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Background: In recent years, several treatment modalities have proved to be effective in the treatment of neuroendocrine tumours (NETs). However, there is currently no consensus on the sequence in which these options are best used., Methods: In this observational study, we analysed the treatment modalities and sequences of all patients included in the Swiss NeuroEndocrine Tumour registry (SwissNET). SwissNET is a national registry, which has prospectively included patients with a NET from all regions of Switzerland since 2008., Results: The registry includes 1366 patients; 1063 had documented therapies after the main diagnosis and were included in the analysis. The median follow-up time was 1.86 years. The most common primary site was the small intestine (291 patients, 27%) followed by pancreas (254 patients, 24%), lung (172 patients, 16%) and appendix (163 patients, 15%). A total of 167 different therapy sequences were observed. In 708 (67%) patients, surgery was the only treatment. The sequence of surgery followed by chemotherapy was most frequently documented in poorly (G3) differentiated (24 patients, 60%) and pancreatic (15 patients, 34%) NETs. Tumours treated with surgery followed by biotherapy or followed by peptide receptor radionuclide therapy (PRRT) were predominantly well-differentiated G1 NETs of the small intestine. In patients who were treated with either PRRT or systemic therapy (chemotherapy or molecular therapy) or both, PRRT was used more frequently than systemic therapy in patients with a small intestinal NET (35 patients, 62% vs 30, 54%), whereas the opposite held true in pancreatic (44 patients, 59% vs 56, 70%) and lung NETs (6 patients, 14% vs 40, 97%). If both chemotherapy and molecular therapy were used, chemotherapy was applied prior to molecular therapy in 13 of 19 (68%) patients with a pancreatic NET., Conclusion: Surgery represents the treatment of choice in most patients with a NET irrespective of tumour stage. In patients receiving additional treatment, an impressive variety of treatment sequences were documented. In small intestinal NETs, patients received PRRT more often than chemotherapy, whereas the opposite holds true for patients with pancreatic and lung NETs.

Although the benefits of regular exercise on cardiovascular risk factors are well established for people with type 1 diabetes (T1D), glycemic control remains a challenge during exercise. Carbohydrate consumption to fuel the exercise bout and/or for hypoglycemia prevention is an important cornerstone to maintain performance and avoid hypoglycemia. The main strategies pertinent to carbohydrate supplementation in the context of exercise cover three aspects: the amount of carbohydrates ingested (i.e., quantity in relation to demands to fuel exercise and avoid hypoglycemia), the timing of the intake (before, during and after the exercise, as well as circadian factors), and the quality of the carbohydrates (encompassing differing carbohydrate types, as well as the context within a meal and the associated macronutrients). The aim of this review is to comprehensively summarize the literature on carbohydrate intake in the context of exercise in people with T1D.

Background: Programming of His-bundle pacing may be challenging because current implantable pulse generators are not specifically designed for this pacing modality., Objective: The purpose of this study was to evaluate electrical parameters in order to propose preset programming options with different configurations., Methods: Data were collected from 50 patients with His pacing leads connected to various ports (atrial, right ventricular, or left ventricular) of pacemakers and defibrillators during a detailed device interrogation, which included capture thresholds with various pacing vectors, measurement of timing intervals, and performance of automatic threshold algorithms., Results: His-bundle pacing thresholds were significantly lower during unipolar pacing compared to bipolar and extended bipolar polarities. However, current drain was offset due to lower impedance. The His pace-right ventricular sensed intervals were measured at 40-150 ms (mean 85 ± 25 ms), with the longest delays in patients with uncorrected right bundle branch block and selective His capture. This has implications for ventricular safety pacing windows (which were inactivated without evidence of crosstalk) and delays to minimize unnecessary ventricular backup pacing (which was also affected by refractory periods). The measured intervals also impacted the performance of automatic threshold algorithms, which performed differently depending on which port the His lead was connected to and did not distinguish between His and myocardial capture., Conclusion: Our report provides data that could serve to configure automated programming settings to simplify management of His-bundle pacing., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

We evaluated the efficacy and safety of short-term fully closed-loop insulin delivery using faster versus standard insulin aspart in type 2 diabetes. Fifteen adults with insulin-treated type 2 diabetes underwent 22 hours of closed-loop insulin delivery with either faster or standard insulin aspart in a double-blind randomized crossover design. Basal-bolus regimen was replaced by model predictive control algorithm-directed insulin delivery based on sensor glucose levels. The primary outcome was time with plasma glucose in target range (5.6-10.0 mmol/L) and did not differ between treatments (mean difference [95% CI] 3.3% [-8.2; 1.7], P = 0.17). Mean glucose and glucose variability were comparable, as was time spent below and above target range. Hypoglycaemia (<3.5 mmol/L) occurred once with faster insulin aspart and twice with standard insulin aspart. Mean total insulin dose was higher with faster insulin aspart (mean difference [95% CI] 3.7 U [0.7; 6.8], P = 0.021). No episodes of severe hypoglycaemia or other serious adverse events occurred. In conclusion, short-term fully closed-loop in type 2 diabetes may require higher dose of faster insulin aspart compared with standard insulin aspart to achieve comparable glucose control., (© 2019 John Wiley & Sons Ltd.)

Self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM) are commonly used by type 1 diabetes (T1D) patients to measure glucose concentrations. The proposed adaptive basal-bolus algorithm (ABBA) supports inputs from either SMBG or CGM devices to provide personalised suggestions for the daily basal rate and prandial insulin doses on the basis of the patients' glucose level on the previous day. The ABBA is based on reinforcement learning, a type of artificial intelligence, and was validated in silico with an FDA-accepted population of 100 adults under different realistic scenarios lasting three simulated months. The scenarios involve three main meals and one bedtime snack per day, along with different variabilities and uncertainties for insulin sensitivity, mealtime, carbohydrate amount, and glucose measurement time. The results indicate that the proposed approach achieves comparable performance with CGM or SMBG as input signals, without influencing the total daily insulin dose. The results are a promising indication that AI algorithmic approaches can provide personalised adaptive insulin optimization and achieve glucose control-independent of the type of glucose monitoring technology.

Open source artificial pancreas systems (OpenAPS) have gained considerable interest in the diabetes community. We analyzed continuous glucose monitoring (CGM) records of 80 OpenAPS users with type 1 diabetes (T1D). A total of 19 495 days (53.4 years) of CGM records were available. Mean glucose was 7.6 ± 1.1 mmol/L, time in range 3.9-10 mmol/L was 77.5 ± 10.5%, <3.9 mmol/L was 4.3 ± 3.6%, <3.0 mmol/L was 1.3 ± 1.9%, >10 mmol/L was 18.2 ± 11.0% and > 13.9 mmol/L was 4.1 ± 4.0%, respectively. In 34 OpenAPS users, additional CGM records were obtained while using sensor-augmented pump therapy (SAP). After changing from SAP to OpenAPS, lower mean glucose (-0.6 ± 0.7; P < 0.0001), lower estimated HbA1c (-0.4 ± 0.5%; P < 0.0001), higher time in range 3.9-10 mmol/L (+9.3 ± 9.5%; P < 0.0001), less time < 3.0 mmol/L (-0.7 ± 2.2%; P = 0.0171), lower coefficient of variation (-2.4 ± 5.8; P = 0.0198) and lower mean of daily differences (-0.6 ± 0.9 mmol/L; P = 0.0005) was observed. Glycaemic control using OpenAPS was comparable with results of more rigorously developed and tested AP systems. However, OpenAPS was used by a highly selective, motivated and technology-adept cohort, despite not being approved for the treatment of individuals with T1D., (© 2019 John Wiley & Sons Ltd.)

Inpatient diabetes management of those on hemodialysis poses a major challenge. In a post hoc analysis of a randomized controlled clinical trial, we compared the efficacy of fully automated closed-loop insulin delivery vs. usual care in patients undergoing hemodialysis while in hospital. Compared to control patients receiving conventional subcutaneous insulin therapy, those patients receiving closed-loop insulin delivery significantly increased the proportion of time when a continuous glucose monitor was in the target range of 5.6-10.0 mmol/l by 37.6 percent without increasing the risk of hypoglycemia. Thus, closed-loop insulin delivery offers a novel way to achieve effective and safe glucose control in this vulnerable patient population., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Non-targeted metabolic profiling using high-resolution mass spectrometry (HRMS) is a standard approach for pathway identification despite technical limitations., Objectives: To assess the performance of combining targeted quadrupole (QQQ) analysis with HRMS for in-depth pathway profiling., Methods: Serum of exercising patients with type 1 diabetes (T1D) was profiled using targeted and non-targeted assays., Results: Non-targeted analysis yielded a broad unbiased metabolic profile, targeted analysis increased coverage of purine metabolism (twofold) and TCA cycle (three metabolites)., Conclusion: Our screening strategy combined the benefits of the unbiased full-scan HRMS acquisition with the deeper insight into specific pathways by large-scale QQQ analysis.

Background: Glucose management is challenging in patients who require nutritional support in hospital. We aimed to assess whether fully closed-loop insulin delivery would improve glycaemic control compared with conventional subcutaneous insulin therapy in inpatients receiving enteral or parenteral nutrition or both., Methods: We did a two-centre (UK and Switzerland), open-label, randomised controlled trial in adult inpatients receiving enteral or parenteral nutrition (or both) who required subcutaneous insulin therapy. Patients recruited from non-critical care surgical and medical wards were randomly assigned (1:1) using a computer-generated minimisation schedule (stratified by type of nutritional support [parenteral nutrition on or off] and pre-study total daily insulin dose [<50 or ≥50 units]) to receive fully closed-loop insulin delivery with faster-acting insulin aspart (closed-loop group) or conventional subcutaneous insulin therapy (control group) given in accordance with local clinical practice. Continuous glucose monitoring in the control group was masked to patients, ward staff, and investigators. Patients were followed up for a maximum of 15 days or until hospital discharge. The primary endpoint was the proportion of time that sensor glucose concentration was in target range (5·6-10·0 mmol/L), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01774565., Findings: Between Feb 8, 2018, and Sept 21, 2018, 90 patients were assessed for eligibility, of whom 43 were enrolled and randomly assigned to the closed-loop group (n=21) or the control group (n=22). The proportion of time that sensor glucose was in the target range was 68·4% [SD 15·5] in the closed-loop group and 36·4% [26·6] in the control group (difference 32·0 percentage points [95% CI 18·5-45·5; p<0·0001]). One serious adverse event occurred in each group (one cardiac arrest in the control group and one episode of acute respiratory failure in the closed-loop group), both of which were unrelated to study interventions. There were no adverse events related to study interventions in either group. No episodes of severe hypoglycaemia or hyperglycaemia with ketonaemia occurred in either study group., Interpretation: Closed-loop insulin delivery is an effective treatment option to improve glycaemic control in patients receiving nutritional support in hospital., Funding: Diabetes UK, Swiss National Science Foundation, National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome Trust, and European Foundation for the Study of Diabetes., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY 4·0 license. Published by Elsevier Ltd.. All rights reserved.)

We investigated the short-term effects of dapagliflozin as adjunct to insulin on insulin sensitivity, postprandial glucose excursions and ketone body production in type 1 diabetes mellitus (T1DM). A total of seven male patients completed the randomized, double-blind, placebo-controlled cross-over trial, receiving 10 mg of dapagliflozin daily for 3 days, followed by placebo, or the reverse. At Day 3, hyperinsulinaemic, euglycaemic clamps and oral glucose tolerance test clamps with repeated blood sampling were performed. Required glucose infusion and blood glucose excursions did not differ significantly between dapagliflozin treatment and placebo (P = 0.491; P = 0.342). Prior to oral glucose, total ketone bodies showed a higher trend following dapagliflozin treatment (P = 0.051). Following oral glucose, total ketone bodies decreased while concentrations of total GLP-1 were higher following dapagliflozin (P = 0.009). Non-esterified free fatty acids did not differ between dapagliflozin treatment and placebo and ketonuria was absent under both conditions. In T1DM, short-term addition of dapagliflozin to insulin influenced neither postprandial glucose excursions nor insulin sensitivity. Following oral glucose, total ketone bodies decreased in parallel with an increase in GLP-1 concentrations, which were higher under dapagliflozin treatment as compared with placebo., (© 2018 John Wiley & Sons Ltd.)

Background: Handheld ECG recorders may have algorithms which automatically inform the user of presence of arrhythmia. The main objectives of this study were to evaluate the accuracy of the arrhythmia diagnosis algorithm of Beurer ME90 recorder to diagnose atrial fibrillation (AF)/flutter, and to evaluate whether recording technique (finger versus precordial) affects diagnostic performance., Methods: Consecutive patients admitted at the cardiology ward of a tertiary care hospital were enrolled. Handheld ECG recordings were performed by holding the device between index fingers (lead I), and by applying it to the chest (modified V4, mV4), with 12‑lead ECGs serving as the gold standard for presence of arrhythmia., Results: A total of 127 patients were included. The automatic arrhythmia detection algorithm identified all 16 cases of AF, but specificity was poor (62-77%, with slightly better specificity of mV4 compared to lead I). Specificity improved to 84% (95% CI 76-91%) if both lead I and mV4 recordings had to be positive for diagnosis, with a positive predictive value of 48% (95% CI 30-67%). Interpretation of the tracings by an electrophysiologist was 100% specific. Atrial flutter with regular ventricular response was however missed by automatic and manual interpretation., Conclusions: The automatic arrhythmia algorithm of the BeurerME90 device has excellent sensitivity for diagnosing AF, but with low specificity. Strategies such as first recording lead I (more practical to perform), and in case of arrhythmia detection, confirming with an mV4 recording, may be applied to reduce false positive readings requiring manual confirmation by a healthcare professional., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: In patients with diabetes, hospitalization can complicate the achievement of recommended glycemic targets. There is increasing evidence that a closed-loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabetes. We wanted to investigate whether a closed-loop system could also improve glycemic control in patients with type 2 diabetes who were receiving noncritical care., Methods: In this randomized, open-label trial conducted on general wards in two tertiary hospitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed-loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge., Results: The mean (±SD) percentage of time that the sensor glucose measurement was in the target range was 65.8±16.8% in the closed-loop group and 41.5±16.9% in the control group, a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001); values above the target range were found in 23.6±16.6% and 49.5±22.8% of the patients, respectively, a difference of 25.9±3.4 percentage points (95% CI, 19.2 to 32.7; P<0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P<0.001). There was no significant between-group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P=0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P=0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group., Conclusions: Among inpatients with type 2 diabetes receiving noncritical care, the use of an automated, closed-loop insulin-delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565 .).

Whereas exercise training is key in the management of patients with cardiovascular disease (CVD) risk (obesity, diabetes, dyslipidaemia, hypertension), clinicians experience difficulties in how to optimally prescribe exercise in patients with different CVD risk factors. Therefore, a consensus statement for state-of-the-art exercise prescription in patients with combinations of CVD risk factors as integrated into a digital training and decision support system (the EXercise Prescription in Everyday practice & Rehabilitative Training (EXPERT) tool) needed to be established. EXPERT working group members systematically reviewed the literature for meta-analyses, systematic reviews and/or clinical studies addressing exercise prescriptions in specific CVD risk factors and formulated exercise recommendations (exercise training intensity, frequency, volume and type, session and programme duration) and exercise safety precautions, for obesity, arterial hypertension, type 1 and 2 diabetes, and dyslipidaemia. The impact of physical fitness, CVD risk altering medications and adverse events during exercise testing was further taken into account to fine-tune this exercise prescription. An algorithm, supported by the interactive EXPERT tool, was developed by Hasselt University based on these data. Specific exercise recommendations were formulated with the aim to decrease adipose tissue mass, improve glycaemic control and blood lipid profile, and lower blood pressure. The impact of medications to improve CVD risk, adverse events during exercise testing and physical fitness was also taken into account. Simulations were made of how the EXPERT tool provides exercise prescriptions according to the variables provided. In this paper, state-of-the-art exercise prescription to patients with combinations of CVD risk factors is formulated, and it is shown how the EXPERT tool may assist clinicians. This contributes to an appropriately tailored exercise regimen for every CVD risk patient.

Background: Handheld ECG event recorders are useful for rhythm monitoring but only record a single lead, which may limit interpretation. We sought to investigate if a multi-lead ECG may be reconstituted using this device, and aimed to evaluate diagnostic accuracy., Methods: A commercially-available handheld bipolar ECG event recorder was used to reconstruct a 9-lead ECG (leads I, II and III, V1-6). Tracings were analyzed independently by a cardiologist and a fellow., Results: A total of 52 patients were evaluated. Accuracy was excellent (85-98%) for identifying atrial fibrillation, atrioventricular block, bundle branch block and left ventricular hypertrophy, but lower (77-88%) for ST-segment changes and prolonged QTc., Conclusions: A 9-lead ECG can be reconstituted using a handheld single-lead ECG event recorder, and provides good diagnostic accuracy for common findings., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Subclinical hypothyroidism, defined as an elevated level of thyrotropin hormone (TSH) and normal thyroxin, is more frequent in women and above 65 years old. This condition is associated with an increased cardiovascular risk, in particular with TSH > 10,0 mIU/L. Although overt hypothyroidism is rare (prevalence of 0,3 %), levothyroxine has become the most prescribed medication in the US, while its indications are still debated. The European-funded TRUST trial showed no improvement in Hypothyroid Symptoms and Tiredness scores among patients ≥ 65 years with subclinical hypothyroidism treated with levothyroxine, and no improvement in blood pressure, weight, muscle strength and cognition. The results of this study call for a revision of the current international recommendations on the treatment of subclinical hypothyroidism., Competing Interests: Les auteurs de cet article ont participé à des publications de la Thyroid Studies Collaboration (N.R. investigateur principal) et au déroulement de l’étude TRUST (tous les coauteurs ; N.R. investigateur principal pour la Suisse). Ces travaux de recherche ont été soutenus par des fonds de recherche de l’Union européenne (programme EU-FP7-HEALTH-2011, grant 278148), du Fonds national suisse (SNSF 320030‑150025, N.R.), de la Fondation Velux (Projet 974a) et de la Fondation suisse de cardiologie. Les autres projets de recherche des auteurs sont soutenus par le Fonds national suisse (T.H.C., C.B., M.R.B., N.R.), la Fondation Leenaards (G.P.S.) et la Société suisse d’endocrinologie et diabétologie (T.H.C., G.P.S.). Les auteurs n’ont pas de conflit d’intérêts potentiels à déclarer.

Objective: Tight glycemic control and aggressive treatment of additional cardiovascular risk factors can substantially reduce risk of diabetes-related complications. In 2013, the Swiss Society of Endocrinology and Diabetology (SSED) established national criteria on good disease management in diabetes, but little is known about compliance in clinical care. Here we assessed to what extent patients from two tertiary care centers in the German-speaking part of Switzerland enrolled in the Swiss Diabetes (SwissDiab) Registry adhere to the SSED criteria., Research Design and Methods: SwissDiab is a prospective observational cohort study of patients regularly treated at Swiss tertiary diabetes centers. Data were collected through standardized annual health examinations. Baseline participant descriptive statistics, stratified by diabetes mellitus type 1 (DM1) and type 2 (DM2), were compared with SSED targets for glycemic control, blood pressure, blood lipids, weight maintenance, and ophthalmic examination., Results: By the end of 2016, 604 participants with DM1 (40%) and DM2 (60%) had data available for analyses, 36% and 29% women, respectively. At baseline, all the SSED targets were met with two exceptions: a glycated hemoglobin A1c value <7% was measured in 32% of participants with DM1 (SSED target: ≥40%) and 47% and 56% of overweight or obese participants with DM1 and DM2, respectively, received nutritional counseling in the previous year (SSED target: ≥80%)., Conclusions: The SSED targets for good disease management in diabetes were achieved in the majority of participants at the time of enrollment, but results also highlight areas where disease management can be improved, particularly the role of nutrition counseling., Competing Interests: Competing interests: None declared.

Aims: To compare cardiac function when pacing from the right or left ventricular apex in patients with preserved left ventricular systolic function, at 1-year follow-up., Methods: Prospective, multicentre centre randomizing conventional right ventricular apical (RVA) versus left ventricular apical (LVA) pacing using a coronary sinus lead in patients requiring ventricular pacing for bradycardia. Follow-up was performed using 3D-echocardiography at 6 and 12 months., Results: A total of 36 patients (age 75.4 ± 8.7 years, 21 males) were enrolled (17 patients in the RVA group and 19 patients in the LVA group). A right ventricular lead was implanted in 8 patients in the LVA group, mainly because of high capture thresholds. There were no differences in the primary endpoint of LVEF at 1 year (60.4 ± 7.1% vs 62.1 ± 7.2% for the RVA and LVA groups respectively, P = 0.26) nor in any of the secondary endpoints (left ventricular dimensions, left ventricular diastolic function, right ventricular systolic function and tricuspid/mitral insufficiency). LVEF did not change significantly over follow-up in either group. Capture thresholds were significantly higher in the LVA group, and two patients had unexpected loss of capture of the coronary sinus lead during follow-up., Conclusions: Left univentricular pacing seems to be comparable to conventional RVA pacing in terms of ventricular function at up to 1 year follow-up, and is an option to consider in selected patients (e.g. those with a tricuspid valve prosthesis)., (Copyright © 2017 Indian Heart Rhythm Society. Production and hosting by Elsevier B.V. All rights reserved.)

Background Exercise rehabilitation is highly recommended by current guidelines on prevention of cardiovascular disease, but its implementation is still poor. Many clinicians experience difficulties in prescribing exercise in the presence of different concomitant cardiovascular diseases and risk factors within the same patient. It was aimed to develop a digital training and decision support system for exercise prescription in cardiovascular disease patients in clinical practice: the European Association of Preventive Cardiology Exercise Prescription in Everyday Practice and Rehabilitative Training (EXPERT) tool. Methods EXPERT working group members were requested to define (a) diagnostic criteria for specific cardiovascular diseases, cardiovascular disease risk factors, and other chronic non-cardiovascular conditions, (b) primary goals of exercise intervention, (c) disease-specific prescription of exercise training (intensity, frequency, volume, type, session and programme duration), and (d) exercise training safety advices. The impact of exercise tolerance, common cardiovascular medications and adverse events during exercise testing were further taken into account for optimized exercise prescription. Results Exercise training recommendations and safety advices were formulated for 10 cardiovascular diseases, five cardiovascular disease risk factors (type 1 and 2 diabetes, obesity, hypertension, hypercholesterolaemia), and three common chronic non-cardiovascular conditions (lung and renal failure and sarcopaenia), but also accounted for baseline exercise tolerance, common cardiovascular medications and occurrence of adverse events during exercise testing. An algorithm, supported by an interactive tool, was constructed based on these data. This training and decision support system automatically provides an exercise prescription according to the variables provided. Conclusion This digital training and decision support system may contribute in overcoming barriers in exercise implementation in common cardiovascular diseases.

This paper aims to compare the metabolic effects of glucose-fructose co-ingestion (GLUFRU) with glucose alone (GLU) in exercising individuals with type 1 diabetes mellitus. Fifteen male individuals with type 1 diabetes (HbA1c 7.0% ± 0.6% (53 ± 7 mmol/mol)) underwent a 90 min iso-energetic continuous cycling session at 50% VO 2max while ingesting combined glucose-fructose (GLUFRU) or glucose alone (GLU) to maintain stable glycaemia without insulin adjustment. GLUFRU and GLU were labelled with 13 C-fructose and 13 C-glucose, respectively. Metabolic assessments included measurements of hormones and metabolites, substrate oxidation, and stable isotopes. Exogenous carbohydrate requirements to maintain stable glycaemia were comparable between GLUFRU and GLU ( p = 0.46). Fat oxidation was significantly higher (5.2 ± 0.2 vs. 2.6 ± 1.2 mg·kg -1 ·min -1 , p < 0.001) and carbohydrate oxidation lower (18.1 ± 0.8 vs. 24.5 ± 0.8 mg·kg -1 ·min -1 p < 0.001) in GLUFRU compared to GLU, with decreased muscle glycogen oxidation in GLUFRU (10.2 ± 0.9 vs. 17.5 ± 1.0 mg·kg -1 ·min -1 , p < 0.001). Lactate levels were higher (2.2 ± 0.2 vs. 1.8 ± 0.1 mmol/L, p = 0.012) in GLUFRU, with comparable counter-regulatory hormones between GLUFRU and GLU ( p > 0.05 for all). Glucose and insulin levels, and total glucose appearance and disappearance were comparable between interventions. Glucose-fructose co-ingestion may have a beneficial impact on fuel metabolism in exercising individuals with type 1 diabetes without insulin adjustment, by increasing fat oxidation whilst sparing glycogen.

Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches., Methods: We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr 2 ). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo., Results: We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr 2 on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr 2 upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr 2 -targeted imaging and radiopeptide therapy., Conclusion: We present an approach that uses epigenetic modifiers to improve sstr 2 targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Glycogen is a major substrate in energy metabolism and particularly important to prevent hypoglycemia in pathologies of glucose homeostasis such as type 1 diabetes mellitus (T1DM). (13) C-MRS is increasingly used to determine glycogen in skeletal muscle and liver non-invasively; however, the low signal-to-noise ratio leads to long acquisition times, particularly when glycogen levels are determined before and after interventions. In order to ease the requirements for the subjects and to avoid systematic effects of the lengthy examination, we evaluated if a standardized preparation period would allow us to shift the baseline (pre-intervention) experiments to a preceding day. Based on natural abundance (13) C-MRS on a clinical 3 T MR system the present study investigated the test-retest reliability of glycogen measurements in patients with T1DM and matched controls (n = 10 each group) in quadriceps muscle and liver. Prior to the MR examination, participants followed a standardized diet and avoided strenuous exercise for two days. The average coefficient of variation (CV) of myocellular glycogen levels was 9.7% in patients with T1DM compared with 6.6% in controls after a 2 week period, while hepatic glycogen variability was 13.3% in patients with T1DM and 14.6% in controls. For comparison, a single-session test-retest variability in four healthy volunteers resulted in 9.5% for skeletal muscle and 14.3% for liver. Glycogen levels in muscle and liver were not statistically different between test and retest, except for hepatic glycogen, which decreased in T1DM patients in the retest examination, but without an increase of the group distribution. Since the CVs of glycogen levels determined in a "single session" versus "within weeks" are comparable, we conclude that the major source of uncertainty is the methodological error and that physiological variations can be minimized by a pre-study standardization. For hepatic glycogen examinations, familiarization sessions (MR and potentially strenuous interventions) are recommended. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Diabetes mellitus is spreading throughout the world and diabetic individuals have been shown to often assess their food intake inaccurately; therefore, it is a matter of urgency to develop automated diet assessment tools. The recent availability of mobile phones with enhanced capabilities, together with the advances in computer vision, have permitted the development of image analysis apps for the automated assessment of meals. GoCARB is a mobile phone-based system designed to support individuals with type 1 diabetes during daily carbohydrate estimation. In a typical scenario, the user places a reference card next to the dish and acquires two images using a mobile phone. A series of computer vision modules detect the plate and automatically segment and recognize the different food items, while their 3D shape is reconstructed. Finally, the carbohydrate content is calculated by combining the volume of each food item with the nutritional information provided by the USDA Nutrient Database for Standard Reference., Objective: The main objective of this study is to assess the accuracy of the GoCARB prototype when used by individuals with type 1 diabetes and to compare it to their own performance in carbohydrate counting. In addition, the user experience and usability of the system is evaluated by questionnaires., Methods: The study was conducted at the Bern University Hospital, "Inselspital" (Bern, Switzerland) and involved 19 adult volunteers with type 1 diabetes, each participating once. Each study day, a total of six meals of broad diversity were taken from the hospital's restaurant and presented to the participants. The food items were weighed on a standard balance and the true amount of carbohydrate was calculated from the USDA nutrient database. Participants were asked to count the carbohydrate content of each meal independently and then by using GoCARB. At the end of each session, a questionnaire was completed to assess the user's experience with GoCARB., Results: The mean absolute error was 27.89 (SD 38.20) grams of carbohydrate for the estimation of participants, whereas the corresponding value for the GoCARB system was 12.28 (SD 9.56) grams of carbohydrate, which was a significantly better performance ( P=.001). In 75.4% (86/114) of the meals, the GoCARB automatic segmentation was successful and 85.1% (291/342) of individual food items were successfully recognized. Most participants found GoCARB easy to use., Conclusions: This study indicates that the system is able to estimate, on average, the carbohydrate content of meals with higher accuracy than individuals with type 1 diabetes can. The participants thought the app was useful and easy to use. GoCARB seems to be a well-accepted supportive mHealth tool for the assessment of served-on-a-plate meals.

Aims: Manufacturers of implantable cardioverter defibrillators (ICDs) recommend that cell phones be maintained at a distance of ∼15 cm from the implanted device in order to avoid risk of dysfunction due to electromagnetic interference (EMI). Data relating to this issue are outdated and do not reflect modern technology. Our aim was to evaluate whether EMI is still an issue with contemporary ICDs and smartphones., Methods and Results: Consecutive patients implanted with a wireless-enabled ICD were tested for potential interference with two models of recent 4G smartphones in conditions intended to maximize risk of EMI. A magnet effect (due to the phone speakers) was tested by placing the smartphones in the standby mode directly over the ICD generator. The presence of EMI artefacts on the real-time electrograms was evaluated by placing the smartphones in the standby, dialling, and operating modes directly over the generator casing and over the parasternal region in the vicinity of the ventricular lead. A total of 63 patients equipped with 29 different models of single, dual, or biventricular ICDs from five major manufacturers were included. None of the patients showed any evidence of interference with the smartphones during any of the 882 tests., Conclusion: The risk of EMI between modern smartphones and contemporary ICDs is low. This is probably due to the filters incorporated in the ICDs and low emission by the phones, as well as the small size of the magnets in the smartphones tested., Study Registration: NCT02330900 (http://www.clinicaltrials.gov)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Context: Apelin and arginine vasopressin are antagonists in the regulation of body fluid and osmotic homeostasis. There are no data about apelin levels in patients with polyuria-polydipsia syndrome (PPS)., Objective: To investigate plasma apelin levels and plasma apelin to copeptin ratios in patients with PPS and healthy volunteers using copeptin as a surrogate marker for arginine vasopressin., Design, Participants, and Setting: We included 41 patients with PPS in this post hoc analysis of a prospective study performed in tertiary care hospitals in Switzerland and Germany and 113 healthy volunteers as a control group., Outcome Measures: Plasma apelin and copeptin levels were measured in 15 patients with complete central diabetes insipidus (DI), seven patients with complete nephrogenic DI, 19 patients with primary polydipsia (PP), and 113 healthy volunteers., Results: Plasma apelin levels were highest in patients with complete nephrogenic DI (413 pmol/L; interquartile range, 332-504 pmol/L; P = .01) and lower in patients with PP (190 [172-215] pmol/L; P < .001) or complete central DI (209 [174-241] pmol/L; P = .02) as compared to healthy volunteers (254 [225-311] pmol/L). Plasma apelin to copeptin ratio in patients with PP (53 [38-92] pmol/pmol; P > .9) was similar to healthy volunteers (57 [37-102] pmol/pmol). In contrast, the apelin to copeptin ratio was higher in patients with complete central DI (89 [73-135] pmol/pmol; P = .02) and lower in patients with complete nephrogenic DI (7 [6-10] pmol/pmol; P < .001) compared to healthy volunteers., Conclusion: In PP, normal plasma apelin to copeptin ratio attests a normal water homeostasis. In contrast, in patients with central or nephrogenic DI, the increased or decreased apelin to copeptin ratio, respectively, reflects a disturbed osmotic and body fluid homeostasis.

Aims/hypothesis: To investigate exercise-related fuel metabolism in intermittent high-intensity (IHE) and continuous moderate intensity (CONT) exercise in individuals with type 1 diabetes mellitus., Methods: In a prospective randomised open-label cross-over trial twelve male individuals with well-controlled type 1 diabetes underwent a 90 min iso-energetic cycling session at 50% maximal oxygen consumption ([Formula: see text]), with (IHE) or without (CONT) interspersed 10 s sprints every 10 min without insulin adaptation. Euglycaemia was maintained using oral (13)C-labelled glucose. (13)C Magnetic resonance spectroscopy (MRS) served to quantify hepatocellular and intramyocellular glycogen. Measurements of glucose kinetics (stable isotopes), hormones and metabolites complemented the investigation., Results: Glucose and insulin levels were comparable between interventions. Exogenous glucose requirements during the last 30 min of exercise were significantly lower in IHE (p = 0.02). Hepatic glucose output did not differ significantly between interventions, but glucose disposal was significantly lower in IHE (p < 0.05). There was no significant difference in glycogen consumption. Growth hormone, catecholamine and lactate levels were significantly higher in IHE (p < 0.05)., Conclusions/interpretation: IHE in individuals with type 1 diabetes without insulin adaptation reduced exogenous glucose requirements compared with CONT. The difference was not related to increased hepatic glucose output, nor to enhanced muscle glycogen utilisation, but to decreased glucose uptake. The lower glucose disposal in IHE implies a shift towards consumption of alternative substrates. These findings indicate a high flexibility of exercise-related fuel metabolism in type 1 diabetes, and point towards a novel and potentially beneficial role of IHE in these individuals., Trial Registration: ClinicalTrials.gov NCT02068638 FUNDING: Swiss National Science Foundation (grant number 320030&#95;149321/) and R&A Scherbarth Foundation (Switzerland).

Background: Traditionally, basal rate profiles in continuous subcutaneous insulin infusion therapy are individually adapted to cover expected insulin requirements. However, whether this approach is indeed superior to a more constant BR profile has not been assessed so far. This study analysed the associations between variability of BR profiles and acute and chronic complications in adult type 1 diabetes mellitus., Materials and Methods: BR profiles of 3118 female and 2427 male patients from the "Diabetes-Patienten-Verlaufsdokumentation" registry from Germany and Austria were analysed. Acute and chronic complications were recorded 6 months prior and after the most recently documented basal rate. The "variability index" was calculated as variation of basal rate intervals in percent and describes the excursions of the basal rate intervals from the median basal rate., Results: The variability Index correlated positively with severe hypoglycemia (r = .06; p<0.001), hypoglycemic coma (r = .05; p = 0.002), and microalbuminuria (r = 0.05; p = 0.006). In addition, a higher variability index was associated with higher frequency of diabetic ketoacidosis (r = .04; p = 0.029) in male adult patients. Logistic regression analysis adjusted for age, gender, duration of disease and total basal insulin confirmed significant correlations of the variability index with severe hypoglycemia (β = 0.013; p<0.001) and diabetic ketoacidosis (β = 0.012; p = 0.017)., Conclusions: Basal rate profiles with higher variability are associated with an increased frequency of acute complications in adults with type 1 diabetes.

Aim: Depending on intensity, exercise may induce a strong hormonal and metabolic response, including acid-base imbalances and changes in microcirculation, potentially interfering with the accuracy of continuous glucose monitoring (CGM). The present study aimed at comparing the accuracy of the Dexcom G4 Platinum (DG4P) CGM during continuous moderate and intermittent high-intensity exercise (IHE) in adults with type 1 diabetes (T1DM)., Methods: Ten male individuals with well-controlled T1DM (HbA1c 7.0 ± 0.6% [54 ± 6 mmol/mol]) inserted the DG4P sensor 2 days prior to a 90 min cycling session (50% VO2peak) either with (IHE) or without (CONT) a 10s all-out sprint every 10 min. Venous blood samples for reference glucose measurement were drawn every 10 min and euglycemia (target 7 mmol/l) was maintained using an oral glucose solution. Additionally, lactate and venous blood gas variables were determined., Results: Mean reference blood glucose was 7.6 ± 0.2 mmol/l during IHE and 6.7 ± 0.2 mmol/l during CONT (p<0.001). IHE resulted in significantly higher levels of lactate (7.3 ± 0.5 mmol/l vs. 2.6 ± 0.3 mmol/l, p<0.001), while pH values were significantly lower in the IHE group (7.27 vs. 7.38, p=0.001). Mean absolute relative difference (MARD) was 13.3 ± 2.2% for IHE and 13.6 ± 2.8% for CONT suggesting comparable accuracy (p=0.90). Using Clarke Error Grid Analysis, 100% of CGM values during both IHE and CONT were in zones A and B (IHE: 77% and 23%; CONT: 78% and 22%)., Conclusions: The present study revealed good and comparable accuracy of the DG4P CGM system during intermittent high intensity and continuous moderate intensity exercise, despite marked differences in metabolic conditions. This corroborates the clinical robustness of CGM under differing exercise conditions., Clinical Trial Registration Number: ClinicalTrials.gov NCT02068638., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The circular irrigated decapolar nMARQ ablation catheter designed for treating atrial fibrillation (AF) has recently been recalled following two deaths due to esoatrial fistula. Injury to the esophagus has been previously reported in up to 50% of patients using 20-25 W unipolar radiofrequency (RF) energy. Low power of 15 W has been proposed to prevent this complication, but the efficacy of this strategy to avoid AF recurrence is unknown., Methods and Results: Consecutive patients with drug-refractory, symptomatic AF were included. Under electroanatomical navigation, the nMARQ catheter was used to isolate all PVs by applying 15 W of unipolar RF simultaneously from up to 10 poles during 40 seconds. Multiple applications were used for each vein, until isolation was achieved. Follow-up was performed after a 2-month blanking period. A total of 50 patients (37 males, age 58 ± 10 years) were included. All PVs were acutely isolated without requiring touch-up by conventional ablation catheters. Pericardial effusion occurred in two patients, of whom one required periocardiocentesis. Right phrenic nerve palsy occurred in another patient, which partially resolved. There were no cases of esophageal fistula or stroke. After a follow-up of 15 ± 4 months, AF recurred in 27/50 (54%) patients., Conclusion: The recurrence rate of AF with 15 W unipolar applications is high. Despite use of low power, complications such as pericardial effusion and phrenic nerve palsy may occur., (© 2015 Wiley Periodicals, Inc.)

Objective: The aim of this study was first to assess whether first-trimester serum concentrations of placental growth factor (PlGF) differ between patients with and without gestational diabetes (GDM) and second to test whether there is a correlation between glycosylated hemoglobin (HbA1c), a factor recently shown to be useful in predicting GDM, and PlGF., Methods: PlGF was measured at 8-14 weeks with the Kryptor Immunoassay Analyzer (Brahms, Berlin, Germany). Absolute values were converted to multiples of the median using the software provided by the Fetal Medicine Foundation London. GDM was diagnosed using internationally accepted criteria. HbA1c levels were quantified using the TOSOH G7 automated hemoglobin analyzer., Results: From January to December 2014, 328 women were included in the study, 51 (15.5%) of whom developed GDM. First-trimester PlGF quantification does not discriminate between women at risk to develop GDM and controls, while HbA1c is able to do so. No correlation was found between PlGF and HbA1c., Conclusion: Our findings do not lend support to the hypothesis that early PlGF values are different in women who later develop GDM., (© 2015 S. Karger AG, Basel.)

Introduction: Our aim was to investigate the prognostic value of first-trimester glycosylated hemoglobin (HbA1c) in pregnant women with risk factors for developing gestational diabetes mellitus (GDM)., Material and Methods: This is an observational retrospective cohort study conducted at the Department of Obstetrics and Gynecology, University Hospital Bern, Switzerland. We included pregnant women at high risk for GDM (n = 208), who had an HbA1c measurement in the first trimester. We compared HbA1c values of women who later developed GDM with those who did not develop GDM. Diagnosis of GDM was made on the basis of a 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation. We further examined the prevalence of GDM in relation to the first-trimester HbA1c value., Results: The prevalence of GDM in our high-risk group was 14.7%. Women who developed GDM had significantly higher first-trimester HbA1c values [5.43 ± 0.31% (36 ± 3 mmol/mol) vs. 5.23 ± 0.28% (34 ± 3 mmol/mol); p = 0.0026]. Moreover, all pregnant women with HbA1c ≥ 6.0% (42 mmol/mol) developed GDM, whereas those with < 4.5% (26 mmol/mol) did not., Conclusions: Women at risk for GDM have higher first-trimester HbA1c levels and values ≥ 6.0% (42 mmol/mol) are predictive of GDM. This information may be useful for counseling these women and providing appropriate advice on diet and lifestyle modification early in pregnancy., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objectives: Blood lactate measurements are common as a marker of skeletal muscle metabolism in sport medicine. Due to the close equilibrium between the extracellular and intramyocellular space, plasma lactate is a more accurate estimate of muscle lactate. However, whole blood-based lactate measurements are more convenient in field use. The purpose of this investigation was therefore (1) to establish a plasma-converting lactate formula for field use, and (2) to validate the computed plasma lactate levels by comparison to a laboratory standard method., Design and Methods: A total of 91 venous samples were taken from 6 individuals with type 1 diabetes during resting and exercise conditions and assessed for whole blood and plasma lactate using the YSI 2300 analyzer. A linear model was applied to establish a formula for converting whole blood lactate to plasma lactate. The validity of computed plasma lactate values was assessed by comparison to a laboratory standard method., Results: Whole blood YSI lactate could be converted to plasma YSI values (slope 1.66, intercept 0.12) for samples with normal hematocrit. Computed plasma levels compared to values determined by the laboratory standard method using Passing-Bablok regression yielded a slope of 1.03 (95%CI:0.99:1.08) with an intercept of -0.11 (95%CI:-0.18:-0.06)., Conclusions: Whole blood YSI lactate values can be reliably converted into plasma values which are in line with laboratory determined plasma measurements.

Purpose of Review: The primary focus of this review is threefold: first, to summarize available knowledge on exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus (T1DM); second, to elucidate physiological mechanisms predisposing to glycemic variations in patients in T1DM; and third, to describe novel approaches derived from physiological perceptions applicable to stabilize exercise-related glycemia in individuals with T1DM., Recent Findings: Recent studies corroborate the concept that despite partial differences in counter-regulatory mechanisms individuals with T1DM do not fundamentally differ in their glucose response to exercise when compared with healthy individuals if studies are performed under standardized conditions with insulin and glucose levels held close to physiological ranges. Novel approaches derived from a better understanding of exercise-associated glucose metabolism (e.g., the concept of intermittent high-intensity exercise) may provide alternative ways to master the challenges imposed by exercise to individuals with T1DM., Summary: Exercise still imposes high demands on patients with T1DM and increases risks for hypoglycemia and hyperglycemia. Deeper insight into the associated metabolic pathways has revealed novel options to stabilize exercise-associated glucose levels in these patients.

Context: The polyuria-polydipsia syndrome comprises primary polydipsia (PP) and central and nephrogenic diabetes insipidus (DI). Correctly discriminating these entities is mandatory, given that inadequate treatment causes serious complications. The diagnostic "gold standard" is the water deprivation test with assessment of arginine vasopressin (AVP) activity. However, test interpretation and AVP measurement are challenging., Objective: The objective was to evaluate the accuracy of copeptin, a stable peptide stoichiometrically cosecreted with AVP, in the differential diagnosis of polyuria-polydipsia syndrome., Design, Setting, and Patients: This was a prospective multicenter observational cohort study from four Swiss or German tertiary referral centers of adults >18 years old with the history of polyuria and polydipsia., Measurements: A standardized combined water deprivation/3% saline infusion test was performed and terminated when serum sodium exceeded 147 mmol/L. Circulating copeptin and AVP levels were measured regularly throughout the test. Final diagnosis was based on the water deprivation/saline infusion test results, clinical information, and the treatment response., Results: Fifty-five patients were enrolled (11 with complete central DI, 16 with partial central DI, 18 with PP, and 10 with nephrogenic DI). Without prior thirsting, a single baseline copeptin level >21.4 pmol/L differentiated nephrogenic DI from other etiologies with a 100% sensitivity and specificity, rendering a water deprivation testing unnecessary in such cases. A stimulated copeptin >4.9 pmol/L (at sodium levels >147 mmol/L) differentiated between patients with PP and patients with partial central DI with a 94.0% specificity and a 94.4% sensitivity. A stimulated AVP >1.8 pg/mL differentiated between the same categories with a 93.0% specificity and a 83.0% sensitivity., Limitation: This study was limited by incorporation bias from including AVP levels as a diagnostic criterion., Conclusion: Copeptin is a promising new tool in the differential diagnosis of the polyuria-polydipsia syndrome, and a valid surrogate marker for AVP. Primary Funding Sources: Swiss National Science Foundation, University of Basel.

Background: Patients with atrial flutter who are implanted with a pacemaker (PM) or implantable cardioverter-defibrillator (ICD) present with the opportunity to perform a noninvasive pacing study (NIPS) using the right atrial pacing lead to differentiate right from left atrial flutter., Objectives: The purpose of this study was to study the feasibility and accuracy of NIPS to distinguish right from left atrial flutter., Methods: We enrolled consecutive patients scheduled for an electrophysiological study or ablation procedure who were in atrial flutter and who were implanted with a PM or ICD with a functional atrial lead in the right atrial appendage. Flutter tachycardia cycle lengths (TCLs) and postpacing intervals (PPIs) were measured noninvasively via the device during the procedure., Results: A total of 48 (67%) patients were studied. Right atrial flutter was present in 32 patients (of whom 29 had typical cavotricuspid isthmus-dependent flutter) and 16 (33%) patients had left atrial flutter. A PPI-TCL interval of >100 ms was 100% specific and 81% sensitive to identify left atrial flutter, with an overall accuracy of 94% and a c statistic of 0.94 (95% confidence interval 0.87-1.00). A PPI-TCL interval of ≤100 ms had a positive predictive value of 86% for diagnosing typical flutter., Conclusion: NIPS via PMs and ICDs with a PPI-TCL interval of >100 ms can reliably identify left atrial flutter (although we have only validated this cutoff for leads implanted in the right atrial appendage). This simple maneuver may allow planning for left-sided access and may avoid an unnecessary invasive electrophysiological study if left atrial flutter ablation is not to be considered., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: In an artificial pancreas (AP), the meals are either manually announced or detected and their size estimated from the blood glucose level. Both methods have limitations, which result in suboptimal postprandial glucose control. The GoCARB system is designed to provide the carbohydrate content of meals and is presented within the AP framework., Method: The combined use of GoCARB with a control algorithm is assessed in a series of 12 computer simulations. The simulations are defined according to the type of the control (open or closed loop), the use or not-use of GoCARB and the diabetics' skills in carbohydrate estimation., Results: For bad estimators without GoCARB, the percentage of the time spent in target range (70-180 mg/dl) during the postprandial period is 22.5% and 66.2% for open and closed loop, respectively. When the GoCARB is used, the corresponding percentages are 99.7% and 99.8%. In case of open loop, the time spent in severe hypoglycemic events (<50 mg/dl) is 33.6% without the GoCARB and is reduced to 0.0% when the GoCARB is used. In case of closed loop, the corresponding percentage is 1.4% without the GoCARB and is reduced to 0.0% with the GoCARB., Conclusion: The use of GoCARB improves the control of postprandial response and glucose profiles especially in the case of open loop. However, the most efficient regulation is achieved by the combined use of the control algorithm and the GoCARB., (© 2015 Diabetes Technology Society.)

Type 2 Diabetes is characterized by its progressive character. An intensification of the therapy is necessary in most cases over the years and insulin is typically used as an add-on agent when oral antidiabetic regimes are judged to be no longer sufficient. However, insulin can also be used in the initial phase of the disease directly after diagnosis of diabetes. Intermittent worsening of glycemic control (e.g. due to infectious diseases or corticosteroids) may be additional indications for an insulin treatment at an earlier stage. Noticeably, insulin can often be stopped if the triggering event or treatment is reversible, thereby countering the widely spread fear of dependency on insulin. We recommend a rather cautious starting dose of insulin and individual adaptations thereafter. Well-informed patients can also perform such adaptations themselves.

(1) H-MRS is regularly applied to determine lipid content in ectopic tissue - mostly skeletal muscle and liver - to investigate physiological and/or pathologic conditions, e.g. insulin resistance. Technical developments also allow non-invasive in vivo assessment of cardiac lipids; however, basic data about methodological reliability (repeatability) and physiological variations are scarce. The aim of the presented work was to determine potential diurnal changes of cardiac lipid stores in humans, and to put the results in relation to methodological repeatability and normal physiological day-to-day variations. Optimized cardiac- and respiratory-gated (1) H-MRS was used for non-invasive quantification of intracardiomyocellular lipids (ICCL), creatine, trimethyl-ammonium compounds (TMA), and taurine in nine healthy young men at three time points per day on two days separated by one week. This design allowed determination of (a) diurnal changes, (b) physiological variation over one week and (c) methodological repeatability of the ICCL levels. Comparison of fasted morning to post-absorptive evening measurements revealed a significant 37 ± 19% decrease of ICCL during the day (p = 0.0001). There was a significant linear correlation between ICCL levels in the morning and their decrease during the day (p = 0.015). Methodological repeatability for the ICCL/creatine ratio was excellent, with a coefficient of variance of ~5%, whereas physiological variation was found to be considerably higher (22%) in spite of a standardized physiological preparation protocol. In contrast, TMA levels remained stable over this time period. The proposed (1) H-MRS technique provides a robust way to investigate relevant physiological changes in cardiac metabolites, in particular ICCL. The present results suggest that ICCL reveal a diurnal course, with higher levels in the morning as compared to evening. In addition, a considerable long-term variation of ICCL levels, in both the morning and evening, was documented. Given the high methodological repeatability, these effects should be taken into account in studies investigating the metabolic role of ICCL., (Copyright © 2014 John Wiley & Sons, Ltd.)

This study aimed at evaluating a peak oxygen uptake test as a simple diagnostic tool to assess growth-hormone deficiency (GHD) in adults. Based on the findings of multiple growth hormone (GH) samplings after the exercise, a single GH sample taken 15 min postexercise revealed high accuracy in the diagnosis of GHD in the present study. A standardized peak oxygen uptake test may, therefore, provide an accurate alternative to more invasive tests of GHD.

Aims/hypothesis: Ectopic lipids are fuel stores in non-adipose tissues (skeletal muscle [intramyocellular lipids; IMCL], liver [intrahepatocellular lipids; IHCL] and heart [intracardiomyocellular lipids; ICCL]). IMCL can be depleted by physical activity. Preliminary data suggest that aerobic exercise increases IHCL. Data on exercise-induced changes on ICCL is scarce. Increased IMCL and IHCL have been related to insulin resistance in skeletal muscles and liver, whereas this has not been documented in the heart. The aim of this study was to assess the acute effect of aerobic exercise on the flexibility of IMCL, IHCL and ICCL in insulin-sensitive participants in relation to fat availability, insulin sensitivity and exercise capacity., Methods: Healthy physically active men were included. VO(2max) was assessed by spiroergometry and insulin sensitivity was calculated using the HOMA index. Visceral and subcutaneous fat were separately quantified by MRI. Following a standardised dietary fat load over 3 days, IMCL, IHCL and ICCL were measured using MR spectroscopy before and after a 2 h exercise session at 50-60% of VO(2max). Metabolites were measured during exercise., Results: Ten men (age 28.9 ± 6.4 years, mean ± SD; VO(2max) 56.3 ± 6.4 ml kg(-1) min(-1); BMI 22.75 ± 1.4 kg/m(2)) were recruited. A 2 h exercise session resulted in a significant decrease in IMCL (-17 ± 22%, p = 0.008) and ICCL (-17 ± 14%, p = 0.002) and increase in IHCL (42 ± 29%, p = 0.004). No significant correlations were found between the relative changes in ectopic lipids, fat availability, insulin sensitivity, exercise capacity or changes of metabolites during exercise., Conclusions/interpretation: In this group, physical exercise decreased ICCL and IMCL but increased IHCL. Fat availability, insulin sensitivity, exercise capacity and metabolites during exercise are not the only factors affecting ectopic lipids during exercise.

Background: Small benign insulinomas are hard to localise, leading to difficulties in planning of surgical interventions. We aimed to prospectively assess the insulinoma detection rate of single-photon emission CT in combination with CT (SPECT/CT) with a glucagon-like peptide-1 receptor avid radiotracer, and compare detection rates with conventional CT/MRI techniques., Methods: In our prospective imaging study, we enrolled adults aged 25-81 years at centres in Germany, Switzerland, and the UK. Eligible patients had proven clinical and biochemical endogenous hyperinsulinaemic hypoglycaemia and no evidence for metastatic disease on conventional imaging. CT/MRI imaging was done at referring centres according to standard protocols. At three tertiary nuclear medicine centres, we used whole body planar images and SPECT/CT of the abdomen up to 168 h after injection of (111)In-[Lys40(Ahx-DTPA-(111)In)NH2]-exendin-4 ((111)In-DTPA-exendin-4) to identify insulinomas. Consenting patients underwent surgery and imaging findings were confirmed histologically., Findings: Between Oct 1, 2008, and Dec 31, 2011, we recruited 30 patients. All patients underwent (111)In-DTPA-exendin-4 imaging, 25 patients underwent surgery (with histological analysis), and 27 patients were assessed with CT/MRI. (111)In-DTPA-exendin-4 SPECT/CT correctly detected 19 insulinomas and four additional positive lesions (two islet-cell hyperplasia and two uncharacterised lesions) resulting in a positive predictive value of 83% (95% CI 62-94). One true negative (islet-cell hyperplasia) and one false negative (malignant insulinoma) result was identified in separate patients by (111)In-DTPA-exendin-4 SPECT/CT. Seven patients (23%) were referred to surgery on the basis of (111)In-DTPA-exendin-4 imaging alone. For 23 assessable patients, (111)In-DTPA-exendin-4 SPECT/CT had a higher sensitivity (95% [95% CI 74-100]) than did CT/MRI (47% [27-68]; p=0.011)., Interpretation: (111)In-DTPA-exendin-4 SPECT/CT could provide a good second-line imaging strategy for patients with negative results on initial imaging with CT/MRI., Funding: Oncosuisse, the Swiss National Science Foundation, and UK Department of Health., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Intrahepatocellular (IHCL) and intramyocellular (IMCL) lipids are ectopic lipid stores. Aerobic exercise results in IMCL utilization in subjects over a broad range of exercise capacity. IMCL and IHCL have been related to impaired insulin action at the skeletal muscle and hepatic level, respectively. The acute effect of aerobic exercise on IHCL is unknown. Possible regulatory factors include exercise capacity, insulin sensitivity and fat availability subcutaneous and visceral fat mass)., Aim: To concomitantly investigate the effect of aerobic exercise on IHCL and IMCL in healthy subjects, using Magnetic Resonance spectroscopy., Methods: Normal weight, healthy subjects were included. Visit 1 consisted of a determination of VO2max on a treadmill. Visit 2 comprised the assessment of hepatic and peripheral insulin sensitivity by a two-step hyperinsulinaemic euglycaemic clamp. At Visit 3, subcutaneous and visceral fat mass were assessed by whole body MRI, IHCL and IMCL before and after a 2-hours aerobic exercise (50% of VO(2max)) using ¹H-MR-spectroscopy., Results: Eighteen volunteers (12M, 6F) were enrolled in the study (age, 37.6±3.2 years, mean±SEM; VO(2max), 53.4±2.9 mL/kg/min). Two hours aerobic exercise resulted in a significant decrease in IMCL (-22.6±3.3, % from baseline) and increase in IHCL (+34.9±7.6, % from baseline). There was no significant correlation between the exercise-induced changes in IMCL and IHCL and exercise capacity, subcutaneous and visceral fat mass and hepatic or peripheral insulin sensitivity., Conclusions: IMCL and IHCL are flexible ectopic lipid stores that are acutely influenced by physical exercise, albeit in different directions., Trial Registration: ClinicalTrial.gov NCT00491582.

Background: Left ventricular (LV) function may be impaired by right ventricular (RV) apical pacing. The interventricular septum is an alternative pacing site, but randomized data are limited. Our aim was to compare ejection fraction (EF) resulting from pacing the interventricular septum versus the RV apex., Methods: RV lead implantation was randomized to the apex or the mid-septum. LVEF and RVEF were determined at baseline and after 1 and 4 years by radionuclide angiography., Results: We enrolled 59 patients, of whom 28 were randomized to the apical group and 31 to the septal group, with follow-up available in 47 patients at 1 year and 33 patients at 4 years. LVEF in the apical and in the septal groups was 55 ± 8% vs. 46 ± 15% (p=0.021) at 1 year and 53 ± 12% vs. 47 ± 15% (p=0.20) at 4 years. Echocardiography confirmed a mid-septal lead position in only 54% of patients in the septal group, with an anterior position in the remaining patients. In the septal group, LVEF decreased significantly in patients with an anterior RV lead (-10.0 ± 7.7%, p=0.003 at 1 year and -8.0 ± 9.5%, p=0.035 at 4 years), but not in patients who had a mid-septal lead. Left intraventricular dyssynchrony was significantly increased in case of an anterior RV lead. RVEF was not significantly impaired by RV pacing, regardless of RV lead position., Conclusions: Pacing at the RV septum confers no advantage in terms of ventricular function compared to the apex. Furthermore, inadvertent placement of the RV lead in an anterior position instead of the mid-septum results in reduced LV function., (Copyright © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Context: Current treatment guidelines generally suggest using lower and weight-adjusted glucocorticoid replacement doses in patients with insufficiency of the hypothalamic-pituitary-adrenal (HPA) axis. Although data in patients with acromegaly revealed a positive association between glucocorticoid dose and mortality, no comparable results exist in patients with nonfunctioning pituitary adenomas (NFPA)., Objective: Our objective was to assess whether higher glucocorticoid replacement doses are associated with increased mortality in patients with NFPA and HPA axis insufficiency., Design, Participants, and Intervention: We included 105 patients receiving glucocorticoid replacement after pituitary surgery due to NFPA and concomitant HPA axis insufficiency. Patients were grouped according weight-adapted and absolute hydrocortisone (HC) replacement doses. Mortality was assessed using Kaplan-Meier methodology as well as multivariable Cox regression models., Setting: This was a retrospective analysis conducted at a tertiary referral center., Main Outcome: We evaluated overall mortality based on HC replacement doses., Results: Average age at inclusion was 58.9±14.8 yr, and mean follow-up was 12.7±9.4 yr. The groups did not differ according to age, follow-up time, pattern of hypopituitarism, and comorbidities. Kaplan-Meier survival probabilities differed significantly when comparing individuals with differing weight-adjusted HC dose (P=0.001) as well as absolute HC dose (5-19, 20-29, and ≥30 mg, P=0.009). Hazard ratios for mortality increased from 1 (0.05-0.24 mg/kg) to 2.62 (0.25-0.34 mg/kg) to 4.56 (≥0.35 mg/kg, P for trend=0.006) and from 1 (5-19 mg) to 2.03 (20-29 mg) to 4 (≥30 mg, P for trend=0.029), respectively., Conclusion: Higher glucocorticoid replacement doses are associated with increased overall mortality in patients with NFPA and insufficiency of HPA axis. This further substantiates the importance of a balanced and adjusted glucocorticoid replacement therapy in these patients.

Introduction: Many physicians target the interventricular septum for pacemaker implantation, but the lead may inadvertently end up in an anterior position., Aims: We sought to compare two stylet shapes to achieve mid-septal lead placement, as well as the utility of a novel right anterior oblique (RAO) fluoroscopic landmark., Methods and Results: Patients undergoing pacemaker implantation were enrolled into four consecutive groups according to stylet shape: a standard curve [two-dimensional (2D) stylet] or with an additional distal posterior curve [three-dimensional (3D) stylet], and whether RAO fluoroscopy was used. Left oblique anterior (LAO) and postero-anterior (PA) fluoroscopic views were used in all cases. After implantation, validation of right ventricular lead position (septal vs. anterior) was performed by echocardiography. A total of 113 patients were included, of whom lead position could be validated in 106 patients. Septal position was achieved in only 10 of 22 (45%) patients in the 2D stylet group and in 17 of 23 (74%) patients in the 3D stylet group (P = 0.07) when only PA and LAO fluoroscopy were used. Results were significantly improved by additional use of RAO fluoroscopy, with successful septal placement in 25 of 28 (89%) patients in the 2D stylet + RAO group (P = 0.001) and 32 of 33 (97%) patients in the 3D stylet + RAO group (P = 0.015)., Conclusions: A septal lead position was obtained in only about half of the patients when a 2D stylet was used with only LAO and PA fluoroscopic views. A 3D stylet was useful to attain the target position, and additional RAO fluoroscopy significantly improved success rate with both stylet shapes.

Background: Early generation drug-eluting stents (DESs) reduce restenosis and repeat revascularization procedures. However, the long-term safety and efficacy of early generation DES according to diabetic status are poorly established., Methods: A total of 1,012 patients were randomly assigned to treatment with sirolimus-eluting (n = 503) or paclitaxel-eluting stents (n = 509). Serial angiographic follow-up at baseline, 8 months, and 5 years was available in 293 patients with 382 lesions. The primary end point was a composite of major adverse cardiac events (cardiac death, myocardial infarction, and ischemia-driven target lesion revascularization). Clinical and angiographic outcomes through 5-year follow-up were compared between diabetic and nondiabetic patients., Results: Major adverse cardiac events were more common among diabetic than nondiabetic patients at 5 years (25.9% vs 19.2%, hazard ratio [HR] 1.45, 95% CI 1.06-1.99, P = .02). The difference in disfavor of diabetic patients was largely determined by a higher rate of cardiac mortality (11.4% vs 4.3%, HR 2.86, 95% CI 1.69-4.84, P < .0001), whereas the risk of myocardial infarction (6.5% vs 6.8%, HR 1.00, 95% CI 0.55-1.84, P = .99) and ischemia-driven target lesion revascularization (14.4% vs 14.1%, HR 1.09, 95% CI 0.73-1.64, P = .67) was comparable. The risk of stent thrombosis was similar among diabetic and nondiabetic patients (definite or probable: 6.0% vs 4.6%, HR 1.36, 95% CI 0.71-2.67, P = .35). Among 293 patients undergoing serial angiography, very-late lumen loss amounted to 0.42 ± 0.63 mm in diabetic patients and 0.44 ± 0.68 mm in nondiabetic patients (P = .79)., Conclusions: Diabetic patients remain at increased risk for mortality after revascularization with early generation DES during long-term follow-up. Conversely, diabetes is no longer associated with an increased risk of clinical and angiographic restenosis after revascularization with early generation DES., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: The relative safety of drug-eluting stents and bare-metal stents, especially with respect to stent thrombosis, continues to be debated. In view of the overall low frequency of stent thrombosis, large sample sizes are needed to accurately estimate treatment differences between stents. We compared the risk of thrombosis between bare-metal and drug-eluting stents., Methods: For this network meta-analysis, randomised controlled trials comparing different drug-eluting stents or drug-eluting with bare-metal stents currently approved in the USA were identified through Medline, Embase, Cochrane databases, and proceedings of international meetings. Information about study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted., Findings: 49 trials including 50,844 patients randomly assigned to treatment groups were analysed. 1-year definite stent thrombosis was significantly lower with cobalt-chromium everolimus eluting stents (CoCr-EES) than with bare-metal stents (odds ratio [OR] 0·23, 95% CI 0·13-0·41). The significant difference in stent thrombosis between CoCr-EES and bare-metal stents was evident as early as 30 days (OR 0·21, 95% CI 0·11-0·42) and was also significant between 31 days and 1 year (OR 0·27, 95% CI 0·08-0·74). CoCr-EES were also associated with significantly lower rates of 1-year definite stent thrombosis compared with paclitaxel-eluting stents (OR 0·28, 95% CI 0·16-0·48), permanent polymer-based sirolimus-eluting stents (OR 0·41, 95% CI 0·24-0·70), phosphorylcholine-based zotarolimus-eluting stents (OR 0·21, 95% CI 0·10-0·44), and Resolute zotarolimus-eluting stents (OR 0·14, 95% CI 0·03-0·47). At 2-year follow-up, CoCr-EES were still associated with significantly lower rates of definite stent thrombosis than were bare-metal (OR 0·35, 95% CI 0·17-0·69) and paclitaxel-eluting stents (OR 0·34, 95% CI 0·19-0·62). No other drug-eluting stent had lower definite thrombosis rates compared with bare-metal stents at 2-year follow-up., Interpretation: In randomised studies completed to date, CoCr-EES has the lowest rate of stent thrombosis within 2 years of implantation. The finding that CoCr-EES also reduced stent thrombosis compared with bare-metal stents, if confirmed in future randomised trials, represents a paradigm shift., Funding: The Cardiovascular Research Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)