Venous thromboembolism in women : an assessment of hormonal, genetic and other risk factors

Background Venous thromboembolism (VTE) occurs in 1-2 in 1000 individuals per year. VTE is found in both sexes, but women have a higher incidence at younger ages, particularly during the childbearing years. Although several acquired and genetic risk factors for venous thrombosis have been identified, the modes and consequences of combinations of these risk factors are not fully understood. Aim: The overall aim of this thesis was to clarify risk factors for VTE in women. Methods: The ThromboEmbolismHormoneStudy (TEHS) is a nation-wide populationbased case-control study that included 1470 cases and 1590 controls. All participants were recruited prospectively in Sweden from 2003 to 2009. Reports on acquired risk factors for thrombosis were collected through telephone interviews of the participants and genetic risk factors were identified by DNA analyses on blood samples. Results: In Study I we found that risks associated with recognized acquired and genetic risk factors for VTE generally were of similar magnitude in pre-and postmenopausal women. The acquired, transient risk factors were stronger than the genetic factors and the combination of surgery and plaster cast yielded a 50-fold increased risk for VTE in both pre- and postmenopausal women. In study II current use of combined hormonal contraception (CHC) was associated with a five-fold increased risk of VTE, adjusted odds ratio (ORadj)=5.3, 95% confidence interval (CI)=4.0-6.9. In adjusted analyses combinations with desogestrel had the highest risk (OR=11.4, 95% CI=6.0-22.0) followed by drospirenone, etonogestrel, norgestimate, levonorgestrel and norethisterone (OR=2.0, 95% CI=1.1-3.8). Current use of progestogen-only contraception (POC) was not associated with increased risks of VTE (ORadj=0.9, 95% CI=0.7-1.2). In stratified analyses (by dose) current users of “high dose” POC had an increased risk of VTE (ORadj=2.2, 95% CI=1.3-4.0). In study III for the group of propionic acid derivatives, most women used ibuprofen (92%); of the women who used acetic acid derivatives, almost all used diclofenac (97%). In adjusted analyses overall use of NSAIDs was not associated with increased risks of VTE (ORadj=1.0, 95% CI=0.8–1.2). The adjusted OR was 0.9 for propionic acid derivatives (95% CI=0.72–1.10), 1.2 for acetic acid derivatives (95% CI=0.8–1.7) and 1.8 for coxibs (95% CI=0.7–4.3). For users of acetic acid derivatives and coxibs, the adjusted ORs increased by cumulative dose, suggesting a dose–effect relationship for these drugs. Conclusion: Menopausal status has only a minor impact on the risk levels with regard to recognized risk factors for VTE. The risk of VTE associated with the use of CHC varies depending on the type of progestogen used, even after adjustment for individual factors such as smoking and body mass index (BMI). Except for high-dose preparations, POC seems to be a safer alternative to CHC, with no obvious increased risks for VTE. There is no apparent risk of VTE associated with the use of propionic acid derivatives in young and middle-aged women. Key words venous thromboembolism, combined oral contraception, progestogen-only contraception, NSAID, premenopausal, postmenopausal, risk factor, SN

Cognition in Multiple sclerosis with special emphasis on MRI findings and cerebrosterol

Multiple sclerosis (MS) is a progressive inflammatory and degenerative disease of the central nervous system (CNS). This thesis focuses on cognition in MS, with special emphasis on long-term magnetic resonance imaging (MRI) findings and cerebrosterol plasma levels. In study I, the effects of MS on a variety of cognitive aspects were evaluated longitudinally over an eight-year follow-up period in 31 patients who had been diagnosed as having relapsing-remitting MS, secondary progressive MS (SP-MS) or primary progressive MS. A selective pattern of decline was found at baseline in the whole group, with marked decline in information-processing speed (IPS). These deficits in IPS at baseline predicted further cognitive decline over the follow-up period. A differential pattern of cognitive decline over time was noticed in the subgroups, with the most pronounced decline in the SP-MS group; in these patients, the deterioration in visual IPS was clearly more marked than that in auditory IPS. A high disability score (on the expanded disability status scale; EDSS) during follow-up was associated with cognitive decline. These findings indicate that tests measuring IPS are especially strong predictors of cognitive decline over longer periods in patients with MS. In Study II, 25 patients with MS and 25 matched control participants were tested with a picture-naming test (Boston Naming Test; BNT) and a letter-word fluency test (using the letters FAS). In the BNT, the MS patients used less distinct descriptions and substitutions and had significantly more off-target substitutions than the control group. The MS patients were significantly less effective in using strategies for retrieval in the word fluency FAS test than the control participants. These results suggest that language function becomes impaired in MS, with semantically nonspecific naming responses and less effective use of strategies for retrieval in word fluency. In Study III, 22 MS patients were given tasks investigating IPS, covering the following aspects: cognitive (symbol digit modalities test; SDMT), sensory (visual and auditory reaction time tests), motor (finger-tapping speed test) and auditory interhemispheric transfer (verbal dichotic listening test; VDL). These parameters were related to the area of the corpus callosum in the brain (CCA), measured with MRI at baseline and at follow-up nine years later. The relative brain volume (RBV) and the T2 lesion load were taken into account. The results showed that the CCA, but not the RBV or the T2 lesion load, was associated with the SDMT score, and that the higher the annual rate of change in the CCA, the poorer the performance in the left ear VDL, with a subsequently more pronounced advantage in the right ear VDL. These results indicate that corpus callosum is related to a clearly cognitive component, rather than a sensory-motor component. Study IV analyzed the relationships between cognitively demanding information processing (measured with the SDMT), clinical status (EDSS), plasma cerebrosterol 24OHC levels, and MRI-normalized measurement of RBV, grey and white matter volumes, and ventricular cerebrospinal fluid volume in a cross-sectional sample of 21 MS patients. The results showed that slow IPS in SDMT was related to neurodegeneration, particularly loss of grey matter volume, and high cerebrosterol plasma concentrations, reflecting membrane turnover in the CNS. Poor EDSS was associated with high plasma cerebrosterol levels, which is hypothetically a biomarker of MS progression. Conclusions: Deterioration in IPS seems to be a central aspect of cognitive decline in MS. Slow IPS occurs already at an early phase in the disease and predicts long term cognitive decline. The MS patients have less effective strategies for lexical substitution and retrieval than healthy persons. The poor lexical processing in the MS patients could putatively be due to slow IPS, especially in the markedly speed demanding word fluency test. CCA in contrast to RBV and the T2 lesion load, appears to be exclusively related to a cognitively demanding IPS task but not to sensory-motor speed tasks, which suggests that CC is especially important for cognitive speed processes. Slow IPS seems to be primarily associated with low grey matter volume and high plasma concentration level of cerebrosterol while disability appears to be related to high plasma level of cerebrosterol. Since there were no interaction between cerebrosterol and the neurodegenerative predictors, it is putative that the cytotoxic properties of the cerebrosterol independently could cause neuronal cell death and thereby affect IPS independently of neurodegeneration

Periodiseringsfonder - Svenska företags användning av periodiseringsfonder mellan 2003 och 2013

Syfte: Syftet med uppsatsen är att undersöka små svenska aktiebolags användning av peri-odiseringsfonder mellan åren 2003 och 2013 för att utreda om avgiftsbeläggningen haft någon effekt. Metod: Uppsatsen är en explorativ studie med analytisk induktion som ansats. För att uppnå studiens syfte genomförs en kvantitativ analys av sekundärdata i form av årsredovis-ningar. Teoretiska perspektiv: För att ge en bakgrund till problematiken kring avgiftsbeläggning-en avhandlas först periodiseringsfondens historia, obeskattade reserver och resultatutjäm-ning. Därefter beskrivs positiv redovisningsteori, pecking order theory samt ekonomisk psykologi för att förklara utvecklingen. Empiri: Små svenska aktiebolags inställning till periodiseringsfonder undersöks genom en kvantitativ studie av 55 företags årsredovisningar för åren 2003 till 2013. Resultat: Användningen av periodiseringsfonder har minskat något, dock inte i paritet med vad som befarats i tidigare studier. Finanskrisen påverkade företagens framtidstro och risk-benägenhet vilket i sin tur påverkade deras användning av periodiseringsfonder. Till stor del kan de förändringar som skett förklaras genom ekonomisk psykologi

Tuneable interfacial surfactant aggregates mimic lyotropic phases and facilitate large scale nanopatterning.

It is shown that the air-liquid interface can be made to display the same rich curvature phenomena as common lyotropic liquid crystal systems. Through mixing an insoluble, naturally occurring, branched fatty acid, with an unbranched fatty acid of the same length, systematic variation in the packing constraints at the air-water interface could be obtained. The combination of atomic force microscopy and neutron reflectometry is used to demonstrate that the water surface exhibits significant tuneable topography. By systematic variation of the two fatty acid proportions, ordered arrays of monodisperse spherical caps, cylindrical sections, and a mesh phase are all observed, as well as the expected lamellar structure. The tuneable deformability of the air-water interface permits this hitherto unexplored topological diversity, which is analogous to the phase elaboration displayed by amphiphiles in solution. It offers a wealth of novel possibilities for the tailoring of nanostructure

Target Values and Daytime Variation of Bone Turnover Markers in Monitoring Osteoporosis Treatment After Fractures

The serum bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type 1 collagen (CTX) are recommended for monitoring adherence and response of antiresorptive drugs (ARD). BTM are elevated about 1 year after fracture and therefore BTM target values are most convenient in ARD treatment follow-up of fracture patients. In this prospective cohort study, we explored the cut-off values of P1NP and CTX showing the best discriminating ability with respect to adherence and treatment effects, reflected in bone mineral density (BMD) changes. Furthermore, we explored the ability of BTM to predict subsequent fractures and BTM variation during daytime in patients using ARD or not. After a fragility fracture, 228 consenting patients (82.2% women) were evaluated for ARD indication and followed for a mean of 4.6 years (SD 0.5 years). BMD was measured at baseline and after 2 years. Serum BTM were measured after 1 or 2 years. The largest area under the curve (AUC) for discrimination of patients taking ARD or not was shown for P1NP 2% gain in BMD (lumbar spine and total hip) was largest at cut-off values for P1NP <30 μg/L and CTX <0.25 μg/L. Higher P1NP was associated with increased fracture risk in patients using ARD (hazard ratio [HR]logP1NP = 15.0; 95% confidence interval [CI] 2.7–83.3), p = 0.002. P1NP and CTX were stable during daytime, except in those patients not taking ARD, where CTX decreased by 21% per hour during daytime. In conclusion, P1NP <30 μg/L and CTX <0.25 μg/L yield the best discrimination between patients taking and not taking ARD and the best prediction of BMD gains after 2 years. Furthermore, higher P1NP is associated with increased fracture risk in patients on ARD. BTM can be measured at any time during the day in patients on ARD.publishedVersio

Forearm fractures–are we counting them all? An attempt to identify and include the missing fractures treated in primary care

Objective: Norway has a high incidence of forearm fractures, however, the incidence rates based on secondary care registers can be underestimated, as some fractures are treated exclusively in primary care. We estimated the proportion of forearm fracture diagnoses registered exclusively in primary care and assessed the agreement between diagnosis for forearm fractures in primary and secondary care. Design: Quality assurance study combining nationwide data from 2008 to 2019 on forearm fractures registered in primary care (Norwegian Control and Payment of Health Reimbursement) and secondary care (the Norwegian Patient Registry). Setting and patients: Forearm fracture diagnoses in patients aged ≥20 treated in primary care (n = 83,357) were combined with injury diagnoses for in- and outpatients in secondary care (n = 3,294,336). Main outcome measures: Proportion of forearm fractures registered exclusively in primary care, and corresponding injury diagnoses for those registered in both primary and secondary care. Results: Of 189,105 forearm fracture registrations in primary and secondary care, 13,948 (7.4%) were registered exclusively in primary care. The proportion ranged from 4.9% to 13.5% on average between counties, but was higher in some municipalities (>30%). Of 66,747 primary care forearm fractures registered with a diagnosis in secondary care, 62% were incident forearm fractures, 28% follow-up controls, and 10% other fractures or non-fracture injuries. Conclusion: An overall small proportion of forearm fractures were registered only in primary care, but it was larger in some areas of Norway. Failing to include fractures exclusively treated in primary care could underestimate the incidence rates in these areas

Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non‐syndromic traits of the causative gene (e.g., non‐syndromic hypodontia or missing teeth associated with pathogenic variants of EDA “ectodysplasin”). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT “wingless‐type,” TP63 “tumor protein p63”) or the components of complex molecular structures (e.g., connexins, keratins, cadherins)

Determinants of potential drug–drug interaction associated dispensing in community pharmacies in the Netherlands

OBJECTIVE: There are many drug–drug interactions (D–DI) of which some may cause severe adverse patient outcomes. Dispensing interacting drug combinations should be avoided when the risks are higher than the benefits. The objective of this study was to identify determinants of dispensing undesirable interacting drug combinations by community pharmacies in the Netherlands. METHODS: A total of 256 Dutch community pharmacies were selected, based on the dispensing of 11 undesirable interacting drug combinations between January 1st, 2001 and October 31st, 2002. These pharmacies were sent a questionnaire by the Inspectorate for Health Care (IHC) concerning their process and structure characteristics. MAIN OUTCOME MEASURE: The number of times the 11 undesirable interacting drug combinations were dispensed. RESULTS: Two hundred and forty-six questionnaires (response rate 96.1%) were completed. Dispensing determinants were only found for the D–DI between macrolide antibiotics and digoxin but not for the other 10 D–DIs. Pharmacies using different medication surveillance systems differed in the dispensing of this interacting drug combination, and pharmacies, which were part of a health care centre dispensed this interacting drug combination more often. CONCLUSION: Medication surveillance in Dutch community pharmacies seems to be effective. Although for most D–DIs no determinants were found, process and structure characteristics may have consequences for the dispensing of undesirable interacting drug combinations