Body Mass Index's influence on arterial hypertension in Type 1 diabetes - A brief report from IMI-SOPHIA study.

Information on BMI and risk of developing hypertension in type 1 diabetes (T1D) is scarce, and it comes mostly from cross-sectional analyses. This study underscores a risk of developing hypertension in T1D individuals with high BMI, and this risk appears to be higher than in those with type 2 diabetes.

Stable Incidence and Increasing Prevalence of Primary Hyperparathyroidism in a Population-based Study in Scotland.

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%.

Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin-But not through altered drug metabolism in patients with type 2 diabetes.

AIMS: Drug metabolism might be altered in patients with type 2 diabetes. We aimed to evaluate if initiation of glucose-lowering drugs impacts warfarin efficacy and drug metabolism. METHODS: First, we conducted a register-based self-controlled cohort study on Danish and Scottish warfarin users. Warfarin efficacy (international normalized ratio [INR]) was compared before and after initiation of glucose-lowering drugs. Second, we conducted a clinical pharmacokinetic trial comprising treatment-naïve type 2 diabetes patients. Patients ingested probe drugs for drug-metabolizing enzymes (the Basel Cocktail) before initiating glucose-lowering treatment, and after 3 and 12 weeks of treatment. Drug metabolism, glycaemic control, and inflammation were assessed on each visit. RESULTS: In the Danish and Scottish cohorts (n = 982 and n = 44, respectively), initiating glucose-lowering drugs reduced warfarin efficacy. INR decreased from 2.47 to 2.21 in the Danish cohort (mean difference -0.26; 95% CI -0.35; -0.17) and from 2.33 to 2.13 in the Scottish cohort (-0.21; 95% CI -0.52; 0.11) after initiation of glucose-lowering treatment. This impact on INR was more pronounced among individuals with stronger effects of glucose-lowering treatment. In the clinical pharmacokinetic trial (n = 10), initiating metformin did not affect drug metabolism after 3 weeks (geometric mean ratio of CYP3A metabolic ratio: 1.12 [95% CI: 0.95; 1.32]) or 12 weeks of metformin treatment. Glycaemic control improved during treatment, while inflammation remained low and unchanged during treatment. CONCLUSIONS: In conclusion, initiation of glucose-lowering drugs among chronic warfarin users seems associated with a reduction in INR, particularly among individuals with a large decrease in HbA1c . This effect seems unrelated to CYP enzyme activity and warfarin drug metabolism.

Morbidity Associated With Primary Hyperparathyroidism-A Population-based Study With a Subanalysis on Vitamin D.

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.

Identification of 4 New Loci Associated With Primary Hyperparathyroidism (PHPT) and a Polygenic Risk Score for PHPT.

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.

Diabetes status modifies the long-term effect of lipoprotein-associated phospholipase A2 on major coronary events.

AIMS/HYPOTHESIS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has an independent prognostic association with major coronary events (MCE). However, no study has investigated whether type 2 diabetes status modifies the effect of Lp-PLA2 activity or inhibition on the risk of MCE. We investigate the interaction between diabetes status and Lp-PLA2 activity with risk of MCE. Subsequently, we test the resulting hypothesis that diabetes status will play a role in modifying the efficacy of an Lp-PLA2 inhibitor. METHODS: A retrospective cohort study design was utilised in two study populations. Discovery analyses were performed in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort based in Scotland, UK. Participants were categorised by type 2 diabetes control status: poorly controlled (HbA1c ≥ 48 mmol/mol or ≥6.5%) and well-controlled (HbA1c < 48 mmol/mol or <6.5%) diabetes (n = 7420). In a secondary analysis of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial of Lp-PLA2 inhibitor (darapladib) efficacy, 15,828 participants were stratified post hoc by type 2 diabetes diagnosis status (diabetes or no diabetes) at time of recruitment. Lp-PLA2 activity was then divided into population-specific quartiles. MCE were determined from linked medical records in GoDARTS and trial records in STABILITY. First, the interaction between diabetes control status and Lp-PLA2 activity on the outcome of MCE was explored in GoDARTS. The effect was replicated in the placebo arm of STABILITY. The effect of Lp-PLA2 on MCE was then examined in models stratified by diabetes status. This helped determine participants at higher risk. Finally, the effect of Lp-PLA2 inhibition was assessed in STABILITY in the higher risk group. Cox proportional hazards models adjusted for confounders were used to assess associations. RESULTS: In GoDARTS, a significant interaction between increased Lp-PLA2 activity (continuous and quartile divided) and diabetes control status was observed in the prediction of MCE (p < 0.0001). These effects were replicated in the placebo arm of STABILITY (p < 0.0001). In GoDARTS, stratified analyses showed that, among individuals with poorly controlled diabetes, the hazards of MCE for those with high (Q4) Lp-PLA2 activity was 1.19 compared with individuals with lower (Q1-3) Lp-PLA2 activity (95% CI 1.11, 1.38; p < 0.0001) and 1.35 (95% CI 1.16, 1.57; p < 0.0001) when compared with those with the lowest activity (Q1). Those in the higher risk group were identified as individuals with the highest Lp-PLA2 activity (Q4) and poorly controlled diabetes or diabetes. Based on these observations in untreated populations, we hypothesised that the Lp-PLA2 inhibitor would have more benefit in this higher risk group. In this risk group, Lp-PLA2 inhibitor use was associated with a 33% reduction in MCE compared with placebo (HR 0.67 [95% CI 0.50, 0.90]; p = 0.008). In contrast, Lp-PLA2 inhibitor showed no efficacy in individuals with low activity, regardless of diabetes status, or among those with no baseline diabetes and high Lp-PLA2 activity. CONCLUSIONS/INTERPRETATION: These results support the hypothesis that diabetes status modifies the association between Lp-PLA2 activity and MCE. These results suggest that cardiovascular morbidity and mortality associated with Lp-PLA2 activity is especially important in patients with type 2 diabetes, particularly those with worse glycaemic control. Further investigation of the effects of Lp-PLA2 inhibition in diabetes appears warranted. DATA AVAILABILITY: STABILITY trial data are available from clinicaltrials.gov repository through the GlaxoSmithKline clinical study register https://clinicaltrials.gov/ct2/show/NCT00799903 . GoDARTS datasets generated during and/or analysed during the current study are available following request to the GoDARTS Access Managements Group https://godarts.org/scientific-community/ .

Evidence of a Causal Relationship between Serum Thyroid-Stimulating Hormone and Osteoporotic Bone Fractures.

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.

Polymorphism in INSR Locus Modifies Risk of Atrial Fibrillation in Patients on Thyroid Hormone Replacement Therapy.

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.

Independent Observational Analysis of Ulcer Outcomes for SINBAD and University of Texas Ulcer Scoring Systems.

OBJECTIVE: The aim of this study was to compare the University of Texas (UT) and Site, Ischemia, Neuropathy, Bacterial Infection, and Depth (SINBAD) foot ulcer scores in predicting ulcer outcome within a routine diabetes foot clinic. RESEARCH DESIGN AND METHODS: From 2006 to 2018, data were collected from all patients attending an outpatient diabetes foot clinic with an active ulcer not healed within 4 weeks. UT and SINBAD were compared in predicting ulcer outcome. A unified numerical score for UT was constructed and compared with UT grade (depth) and stage scores. Outcomes included death, a healed ulcer, or a nonhealed ulcer, which included major or minor amputation and nonhealing chronic ulcers. RESULTS: Outcomes were available from 1,645 ulcer outcomes in 1,068 patients (mean [SD] age 65.4 [4] years, 72% male), of which 1,108 (67%) healed. With exclusion of death as an adverse outcome, the c-statistic (area under operator curve) was 0.67 (95% CI 0.65-0.71) for UT grade/depth and 0.64 (0.61-0.67) for UT stage. The new unified UT score had an improved c-statistic of 0.71 (0.68-0.74). The c-statistic was 0.72 (0.69-0.75) for SINBAD. There was a stepwise decrease in the proportion of ulcers healed for each increased score on ulcer grading for both grading schemes. CONCLUSIONS: This large and independent observational comparison, in a real-world clinical setting, demonstrated that the UT and SINBAD diabetes foot ulcer grading schemes had similar prognostic ability for predicting foot ulcer outcomes. We have devised and validated a unified numerical scoring system for UT.

Morbidity and mortality in patients with hyperprolactinaemia: the PROLEARS study.

PURPOSE: High serum prolactin concentrations have been associated with adverse health outcomes in some but not all studies. This study aimed to examine the morbidity and all-cause mortality associated with hyperprolactinaemia. METHODS: A population-based matched cohort study in Tayside (Scotland, UK) from 1988 to 2014 was performed. Record-linkage technology was used to identify patients with hyperprolactinaemia that were compared to an age-sex-matched cohort of patients free of hyperprolactinaemia. The number of deaths and incident admissions with diabetes mellitus, cardiovascular disease, cancer, breast cancer, bone fractures and infectious conditions were compared by the survival analysis. RESULTS: Patients with hyperprolactinaemia related to pituitary tumours had no increased risk of diabetes, cardiovascular disease, bone fractures, all-cause cancer or breast cancer. Whilst no increased mortality was observed in patients with pituitary microadenomas (HR = 1.65, 95% CI: 0.79-3.44), other subgroups including those with pituitary macroadenomas and drug-induced and idiopathic hyperprolactinaemia demonstrated an increased risk of death. Individuals with drug-induced hyperprolactinaemia also demonstrated increased risks of diabetes, cardiovascular disease, infectious disease and bone fracture. However, these increased risks were not associated with the degree of serum prolactin elevation (Ptrend > 0.3). No increased risk of cancer was observed in any subgroup. CONCLUSIONS: No excess morbidity was observed in patients with raised prolactin due to pituitary tumours. Although the increased morbidity and mortality associated with defined patient subgroups are unlikely to be directly related to the elevation in serum prolactin, hyperprolactinaemia might act as a biomarker for the presence of some increased disease risk in these patients.

Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits: a Genetics of Diabetes Audit and Research Tayside study (GoDARTS).

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.

Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: A GoDarts study.

AIMS: Metformin is renally excreted and has been associated with the development of lactic acidosis. Although current advice is to omit metformin during illnesses that may increase the risk of acute kidney injury (AKI), the evidence supporting this is lacking. We investigated the relationship between AKI, lactate concentrations and the risk of lactic acidosis in those exposed to metformin. MATERIALS AND METHODS: We undertook a population-based case-control study of lactic acidosis in 1746 participants with Type 2 diabetes and 846 individuals without diabetes with clinically measured lactates with and without AKI between 1994 and 2014. AKI was stratified by severity according to "Kidney Disease: Improving Global Outcomes" guidelines. Mixed-effects logistic and linear regression were used to analyse lactic acidosis risk and lactate concentrations, respectively. RESULTS: Eighty-two cases of lactic acidosis were identified. In Type 2 diabetes, those treated with metformin had a greater incidence of lactic acidosis [45.7 per 100 000 patient years; 95% confidence interval (CI) 35.9-58.3] compared to those not exposed to this drug (11.8 per 100 000 patient years; 95% CI 4.9-28.5). Lactate concentrations were 0.34 mmol/L higher in the metformin-exposed cohort (P < .001). The risk of lactic acidosis was higher in metformin users [odds ratio (OR) 2.3; P = .002] and increased with AKI severity (stage 1: OR 3.0, P = .002; stage 2: OR 9.4, P < .001; stage 3: OR 16.1, P < .001). CONCLUSIONS: A clear association was found between metformin, lactate accumulation and the development of lactic acidosis. This relationship is strongest in those with AKI. These results provide robust evidence to support current recommendations to omit metformin in any illness that may precipitate AKI.

The epidemiology of hyperprolactinaemia over 20 years in the Tayside region of Scotland: the Prolactin Epidemiology, Audit and Research Study (PROLEARS).

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.

Liothyronine use in a 17 year observational population-based study - the tears study.

OBJECTIVE: To look at adverse outcomes for patients on liothyronine compared to l-thyroxine. Some trials have examined the relative merits of liothyronine but none have looked at adverse outcomes in large numbers. STUDY DESIGN: An observational study of all patients prescribed thyroid hormone replacement in Tayside Scotland (population 400 000) from 1997 to 2014. PATIENTS: A study group of patients having ever used liothyronine (n = 400) was compared to those who had only used l-thyroxine (n = 33 955). All patients were followed up until end-point, death or leaving Tayside. MEASUREMENTS: Mortality rates and admissions with cardiovascular disease, atrial fibrillation, fractures, breast cancer and mental diseases were compared. Incident use of bisphosphonates, statins, antidepressants and antipsychotics was compared. RESULTS: Compared to patients only taking l-thyroxine, those using liothyronine had no increased risk of cardiovascular disease [hazard ratio (HR) 1·04; 95% CI 0·70-1·54], atrial fibrillation (HR 0·91: 0·47-1·75), or fractures (HR 0·79: 0·49-1·27) after adjusting for age. There was no difference in the number of prescriptions for bisphosphonates or statins. There was an increased risk of new prescriptions for antipsychotic medication (HR 2·26: 1·64-3·11 P < 0·0001) which was proportional to the number of liothyronine prescriptions. There was a non-significant trend towards an increase in breast cancer and new use of antidepressant medications. During follow-up, median TSH was higher for patients on l-thyroxine alone (2·08 vs 1·07 mU/L; P < 0·001). CONCLUSION: For patients taking long-term liothyronine we did not identify any additional risk of atrial fibrillation, cardiovascular disease or fractures. There was an increased incident use of antipsychotic medication during follow-up.

External validation of a risk assessment model to adjust the frequency of eye-screening visits in patients with diabetes mellitus.

AIMS: To validate a sight-threatening diabetic retinopathy (STDR) risk assessment model to adjust the frequency of eye-screening visits in patients with diabetes mellitus. METHODS: Retrospective follow-up study of patients with diabetes mellitus attending a diabetes center. Anonimyzed data on gender, type and duration of diabetes, HbA1c, blood pressure and the presence and grade of diabetic retinopathy were gathered to estimate risk for STDR for each individual's worse eye over time by means of a prediction model. Receiver operating characteristics (ROC) analysis was performed to determine the diagnostic ability of the model, and a calibration graph was done to see the model fit. RESULTS: 508 screening intervals were analyzed, median diabetes duration was 10years, 87% were type 2 diabetes mellitus, and 3.1% developed STDR before the next screening visit. The area under the ROC curve was 0.74, and the calibration graph showed that model had a good fit. The reduction in screening frequency was 40% compared with fixed annual screening. CONCLUSIONS: Current prediction model used to estimate the risk of developing STDR in patients with diabetes performed well. A personalized screening frequency for diabetic retinopathy could be implemented in practice.

Evaluation of automated image analysis software for the detection of diabetic retinopathy to reduce the ophthalmologists' workload.

AIMS: To assess the safety and workload reduction of an automated 'disease/no disease' grading system for diabetic retinopathy (DR) within a systematic screening programme. METHODS: Single 45° macular field image per eye was obtained from consecutive patients attending a regional primary care based DR screening programme in Valencia (Spain). The sensitivity and specificity of automated system operating as 'one or more than one microaneurysm detection for disease presence' grader were determined relative to a manual grading as gold standard. Data on age, gender and diabetes mellitus were also recorded. RESULTS: A total of 5278 patients with diabetes were screened. The median age and duration of diabetes was 69 years and 6.9 years, respectively. Estimated prevalence of DR was 15.6%. The software classified 43.9% of the patients as having no DR and 26.1% as having ungradable images. Detection of DR was achieved with 94.5% sensitivity (95% CI 92.6- 96.5) and 68.8% specificity (95%CI 67.2-70.4). The overall accuracy of the automated system was 72.5% (95%CI 71.1-73.9). CONCLUSIONS: The present retinal image processing algorithm that can act as prefilter to flag out images with pathological lesions can be implemented in practice. Our results suggest that it could be considered when implementing DR screening programmes.

Post-introduction observation of healthcare technologies after coverage: the Spanish proposal.

OBJECTIVES: When a new health technology has been approved by a health system, it is difficult to guarantee that it is going to be efficiently adopted, adequately used, and that effectiveness, safety, and consumption of resources and costs are in line with what was expected in preliminary investigations. Many governmental institutions promote the idea that efficient mechanisms should be established aimed at developing and incorporating continuous evidence into health technologies management. The purpose of this article is to stimulate the discussion on systematic post-introduction observation of health technologies. METHODS: Literature review and input of HTA experts. RESULTS: The study addresses the key issues related to post-introduction observation and presents a summary of the guide commissioned by the Spanish Ministry of Health, Social Policy and Equality to the Galician HTA agency for the prioritization and implementation of systematic post-introduction observation in Spain. The manuscript describes the prioritization tool developed as part of this project and discusses the main aspects of protocol development, observation implementation, and assessment of results. CONCLUSIONS: The observation of prioritized health technologies after they are introduced in standard clinical practice can provide useful information for health organizations. However, implementing the observation of health technologies can require specific policy frameworks, commitment from different stakeholders, and dedicated funding.