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Cardiometabolic disease is associated with mortality and requirement for ventilation in COVID-19. Symptomatic atherosclerotic cardiovascular disease (CVD) implies the presence of significant endothelial dysfunction and is a risk factor for severe COVID-19. However, many patients with no history of CVD exhibit severe COVID-19. We hypothesised that CVD risk calculators could serve as a proxy for significant endothelial dysfunction and predict COVID-19 outcomes in those without symptomatic CVD. We reviewed 230 patients aged 35 to 65 years, hospitalized with COVID-19 at our institution. 190 patients with no history of symptomatic CVD were included. 23% developed severe respiratory failure (RF, requiring mechanical or non-invasive ventilation), while 4% (7/164) of those without prior end-stage renal disease required renal replacement therapy (RRT). In univariate analysis, age (β = 0.057 ± 0.02, p= 0.02), BMI (β = 0.05 ± 0.03, p = 0.049) and T2DM (β = 0.81 ± 0.41, p = 0.048) predicted RF. In keeping with a link between insulin resistance and severe COVID-19, an association was observed between triglycerides and RF (β = 0.26 ± 0.14, P = 0.058). CVD risk indices QRISK3 (0.07 ± 0.02, P We observed a threshold effect for QRISK3: when 10 year risk of a CV event was > 5% the risk of RF markedly increased (OR: 6.86 (95% CI: 2.30 - 20.5, P5%. A similar trend was observed when analysis was limited to those with T2DM (Ventilatory support in T2DM: QRISK5%: 11/30). All cases of RRT occurred in those with QRISK >5%. CVD risk calculators predict severe COVID-19, supporting a role for subclinical CVD in severe COVID-19. Patients hospitalized with QRISK3 >5% may be candidates for early intervention and enhanced monitoring. Disclosure S. Lockhart: None. A. Sheikh: None. H. Griffiths: None. J. Calvo latorre: None. A. B. Daly: None. L. Sibal: None. Funding National Institute for Health Research

Latika Sibal1, Sharad C Agarwal2, Philip D Home21Wolfson Diabetes and Endocrine Clinic, Addenbrooke's Hospital, Cambridge, UK; 2Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UKBackground: Diabetes mellitus is associated with a high risk of cardiovascular disease. Carotid intima-media thickness (CIMT) is increasingly used as a surrogate marker for atherosclerosis. Its use relies on its ability to predict future clinical cardiovascular end points.Methods: This review examines the evidence linking CIMT as a surrogate marker of vascular complications in people with type 1 and type 2 diabetes. We have also reviewed the various treatment strategies which have been shown to influence CIMT.Conclusions: CIMT measurement is an effective, noninvasive tool which can assist in identifying people with diabetes who are at higher risk of developing microvascular and macrovascular complications. It may also help to evaluate the effectiveness of various treatment strategies used to treat people with diabetes.Keywords: carotid, intima-media thickness, CIMT, diabetes

Endothelium plays a crucial role in the maintenance of vascular tone and structure. Endothelial dysfunction is known to precede overt coronary artery disease. A number of cardiovascular risk factors, as well as metabolic diseases and systemic or local inflammation cause endothelial dysfunction. Nitric oxide (NO) is one of the major endothelium derived vaso-active substances whose role is of prime importance in maintaining endothelial homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in human circulation. Elevated levels of ADMA inhibit NO synthesis and therefore impair endothelial function and thus promote atherosclerosis. ADMA levels are increased in people with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic renal failure. A number of studies have reported ADMA as a novel risk marker of cardiovascular disease. Increased levels of ADMA have been shown to be the strongest risk predictor, beyond traditional risk factors, of cardiovascular events and all-cause and cardiovascular mortality in people with coronary artery disease. Interventions such as treatment with L-arginine have been shown to improve endothelium-mediated vasodilatation in people with high ADMA levels. However the clinical utility of modifying circulating ADMA levels remains uncertain.

Diabet. Med. 27, 37–45 (2010) Abstract Aims Although the limitations of the Friedewald-calculated serum low-density lipoprotein cholesterol (LDL-C) are well recognized, many diabetes and lipid guidelines propose LDL-C as a therapeutic target. The validity of calculated LDL-C in people with Type 1 diabetes (T1DM) is uncertain and the use of alternatives such as non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein measurement unexplored. We have therefore measured LDL-C with the designated reference method and examined some of the potential sources of such bias, including plasma concentrations of other lipids and apolipoproteins. Methods Seventy-four people with T1DM and 80 healthy control subjects were recruited. Fasting samples were collected for analysis of lipid profiles by a beta-quantification (BQ) reference method and by routine laboratory methods including direct HDL-C and calculation of LDL-C using the Friedewald formula. Results Overall, Friedewald LDL-C was 0.29 ± 0.02 (mean ± se) mmol/l (P

Type 1 diabetes is associated with premature arterial disease. Bone-marrow derived, circulating endothelial progenitor cells (EPCs) are believed to contribute to endothelial repair. The hypothesis tested was that circulating EPCs are reduced in young people with type 1 diabetes without vascular injury and that this is associated with impaired endothelial function and increased carotid intima-media thickness (CIMT).We compared 74 people with type 1 diabetes with 80 healthy controls. CD34, CD133, vascular endothelial (VE) growth factor receptor-2 (VEGFR-2) and VE-cadherin antibodies were used to quantify EPCs and progenitor cell subtypes using flow-cytometry. Ultrasound assessment of endothelial function by brachial artery flow-mediated dilatation (FMD) and CIMT was made. Circulating endothelial markers, inflammatory markers and plasma plasminogen activator inhibitor-1 (PAI-1) levels were measured.CD34+VE-cadherin+, CD133+VE-cadherin+ and CD133+VEGFR-2+ EPC counts were significantly lower in people with diabetes (46-69%; p = 0.004-0.043). In people with type 1 diabetes, FMD was reduced by 45% (p0.001) and CIMT increased by 25% (p0.001), these being correlated (r = -0.25, p = 0.033). There was a significant relationship between FMD and CD34+VE-cadherin+ (r = 0.39, p = 0.001), CD133+VEGFR-2+ (r = 0.25, p = 0.037) and CD34+ (r = 0.34, p = 0.003) counts. Circulating high-sensitivity C-reactive protein, PAI-1, interleukin-6 and E-selectin were significantly higher in the diabetes group (p0.001 to p = 0.049), the last two of these correlating with FMD (r = -0.27, p = 0.028 and r = -0.24, p = 0.048, respectively).These findings suggest that abnormalities of endothelial function in addition to pro-inflammatory and pro-thrombotic states are already common in people with type 1 diabetes before development of clinically evident arterial damage. Low EPC counts confirm risk of macrovascular complications and may account for impaired endothelial function and predict future cardiovascular events.

A Diabetes Outcome Progression Trial (ADOPT) was conceived in the hope that the seemingly inexorable decline in islet B-cell function described with metformin, sulfonylureas, and insulin in the UK Prospective Diabetes Study (UKPDS) might be stopped or inhibited to a major degree by peroxisome proliferator–activated receptor-γ agonists, in particular rosiglitazone (1,2). It was already well recognized that the rapid early efficacy of sulfonylureas in lowering glucose was not retained to 12 months, and that metformin and thiazolidinediones had slow onset of action over months, so the design of the study necessarily had to enable decline of measures of blood glucose control to be assessed for a considerable period from 1 year onwards. However, the extent (degree and time) to which this early efficacy of the sulfonylureas in protecting against hyperglycemia would persist was not accurately known. The study also provided a good opportunity to compare durability of effect of the three classes of drugs directly in the context of some shorter-term studies since published (3). Metformin is currently well established as first-line therapy in people with type 2 diabetes, usually after lifestyle measures fail to achieve A1C levels

The aim of the article was to use prospectively collected data on people with type 1 diabetes to examine which routinely collected clinical measures predict the development of peripheral neuropathy in people with type 1 diabetes. Within the Newcastle Diabetes Services, structured data collection at an annual review has been collected since 1985. This includes metabolic measures, cardiovascular risk factors, and markers of complications. From 1990 data collection was standardized and computerized. For this study, all people with type 1 diabetes in the database in both 1992 and 2001 were ascertained. Data were extracted for a diagnosis of peripheral neuropathy (based on neuropathic symptoms, absence of pinprick sensation, and abnormal biothesiometer measurements and/or monofilament sensation) and for the other metabolic and cardiovascular risk measures, as well as markers of other microvascular complications. Associations with the development of neuropathy were sought. Eighteen of 404 people already had peripheral neuropathy in 1992, and 38 others developed neuropathy during follow-up. People who developed neuropathy were older (47 +/- 14 [SD] versus 36 +/- 11 years; P = 0.000), had longer-duration of diabetes (27 +/- 13 versus 18 +/- 10 years; P = 0.001), higher baseline serum cholesterol (5.8 +/- 1.3 versus 5.2 +/- 1.2 mmol/L, P = 0.017), and higher systolic (139 +/- 18 versus 129 +/- 20 mmHg; P = 0.003) and diastolic BP (82 +/- 12 versus 76 +/- 11 mmHg; P = 0.009) than those who remained free of neuropathy. We found no significant difference for BMI and glycated hemoglobin. The multivariate model showed that diastolic BP, duration of diabetes, serum cholesterol, and history of callus/ulcers on the feet predicted the development of peripheral neuropathy. Neuropathy developed in 11.4% of people with type 1 diabetes over a 9-year follow-up, and was predicted by factors normally associated with cardiovascular rather than microvascular disease.

The aim of the article was to use prospectively collected data on people with type 1 diabetes to assess which routinely collected clinical measures predict the development of macrovascular disease in people with type 1 diabetes. Data have been collected in a structured format at an annual review since 1985. For this study, all people with type 1 diabetes in the database in both 1992 and 2001 were ascertained. Data were extracted for a diagnosis of coronary artery disease, stroke, and peripheral vascular disease (macrovascular complications). Presence of other microvascular complications was also ascertained. Forty-one of 404 (10.1%) people had macrovascular disease at the index visit in 1992 and 61 others developed macrovascular complications during follow-up. People who developed macrovascular complications were older (48 +/- 12 versus 36 +/- 11 [SD] years; P = 0.000), had longer duration of diabetes (28 +/- 12 versus 18 +/- 11 years; P = 0.000), higher BMI (26.7 +/- 4.6 versus 25.4 +/- 3.6 kg/m2; P = 0.041), higher base line serum cholesterol (5.9 +/- 1.7 versus 5.2 +/- 1.1 mmol/L, P = 0.007), higher median base line triglyceride levels (1.5 [IQ range 0.9-2.6] versus 1.1 [0.8-1.7] mmol/L; P = 0.002), higher systolic BP (145 +/- 21 versus 129 +/- 20 mmHg; P = 0.000), and higher serum creatinine (102 +/- 57 versus 86 +/- 17 micromol/L; P = 0.038) than those who did not. We found no significant difference in the base line glycated hemoglobin in the two groups. The multivariate model showed that age, duration of diabetes, systolic BP, and serum cholesterol and creatinine levels predicted the development of macrovascular complications, which were also associated with the later development of microalbuminuria. Macrovascular complications developed in 16.8% of people with type 1 diabetes over a 9-year follow-up, and were predicted by potentially modifiable factors including higher BP, BMI, and serum triglyceride and cholesterol levels.

Objective Phaeochromocytoma crisis is a life-threatening emergency that may be undiagnosed because of its numerous, nonspecific manifestations. We analysed, retrospectively, the presentation, management and outcome of patients who were admitted to our institution with phaeochromocytoma crises over a 5-year period. Results Five patients (two males, three females; mean age 34.6 years, range 19-51 years) who presented as emergencies requiring intensive care, with multiple non-specific manifestations and previously undiagnosed pheochromocytoma, were identified. The initial presentation included features of cardiomyopathy (n = 3), atypical pneumonia with myocarditis (n = 1) and acute abdomen (n = 1). Only one of the five cases had a raised blood pressure at the time of the acute presentation. Initiation of beta blockers in four patients was associated with further deterioration in haemodynamic status, labile blood pressure and cardiac arrhythmias, which led to the diagnosis of the underlying phaeochromocytoma. Following intensive supportive therapy and alpha blockade, all five patients recovered and underwent elective surgical removal of phaeochromocytoma, uneventfully. Conclusion Unexplained cardiopulmonary dysfunction, particularly after the institution of beta blockers, should alert clinicians to the possibility of phaeochromocytoma. A high index of suspicion is essential to reduce morbidity and mortality in these patients through early diagnosis and aggressive management.

Objective: To review clinical presentation, management and outcomes following different therapies in patients with pituitary apoplexy. Methods: Retrospective analysis of case-records of patients with classical pituitary apoplexy treated in our hospitals between 1983–2004. Results: Forty-five patients (28 men; mean age 49 years, range 16–72 years) were identified. Only 8 (18%) were known to have pituitary adenomas at presentation. Thirty-four (81%) patients had hypopituitarism at presentation. CT and MRI identified pituitary apoplexy in 28% and 91% cases, respectively. Twenty-seven (60%) patients underwent surgical decompression, whilst 18 (40%) were managed conservatively. Median time from presentation to surgery was 6 days (range 1–121 days). Patients with visual field defects were more likely than those without these signs to be managed surgically (p = 0.01). Complete or near-complete resolution occurred in 93% (13/14), 94% (15/16) and 93% (13/14) of the surgically treated patients with reduced visual acuity, visual field deficit and ocular palsy, respectively. All patients with reduced visual acuity (4/4), visual field deficit (4/4) and ocular palsy (8/8) in the conservative group had complete or near-complete recovery. Only 5 (19%) patients in the surgical group and 2 (11%) in the conservative group had normal pituitary function at follow up. One (4%) patient in the surgical group and 4 (22%) in the conservative group had a recurrence of pituitary adenoma. Conclusions: This large series suggests that the patients with classical pituitary apoplexy, who are without neuro-ophthalmic signs or exhibit mild and non-progressive signs, can be managed conservatively in the acute stage.

The National Institute for Health and Clinical Excellence (NICE) guideline on the management of type 2 diabetes, prepared by the Royal College of Physicians (RCP),[1][1] was the subject of a conference at the College in June 2008. This report highlights some themes of that meeting, concentrating on

Background Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of endothelial nitric oxide synthase (eNOS) that is associated with endothelial dysfunction, and is a risk marker for cardiovascular disease, a significant problem in Type 1 diabetes. The aim of the present study was to measure circulating ADMA, and define its association with endothelial dysfunction and endothelial markers in people with Type 1 diabetes with low likelihood of macrovascular disease. Methods Sixty-one young people with Type 1 diabetes without macrovascular disease or nephropathy and 62 healthy volunteers underwent brachial artery flow-mediated dilatation (FMD) and assay of plasma ADMA and adhesion molecules. Results Age, gender, BMI, lipid profile and renal function were similar in the two groups. People with Type 1 diabetes had impaired FMD compared to healthy controls (5.0 ± 0.4 vs 8.9 ± 0.4%; p < 0.001). Plasma ADMA levels were significantly lower in the people with diabetes compared to healthy controls (0.52 ± 0.12 vs 0.66 ± 0.20 μmol/l, p < 0.001). Plasma ICAM-1, E-selectin and PAI-1 levels were significantly higher in people with diabetes compared to healthy controls (median 201 (IQR 172–226) vs 180 (156–216) μg/l, p = 0.027; 44.2 (32.6–60.9) vs. 33.1 (22.4–51.0) μg/l; p = 0.003 and 70.8 (33.3–85.5) vs 46.3 (23.9–76.8) μg/l, p = 0.035). Plasma ADMA and VCAM-1 levels were positively correlated (r = 0.37, p = 0.003) in people with diabetes. There was no correlation between the plasma ADMA and FMD. Conclusion ADMA levels are not associated with endothelial dysfunction in young adults with Type 1 diabetes without microalbuminuria or known macrovascular disease. This suggests that the impaired endothelial function in these individuals is not a result of eNOS inhibition by ADMA.

Objective To determine the effect of adding nateglinide to therapy with insulin glargine in adults with Type 2 diabetes previously treated with insulin and with poor blood glucose control. Research design and methods In this 16-week, double-blind, placebo-controlled study, people with Type 2 diabetes [n = 55, HbA1c 8.2 ± 1.0 (± sd)%, duration of diabetes 12.8 ± 6.0 years, duration of insulin treatment 6.0 ± 4.0 years] were transferred to single bedtime injection of insulin glargine for a titration period of 4 weeks, and then randomized to nateglinide or matching placebo before meals in addition to insulin glargine. Metformin was continued if taken. Doses of insulin and oral medication were titrated to protocol for the treatment period of 12 weeks. Results Baseline-adjusted self-monitored capillary blood glucose concentration at 12 weeks was significantly lower with nateglinide + insulin glargine compared with placebo + insulin glargine after breakfast [difference −2.3 (95% confidence interval −4.4, −0.2) mmol/l, P = 0.030], before lunch [−2.5 (−4.6, −0.3) mmol/l, P = 0.029], and after lunch [−2.3 (−4.3, −0.4) mmol/l, P = 0.021], but not at other times. Baseline-adjusted HbA1c was not lower with nateglinide + insulin glargine as compared with placebo + insulin glargine [7.8 ± 1.4 vs. 8.3 ± 1.0%, difference −0.43 (−0.98, 0.12)%]. Conclusions Addition of nateglinide before meals to once-daily insulin glargine in people with long-standing diabetes already requiring insulin therapy improves blood glucose control in the early part of the day after breakfast and lunch, but does not provide good control of blood glucose levels overall.

A 75-year-old woman was admitted to hospital with diplopia on leftward gaze. She underwent thyroidectomy several years ago for thyrotoxicosis with subsequent hypothyroidism for which she was on thyroxine replacement. A microcytic, hypochromic anaemia had been diagnosed a few weeks before admission. She gave no history of headache, eye pain or visual loss. On examination, she was pale and had a left sixth nerve palsy. Tenderness over the temporal arteries was notably absent. A diagnosis of mononeuritis was made with a differential diagnosis of isolated ophthalmic Graves’ disease. Biochemical parameters were as shown in Table 1. Abdominal ultrasound and computed tomography scan of the head were unremarkable; in particular, no swelling of the extraocular muscles was noted. An upper gastrointestinal endoscopy and colonoscopy were performed to investigate the anaemia. A mild Campylobacter-like organism test (for Helicobacter pylori infection) proved positive for gastritis, and areas of patchy erythematous mucosa of uncertain significance were seen. Temporal artery biopsy was performed 11 days after admission and while awaiting biopsy results, she was commenced on prednisolone 60 mg daily. Histopathology confirmed giant cell arteritis, showing fragmentation of the internal elastic lamina and an inflammatory cell infiltrate including lymphocytes and multinucleate giant cells (Figure 1). Within a week of commencing steroids, her diplopia improved and resolved completely in 10 days. She was discharged on prednisolone 20 mg daily and followed up in the outpatient clinic. She remains on reducing doses of steroids along with etidronate and calcium supplementation.