bluuebunny/crossref_metadata_2025_split huggingface dataset:
1144-P: Distribution of Prescribed Dose During the First Year of Metformin Monotherapy in the U.S.
Authors: IGLAY KRISTY , SAWHNEY BAANIE , RAJPATHAK SWAPNIL , CRUTCHLOW MICHAEL , FERNANDES GAIL , KHUNTI KAMLESH 
Published: June 2019

International guidelines recommend metformin as initial pharmacotherapy for patients with type 2 diabetes (T2D). Guidelines recommend metformin is up-titrated to a maximally effective (~2000 mg/day) dose based on glycemic control and tolerability; however, the extent to which this dose titration occurs in the real-world setting is unknown. To address this question in a U.S. population, we conducted a retrospective cohort study using the Optum database to evaluate the dose distribution of metformin monotherapy (MM) over 12 months in adult (≥21 years) T2D patients initiating MM during 2013-2016. Of the 30,352 eligible patients, 49% were female and median age was 65 years. The Table describes the distribution of metformin dose over the 12-month follow-up period. The majority (88%) of patients were initiated on MM at ≤1000 mg/day. At 3, 6 and 12 months, 84%, 82% and 80% of MM patients, respectively, were on doses ≤1000 mg/day. At 12 months, only 16% of patients were on a metformin dose &gt;1500 mg/day. Among those who were up-titrated during follow-up (n=5003), the median highest dose of metformin was 1500 mg/d and median time to highest dose was 165 days.
In conclusion, the majority of MM patients were not up-titrated and remained on a sub-maximally effective dose of metformin at 12 months despite international guidelines. Further research will be conducted to examine the relationship between MM dose and glycemic control.

Disclosure
K. Iglay: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. B. Sawhney: Consultant; Self; Merck & Co., Inc. S. Rajpathak: None. M. Crutchlow: Consultant; Spouse/Partner; Crinetics, Novartis Pharmaceuticals Corporation, ProSciento, Soleno Therapeutics, Zealand Pharma A/S. Employee; Self; Merck & Co., Inc. Research Support; Spouse/Partner; Dexcom, Inc. G. Fernandes: None. K. Khunti: Advisory Panel; Self; Amgen Inc., AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Menarini Group, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Servier, Takeda Pharmaceutical Company Limited.
115-OR: Epinephrine Contributes to Hypoglycemia-Associated Autonomic Failure (HAAF)
Authors: YIMAGOU ERIC LONTCHI , ALEKSIC SANDRA , UPADHYAY LAXMI , SHARMA SHIKSHA , CAREY MICHELLE , GOYAL AKANKASHA , YOU JEE YOUNG , HULKOWER RAPHAEL , MURTHI SWETHA , MITCHELL WILLIAM G. , SHAMOON HARRY , HAWKINS MEREDITH 
Published: June 2019

Recurrent hypoglycemia leads to HAAF, with blunted counterregulatory hormone responses to subsequent hypoglycemic episodes. A recent report suggested inter-individual differences in susceptibility to HAAF (JCEM 102:3571, 2017). Since adrenergic receptor blockade prevents HAAF (Diabetes 60:602, 2011), we investigated to what extent the rises in plasma epinephrine (EPI) associated with hypoglycemia predict the development of HAAF.
Healthy non-diabetic subjects (n=18, age 43±2years, BMI 25±1 kg/m2) underwent two 2-hour hypoglycemic clamp studies (nadir 54mg/dl; 0-2h and 4-6 h) on Day 1 followed by a third 2-hour hypoglycemic clamp on Day 2. Twelve subjects (67%) developed HAAF by the third episode, as defined by at least 20% reductions in peak EPI levels (peak EPI 1st vs. 3rd episode: HAAF subjects 1072±156 vs. 530±87pg/ml, p&lt;0.001). Importantly, peak EPI levels during the 1st hypoglycemic episode were ∼83% higher in the subjects who developed HAAF compared to those who did not (p=0.02).
To specifically define the role of EPI in the pathogenesis of HAAF, we challenged an additional seven non-diabetic subjects (age 32±4 years, BMI 25±1 kg/m2) with two 2-hour infusions of EPI (0.03 μg/kg/min;0-2h and 4-6 h) on Day 1 followed by 200-minute stepped hypoglycemic clamps (90, 80, 70 and 60 mg/dl, each for 50 minutes) on Day 2. Compared to saline, EPI infusion on Day 1 induced 40% and 28% reductions in epinephrine response to hypoglycemia at the 70 and 60 mg/dl glucose steps on Day 2, respectively (all p&lt;0.05). There were parallel reductions in hypoglycemic symptoms (all p&lt;0.05). Furthermore, the rate of glucose infusion was higher at all steps after EPI infusion (all p&lt;0.05), consistent with a trend towards lower endogenous glucose production (6,6-D2-glucose).
Thus, rises in EPI similar to those seen with hypoglycemia reproduce key features of HAAF in non-diabetic subjects. Marked inter-individual variability in EPI levels in response to hypoglycemia may explain why some people are more prone to develop HAAF.

Disclosure
E. Lontchi Yimagou: None. S. Aleksic: None. L. Upadhyay: None. S. Sharma: None. M. Carey: None. A. Goyal: None. J. You: None. R. Hulkower: None. S. Murthi: None. W.G. Mitchell: None. H. Shamoon: None. M. Hawkins: Other Relationship; Self; Novo Nordisk Inc.

Funding
American Diabetes Association (1-18-PMF-024 to E.L.Y.); National Institutes of Health (R01DK079974)
1155-P: Effect of Endoscopic Duodenal-Jejunal Bypass Liner on Parameters of Insulin Sensitivity and Secretion in Subjects with Type 2 Diabetes Mellitus and Obesity
Authors: KUDLACKOVA MICHAELA , MRAZ MILOS , HALUZIK MARTIN , PELIKANOVA TEREZIE , BENES MAREK , LAPESOVA DANUSE , KOBROVA DANA , VLASAKOVA ZUZANA , BRIZOVA OLGA , LACINOVA ZDENKA 
Published: June 2019

Duodenal-jejunal by-pass liner (DJBL) is an endoscopically implantable device designed to non-invasively mimic the effects of surgical gastric by-pass. However, the exact mechanisms responsible for improved glucose control associated with DJBL are still unclear. The aim of our study was to assess the effect of DJBL on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM) and obesity. Twenty-one obese subjects with T2DM (15 males, age 52.3 ± 11.2 years) underwent the implantation of the EndoBarrier DJBL (GI Dynamics, U.S.). Anthropometric, biochemical and hormonal parameters were measured before and 10 months after the implantation of DJBL. Insulin sensitivity was assessed using euglycemic-hyperinsulinemic clamp. Standard parameters including glucose disposal rate (M) and metabolic clearance rate of glucose (MCG) were calculated based on clamp results. Over 10 months the implantation of DJBL decreased body weight (body mass index 41.6 ± 6.1 vs. 37.5 ± 4.2 kg/m2, p&lt;0.001) and improved glucose control (fasting blood glucose 10.5 ± 2.5 vs. 8.4 ± 2.4 mmol/l, p&lt;0.001; HbA1C 74.7 ± 17.8 vs. 55.6 ± 12.4 mmol/mol, p&lt;0.001). These improvements were accompanied by a marked increase in insulin sensitivity as shown by the results of the euglycemic-hyperinsulinemic clamp (M 1.5 ± 0.8 vs. 2.6 ± 1.0 mg.kg-1.min-1, p&lt;0.001; MCG 1.4 ± 0.7 vs. 2.6 ± 0.2 mg.kg-1.min-1, p&lt;0.001). In contrast, insulin secretion was not affected by DJBL (fasting insulin 21.8 ± 13.0 vs. 18.5 ± 9.5 mIU/l, p=0.312; C-peptide 2.7 ± 1.1 vs. 2.4 ± 1.1 nmol/l, p=0.172). To conclude the improvement in glucose control associated with the implantation of Endobarrier DJBL is primarily caused by increased insulin sensitivity rather than augmented insulin secretion.

Disclosure
M. Kudlackova: None. M. Mraz: None. M. Haluzik: None. T. Pelikanova: None. M. Benes: None. D. Lapesova: None. D. Kobrova: None. Z. Vlasakova: None. O. Brizova: None. Z. Lacinova: None.

Funding
Institute for Clinical and Experimental Medicine (IN00023001)
1158-P: Type 2 Diabetes Patients Subtype Analysis: Unbiased Machine Learning for Future Personalized T2D Care
Authors: CHEN LI , FENG LINGGE , TANG CUI , ZHANG YI 
Published: June 2019

Dorzagliatin (HMS5552) that achieved POC in a recent Ph II trial, demonstrated its potential to treat type 2 diabetes (T2D) patients through a personalized medicine approach in a biomarker guided patient selection study. We here by conducted a data-driven unsupervised clustering analysis on the full analysis set (221 patients) of Dorzagliatin Ph II trail using clinically relevant biomarkers, which generated six clusters. An ANOVA test was done for those variables between clusters, and 40 of them are significantly different (P &lt; 0.05). The study showed that each cluster possesses unique characters related to disease stage of T2D and the stage is progressing to one direction which starts from mild to severe loss of pancreas β-cell function accompany with progressively increase of insulin resistance. Cluster 1 shared similar feature as those in previous Ph Ic study, in which, QD dose of Dorzagliatin offered better response rate of 100%, while in Ph II based cluster, the 75mg QD dose group achieved 1.88% reduction in HbA1c from baseline with the 75mg BID offered HbA1c reduction of 0.95%. However, in Cluster 2 and 4, there are clear trends that BID is more effective than QD in glycemic control as well as improving β-cell function and reduction of insulin resistance. In Cluster 4, it is observed FPG reduction of 1.57mmol/L, PPG reduced of 2.73mmol/L, HOMA-β improvement of 12.22, and HbA1c reduction of 1.69% in 75mg BID dose group, with corresponding changes in 75 QD group of 0.35 mmol/L, 1.7mmol/L, 9.24 and 0.26% respectively adjusted by placebo. The results suggested that the AI methodology is able to differentiate T2D patients into different subclass according to the severity of the disease state, and 75mg BID Dorzagliatin seems offered a minimum therapeutic effective dose (MTED) to all patient population, and 75mg QD regiment is a preferred option for the early stage T2D condition.

Disclosure
L. Chen: Employee; Self; Hua Medicine. L. Feng: Employee; Self; Hua Medicine. C. Tang: Employee; Self; Hua Medicine. Y. Zhang: Employee; Self; Hua Medicine.

Funding
Hua Medicine
1159-P: Metformin Monotherapy Changes Gut Microbiota in Newly Diagnosed Type 2 Diabetes
Authors: HUNG WEI CHUN , HUNG WEI-WEN 
Published: June 2019

Current clinical guidelines suggest metformin as the first-line therapy to treat type 2 diabetes. Despite its use for over 60 years, the precise mechanisms of metformin are still not fully discovered. Traditionally, liver was thought to be the main target of metformin action. More recently, gut has become the center of attention due to the increasing evidences suggesting the antidiabetic effect of metformin is derived from the gut. We aimed to evaluate the antidiabetic effects of metformin and the changes of gut microbiota in newly-diagnosed and drug-naive type 2 diabetes. We recruited 22 patients with newly-diagnosed and drug-naive type 2 diabetes from the outpatient clinic in a university hospital in southern Taiwan. Before and after metformin monotherapy for three months, we collected the biochemical data and measured fecal microbiota by quantitative real-time PCR with 16S rRNA gene sequencing. At the end of three months, there were totally 14 patients continued on metformin monotherapy and completed the collection of stool samples. Our results discovered that body-mass index, HbA1C, and fasting blood glucose decreased while HDL-C increased significantly after metformin monotherapy for three months. There were no significant changes in cholesterol, triglyceride, LDL-C, and HOMA-IR. Using quantitative real-time PCR with 16S rRNA gene sequencing, we found that Akkermansia and Escherichia increased significantly. The two major phylum of Firmicutes and Bacteroidetes did not have significant changes after three-month metformin monotherapy. We revealed that the antidiabetic effects of metformin associated with the changes of microbiota including Akkermansia and Escherichia. Understanding the interaction between metformin and gut microbiota in newly-diagnosed type 2 diabetes can help to identify important microbiota species related to the antidiabetic effect of metformin. In the future, gut microbiota has the potential to serve as a new therapeutic tool or target in treating type 2 diabetes.

Disclosure
W. Hung: None. W. Hung: None.

Funding
Kaohsiung Medical University
1160-P: The Risk Factors of Bullous Pemphigoid and Associated Risk between Bullous Pemphigoid and Dipeptidyl Peptidase-IV Inhibitors in Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study
Authors: GUO JIA-YIN , CHEN HSIN HUNG , YANG YU-CIH , CHEN CHING-CHU 
Published: June 2019

Objective: Bullous pemphigoid (BP) is the most common autoimmune blistering skin disorder with unclear etiology. Previous reports showed that BP may be associated with the use of some drugs. This study aimed to evaluate the risk factors for the development of BP and the relationship of BP with the administration of DPP-4i in patients with type 2 diabetes mellitus (T2DM).
Research Design and Methods: Using the National Health Insurance Research Database (NHIRD) from 2009 to 2013, there were 87,029 patients with T2DM. We excluded patients with T2DM without taking any antidiabetic agents and the development of BP before the use of DPP-4i or before they were selected. We identified individuals with T2DM and the use of DPP-4i 84 days or greater as a DPP-4i cohort and subjects never use DPP-4i as a control cohort. They were frequency matched on gender and age within 5 years at a ratio of 1:2.
Results: We identified 14,178 individuals taking DPP-4i and 28,374 matched cohorts without taking DPP-4i. There were 17 BP events in control cohort and 15 BP events in DPP-4i cohort. The incidence of BP was higher in DPP-4i cohort than in control cohort (1.41 vs. 0.59 per 1000 person-years; adjusted HR 2.14, 95% CI = 1.02-4.50). Patients with dementia had a higher associated risk to develop BP (adjusted HR 3.55, 95% CI = 1.30-9.66). The associated risk was lower in patients taking metformin (adjusted HR 0.38, 95% CI = 0.18-0.79) and higher in patients taking spironolactone (adjusted HR 3.06, 95% CI = 1.25-7.51). The cumulative incidence of BP in DPP-4i cohort was higher than in control cohort (log-rank test, p = 0.01).
Conclusion: DPP-4 inhibitors were associated with an increased risk of the development of BP in patients with T2DM. Patients with dementia and taking spironolactone had a higher associated risk. The development of BP in metformin users is significantly lower than in metformin non-user.

Disclosure
J. Guo: None. H. Chen: None. Y. Yang: None. C. Chen: None.
1162-P: DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion via Stimulation of GLP-1 Secretion
Authors: KIM JIN HEE , KIM YOUJIN , KIM RYEONG-HYEON , KIM MI-KYUNG , PARK HYUNKI , LEE MINYOUNG , CHO YONGIN , BAE JAEHYUN , LEE SANG BAE , LEE INKUK , LEE HYANGKYU , KIM CHUL HOON , KANG EUN SEOK 
Published: June 2019

Unlike other G protein-coupled receptor (GPR)119 agonists, DA-1241 has shown long-term beneficial effects on glucose and lipid metabolism in previous studies. In this study, we investigated the antidiabetic effects of DA-1241 in vitro and in vivo. The efficacy of DA-1241 was evaluated by assessing the changes in glucagon-like peptide-1 (GLP-1) levels, gluconeogenesis, and hepatic autophagy. DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks (n=34), and serum insulin and GLP-1 levels were measured by oral glucose tolerance tests at week 8. The effects of DA-1241 on gluconeogenic enzyme expression and autophagic flow were evaluated in HepG2 cells and livers isolated from LC3-GFP-transgenic mice. DA-1241 improved oral glucose tolerance (no significant effect on intraperitoneal glucose tolerance test) with an increase in serum GLP-1 and insulin levels. Fasting blood glucose level decreased, and the insulinogenic index was improved after DA-1241 treatment in HFD-fed mice. However, no significant increase in insulin secretion in INS1E cells and isolated mouse islet with DA1241 treatment. DA-1241 reduced gluconeogenic enzyme expression and blocked autophagic flow in HepG2 cells. Additionally, DA1241 induced GFP fragmentation in liver from LC3-GFP-transgenic mice. These findings suggested that DA-1241 augmented glucose-dependent insulin release via improvement in GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.

Disclosure
J. Kim: None. Y. Kim: None. R. Kim: None. M. Kim: None. H. Park: None. M. Lee: None. Y. Cho: None. J. Bae: None. S. Lee: None. I. Lee: None. H. Lee: None. C. Kim: None. E. Kang: None.
1172-P: GLUT4-Overexpressing Engineered Muscle Tissue Implants as a Potential Novel Therapy for Type 2 Diabetes: Lessons from Diabetic Mice
Authors: BECKERMAN MARGARITA , KARNIELI EDDY , HAREL CHAVA , KLIP AMIRA , BILAN PHILIP J. , GALLAGHER EMILY , LEROITH DEREK , LEVENBERG SHULAMIT 
Published: June 2019

In spite of current therapy protocols many T2DM patients fail to achieve blood glucose homeostasis goals. Insulin resistance in T2DM is associated with impaired GLUT4 function and cellular content. Thus, our aim was to improve overall glucose homeostasis by constructing engineered muscle tissue, using genetically modified skeletal muscle cells that over-express the GLUT4 transporter (OEG4). The OEG4 cells were grafted on biodegradable scaffolds and cultured to allow the formation of engineered muscle tissue constructs (EMC). Using an in-vitro 2-deoxyglucos (DOG) uptake assay, the OEG4-EMCs showed a 1.8-fold increase in DOG uptake with insulin stimulation, compared to unmodified controls. For in-vivo efficacy evaluation OEG4-EMCs and empty constructs, not seeded with cells, as control were implanted in the abdominal wall of immunodeficient recombination-activating gene 1 (Rag1)/MKR mice model of T2DM. Following i.p glucose tolerance test mice implanted with OEG4-EMCs had significantly (p&lt;0.05) reduced maximal blood glucose levels (185+/-14.8 mg/dL), compared to diabetic controls group (294+/-23 mg/dL) and similar to nondiabetic mice (188+/-8.1 mg/dL). In addition, glucose levels returned to basal levels faster than in the control group. Since, EMC implants improved diabetic mice overall glucose homeostasis our data support the potential of such implants as novel therapeutic mode for T2DM therapy.

Disclosure
M. Beckerman: None. E. Karnieli: None. C. Harel: None. A. Klip: None. P.J. Bilan: None. E. Gallagher: None. D. LeRoith: Advisory Panel; Self; AstraZeneca, MannKind Corporation. S. Levenberg: None.

Funding
Rina and Avner Schneur Charitable Giving Fund
1175-P: Circulating CD4+/CD8+ PD-1+ T Cells Are Increased during the Partial Remission Phase in Patients with Type 1 Diabetes
Authors: ZHONG TING , LI XIA , ZHOU ZHIGUANG 
Published: June 2019

Programmed death-1 (PD-1) critically regulates T cell tolerance, but the role of PD-1/PD-L1 in the pathogenesis of type 1 diabetes (T1D) patients remains unclear. In this study, we investigated circulating PD-1+/PD-L1+ T cells and their changes during the partial remission (PR) phase in T1D. 79 patients with T1D and 21 normal controls were enrolled, and grouped into 4 groups based on remission phase. The percentage of circulating PD-1+/PD-L1+ T cells, Treg, IL-35-Treg and Breg cells was analyzed by flow cytometry. The results showed that the expression of PD-1 in CD4+/CD8+ T cells was significantly decreased at the onset of T1D, and recovered to a high level during the remission phase. The honeymoon phase was accompanied by the increase of PD-1 expression, suggesting that PD-1 may be a new target for diagnosis and intervention.

Disclosure
T. Zhong: None. X. Li: None. Z. Zhou: None.
1180-P: Development of “Smart mRNAs” that Synthesize Corrective Proteins during Abnormal Metabolic States
Authors: JAFFREY SAMIE 
Published: June 2019

Diabetes and related disorders are associated with abnormal cellular metabolism, abnormal levels of various intracellular metabolites, and most importantly, impaired cellular responses which would normally correct these abnormalities. As a result, various tissues, such as liver, adipose, and skeletal muscle, exhibit altered cellular signaling and physiologic responses, which ultimately lead to the clinical signs and symptoms of diabetes. A major goal of synthetic biology is to develop new gene therapy approaches in which proteins are expressed in disease-affected tissues to correct these diverse metabolic abnormalities. However, a major challenge is to develop approaches in which the corrective proteins are only expressed when the cells exhibit metabolic derangements. Here we describe the first "smart mRNAs." These are mRNAs that can be expressed using standard gene therapy approaches, but are only translated when specific diabetes-associated metabolites are present. We describe how the 5' untranslated regions in mRNAs can be designed so that they bind diabetes-associated metabolites, and subsequently induce the translation of the encoded protein. We demonstrate the translational control that can be achieved with this new class of mRNA in various cell types, and we show how translation can be regulated by various metabolites and signaling states associated with diabetes. Lastly, we discuss how smart mRNAs can be used therapeutically in animal models in order to develop organs with restored cellular and signaling functions.

Disclosure
S. Jaffrey: Stock/Shareholder; Self; Gotham Therapeutics, Lucerna Biosciences.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-18-VSN-02)
1181-P: Effect and Feasibility of High Dose Eplerenone in Type 2 Diabetes: A Mirad Substudy
Authors: BRANDT-JACOBS NIELS HØEG , RASMUSSEN JON BJARKE , JOHANSEN MARIE-LOUISE , ROSSIGNOL PATRICK , FABER JENS , SCHOU MORTEN , KISTORP CAROLINE MICHAELA 
Published: June 2019

The use of mineralocorticoid receptor antagonists (MRA) as anti-hypertensive therapy has been limited due to concern of potential hyperkalemia among patients with T2D. The aim of this study was to investigate the effect on blood pressure (BP) and feasibility of use of selective MRA eplerenone in T2D. We randomized 140 patients with T2D and established or high risk of cardiovascular disease to either eplerenone or placebo for 26 weeks. Target study medication dose was 200 mg/day or 100mg/day for patients with an eGFR &gt;60 or 40-60 ml/min/1,73m2, respectively. Outcomes of this substudy was change in 24h-ABPM, office-BP from baseline and incident hyperkalemia (s-K ≥ 5.5 mmol/L). A decrease was found in office systolic BP, in the eplerenone group as compared with placebo (-6 mmHg, [-11; -1], P=0.03). Mean 24h-systolic- (SBP) and diastolic BP (DBP) decreased significantly with eplerenone (SBP: -5 mmHg [-8; -2], P &lt;0.001; DBP: -3 mmHg [-4; -1] P &lt;0.001). The difference in 24h ABPM-change between groups at end-of-study being borderline significant (-3 mmHg [-7; 1], P=0.1). Number of patients with incident hyperkalemia did not differ (eplerenone vs. placebo 6 vs. 2, P = 0.27); with no incidences of severe hyperkaliemia (s-K ≥6.0 mmol/L). We conclude eplerenone to be a feasible option in the treatment of T2D patients with hypertension and normal mean eGFR.
Figure: 24-h ABPM change; comparison of baseline and end-of-study.

Disclosure
N. Høeg Brandt-Jacobs: None. J.B. Rasmussen: None. M. Johansen: None. P. Rossignol: None. J. Faber: None. M. Schou: None. C.M. Kistorp: None.