Optimizing medication therapy in older hospitalized patients. Identifying potentially inappropriate medications and testing an interdisciplinary intervention

The overall aim of this thesis is to provide knowledge on potentially inappropriate medications (PIMs) in hospitalized older patients and to investigate how clinical pharmacist services in an interdisciplinary setting can contribute to medication optimization and improve patient outcomes. First, we used national health registers to investigate how admissions to Norwegian geriatric hospital wards affected PIM use. More than half of the 715 patients included in the study used PIMs after discharge. Hospitalization did not reduce the use of PIMs but may have increased use depending on how we measured PIMs. Second, we designed a 5-step intervention, introducing a clinical pharmacist in the ward teams working by the integrated medicines management (IMM) model to optimize medication use and improve communication with primary care. The intervention was tested in older patients ≥70 years admitted to two internal medicines wards at the University Hospital of North Norway. We applied a non-blinded randomized controlled trial, where 516 acutely admitted patients were randomized into an intervention group and a standard care group (1:1). The primary outcome was the rate of emergency medical visits (readmissions and emergency department visits) 12 months after discharge. Many medication discrepancies and MRPs were identified and solved in intervention patients, suggesting that the intervention optimized medication use. However, no significant reduction in the rate of emergency medical visits was observed in intervention patients versus control patients, nor did we observe any significant effects on time to the first emergency medical visit, 30-days readmissions rate, length of index hospital stay or mortality. Overall, this thesis demonstrates a need to optimize medication therapy in older hospitalized patients. Including clinical pharmacists' services in hospital wards teams may contribute to optimizing medication use, but there is a need for further studies to identify interventions that simultaneously produce meaningful improvements in patient outcomes

Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical practice

Cardiovascular complications, characterized by endothelial dysfunction and accelerated atherosclerosis, are the leading cause of morbidity and mortality associated with diabetes. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Overproduction and/or insufficient removal of these free radicals result in vascular dysfunction, damage to cellular proteins, membrane lipids and nucleic acids. Despite overwhelming evidence on the damaging consequences of oxidative stress and its role in experimental diabetes, large scale clinical trials with classic antioxidants failed to demonstrate any benefit for diabetic patients. As our understanding of the mechanisms of free radical generation evolves, it is becoming clear that rather than merely scavenging reactive radicals, a more comprehensive approach aimed at preventing the generation of these reactive species as well as scavenging may prove more beneficial. Therefore, new strategies with classic as well as new antioxidants should be implemented in the treatment of diabetes

1α,25-Dihydroxyvitamin D3 Stimulates Activator Protein 1 DNA-Binding Activity by a Phosphatidylinositol 3-Kinase/Ras/MEK/Extracellular Signal Regulated Kinase 1/2 and c-Jun N-Terminal Kinase 1-Dependent Increase in c-Fos, Fra1, and c-Jun Expression in Human Keratinocytes

1α,25-Dihydroxyvitamin D3 added to human keratinocytes increases differentiation through an activation of the transcription factor activator protein 1. We have previously reported that the 1α,25-dihydroxyvitamin D3-induced increase of activator protein 1 DNA binding activity is mediated by a protein kinase C-independent mechanism. The purpose of this study was to investigate further the mechanisms by which 1α,25-dihydroxyvitamin D3 modulates activator protein 1 DNA binding activity in cultured normal human keratinocytes. Western blotting experiments revealed that 1α,25-dihydroxyvitamin D3 caused a rapid and transient activation of the mitogen-activated protein kinases, extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1. 1α,25-Dihydroxyvitamin D3 also enhanced the expression of the activator protein 1 subunits, c-Fos, Fra1, and c-Jun as determined by northern and western blotting. The 1α,25-dihydroxyvitamin D3-induced activator protein 1 DNA binding activity was completely blocked by the MEK inhibitor PD 98059 indicating that the MEK/extracellular signal regulated kinase pathway is involved in the activation of activator protein 1. Transfection experiments showed that 1α,25-dihydroxyvitamin D3 also increased the activator protein 1-dependent transactivation, which was completely blocked by expression of a dominant negative Ras, suggesting that the 1α,25-dihydroxyvitamin D3-induced activator protein 1 activity involves Ras-dependent signaling. Furthermore, preincubation of the keratinocytes with the specific phosphatidylinositol 3-kinase inhibitors, Wortmannin and LY294002, demonstrated that the 1α,25-dihydroxyvitamin D3-induced activation of extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1 required phosphatidylinositol 3-kinase activity. Finally, preincubation of keratinocytes with a polyclonal antibody against the membrane receptor annexin II, blocked the 1α,25-dihydroxyvitamin D3-induced activation of extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1. Taken together, our results indicate that 1α,25-dihydroxyvitamin D3, via binding to the membrane receptor annexin II, induces activation of the phos-phatidylinositol 3-kinase/Ras/MEK/extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1 signal transduction pathway resulting in increased expression of c-Fos, Fra1, and c-Jun, and subsequently increased activator protein 1 DNA binding activity and gene transcription

Is anticholinergic and sedative drug burden associated with postdischarge institutionalization in community-dwelling older patients acutely admitted to hospital? A Norwegian registry-based study

Purpose: Investigate the association between anticholinergic (AC) and sedative (SED)drug burden before hospitalization and postdischarge institutionalization (PDI) incommunity-dwelling older patients acutely admitted to hospital.Methods: A cross-sectional study using data from the Norwegian Patient Registryand the Norwegian Prescription Database. We studied acutely hospitalizedcommunity-dwelling patients≥70 years during 2013 (N=86 509). Patients acutelyadmitted to geriatric wards underwent subgroup analyses (n=1715). We calculateddrug burden by the Drug Burden Index (DBI), use of AC/SED drugs, and the number of AC/SED drugs. Piecewise linearity of DBI versus PDI and a knot point(DBI=2.45) was identified. Statistical analyses included an adjusted multivariable logistic regression model.Results: In the total population, 45.4% were exposed to at least one AC/SED drug,compared to 52.5% in the geriatric subgroup. AC/SED drugs were significantly asso-ciated with PDI. The DBI with odds ratios (ORs) of 1.11 (95% CI 1.07–1.15) forDBI Conclusions: The use of AC/SED drugs was highly prevalent in older patients beforeacute hospital admissions, and significantly associated with PDI. The number, or justusing AC/SED drugs, gave similar associations with PDI compared to applying theDBI. Using AC drugs showed higher sensitivity, indicating that to reduce the risk ofPDI, a clinical approach could be to reduce the number of AC drugs

Investigation of the presence of human or bovine respiratory syncytial virus in the lungs of mink (Neovison vison) with hemorrhagic pneumonia due to Pseudomonas aeruginosa

<p>Abstract</p> <p>Background</p> <p>Hemorrhagic pneumonia is a disease of farmed mink (<it>Neovison vison</it>) caused by <it>Pseudomonas aeruginosa</it>. The disease is highly seasonal in Danish mink with outbreaks occurring almost exclusively in the autumn. Human respiratory syncytial virus (RSV) has been shown to augment infection with <it>P. aeruginosa</it> in mice and to promote adhesion of <it>P. aeruginosa</it> to human respiratory cells.</p> <p>Findings</p> <p>We tested 50 lung specimens from mink with hemorrhagic pneumonia for bovine RSV by reverse transcriptase polymerase chain reaction (PCR) and for human RSV by a commercial real-time PCR. RSV was not found.</p> <p>Conclusions</p> <p>This study indicates that human and bovine RSV is not a major co-factor for development of hemorrhagic pneumonia in Danish mink.</p

Influence of obesity-related risk factors in the aetiology of glioma

BACKGROUND: Obesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: Genetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity-related traits was used to infer evidence for a causal relationship. RESULTS: No convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma-glioblastoma (GBM) or non-GBM tumours. CONCLUSIONS: This study provides no evidence to implicate obesity-related factors as causes of glioma

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetic and biological characterization of the anorexic anx/anx mouse

Pathological deviations in body weight is a major health problem. It is currently unclear how normal body weight and food intake is controlled. There is even less understanding of the mechanisms behind abnormal eating behavior as in anorexia and obesity. Major support for the concept of genetic control of body weight and food intake has emerged from different animal models as well as twin- and family- studies in humans. A number of genes have been found which have an effect on food intake and body weight in animals. Some of these genes have similar effects in humans. The mouse anorexia (anx) mutation arose spontaneously in 1976. It causes a lethal phenotype with a pronounced eating disturbance. Mutant mice (anx/anx) are characterized by poor appetite, reduced body weight, emaciated appearance and abnormal behavior including body tremors, head weaving, hyperactivity and uncoordinated gait. The anx gene was previously linked to the nonagouti (a) locus on mouse Chromosome 2. We have mapped the anx mutation to a 0.2 cM interval on Chromosome 2 by simple sequence polymorphism marker genotyping of 2422 F2 progeny from two different intercrosses. Markers from this interval were used to construct a physical map, consisting of YAC, BAC, PAC and PI clones, spanning the interval. The clones were shotgun sequenced and candidate genes identified. Several histochemical alterations of peptides regulating food intake in the arcuate nucleus in the hypothalamus of anx/anx mice were found, using in situ hybridization and immunohistochemistry. Levels of neuropeptide Y- (NPY) and agouti gene-related protein- (AGRP) like immunoreactivities were increased in cell bodies and decreased in terminals in anx/anx mice, whereas no changes were observed in the respective mRNA levels. In contrast, markers of pro- opiomelanocortin (POMC) neurons, such as POMC, cocaine- and amphetamine-regulated transcript (CART) and the NPY receptors Y1 and Y5, had decreased mRNA levels. Taken together these results indicate that the phenotype of the anx/anx mouse may be related to the arcuate neurons themselves rather than to a particular neuropeptide. Striatal dopamine and its metabolites were significantly lower in anx/anx mice. In addition, the activity of Na+, K+-ATPase in striatal medium spiny neurons was significantly increased in anx/anx mice compared to normal littermates. Furthermore, addition of dopamine in vitro, which normally inhibits the NA+, K+-ATPase, failed to suppress the increased activity in anx/anx neurons. This suggests an abnormal dopaminergic transmission in the striaturn of anx/anx mice. The identification of the anx gene and its product(s) may improve the understanding of food intake regulation. The fact that the anx mutation affects many of the known hypothalamic feeding regulatory molecules makes the anx gene an interesting target for development of new tools and/or pharmaceuticals for the treatment of eating disorders