Efficacy and safety of warfarin treatment in venous thromboembolic disease

Background As a major cause of morbidity and mortality treatment of venous thromboembolism is important, with the correct use of anticoagulants it is possible to greatly reduce both mortality and morbidity. Warfarin is among the most widely used anticoagulants being effective in treatment and prevention of venous thromboembolism with few negative side effects other than bleeding complications. With a narrow therapeutic window warfarin treatment requires constant monitoring and adjustments to stay effective without an increased bleeding risk. The aim of this thesis was to study the efficacy and safety of warfarin treatment in venous thromboembolic disease. Methods Using AuriculA, the Swedish national quality register for atrial fibrillation and anticoagulation, a cohort was created of patients registered with warfarin treatment during the study time January 1st 2006 to December 31th 2011, including all different indications for anticoagulation. In all four studies the study design was retrospective with information added to the cohort from the Swedish national patient register about background data and endpoints in form of bleeding complications in all studies and thromboembolic events in study 1 and 2. In study 3 and 4 information was added from the cause of death register about occurrence of death and in study 3 cause of death. In study 3, information from the prescribed drugs register about retrieved prescriptions of acetylsalicylic acid was added. Results In study 1 the mean TTR was found to be high both among patients managed at primary healthcare centres and specialised anticoagulation clinics at 79.6% and 75.7%. There was no significant difference in rate of bleeding between the two types of managing centres being 2.22 and 2.26 per 100 treatment years. In study 2 no reduction in complication rate with increasing centre TTR was seen for patients with atrial fibrillation with few centres having centre TTR below 70% (2.9%), in contrast to previous findings by Wan et al(1). For those with warfarin due to VTE where a larger proportion of the centres had centre TTR below 70% (9.1%) there was a reduction in complication rate with increasing centre TTR. Among the 13859 patients with treatment for VTE in study 3 age (HR 1.02, CI 95% 1.01-1.03), hypertension (HR 1.29, CI 95%1.02-1.64), Cardiac failure (HR 1.55, CI 95% 1.13-2.11), chronic obstructive pulmonary disease (HR 1.43, CI 95% 1.04- 1.96), alcohol abuse (HR 3.35, CI 95% 1.97-5.71), anaemia (HR 1.77, CI 95% 1.29-2.44) and a history of major bleeding (HR 1.75, CI 95% 1.27-2.42) increased the risk of bleeding during warfarin treatment. In study 4 both those with high iTTR and those with low INR variability had a low rate of bleedings at 1.27 (1.14-1.41) or 1.20 (0.94-1.21) per 100 treatment years compared to those with low iTTR and high INR variability having a rate of bleeding at 2.91 (2.61-3.21) or 2.61 (2.36-2.86) respectively. Those with the combination of both low iTTR and high INR variability had an increased risk of bleeding, hazard ratio HR 3.47 (CI 95 % 2.89-4.17). The quartile with both the lowest iTTR and the highest INR variability had an increased risk of bleeding with a hazard ratio 4.03 (3.20-5.08) and 3.80 (CI 95%, 3.01-4.79) compared to the quartile with the highest iTTR and lowest INR variability. Conclusion It is possible to achieve a safe warfarin treatment both in specialised anticoagulation centres and in primary health care. At initiation of treatment some of the patients at high risk of bleeding can be identified using knowledge about their background. With the use of quality indicators as TTR and INR variability during treatment those at high risk of complications can be identified and analysing treatment quality on centre level gives an opportunity to identify improvement areas among managing centres. With the addition of new treatment options warfarin can still be the most suitable option for some patients, being safe and effective when well managed

Modelling groundwater response to acidification

The observed acidification of lakes and forest soils in Sweden has raised concem over the future of groundwater resources. Many of the processes which effect groundwater quality occur above the water table in the insaturated soil. Models of the hydrology and chemistry in this zone were developed and the results of that work are presented in this report. The overall objective of this project was to obtain a better understanding of the chemical and hydrological processes involved in the acidification of soil and groundwater in order to estimate future changes due to changes in acid deposition in relation to other acidifying processes. This work concluded of this report is that the groundwater in Sweden is vulnerable to acid deposition and that drastic reductions in emissions are necessary to protect this water. The model development provides a set of tools which are generally applicable to the hydrochemistry of acidification. They demand limited calibration and the requirements for input data and parameter values can usually be met. This makes it possible to use the models for assessment of groundwater acidification. The spatial and climatic variabilities of parameters and driving variables, however, are large. The uncertainties introduced by this variability must be considered when the results are used for decision making

Svensk Kärnbränslehantering AB Swedish Nuclear Fuel and Waste Management Co Box 250, SE-101 24 Stockholm Phone +46 8 459 84 00 Chlorine cycling and fates of 36 Cl in terrestrial environments Chlorine cycling and fates of 36 Cl in terrestrial environments

This report concerns a study which was conducted for SKB. The conclusions and viewpoints presented in the report are those of the authors. SKB may draw modified conclusions, based on additional literature sources and/or expert opinions. A pdf version of this document can be downloaded from www.skb.se. 3 Abstract Cl), a radioisotope of chlorine (Cl) with a half-life of 301,000 years, is present in some types of nuclear waste and is disposed in repositories for radioactive waste. As the release of 36 Cl from such repositories to the near surface environment has to be taken into account it is of interest to predict possible fates of 36 Cl under various conditions as a part of the safety assessments of repositories for radioactive waste. This report aims to summarise the state of the art knowledge on Cl cycling in terrestrial environments. The view on Cl cycling in terrestrial environments is changing due to recent research and it is clear that the chloride ion (Cl -) is more reactive than previously believed. We group the major findings in three categories below according to the amount of data in support of the findings. From the result presented in this report it is evident that: • There is an ubiquitous and extensive natural chlorination of organic matter in terrestrial ecosystems. • The abundance of naturally formed chlorinated organic compounds (Cl org ) frequently exceeds the abundance of Cl -, particularly in soils. Thereby Cl org in many cases dominates the total Cl pool. • This has important implications for Cl transport. When reaching surface soils Cl -will not be a suitable tracer of water and will instead enter other Cl pools (Cl org and biomass) that prolong residence times in the system. • Cl -dominates import and export from terrestrial ecosystems while Cl org and biomass Cl can dominate the standing stock Cl within terrestrial ecosystems. • Both Cl and Cl org pools have to be considered separately in future monitoring programs addressing Cl cycling. Further, there are also indications (in need of confirmation by additional studies) that: • There is a rapid and large uptake of Cl -by organisms and an accumulation in green plant parts. A surprisingly large proportion of total catchment Cl (up to 60%) can be found in the terrestrial biomass. • Emissions of total volatile organohalogens could be a significant export pathway of Cl from the systems. • Some of the Cl org may be very persistent and resist degradation better than average organic matter. This may lead to selective preservation of some Cl org (with associated low bioavailability). • There is a production of Cl org in tissues of e.g. plants and animals and Cl can accumulate as chlorinated fatty acids in organisms. Most other nevertheless important aspects are largely unknown due to lack of data. Key unknowns include: • The development over time of major Cl pools and fluxes. As long as such data is lacking we cannot assess net changes over time. • How the precesses behind chlorination, dechlorination and transport patterns in terrestrial systems are regulated and affected by environmental factors. • The ecological roles of the chlorine cycling in general. • The ecological role of the microbial chlorination in particular. • The chlorine cycling in aquatic environments -including Cl -and Cl org pools in sediment and water, are largely missing. Given the limited present information available, and particularly the lack of data with a temporal dimension and the lack of process understanding, predictive models are challenging. We also summarize currently available methods to study Cl in the environment. SKB TR-13-26 Sammanfattning 36 Cl), en radioisotop med en halveringstid på 301 000 år, förekommer i vissa typer av radioaktivt avfall. För att kunna förutse vad som händer om 36 Cl når markytan är det viktigt att veta hur klor kan omvandlas och transporteras i olika ekosystem. Denna rapport syftar till att sammanfatta kunskapsläget om klor i naturmiljöer med fokus på landmiljöer. Synen på klor i naturen är under omfattande förändring till följd av de senaste decenniernas forskning. Det står nu helt klart att klorid (Cl -) som tidigare betraktats som icke-reaktiv och totalt dominerande, istället är i hög grad reaktiv och inte alltid utgör den dominerande klorformen. Utifrån de studier som presenteras i rapporten är det tydligt att: • Det sker en omfattande naturlig klorering av organiskt material i många miljöer och inte minst i ytliga marklager. • Mängden organiskt bunden klor (Cl org ) är i många miljöer betydligt högre än mängden Cl -. Därmed dominerar Cl org ofta det totala klorförrådet i exempelvis mark. • Detta har stor inverkan på transporten av klor eftersom Cl org till stor del finns i partikulärt organiskt material medan Cl -är mycket vattenlösligt. Cl -som når ytliga marklager är t ex inte lämpligt som spårämne för markvattenflöden såsom tidigare antagits. Cl -kommer till stor del att bindas in till Cl org -förrådet och därmed förlänga uppehållstiden i ekosystemen. • Cl -dominerar både importen och exporten från terrestra ekosystem medan Cl org kan dominera stationära klorförråd i systemen. • Framtida mätningar med syfte att klargöra kloromsättning och klorflöden behöver beakta Cl -och Cl org separat. Därtill finns ett antal troligen viktiga indikationer som skulle behöva bekräftas av ytterligare studier. Dessa inkluderar att: • Det sker ett snabbt och omfattande upptag av Cl -av organismer och klor tycks ackumuleras i grön växtbiomassa. En stor andel av den totala klormängden i avrinningsområden (upp till 60% i en studie) har påträffats i den terrester biomassa. • Avgång av flyktiga klorerade kolväten kan vara en stor okänd exportväg för klor från ekosystem. • En del Cl org verkar vara betydligt mer motståndskraftigt mot nedbrytning än det genomsnittliga organiska materialet. Detta kan leda till att Cl org bevaras selektivt i mark och därmed också mindre tillgängligt för mikroorganismer. • Det sker en klorering av organiskt material i levande biomassa och klor kan ansamlas som klorerade fettsyror i organismer. Övriga aspekter på klor i naturen är till stora delar okända. Centrala okända aspekter inkluderar: • Hur klor-förråden utvecklas över tid. Detta är centralt för att förstå förändringar över tid och reglering i förråden. • Reglering av klorerings-, deklorerings-och transportprocesser, samt hur dessa påverkas av olika miljövariabler och miljöförhållanden. • Den ekologiska förklaringen till varför så många organismer utför klorering av organiskt material. • Omsättning av klor i akvatiska system. Här saknas separata data gällande Cl -och Cl org både i sediment och i vattenfasen. Rapporten fokuserar framför allt på terrestra aspekter av klorcykeln och innehåller också information om vanliga metoder för mätning av olika klorföreningar

Individuella basgruppsunderlag - ett verktyg för synliggörande av individuell kunslapsinhämtning och -bearbetning samt reflektion i basgruppsarbetet

År 2005 introducerades individuella basgruppsunderlag (IBU) vid Miljövetarprogrammet som en del i det kontinuerliga utvecklingsarbete som pågår i lärargruppen. Motivet var primärt att synliggöra den enskilda studentens insatser och lärande men även att ge lärarna ett verktyg till säkrare bedömning av studentens aktiva deltagande i basgruppsarbetet. Då IBU är ett i PBLsammanhang nytt verktyg har vi sett ett behov av att utvärdera och dokumentera dess potential som ett stöd i studenternas lärande och som en förstärkning av möjligheterna att examinera den enskilde studentens insatser i basgruppen. Studien har visat att IBU:er har skapat möjligheter att stödja studenters lärande genom att synliggöra, såväl för studenten själv som handledaren, var i lärandeprocessen studenten befinner sig och erbjuder därigenom en möjlighet till stöd för studenternas metakognitiva kompetens, till stor del skapad genom dokumentationsprocessen. De intervjuade lärarna beskriver att IBU:er stärker möjligheten att bedöma studenternas förberedelser inför basgruppsmötet och därmed också examinera studentens aktiva deltagande i basgruppsarbetet

Individuella basgruppsunderlag : ett verktyg för synliggörande av individuell kunskapsinhämtning och -bearbetning samt reflektion i basgruppsarbetet

År 2005 introducerades individuella basgruppsunderlag (IBU) vid Miljövetarprogrammet som en del i det kontinuerliga utvecklingsarbete som pågår i lärargruppen. Motivet var primärt att synliggöra den enskilda studentens insatser och lärande men även att ge lärarna ett verktyg till säkrare bedömning av studentens aktiva deltagande i basgruppsarbetet. Då IBU är ett i PBLsammanhang nytt verktyg har vi sett ett behov av att utvärdera och dokumentera dess potential som ett stöd i studenternas lärande och som en förstärkning av möjligheterna att examinera den enskilde studentens insatser i basgruppen. Studien har visat att IBU:er har skapat möjligheter att stödja studenters lärande genom att synliggöra, såväl för studenten själv som handledaren, var i lärandeprocessen studenten befinner sig och erbjuder därigenom en möjlighet till stöd för studenternas metakognitiva kompetens, till stor del skapad genom dokumentationsprocessen. De intervjuade lärarna beskriver att IBU:er stärker möjligheten att bedöma studenternas förberedelser inför basgruppsmötet och därmed också examinera studentens aktiva deltagande i basgruppsarbetet

Individuella basgruppsunderlag - ett verktyg för synliggörande av individuell kunslapsinhämtning och -bearbetning samt reflektion i basgruppsarbetet

År 2005 introducerades individuella basgruppsunderlag (IBU) vid Miljövetarprogrammet som en del i det kontinuerliga utvecklingsarbete som pågår i lärargruppen. Motivet var primärt att synliggöra den enskilda studentens insatser och lärande men även att ge lärarna ett verktyg till säkrare bedömning av studentens aktiva deltagande i basgruppsarbetet. Då IBU är ett i PBLsammanhang nytt verktyg har vi sett ett behov av att utvärdera och dokumentera dess potential som ett stöd i studenternas lärande och som en förstärkning av möjligheterna att examinera den enskilde studentens insatser i basgruppen. Studien har visat att IBU:er har skapat möjligheter att stödja studenters lärande genom att synliggöra, såväl för studenten själv som handledaren, var i lärandeprocessen studenten befinner sig och erbjuder därigenom en möjlighet till stöd för studenternas metakognitiva kompetens, till stor del skapad genom dokumentationsprocessen. De intervjuade lärarna beskriver att IBU:er stärker möjligheten att bedöma studenternas förberedelser inför basgruppsmötet och därmed också examinera studentens aktiva deltagande i basgruppsarbetet

Analysis of climate-induced hydrochemical variations in till aquifers

An investigation of the relations between climatological factors and short term variabilityin groundwater storage and hydrochemistry in till aquifers is performed. The analysis isbased on a simple empirical hydrological model, the PULSE model, and groundwaterrecords from four sites in Sweden.The model proved to be capable of describing the dynamics of groundwater levels ordischarge, and at one of the sites it was possible to describe hydrochemical variations aswell. The application to the remaining three sites illustrated that groundwater chemistryshows a much more complex pattem of variations than does corresponding streamflowin this type of basin. The importance of areal variabilities within the recharge area isdiscussed and illustrated by a distribution of the model into two submodels when applyingit to one of the basins

Venous thromboembolism and cancer risk

Cancer increases the risk of venous thromboembolism (VTE) and about 20 % of all VTE are associated with cancer. VTE can also be used as a marker for occult cancer. The objective was to examine the correlation between VTE and cancer regarding predictors for a subsequent cancer diagnosis. Patients treated for VTE between January 1st 2006 and December 31th 2011 were extracted from the Swedish national quality register AuriculA and crossmatched with the Swedish National Patient Register. In total 7854 patients corresponding to 14284 treatments years were examined. Primary VTE was found in 6451 patients, with 3936 first and 2515 recurrent VTE. There were 1403 patients with secondary VTE. After a first or recurrent primary VTE the incidence of cancer diagnose was high being 9.4-10.0 % the first year compared to 2.7-2.5 % during the second year. Cancer in the digestive organs was the most common type of cancer among those with first primary VTE with 19.2 % of diagnoses. In multivariable analysis age was found to increase the risk of cancer diagnosis after both first and recurrent primary VTE HR 1.02 (CI 1.02-1.03) and HR 1.02 (CI 1.01-1.03). For a first primary VTE anemia HR 2.13 (CI 1.48-3.08) and male sex HR 1.38 (CI 1.09-1.76) increased the risk while hypertension HR 0.74 (0.57-0.96), dementia HR 0.30 (CI 0.10-0.95) and history of major bleeding HR 0.52 (CI 0.28-0.97) reduced the risk of a subsequent cancer diagnosis. There is a substantial proportion of patients being diagnosed with cancer the first year after a primary VTE, anaemia and male sex confers an increased risk

Warfarin treatment complications do not correlate to cTTR when above 70.

The mean time in target range for each centre, cTTR, has previously been shown to correlate to the rate of complications in poorly managed warfarin treatment. However less is known about the correlation when warfarin treatment is well managed

Phosphorylation based Models of Neurodegenerative Diseases

Aberrant protein phosphorylation is a hallmark of neurodegenerative diseases, such as Alzheimer's disease (AD) and tauopathies. Pathological phosphorylation is commonly observed as intracellular tau containing deposits correlating with neuronal death. Tau is a cytoskeletal protein, key to the stabilisation of the microtubules (MT), important ,for structural integrity and protein trafficking. Tau's ability to promote MTs is regulated by protein phosphorylation by kinases/phosphatases. In spontaneous AD, the activity/expression of kinases are enhanced w$ilst phosphatases are decreased. Alterations in phosphorylation have significant regulatory effects on neuronal signalling which may lead to deficits in neuronal signalling prior to neuronal death. Using cultured rat hippocampal neurons and pharmacological inhibitors of serine/threonine (Okadaic acid and Cantharidin) and tyrosine (Sodium orthovanadate) phosphatases, the consequences of increased phosphorylation for neuronal signalling were investigated. Using Fura-2 Ca2+ imaging, serine/threonine phosphatase inhibition was determined to exert bidirectional modulation on neuronal excitability. Low level short duration inhibition enhanced, whilst str9nger or more prolonged inhibition suppressed Ca2 + responses towards stimulation. Suppression of excitability was coincident with' a reduction in receptor expression and an increase in cytoskeletal phosphorylation. The data mimic changes in signalling utilising alternative means of modelling AD, suggesting that common ' phosphorylation cascades may be active within these models and in the disease process. Acute inhibition of tyrosine phosphatases evoked a prolonged Ca2 + response dependent on the activation of trans-plasma membrane Ca2+ channels. Prolonged inhibition of tyrosine phosphatases enhanced neuronal excitability. A novel sponge toxin polymeric 1,3-alkylpyridinium salts was employed as an agent for inducing tau over-expression in cultured neurons and further Ca2 + imaging studies conducted. Modulation on excitability was observed to be dependent on the level oftau expression. Overall, this thesis furthers the understanding of phospho-regulation of neuronal signalling ~oth physiologically, and pathologically and provides preliminary data for novel roles of tau in neuronal signalling regulation.EThOS - Electronic Theses Online ServiceGBUnited Kingdo