid component is absorbed to a sufficient extent. The effect of the two-compound ointment on HPA axis function was assessed in two studies. Study 1 was a four-week, double-blind study which compared the effects of the two-compound ointment with betamethasone 0.5 mg/g (as dipropionate; Diprosone) ointment in 24 patients with extensive psoriasis (involving 15-30% of the body surface area). No patients receiving the two-compound ointment had HPA axis suppression. Study 2 assessed HPA axis function after four and 52 weeks in a subset of patients (n = 19) participating in a long-term safety study. Patients were treated with the two-compound ointment for the first four weeks followed by 48 weeks of treatment as needed with either 1) two-compound ointment; 2) two-compound ointment alternating with calcipotriene four-weekly or 3) calcipotriene. No patients using the two-compound ointment for all 52 weeks or alternating four-weekly with calcipotriene had HPA axis suppression.

Objective: To describe mortality and disease-specific morbidities in patients with mild primary hyperparathyroidism (PHPT)., Design: Retrospective population-based observational study., Setting: Tayside, Scotland, from 1997 to 2006., Participants: Patients with mild PHPT were selected from a predefined PHPT cohort between 1997 and 2006., Main Outcome Measures: Standardised mortality ratios (SMRs) were examined for all-cause mortality, as well as cardiovascular and cancer mortality. Standardised morbidity ratios and standardised incidence ratios were also calculated for eleven observed co-morbidities., Results: In total, there were 1683 (69.1% female) patients identified with mild PHPT in Tayside. Patients were found to have an increased risk of all-cause mortality and cardiovascular mortality (SMR-all cause 2.62, 95% CI 2.39-2.86; SMR-cardiovascular 2.68, 95% CI 2.34-3.05). Patients with mild PHPT had a significantly increased risk of developing cardiovascular and cerebrovascular disease, renal dysfunction and fractures compared to the age- and sex-adjusted general population., Conclusions: Mortality and morbidity were increased for patients with mild untreated PHPT, which is similar to more severe PHPT.

Background/aims: Automated grading has the potential to improve the efficiency of diabetic retinopathy screening services. While disease/no disease grading can be performed using only microaneurysm detection and image-quality assessment, automated recognition of other types of lesions may be advantageous. This study investigated whether inclusion of automated recognition of exudates and haemorrhages improves the detection of observable/referable diabetic retinopathy., Methods: Images from 1253 patients with observable/referable retinopathy and 6333 patients with non-referable retinopathy were obtained from three grading centres. All images were reference-graded, and automated disease/no disease assessments were made based on microaneurysm detection and combined microaneurysm, exudate and haemorrhage detection., Results: Introduction of algorithms for exudates and haemorrhages resulted in a statistically significant increase in the sensitivity for detection of observable/referable retinopathy from 94.9% (95% CI 93.5 to 96.0) to 96.6% (95.4 to 97.4) without affecting manual grading workload., Conclusion: Automated detection of exudates and haemorrhages improved the detection of observable/referable retinopathy.

Context: For patients on T(4) replacement, the dose is guided by serum TSH concentrations, but some patients request higher doses due to adverse symptoms., Objective: The aim of the study was to determine the safety of patients having a low but not suppressed serum TSH when receiving long-term T(4) replacement., Design: We conducted an observational cohort study, using data linkage from regional datasets between 1993 and 2001., Setting: A population-based study of all patients in Tayside, Scotland, was performed., Patients: All patients taking T(4) replacement therapy (n = 17,684) were included., Main Outcome Measures: Fatal and nonfatal endpoints were considered for cardiovascular disease, dysrhythmias, and fractures. Patients were categorized as having a suppressed TSH (4.0 mU/liter)., Results: Cardiovascular disease, dysrhythmias, and fractures were increased in patients with a high TSH: adjusted hazards ratio, 1.95 (1.73-2.21), 1.80 (1.33-2.44), and 1.83 (1.41-2.37), respectively; and patients with a suppressed TSH: 1.37 (1.17-1.60), 1.6 (1.10-2.33), and 2.02 (1.55-2.62), respectively, when compared to patients with a TSH in the laboratory reference range. Patients with a low TSH did not have an increased risk of any of these outcomes [hazards ratio: 1.1 (0.99-1.123), 1.13 (0.88-1.47), and 1.13 (0.92-1.39), respectively]., Conclusions: Patients with a high or suppressed TSH had an increased risk of cardiovascular disease, dysrhythmias, and fractures, but patients with a low but unsuppressed TSH did not. It may be safe for patients treated with T(4) to have a low but not suppressed serum TSH concentration.

Introduction: The main goals of transsphenoidal pituitary surgery are total removal of pituitary adenomas (PAs) and preservation of normal pituitary functions. Achieving these goals is dependent upon the precise localisation of PAs during surgery, particularly secreting microadenomas. However, some microadenomas are invisible on preoperative imaging and during surgery, leading some surgeons to perform total hypophysectomy in many patients to achieve cure at the expense of panhypopituitrism. We have examined optical detection systems to identify PAs intraoperatively. This paper reports our preliminary findings., Methods: A prospective observational study design., Technique: Patients were given 20 mg/kg body weight 5-aminolevulinic acid (ALA) mixed in 30 ml of orange juice, orally 3 h before surgery. Surgery was performed in the supine position, under image guidance, through the right nostril using Storz 0 degree endoscope assisted with microsurgery as required. The endoscope was attached to photodiagnostic filters (PD) allowing switching the light from white to blue at the flick of a foot pedal. After the dura of the floor of the sella was incised a laser probe was inserted into the pituitary gland to identify the ALA-induced protoporphyrin IX spectroscopy at 632 nm, using an optical biopsy system (OBS). Once the adenoma was identified by the OBS it was exposed and examined by the PD system to detect fluorescence. The PA was removed and its type was confirmed by histopathology and correlated to the OBS and PD system findings., Patients: Thirty consecutive patients were studied: 14 were non-functioning macroadenomas (NFA), 12 were secreting PAs and 4 pituitary cysts. The secreting PAs were GH (2), ACTH (3), prolactin (2) and gonadotrophins (5). Six were microadenomas (3 ACTH, 1 GH, 2 prolactin) and 20 were macroadenomas, of which 12 were invading macroadenomas. Twenty-four of these were examined by the OBS and the PD systems and six were examined by the PD system only. The true positive (sensitivity) of the PD and OBS systems were 80.8% (21/26) and 95.5% (21/22) respectively. The true negative (specificity) of PD and OBS were 75% (3/4) and 100% (2/2) respectively. The false negative rate of PD was 19.2% (5/26) and for OBS was 4.5% (1/22), while the false positive rate for PD was 25% (1/4) and for OBS was 0., Conclusion: Intraoperative optical identification of pituitary adenomas is a feasible and reliable way to localize pituitary adenomas during transsphenoidal surgery and it may lead to improved cure rate and preservation of normal pituitary functions.