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Charlotte Steffensen,1 Reimar W Thomsen,2 Allan Vaag,3 Henning Beck-Nielsen,4 Jens Sandahl Christiansen,1 Torben Hansen,5,6 Oluf Borbye Pedersen,5,6 Jørgen Rungby11Aarhus University Hospital, Department of Medicine, Aarhus, 2Aarhus University Hospital, Institute of Clinical Medicine, Department of Clinical Epidemiology, Aarhus, 3Copenhagen University Hospital "Rigshospitalet", Department of Endocrinology, Copenhagen, 4Odense University Hospital, Department of Endocrinology, Odense, 5The Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, 6Faculty of Health Sciences, University of Aarhus, Aarhus, DenmarkAbstract: Here we provide an overview of the rationale and methods of a series of planned population based studies within the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Project. The project aims to support and evaluate ongoing political and administrative efforts to implement nationwide guidelines for maintaining metabolic control in newly diagnosed type 2 diabetes (T2D) patients to prevent diabetic complications and improve quality of life. The DD2 is designed as a prospective cohort study (collection of epidemiological data) supplemented by randomized clinical intervention trials (on physical exercise and individualized pharmacological treatment) and the establishment of a biobank comprised of material from a large number of newly diagnosed T2D patients. Inclusion of the majority of newly diagnosed T2D patients as they are diagnosed at their general practitioner or diabetes hospital outpatient clinics and entered into the DD2 cohort will establish a nationwide database comprising a large number of future incident cases of T2D in Denmark. These cases will form the project cohort of the DD2. Within the first 6 months of diagnosis, all patients will be invited to contribute to a biobank of DNA, plasma, urine, and tissue sampling. The DNA biobank will enable future studies of the effect of pharmacological treatment and outcome in subsets of patients with specific genetic risk profiles covering disease etiology and specific drug kinetics and metabolism. We will also perform two clinical intervention trials examining: the effectiveness of physical exercise on diabetes-related outcomes and the impact of trial outcomes on individualized pharmacological treatment. Moreover, the DD2 will serve as a platform for testing and developing new antidiabetic drugs. All together, we expect this study to contribute to substantially improved diabetes care in T2D patients locally and abroad.Keywords: type 2 diabetes, prognosis, intervention, physical exercise

Jens Steen Nielsen,1 Reimar W Thomsen,2 Charlotte Steffensen,2 Jens S Christiansen31Department of Endocrinology M, Odense University Hospital, Odense, 2Department of Clinical Epidemiology, 3Department of Endocrinology, Aarhus University Hospital, Aarhus, DenmarkAbstract: This paper aims to describe the patient enrollment system and implementation strategy for the new nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. The paper will also describe the design, current content, and pilot testing of the DD2 registration form. The challenge of the DD2 project was to construct a registration system functioning in the entire Danish health care system, where new type 2 diabetes patients are initially met, and with the capacity to enroll 200 newly diagnosed diabetes patients per week nationwide. This requires a fast and simple registration that is part of everyday clinical practice in hospital outpatient clinics and general practitioner (GP) clinics. The enrollment system is thus built on a tested, rational design where patients need only one visit and only specific limited data about physical activity, anthropometric measures, and family history of diabetes are collected during a brief patient interview. Later, supplemental data will be extracted by computerized linkage with existing databases. The feasibility of this strategy was verified in a pilot study. For maximum flexibility, three different ways to fill in the DD2 registration form were provided and an interactive webpage was constructed. The DD2 project also involves collection of blood and urine samples from each diabetes patient, to be stored in a biobank. Clinicians may obtain the samples themselves or refer patients to the nearest clinical biochemical department. GPs have the additional option of referring patients to the nearest hospital outpatient diabetes clinic to obtain interview data, clinical data, and samples. At present, the enrollment system is in use at 17 hospital outpatient diabetes clinics and 45 GP clinics nationwide, together enrolling 40 new type 2 diabetes patients per week in the DD2 project. A total of 990 patients have now been enrolled and the DD2 is ready to expand nationwide.Keywords: DD2, type 2 diabetes, logistics, implementation, data registration, health information technology

Introduction: Prospectively gated 64-slice CT coronary angiography (CTCA) may be contraindicated for heart rates (HRs) over 65 beats per minute (bpm) due to reduced diagnostic sensitivity. Newer CT scanners typically provide 128 or more slices and superior temporal resolution compared with older models; consequently, diagnostic accuracy for current technology prospectively gated CTCA may be adequate at HRs above 65 bpm. The aim of this systematic review was to investigate the diagnostic accuracy of CTCA using 128-slice or greater CT technology when compared with conventional coronary angiography for patients with HRs >65 bpm., Methods: A systematic search of PubMed, CINAHL, EMBASE and Scopus was performed as well as unpublished databases, sources and reference lists. Titles and abstracts were screened by two independent reviewers. Full-text screening was then performed. Studies that determined diagnostic accuracy of coronary artery stenosis in adult patients with high heart rates utilising prospectively gated 128 detector or greater scanners were included. Studies that were included in the review underwent critical appraisal using the QUADAS-2 tool., Results: Ten studies were included in the systematic review, with nine of these included in a diagnostic test accuracy meta-analysis, including six of which reported data at the patient level. Meta-analysis indicated very high pooled sensitivity 100% (95% CI 0.99, 1.00); however, pooled specificity was less at 79% (95% CI 0.69, 0.88)., Conclusions: Prospectively gated CT coronary angiography may be justifiable at heart rates above 65 bpm if performed on a 128-slice or greater CT unit. Caution regarding the implication of a positive result is recommended due to reduced specificity. Further evidence is required before consideration of a new higher heart threshold., (© 2021 The Authors. Journal of Medical Radiation Sciences published by John Wiley & Sons Australia, Ltd on behalf of Australian Society of Medical Imaging and Radiation Therapy and New Zealand Institute of Medical Radiation Technology.)

This case report describes a 57-year-old male with symptoms of tardive akathisia after long-term metoclopramide treatment. As metoclopramide is a dopamine receptor antagonist, it has the potential to cause drug-induced movement disorders, including akathisia, which is characterised by an inner restlessness resulting in a need for constant movement. Tardive akathisia, in contrast to acute akathisia, evolves after prolonged exposure to the triggering medication and can be a permanent condition. Treatment duration of metoclopramide should be restricted, and awareness of neurological side effects is important.

Medical imaging is an ever changing field with significant advancements in techniques and technologies over the years. Despite being constantly challenged by change, it can be difficult to introduce changes into healthcare settings. In this article we introduce the principles of change management to achieve an evidence-based practice in radiography., Competing Interests: Conflict of interest statement Zachary Munn, Alexa Mcarthur and Zoe Jordan are employed by JBI, an evidence-based healthcare research and development organisation situated within the University of Adelaide. Gordon Mander is employed by Queensland Health and is a former JBI HDR student. Caitlin Steffenson is employed by Phillips Australia and is a former JBI HDR student., (Copyright © 2020 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

Evidence-based healthcare is an approach to practice whereby decision making and service delivery considers the best available evidence, patient choice, local resources and clinical expertise. Although sound in theory, compliance with evidence-based practice is often far from optimal. To address this, related fields such as knowledge translation and implementation science have emerged, which largely focus on methods and techniques to facilitate the transfer of evidence into practice. This introductory article explains the key concepts of evidence-based healthcare by using the JBI Model as a framework to highlight the lifecycle of evidence-based information. Throughout the article we refer to exemplars from medical radiation to highlight these concepts., (Copyright © 2020 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

Objective: The purpose of this review is to investigate the effectiveness of adjusting radiographic technique parameters on image quality of projectional radiographs acquired on a direct digital radiography system., Introduction: Projectional radiography performed with direct digital detectors is now commonplace in many medical imaging departments across the world. While the acquisition technology has advanced, it appears that many sites have not optimized their radiographic technique factors for this new technology. The aim of this review is to uncover evidence to support the continued use of these traditional technique parameters or to suggest changes in clinical practice that would produce optimized results., Inclusion Criteria: The review will consider studies that include projectional radiographs acquired on a direct digital radiography system of the axial and appendicular skeleton. Only studies that investigate a human subject (living or post-mortem), or an anthropomorphic phantom will be included. Studies that directly investigate the effect of changing a technique parameter on the resultant image quality and the effect on patient dose will be included., Methods: A comprehensive search of both published and unpublished literature will be performed to uncover studies meeting the inclusion criteria. Studies will be screened for inclusion by two reviewers and disagreements resolved through discussion or with a third reviewer. Studies included in final analysis will be critically appraised for methodological quality. Data will be extracted by a single reviewer and checked by the author team for accuracy. Statistical meta-analysis and subgroup analyses will be performed as appropriate, and a Summary of Findings created., Systematic Review Registration Number: PROSPERO CRD42019137806.

Objective: The objective of this review is to determine the diagnostic accuracy of computed tomography coronary angiography (CTCA) using recent scan technologies for detecting coronary artery disease (CAD) in adults with high heart rates., Introduction: Invasive coronary angiography is the gold standard for detecting significant CAD, but it is costly and carries risks of complications. Computed tomography coronary angiography has a high sensitivity for diagnosing CAD, although image quality may be affected by elevated heart rates. Recent technological advances in scanner design may increase the diagnostic accuracy of CTCA., Inclusion Criteria: This review will consider diagnostic test accuracy studies that include adults 18 years and older with a heart rate greater than 65 beats per minute who have undergone CTCA to diagnose CAD (greater than 50% stenosis). Eligible studies will compare invasive coronary angiography with computed tomography scanner technologies that use either single- or dual-source scanner configuration in prospective electrocardiogram scan acquisition mode, and with a total scanner coverage equal to or greater than 128 detector-rows. Studies published in English from 2007 will be considered., Methods: PubMed, Embase, CINAHL and Scopus will be searched, along with Google Scholar, the NIHR-HTA register, computed tomography vendors and conference abstracts. Screening of potential titles and abstracts, retrieval of full-text studies, assessment of methodological quality and data extraction will be performed independently by two reviewers. Meta-analyses will be performed, if possible, and a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Summary of Findings presented.

Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol ≤50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60±10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Pregnancy in Cushing's syndrome (CS) is extremely rare due to the influence of hypercortisolism on the reproductive axis. Purpose of this study is to investigate whether the etiology of CS in pregnancy determines a different impact on the fetal/newborn and maternal outcomes. We performed a systematic review of cases published in the literature from January 1952 to April 2015 including the words "Cushing AND pregnancy". We included 168 manuscripts containing 220 patients and 263 pregnancies with active CS during pregnancy and with a history of CS but treated and cured hypercortisolism at the time of gestation. Adrenal adenoma was the main cause of active CS during pregnancy (44.1 %). Women with active CS had more gestational diabetes mellitus (36.9 vs. 2.3 %, p = 0.003), gestational hypertension (40.5 vs. 2.3 %, p < 0.001) and preeclampsia (26.3 vs. 2.3 %, p = 0.001) than those with cured disease. The proportion of fetal loss in active CS was higher than in cured CS (23.6 vs. 8.5 %, p = 0.021), as well as global fetal morbidity (33.3 vs. 4.9 %, p < 0.001). The predictors of fetal loss in active CS were etiology of hypercortisolism [Odds Ratio -OR-for pregnancy-induced CS 4.7 (95 % Confidence Interval-CI 1.16-18.96), p = 0.03], publication period [OR for "1975-1994" 0.10 (95 % CI 0.03-0.40), p = 0.001] and treatment during gestation (p = 0.037, [OR medical treatment 0.25 (95 % CI 0.06-1.02), p = 0.052], [OR surgical treatment 0.34 (95 % CI 0.11-1.06), p = 0.063]). The period of diagnosis of CS (before, during or after pregnancy) was the only predictor of overall fetal morbimortality [OR for diagnosis during pregnancy 4.66 (95 % CI 1.37-15.83), p = 0.014]. Patients with active CS, especially in pregnancy-induced CS, experienced more problems in pregnancy and had the worst fetal prognosis in comparison to other causes. Diagnosis of CS during pregnancy was also associated with worse overall fetal morbimortality. Both medical treatment and surgery during pregnancy appeared to be protective in avoiding fetal loss.

Objective: Type 2 diabetes (T2D) and Cushing's syndrome (CS) share clinical characteristics, and several small studies have recorded a high prevalence of hypercortisolism in T2D, which could have therapeutic implications. We aimed to assess the prevalence of endogenous hypercortisolism in T2D patients., Design: Systematic review and meta-analysis of the literature., Methods: A search was performed in SCOPUS, MEDLINE, and EMBASE for original articles assessing the prevalence of endogenous hypercortisolism and CS in T2D. Data were pooled in a random-effect logistic regression model and reported with 95% confidence intervals (95% CI)., Results: Fourteen articles were included, with a total of 2827 T2D patients. The pooled prevalence of hypercortisolism and CS was 3.4% (95% CI: 1.5-5.9) and 1.4% (95 CI: 0.4-2.9) respectively. The prevalence did not differ between studies of unselected patients and patients selected based on the presence of metabolic features such as obesity or poor glycemic control (P = 0.41 from meta-regression). Imaging in patients with hypercortisolism (n = 102) revealed adrenal tumors and pituitary tumors in 52 and 14% respectively., Conclusions: Endogenous hypercortisolism is a relatively frequent finding in T2D, which may have therapeutic implications., (© 2016 European Society of Endocrinology.)

Background: Hypercortisolism is prevalent in type 2 diabetes (T2D), but analytical and functional uncertainties prevail. Measurement of salivary cortisol is considered an expedient screening method for hypercortisolism, but its usefulness in the context of T2D is uncertain., Aim: To compare late-night salivary cortisol (LNSC) with the 1 mg overnight dexamethasone suppression test (DST), which was considered 'reference standard', in T2D., Patients and Methods: A total of 382 unselected and recently diagnosed patients with T2D underwent assessment of LNSC and DST, and the test outcome was related to age, gender, body mass index (BMI) and haemoglobin A1c levels. We used the following cut-off values: LNSC ≤ 3·6 nmol/l and DST ≤ 50 nmol/l., Results: The median (range) levels of LNSC and DST were 6·1 (0·3-46·2) nmol/l and 34 (11-547) nmol/l, respectively. Hypercortisolism was present in 86% based on LNSC values and 22% based on DST. LNSC, as compared to DST, had the following test characteristics: sensitivity: 85% (95% CI: 7-92%), specificity: 14% (95% CI: 10-19%), positive predictive value: 22% (95% CI: 17-27%), negative predictive value: 76% (95% CI: 63-87%), and overall accuracy: 30% (95% CI: 25-34%). LNSC and DST values were not associated with haemoglobin A1c, BMI and age in this cohort of patients with T2D., Conclusion: The LNSC is characterized by very low specificity and poor positive predictive value as compared to the DST, resulting in an overall low accuracy. Further methodological and clinical studies are needed to substantiate the relevance of cortisol status in T2D., (© 2016 John Wiley & Sons Ltd.)

A 48-year-old woman presented with galactorrhoea, moderate hyperprolactinaemia (0.97 IU/l) and a pituitary macroadenoma (10 × 7 × 6 mm). Over a period of six years the patient had developed overt acromegalic features and was subsequently diagnosed with acromegaly while treated with dopamine receptor agonist. Acromegaly should always be considered in patients presenting with hyperprolactinaemia and a pituitary adenoma.

Treatment with dopamin agonists, particularly cabergoline, is the primary and preferred therapy for prolactinomas and symptomatic hyperprolactinaemia due to its effectiveness and tolerability. However, an association has been demonstrated between fibrotic heart valve disease and high-dose dopamin agonist use in patients with Parkinson's disease in several echocardiographic studies. Such observations have prompted a number of studies of valvular function in cabergoline-treated hyperprolactinaemia patients. These studies have failed to show an increased prevalence of clinically significant valvular regurgitation.

Background: Increased risk of heart valve disease during treatment with certain dopamine agonists, such as cabergoline, has been observed in patients with Parkinson's disease. The same compound is used to treat hyperprolactinemia, but it is unknown whether this also associates with heart valve disease., Objectives: The objective of the study was to assess the incidence of diagnosed heart valve disease and cardiac valve surgery among patients with hyperprolactinemia, compared with a general population cohort in Denmark., Design: This was a nationwide, population-based, cohort study based on a nationwide hospital registry., Methods: We identified 2381 hyperprolactinemia patients with a first-time diagnosis recorded from 1994 through 2010 in the registry, with no previous hospital diagnosis of heart valve disease. Each patient was compared with 10 age- and gender-matched comparison cohort members from the general population. The association between hyperprolactinemia and heart valve disease was analyzed with Cox's proportional hazards regression, controlling for potential confounding factors. To assess the risk of cardiac valve surgery and avoid ascertainment bias, a subanalysis was made in a cohort of 2,387 hyperprolactinemia patients with no previous cardiac valve surgery and 23,870 comparison cohort members., Results: Nineteen hyperprolactinemic patients (0.80%) were diagnosed with heart valve disease during a total of 17,759.8 yr of follow-up, compared with 75 persons (0.31%) in the comparison cohort during 179,940.6 yr of follow-up [adjusted hazard ratio 2.27 (95% confidence interval 1.35-3.82)]. Seven of the 10 patients treated with cabergoline and diagnosed with heart valve disease were asymptomatic and diagnosed on the basis of an echocardiography performed as a safety measure. However, only two patients with hyperprolactinemia (0.08%) underwent surgery, compared with 28 persons in the general population cohort (0.12%) [adjusted hazard ratio 0.55 (95% confidence interval 0.13-2.42)]., Conclusions: Data from the present register-based study do not support that hyperprolactinemia or its treatment is associated with an increased risk of clinically significant heart valve disease.

Introduction: Epidemiological evidence suggests an association between type 2 diabetes (T2DM) and Alzheimer's disease (AD), in that one disease increases the risk of the other. T2DM and AD share several molecular processes which underlie the tissue degeneration in either disease. Disturbances in insulin signaling may be the link between the two conditions. Drugs originally developed for T2DM are currently being considered as possible novel agents in the treatment of AD., Areas Covered: This review discusses the potential role of glucagon-like peptide -1 (GLP-1) treatment in AD. GLP-1 receptors are expressed in areas of the brain important to memory and learning, and GLP-1 has growth-factor-like properties similar to insulin. A key neuropathological feature of AD is the accumulation of amyloid-beta (Aβ). In preclinical studies, GLP-1 and longer lasting analogues have been shown to have both neuroprotective and neurotrophic effects, and to protect synaptic activity in the brain from Aβ toxicity., Expert Opinion: A convincing amount of evidence has shown a beneficial effect of GLP-1 agonist treatment on cognitive function, memory and learning in experimental models of AD. GLP-1 analogues may therefore be the new therapeutic agent of choice for intervention in AD.

Overt Cushing's syndrome is a rare disorder with an annual incidence of 2-3/million of which benign adrenal adenomas account for 0.6/million. The female:male ratio is 3:1. Preliminary data indicate a high proportion of subclinical Cushing's syndrome in certain risk populations such as patients with type 2 diabetes or osteoporosis. The clinical implications of these observations are presently unclear. Surgery remains first line treatment for overt disease and initial cure or remission is obtained in 65-85% of patients with Cushing's disease. Late recurrences, however, occur in up to 20% and the risk does not seem to plateau even after 20 years of follow-up. A 2- to 3-fold increase in mortality is observed in most studies, and this excess mortality seems confined to patients in whom initial cure was not obtained. Cushing's syndrome continues to pose diagnostic and therapeutic challenges and life-long follow-up is mandatory., (Copyright © 2010 S. Karger AG, Basel.)

Enzymatic crosslinking provides valuable means for modifying functionality and structural properties of different polymers. Tyrosinases catalyze the hydroxylation of various monophenols to the corresponding o-diphenols, and the subsequent oxidation of o-diphenols to the corresponding quinones, which are highly reactive and can further undergo non-enzymatic reactions to produce mixed melanins and heterogeneous polymers. Tyrosinases are also capable of oxidizing protein- and peptide-bound tyrosyl residues, resulting in the formation of inter- and intra-molecular crosslinks. Tyrosinases from apple (AT), potato (PT), the white rot fungus Pycnoporus sanguineus (PsT), the filamentous fungus Trichoderma reesei (TrT) and the edible mushroom Agaricus bisporus (AbT) were compared for their biochemical characteristics. The enzymes showed different features in terms of substrate specificity, stereo-specificity, inhibition, and ability to crosslink the model protein, alpha-casein. All enzymes were found to produce identical semiquinone radicals from the substrates as analyzed by electron spin resonance spectroscopy. The result suggests similar reaction mechanism between the tyrosinases. PsT enzyme had the highest monophenolase/diphenolase ratio for the oxidation of monophenolic L-tyrosine and diphenolic L-dopa, although the tyrosinases generally had noticeably lower activity on monophenols than on di- or triphenols. The activity of AT and PT on tyrosine was particularly low, which largely explains the poor crosslinking ability of the model protein alpha-casein by these enzymes. AbT oxidized peptide-bound tyrosine, but was not able to crosslink alpha-casein. Conversely, the activity of PsT on model peptides was relatively low, although the enzyme could crosslink alpha-casein. In the reaction conditions studied, TrT showed the best ability to crosslink alpha-casein. TrT also had the highest activity on most of the tested monophenols, and showed noticeable short lag periods prior to the oxidation.