Percutaneous dilatational tracheostomy is a common procedure in intensive care. This guideline from the Danish Society of Intensive Care Medicine (DSIT) and the Danish Society of Anesthesiology and Intensive Care Medicine (DASAIM) describes indications and contraindications, timing, complications compared to surgical tracheostomy, anaesthesia and technique, decannulation strategy, as well as training and education.

Severe pain is usual after laparoscopic ventral hernia repair (LVHR). Mesh fixation with titanium tacks may play a key role in the development of acute and chronic pain and alternative fixation methods should therefore be investigated. This PhD thesis was based on three studies and aimed too: 1) assess the intensity and impact of postoperative pain by detailed patient-reported description of pain and convalescence after LVHR (Study I), 2) evaluate the feasibility of fibrin sealant (FS) for mesh fixation in an experimental pig model (Study II), and 3) investigate FS vs. tacks for mesh fixation in LVHR in a randomised, double-blinded, clinical controlled study with acute postoperative pain as the primary outcome (Study III). In Study I - a prospective descriptive study - 35 patients were prospectively included and underwent LVHR. Scores of pain, quality of life, convalescence, fatigue, and general well-being were obtained from each patient. Follow-up was six months. Average pain from postoperative day (POD) 0-2 and POD 0-6 measured on a 0-100 mm visual analogue scale (VAS) was 61 and 48, respectively. Pain scores reached preoperative values at POD 30. The incidence of severe chronic pain was 7%. No parameter predicted postoperative pain significantly. Significant correlations were found between pain, and general well-being (rS= -0.8, p < 0.001), satisfaction (rS= -0.67, p < quality of life score (rS= -0.63, p < 0.001) six months postoperatively. Patients resumed normal daily activity at POD 14. In Study II - a randomised experimental study in pigs - nine pigs were operated laparoscopically with insertion of two different meshes fixed with either FS or tacks. All pigs were euthanized on POD 30. The primary outcome parameter was strength of ingrowth between the mesh and the anterior abdominal wall. A mechanical peel test was performed for each tissue sample. The secondary outcome parameters were grade and strength of adhesions to the mesh, shrinkage and displacement/folding of the mesh and histological parameters. All nine pigs survived without complications until sacrifice. No meshes were displaced from their initial position at autopsy, but in two cases mesh folding was observed. No significant difference in strength of ingrowth was found between different fixation methods or mesh types. Furthermore, no significant difference was found in grade or strength of adhesions or any histological parameters. In Study III - a randomised, controlled, double-blinded, multicenter trial - 40 patients with umbilical hernia defects between 1.5-5 cm, were randomly assigned to receive FS or titanium tacks for mesh fixation in LVHR. Patients, care givers and those assessing the outcomes were blinded to group assignment. The primary outcome was average pain from POD 0-2 (VAS score). Secondary outcome parameters were fatigue, general well-being and time to resume normal daily activity. Follow-up was one month for all. Patients in the FS group reported significantly less pain at POD 0-2 (median VAS 38 (range 6-98) vs. 60 (18-96), p = 0.01). Absolute VAS score difference between groups was 20 mm (95% CI 4-35 mm) at activity, and 19 mm (95% CI 3-34 mm) at rest. Patients in the FS group reported significantly less discomfort from POD 0-2 and POD 0-10, compared with the tack group. No significant difference was found in fatigue score between groups. No significant difference in hospital stay, hernia diameter, or morphine consumption in the post anesthesia care unit was found between groups. Patients in the FS group resumed normal daily activity at POD 7 (1-66) versus POD 18 (1-95) in the tack group (p = 0.03). No recurrences were observed. No adverse events or side effects were observed. No significant differences in predefined complications were found between groups. In conclusion, pain is a significant clinical problem after LVHR with impact on general well-being, quality of life and patient satisfaction. This issue must have first priority in future ventral hernia repair research. It is now documented, that the simple application of fibrin glue instead of titanium tacks for mesh fixation in LVHR of defects < 5 cm significantly reduced acute pain, discomfort and the period of convalescence. Long-term follow-up will show the value of FS fixation in terms of chronic pain and recurrence. As FS potentially may solve many of the outcome problems associated with LVHR, future studies should include larger hernia defects including large incisional hernias, as the operative technique may be different.

The present thesis consists of one published article and one draft manuscript. Interest in the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) was reignited by the discovery that GIP receptor deficient mice were unable to gain weight in response to high fat feeding. However, the path from processing of the prohormone to regulation of secretion and establishment of its role in the complicated network of mediators involved in energy mobilization is not fully understood. The biologically active GIP1-42 was found in vivo to be dependent on processing from the immature prohormone by proprotein convertase 1/3 (PC1/3) in the intestinal K-cell. Even so, ~50% of GIP immunoreactive cells do not express PC1/3 raising the possibility that subsets of K-cells exist in which the precursor may be cleaved at alternative sites. Cell line studies did demonstrate that another convertase in endocrine cell types, PC2, mediated cleavage at alternative sites liberating larger and smaller GIP fragments. It was possible to detect fragments of similar size in gel filtration extracts of murine upper jejunum, but the identity, mechanism of processing and function of these immunoreactivities remains uncertain. Once correctly processed GIP1-42 is secreted in response to food intake. The K-cell is believed to directly sense and respond to nutrients in the intestine, but as the molecular profiling of this cell type has just begun, the nutrient sensing machinery and possible feedback regulation are still poorly characterized. When secreted to the blood stream, GIP acts as a mediator of energy mobilization in a complex network with other hormones. An acute and established function of GIP is to exert its incretin function thereby enhancing glucose stimulated insulin secretion necessary for prompt disposal of nutrients, yet GIP also stimulates glucagon secretion to increase blood glucose. In the diabetic state the insulinotropic effect of GIP is impaired and an early inexpedient glucagon stimulation in response to a meal further counteracts effects of insulin and worsens glycaemic control. A demonstration that GIP receptor deficient mice were resistant to diet induced obesity let to the categorization of GIP as a fat promoting hormone and direct insulin-mimetic effects in adipose tissue has been proposed. We were able to demonstrate a redundancy for the GIP receptor in incorporation of lipids into adipocytes. We also observed that GIP receptor deficient mice could respond normally to high fat feeding with increased fat mass, but failed to increase lean mass. Mice with rescue of the GIP receptor in adipose tissue normalized the body composition in response to high fat diet, but the mice had a lower total body weight. In contrast, the GIP receptor expressed in the pancreatic beta-cell was able to promote lean mass gain on a low fat diet, but not on a high fat diet. Overall, we have established principal requirements for GIP maturation. Furthermore, we have demonstrated that neither beta-cell nor adipocyte GIP receptor expression can replace the endogenous GIP receptor in regulation of body weight and body composition.

The clinical epidemiological studies included in this thesis fall into three parts. The first part includes studies on birth outcome in women with ulcerative colitis. The second part includes pharmacoepidemiological studies on birth outcome after anti-inflammatory drug therapy in pregnancy, including patients with ulcerative colitis and Crohn's disease. The third part (and the latest publications) includes birth outcome in women with Crohn's disease; and the methods of cohort establishment in these studies are developed and improved due to the knowledge gathered from conducting the earlier studies. The birth outcomes in women with ulcerative colitis are examined in a nationwide, Danish, cohort of women based on data from the Danish National Hospital Discharge Registry and the Danish Medical Birth Registry, and within a Hungarian case-control data set. Our data suggest: 1) Significantly increased risk of preterm birth when women give birth 0-6 months after establishment of the diagnosis. It is considered whether the increased risk may be influenced by disease activity around the time of establishing the diagnosis. 2) No increased risk of giving birth to children with low birth weight, intrauterine growth retardation or congenital abnormalities (evaluated overall). 3) Significantly increased risk of some selected congenital abnormalities (limb deficiencies, obstructive urinary and multiple congenital abnormalities). No other studies have examined the risk of selected congenital abnormalities in children born by women with ulcerative colitis. The pharmacoepidemiological studies on birth outcomes after use of anti-inflammatory drug therapy in pregnancy, including women with ulcerative colitis and Crohn's disease, are based on data from the Hungarian case-control data set, a countywide Danish prescription Database, the Danish National Hospital Discharge Registry, the Danish Medical Birth Registry, and review of selected medical records. After exposure to sulfasalazine during pregnancy our data suggest. No significantly increased overall relative risk of congenital abnormalities and no significantly increased risks of selected congenital abnormalities. After exposure to 5-aminosalicylic acid during pregnancy our data suggest. No significantly increased relative risk of low birth weight, intrauterine growth retardation or congenital abnormalities (evaluated overall). A significantly increased relative risk of preterm birth and stillbirth in ulcerative colitis women, compared to women with no prescription of reimbursed medicine in pregnancy - and also after comparing with women with chronic inflammatory bowel disease not taking 5-aminosalicylic acid during pregnancy. It is not clear whether these associations are causal or influenced by confounding by disease activity in particular. After maternal exposure to azathioprine/6-mercaptopurine during pregnancy our data suggest. An increased relative risk of preterm birth, congenital abnormalities, and perinatal mortality - also after using controls with similar underlying diseases. It is difficult to rule out an influence of uncontrolled confounding. These were the first published data from a controlled observational study on exposed women with chronic inflammatory bowel disease. After preconceptional paternal use of azathioprine/6-mercaptopurine our data suggest An increased risk of congenital abnormalities, although not significantly increased. The birth outcomes in women with Crohn's disease are examined in nationwide sub-cohorts classified according to type of anti-inflammatory drug exposure during pregnancy, and based on data from the Danish National Hospital Discharge Registry, the nationwide Danish Prescription Database and the Danish Medical Birth Registry. Furthermore, birth outcomes are examined in Crohn's disease women with disease activity during pregnancy, based on data from review of hospital records, the Danish National Hospital Discharge Registry and the Danish Medical Birth Registry. Our data suggest: 1) The risk of adverse birth outcomes in women with Crohn's disease varies according to the type of anti-inflammatory drug therapy in pregnancy. 2) Reassuring results according to low birth weight, intrauterine growth retardation, preterm birth and congenital abnormalities after use of sulfasalazine/5-aminosalicylic acid or steroids. 3) Worrisome findings of a significantly increased risk of preterm birth and an increased risk of congenital abnormalities (not significantly increased) after prescription of azathioprine/6-mercaptopurine during pregnancy. Some residual confounding by disease activity may have been left in the analyses of preterm birth. In Crohn's disease women with disease activity during pregnancy our data suggest: 1) A significantly increased relative risk of preterm birth in women with the highest degree of disease activity during pregnancy. 2) Disease activity does not seem to increase the risk of low birth weight, intrauterine growth retardation or congenital abnormalities. This study is the first epidemiological study of the risk of adverse birth outcomes in Crohn's disease women with disease activity during pregnancy, compared to women with no activity during pregnancy, and in which confounders have been taken into consideration. Exceeding the studies included in my previous PhD thesis, this thesis provides new evidence on the following subjects: i) the risk of selected congenital abnormalities in children of women with ulcerative colitis, ii) pharmacoepidemiological studies on the risk of adverse birth outcome after maternal azathioprine/6-mercaptopurine exposure in pregnancy, and the risk of congenital abnormalities in children fathered by men treated with azathioprine/6-mercaptopurine before conception, iii) the risk of adverse birth outcome in women with Crohn's disease according to type of anti-inflammatory drug treatment in pregnancy (sulfasalazine/5-aminosalicylic acid, steroids or azathioprine/6-mercaptopurine), and iv) the impact of disease activity in women with Crohn's disease on adverse birth outcome. We learned from the studies in this thesis that the traditional way of reporting birth outcome in women with chronic inflammatory bowel disease, i.e. without having valid information on the type of underlying disease, concurrent therapeutic drug treatment and disease activity, is of limited value. The studies show that the risk of specific adverse birth outcome in women with ulcerative colitis and Crohn's disease depends on several factors including the time of birth in relation the début of disease, the type of underlying disease (ulcerative colitis or Crohn's disease), the type of anti-inflammatory drug treatment during pregnancy, and the degree of disease activity during pregnancy. At the same time one also has to realize that the existing evidence is still limited, especially in the field of reproductive safety after therapeutic drug treatment during pregnancy and possible effects of preconceptional therapeutic drug exposure.

Atherosclerosis and PS are prevalent chronic immunoinflammatory diseases with pathophysiological, clinical and epidemiological similarities. Results suggest that PS may be an independent risk factor for cardiovascular disease. Participation of similar immunoinflammatory and prothrombotic mechanisms in PS and cardiovascular disease is supported by evidence that treatment with methotrexate in patients with PS is associated with reduced cardiovascular risk. Furthermore, PS is associated with surrogate markers of cardiovascular disease, e.g. endothelial dysfunction and coronary calcification, and with markers of increased platelet activity. However, results of epidemiological studies of the risk of cardiovascular disease in PS have been conflicting, and surveillance bias has been proposed to contribute to the observed association. Although similar considerations of shared immunoinflammatory pathways with PS can be applied to AF and VTE very little is known about the interaction between PS and these common diseases. With the underlying hypothesis that PS had detrimental effects on all prespecified adverse cardiovascular endpoints the objective of the current thesis was to examine in these patients: 1) the risk of atherothrombotic events and compare it with the risk in patients with DM; 2) the risk of AF and ischaemic stroke; 3) the risk of VTE; and 4) the prognosis after first-time MI. By use of the unique Danish nationwide registries approximately 40,000 patients with PS, including approximately 3000 patients with severe PS were identified in the study period 1997-2006. Paper I provided a comparison of cardiovascular risk between patients with PS, approximately 127,000 patients with DM, and the general population, respectively. Patients with PS were at increased risk of all endpoints including, MI, stroke, invasive coronary revascularization, cardiovascular death, and a composite cardiovascular endpoint (MI, stroke, and cardiovascular death). For the composite endpoint the rate ratios (RRs) were 1.20 (95% confidence interval [CI] 1.14-1.25), 1.58 (CI 1.36-1.85), and 1.59 (CI1.56-1.63) for mild PS, severe PS, and DM, respectively. Paper II documented an up to 2.5 fold increase in risk of AF and ischaemic stroke in patients with PS, with the highest risk estimates for young patients with severe disease. The main results of paper III were that patients with PS had an increased risk of VTE with RR 1.35 (CI 1.21-1.49) and RR 2.06 (CI 1.63-2.61) for mild and severe PS, respectively. Paper IV on post-MI prognosis included 615 patients with PS and a recent MI. The results documented that after first-time MI, these patients had an increased risk of a composite of recurrent MI, stroke, and cardiovascular death with hazard ratio 1.26 (CI 1.12-1.41) as compared to patients without PS. In conclusion, this thesis demonstrated that all patients with PS were at increased risk of atherothrombotic events and that the risk with severe PS was comparable to that of patients with DM. Furthermore, the thesis provided novel evidence of PS as a possible risk factor for AF and VTE. Finally, we demonstrated an association between PS and adverse prognosis following first-time MI. The results add importantly to evidence indicating that PS is an independent cardiovascular risk factor and should form the background for studies of interventions aimed at improved primary and secondary prevention of cardiovascular disease in patients with PS.