Antiglobulins in relation to rheumatic diseases : development of ELISA assays and their application in prospective and family surveys

Imperial Users onl

Challenges, considerations, and approaches for developing a cost-effectiveness model for the adjuvant treatment of muscle-invasive urothelial carcinoma:with a spotlight on nivolumab versus placebo

Aims: To present alternative approaches related to both structural assumptions and data sources for the development of a decision analytic model for evaluating the cost-effectiveness of adjuvant nivolumab compared with surveillance in patients with high-risk muscle-invasive urothelial carcinoma (MIUC) after radical resection. Methods and results: Alternative approaches related to both structural assumptions and data sources are presented to address challenges and data gaps, as well as discussion of strengths and limitations of each approach. Specifically, challenges and considerations related to the following are presented: (1) selection of a modeling approach (partitioned survival model or state transition model) given the available evidence, (2) choice of health state structure (three- or four-state) to model disease progression and subsequent therapy, (3) modeling of outcomes from subsequent therapy using tunnel states to account for time-dependent transition probabilities or absorbing health states with one-off costs and outcomes applied, and (4) methods for modeling health-state transitions in a setting where treatment has curative intent and available survival data are immature. Conclusions: Multiple considerations must be taken into account when developing an economic model for new, emerging oncology treatments in early lines of therapy, all of which can affect the model’s overall ability to estimate (quality-adjusted) survival benefits over a lifetime horizon. This paper identifies a series of key structural and analytic considerations regarding modeling of nivolumab treatment in the adjuvant MIUC setting. Several alternative approaches with regard to structure and data have been included in a flexible cost-effectiveness model so the impact of the alternative approaches on model results can be explored. The impact of these alternative approaches on cost-effectiveness results are presented in a companion article. Our findings may also help inform the development of future models for other treatments and settings in early-stage cancer

Cost-effectiveness of nivolumab versus surveillance for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence:a US payer perspective

Aim: To evaluate the cost-effectiveness of adjuvant nivolumab compared with surveillance for the treatment of patients with high-risk muscle-invasive urothelial carcinoma (MIUC) after radical resection from a US healthcare payer perspective and to investigate the impact of alternative modeling approaches on the cost-effectiveness results. Material and methods: A four-state, semi-Markov model consisting of disease free, local recurrence, distant recurrence, and death health states was developed to investigate the cost-effectiveness of nivolumab compared with surveillance over a 30-year time horizon. The model used data from the randomized CheckMate 274 trial (NCT02632409) and published literature to inform transitions among health states, and inputs on cost, utility, adverse event, and disease management. Scenario analyses were conducted to investigate the impact of model structure and key assumptions on the results. One-way deterministic and probabilistic sensitivity analysis were conducted to investigate the robustness of the results. Results: Total expected costs were higher with nivolumab ($162,278) compared with surveillance ($63,027). Nivolumab was associated with improved survival (1.61 life-years gained compared with surveillance) and an incremental gain of 0.98 quality-adjusted life-years (QALYs). Although total treatment costs were higher for nivolumab, cost offsets were observed because of delayed or avoided recurrences and deaths experienced with nivolumab compared with observation. The incremental cost-effectiveness and cost-utility ratios were $61,462/life-year and$100,930/QALY. Limitations: At the time of analysis, CheckMate 274 had limited follow-up on disease-free survival and no overall survival data. The limited evidence necessitated assumptions on modeling survival after each type of recurrence. Conclusions: Nivolumab is estimated to be a life-extending and cost-effective option for adjuvant treatment of MIUC for patients who are at high risk of recurrence after undergoing radical resection in the United States. Using a threshold of $150,000/QALY, the cost-effectiveness conclusions remained consistent across the scenario and sensitivity analyses conducted

Integration of sequence data from a consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10-6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. © 2014 Plenge et al

Athygli í vítaspyrnum. Spá reyndir fótboltamarkmenn betur fyrir um stefnu vítaspyrna en óreyndir?

Rannsóknir hafa sýnt að afreksíþróttamenn standa sig betur á hugrænum prófum sem sniðin eru að þeirra íþróttagreinum. Þær hafa meðal annars sýnt að afreksíþróttamenn spá betur fyrir um komandi atburði og að þeir eigi auðveldara með að skipta athyglinni á milli verkefna sem þarf að framkvæma samtímis. Í þessari rannsókn var kannað hvort reyndir fótboltamarkmenn spá betur fyrir um stefnu og hæð vítaspyrna en óreyndir og hvort reyndir markmenn truflist síður við að birt séu óvænt áreiti samhliða meginverkefninu að verja vítaspyrnur. Þátttakendur voru 15 karlkyns afreksfótboltamarkmenn og 15 karlmenn sem höfðu lítinn áhuga og reynslu af fótbolta. Þátttakendur horfðu á myndbönd sem sýndu leikmenn hlaupa að bolta á vítaspyrnupunkti en um leið og sparkað var í boltann varð skjárinn svartur og áttu þátttakendur að spá hvert skotið var með því að ýta á samsvarandi takka á lyklaborði. Niðurstöður sýndu að reyndu markmennirnir voru marktækt betri að spá fyrir um stefnu vítaspyrna en óreyndu. Ályktað er að reynsla reyndu markmannana fengin við raunaðstæður hafi skilað þeim ávinningi að leysa verkefnið við myndbandsaðstæður. Enginn truflun varð á frammistöðu reyndra né óreyndra þegar óvænt áreiti birtust með vítaspyrnunum. Ekki er því hægt að álykta um athyglisauðlindina sem reyndir og óreyndir lögðu í verkefnið

"I'm not in the mood for a party tonight." The Orwellian Roots of the Pinteresque

This essay discusses the substantial and hitherto largely unacknowledged debt that Harold Pinter’s plays owe to George Orwell’s grand statement and last novel, Nineteen Eighty-Four. The main focus will be on attributes and themes of Pinter’s plays which have been widely acknowledged by critics as so typical of his works that the adjective “Pinteresque” has been ascribed to them, such as the volatility of the past, enclosed spaces, intrusion and the power struggles inherent in language. By investigating close parallels between Pinter’s plays on one hand, particularly The Birthday Party, his first major play, as well as the “memory play” Old Times, and Nineteen Eighty-Four on the other, Pinteresque features will be shown to be also Orwellian in nature. Pinter repeatedly brought the Orwellian vision of a major political struggle to the stage cloaked as a microcosmic battle of wills, much as Orwell did himself in the final third of Nineteen Eighty-Four. Starting with a discussion of the background of The Birthday Party and moving on to separate chapters about the past, enclosed spaces, and language, the politically Orwellian aspect of Pinter’s oeuvre, generally believed to have been of little weight until his overtly political plays in the 1980s and his increasing political activism, will thus be shown to be of vital importance from his earliest works onwards

Jaðarskattar og tekjutengingar. Jaðarskerðingar af völdum skatta- og bótareglna á Íslandi

Höfundur lokaði aðgangi til 1.1. 2113. Engin undanþágubeiðni barst frá Viðskiptafræðideild og var því ritgerðin opnuð af umsjónarmanni Skemmu.Í ritgerð þessari er leitast við að svara rannsóknarspurningunni: Hver er virk jaðarskerðing (e. effective marginal tax rate) vegna viðbótartekjuöflunar á Íslandi? Til þess að svara spurningunni var tekið saman yfirlit yfir helstu lög og reglur um skatta, bætur og afslætti af sköttum og þjónustugjöldum, miðað við stöðuna 1. janúar 2013. Jaðarskerðingaráhrif þessa regluverks voru síðan greind og því næst tekin nokkur dæmi um hvernig ólíkar skerðingarreglur leggjast saman í rauntilvikum. Öll raundæmi sem reiknuð voru um virkar jaðarskerðingar áttu það sammerkt að skerðingarnar fóru vaxandi í fyrstu uns ákveðnu hámarki hafði verið náð – þá fóru þær minnkandi á nýjan leik. Í tilviki launþega sem áttu rétt á algengum bótategundum gátu skerðingar auðveldlega farið í 60–66%. Skerðingarnar gátu náð 77% þegar sjálfstæður atvinnurekstur átti í hlut. Námsmaður í vinnu með námi sem þáði húsaleigubætur gat lent í 84% jaðarskerðingu á ákveðnu bili. Við athugun regluverks kom einnig í ljós að sú staða getur alloft komið upp að aðilar tapi á viðbótarkrónu í tekjum. Krónutöluskattar, það er útvarspgjald og gjald í Framkvæmdasjóð aldraðra, eru dæmi um slíkt en einnig afsláttur af fasteignagjöldum í Reykjavík og leikskólagjöldum í Hafnarfirði og Mosfellsbæ. Fari menn yfir tekjumörk sem skapa gjaldskyldu krónutöluskatts eða draga úr afsláttum verða þeir því verr settir nema þá og því aðeins að tekjuaukning þeirra sé veruleg. Í ritgerðinni er einnig bent á leiðir til þess að draga úr jaðarskerðingum, til dæmis með því að auka yfirsýn í málaflokknum, tryggja að allar skerðingar séu hlutfallslegar, yfirfara skerðingarreglur barnabóta og setja markmið um hámarks virka jaðarskerðingu

"Get a car, you loser!" : The roots of car-dependency in Reykjavík (and how to break free from it).

This thesis is submitted for the title Master of Science in European Urban Studies at the Faculty of Architecture and Urbanism, Bauhaus-Universität Weimar.The most influential document of planning policy in the history of Iceland is arguably The Reykjavík Municipal Plan, 1962-1983, which was published and unanimously approved by every city council member in 1965. It‘s main author was Danish urban planner and professor, Peter Bredsdorff, and therefore the municipal plan was referred to as „the Danish Plan.“ Ironically, few Danes would consider this plan to have anything to do with Danish urban planning as we know it today. Essentially the plan that turned Reykjavík to a suburban, private car dependant city. As car dependancy grew, active modes of transport were less apparent and public transport stagnated or fell behind. This research would focus mainly on a) finding the roots of car dependancy in history, economic and social influences, and what has stood in the way for Iceland to change course and join the likes of Bergen in Norway, where a light rail system was opened in 2010 and has transformed the city

Samanburður á skilvirkni evrópskra handknattleiksmanna

Nútímasamfélag byggir á framleiðslu flókinna samsettra afurða. Þetta kallar á endurbætta framleiðnimælikvarða þar sem tekið er tillit til sérhæfingar framleiðenda. Í þessari ritgerð eru rakin atriði um hvernig hugsanlega megi þróa slíka mælikvarða. Sem sýnidæmi verður rakið hvernig vega má framleiðsluþætti 124 evrópskra landsliðsmanna í handknattleik úr 14 landsliðum og byggt verður upp líkan til að meta skilvirkni þeirra. Leikmenn eru metnir út frá frammistöðu sinni á Evrópumótum A-landsliða karla í handknattleik sem fóru fram árin 2010 og 2012. Litið er á leikmenn eins og fyrirtæki sem framleiða afurðir (mörk, stoðsendingar o.fl.). Þær afurðir sem teknar eru til skoðunar eru; mörk, stoðsendingar, skotnýting, tapaðir boltar, fiskuð víti, tveggja mínútna brottvísanir, stolnir boltar, varin skot og víti dæmd á sig. Markmið rannsóknarinnar er að búa til margþátta líkan sem mælir tæknilega skilvirkni leikmanna í einni tölu á bilinu 0 til 1. Þeir leikmenn sem fá gildið 1 teljast skilvirkir en aðrir óskilvirkir. Óskilvirkni er lýst með lægri tölu. Í stað þess að einblína á umbreytingu aðfanga í afurðir eins og gert er í hefðbundnum skilvirknimælingum er litið á mestu framleiðslu á hverri afurð fyrir sig og búinn til framleiðslumöguleikajaðar sem mælir hámarks samsetningar af þeim afurðum sem hægt er að framleiða. Jaðarinn endurspeglar besta viðmið og leikmenn eru bornir saman við hann. Þeir leikmenn sem endurspegla jaðarinn eru skilvirkir en þeir sem lenda innan við hann eru óskilvirkir. Notast er við slembijaðargreiningu við gerð jaðarsins. Við mat má t.d. notast við aðferð Bayes og Markov Chain Monte Carlo (MCMC) hermun. Mismunandi vægi er fundið á afurðir þar sem þær kunna að vera mismikilvægar og farið verður yfir þrjár ólíkar aðferðir við vogun þeirra. Sú fyrsta vegur afurðir jafnt, aðferð tvö fær vægi á afurðir út frá línulegri aðhvarfsgreiningu, þar sem skoðað er framlag hverrar afurðar til sigurhlutfalls liðs og sú síðasta fær vægi út frá gögnunum og um leið lögun framleiðslumöguleikajaðarsins. Stuðlamat aðhvarfsgreiningar og þ.a.l. vogun afurða, komu ekki nægilega vel út vegna takmarkana í gögnum, til að hægt væri að notast við aðferðina við vogun. Í þessu úrtaki er talið heppilegra að vega afurðir jafnt eða út frá gögnum. Til að taka sýnidæmi verður framkvæmd MCMC hermun sem gerir ráð fyrir því að framleiðsla leikmanna samanstandi af tveimur framleiðsluþáttum, mörkum og stoðsendingum. Athygli er vakin á því að punktmat á skilvirkni leikmanna getur reynst óáreiðanlegt við túlkun niðurstaða en aðferð Bayes gerir það að verkum að staðalfrávik skilvirkninnar er metið og þ.a.l. er hægt að athuga hversu áreiðanlegt punktmatið er. Með notkun á MCMC hermun er hægt að fá mat á margþátta líkön, flókna útreikninga og aðferðin nýtist einnig í að athuga gæði niðurstaða.Modern society is based on the production of complex composite outputs. This calls for improved productivity measurements that take into account the specialization of producers. This thesis discusses how such measurements can possibly be developed. As a demonstration it will be shown how to weigh production factors of 124 handball players from 14 international teams and a model that evaluates their efficiency will be built. Players are evaluated based on their performance on the 2010 and 2012 European men‘s handball championship. In the thesis players are viewed as firms that produce outputs (goals, assists etc.). The outputs that are used in the model are; goals, assists, shot efficiency, turnovers, free throw achieved, two minutes suspensions, steals, blocks and free throw conseded. The goal of this thesis is to make a multivariate model that measures the technical efficiency of players which takes value between 0 and 1. Players are efficient if their technical efficiency takes the value 1, otherwise they are not. Instead of focusing on how well players convert inputs into outputs, I look at the best players in different regions of output space and trace out a production possibility frontier which measures the maximum feasible combinations of outputs which can be produced. Players are compared to the frontier which represents best practise. The players that represent the frontier are efficient but players who lie inside it are not. Stochastic frontier analysis is used to trace out the frontier. Bayesian approach and Markov Chain Monte Carlo (MCMC) simulation can be used to estimate the model. Three different approaches to select weights for the outputs are discussed. The first approach weighs outputs equally, the second uses regression that estimates the effect of each output on team winning percentage and the third one weighs outputs based on the data and the shape of the production possibility frontier. Results from the regression do not support that the approach can be used to weigh outputs effectively. It is a better choice to use the other two approaches to weigh outputs due to limitations in the database. As an illustration a MCMC simulation will be implemented that assumes players production consists of two production factors, goals and assists. Results are given by point estimates and therefore they should be interpreted with caution. However, the Bayesian approach provides standard deviation for each player‘s efficiency and therefore it is possible to estimate whether the point estimates are reliable or not. Using MCMC simulation makes it possible to estimate multivariate models, complicated calculations and it can also be used to estimate the quality of the results