Cost-utility analysis of Interferon Beta-1b in the treatment of different types of Multiple Sclerosis

Background Economic evaluation of treatments in multiple sclerosis (MS) presents a challenge. The disease affects a number of different body functions and leads to severe disability over time, without however a strong effect on mortality. At onset, the majority of patients will have relapsing-remitting disease (RRMS) and will then convert to secondary-progressive disease (SPMS) overtime. However, the course of the disease is unpredictable, and the conversion to SPMS can take place at different times since onset and at different levels of disability for different patients. Relapses appear to occur with the same frequency at all levels of disability, but will diminish over time. The effectiveness of treatments can be measured in different ways such as disease activity, the number and the severity of relapses or the progression of functional disability, regardless of the type of MS. However, improvements in outcome achieved over a short term may have an effect on the disease in the longer term, and effectiveness data from clinical trials must therefore be extrapolated to the longer term, using modelling techniques. This requires good epidemiological data on the natural course of the disease, where disease progression is expressed with the same measures as in the clinical trials. Also to perform economic evaluations, a global outcome measure is required to capture the impact of treatments on the disease and the most frequently used such measure is quality-adjusted life years (QALYs). However, for QALYs to be used in cost-effectiveness analysis of MS, they must be related to a measure of the disease and disease progression. The Expanded Disability Status Scale (EDSS) provides a good measure of the disease and has been widely used in epidemiological studies and clinical trials, in all types of MS. Lastly, detailed economic data that can be related to the different levels of disability (EDSS) are required. Objective We have earlier proposed a basic framework for cost-effectiveness modelling in MS, and the original model has been updated, as new data have become available. The current study proposes a further development of the modelling technique and estimates the cost-effectiveness of treatment with interferon b-1b (IFNB-1b) in a defined patient population with active disease, both RRMS and SPMS, from a societal perspective in Sweden. Methods The framework of the earlier Markov model is used, where states are defined according to EDSS. Transition probabilities for the first years in the model are calculated from clinical trial data, and for the extrapolation from a large epidemiological database on the natural history of MS. In view of the fact that the number of relapses at given levels of disability did not differ between patients with RRMS or SPMS in any of the three datasets used in this analysis, and that conversion from RRMS to SPMS did not occur at well defined levels of disability, we combined data from two large clinical trials in RRMS and SPMS. Patients were selected on whether or not they had active disease at enrolment, defined as an increase in the EDSS by at least 1 point (0.5 points for scores between EDSS 6 and 7) or at least 2 relapses in the preceding 2 years. This allows simulating treatment start at any stage and for any type of the disease and estimating long-term consequences within the same model. The combination of the two types of MS is further supported by the fact that it has been shown in 3 observational studies that costs and quality of life at given EDSS levels are not different for patients with different types of the disease. Transition probabilities between the Markov states are estimated for both the clinical trial and the natural history cohorts using an ordered probit model. Transitions thus depend on several factors, including what state a patient is in, whether or not she/he has a relapse, age, age at onset of the disease, time since onset of the disease, age at treatment start. The base case simulations use mean costs and mean utilities in each state from a large observational study in Sweden. However, the model allows calculating acceptability curves, i.e. the probability with which the cost effectiveness ratio of a treatment scenario is below given levels of willingness-to-pay for a QALY, using the entire distribution of costs and utilities at each EDSS level. Costs and benefits are discounted with 3%. Results The base case assumes treatment with IFNB-1b during 36 months, with no further effect when treatment is stopped, and includes both patients with active RRMS and SPMS. Sensitivity analysis is presented for treatment during 54 months. The annual cost of IFNB-1b treatment was 102 587 SEK plus 1600 SEK for special monitoring, and was adjusted for compliance in the clinical trial. In the base-case treatment adds 13 000 to costs over 10 years, and the cost per QALY gained is 71 400 SEK. When the time horizon is increased to 15-25 years, treatment dominates no treatment (higher utility and lower cost). With treatment during 54 months, the cost per QALY is 353 800 SEK, all costs included. When treatment is started early, the cost-effectiveness ratio is higher, e.g. 643 100 SEK in state 2, as patients in these states progress only very slowly. In the net benefit approach, there is a 80% probability that the treatment initiated in states 3 or 4 (EDSS 4.0-5.5) is cost-effective, if the willingness to pay for a QALY is 400 000 to 600 000 SEK. At that level of willingness to pay, the probability in state 2 is 45%. Conclusions With this new model, which combines active RRMS and SPMS, the effect of early treatment on the long-term outcome can be estimated for the first time using patient-level clinical data for RRMS and SPMS, as well as natural history data. The combination of the two types of MS into one model is supported by the finding that, at given levels of EDSS, there was no difference in the number of annual relapses in the three clinical datasets used, nor in the mean cost and mean utilities in the observational study. The model is more flexible than previous models, as it includes individual patient demographics and the entire distribution of costs and utilities in the different states. It thus represents a valuable tool to estimate the cost-effectiveness of treating different patient groups with IFNB-1b.MS; Cost-effectiveness

Автоматизированная система обеспечения оптимальных условий выращивания сельскохозяйственных культур в защищенном грунте

Mosquitoes of the Anopheles (An.) and Aedes (Ae.) genus are principal vectors of human diseases including malaria, dengue and yellow fever. Insecticide-based vector control is an established and important way of preventing transmission of such infections. Currently used insecticides can efficiently control mosquito populations, but there are growing concerns about emerging resistance, off-target toxicity and their ability to alter ecosystems. A potential target for the development of insecticides with reduced off-target toxicity is the cholinergic enzyme acetylcholinesterase (AChE). Herein, we report cloning, baculoviral expression and functional characterization of the wild-type AChE genes (ace-1) from An. gambiae and Ae. aegypti, including a naturally occurring insecticide-resistant (G119S) mutant of An. gambiae. Using enzymatic digestion and liquid chromatography-tandem mass spectrometry we found that the secreted proteins were post-translationally modified. The Michaelis-Menten constants and turnover numbers of the mosquito enzymes were lower than those of the orthologous AChEs from Mus musculus and Homo sapiens. We also found that the G119S substitution reduced the turnover rate of substrates and the potency of selected covalent inhibitors. Furthermore, non-covalent inhibitors were less sensitive to the G119S substitution and differentiate the mosquito enzymes from corresponding vertebrate enzymes. Our findings indicate that it may be possible to develop selective non-covalent inhibitors that effectively target both the wild-type and insecticide resistant mutants of mosquito AChE

Characterization of Ricin and R. communis Agglutinin Reference Materials

Ricinus communis intoxications have been known for centuries and were attributed to the toxic protein ricin. Due to its toxicity, availability, ease of preparation, and the lack of medical countermeasures, ricin attracted interest as a potential biological warfare agent. While different technologies for ricin analysis have been established, hardly any universally agreed-upon gold standards are available. Expert laboratories currently use differently purified in-house materials, making any comparison of accuracy and sensitivity of different methods nearly impossible. Technically challenging is the discrimination of ricin from R. communis agglutinin (RCA120), a less toxic but highly homologous protein also contained in R. communis. Here, we established both highly pure ricin and RCA120 reference materials which were extensively characterized by gel electrophoresis, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI MS/MS), and matrix-assisted laser desorption ionization-time of flight approaches as well as immunological and functional techniques. Purity reached >97% for ricin and >99% for RCA120. Different isoforms of ricin and RCA120 were identified unambiguously and distinguished by LC-ESI MS/MS. In terms of function, a real-time cytotoxicity assay showed that ricin is approximately 300-fold more toxic than RCA120. The highly pure ricin and RCA120 reference materials were used to conduct an international proficiency test.Peer reviewe

Adaptation of television show in Latvia and its features in audience assessment: "X Faktors" case study

Bakalaura darba tēma ir „Televīzijas šova adaptācija Latvijā un tās īpatnības auditorijas vērtējumā: "X Faktors" gadījuma analīze”. Darba mērķis ir noskaidrot kā šovs „X Faktors” tiek pielāgots Latvijas auditorijai, un kā auditorija vērtē šovu „X Faktors”. Pētījuma problēma ir televīzijas šova „The X Factor” adaptācijas producēšana Latvijā, realitātes šova „X Faktors” veiksmīga vai neveiksmīga pielāgošana auditorijas vērtējumā. Galvenā teorētiskā bāze ir mediju lietojuma un apmierinājuma teorija, televīzijas, realitātes televīzijas, talantu šovu un auditorijas koncepti. Metodoloģijas daļā aprakstītas pētniecības metodes – gadījuma studijas, aptauja un daļēji strukturēta intervija. Darba rezultātā tika noskaidrotas šova „X Faktors” kopīgās un atšķirīgās iezīmes salīdzinot ar oriģinālšovu kā arī auditorijas vērtējums par šovu „X Faktors”.The theme of bachelor thesis is „Adaptation of television show in Latvia and its features in audience assessment: "X Faktors" case study”. The aim of the work is to find out how the show "X Faktors" is adapted to Latvian audience, and how the audience assesses show “X Faktors”. The research problem is the production of the adaptation of television show "The X Factor" in Latvia, successful or unsuccessful adaptation of the reality show "X Faktors" in audience assessment. Media uses and gratification theory, television, reality television, talent shows and audience concepts are the main theoretical base. The methodology chapter describes research methods – case studies, survey and semi-structured interview. The results of the work show the common and distinctive features of the show "X Faktors" compared to original version and the audience assessment for the show „X Faktors”

University Services for regional Development : Ideas on Stakeholder Based Quality Management in a Region

Background Regional Development is a permanent activity of change including long range visions and goals. This work includes both continuous and breakthrough change. Quality management practises are used for organisational improvement and could be seen as one way of supporting effective change management. Provided we can view a region as an organisation we could also view it as a process. Dealing with the region as a system of processes might make it possible to use quality management practices to support more effective regional development. Based on an analysis of the presentation of the current state and the visionary state it should be possible to analyse proposed change strategies from a process perspective. Purpose The general purpose of the study is to see how universities could contribute to regional development. Specific research questions in this study are: For a region how can the present state, the visionary state and the chosen change strategies, be described with Quality Management values and methodologies with focus on the process view How do the regional university mission, vision and goals align with defined regional objectives? Methodology A literature survey for how Quality Management has been used for regional development is carried out to create a structure for the data collection. The region of Gotland is chosen as an example for a region. The reason for this is that Gotland is a small region consisting of an island providing clear boundaries. There is only one university, which makes it easier to study the links between university and region. Available regional visions are studied as well as main presentation of regional performance with focus on the region of Gotland. The main organizational stakeholders are identified and studied. Data is gathered from web sites and from interviews. The categorisation of information is based on a process perspective using process based system models adapted to the initial literature survey. The current change process is also portrayed. In order to see how the local university performance and plans align with the regional plans the Gotland University web-site is studied for relevant documents. Main results Regional performance can seemingly be described using process based system models. The stakeholder approach can in a meaningful way be used to describe main regional requirements

Planning the Bothnian Sea

In all parts of the world the sea is a source of life, of energy, of food, of commerce, of fun. Its water, wind, and waves are all in demand – as a playground for pleasure-seekers and nature-lovers, as a highway for international commerce, as a home for unique communities of wildlife and people. All this is also true for the Bothnian Sea, a part of the northern European Baltic Sea between Finland and Sweden. The Bothnian Sea is used by two neighbouring highly developed societies. There are many demands on its resources, and its open spaces are highly coveted areas for developments such as wind power farms. This relatively sparsely habitated corner of the world is also, at least at times, a place of wild seas and ancient heritage. Like planning on land, maritime spatial planning is a process that has to incorporate ideals of the public good and the various politically-anchored ways to define this, taking in to account private development interests as well as the physical realities of limited natural resources and fragile ecosystems. This book provides an introduction to the Bothnian Sea and the ideas around maritime spatial planning for its offshore areas. We have tried to present a balance between the perspectives of competing interests. As this has been a pilot initiative, we have not aimed to give you ready answers, but instead try to provoke further debate. The Bothnian Sea and its future are in your hands. The edito

Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae : Functional Characterization and Comparisons with Vertebrate Orthologues

Mosquitoes of the Anopheles (An.) and Aedes (Ae.) genus are principal vectors of human diseases including malaria, dengue and yellow fever. Insecticide-based vector control is an established and important way of preventing transmission of such infections. Currently used insecticides can efficiently control mosquito populations, but there are growing concerns about emerging resistance, off-target toxicity and their ability to alter ecosystems. A potential target for the development of insecticides with reduced off-target toxicity is the cholinergic enzyme acetylcholinesterase (AChE). Herein, we report cloning, baculoviral expression and functional characterization of the wild-type AChE genes (ace-1) from An. gambiae and Ae. aegypti, including a naturally occurring insecticide-resistant (G119S) mutant of An. gambiae. Using enzymatic digestion and liquid chromatography-tandem mass spectrometry we found that the secreted proteins were post-translationally modified. The Michaelis-Menten constants and turnover numbers of the mosquito enzymes were lower than those of the orthologous AChEs from Mus musculus and Homo sapiens. We also found that the G119S substitution reduced the turnover rate of substrates and the potency of selected covalent inhibitors. Furthermore, non-covalent inhibitors were less sensitive to the G119S substitution and differentiate the mosquito enzymes from corresponding vertebrate enzymes. Our findings indicate that it may be possible to develop selective non-covalent inhibitors that effectively target both the wild-type and insecticide resistant mutants of mosquito AChE