Neoadjuvant tyrosine kinase inhibitor therapy in locally advanced differentiated thyroid cancer: a single centre case series.

OBJECTIVE: Primary surgical resection remains the mainstay of management in locally advanced differentiated thyroid cancer. Tyrosine kinase inhibitors have recently shown promising results in patients with recurrent locally advanced differentiated thyroid cancer. This study discussed four patients with locally advanced differentiated thyroid cancer managed with tyrosine kinase inhibitors used prior to surgery in the 'neoadjuvant' setting. METHOD: Prospective data collection through a local thyroid database from February 2016 identified four patients with locally advanced differentiated thyroid cancer unsuitable for primary surgical resection commenced on neoadjuvant tyrosine kinase inhibitor therapy. RESULTS: All cases had T4a disease at presentation. Three cases tolerated tyrosine kinase inhibitor therapy for more than 14 months while the last case failed to tolerate treatment at 1 month. All patients subsequently underwent total thyroidectomy to facilitate adjuvant radioactive iodine treatment. Disease-specific survival remains at 100 per cent currently (range, 29-75 months). CONCLUSION: Neoadjuvant tyrosine kinase inhibitors in locally advanced differentiated thyroid cancer can be effective in reducing primary tumour extent to potentially facilitate a more limited surgical resection for local disease control.

Patient Preparation and Radiation Protection Guidance for Adult Patients Undergoing Radioiodine Treatment for Thyroid Cancer in the UK.

Radioactive iodine is a highly effective treatment for thyroid cancer and has now been used in clinical practice for more than 80 years. In general, the treatment is well tolerated. However, it can be logistically quite complex for patients due to the need to reduce iodine intake and achieve high levels of thyroid-stimulating hormone prior to treatment. Radiation protection precautions must also be taken to protect others from unnecessary radiation exposure following treatment. It has been well documented by thyroid cancer patient support groups that there is significant variation in practice across the UK. It is clear that some patients are being asked to observe unnecessarily burdensome restrictions that make it more difficult for them to tolerate the treatment. At the instigation of these support groups, a multidisciplinary group was assembled to examine the evidence and generate guidance on best practice for the preparation of patients for this treatment and the management of subsequent radiation protection precautions, with a focus on personalising the advice given to individual patients. The guidance includes advice about managing particularly challenging situations, for example treating patients who require haemodialysis. We have also worked together to produce a patient information leaflet covering these issues. We hope that the guidance document and patient information leaflet will assist centres in improving our patients' experience of receiving radioactive iodine. The patient information sheet is available as Supplementary Material to this article.

Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.

AIM: To describe the effect of the stringent lockdown measures, introduced in the UK on 23 March 2020 to curtail the transmission of COVID-19, on glycaemic control in people with type 1 diabetes using flash glucose monitoring. METHODS: We undertook an observational study of 572 individuals with type 1 diabetes for whom paired flash glucose monitoring data were available between early March and May 2020. The primary outcome was change in flash glucose monitoring variables. We also assessed clinical variables associated with change in glycaemic control. RESULTS: Percentage of time in range increased between March and May 2020 [median (interquartile range) 53 (41-64)% vs 56 (45-68)%; P < 0.001], with associated improvements in standard deviation of glucose (P <0.001) and estimated HbA1c (P <0.001). There was a small reduction in the number of individuals meeting the hypoglycaemia target of <5% per day (64% vs 58%; P = 0.004). Comparing changes in flash glucose monitoring data from March to May in 2019 with the same period in 2020 confirmed that these differences were confined to 2020. Socio-economic deprivation was an independent predictor of a ≥5% reduction in time in range during lockdown (odds ratio 0.45 for people in the two most affluent Scottish Index of Multiple Deprivation quintiles; P <0.001). CONCLUSIONS: Lockdown was not associated with a significant deterioration in glycaemic control in people with type 1 diabetes using flash glucose monitoring. However, socio-economic deprivation appeared to increase the risk of decline in glycaemic control, which has implications for how support is focused in challenging times.

Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer.

AIMS: Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine. MATERIALS AND METHODS: A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were 'lenvatinib' and 'thyroid cancer'. RESULTS: Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic blood pressure ≥85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient's blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes. CONCLUSIONS: Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen.

The effect of DAFNE education, continuous subcutaneous insulin infusion, or both in a population with type 1 diabetes in Scotland.

AIM: To investigate the effect of DAFNE and continuous subcutaneous insulin infusion in clinical practice. METHODS: Within NHS Lothian, continuous subcutaneous insulin infusion started in 2004 and DAFNE education began in 2006. We extracted anonymized data from the national database for all those aged > 18 years with type 1 diabetes having a Dose Adjustment For Normal Eating course or continuous subcutaneous insulin infusion start date (n = 4617). RESULTS: In total, 956 persons received DAFNE education, and 505 had received an insulin pump, 208 of whom had DAFNE education followed by insulin pump. Mean (SD) HbA1c before DAFNE education was 68 (15) mmol/mol (8.4% [1.4%]) and 66 (13) mmol/mol (8.2% [1.2%]) before continuous subcutaneous insulin infusion. In the year following DAFNE education, the mean fall in within-person HbA1c was 3.8 mmol/mol (95% CI 4.0 to 3.4; 0.3% [0.4% to 0.3%]). Those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]) experienced the largest decline (15.7 mmol/mol [1.4%]). Those in the lowest HbA1c band at initiation (< 53 mmol/mmol [7.0%]) experienced a rise. In the year following continuous subcutaneous insulin infusion initiation there was a mean fall in within-person HbA1c of 6.6 mmol/mol (6.8 to 6.4; 0.6% [0.6% to 0.6%]). In those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]), the mean fall in HbA1c was 22.2 mmol/mol (23 to 21; 2.0% [2.1% to 1.9%]). Continuous subcutaneous insulin infusion effectiveness was not different with or without DAFNE education. The effects of both interventions were sustained over 5 years. CONCLUSIONS: Both DAFNE education and insulin pump therapy had the greatest effect on HbA1c in those with higher baseline values. There was little difference to attained HbA1c when Dose Adjustment For Normal Eating education was introduced before insulin pump therapy.

Diurnal profile of interstitial glucose following dexamethasone prophylaxis for chemotherapy treatment of gynaecological cancer.

AIMS: Hyperglycaemia, a side-effect of acute glucocorticoid exposure, is associated with poor outcome in those undergoing chemotherapy. The incidence, risk factors and diurnal profile of glucocorticoid-induced glucose dysregulation in the context of chemotherapy treatment remain incompletely understood. METHODS: Blinded continuous interstitial glucose monitoring was performed on 16 women without diabetes for 24 h prior to and 5 days following carboplatin/paclitaxel chemotherapy combined with dexamethasone treatment for gynaecological cancer. At the end of the treatment period, glucose data were analysed and integrated with baseline metabolic and anthropomorphic variables. RESULTS: 15/16 (94%) women exhibited elevated glucose levels (> 11.1 mmol/l). Peak glucose levels were highest on the day of treatment (median 14.45 mmol/l, range 10.2-22.2 mmol/l) and total time spent with an elevated interstitial glucose level was highly variable (median 3.6 h, range 0.0-55.1 h). Peak interstitial glucose levels occurred predominantly, but not exclusively, in the afternoon (13.00-15.00) and evening (19.00-22.00); however elevated levels were noted throughout the 24-h period. Baseline HbA1c was independently associated with severity and duration of elevated glucose levels in a regression adjusted for baseline BMI. CONCLUSIONS: These data report for the first time that high glucose levels are encountered by nearly all women following this regimen, the severity and duration of which are independently associated with HbA1c . Further work is required to determine if controlling glucose levels during treatment influences outcome.

Fatal haemorrhage following fine needle aspiration of the thyroid.

Fine needle aspiration is routinely performed as part of the assessment of thyroid nodules. It is generally regarded as a very safe procedure, though rarely significant bleeding can occur in its aftermath. A 79-year-old female was referred for assessment of an incidental thyroid nodule which had been identified on computed tomography of the chest and extended into the retrosternal space. The patient was referred for fine needle aspiration under ultrasound guidance. Three passes were made with a 25 gauge needle into the nodule; a haemorrhagic aspirate was obtained and sent for cytological examination. Several hours later, the patient developed a cough and progressive breathlessness and died at home before she could be taken to hospital. The key finding from the post-mortem was extensive haemorrhage within the capsule of thyroid. In the absence of another identifiable aetiology, the cause of death was considered to be acute haemorrhage into the thyroid gland. Thyroid fine needle aspiration is generally a safe procedure, but it is important to recognise that, rarely, major complications can occur.

Clinically significant chronic liver disease in people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

BACKGROUND: Type 2 diabetes is an independent risk factor for chronic liver disease, however disease burden estimates and knowledge of prognostic indicators are lacking in community populations. AIMS: To describe the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with Type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease. DESIGN: Prospective cohort study. METHODS: Nine hundred and thirty-nine participants in the Edinburgh Type 2 Diabetes Study underwent investigation including liver ultrasound and non-invasive measures of non-alcoholic steatohepatitis (NASH), hepatic fibrosis and systemic inflammation. Over 6-years, cases of cirrhosis and hepatocellular carcinoma were collated from multiple sources. RESULTS: Eight patients had known prevalent disease with 13 further unknown cases identified (prevalence 2.2%) and 15 incident cases (IR 2.9/1000 person-years). Higher levels of systemic inflammation, NASH and hepatic fibrosis markers were associated with both unknown prevalent and incident clinically significant chronic liver disease (allP < 0.001). CONCLUSIONS: Our study investigations increased the known prevalence of clinically significant chronic liver disease by over 150%, confirming the suspicion of a large burden of undiagnosed disease. The disease incidence rate was lower than anticipated but still much higher than the general population rate. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Ongoing work, with longer follow-up, including analysis of rates of liver function decline, will be used to define optimal risk prediction tools.

Hepatic steatosis and non-alcoholic fatty liver disease are not associated with decline in renal function in people with Type 2 diabetes.

AIMS: We aimed to determine whether the presence of hepatic steatosis and/or non-alcoholic fatty liver disease was associated with decline in renal function or onset of microalbuminuria in a cohort of people with Type 2 diabetes, including those managed in both primary and secondary care. METHODS: Nine hundred and thirty-three patients from the Edinburgh Type 2 Diabetes Study, a cohort of Scottish men and women aged 60-74 years with Type 2 diabetes, underwent assessment for hepatic steatosis by liver ultrasonography 1 year after recruitment. Non-alcoholic fatty liver disease was defined as the presence of steatosis following exclusion of secondary causes of liver disease. Patients were followed for 4 years and decline in renal function was assessed by the change in estimated glomerular filtration rate over time. RESULTS: Of the 933 subjects, 530 had hepatic steatosis and, of those with hepatic steatosis, 388 had non-alcoholic fatty liver disease. Neither hepatic steatosis nor non-alcoholic fatty liver disease were significantly associated with rate of decline in renal function, with the mean rate of decline in estimated glomerular filtration rate being -1.55 ml min(-1) 1.73 m(-2) per year for participants with hepatic steatosis compared with -1.84 ml min(-1) 1.73 m(-2) for those without steatosis (P = 0.19). Similar results were obtained when the analysis was restricted to participants with and without non-alcoholic fatty liver disease (-1.44 vs. -1.64 ml min(-1) 1.73 m(-2) per year, respectively; P = 0.44). Additionally, neither hepatic steatosis nor non-alcoholic fatty liver disease were associated with the onset or regression of albuminuria during follow-up (all P ≥ 0.05). CONCLUSIONS: The presence of hepatic steatosis/non-alcoholic fatty liver disease was not associated with decline in renal function during a 4-year follow-up in our cohort of older people with Type 2 diabetes.

Predictors of treatment failure, incipient hypothyroidism, and weight gain following radioiodine therapy for Graves' thyrotoxicosis.

BACKGROUND: Following radioiodine ((131)I) therapy, both late recognition of hypothyroidism and treatment failure may result in adverse outcomes. AIM: We sought to assess indicators of both incipient hypothyroidism and treatment failure following (131)I and determine factors predictive of weight gain. SUBJECTS AND METHODS: Retrospective study of 288 patients receiving (131)I for treatment of Graves' thyrotoxicosis. Primary outcome measures were thyroid status and weight change at 1 yr following (131)I. RESULTS: The treatment failure rate at 1 yr was 13.5%. Hypothyroidism developed in 80.9%, with 58.5% of patients having levels of free T4 (fT4) <6 pmol/l at diagnosis. Patients receiving thionamides before and after (131)I had significantly higher levels of treatment failure (23.3%) than those with no thionamide exposure (6.3%, p=0.003), but also had more active Graves' disease. Following (131)I, development of a detectable TSH or low-normal fT4 levels was not associated with recurrent thyrotoxicosis. Median weight gain was 5.3 kg, although patients with nadir fT4 levels <6 pmol/l gained an average 2 kg more than those with levels >6 pmol/l (p=0.05). The main predictor of weight gain was fT4 level immediately prior to treatment; those in the lowest tertile gained a median 3.1 kg whilst those in the highest tertile gained 7.4 kg (median difference 4.3 kg; 95% confidence interval: 2.5-6.2). CONCLUSIONS: Marked hypothyroidism following (131)I is common and often occurs early. Simple biochemical parameters may help identify incipient hypothyroidism and potentially limit excess weight gain. Treatment failure is common in patients with severe thyrotoxicosis and in such cases larger doses of (131)I may be warranted.

Can UK healthcare workers remotely support medical education in the developing world?: Focus group evaluation.

OBJECTIVES: To evaluate the feasibility of providing regular, live, text-based teaching to medical students and junior doctors in Somaliland using a dedicated case-based medical education website (www.MedicineAfrica.com). DESIGN: Review of MedicineAfrica database for details of teaching sessions held in Somaliland from December 2008-October 2010 and evaluation of user experiences through focus groups. SETTING: King's College Hospital, London, UK and Ahmoud University, Borama, Somaliland. PARTICIPANTS: Final year medical students, newly graduated interns and second year interns at Ahmoud University, Borama, Somaliland. MAIN OUTCOME MEASURES: Qualitative and quantitative user rating of online case-based tutorials in the context of pre-existing educational opportunities available to them. RESULTS: Regular online teaching sessions are received enthusiastically by students and junior doctors and are reported to improve their clinical practice. CONCLUSIONS: Despite technological limitations in Somaliland, a live text-based teaching service can be delivered effectively and streamlined with local curricula. This represents an alternative to traditional static teaching methodologies currently used in international medical education.

Prevalence of abnormal plasma liver enzymes in older people with Type 2 diabetes.

AIMS: To determine the prevalence and distribution of abnormal plasma liver enzymes in a representative sample of older adults with Type 2 diabetes. METHODS: Plasma concentrations of alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase were measured in a randomly selected, population-based cohort of 1066 men and women aged 60-75 years with Type 2 diabetes (the Edinburgh Type 2 Diabetes Study). RESULTS: Overall, 29.1% (95% CI 26.1-31.8) of patients had one or more plasma liver enzymes above the upper limit of the normal reference range. Only 10.1% of these patients had a prior history of liver disease and a further 12.4% reported alcohol intake above recommended limits. Alanine aminotransferase was the most commonly raised liver enzyme (23.1% of patients). The prevalence of abnormal liver enzymes was significantly higher in men (odds ratio 1.40, 95% CI 1.07-1.83), in the youngest 5-year age band (odds ratio 2.02, 95% CI 1.44-2.84), in patients with diabetes duration < 5 years (odds ratio 1.38, 95% CI 1.01-1.90), plasma HbA(1c) ≥ 58 mmol/mol (7.5%) (odds ratio 1.43, 95% CI 1.09-1.88), obese BMI (odds ratio 2.84, 95% CI 1.59-3.06) and secondary care management for their diabetes (odds ratio 1.40, 95% CI 1.05-1.87). However, all these factors combined accounted for only 7.6% of the variation in liver enzyme abnormality. CONCLUSIONS: The prevalence of elevated liver enzymes in people with Type 2 diabetes is high, with only modest variation between clinically defined patient groups. Further research is required to determine the prognostic value of raised, routinely measured liver enzymes to inform decisions on appropriate follow-up investigations.

A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3.

AIMS/HYPOTHESIS: Impaired fibrin clot lysis is a key abnormality in diabetes and complement C3 is one protein identified in blood clots. This work investigates the mechanistic pathways linking C3 and hypofibrinolysis in diabetes using ex vivo/in vitro studies. METHODS: Fibrinolysis and C3 plasma levels were determined in type 1 diabetic patients and healthy controls, and the effects of glycaemia investigated. C3 incorporation into fibrin clots and modulation of fibrinolysis were analysed by ELISA, immunoblotting, turbidimetric assays and electron and confocal microscopy. RESULTS: Clot lysis time was longer in diabetic children than in controls (599 ± 18 and 516 ± 12 s respectively; p < 0.01), C3 levels were higher in diabetic children (0.55 ± 0.02 and 0.43 ± 0.02 g/l respectively; p < 0.01) and both were affected by improving glycaemia. An interaction between C3 and fibrin was confirmed by the presence of lower protein levels in sera compared with corresponding plasma and C3 detection in plasma clots by immunoblot. In a purified system, C3 was associated with thinner fibrin fibres and more prolongation of lysis time of clots made from fibrinogen from diabetic participants compared with controls (244 ± 64 and 92 ± 23 s respectively; p < 0.05). Confocal microscopy showed higher C3 incorporation into diabetic clots compared with controls, and fully formed clot lysis was prolonged by 764 ± 76 and 428 ± 105 s respectively (p < 0.05). Differences in lysis, comparing diabetes and controls, were not related to altered plasmin generation or C3-fibrinogen binding assessed by plasmon resonance. CONCLUSIONS/INTERPRETATION: C3 incorporation into clots from diabetic fibrinogen is enhanced and adversely affects fibrinolysis. This may be one novel mechanism for compromised clot lysis in diabetes, potentially offering a new therapeutic target.

Severe hypoglycaemia and late-life cognitive ability in older people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

OBJECTIVE: To determine the association between lifetime severe hypoglycaemia and late-life cognitive ability in older people with Type 2 diabetes. METHODS: Cross-sectional, population-based study of 1066 men and women aged 60-75 years, with Type 2 diabetes. Frequency of severe hypoglycaemia over a person's lifetime and in the year prior to cognitive testing was assessed using a previously validated self-completion questionnaire. Results of age-sensitive neuropsychological tests were combined to derive a late-life general cognitive ability factor, 'g'. Vocabulary test scores, which are stable during ageing, were used to estimate early life (prior) cognitive ability. RESULTS: After age- and sex- adjustment, 'g' was lower in subjects reporting at least one prior severe hypoglycaemia episode (n = 113), compared with those who did not report severe hypoglycaemia (mean 'g'-0.34 vs. 0.05, P < 0.001). Mean vocabulary test scores did not differ significantly between the two groups (30.2 vs. 31.0, P = 0.13). After adjustment for vocabulary, difference in 'g' between the groups persisted (means -0.25 vs. 0.04, P < 0.001), with the group with severe hypoglycaemia demonstrating poorer performance on tests of Verbal Fluency (34.5 vs. 37.3, P = 0.02), Digit Symbol Testing (45.9 vs. 49.9, P = 0.002), Letter-Number Sequencing (9.1 vs. 9.8, P = 0.005) and Trail Making (P < 0.001). These associations persisted after adjustment for duration of diabetes, vascular disease and other potential confounders. CONCLUSIONS: Self-reported history of severe hypoglycaemia was associated with poorer late-life cognitive ability in people with Type 2 diabetes. Persistence of this association after adjustment for estimated prior cognitive ability suggests that the association may be attributable, at least in part, to an effect of hypoglycaemia on age-related cognitive decline.

Prevalence and markers of advanced liver disease in type 2 diabetes.

BACKGROUND: Type 2 diabetes is a risk factor for progression of non-alcoholic fatty liver disease (NAFLD) to fibrosis and cirrhosis. We examined the prevalence of advanced liver disease in people with type 2 diabetes and analysed the effectiveness of liver function tests (LFTs) as a screening tool. METHODS: Participants (n = 939, aged 61-76 years) from the Edinburgh Type 2 Diabetes Study, a randomly selected population of people with type 2 diabetes, underwent abdominal ultrasonography. Hyaluronic acid (HA) and platelet count/spleen diameter ratio (PSR) were used as non-invasive markers of hepatic fibrosis and portal hypertension. Subjects were screened for secondary causes of liver disease that excluded them from a diagnosis of NAFLD. The efficacy of LFTs [alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT)] in screening for liver disease was determined. RESULTS: Cirrhosis was identified by ultrasound in four participants (0.4%). Ten (1.1%) had evidence of portal hypertension (PSR < 909), and two (0.2%) had hepatocellular carcinoma. Fifty-three participants (5.7%) had evidence of hepatic fibrosis (HA > 100 ng/ml in the absence of joint disease); a further 169 had HA > 50 ng/ml. In participants with NAFLD-related fibrosis (HA > 100 ng/ml), 12.5% had an elevated ALT level and 17.5% had an elevated GGT level. CONCLUSION: The prevalence of hepatic fibrosis and cirrhosis were lower than expected. The use of LFTs to screen for liver disease missed most cases of fibrosis predicted by raised HA levels.

Association of retinal arteriolar dilatation with lower verbal memory: the Edinburgh Type 2 Diabetes Study.

AIMS/HYPOTHESIS: Retinal vascular calibre changes may reflect early subclinical microvascular disease in diabetes. Because of the considerable homology between retinal and cerebral microcirculation, we examined whether retinal vascular calibre, as a proxy of cerebral microvascular disease, was associated with cognitive function in older people with type 2 diabetes. METHODS: A cross-sectional analysis of 954 people aged 60-75 years with type 2 diabetes from the population-based Edinburgh Type 2 Diabetes Study was performed. Participants underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests. The Mill Hill Vocabulary Scale was used to estimate pre-morbid cognitive ability. Retinal vascular calibre was measured from an image field with the optic disc in the centre using a validated computer-based program. RESULTS: After age and sex adjustment, larger retinal arteriolar and venular calibres were significantly associated with lower scores for the Wechsler Logical Memory test, with standardised regression coefficients -0.119 and -0.084, respectively (p < 0.01), but not with other cognitive tests. There was a significant interaction between sex and retinal vascular calibre for logical memory. In male participants, the association of increased retinal arteriolar calibre with logical memory persisted (p < 0.05) when further adjusted for vocabulary, venular calibre, depression, cardiovascular risk factors and macrovascular disease. In female participants, this association was weaker and not significant. CONCLUSIONS/INTERPRETATION: Retinal arteriolar dilatation was associated with poorer memory, independent of estimated prior cognitive ability in older men with type 2 diabetes. The sex interaction with stronger findings in men requires confirmation. Nevertheless, these data suggest that impaired cerebral arteriolar autoregulation in smooth muscle cells, leading to arteriolar dilatation, may be a possible pathogenic mechanism in verbal declarative memory decrements in people with diabetes.

The use of ultrasound to diagnose hepatic steatosis in type 2 diabetes: intra- and interobserver variability and comparison with magnetic resonance spectroscopy.

AIM: To compare ultrasound gradings of steatosis with fat fraction (FF) on magnetic resonance spectroscopy (MRS; the non-invasive reference standard for quantification of hepatic steatosis), and evaluate inter- and intraobserver variability in the ultrasound gradings. MATERIALS AND METHODS: Triple grading of hepatic ultrasound examination was performed by three independent graders on 131 people with type 2 diabetes. The stored images of 60 of these individuals were assessed twice by each grader on separate occasions. Fifty-eight patients were pre-selected on the basis of ultrasound grading (normal, indeterminate/mild steatosis, or severe steatosis) to undergo (1)H-MRS. The sensitivity and specificity of the ultrasound gradings were determined with reference to MRS data, using two cut-offs of FF to define steatosis, ≥9% and ≥6.1%. RESULTS: Median (intraquartile range) MRS FF (%) in the participants graded on ultrasound as normal, indeterminate/mild steatosis, and severe steatosis were 4.2 (1.2-5.7), 4.1 (3.1-8.5) and 19.4 (12.9-27.5), respectively. Using a liver FF of ≥6.1% on MRS to denote hepatic steatosis, the unadjusted sensitivity and specificity of ultrasound gradings (severe versus other grades of steatosis) were 71 and 100%, respectively. Interobserver agreement within one grade was observed in 79% of cases. Exact intraobserver agreement ranged from 62 to 87%. CONCLUSION: Hepatic ultrasound provided a good measure of the presence of significant hepatic steatosis with good intra- and interobserver agreement. The grading of a mildly steatotic liver was less secure and, in particular, there was considerable overlap in hepatic FF with those who had a normal liver on ultrasound.

R D Lawrence Lecture 2010. The brain as a target organ in Type 2 diabetes: exploring the links with cognitive impairment and dementia.

Type 2 diabetes is associated with cognitive impairment and dementia, but the precise underlying mechanisms remain unresolved. Very high blood glucose concentrations are associated with mood changes and poor memory function, possibly by causing alterations in cerebral blood flow or osmotic changes in neurones, and correction of acute hyperglycaemia appears beneficial. Chronic hyperglycaemia may cause structural changes in the brain, such as cerebral microvascular disease, and there are strong associations between the presence of retinal microvascular abnormalities and cognitive function. Functional insulin deficiency in the brain may also be a factor, but trials with rosiglitazone in people with diabetes and other trials in people with Alzheimer's disease have shown no specific benefit of insulin sensitization. There is an association between hypoglycaemia and cognitive impairment in people with Type 2 diabetes; part of that association may simply be a consequence of the fact that people with cognitive impairment find it more difficult to manage their diabetes and so are more prone to hypoglycaemia. The potential for hypoglycaemia to cause harm to the brain has been debated for many years, and the issue remains unresolved. An ongoing prospective study of risk factors for cognitive impairment in people with Type 2 diabetes (Edinburgh Type 2 Diabetes Study) should improve our understanding of the aetiology of cognitive impairment and inform the design of future intervention trials.